1. INTRODUCTION
There is increase incidence of
cardiovascular diseases world wide. Among them ischemic heart diseases,
hypertensive heart diseases, and myocardial diseases are most important as they
lead to Left ventricular dysfunction. LV dysfunction may be due to impairment
of its systolic function or diastolic function or both. The systolic
dysfunction means inability of LV to eject blood into high-pressure aorta that
means reduced ejection fraction. The term diastolic dysfunction means that the
ventricle can not accept blood at its usual low pressure; ventricular filling
is slow, delayed, or incomplete unless atrial pressure increases consequently. When diastolic dysfunction is sufficient to
produce pulmonary congestion (that is a damping up of blood into the lungs),
diastolic heart failure is said to be present. . (Gaasch et al , 1994).
Diastolic dysfunction of left
ventricle alters the LV diastolic pressure-volume relation, which in turn leads
to an impaired capacity to fill. It may exit with little or no systolic
dysfunction in its mildest form, diastolic dysfunction may manifest only as a
slow or delayed pattern of relaxation and filling. ,with normal or only mild
elevation of LV diastolic pressure .Transmission of this higher end diastolic
pressure to the pulmonary circulation may cause pulmonary congestion, which
leads to dyspnoea and subsequent right sided heart failure with mild
dysfunction, late filling increases until the ventricular end diastolic volume returns to normal. In severe cases the
ventricle becomes so stiff that the atrial muscle fails and diastolic volume
can not be normalized with elevated filling pressure. In other patterns, LV
filling may be sufficiently impaired to cause a substantial rise in Left atrial
pressure. Under these circumstances, diastolic dysfunction may manifest as
overt congestive heart failure even in the presence of normal or near normal
systolic function (Gaasch et al, 1994).
Diastolic dysfunction is related
by at least two distinct properties of the heart-the passive elastic properties
and active relaxation of the myocardium. With the loss of elastic properties of
heart, there is reduction in compliance and with impairment of relaxation there
is increase in myocardial wall tension during diastole, both of which cause
increased pulmonary venous pressure, (Paul et al, 1996).
Coronary artery diseases,
hypertensive heart disease, ageing are all associated with diastolic
dysfunction. (Spencer et al, 1997).
Hypertension is a major cause of
diastolic dysfunction; it leads to left ventricular hypertrophy and increased
connective tissue content, both of which decrease cardiac compliance. The
hypertrophied ventricle has a steeper diastolic pressure volume relationship;
therefore a small increase in left ventricular end diastolic volume causes a
marked increase in left ventricular end diastolic pressure. . (Lorell BH et al,
2000).
Ischemia leads to impaired relaxation
of the ventricle which involves the active transport of calcium ions into the
sarcoplasmic reticulumn, which allows the dissociation of myosin-actin cross
bridges. Hypoxia inhibits the dissociation process by altering the balance of
the ATP to ADP ratio, which may contribute to diastolic dysfunction. (Nayler WG et al, 1997).
Heart rate determines the time
that is available for diastolic filling, coronary perfusion, and ventricular
relaxation. Tachycardia adversely affects diastolic function by several
mechanisms; it decreases LV filling and coronary perfusion time, it increases
myocardial oxygen consumption and causes incomplete relaxation because the
stiff heart can not increase its velocity of relaxation as heart rate increases
(Benjamin EJ et al, 1994).
Diastolic dysfunction is more
common in elderly persons, partly because of increased collagen cross-linking,
increase smooth muscle content and loss of elastic fibres. (Wei JY et al, 1992).
Heart failure can
be classified into two broad categories: HF with LV systolic dysfunction and HF
with preserved systolic function termed diastolic dysfunction. Systolic
dysfunction is associated with reduced ejection fraction, abnormalities in
systolic function, cardiac remodeling with increase LV diastolic volume,
whereas in Diastolic dysfunction ejection fraction is preserved, abnormalities
in relaxation of ventricles during diastole, ventricular filling is slow or
incomplete as the myofibrils are unable to rapidly or completely return to
resting length(Zile et al, 2001 ).
Diastolic
dysfunction leading to diastolic heart failure can occur alone or in
combination with systolic heart failure. In patients with isolated diastolic
heart failure the only abnormality in the pressure volume relationship occurs
during diastole, when there are increased diastolic pressures with normal
diastolic volumes. When diastolic pressure is markedly elevated, patients are
symptomatic at rest or with minimal exertion. With treatment diastolic volume
and pressure can be reduced and patient become less symptomatic, but the
diastolic pressure volume relationship remains abnormal. (McDermott MM et al,
2001)
The prevalence of
the diastolic dysfunction without diastolic heart failure and the prevalence of
mild diastolic heart failure (NYHA class II) are not known. At present there
are 5 million American have congestive heart failure and 500000 new cases are diagnosed
yearly. Both systolic and diastolic dysfunction can cause congestive heart
failure. All patients with systolic dysfunction have concomitant diastolic
dysfunction .On average 40-60% patients with congestive heart failure have
diastolic heart failure and prognosis of this patient is better then those with
systolic heart failure.(Senni M et al,1998, McCullough PA et al, 2002).
Morbidity from diastolic
dysfunction is quite high which necessitates frequent outpatient visits,
hospital admissions, and the expenditure of significant health care resources.
The one year readmission rate approaches 50% in patients with diastolic heart
failure. This morbidity rate is nearly identical to that for patients with
systolic heart failure. (Phil bin EF et al.1997,Senni M et al,1998,Dauterman KW
et al,1998.).
The prognosis of patient with
diastolic heart failure although less ominous than that for patients with
systolic heart failure, thus exit that for age matched control patients(Setaro
JF et al, 1992;Judge KW et al, 1991;Brogen WC et al, 1992)The annual mortality rate for patients with diastolic
heart failure approximates 5%to 8%. In comparison, the annual mortality for
patients with systolic heart failure approximates 10-15%,whereas that for age matched
controls approaches 1%.In patients with diastolic heart failure, the prognosis
is also affected by pathological origin of the diseases. Thus, when patients
with coronary artery disease are excluded, the annual mortality rate for
isolated heart failure approximates2-3 %( Judge KW et al, 1991; Brogen WC et al,
1992).
Clinically it is difficult to differentiate
systolic and diastolic dysfunction; this can be accomplished by
echocardiography. Ideally the diagnosis of diastolic dysfunction should
be confirmed by documenting
elevation of left ventricular diastolic pressure by cardiac
catheterization, but this is often impractical., therefore noninvasive
procedures such as echocardiography and
plasma biochemical markers are widely used now. Doppler echocardiography, a non-invasive and
simple procedure provides insight into left ventricular diastolic dysfunction (Appleton
et al, 1988; Appleton et al, 1993; Pai et al, 1996.).
Although Doppler echocardiography has been
used to examine left ventricular diastolic filling dynamics, the limitations of
this technique suggest the need for other measures of diastolic dysfunction. (Rodecki et al , 1993).
The strongest correlations have been reported
for BNP with LV diastolic wall stress consistent with
stretch-mediated BNP secretion (Tschope C et al, 2005).
BNP levels
increase with greater severity of overall diastolic dysfunction,
independent of LVEF, age, sex, body mass index, and renal function,
and the highest levels are seen in subjects with restrictive filling
patterns, the lowest in asymptomatic prolonged relaxation pattern.((Lubien E et
al ,2002;Troughton et al, 2004).
Peptide
levels correlate with indexes of filling pressure—including
transmitral early filling velocity (E)—as well as with
indexes of compliance and myocardial relaxation. In subjects with
normal LVEF, BNP (>100 pg/ml) are the strongest independent predictor
of severe diastolic dysfunction; low peptide levels (<140 pg/ml)
exhibit very high negative predictive value (>90%) for diastolic
dysfunction (Tschope C et al, 2005).
The family of natriuretic peptides contains
three major major polypeptides –atrial (ANP), brain (BNP) and Ctype (CNP). BNP
formed by32 amino acids, which was firstly purified from brain, is produced
predominantly by cardiac ventricular myocardium, much less by atrial
myocardium. Synthesis and secretion of both peptides is stimulated by increased
cardiac wall stress during volume and/or pressure overload, results in
diuresis, natriuresis, vasodilatation and renin-angiotensin aldosterone system
(RAAS) inhibition. This mechanism consequently leads to blood pressure lowering
(Levin et al, 1998).
B-natriuretic peptide (BNP), a cardiac
neurohormone, secreted from the ventricles in response to ventricular volume expansion
and pressure overload. (Cheung et al 1998). BNP levels are known to be elevated
in patients with symptomatic LV dysfunction and correlate to NYHA class and prognosis;
BNP levels may also reflect diastolic dysfunction (YAmomoto et al, 1997, Yu CM
et al , 1996).
Multiple studies
established the additive value of BNP to history, clinical examination and
chest X-ray for facilitating the diagnosis of HF in patients presenting with
dyspnoea at an emergency department (Maisel et al, 2002; McCullough et al, 2002; Januzzi et al, 2006).
The increased levels of BNP correlate well with impaired
LV ejection fraction(Gustafsson et al,
2005) and could be also used for detection of an asymptomatic LV
systolic dysfunction (Costello-Boerrigter et al, 2006). The NPs also reflect the actual homodynamic
status of the patients in agreement with homodynamic parameters such as
pulmonary capillary wedge pressure (Kazanegra et al, 2001) and left ventricular end-diastolic pressure
(Richards et al, 1993).
Well et al,2005, reported that BNP had the 79% sensitivity
and 92% specificity in diagnosing LV diastolic dysfunction, Labein et al 2002,reported
the sensitivity 82% and specificity 85%,whereas Ilgen Karaca et al 2007, showed
sensitivity 80% and specificity 100% in
identifying asymptomatic diastolic dysfunction.
Diastolic
dysfunction, which is a common cause of HF in the elderly, is also associated
with elevated BNP values, although these values are not as high as in patients
with systolic dysfunction. Together with diastolic abnormalities on
echocardiography, BNP might help to assess the diagnosis of diastolic HF (Lubien
et al, 2002).
Heart disease is a major health problem
throughout the world including Bangladesh. Among heart diseases heart failure
is a common clinical disorder. Mortality and morbidity rates are high.
Approximately 900,000 patients require hospitalization annually and up to
200000 patients die from this condition (Carbajal EV, 2003). The incidence is
gradually increasing.
In the developing countries like Bangladesh
with increase of life expectancy from 41 to 61 years and control of common
infectious diseases and improvement of life style, cardiovascular diseases as
well as mortality caused by it is showing an increasing trends (Haque, 2002).
A study in Dhaka Medical college showed that
cardiovascular disease was the 2nd cause of death in 1974 and it was
the 1st cause of death in 1976(Malik, 1979).
A study in
National institute of Cardiovascular Diseases, Dhaka, Bangladesh showed that
heart failure is most commonly prevalent in the 50-59 years age group. The
commonest cause of heart failure was ischemic heart disease(44.97%)followed by
hypertension(22.96%)and valvular heart disease(21%).Among heart failure patient
67% have left heart failure and 33% have
right heart failure(Islam KHQ et al,1998).
Very few works in Bangladesh on diastolic
dysfunction & Plasma BNP in heart failure have been done. Aziz (2001) had
shown LV diastolic dysfunction in acute coronary syndrome, 14(20%) having
restrictive pattern, whereas 56(80%) impaired relaxation and 2(37.5%) pseudo
normal pattern. Smoking was found as the most common risk factor followed by
hypertension, hyperlipidaemia and diabetes mellitus. In another study, Alam (2006), showed significant rise of plasma
BNP in heart failure. Very recently a study by Hoque MM et al, 2010, showed
plasma BNP role for clinical staging of heart failure.
Rationale
of the study—
Diastolic dysfunction
is responsible for 40-60% of CHF, 50% rehospitalization in abroad annually, and
mortality is as worse as systolic dysfunction.
No enough work is
done in our country regarding LV diastolic dysfunction.
But a large
proportion of our people are suffering from hypertension, CAD, diabetes that
are considered as risk factors for LV diastolic dysfunction.
Increased level of Plasma BNP now days play an important
value in detecting LV diastolic dysfunction.
Although diastolic
dysfunction can be detect by echocardiography, but where it is not available we
can use plasma BNP level in diagnosis of suspected LV diastolic dysfunction.
So. Early
diagnosis of LV diastolic dysfunction through plasma BNP level in patients with
risk factors and appropriate treatment
will be cost effective as well as beneficial for these patients and will
prevent or early diastolic heart failure and also late systolic failure, reduces
repeated hospitalization, ultimately reduces mortality.
HYPOTHESIS:
Raised Plasma BNP level is useful for diagnosis of
LV diastolic dysfunction.
To
find out the performance of
plasma BNP level in diagnosis of LV
Diastolic dysfunction.
Specific Objectives:
1. To measure plasma BNP level in clinically suspected high risk
population for diastolic dysfunction
2.To do Echocardiography to detect the presence
(group-1) or absence of (group-II) LV
diastolic dysfunction.
3. To assess the performance of plasma BNP
level in respect of Echocardiographic findings for diagnosis of LV diastolic
dysfunction.
4. to correlate plasma BNP level
with severity of LV diastolic dysfunction..
3. REVIEW OF LITERATURE
3.1 NORMAL DIASTOLE
For understanding of the
mechanism of diastolic function and dysfunction, knowledge of normal diastole
is necessary. Cardiac cycle is composed of systole and diastole. Diastole
consists of four homodynamic phases (Fig.1)
The relaxation phase of the cardiac cycle: This phase consists of 4
components:
isovolumic relaxation
rapid filling
slow filling (diastasis)
atrial contraction
The first phase (isovolumic
relaxation) extends from aortic valve closure to mitral valve opening, during
which the left ventricular volume remains constant as left ventricular pressure
falls with myocardial relaxation. Although overall left ventricular volume does
not change during this phase, changes in left ventricular shape may occur.
The second phase (rapid
filling phase) which begins when left ventricular pressure falls below left
atrial pressure, opening the mitral valve. During this phase, left ventricular
pressure falls despite increasing left ventricular volume. This creates a
vacuum that assists in diastolic filling. Rapid filling continues until the
pressure in the atrial and ventricular chamber equalizes and ventricular filling
stops, marking the beginning of the third phase.
During third phase
(Diastasis) left atrial and left ventricular pressure are in equilibrium and
filling occurs.
The Final phase of
diastole is known as atrial contraction phase, which contributes about 15-25
percent of the total left ventricular filling in normal subject (Guyton and
Hall, 2006).
Fig.1.Events of the cardiac cycle
for the left ventricular function showing
Changes in left atrial pressure,
left ventricular pressure, aortic pressure, ventricular volume, the electrocardiogram,
and the phonocardiogram.(Guyton and Hall,2006).
3.2 LEFT VENTRICULAR DIASTOLIC DYSFUNCTION:
3.2.1 BACKGROUND
During the past 20 years, there
has been considerable interest in the clinical evaluation of the left
ventricular diastolic function. In this period physiologist and clinician
recognized the importance of diastolic properties of the heart in the genesis
of ventricular dysfunction. Although several conditions produce concomitant
alterations in systolic and diastolic function some drugs and pathological
conditions influence this process independently. Abnormal diastolic function
may be a consequence of systolic abnormalities. In some patients, especially in
acute and chronic coronary artery disease, symptoms diastolic predominate even
though a variable extent of systolic dysfunction is present. In a small group
of patients abnormalities in diastolic function occur in the absence of
significant systolic abnormalities (Lee, 1989). During 1970s, investigators
studied the pathophysiology of diastole and mechanism causing left ventricular
diastolic dysfunction (LVDD) (Glanz, 1976). During 1980s numerous articles
reflecting the clinical importance of diastolic dysfunction were published.
These studies documented the frequency of congestive heart failure (CHF) in the
presence of normal left ventricular systolic function (Dougherty et al, 1984).
In 1990s, it was seen that CHF caused by abnormal diastolic function may be far
more common than previously recognized (Spencer and Lange, 1970). The diastolic
disorder must be distinguished from systolic abnormalities because the
pathophysiology, therapy and the prognosis are significantly different. (Gaasch
and LeWinter, 1994).
3.2.2 MECHANISM OF DIASTOLIC DYSFUNCTION
Three major factors can
contributes to diastolic dysfunction in patients with cardiac disease ( Bonow
et al ,1992):
• Slowed and incomplete myocardial relaxation
• Impaired left ventricular filling
• Altered passive elastic properties of the ventricle
resulting in increased
Measurements of diastolic properties are more complicated than those of
systolic function, as high-fidelity pressure measurements and/or simultaneous
left ventricular pressure-volume measurements are usually required. The above
contributors to diastolic dysfunction are assessed by the following methods:
• Abnormalities in relaxation by changes in the time constant
of the
• Filling abnormalities by changes in the filling rate and the
time-to-peak
• Changes in passive elastic properties by changes in the
diastolic pressure-
- Loading
condition: The motive force for early diastolic filling is determined
by the pressure gradient between left atrium (LA) and the left ventricle (LV)
at the time of mitral valve opening. This atrioventricular pressure
gradient (AVG) of a patient at a given time is affected primarily by his/her
intravascular fluid status or vasoactive medication that may have been
administered.
 |
Diastolic dysfunction:
|
Cardiac ischemia Hypertension Aging Obesity Diabetes Myocardial disorders Infiltrative disease (e.g., Noninfiltrative diseases (e.g., Endomyocardial diseases Hypereosinophilic syndrome Storage diseases Glycogen storage disease Hemochromatosis Pericardial disorders Constrictive pericarditis Effusive-constrictive Pericardial effusion |
A. Normal
transmitral Doppler flow velocity pattern
B. Normal
Pulmonary vein Doppler Flow velocity pattern
|
- Mitral (left ventricular) inflow(Fig 6)
- Peak E wave velocity: 53-105cm/sec
- Peak A wave velocity: 26-70 cm/sec
- E/A ratio
:>1
- E Deceleration time(DT): 160-220 cm/sec
- Isovolumetric relaxation time (IVRT): 80-100cm/sec
- E/A ratio:<1.0
- Deceleration time(DT):>240ms
- IVRT :> 110 sec.
- Pulmonary venous AR velocity :<25cm
- S/D ratio :> 1.
ANP BNP CNP Urodilatin Names Atrial natriuretic Brain natriuretic C-type natriuretic peptide Occurrenc-e Atrium of mammals dependent on Mostly in ventricle, but is Mostly in vascular tissue Formed in the kidneys and Number of amino acids 28 32 22 to 53 32(ANP+4) Properties/Function Regulation of salt and water (natriuresis,vasodilation, Vasodilatation Regulate on of water and Na+ reassertion in renal collecting ducts
Discovery 1985, de Bold 1988,Sudoh 1990, Sudoh et al. 1986,Frossmann 
3.3.7 Role of
peptide(ANP)/natriuretic factor(ANF)
peptide/B-type natriuretic peptide
pressure in heart
also in brain
excreted with urine
balance, effects on blood pressure
rennin and aldosterone antagonism)
the
plasma BNP in diagnosing diastolic dysfunction
Although BNP has been consistently shown in a number
of studies to have a high sensitivity and specificity in diagnosing systolic
heart failure, (Maisel A, 2001; Cowie et al, 1997; Hobbs et al, 2002;
Dao et al, 2001; Vasan et al , 2002) but its role in the diagnosis of diastolic
dysfunction is less certain.
3.3 9 BNP as
prognostic indicators in heart failure
3.3.10 BNP in
Table IV. Difference between systolic and
Systolic Heart
Normal or low blood
Low ejection
Systolic and diastolic
Treatment well
Role of myocardial
Table V.Risk factors for heart failure (Abraham
Diabetes
Valvular heart disease Tgyroid
Obesity
Metabolic syndrome F/H of cardiomyopathy
Excessive alcohol
Smoking
Aging Treat precipitating factors and Prevent and treat hypertension Surgically remove diseased Improve left ventricular ACE inhibitors Calcium channel blockers Regress left ventricular ACE inhibitors and ARBs Aldosterone antagonists Beta blockers Calcium channel Maintain atrioventricular Beta blockers (preferred) Calcium channel blockers (second-line agents) Digoxin Optimize circulating volume (homodynamic). ACE inhibitors Aldosterone antagonists (theoretical benefit) Salt and water Improve survival. Beta blocker ACE inhibitors Prevent relapse by intensifying Control blood pressure. Dietary counseling (sodium) Monitoring volume status (daily
monitoring of patients with heart failure
diastolic heart failure(Gary S et al, 2008).
Failure
Concentric
hypertrophy
pressure Systolic
hypertension
fraction
impairment Diastolic
impairment by
established
Treatment not well established
ischemia important
W.Tet al, 2008).
Mediastinal irradiation
disorders
cardiotoxic agents
consumption skeletal
myopathies
Nutritional defeciences
underlying disease.
and ischemic heart disease.
pericardium.
relaxation.
hypertrophy (decrease wall thickness and remove excess collagen).
blockers
synchrony by managing tachycardia (tachyarrhythmia).
(controversial) Atrioventricular node ablation (rare cases)
restriction Diuresis, dialysis, or plasmapheresis
outpatient follow-up.
weights and diuretic adjustment) Institute exercise program.
Table
VIII. Age distribution between diastolic dysfunction group
And without diastolic dysfunction group
Age (years) Diastolic dysfunction p-value (n = 76) Absent (n = 24) <50
29(38.2) 20(83.3) <0.001S*** ?50
47(61.8) 4(16.7) Mean ± SD 53.1 44.5 <0.001S***
Sex
Diastolic dysfunction P-value Present (n = 76) Absent (n = 24) Male
21(27.6) 7(29.2) 0.884ns Female
55(72.4) 17(70.8)
Findings Group Impaired relaxation (n = 58) Pseudonormal (n = 7) Restrictive (n = 11) Mitral flow DT (msec) Normal (160-220) Impaired>220) Restrictive <160
6(10.3) 52(89.7)
7(100) .
11(100.0) E/A ratio < 1.0 1 – 1.5 > 1.5 57(96.6) 2(3.4) 0(0.0) 1(14.3) 6(85.7) 0(0.0) 0(0.0) 0(0.0) 11(100.0) IVRT (msec) Normal (80-100) Impaired (>100) Restrictive<70
8(13.8) 50(86.2)
7(100.0)
0(0.0) 0(0.0) 11(100.0)
Pulmonary venous flow S/D ratio Normal (?1) Abnormal (<1)
58(100.0)
7(100.0)
11(100.0) AR (cm/sec) Normal (<22) Abnormal (?35)
38(66.7) 19(33.3)
7(100.0)
2(18.2) 9(81.8)
Table IX. Sex distribution
Present (Group-I)
(Group-II)
± 1.3
± 1.4
between groups:
Table.
XI. Comparison of risk factors between groups:
Risk factors
Diastolic dysfunction P-value Present (n = 76)
Absent (n = 24)
Diabetes mellitus#
21(27.6) 4(16.7) 0.279ns Hypertension*
73(96.1) 22(91.7) 0.346ns Smoking#
10(13.2) 4(16.7) 0.925ns Dyslipidaemia#
11(14.5) 1(4.2) 0.320ns Coronary artery disease#
26(34.2) 6(25.0) 0.399ns
Table
XII. Comparison of clinical characteristics in different types of diastolic
dysfunction
Clinical characteristics
Types of diastolic dysfunction P-value Impaired relaxation (n = 58) Pseudonormal (n = 7) Restrictive (n = 11) Symptoms
Dyspnoea
50(86.2) 6(85.7) 11(100.0) 0.421ns Chest pain
51(89.5) 7(100.0) 10(90.9) 0.665ns Signs
Systolic BP ?140 mmHg >140 mmHg
9(15.5) 49(84.5)
1(14.3) 6(85.7)
2(18.2) 9(81.8) 0.969ns Diastolic ?95 mmHg >95 mmHg
10(17.2) 48(82.8)
2(28.6) 5(71.4)
4(36.4) 7(63.6) 0.317ns
Table XIII. Comparison of 2D
& M-mode echocardiographic characteristics among three types of diastolic
dysfunction
2D & M-mode
Types of diastolic dysfunction p-value Impaired relaxation (n = 58)
Pseudonormal (n = 7) Restrictive (n = 11) LA (mm)
34.3 ± 4.3 36.4 ± 4.5 38.3 ± 5.7 0.027S LVIDd (mm)
45.3 ± 5.9 49.1 ± 5.7 50.5 ± 5.3 0.012S LVIDs (mm)
29.7 ± 5.2 34.3 ± 6.2 35.4 ± 5.6 0.002S EF (%)
65.1 ± 7.2 60.3 ± 8.7 59.5 ± 5.9 0.027S
Table
Echocardiography
XIV. 2D & M-mode echocardiography between groups
2D & M-mode
Diastolic dysfunction p-value Present (n = 76) Absent (n = 24)
LA (mm)
35.1 ± 4.7 33.5 ± 4.0 0.118ns LVIDd (mm)
46.4 ± 6.1 46.1 ± 6.2 0.853ns LVIDs (mm)
30.9 ± 5.7 31.7 ± 6.3 0.581ns Ejection fraction (%)
63.8 ± 7.5 60.7 ± 4.2 0.014s
ns =not significant;
Echocardiography findings
s=significant
Table
XV. Comparison of plasma BNP level between groups:
Table
Group
Plasma BNP (pg/ml)
p-value Mean SEM
Impaired relaxation (n = 58)
211.4 50.6
Pseudonormal (n = 7) 247 15.8
0.417 Restrictive (n = 11)
351 90.6
XVI. Plasma BNP level in different types of diastolic dysfunction
Table
Plasma BNP level (pg/ml)
Diastolic dysfunction
Total Present
Absent
> 60
73 03 76 ? 60
03 21 23
Total
75
24
99
XVII. Accuracy of plasma BNP at cut-off value of 60 in detecting diastolic
dysfunction
|
Plasma BNP level (pg/ml) |
Diastolic dysfunction
|
Total |
|
|
Present
|
Absent
|
||
|
> 75
|
68 |
01 |
69 |
|
? 75
|
07 |
23 |
30 |
|
Total
|
75 |
24 |
99 |
Table
XIX. Accuracy of plasma BNP at cut-off value of 85 in detecting diastolic
dysfunction
|
Plasma BNP level (pg/ml) |
Diastolic dysfunction
|
Total |
|
|
Present
|
Absent
|
||
|
> 85
|
67 |
00 |
67 |
|
? 85
|
08 |
24 |
32 |
|
Total
|
75 |
24 |
99 |
|
BNP |
Components
|
||||||
|
Sensitivity (%) |
Specificity (%) |
PPV (%)
|
NPV (%) |
LR+ |
LR- |
Diagnostic accuracy (%) |
|
|
60
|
97.4 |
87.5 |
96.1 |
91.3 |
7.8 |
0.03 |
95 |
|
75
|
90.8 |
95.8 |
98.6 |
76.7 |
21.6 |
0.09 |
92 |
|
85
|
89.5 |
100.0 |
100.0 |
75.0 |
0.9 |
0.0 |
92 |
Omland, T.(2004)Heart failure in the emergency department-Is B-type natriuretic
peptide a better Prognostic indicator than clinical assessment. J Am Coll Cardiol,44,1334-1336.
Plasma BNP level (pg/ml)
Diastolic dysfunction
Odds Ratio (95% of CI)
p-value Present (n = 76) Absent (n = 24)
> 60
74(97.4) 3(12.5)
255.5 (40.0 – 1631.7)
< 0.001 S***
? 60
2(2.6) 21(87.5)
Passive stiffness.
isovolumic left ventricular pressure
decay
Filling
Volume relationship.
In a given patient, impairment
of one or more of these parameters will result in decreased left ventricular
chamber distensibility as manifested by an increase in diastolic pressure at
any given left ventricular volume.
For the last 10-15 years, there
has been continuing interest in the diastolic mechanism of left ventricular
dysfunction. In contrast to systolic heart failure, which results from impaired
cardiac tension development and shortening, diastolic dysfunction results from
abnormalities in ventricular filling.
Physiology of normal and abnormal diastolic filling: major determinants
A. Excitation-contraction and repolarization-relaxation coupling Diastolic
dysfunction is caused by at least, two distinct yet interrelated properties of
the heart, the passive elastic properties and active relaxation of the
myocardium (Fig.2). With the loss of elastic properties of the heart, there is
an increase in myocardial wall tension during diastole, both of which cause
increased pulmonary venous pressure (Paul et al, 1996). Intracellular calcium
is critically important determinant of normal myocardial contraction and
relaxation. In the myocardial cell the coupling mechanism of
excitation–contraction-relaxation are highly dependent on the release of
calcium into the cytosol and its receptors within the sarcoplasmic reticulum
(Morgan, 1991; Grossman, 1991). Beginning with an action potential that
initiates myocardial contraction there is an influx of calcium across the cell
membrane into the myocardial cell. The calcium at this increased contraction
interacts with the regulatory protein of the myofilaments and allows cross
bridge attachments to form between actin and myosin filaments. This
intracellular reaction is the molecular basis for cardiac muscle tension
development and shortening. Adenosin tri-phosphate (ATP) derived from a catalytic
c site at the end of myosin molecule permits actin-myosin cross bridge
detachment. For contraction to recess myocardial relaxation must take place and
the ability to relax is in turn dependent on reestablishment of low systolic
calcium contraction. This process in which calcium shifts out of the cytoplasm
is critically dependent on sarcoplasmic reticulum (SR) transporting ATPase
(Fig.3). Clearly these mechanisms require energy and support the hypothesis
that myocardial relaxation is largely an active process (Walsh, 1994).
B. Haemodynamics determinants
Diastolic filling is influenced
by many homodynamic factors, which may affect different techniques of
measurement of diastolic function they are:
Because the AVG is the critical
determinant of early diastolic filling as measured invasively or approximately
noninvasively and transient alteration in this parameter has a profound effect
on LV filling indexes (Choong et al, 1987).
b. The time constant: of
isovlumic relaxation (T), a measurement of the isovolumic relaxation rates is
an important determinant of early diastolic filling. In healthy human being, a
shortening of T (i.e. an increased rate of relaxation) produce a decrease in LV
minimal pressure with evidence of ‘suction’ during early diastolic filling
(Udelson et al, 1990).By the same principle it is theorized that in-patients
with diastolic dysfunction (DD) caused by impaired isovolumic relaxation, LV
pressure decreases less precipitously and early diastolic filling is impaired.
c. Heart rate: is an
important determinant of diastolic filling. As the heart rate increases,
diastasis (the third phase of ventricular filling) disappears and ultimately
early and late filling are fused. Another effect of increasing heart rate on
diastolic function has been observed in patients with ischemic heart disease
(IHD) or cardiac hypertrophy that become ischemic, with higher rates, the LV
diastolic dispensability decreased (Aroesty et al, 1985).
d. Normal diastolic filling:
is dependent on synchronized contraction and relaxation between LA and the LV
itself (Brutsaert et al, 1993). In the clinical setting it is commonly observed
that patients with left sided heart failure have poor exercise capacity during
atrial fibrillation because of the loss of atrioventricular synchrony (Keshima
et al, 1993)
e. The passive properties:
of the left ventricle include myocardial elasticity (the change in cardiac
muscle length for a given change in tension) and left ventricular chamber
compliance (the change in the volume in the left ventricle for a given change
in the left ventricular pressure).
f. Pericardial restraint:
is a well-recognized factor influencing diastolic filling (Janichi, 1990; Hoil
et al, 1991) and amplifies the phenomenon known as ventricular interdependence
(Caroll et al,1986).
Fig.2.
Mechanism of diastolic dysfunction (Paul et al, 1996)
Diastolic dysfunction:
Passive
elastic property? Compliance
Active
relaxation ? Wall tension
Pulmonary
venous pressure
Wall tension
Compliance
Active relaxation
Passive elastic
properties
Mechanism at cellular level
Fig.3.The stepwise process in myocardial
contraction-relaxation cycle centers around fairly rapid changes in free
calcium concentration. involves: membrane depolarization promoting
myocyte Ca2+ entry through slow (L-type) Ca2+
channels .this initial process causes significant additional sarcoplasmic
reticular Ca2+ release .Ca2+
interaction with troponin leads to subsequent promotion of actin-myosin
interactions and muscle contraction.. Relaxation
can only occur rapidly if the free calcium is rapidly removed. Calcium transport for purpose of establishing
the basal state occurs through the action of a calcium-ATPase, which handles up
to 90% of free calcium by re-storage back into the sarcoplasmic reticulum.
The remaining 10% is removed through Na+/Ca2+
exchange mechanisms and other mechanisms.( Weinberger, H., Diagnosis and
Treatment of Diastolic HeartFailure,1999).
C. Hormonal influence on diastole
It is known that the sympathetic
nervous system plays an important role in patients with diastolic heart
failure. Catecholamines have been demonstrated to improve contractility and to
increase the rate of relaxation in human being (Starling et al, 1987).Beta adrenergic stimulation appears to improve
cardiac relaxation to a greater extant than it improves contraction (Parkeret
et al,1991). This disproportionate lusitropic (relaxation properties) effect of
beta adrenergic stimulation is most likely mediated by increased intracellular
cyclic adenosine monophosphate (cAMP) and cAMP-dependant protein kinase
activity. cAMP is an important regulator of intracellular function especially
those involving calcium. The renin angiotensin
system also plays an important role in diastolic LV filling and heart
failure. By reducing after load and augmenting cardiac output, angiotensin
converting enzyme inhibitors provide greater functional capacity and prolong
survival in patients with LV dysfunction after myocardial infraction (Pfeffer et
al, 1992).there is also considerable evidence that rennin-angiotensin system
and in particular local production of angiotensin II in the heart, may play an
important role in hypertrophy and diastolic heart failure (Lorell et al, 1994).
3.2.3AETIOLOGY OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION
On average, 40 percent of patients with heart
failure have preserved systolic function. (Vasan et al, 1995; Senni et al,
1998).The incidence of diastolic heart failure increases with age, and it is
more common in older women. (Mc Cullough et al , 2002; Ahmed et al, 2003).
Hypertension and cardiac ischemia are the most common causes of diastolic heart
failure (Table 1). Common precipitating factors
include volume overload; tachycardia; exercise; hypertension; ischemia;
systemic stressors (e.g., anemia, fever, infection, thyrotoxicosis); arrhythmia
(e.g., atrial fibrillation, atrioventricular nodal block); increased salt
intake; and use of nonsteroidal anti-inflammatory drugs.
3.2.3.1 Hypertension & diastolic dysfunction
Chronic hypertension is the most common cause of
diastolic dysfunction and failure. It leads to left ventricular hypertrophy and
increased connective tissue content, both of which decrease cardiac compliance.
(Lorell et al ,2000). The hypertrophied ventricle has a steeper diastolic
pressure-volume relationship; therefore, a small increase in left ventricular
end-diastolic volume (which can occur with exercise, for example) causes a
marked increase in left ventricular end-diastolic pressure.
The development of diastolic
dysfunction in the hypertensive heart disease is the combined end-result of
increased wall tension, increased myocardial collagen content and elevated
myocardial ACE activity (Shapiro et al, 1998; Wheeldon et al,1994).
Hypertrophy of the myocardial
cell itself may slow diastolic relaxation by producing an abnormality in the handling of calcium
ion. This effect appears to be mediated by defective sodium-calcium exchange,
making the cell less effective in extruding cytosolic calcium and leading to a
prolongation of the myocyte relaxation time (Naqvi et al ,1994).
TABLE 1: Causes of Diastolic Dysfunction and Heart Failure.
(Mc Cullough et al , 2002)
Causes are listed in
order of prevalence.
Increased levels of atrial
natriuretic peptide (ANP) and B type natriuretic peptide (BNP) have also been
associated with impaired diastolic filling (Lang et al, 1994).Increased
atrial wall tension that observed in
atria & ventricle of hypertensive hearts,
results in increased level of
ANP&,BNP.(Lokatta & Yin, 1982).
Myocardial fibrosis commonly
present in the subendocardium of hypertrophied hearts, increases the stiffness
and reduces the LV chamber
distensibility ,also active process of myocardial relaxation may be abnormal in
hypertrophied hearts(Lorell & Grossman, 1987).Thus both active and passive
process of diastolic function will be impaired by hypertension.
A close association was also
found in Bangladeshi population between hypertension and diastolic dysfunction
(Rahman, 1997; Rahman M ,1999).
3.2.3.2 Chronic Myocardial Ischemia & left ventricular diastolic
dysfunction:
One of the most common cardiac diseases
associated with abnormal LV diastolic function is myocardial
ischemia. The slowing or failure of myocyte relaxation causes a
fraction of actin-myosin cross bridges to continue to generate
tension throughout diastole—especially in early diastole—creating a
state of “partial persistent systole.” Two kinds of
ischemia can alter diastolic function: (1) demand ischemia, created
by an increase in energy use and oxygen demand that outweighs the
necessary myocardial supply, and (2) supply ischemia, caused by a
decrease in myocardial blood flow and oxygen demand without a change
in energy use.
During demand ischemia, diastolic dysfunction may
be related to myocardial ATP depletion with a concomitant increase
in adenosine diphosphate, resulting in rigor bond formation. (Eberli
et al , 2000). Consequently, LV pressure decay is impaired and the
left ventricle is stiffer than normal during diastole. Although
ischemia is also associated with persistence of an increased
intracellular calcium concentration during diastole, it is not clear
if elevated calcium levels contribute directly to diastolic
dysfunction. (Eberli et al , 2000).
Supply ischemia results from a marked reduction
in coronary flow. The net effect is inadequate coronary perfusion
even in the resting state. Acute supply ischemia causes an initial
transient downward and rightward shift of the diastolic
pressure-volume curve such that end-diastolic volume increases
relative to end-diastolic pressure, creating a
“paradoxical” increase in diastolic compliance (Apstein et al, 1987).
By contrast, diastolic compliance substantially falls during demand
ischemia. (Varma et al, 2000; Varma et
al, 2001).
These opposite initial compliance changes with
demand and supply ischemia may be explained by differences in
pressure and volume within the coronary vasculature, by the
mechanical effects of the normal myocardium adjacent to the ischemic
region, and by tissue metabolic factors. However, the differences
between supply and demand ischemia are transient: after more than 30
minutes of sustained ischemia, both types of ischemia result in
decreased diastolic compliance. (Varma et al, 2000; Varma et al, 2001).
3.2.3.3
Diabetes & left ventricular diastolic dysfunction:
Many conditions besides aging are associated with
and are likely to contribute to diastolic dysfunction and diastolic heart
failure such as hypertension, coronary artery disease, atrial fibrillation, and
diabetes. Diabetes has such an important influence on the development of CHF
that it has been incorporated as a risk factor in the American College of
Cardiology/American Heart Association guidelines ( Hunt et al ,2001).
One of the factors that are associated with the
development of diabetic cardiomyopathy is hyperglycemia. Increasing evidence
suggests that altered substrate supply and utilization by cardiac myocytes
could be the primary injury in the pathogenesis of this specific heart muscle
disease. However, even in type 2 diabetic patients without cardiac involvement,
uncontrolled hyperglycemia is described to provoke diastolic left ventricular
dysfunction (Von et al, 2004; Grandi et al ,2006). Alteration in left
ventricular diastolic function seems to be related to concentrations of fasting
plasma glucose and glycated hemoglobin even below the threshold of diabetes (Celentano
et al, 1995). Furthermore, each 1% increase in HbA1c value has been
associated with an 8% increase in the risk of heart failure ( Iribarren et al ,2001),
and glycosylated hemoglobin > 8 has also been associated with diastolic
dysfunction ( Sanchez-Barriga et al 2001), although the glycemic control may
not reverse the diastolic dysfunction ( Cosson et al, 2003; Freire et al , 2006).
Other changes closely associated with
abnormalities in diastolic function in diabetic patients are the impairment of
gene expression to what has been called the fetal gene program, leading to
myocardial impairment of calcium handling and altered regulation of genes for a
and b-myosin heavy chains (Bell et al ,2003; Loweis et al, 2002).
Of note, impairment of diastolic performance is
non-specific and frequently observed in many diseases such as hypertension,
hypertrophic cardiomyopathy and coronary artery disease, while systolic
function remains intact. However, alterations in diastolic function have been
observed in diabetic patients without any co-morbidities and before
cardiovascular traditional complications. Investigations using cardiac
catheterization showed alterations in left ventricular diastolic filling
pressures in diabetic patients without any significant coronary artery disease
or systolic dysfunction (Regan et al, 1977; D? Elia et al, 1979). Raev et al, showed
alterations in diastolic function in young type 1 diabetic patients without
cardiovascular disease and suggested that these alterations could be the
earliest signs of the diabetic cardiomyopathy. Their findings were quite
plausible because diastolic abnormalities generally occur 8 years after the onset
of type 1 diabetes, and systolic dysfunction establishment has been described
even later in the disease evolution (Cosson et al, 2003).
With the advent of recent echocardiographic
techniques such as tissue Doppler imaging and color M-mode, the ability to
accurately detect diastolic dysfunction has significantly improved. Boyer et
al. detected altered left ventricular filling in 46% in asymptomatic
normotensive type 2 diabetic patients when screened by conventional Doppler,
whilst newer techniques showed diastolic dysfunction in 75% of patients (Boyer
et al, 2004).
A more recent study in patients with type 2
diabetes free of any detectable cardiovascular disease found that 47% of the
subjects had diastolic dysfunction, of which 30% had the first stage dysfunction
— impaired relaxation, and 17% had second stage dysfunction — pseudonormal
filling, a more advanced abnormality of left ventricular relaxation and
compliance, which otherwise would be classified as having a normal diastolic
physiology (Zabalgoitia et al, 2001).
These new techniques, especially tissue Doppler
image and color M-mode, have provided information to overcome some technical
limitations concerning traditional Doppler echocardiographic studies of
diastolic function. Until recently, the existence of the pseudonormal left
ventricular filling pattern, a second stage of diastolic dysfunction, was not
evaluated in all the earlier studies. Therefore it is possible that many
patients with diabetic diastolic dysfunction with a pseudonormal pattern would
not have missed this diagnosis if these new techniques had been available by
the time the studies were done. Furthermore, this may account for the
discrepancies previously related to the prevalence of diastolic dysfunction,
especially in a young diabetic population.
The problem of diabetes and metabolic syndrome
appearing in young ages should prompt early interventions because by the time
type 2 diabetes is diagnosed, more than 30–50% of patients will already have
some evidence of vascular disease (Sattar et al , 2002; Davidson M.B ,2003).
3.2.3.4 Aging
& diastolic dysfunction
Diastolic dysfunction is more common in elderly
persons, partly because of increased collagen cross-linking, increased smooth
muscle content, and loss of elastic fibers (. Wei et al, 1992 ; Gaasch et al, 1994). These changes tend
to decrease ventricular compliance, making patients with diastolic dysfunction
more susceptible to the adverse effects of hypertension, tachycardia, and
atrial fibrillation. In addition to age related alteration in passive
elasticity, an age related reduction in calcium ion sequestration by the
sarcoplasmic reticulam was also observed (Lokatta & Yin, 1982).
3.2.4 Pathophysiology of diastolic dysfunction & diastolic heart
failure:
Diastole is the process by which the heart
returns to its relaxed state. During this period, the cardiac muscle is
perfused. Conventionally, diastole can be divided into four phases:
isovolumetric relaxation, caused by closure of the aortic valve to the mitral
valve opening; early rapid ventricular filling located after the mitral valve
opening; diastasis, a period of low flow during mid-diastole; and late rapid
filling during atrial contraction. (Kovacs et al, 2000). Broadly defined,
isolated diastolic dysfunction is the impairment of isovolumetric ventricular
relaxation and decreased compliance of the left ventricle. With diastolic
dysfunction, the heart is able to meet the body’s metabolic needs, whether at
rest or during exercise, but at a higher filling pressure. Transmission of
higher end-diastolic pressure to the pulmonary circulation may cause pulmonary
congestion, which leads to dyspnea and subsequent right-sided heart failure.
With mild dysfunction, late filling increases until the ventricular
end-diastolic volume returns to normal. In severe cases, the ventricle becomes
so stiff that the atrial muscle fails and end-diastolic volume cannot be
normalized with elevated filling pressure. This process reduces stroke volume
and cardiac output, causing effort intolerance. Fig 4 summarizes the
pathophysiology of diastolic dysfunction & diastolic heart failure.
3.2.5 Clinical presentation & Diagnosis of Left ventricular
diastolic dysfunction
In the clinical setting the
coexistence of systolic and diastolic dysfunction in patients with symptomatic
HF occurs very often. In fact, LV stiffness (or compliance) is related to the
length of myocardial fibers, reflecting in its turn on LV end-diastolic
dimensions. LV diastolic function, through the influence on left atrial and
capillary wedge pressures, determines the onset of symptom in patients with
prevalent LV systolic dysfunction too.In parallel to the ultra-structural
level, the clinical progression of HF may follow two different routes. In the
first one, as it happens after acute myocardial infarction, post-infarction LV
dilation (= remodeling) leads to systolic
dysfunction and/or systolic heart failure. In the second one, LV
structural abnormalities (= LV concentric geometry) induce functional
alterations of DD. When diastolic
dysfunction becomes symptomatic – that is, when dyspnoea occurs – diastolic heart failure rises. (Galderisi et al ,1992).
The majority of patients affected
by isolated diastolic HF show symptoms not at rest but in relation to stress
conditions (II NYHA class). Symptoms can be induced or worsened by, firstly,
physical exercise but also by events as anemia, fever, tachycardia and some
systemic pathologies. In particular, tachycardia reduces the time needed for
global LV filling, thus inducing an increase of left atrial pressure and
consequent appearance of dyspnoea, because of accumulation of pulmonary extra
vascular water. (Galderisi et al , 1992).
The diagnosis of HF can be
performed obviously by the simple clinical examination but the identification
of the diastolic origin needs an instrumental assessment. In fact, the
objective examination of patients with diastolic HF allows noticing the same
signs occurring for systolic HF and even the thoracic X-ray can not be useful
to distinguish the two entities. ECG can show signs of LVH, due to hypertensive
cardiomyopathy or other causes. DD may be asymptomatic and, therefore,
identified occasionally during a Doppler echocardiographic examination .The
diagnostic importance of this tool rises from the high feasibility of transmitral
Doppler indexes of diastolic function, shown even in studies on population (Galderisi et al ,1992).
It is suitable and accurate also for serial
evaluations over time. To date, standard Doppler indexes may be efficaciously
supported by the evaluation of pulmonary venous flow( Masuyama
et al,1995) and by new ultrasound technologies as Tissue Doppler( Nagueh et al, 1997) and color M-mode derived flow
propagation rate(Garcia et al, 2000).
The application of maneuvers (Valsalva, leg
lifting) (Nishimora et al, 1997; Pozzoli et al ,1997) to Doppler transmitral
pattern and/or different combination of standard transmitral Doppler with the
new tools (ratio between atrial reverse velocity duration and transmitral A
velocity duration, ratio between transmitral E peak velocity and Tissue Doppler
derived Em of the mitral annulus or flow propagation velocity (Vp) are
sufficiently reliable to predict capillary wedge pressure and to distinguish
accurately variations of LV end-diastolic pressure(Ommen et al, 2000;Garcia et al, 1997) .
Some of these tools are effective even in
particular situations as sinus tachycardia (Nagueh et al, 2000) and atrial
fibrillation (Nagueh et al, 1996) . Alone or, better, combined together, these
tools permits to recognize normal diastole as well as to diagnose and follow
the progression of DD from the pattern of abnormal relaxation (grade I of DD)
until pseudonormal (grade II) and restrictive (grade III-IV) patterns .
Fig 4: Algorithm for pathophysiology of diastolic dysfunction &
Diastolic heart failure. ( Mandinov L et al , 2000).
3.2.5.2 Doppler Assessment of Diastolic Function
There has been a great deal of interest in using
mitral inflow velocity patterns to evaluate LV diastolic properties.(Nishimora
et al,989; Oh JK et al , 2006; DeMaria et al, 1999). Transmitral filling
velocities reflect the pressure gradient between the LA and LV during diastole
(Nishimora et al , 1989) (Fig 5.). In early diastole pressure in the LV
normally falls below that in the LA, producing an increase in velocity due to
rapid transmitral inflow (E wave). Flow decelerates as the pressures
equilibrate in mid-diastole. In late diastole LA contraction restores a small
gradient, causing transmitral flow to accelerate to a second peak (A wave) that
is of less magnitude than the E wave. In individuals in whom early LV
relaxation is impaired, the transmitral pressure gradient is blunted, resulting
in a decrease in both the velocity of early filling and rate of E-wave
deceleration (Oh JK et al , 2006) (Fig 5.).
Conversely, in patients with marked increases of
LA pressure and LV stiffness, early diastolic filling velocities are high,
deceleration is rapid, and late filling following atrial contraction is
markedly reduced. This is the so-called restrictive
pattern of LV filling (Fig 5).
Accordingly, an E-wave velocity that is
substantially less than the A-wave velocity and is accompanied by a prolonged
deceleration time represents evidence of impaired early diastolic relaxation by
Doppler, whereas an increased E-wave velocity and decreased A-wave velocity
(E/A ratio >2.5:1 or 3:1) accompanied by a diminished deceleration time
(<160 ms) is indicative of a noncompliant LV with markedly elevated left
atrial pressures (Oh JK et al , 2006). A restrictive pattern occurs with
restrictive cardiomyopathy or advanced LV dysfunction of any cause and in
pericardial disease (Appleton et al ,1988).
The normal pulmonary venous flow usually has a
biphasic (occasionally triphasic) flow with a slightly greater systolic (S
wave) than diastolic wave (D wave) and a small retrograde flow wave during
atrial contraction (AR) The AR wave may become larger with increasing age. (Fig.
5).
Transmitral pulsed wave (PW)
Doppler flow velocities are recorded within the apical four chamber or apical
long axis views and several measurements can be used to define left ventricular
filling homodynamic.
As the mitral valve is
funnel-shaped, the velocities increase progressively across the mitral valve
apparatus towards the outlet of the mitral funnel.
For reasons of reproducibility,
all transmitral PW Doppler flow measurements should be made with the sample
volume in the same position at the outlet of the mitral valve funnel. Figure 6
diagrammatically shows the normal transmitral Doppler flow velocity pattern and
the parameters which can be measured.
The isovolumic relaxation
period (IRP), is the time interval between aortic valve closure and mitral
valve opening and can be measured from the simultaneous Doppler and M-mode
echocardiograms or more accurately from a simultaneously recorded
phonocardiogram and transmitral Doppler curve.IRP reflects the speed of the
initial part of myocardial relaxation. Prolonged IRP is a sensitive marker of
abnormal myocardial relaxation. Normal transmitral blood flow is laminar and
relatively low in velocity (usually < 1 m/sec).
There is an early diastolic
velocity caused by the continued myocardial relaxation resulting in a LV
pressure below LA pressure which causes the mitral valve to open and rapid LV
filling to occur (E wave).E wave acceleration is directly determined by LA
pressure and inversely related to myocardial relaxation. Viscoelastic
properties and compliance of the myocardium then come into play, raising LV
pressure and resulting in a decreased transmitral flow velocity.
The rate of fall in velocity is represented by
the deceleration time (DT) and is a measure of how rapidly early diastolic
filling stops. DT becomes shorter when LV compliance decreases. . The A wave is
associated with atrial contraction and is an important index of diastolic
function (Ohno M. et al , 1994)
The normal pulmonary vein flow pattern is
diagrammatically in figure 6.
It is usually biphasic with a predominant
systolic forward flow (S wave) and a less prominent diastolic forward flow wave
(D wave).Occasionally, there may be a triphasic flow pattern with two distinct
systolic flow waves of which the initial flow into the left atrium results from
atrial relaxation followed by a further inflow due to the increase in pulmonary
venous pressure. The D-wave occurs when there is an open conduit between the
pulmonary vein, LA and LV and reflects the transmitral Ewave.A retrograde flow wave into the pulmonary vein (AR wave)
occurs during atrial contraction and its amplitude and duration are related to
LV diastolic pressure, LA compliance and heart rate. In normal subjects, the
amplitude of the AR wave is generally less than 25 cm/sec and its duration is
shorter than the A wave of the transmitral A wave. (Klein et al, 1991).
Table II.Diagnosis
of LV diastolic dysfunction (Spencer & Lang. 1997)
·
Clinical features of LV dysfunction
·
Find out suspected aetiology of diastolic
dysfunction
·
Rule out other causes of dyspnoea or CCF eg.
Significant vavular
Diseases, congenital heart disease, pericardial or
pulmonary disease.
·
ECG
o
Left ventricular hypertrophy
o
Left atrial enlargement
o
Features of ischemic heart disease
·
Chest X-ray- normal in size(in isolated
diastolic dysfunction)
·
Echocardiography
o
Prolonged isovolumic relaxation time
o
Prolonged deceleration time
o
Decreased E to A ratio on mitral flow
o
Abnormal pulmonary venous flow pattern
·
Cardiac catheter—–Increased LVEDP
.Figure-6.This diagram shows intracardiac
pressure tracings from the left ventricle and left atrium with the
corresponding Doppler mitral (MVF) and pulmonary vein flow (PVF) velocity
patterns
Following table contains a list
of ranges of normal parameters of left ventricular Doppler diastolic filling
and pulmonary venous flow (Conooly H. M &Oh J.K. 2008).
·
Pulmonary
venous flow(Fig.6)
o
Peak S wave : 40-90 cm/sec
o
Peak D wave : 30-70 cm/sec
o
S/D ratio :>1
o
Peak atrial reversal (AR) velocity: <
25cm/sec
C .Doppler assessment of
diastolic dysfunction(Conooly, H. M &Oh,J.K. 2008).
By means of Doppler mitral flow
along with pulmonary venous flow velocity, four patterns of diastolic
dysfunction have been identified indicating progressive impairement.
Grade 1 (mild dysfunction) =impaired
relaxation with normal filling pressure
Grade 2 (moderate dysfunction)
=pseudo normalized mitral inflow pattern
Grade 3 (severe reversible
dysfunction) =reversible restrictive (high filling pressure)
Grade 4 (severe irreversible
dysfunction) =irreversible restrictive (high filling pressure)
GRADE 1 DIASTOLIC
DYSFUNCTION OR MILD DIASTOLIC DYSFUNCTION
An early abnormality of diastolic filling is
abnormal myocardial relaxation. Typical cardiac conditions that produce
abnormal relaxation are LV hypertrophy, myocardial ischemia or infarction, as
well as aging. During this stage of diastolic dysfunction, an adequate
diastolic filling period is critical to maintain normal filling without
increasing filling pressure. As long as LA pressure remains normal, the
pressure crossover between the LV and LA occurs late and the early transmitral
pressure gradient is decreased. Consequently, the IVRT is prolonged. Mitral E
velocity is decreased and A velocity is increased, producing an E/A ratio of
less than 1, with prolonged DT. Pulmonary vein diastolic forward flow velocity
(PVd) parallels mitral E
Velocity and is also decreased with compensatory
increased flow in systole. The duration and velocity of pulmonary vein atrial
flow reversal (PVa) are usually normal, but they may be increased if atrial
compliance decreases or LV end-diastolic pressure is high.
Doppler features are (Fig.7):
GRADE 2 DIASTOLIC
DYSFUNCTION OR MODERATE DIASTOLIC DYSFUNCTION (Pseudo
normal)
This stage is also referred to as the pseudo
normalized mitral flow filling pattern, and it represents a moderate stage of
diastolic dysfunction. (Oh JK et al.2006; Redfield MM et al.2003; Munagala VK
et al. 2003). As diastolic function worsens, the mitral inflow pattern goes
through a phase resembling a normal diastolic filling pattern, that is, due to
an increase in left atrial pressure that compensates for the slowed rate of
left ventricular relaxation results in restoration of normal pressure gradient
between LA and LV.Pulmonary venous abnormality occurs in pseudo normalized
pattern. (S/D ratio altered and there is large atrial reversal velocity).
Doppler features are (Fig.7)
o
E/A ratio of 1 to 1.5
o
normal DT (160 to 240 msec)
o
IVRT: 80-100ms
o
S/D ratio:<1
o
AR velocity:>25cm
This is the result of a moderately increased LA
pressure superimposed on delayed myocardial relaxation. There are several means
to differentiate the pseudo normal pattern from a true normal pattern in
patients with grade 2 dysfunction:
A decrease in
preload, by having the patient sit or perform the Valsalva maneuver, may be
able to unmask the underlying impaired relaxation of the LV, decreasing the E/A
ratio by more than 0.5. If A velocity increases with the Valsalva maneuver, it
is a positive sign.
GRADE 3-4 DIASTOLIC
DYSFUNCTION OR SEVERE DIASTOLIC DYSFUNCTION
Severe diastolic dysfunction is also termed
restrictive filling or physiology and can be present in any cardiac abnormality
or in a combination of abnormalities that produce decreased LV compliance and
markedly increased LA pressure. Examples include decompensated congestive
systolic heart failure, advanced restrictive cardiomyopathy, severe coronary
artery disease, acute severe aortic regurgitation, and constrictive
pericarditis. Early rapid diastolic filling into a less compliant LV causes a
rapid increase in early LV diastolic pressure, with rapid equalization of LV
and LA pressures producing a shortened DT. Atrial contraction increases LA
pressure, but A velocity and duration are shortened because LV pressure
increases even more rapidly. When LV diastolic pressure is markedly increased,
there may be diastolic mitral regurgitation during mid-diastole or with atrial
relaxation. Therefore restrictive filling with severe diastolic dysfunction is
characterized by increased E velocity, decreased A velocity (<<E) and
shortened and Systolic forward flow velocity in the pulmonary vein is decreased
because of increased LA pressure and decreased LA compliance.
Doppler features are (Fig. 7):
o E/A
ratio greater than 2
o DT
(<160 ms)
o IVRT
(<70 ms).
o AR
velocity:>35cm
o S/D
ratio:<1
The Valsalva maneuver may reverse the restrictive
filling pattern to grade 1 to 2 patterns, indicating the reversibility of high
filling pressure (grade 3 diastolic filling). However, even if the restrictive
filling pattern does not change with the Valsalva maneuver, reversibility
cannot be excluded because the Valsalva maneuver may not be adequate or filling
pressure is too high to be altered by the Valsalva maneuver.
The transmitral pressure gradient or the
relationship between LA and LV pressures is accurately reflected by mitral
inflow Doppler velocities.Oh JK et al 2006). Diastolic filling is usually
classified initially on the basis of the peak mitral flow velocity of the early
rapid filling wave (E), peak velocity of the late filling wave caused by atrial
contraction (A), the E/A ratio, and deceleration time (DT), which is the time
interval for the peak E velocity to reach zero baseline ( Fig.7 ).
Fig. 7: Summary of the Doppler flow patterns
across the mitral inflow, pulmonary venous flow in normal and different
diastolic dysfunction, also relation with NYHA classes of heart failure (Garcia
MJ et al, 1996).
3.3 Natriuretic Peptide:
3.3.1 General consideration
Natriuretic peptides, atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP) produced in the heart are a family of endogenous
polypeptide mediators mainly of cardiac origin with natriuretic with
vasodilator effects. They are sometimes named cardiac hormones (Yamamoto et al,
1996).It constitutes a complex system involving the regulation of sodium
balance and blood pressure (Betowski J et al, 2002).B-type natriuretic peptide
(BNP) was first identified in the porcin brain in 1988, but was subsequently
found to be present in ventricular myocardium, the main source of circulating BNP
(Omland T, 2004).
Other member of this family such
as A-type natriuretic peptides (ANP) C-type natriuretic peptides (CNP),
Dendroaspis natriuretic peptides (DNP) and urodilation (ularitide) discovered.
They are involved in cardiovascular homeostasis, cell-proliferation,
reproductive biology and immune response. Plasma BNP level significantly
increases in systolic heart failure, diastolic heart heart failure, acute
coronary syndrome, right ventricular dysfunction, mitral regurgitation, Age,
renal dysfunction(Troughton R et al, 2004). Koitabashi et al, (2005) found that
BNP level also increases in atrial fibrillation. The higher BNP levels in older
women and men probably reflect diastolic dysfunction (Massie BM, 2003).
The discovery of ANP results from
histological observation of ‘dense bodies’ in atrium explaining its
denomination atrial whose volume increased in animals receiving a sodium
overload. The injection of extracts of these ‘dense bodies’ induced diuresis
and natriuresis and responds to various hypertrophic agonists such as
endothelin-1 (Kerkela R et al, 2002).
ANP is a 28-amino acid
polypeptide secreted by atrial myocytes in response to distension. BNP, thus
named because it was first discovered in brain, is a 32-amino acid mainly
secreted by ventricles in response in response to stretc. B-type natriuretic
peptide (BNP) is a cardiac neuro hormone secreted from the ventricles in
response to ventricular volume expansion and pressure overload. The synthesis
of nBNP occurs through a preprohormone (Elin RJ, 2004). CNP is a 22-amino acid
polypeptide formed in brain and in vascular endothelium. It is a newly
discovered factor that stimulates vasorelaxation and inhibits cell
proliferation (Potter LR et al, 1998). The chemical structure of ANP, BNP and
CNP presents a ring formed by a disulfide bond between 2 cysteine residues.
3.3.2 Biochemistry and molecular Biology:
The natriuretic peptide family
consists of three peptides: atrial nanatriuretic peptide, brain natriuretic
peptide, and c-type natriuretic peptide. The precursor prohormone for each is
encoded by a separate gene. The tissue specific and regulation of each peptide
are unique.
Brain natriuretic peptide was
originally identified in extracts of porcine brain. It is present in human
brain, but there is considerably more in the cardiac ventricles. Human
pro-brain natriuretic peptide contains 108 aminoacids; processing releases a
mature 32-amino-molecule and an amino-terminal fragment (Fig.8). Both circulate
in the plasma, and the concentrations are high in patients with ventricular
hypertrophy or congestive heart failure. (Vesely D et al, 1994). N-terminal
probrain natriuretic peptide has proven to be a powerful tool in the diagnostic
assaesment of dyspnoea as a result of its ability to confirm or exclude the
presence of acute congestive heart failure (Baggish et al, 2004).
Fig .8: Structure of BNP (Processing
of a 108-Amino Acid proBNP Into an Active Form of C-Terminal 32-Amino Acid BNP ,Goetze
JP, 2004)
BNP is a useful biochemical
marker in diagnosis, prognosis, assessment of severity and guide to therapy of
heart failure.
3.3.4 Distribution:
Research about an endocrine
/paracrine role for the heart was started from 1956; it was mainly through the
works that the principle of the arterial extract responsible for diuresis and
natriuresis was identified to be ANP. This was followed by a period of active
research where more members of the family, such as BNP, was isolated from the
venom of the snake Dendroaspis
angusticeps and later identified in
human by researches in the Mayo Clinic, Rochester, USA.Anp and BNP (first
identified in brain) are predominantly produced and secreted by the cardiac
monocytes hence collectively called cardiac Natriuretic peptides. The largest
sector of ANP in humanis left atrium. The ability of other chambers to secret
ANP is the right atrium, right ventricle and left ventricle.
3.3.3 .Table.III Natriuretic peptides discovered to date:
However extra cardiac ANP
secretion is too small to make
significant changes to the plasma levels of ANP. (Nohria A et al., 2006).
BNP on the other hand, is principally secreted
from cardiac ventricles. Apart from ventricles, amniotic tissue produces large
amount of BNP. CNP is largely produced from extra cardiac site such as brain,
vascular endothelium, kidney, testis, ovary, uterus etc. CNP mRNA in heart was
detected by reverse transcriptase-polymerase chain reaction (RT-PCR) but not
with northern blotting, indicating that the CNP gene expression in the heart is
meager. Studies on urodilation are limited. Little is known about their tissue
specific expression except that is highly secreted from renal tubules and
abundant in urine. (Nohria A et al., 2006).
3.3.5 Elimination
Metabolism by neutral endopeptidase:
Neutral endopeptidase a
metaloendopeptidase with zinc at its active centre, serves as the key enzyme
responsible for Natriuretic Peptidase metabolism. This enzyme is maximally
found in the brush border of the proximal convoluted tubule and is also found
in the lungs, heart, intestine, seminal vesicle and neutrophils. NEP degrades
the natriuretic peptides in the rank order of CNP>ANP>BNP. Urodilatin can
also be metabolized by NEP in vitro but this is not physiologically relevant as
the majority of the urodilatin is locally produced in the kidney and excreted
through urine. ANP is also metabolized to certain other enzymes, such as
insulin degrading enzyme. (Nohria A et al., 2006).
Lysosomal degradation:
Natriuretic peptides receptor-C
represents >90% of all the natriuretic peptides receptors in the body and
binds to ANP, BNP and CNP. Apart from the G1 mediated cell signaling roles,
NPR-C facilitates the lisosomal degradation of all known natriuretic peptides.
Although the precise molecular mechanisms are not known.
Urinary excretion:
Urodilatin is an exception as it
is mostly produced in the kidneys and other elimination pathways do not get
much opportunity to metabolize them before they are micturated.
3.3.6 Functions of natriuretic peptides:
The natriuretic peptides can affect
systemic blood pressure by several mechanisms, modification of renal function
and vascular tone, counteracting the renin angiotensin aldosterone system and
action on brain regulatory sites. These systems maintain a condition which
ensures relative constancy of blood electrolytes and water content and
circulating homeostasis.
Main biologic of natriuretic
peptide is as follows:
#Cause natriuresis
#Cause vasodilatation
#Suppression of rennin action
#Suppression of aldosterone action
#Suppression of sympathetic activity
#Inhibition of growth of vascular smooth
muscle (Nohria A et al., 2006).
Recent studies have
demonstrated that BNP levels in patients with diastolic dysfunction are higher
than that in normal controls (Bettencourt P et al, 1999),
but it was less than that in patients with systolic dysfunction (Maisel A et al, 2001).The
sensitivity and specificity of elevated BNP in detecting prolonged isovolumic
relaxation time and increased left end-diastolic pressure were 0.63–0.85 and
0.70–0.76, respectively (Yamamoto et al, 1996).
Recent study by Motrram et al,2003 on a small
patient population has indicated that, although the plasma level of BNP in
patients with hypertension-caused diastolic dysfunction was higher than those
with normal diastolic function, more than 70% patients with diastolic
dysfunction had BNP levels within the normal range.
Lubien and
colleagues measured plasma BNP levels in patients referred for echocardiography
other than for assessment of abnormal systolic function, valve disease,
possible endocarditis, or possible intracardiac thrombus (Lubein E et al,
2002). Those patients with abnormal LV diastolic function, had a mean plasma
BNP concentration of 286±31pg/ml while the normal LV group had a mean BNP
concentration of 33±3pg/ml. Plasma concentrations were particularly elevated in
patients with restrictive filling patterns and in those with symptoms .A BNP
value of 62pg/ml (18pmol/l) gave a sensitivity of 85%, specificity of 83% and
an accuracy of 84% for detecting isolated diastolic dysfunction.
Therefore, in patients with normal systolic left
ventricular function and no valve disease, an elevated plasma BNP concentration
is highly suggestive of clinically significant diastolic dysfunction. This
suspicion should be even stronger if the Doppler examination is also abnormal.
3.3.8 Role of plasma BNP in diagnosing heart failure:
The plasma concentrations of both
ANP and BNP are increased in patient with asymptomatic and symptomatic left
ventricular dysfunction, permitting their use in reaching diagnosis of heart
failure. The value of rapid bedside measurement of plasma BNP for
distinguishing between CHF and a pulmonary cause of dyspnoea has been best
evaluated in a seven-centre, multinationational study of 1586 patients
presenting to the emergency room with a major complaint of acute dyspnoea(.Maisel
As et al ,2002).
In the B-Type Natriuretic Peptide
for Acute Shortness of Breath Evaluation study (Mueller et al, 2006), patients
presenting to the emergency department with acute dyspnea were randomly
assigned to undergo either a single measurement of BNP or not. Based largely on
the findings of the BNP Multinational Study, clinicians were advised that a
plasma BNP concentration <100 pg/mL made the diagnosis of congestive heart
failure unlikely, whereas a level >500 pg/mL made it highly likely. For BNP
levels between 100 pg/mL and 500 pg/mL, the use of clinical judgment and
additional testing was encouraged. The decision cut-points recommended in
Europe for NT-proBNP are 100pg/ml for males and 150pg/ml for women, and in the
USA 125pg/ml for both genders (The Task Force for the Diagnosis and
Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis
and treatment of chronic heart failure. Eur Heart J. 2001).
BNP has been suggested as a means of identifying
those heart failure patients at high risk of death or hospitalization, in order
to target therapy and enable selection for tertiary or quaternary services.
Plasma BNP concentrations are higher in patients
with more severe symptoms and in those with more severe cardiac damage. (Valli
N et al, 2001).
A raised BNP is able to differentiate between
moderate and severe impairment of left ventricular function. (Krugers et
al.2001). In addition, BNP also correlates well with cardiopulmonary exercise
capacity and with composite measures of heart failure severity, such as the
Heart Failure Survival Score. (Koglin J et al, 2001).
BNP is an independent predictor of death in
patients with chronic heart failure, and is superior to atrial natriuretic
peptide (ANP) for predicting mortality (Tsutamoto T et al, 1997). In this
study, each 10pg/ml increase in plasma BNP was associated with a 3% increase in
the risk of cardiac death over the follow-up period. BNP is also an independent
predictor of all-cause mortality in patients with asymptomatic or minimally
symptomatic left ventricular dysfunction, being superior to norepinephrine and
left ventricular volumes (Tsutamoso T et al, 1999).
In patients with acute heart failure, BNP has
been shown to be an independent predictor of cardiovascular mortality, (YuCM et
al, 1999) and is also predictive of outcome in patients hospitalized with
decompensated heart failure. (Cheng V et al, 2001) Importantly, this last study
suggested that measuring plasma BNP concentrations before discharge may help to
identify patients with heart failure who are at a low risk of re-admission
within the next month.
BNP may have a role in selecting patients with
advanced heart failure for transplantation. One recent study looked at patients
with severe left ventricular function and heart failure. BNP concentrations
were the strongest predictor of mortality at four years of follow-up. (Stanck B
et al, 2001). In an ambulant heart failure clinic population, plasma BNP was at
least equivalent to the Heart Failure Survival Score (which is commonly used
for assessing patients for transplantation) in risk stratification (Koglin J et
al, 2001).
A recent study looking at 452 ambulatory patients
with left ventricular dysfunction in whom there was a high rate of sudden death
found that the BNP concentration was the only independent predictor of sudden
death (Berger R et al, 2002).
Plasma BNP concentrations are known to fall
rapidly on treatment of patients with heart failure. (Richards AM et al, 1993; MaiseI A et al, 2001). In the
clinic setting, patients whose functional status improved between visits showed
a statistically significant reduction in plasma BNP concentration of about 50%;
other variables such as NT-proANP and ANP or ejection fraction showed no
statistically significant change (Lee SC et al, 2002). However, the monitoring
of therapy by measuring plasma BNP concentration is complicated by the wide
variation of plasma BNP levels reported in patients with symptomatic heart
failure, which may make titration to a ‘target’ dose of BNP difficult.
Furthermore, recent data show a progressive rise in a variety of natriuretic
peptides as patients’ renal function deteriorates (Cattakotti A et al, 2001). As
yet it is unclear what reduction in creatinine clearance is necessary for this
effect appear; it may be relatively modest but nevertheless has implications
for targeting of therapy. Reducing the plasma BNP concentration in the clinical
setting by stepping up the diuretic dose may result in the patient developing
worsening renal function, which may offset the expected reduction in BNP.
Therefore, to titrate drugs against BNP is therefore not as simple an idea as
it first appears.
Nevertheless, there is some evidence of the
possible benefit of a BNP-guided approach to therapy (with diuretics and ACE
inhibitors) from a randomized trial conducted in 69 patients with symptomatic
heart failure due to left ventricular systolic dysfunction (Troughton RW et al,
2000).
BNP may also find a role in guiding introduction
of therapy for patients with heart failure. One study conducted in patients
with chronic stable heart failure due to left ventricular systolic dysfunction
suggested that the beta-blocker carvedilol was most efficacious in patients
with higher pre-treatment BNP concentrations (82.5pg/ml)(Richards AM et al,
1999). This hypothesis has not been examined in a prospective randomized trial.
However, a similar finding for NT-proBNP has also been reported. (Richards AM
et al, 2001). Further work is required before BNP measurement can have a role
in guiding the introduction of beta-blockade (and other therapies) in heart
failure.
3.3.11 Recombinant human BNP (Nesiritide) therapy in heart
Failure
Nesirtide is the newest drug that has been
approved to treat patients with ADHF. Nesiritide is a recombinant formulation
of endogenous B-type natriuretic peptide (BNP. BNP has vasodilatory properties
and is helpful for relieving signs and symptoms and improving the markedly
abnormal homodynamic changes that occur with ADHF. BNP is secreted by the left
ventricle in response to stretching of the myocytes that occurs when left
ventricular end-diastolic pressure (preload) is increased.
In addition to its vasodilatory properties, BNP
has natriuretic effects and neurohormonal antagonism (Abraham WT et al, 1998).
In fact, in contrast to neurohormones such as norepinephrine, aldosterone, and
angiotensin II, which can lead to harmful changes, BNP is a useful
counter-regulatory hormone that plays an important role in cardiovascular
hemostasis. As the severity of heart failure increases, greater amounts of BNP
are secreted by the ventricles in response to greater preload in an attempt to
unload the heart and improve function. Unfortunately, the physiological
activity of BNP is “overwhelmed” by the vasoconstrictive and
fluid-retaining properties of other hormones (angiotensin, aldosterone, and nor-epinephrine).
This increase in the level of BNP is the basis for the point-of-care test for
BNP that has been used to diagnose heart failure in an emergent setting (Maisel
AS et al, 2002). Homodynamic changes that occur with the use of nesiritide
include reduction in pulmonary artery pressures and left ventricular pressures
(pulmonary capillary wedge pressure [PCWP], which is a measure of preload). In
the patient in the case study, nesiritide was chosen because of its
effectiveness in alleviating signs and symptoms and improving homodynamic
status, its ease of administration, its lack of toxicity, and its mild
diuretic/natriuretic properties. Inotropic agents were not indicated because
the patient’s condition was relatively stable, with a good blood pressure and
no indications of hypo perfusion or cardiogenic shock.
The role of nesiritide in the treatment of acute
heart failure has been investigated in several trials. In a 2-part trial,
Colucci et al, 2000, studied patients with acute heart failure: one part was an
efficacy trial (nesiritide vs. placebo); the other part was a comparative trial
(nesiritide vs. standard of care, which could include the administration of
dobutamine, milrinone, nitroglycerin, or nitroprusside at the discretion of the
investigator). In the efficacy trial, a bolus of 0.3 or 0.6 µg/kg was given and
then nesiritide was infused at 2 different doses, either 0.015 µg/kg per minute
or 0.03 µg/kg per minute. In the comparative trial, the bolus and maintenance
doses of nesiritide were the same; however, nesiritide was compared with
standard care as just described. In both trials, the end points were reduction
in PCWP and improvement in signs and symptoms of heart failure, as measured by
using a global clinical assessment scale. Patients included in the trial had
marked homodynamic dysfunction as indicated by a baseline mean PCWP of 28 mm
Hg, a mean cardiac index (calculated as cardiac output in liters per minute
divided by body surface area in square meters) of 1.8, and a mean left
ventricular ejection fraction of 0.22. In the efficacy trial, compared with
placebo, nesiritide improved homodynamic function and global clinical
assessment scores. In the comparative trial, treatment with nesiritide and
standard therapy resulted in similar improvements in signs and symptoms. The
most common adverse effect of nesiritide was hypotension, both asymptomatic and
symptomatic.
The Vasodilatation in the Management of Acute
Congestive Heart Failure (VMAC) trial was done to compare the effects of
nesiritide with the effects of another vasodilator, nitroglycerin. In this
large trial, patients with ADHF and resting dyspnea were randomized to receive
intravenous nitroglycerin (dosage adjusted by investigator), intravenous
nesiritide (either in a fixed dosage of a 2 µg/kg bolus followed by an infusion
at 0.01 µg/kg per minute or an adjustable dose), or placebo in addition to
standard therapy for heart failure. The investigators decided whether to
monitor each patient invasively with a pulmonary artery catheter. This
pulmonary artery catheter was used for monitoring in about half of the patients
(60 of 143 patients receiving nitroglycerin, 124 of 204 patients receiving
nesiritide, and 62 of 142 receiving placebo). This predetermined stratification
and the dosing strategy were an attempt to replicate actual common practice in
managing patients with heart failure without the aid of homodynamic monitoring.
Although both nesiritide and nitroglycerin
decreased PCWP, nesiritide reduced PCWP significantly more than standard care
plus intravenous nitroglycerin or standard care plus placebo reduced PCWP in
the first 3 hours of therapy. The superior reduction of PCWP with nesiritide
was largely sustained for 24 hours during the infusion. After 3 hours, patients
in the nesiritide groups experienced a significant improvement in dyspneic
symptoms compared with the patients who received the placebo but did not show
any improvement compared with patients who received nitroglycerin. After 24
hours, both patients treated with nitroglycerin and patients treated with
nesiritide had similar improvements in dyspneic symptoms.
Significantly more patients treated with
nitroglycerin than patients treated with nesiritide experienced adverse effects
during the first 24 hours of drug infusion. The most common adverse effect (in
both groups) was headache, which occurred to a greater extent in the
nitroglycerin group (20%) than in the nesiritide group (8%). Additionally, more
patients treated with nitroglycerin (5%) than patients treated with nesiritide
(1%) experienced abdominal and catheter-associated pain. Hypotension occurred
in both groups. During the first 24 hours after administration of the drug, 8%
of patients receiving nesiritide had asymptomatic hypotension and 4% had
symptomatic hypotension. Similarly, among patients treated with nitroglycerin,
8% had asymptomatic hypotension and 5% had symptomatic hypotension, although
the duration of the hypotension was longer in the group that received
nesiritide therapy. Thirty-day readmission rates and 6-month mortality rates
did not differ significantly between the 2 groups.
The VMAC trial provides the evidence to support
the currently recommended initial dose of nesiritide, a bolus of 2 µg/kg followed
by a maintenance infusion of 0.01 µg/kg per minute. This study indicates a role
for nesiritide in the treatment of ADHF.
In the Prospective Randomized Evaluation of
Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) study (Burger AJ
et al, 2002); the incidence of ventricular tachycardia was compared between
patients with ADHF receiving dobutamine and patients with ADHF receiving
nesiritide. In that study, 24-hour Holter monitors were used to detect
arrhythmias during infusions of dobutamine and nesiritide. Patients given
dobutamine infusions experienced significantly more episodes of ventricular
ectopy (tachycardia, premature ventricular contractions, couplets, triplets)
than did patients given nesiritide infusions. The occurrence of ventricular
arrhythmias can be a problem in patients with acute heart failure because
potentially lethal arrhythmias may occur. The commonly used inotropic agents,
dobutamine and milrinone, increase the incidence of both atrial and ventricular
arrhythmias (Califf R et al, 2002).
3.4. Heart Failure:
A pathophysiological state in
which an abnormality of cardiac function is responsible for the failure of the
heart to pump blood at a rate commensurate with the requirements of the metabolizing
tissues (Gary S et al, 2008).
3.4.1. Systolic versus Diastolic Heart Failure (Gary S et al, 2008)
A more contemporary distinction
in patients with heart failure is to characterize the particular structural
abnormalities with cardiac imaging techniques, and the majority of clinical
studies in heart failure have used this phenotype. Systolic dysfunction
describes a large, dilated, and often eccentrically hypertrophied ventricle in
which output is limited by impaired ejection during systole, whereas diastolic
dysfunction refers to a thickened, small cavity ventricle in which filling is
limited because of abnormalities during diastole (Table -IV).
These terms are most appropriately defined in
terms of altered ventricular performance and geometry rather than systemic homodynamic
or overt symptoms as they can manifest with almost identical symptomatology. It
is also clear that systolic and diastolic dysfunction frequently coexist in
patients with heart failure because systolic dysfunction, notably on exercise,
can directly influence diastolic function. Systemic symptoms may not correlate
with the degree of ventricular dysfunction as assessed by contraction during
systole at rest.
Table V showed the risk factors
for heart failure ( Abraham. et al, 2008).
3.4.2 Clinical
features
of diastolic heart failure (Redfield et al, 2008)
Patients with HFnlEF were shown to have similar
pathophysiological characteristics compared with HF patients with a reduced EF
including severely reduced exercise capacity, neuroendocrine activation, and
impaired quality of life despite normal EF, normal left ventricular (LV)
volume, and an increased LV mass-to-volume ratio(Kitzman DW et
al,.2002).(TableVI)
Table- VI Clinical Features of Heart
Failure with Normal Ejection Fraction (Framingham criteria for
diagnosis of heart failure*)( Redfield M,2008)
Major criteria Paroxysmal
nocturnal dyspnea or orthopnea
Jugular venous distention (or CVP > 16 mm Hg)
Rales or acute pulmonary edema
Cardiomegaly
Hepatojugular reflex
Response to diuretic (weight loss >4.5 kg in 5 days)
Minor criteria : Ankle
edema
Nocturnal
cough
Exert ional dyspnea
Pleural effusion
Vital capacity < two thirds
of normal
Hepatomegaly
Tachycardia (>120 bpm)
Demographic features: Elderly; female > male
Underlying CV disease: Hypertension, coronary
disease, diabetes,
Atrial fibrillation
Co morbidities: Obesity, renal dysfunction
Doppler echocardiography results:
LV size ————— Normal
to ? (small subset with?) LV mass
LV mass ————— LVH
common but frequently absent;
? Relative
wall thickness (> 0.45)
Left atrium —————- Enlarged
Diastolic dysfunction —— Grade
I-IV (? diastolic dysfunction severity, BP,
Volume
status)
Other features
————– PH, wall motion abnormality, RV enlargement
Pertinent negatives ——– Rule
out valve disease, pericardial disease, ASD
BNP or NT-proBNP: ? but HFnlEF < HFrEF
Exercise testing : ? VO2 peak
Exaggerated hypertensive response in
many
Chronotropic incompetence in subset
Chest radiogram: Similar
to HFrEF, cardiomegaly, pulmonary venous
Hypertension, edema, pleural effusion
Electrocardiogram:
Variable
*Two major or
one major and two minor criteria
3.4.3 Prevalence of
diastolic heart failure
The studies performed until now have assessed the
prevalence of HF with normal EF, using standard echocardiography without
Doppler. In a first meta-analysis of 1995, the investigators of the Framingham
Heart Study (Vasan RS et al,1995) showed wide variability in the prevalence of
this kind of HF (range = 13–74%) while a subsequent study involving the
Framingham offspring cohort pointed out a 51% prevalence of overall HF(Vasan RS,
1999). Very recently, Hogg et al collected ten “cross-sectional”
studies on population, in the United States as in several European countries,
and found very high variability of HF with normal EF. The explanation of this
variability is related mostly to different age and gender of participants. It
has to be considered that this kind of HF is particularly frequent in the
elderly population, occurs more often in the female gender and is associated
much more with arterial hypertension and atrial fibrillation than to coronary
heart disease (Hogg K et al, 2004).
3.4.4 Prognosis of
diastolic heart failure
3.4.5 Management of diastolic dysfunction & diastolic heart failure
Primary prevention of diastolic heart failure
includes smoking cessation and aggressive control of hypertension,
hypercholesterolemia, and coronary artery disease. Lifestyle modifications such
as weight loss, smoking cessation, dietary changes, limiting alcohol intake,
and exercise are equally effective in preventing diastolic and systolic heart
failure. Diastolic dysfunction may be present for several years before it is
clinically evident.
Early diagnosis and treatment is important in
preventing irreversible structural alterations and systolic dysfunction.
However, no single drug has pure lusitropic properties (i.e., selective
enhancement of myocardial relaxation without inhibiting left ventricular
contractility or function). Therefore, medical therapies for diastolic
dysfunction and diastolic heart failure often are empirical and not as well
defined as therapies for systolic heart failure. On the surface, it appears
that the pharmacologic treatments of diastolic and systolic heart failure do
not differ dramatically; however, the treatment of diastolic heart failure is
limited by the lack of large and conclusive randomized control trials. (Hunt SA
et al, 2001). Furthermore, the optimal treatment for systolic heart failure may
exacerbate diastolic heart failure. Most clinical trials to date have focused
exclusively on patients with systolic heart failure; only recently have trials
addressed the treatment of diastolic heart failure.
Although conclusive data on specific therapies
for diastolic heart failure are lacking, the American College of Cardiology and
the American Heart Association joint guidelines (Hunt SA et al, 2001) recommend
that physicians address blood pressure control, heart rate control, central
blood volume reduction, and alleviation of myocardial ischemia when treating
patients with diastolic heart failure. These guidelines target underlying
causes and are likely to improve left ventricular function and optimize
hemodynamics.Table VII lists treatment goals for diastolic heart failure.
TABLE VII.Goals for Treating
diastolic dysfunction & Diastolic Heart
Failure (Hunt SA et al, 2001) .
ACE =
angiotensin-converting enzyme; ARB = angiotensin receptor blocker.
·
IMPROVING
LEFT VENTRICULAR FUNCTION
When treating a patient with diastolic
dysfunction, it is important to control the heart rate and prevent tachycardia
to maximize the diastolic filling period. Beta blockers are particularly useful
for this purpose; however, they do not directly affect myocardial relaxation.
In addition to slowing heart rate, beta blockers have proven benefits in
reducing blood pressure and myocardial ischemia, promoting regression of left
ventricular hypertrophy, and antagonizing the excessive adrenergic stimulation
during heart failure. Beta blockers have been independently associated with
improved survival in patients with diastolic heart failure. (Chen HH et al,
2000). These medications should be used to treat diastolic heart failure,
especially if hypertension, coronary artery disease, or arrhythmia is present.
·
OPTIMIZING
HEMODYNAMICS
Optimizing homodynamic primarily is achieved by
reducing cardiac preload and after load. Angiotensin-converting enzyme (ACE)
inhibitors and angiotensin receptor blockers (ARBs) directly affect myocardial
relaxation and compliance by inhibiting production of or blocking angiotensin
II receptors, thereby reducing interstitial collagen deposition and fibrosis. (Aggomachalelis
N 1996; Mitsunami K,1998). The indirect benefits of optimizing homodynamic
include improving left ventricular filling and reducing blood pressure. More
importantly, there is improvement in exercise capacity and quality of life (Warner
JG et al, 1999). One retrospective study (Philbin EF et al, 2000) showed that
improved survival was associated with ACE inhibitor therapy in patients with
diastolic heart failure. One arm of the CHARM (Candesartan in Heart Failure
Assessment of Reduction in Morbidity and Mortality) trial, (Yusuf S et al, 2003)
which studied the effect of candesartan (Atacand) in patients with normal
ejection fraction for 36.6 months, did not show a significant mortality
benefit. However, it reduced the incidence of hospitalization for CHF
exacerbation.
Diuretics are effective in managing optimal
intravascular volume, and they minimize dyspnea and prevent acute heart failure
in patients with diastolic dysfunction. Although diuretics control blood
pressure, reverse left ventricular hypertrophy, and reduce left ventricular
stiffness, some patients with diastolic heart failure are sensitive to the
preload reduction and may develop hypotension or severe prerenal azotemia.
Intravenous diuretics should only be used to relieve acute symptoms.
The hormone aldosterone promotes fibrosis in the
heart and contributes to diastolic stiffness. The aldosterone antagonist
spironolactone (Aldactone) has been studied in a large clinical trial of
systolic heart failure, (Pitt B et al, 1999), which showed a reduction in
mortality related to heart failure. However, the specific effects of
spironolactone on diastolic dysfunction are unclear.
Calcium channel blockers have been shown to
improve diastolic function directly by decreasing cytoplasmic calcium
concentration and causing myocardial relaxation or indirectly by reducing blood
pressure, reducing or preventing myocardial ischemia, promoting regression of
left ventricular hypertrophy, and by slowing the heart rate. However,
nondihydropyridine calcium channel blockers (e.g., diltiazem [Cardizem]) and
verapamil (Calan) should not be used in patients with bradycardia, conduction
defects, or severe heart failure caused by left ventricular systolic dysfunction
(Gutierrez C et al, 2004). Instead, nondihydropyridines, such as diltiazem and
verapamil, should be used for rate control and angina when beta blockers are
contraindicated or ineffective. Finally, large randomized controlled trials
have not proved that calcium channel blockers reduce mortality in patients with
isolated diastolic dysfunction.
Vasodilators (e.g., nitrates, hydralazine
[Apresoline]) may be useful because of their preload-reducing and anti-ischemic
effects, particularly when ACE inhibitors cannot be used. The Vasodilator Heart
Failure Trial, (Cohn JN et al, 1990), however, did not show significant
survival benefit in patients with diastolic heart failure. Vasodilators should
be used cautiously because decreasing preload may worsen cardiac output. Unlike
other medications used for diastolic heart failure, vasodilators have no effect
on left ventricular regression.
The exact role of digoxin for treating patients
with diastolic heart failure remains unclear. Digoxin can be deleterious in
older patients with left ventricular hypertrophy and hypertrophic obstructive
cardiomyopathy; therefore, digoxin is only appropriate for patients with
diastolic heart failure and atrial fibrillation. (Digitalis investigation group,
1997).
4.
MATERIALS AND METHOD
4.1 Place & Period of Study:
It was a Cross sectional study
and carried out in the department of cardiology, Sir Salimullah Medical College,
Dhaka, from September 2009 to august 2010.
4.2 Study population:
100 total consecuative patients were selected from the department
of cardiology, having history of the risk factors for diastolic dysfunction such
as ischemic heart disease, hypertension, diabetics, and hyperlipidemia without
definite features of overt heart failure on the basis of inclusion and
exclusion criteria. Patients of acute myocardial
infarction were excluded by ECG and biomarkers.
4.2.1 Inclusion criteria:
Patients of
both sexes.
Patients of ?
18 years.
Patients
having risk factors for diastolic dysfunction.
eg. IHD,Hypertension, Diabetes,
Hyperlipidemia,
etc. (having clinically
Suspected
diastolic dysfunction)
4.2.2Exclusion criteria:
Patients with
EF<50%.
Patients with
LVED dimension >55mm.
Heart failure.
Patients with ACS.
Valvular heart
diseases.
Cardiomyopathies.
Pericardial
diseases.
Cardiac cause
of stroke.
Poor echo
window.
Patients with
renal failure, hepatic failure.
Hyperthyroidism,
undue tachycardia.
4.2.3 Grouping of patients:
The selected Patients were
grouped into two-Group-I having diastolic dysfunction and Group–II without
diastolic dysfunction on the basis of Doppler echocardiographic findings.
Plasma BNP level was done in both Groups.
4.2.4 Ethical
Issue:
The study protocol
was approved by Institutional ethical committee.
4.3 Study Methods:
4.3.1 Informed written consents
were taken from all patients included in
The study. (Appendix-I).
After taking History and clinical examination,
echocardiography was done by two cardiologists .Blood was send for plasma BNP
level and for other needed investigations in all 100 selected
patients.Cardiologists who done the echocardiography were blinded to plasma
level of BNP. All findings were recorded in the structured questionnaire (Appendix-I1).
4.3.2 Clinical evaluation:
a) History
Proper history regarding risk
factors of diastolic dysfunction was taken and previous documented history,
investigations were evaluated carefully to exclude heart failure.
I) Ischemic heart disease:
Patients were considered having ischemic heart
disease documented by history, ECG, echocardiography.
II) Hypertension:
Patients were considered as hypertensive having systolic blood pressure
>140 mm hg and diastolic >90 mm hg (JNC’7) with or without treatment.
III) Diabetes:
Patients were considered as
diabetic having fasting blood sugar ?7 mmol/L (WHO diabetes criteria 2009).
IV) Hyperlipidemia:
Patients were considered
hyperlipidemic having—lipid profile above normal.
TCL: ?160 mg/dl,
LDL: ?130 mg/dl, TG: ?200mg/dl (NCEP,2002).
b) Clinical examination:
During clinical examination, emphasis
was given on pulse, blood pressure, jugular
venous pressure, 3rd and 4th heart sounds ,and basal crepitations to
exclude heart failure.
4.3.3 Laboratory investigations:
Following cardiac and biochemical
tests were carried out in all subjects.
I)
ECG:
12 lead electrocardiogram
was
performed to observe any previous evidence of IHD, MI, LVH.
II) Echocardiography:
Echocardiographic instrument:
Echocardiographic machine which were used for the study had conventional (2D
and M mode) with Doppler and color flow imaging facility. At SSMC it was VIVID
7 Dimension. Version 7.x.x (2007) and Philips (i.E. 33 Ultrasound System) 2007,
and the system was equipped with 2.5 and 3.5 MHZ transducers. All patients first underwent 2D & M mode
echocardiography and analyzed for chamber enlargement, ventricular hypertrophy,
wall motion abnormalities, and systolic function. Wall motion abnormalities
were graded from normal to dyskinesia.
Doppler assessment was performed,
by apical four chamber view to assess transmitral flow and pulmonary flow patterns.
Pulsed Doppler sample volume was placed on the tips of mitral valve leaflets,
whereas sample volume was placed 1-2
cm deep in right upper pulmonary vein for assessment of
pulmonary venous flow. Flow patterns across the mitral inflow i.e. E and A wave
velocities, E/A ratio, decelaration time (DT) of E wave, isovolumetric
relaxation time (IVRT).Similarly flow patterns across the pulmonary inflow i.e.
and D wave velocities, S/D ratio, atrial reversal (AR) were measured .Normal values
for Doppler parameters were already mentioned. (page-40). As per values of
transmitral and transpulmonary venous inflow parameters, different types/grades
of diastolic dysfunction were classified.
They were absent, abnormal relaxation, pseudonormal, and restrictive patterns
(definitions on page-42-44). All Doppler values were recorded. Flow spectral
was also printed on Polaroid paper with a printer.
Working Definitions of diastolic dysfunction parameters:
Normal
ventricular function:
Defined by normal LV end-diastolic (35-55mm)
and end-systolic (25-36mm) dimensions, no major wall motion abnormalities, an
ejection fraction>55%, no evidence of impaired or restrictive relaxation
abnormalities.
Diastolic dysfunction:
Impaired relaxation:
Defined as an E/A ratio of<1
or DT>240ms in patients<55 years of age, and E/A<0.8 and DT>240ms
in patients >55years age or.IVRT >100ms .with abnormal E/A ratio. And /or
DT>240ms.
Pseudo-normal:
Defined as E/A ratio 1 to 1.5 and
DT>240ms.Confirmation included
Pvd/Pvs>1.5 or IVRT <100ms or by
reversal of the E/A ratio <1 by valslva when possible.
Restrictive like:
Defined as DT<160ms with ?1 of the
followings: left atrial size>50mm, E/A ratio>1.5 or IVRT<70ms, Pvd/Pvs>1.5,
and pulmonary A” reversal >35cm/sec.
Chamber Abnormalities: Left atrial enlargement defined as atrial size
±50mm..LV hypertrophy defined as mean LV thickness of septum and posterior wall
±12mm. patients with HOCM was excluded.
III) Estimation of plasma BNP
level:
Collection Blood sample:
With full aseptic precaution, 3
ml of blood from anticubital vein was taken from each study subject collected in a plastic
test tube containing EDTA(axis shield diagnostic 2003).Plasma was separated by
centrifuging the blood at 3000 rpm for 10 minutes and 1.8 ml of plasma was
collected in a ependroffs tube and preserved at -35?C,until analysis.
Estimation was done by micro particle enzyme
immune assay (MEIA) principle in AxSYM system (Axis-Shield diagnostics, 2003), in
the biochemistry lab, BSMMU.
IV) Fasting blood sugar .
V) Lipid profile: after overnight
fasting (8-10 hours) morning venous blood was taken for plasma lipid
estimation.
VI) Serum creatinine label was
done for exclusion of renal impairment.
4.3.4 Measurement of accuracy of plasma BNP for diagnosis of diastolic
dysfunction (Park K, 2005):
The present study was intended to
find out the accuracy or validity of plasma BNP level as a screening test in
detecting diastolic dysfunction. Before going to the test findings; it would be
worthwhile to interpret the components of accuracy of a screening test. In the
following table, the letter ‘a’ denotes those individuals found positive on
test who have the disease being studied (i.e. true positive), while ‘b’
includes those who exhibit a positive test result but who do not have the disease
(i.e. false positive).The letter ‘c’ is the number of negative test results
having disease (i.e. false negative) and the letter‘d’ is the number of negative
results who do not have the disease (i.e. true negative).
Table: measurement of accuracy
plasma BNP for diagnosis of diastolic dysfunction:
Established diagnosis
Screening Test Total
Diseased Non-diseased
Positive a b
(a+b)
Negative c d
(c+d)
Total (a+c) (b+d)
(a+b+c+d)
The following measures are used to evaluate a screening test:
1. Sensitivity= a/(a+c)×100
2. Specificity= d/(b+d)×100
3. Positive predictive valueof
the test (PPV) =a/ (a+b) ×100
4. Negative predictive value of
the test (NPV) =d/(c+d) ×100
5. Percentage of false+ve=b/ (a+b)
×100
6. Percentage of false—ve=c/(c+d)
×100
Diagnostic accuracy= (a+d)/ (a+b+c+d)
×100
7. Positive likelihood ratio (LR+
)
Probability of positive test
result in a person with the disease
=
Probability of positive test result in a person without the disease
a/(a+c) SEN TP
rate
=
= =
b/(b+d) 1-SPE FP
rate
(LR+ )=1: has no
diagnostic value
(LR+ ) >1: persons
with diseas are more likely to have a positive test result
Than non diseased.
(LR+ ) >10: test
has high diagnostic value.
8. Negative likelihood ratio (LR–)
Probability of negative test result in a
person with the disease
=
Probability of negative test result in a person without the disease
c/(a+c) 1- SEN FN rate
=
= =
d/(b+d) SPE TN
rate
((LR–)=1: has no
diagnostic value
((LR–) <1: persons
with disease are less likely to have a negative test result
Than persons without disease.
((LR–) ?0.1: test has
high diagnostic value.
4.3.5Data processing and statistical analysis:
Data were processed and analyzed
using SPSS (Statistical Packages for Social Sciences), version 11.5. Test
statistics used to analyze the data were Chi-square (?2) Probability
Test (For comparison of data presented on categorical scale) and Student’s
t-Test (for data presented on continuous scale). Risk of developing diastolic
dysfunction was estimated using Odds Ratio (with 95% confidence interval for
Odds Ratio). ANOVA statistics was employed to compare the plasma BNP among the
three types of diastolic dysfunction. Receiver operating characteristic curve
was analyzed to determine the best cut-off point at which optimum sensitivity,
specificity, PPV and NPV can be obtained in diagnosing diastolic dysfunction
using plasma BNP. Level of significance was set at 0.05 and p-value < 0.05
was considered significant.
STUDY FLOW CHART
100 selected Patients on the basis of
inclusion & exclusion criteria attending to the cardiology department (September
2009-auguest 2010),SSMC, Dhaka.
Doppler
Echocardiography
—————————————————————————–
Group -I
Group-II
Patients having
patients without
Diastolic dysfunction (no-76) Diastolic dysfunction
(no-24)
Impaired relaxation Pseudonormal Restrictive
(n=58)
(n=7) (n=11)
BNP level BNPlevel
Results
5. RESULTS
In total 100 selected patients on
the basis of inclusion & exclusion criteria for the study,76 patients with diastolic
dysfunction were screened out by Doppler echocardiography,and 24 had no diastolic dysfunction.Plasma BNP level was done in all .
5.1 Age distribution between groups:
Table I demonstrates that the subjects of the
diastolic dysfunction (group-I) were relatively older than those of without
diastolic dysfunction (group-II). With 61.8% subjects in the former Group being
50 or > 50 years old as opposed to
16.7% in the later group. The mean ages of the subjects in the study and the
control groups were 53.1±1.3 years and 44.5±1.4 years respectively (p <
0.001).
# Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
s*** = significant at p
value<0.001
n=total number of patients.
5.2 Sex distribution between groups:
In diastolic dysfunction group females were
predominant (over 72.4%) but the result is not statically significant of sex (p
= 0.884).Male: Female ratio was 2:1 in group with diastolic dysfunction.
# Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
Ns= not significant
5.3 Age distribution among different types of diastolic dysfunction:
Age distribution among diastolic
dysfunction groups demonstrates that 62.1% patients in impaired relaxation,
85.7% in pseudonormal and 54.5% in restrictive groups were < 60 years old.
The rest of the respective groups (37.9% in impaired relaxation, 14.3% in
pseudonormal and 45.5% in restrictive groups) were 60 or > 60 years old
(Figure 9).
Fig.9: Comparison of age among different
types of diastolic dysfunction.
5.4 Comparison of sex among Different diastolic dysfunction groups :
About 22% of patients, 57.1% in
pseudonormal and 36.4% in restrictive groups were male. Female predominance was
observed in impaired relaxation and restrictive group, while the pseudonormal
group had no significant difference with respect to sex (Figure 10).
Fig.10: Comparison of sex among different
types of diastolic dysfunction.
5.5. Echocardiographic
characteristics among different types of diastolic dysfunction :
Of the 76 patients with diastolic
dysfunction, 58 had impaired relaxation, 7 pseudonormal and 11 restrictive
like. Diastolic function indicators calculated by Doppler echocardiography are
shown in table X. Majority (89.7%) of the subjects with impaired relaxation had
impaired DT (> 220 msec), 100% with pseudonormal <220msec and 100% of
restrictive variety have <160msec. Majority (96.6%) of the impaired group
had E/A ratio < 1, 85.7% of the pseudonormal had E/A ratio 1 – 1.5 and all
of the restrictive-like had E/A ratio > 1.5. IVRT was found impaired
(>100 ms) in 86.2% of impaired relaxation, 80-100ms in 100% of pseudonormal
and <70ms 100% of restrictive types of diastolic dysfunction. However, all
patients in pseudonormal group exhibited abnormal S/D ratio<1 and peak
AR>35cm/sec as compared to 100% and 81.8% in restrictive group respectively.
Table X. Echocardiographic findings among diastolic dysfunction groups :
DT=deceleration time; IVRT=
isovolumetric relaxation time; AR=atrial
reversal velocity.
5.6 Comparison of risk
factors between diastolic dysfunction group and group
without diastolic dysfunction:
Table XI demonstrates Risk factors
profile between groups. No statistically significant difference in proportion
were observed between groups in relation to diabetes, hypertension, smoking
habit, dyslipidemia and coronary artery disease was observed. However, all
these risk factors were higher in diastolic dysfunction group than without
diastolic dysfunction.
# Chi-square (c2)
Test was employed to analyze the data;
* Fisher Exact Test was done to
analyze the Data;
Figures in the
parenthesis denote corresponding percentage.
Ns=not
significant
5.7 Clinical characteristics indifferent type of diastolic dysfunction
groups:
Table XII compares the symptoms
and signs those who developed diastolic dysfunction. Majority of the patients
among the three groups exhibited dyspnoea (86.2% in impaired relaxation, 85.7%
in pseudonormal and 100% in restrictive group)
and chest pain (89.5% in impaired relaxation, 100% in pseudonormal and
90% in restrictive group). In terms of signs, abnormal systolic and diastolic
blood pressure was found in patients among impaired relaxation, pseudonormal
and restrictive group. The groups were identically distributed in terms of
clinical symptoms and signs.
#Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
ns =not significant
5.8 2D & M-mode
echocardiographic characteristics of patients with DD:
The 2D & M-mode
echocardiography findings of patients demonstrate that LA, LVIDd and LVIDs were
significantly lowest in impaired relaxation group compared to pseudonormal and
restrictive groups (p = 0.027, p = 0.012 and p = 0.002 respectively), while,
ejection fraction was significantly highest in impaired relaxation group that
those in pseudonormal and restrictive groups (p = 0.027) (Table XIII).
# Data were analyzed using ANOVA
statistics and were presented as Mean ± SD. S=significant
5.9 2D & M-mode echocardiographic findings between groups:
Table XIV compares the 2D &
M-mode echocardiography findings between those who developed diastolic
dysfunction and those who did not.. The mean LA, LVIDd, LVIDs were almost same
both the groups (35.1 ± 4.7 vs. 33.5 ± 4.0 mm, p = 0.118; 46.4 ± 6.1 vs. 46.1 ±
6.2 mm, p = 0.853 and 30.9 ± 5.7 vs. 31.7 ± 6.3 mm, p = 0.581 respectively).
However, ejection fraction was significantly higher in the former group than
that in later group (63.8 ± 7.5 vs. 60.7 ± 4.2, p = 0.014).
# Student t Test was employed to analyze
the data; presented as Mean ± SD.
5.10. Plasma BNP level between groups:
Majority (97.4%) of the subjects with
diastolic dysfunction had plasma BNP 60 or > 60 pg/ml as opposed to 12.5% of
subjects without diastolic dysfunction. The ability of plasma BNP (at cut-off
value of 60 pg/ml) to predict diastolic dysfunction in patients with normal
systolic function is 255 times higher than that
with plasma BNP ? 60 pg/ml (p
<0.001) (Table XVI).
#Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
S***=highly
significant
5.11 Plasma BNP level in different types of diastolic dysfunctions:
From table XVI it appears that
mean plasma BNP increases with the severity of diastolic dysfunction (from
impaired relaxation to restrictive like filling), though the differences among
the groups were not statistically significant (p = 0.417). But plasma BNP
gradually rises from impaired relaxation
variety to restrictive variety.
(Fig 11)
Data were
analyzed using ANOVA statistics and were presented as mean ± SD.
Fig.11: Level of plasma BNP in different
types of diastolic dysfunction
5.12. Accuracy of plasma BNP level in
diagnosing diastolic dysfunction:
Table
XVII – XX & Figure 12 showed the ability of BNP to detect diastolic
dysfunction. At different cut off value.
The area under the curve (AUC) for the receiver-operating characteristics (ROC)
curve with BNP used to detect any abnormal diastolic dysfunction was 0.98 (95%
confidence interval, 0.953 to 1.002; p < 0.001). A BNP level of 60 pg/ml had
a higher sensitivity of 97.4%, a specificity of 87.5%, a positive predictive value
of 96.1% and an accuracy of 95% for detecting diastolic dysfunction.
Table
XVIII. Accuracy of plasma BNP at cut-off value of 75 in detecting diastolic
dysfunction
Table
XX. Accuracy of BNP level in diagnosing diastolic dysfunction:
With increase in
cut-off values of plasma BNP from 60 to 75 and 85 pg/ml, the specificities and
PPVs (positive predictive values) increase to their highest compromising with
their sensitivities and NPVs (negative predictive values).
Fig. 12: Accuracy of BNP level in diagnosing diastolic dysfunction
6. DISCUSSION
Recently there has been increasing interest regarding the
contribution of diastolic dysfunction to the signs snd symptoms of heart
failure. Brain natriuretic peptide, a marker of neurohormonal activation
secreted by cardiomyocytes in response to ventricular wall stretch, has a basic
role in cardiovascular remodeling and volume homeostasis (Maeda K et al, 1998).
It is widely used now as a marker for various
cardiovascular diseases. Especially in heart failure it is used for diagnosis, risk stratification or prognosis,
and treatment monitoring (Mueller C et al, 2007).
Recent studies have demonstrated that left ventricular
diastolic dysfunction contributes to plasma BNP level and thus it is useful for
diagnosis of diastolic dysfunction (Tschope C et al, 2005).
This study was undertaken to find out the plasma BNP level in
patients with risk factors for diastolic dysfunction before features of overt
heart failure, also its validity as a screening test to early diagnose and
detect severity diastolic dysfunction.
Nijland et al,1997,found 12(13%) patients in restrictive
type and other 83(87%) included impaired
relaxation and pseudonormal.Poulsen(1999) found 38% impaired relaxation
& other varieties included 24%.
In Bangladesh, Aziz(2001) showed that,among 170patients,
98(57%) had diastolic dysfunction by echocardiography whose 35 were impaired
relaxation variety,21 pseudonormal and 14 had restrictive patterns.
In this study,76(76%) patients out of 100 ,had diastolic dysfunction detected
by Doppler echocardiography.Majority were impaired relaxation variety (n=58), then
restrictive variety (n=11), only 7 patients were pseudonormal (Table –X).Impaired
relaxation variety and restrictive variety were more common in female than male(77.6%
vs.22.4%and 63.6%vs.36.4% respectively)(Fig.10), whereas pseudonormal was more
in male (57%vs.42.9%).
It is known that
the prevalence of diastolic dysfunction increases with age. Its incidence is
reported to be 15-25% in patients <60 years of age, 35-40% between 60-70
years and above 50% over 70 years (Luchi RJ et el, 1982; Wong WF et al, 1989; Wei
I et al, 2005).
In this study, Majority of the study population were over
50 years (61.8%), mean age was 53.1±1.3 years (Table-VIII) and most of patients
were female (72.4%) (Table-IX), it is similar like other studies.
Regarding the risk factors, hypertension 73(96.1%), coronary
artery disease26(34.2%), diabetes21(27.6%)(Table-XI) were more prevalent in
patients with diastolic dysfunction, having similarities with the study of
Lubien BS et al, 2001, who found hypertension in 58%,diabetes in 35%,coronary
artery disease in 26% patients. Aziz(2001) found smoking as the commonest risk factor (67%) followed
by hypertenstion(38%), dyslipidemia(31%) and diabetes (20%).
2D and M mode echocardiographic parameters (Table XIII)
were significantly poor in restrictive than impaired relaxation group (LA:
38.3±5.7vs. 34.3±4.3 mm, p value<0.02; LVIDd: 50.5±5.3 vs.45.3±5.9 mm, p
value<0.01; LVIDs: 35.4±5.6 vs.29.7±5.2 mm, p value<0.002; EF: 59.5±5.9
vs. 65.1±7.2% p value<0.02).This findings were consistent with that of
Nijland et al, 1997. So, restrictive variety of diastolic dysfunction is
associated with poor echocardiographic characteristics.
Brain natriuretic peptide, a marker of neurohormonal
activation secreted by cardiomyocytes in response to ventricular wall stretch,
has a basic role in cardiovascular remodeling and volume homeostasis (Maeda K
et al, 1998).
It is widely used now as a marker for various
cardiovascular diseases. Especially in heart failure it is used for diagnosis, risk stratification or prognosis, and
treatment monitoring (Mueller C et al, 2007).
Recent studies have demonstrated that left ventricular
diastolic dysfunction contributes to plasma BNP level and thus it is useful for
diagnosis of diastolic dysfunction (Tschope C et al, 2005).
Bettencourt P et al, 1999,
have demonstrated that BNP levels in patients with diastolic dysfunction are
higher than that in normal controls but it was less than that in patients with
systolic dysfunction (Maisel A et
al ,2001).
Lubien and colleagues (2002), showed that, patients with
abnormal LV diastolic function had a mean plasma BNP concentration of
286±31pg/ml while the normal LV group had a mean BNP concentration of
33±3pg/ml. Plasma concentrations were particularly elevated in patients with
restrictive filling patterns and in those with symptoms.Karaca et al, 2007
showed raised plasma BNP(66.17±17.56pg/ml) in asymptomatic diastolic
dysfunction, but BNP level
12.0±4.97pg/ml with normal filling pattern.
In our study, Plasma BNP level was found high in
individuals with isolated diastolic dysfunction group(Table.XV) than without diastolic dysfunction group (
mean 225.8±41.1 pg/ml vs. 38.7±4.8 pg/ml, p value <0.001),which is highly
significant and consistent with other studies.
Among the
variety of diastolic dysfunction, we
found that, plasma BNP level was gradually
increased(Table.XVI) & Fig.11, from impaired relaxation variety(211.4pg/ml)
to restrictive variety (351.opg/ml) that
was similar to findings found by Lubien et al,2002,wereas But the
differences among the groups were not as much
as in other studies. The cause may be due to the fact ,that our
patients had no features of overt heart
failure, asymptomatic or only mildly symptomatic.
Angela BS et al, 2005,showed brain natriuretic peptide was
significantly higher in patients with severe diastolic dysfunction than in
those without (459±462pg/mL vs. 142±166pg/mL, p<0.001) and a
level?138pg/mL appeared to be the best limit for severe diastolic dysfunction,
with accuracy, 70%, sensitivity, 72%, and specificity, 70% ). Alternatively, a
brain natriuretic peptide level?402pg/mL had the highest sensitivity (93%) and
positive predictive value (85%), but the specificity was low (38%). Finally, a
?46pg/ml level, with a 93% negative predictive value, reliably identified
patients free of severe diastolic dysfunction
Wei et al, 2005, assessed the value of BNP in the
diagnosis of left ventricular diastolic dysfunction in hypertensive patients.
The results showed that BNP, when rapidly tested at bedside, has a moderate
sensitivity but an excellent specificity in detecting ventricular diastolic
dysfunction.
The clinical implications of these findings are
that, it is a very useful tool to confirm the diagnosis prompted by other
diagnostic means, such as echocardiography.
Karaga I et al, 2007,
showed a BNP cut off value of 37.0 pg/ml had a sensitivity of 80%,specificity of 100%,PPV
of 100%, a NPV of 23% and accuracy of 88% in asymptomatic hypertensive patients
with impaired relaxation variety.
Wei et al, 2005, reported that BNP at cut off value>40pg/ml had the
79% sensitivity and 92% specificity in diagnosing LV diastolic dysfunction.
Lubien et al, 2002, reported a BNP value of 62pg/ml gave a
sensitivity of 85%, specificity of 83% and an accuracy of 84% for detecting
isolated diastolic dysfunction..Suziki M et al, 2000, showed BNP cut off value
as 41 pg/ml.
In our
study , at different cut off value (60pg/ml,75pg/ml, 85pg/ml)(Table XVII-XX,
& Fig.12 )of plasma BNP, we found different sensitivity (97.4%, 90.8%,89.5%
respectively), different specificity (87.5%,95.8%,100.0% respectively),and
different diagnostic accuracy (95%,92%,92% respectively). The area under the
curve (AUC) for the receiver-operating characteristics (ROC) curve with BNP
used to detect any abnormal diastolic dysfunction was 0.98 (95% confidence
interval, 0.953 to 1.002; p < 0.001). A BNP level of 60 pg/ml had a higher
sensitivity of 97.4%, a specificity of 87.5%, a positive predictive value of
96.1% and an accuracy of 95% for detecting diastolic dysfunction, which was
nearly similar to that found by Lubien et al, 2002.
Redfield MM et al, 2003, found that
preclinical diastolic dysfunction in the community is common and is
independently predictive of the future development of heart failure and cardiac
death. So it is necessary to diagnose diastolic dysfunction at early stage
before overt heart failure.
Optimal catheterization of
diastolic function requires simultaneous
measurement of LV pressure and volume to
generate pressure-volume curve, but it is an invasive procedure and not fesible
to everywhere. Also Doppler echocardiographic characteristics varies with heart
rate, contractility,preload,afterload,valvular regurgitation and position of
the sample volume(Grodecki PV et al, 1993).So, a simple blood test that reflects diastolic dysfunction with
normal systolic function would be of clinical benefit.
Based on the results of our
study, it can be assumed that plasma BNP level not only increase in
high risk patients with diastolic dysfunction, but also
rises gradually as the severity of diastolic dysfunction incrases.So it offers
a simple tool for assessing patients at high risk of diastolic dysfunction and,
consequently, of worse outcome in the first-step screening of large
populations or in patients with technically inadequate Doppler echocardiography.
Maisel A et al, 2001 documented
that a rapid assay of plasma can accurately rule out abnormal echocardiographic
findings, either systolic or diastolic.
A few works in Bangladesh was
done regarding plasma BNP and heart failure by Hoque, m.m.(2010), and
Alam,M.S.(2006) but no work was done in relation to isolated diastolic
dysfunction.We think this is the first work done in Bangladesh.
So, we propose here, that raised
plasma BNP level can accurately predict diastolic dysfunction and clinical
grading of diastolic dysfunction seen on echocardiography. Although plasma BNP
level cannot differentiate between systolic and diastolic dysfunction, a low
level of plasma BNP in the setting of normal systolic function by
echocardiography may be able to rule out clinically suspected diastolic
dysfunction in high risk patients seen on echocardiograpgy.
7. SUMMARY
The study was done to find out the ability of raised plasma
BNP to diagnose diastolic dysfunction on the basis of Doppler echocardiography,
in patients who had no documented features of heart failure but had risk
factors for diastolic dysfunction like IHD, hypertension, diabetes, dyslipidemia.These
patients were defined as high risk patients for development of heart failure.
This work was carried out in the department of cardiology, Sir
Salimullah Medical College, Mitford Hospital, Dhaka and measurement of plasma
BNP was done in the Biochemistry department of BSMMU , Dhaka from September
2008 to August 2010.100 patients were selected on the basis of inclusion and
exclusion criteria.
Doppler echocardiography was done in all selected patients by
two cardiologists who were blinded to BNP report. On the basis of Doppler findings,
76 patients had diastolic dysfunction, 24 patients had no diastolic
dysfunction. Plasma BNP level was measured by AxSYMsystem in both groups.
Among diastolic dysfunction group (76), 58 patients had
impaired lexation variety, 7 were pseudonormal and 11 patients were restrictive
type. Majority of the subjects with diastolic dysfunction were older than 50
years and female 55(72.4%), the mean age was 53.1±1.3 years. Male: female ratio
was 2:1. Impaired relaxation variety and restrictive variety were more common
in female than male (77.6% vs.22.4%and 63.6%vs.36.4% respectively), whereas
pseudonormal was more in male (57%vs.42.9%).Risk factors were common in both
groups so no significant defference regarding risk factors were found, but Ischemic
heart disease(34.2%vs.25.0%),hypertension(96.1% vs. 91.7%), diabetes (27.6%
vs.6.7%) and dyslipidemia(14.5% vs.4.2%) were slightly higher in diastolic
dysfunction group than other without diastolic dysfunction. Most of the patients
with diastolic dysfunction were hypertensive 73(96.1%),were
ischemic26(34.2%) and 21(27.6%) were
diabetic.2D & M mode echocardiographic findings were poorer in restrictive
variety than impaired relaxation variety(LA
38.3±5.7mm vs.34.3±4.3mm;LVIDd 50.5±5.3 vs.45.3±5.9 mm;LVIDs 35.4±5.6
vs.29.7±5.2mm;EF% 59.5±5.9 vs. 65.1±7.2 respectively).
Plasma BNP level was
significantly raised in diastolic dysfunction group than
non diastolic group( mean 225.8±41.1pg/ml vs.38.7±4.8 pg/ml
;p value<0.001).
Majority (97.4%) of the subjects had plasma BNP level 60
or>60 pg/ml
As opposed to 12.5% of subjects without diastolic
dysfunction.
The Plasma BNP increased
with the severity of diastolic dysfunction (211.4pg/ml in impaired relaxation;
247 pg/ml in pseudonormal; 351pg/ml in restrictive), though the
differences among types of diastolic
dysfunction were not statistically significant(p value<0.417).
Considering the cut off value of plasma BNP,our study
showed at different cut off value (60pg/ml,75pg/ml, 85pg/ml) of plasma BNP,
different sensitivity (97.4%, 90.8%,89.5% respectively) ,different specificity
(87.5%,95.8%,100.0% respectively),and different diagnostic accuracy
(95%,92%,92% respectively). The area under the curve (AUC) for the
receiver-operating characteristics (ROC) curve with BNP used to detect any
abnormal diastolic dysfunction was 0.98 (95% confidence interval, 0.953 to
1.002; p < 0.001). A BNP level of 60 pg/ml had a higher sensitivity of 97.4%, a
specificity of 87.5%, a positive predictive value of 96.1% and an accuracy of
95% for detecting diastolic dysfunction,
This study suggests that raised plasma BNP level may serve
as promising biomarker for early diagnosis and assessment of severity of diastolic dysfunction in clinically suspected
patients.
8. CONCLUSION & RECOMMENDATION
LV diastolic dysfunction is present in very early stage of patients
with coronary artery disease, hypertension, diabetes and dyslipidemia.Recent
studies have demonstrated that 40% to 50% of heart failure patients have normal
ejection function and diastolic dysfunction is the presumed cause of symptoms
in these individuals. So early recognition is needed. In this respect, raised
plasma BNP play an important role in early diagnosis of diastolic dysfunction
and also recognition of its severity.
Use of this test with other non-invasive like Doppler
echocardiography may lead to a more accurate early diagnosis of diastolic dysfunction.
But further evalution is needed to establish BNP as a ‘gold standard’ for early
diagnosis of diastolic dysfunction.
Various studies recommend using >100pg/ml as a cut off
value in the diagnosis of symptomatic
heart failure.
But in different studies, there was different cut off value
for diagnostic accuracy of diastolic
dysfunction, so it is necessary to determine new cut off value for early
diagnosis of diastolic dysfunction.
9.
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.Figure-6.This diagram shows intracardiac
pressure tracings from the left ventricle and left atrium with the
corresponding Doppler mitral (MVF) and pulmonary vein flow (PVF) velocity
patterns
Following table contains a list
of ranges of normal parameters of left ventricular Doppler diastolic filling
and pulmonary venous flow (Conooly H. M &Oh J.K. 2008).
·
Pulmonary
venous flow(Fig.6)
o
Peak S wave : 40-90 cm/sec
o
Peak D wave : 30-70 cm/sec
o
S/D ratio :>1
o
Peak atrial reversal (AR) velocity: <
25cm/sec
C .Doppler assessment of
diastolic dysfunction(Conooly, H. M &Oh,J.K. 2008).
By means of Doppler mitral flow
along with pulmonary venous flow velocity, four patterns of diastolic
dysfunction have been identified indicating progressive impairement.
Grade 1 (mild dysfunction) =impaired
relaxation with normal filling pressure
Grade 2 (moderate dysfunction)
=pseudo normalized mitral inflow pattern
Grade 3 (severe reversible
dysfunction) =reversible restrictive (high filling pressure)
Grade 4 (severe irreversible
dysfunction) =irreversible restrictive (high filling pressure)
GRADE 1 DIASTOLIC
DYSFUNCTION OR MILD DIASTOLIC DYSFUNCTION
An early abnormality of diastolic filling is
abnormal myocardial relaxation. Typical cardiac conditions that produce
abnormal relaxation are LV hypertrophy, myocardial ischemia or infarction, as
well as aging. During this stage of diastolic dysfunction, an adequate
diastolic filling period is critical to maintain normal filling without
increasing filling pressure. As long as LA pressure remains normal, the
pressure crossover between the LV and LA occurs late and the early transmitral
pressure gradient is decreased. Consequently, the IVRT is prolonged. Mitral E
velocity is decreased and A velocity is increased, producing an E/A ratio of
less than 1, with prolonged DT. Pulmonary vein diastolic forward flow velocity
(PVd) parallels mitral E
Velocity and is also decreased with compensatory
increased flow in systole. The duration and velocity of pulmonary vein atrial
flow reversal (PVa) are usually normal, but they may be increased if atrial
compliance decreases or LV end-diastolic pressure is high.
Doppler features are (Fig.7):
GRADE 2 DIASTOLIC
DYSFUNCTION OR MODERATE DIASTOLIC DYSFUNCTION (Pseudo
normal)
This stage is also referred to as the pseudo
normalized mitral flow filling pattern, and it represents a moderate stage of
diastolic dysfunction. (Oh JK et al.2006; Redfield MM et al.2003; Munagala VK
et al. 2003). As diastolic function worsens, the mitral inflow pattern goes
through a phase resembling a normal diastolic filling pattern, that is, due to
an increase in left atrial pressure that compensates for the slowed rate of
left ventricular relaxation results in restoration of normal pressure gradient
between LA and LV.Pulmonary venous abnormality occurs in pseudo normalized
pattern. (S/D ratio altered and there is large atrial reversal velocity).
Doppler features are (Fig.7)
o
E/A ratio of 1 to 1.5
o
normal DT (160 to 240 msec)
o
IVRT: 80-100ms
o
S/D ratio:<1
o
AR velocity:>25cm
This is the result of a moderately increased LA
pressure superimposed on delayed myocardial relaxation. There are several means
to differentiate the pseudo normal pattern from a true normal pattern in
patients with grade 2 dysfunction:
A decrease in
preload, by having the patient sit or perform the Valsalva maneuver, may be
able to unmask the underlying impaired relaxation of the LV, decreasing the E/A
ratio by more than 0.5. If A velocity increases with the Valsalva maneuver, it
is a positive sign.
GRADE 3-4 DIASTOLIC
DYSFUNCTION OR SEVERE DIASTOLIC DYSFUNCTION
Severe diastolic dysfunction is also termed
restrictive filling or physiology and can be present in any cardiac abnormality
or in a combination of abnormalities that produce decreased LV compliance and
markedly increased LA pressure. Examples include decompensated congestive
systolic heart failure, advanced restrictive cardiomyopathy, severe coronary
artery disease, acute severe aortic regurgitation, and constrictive
pericarditis. Early rapid diastolic filling into a less compliant LV causes a
rapid increase in early LV diastolic pressure, with rapid equalization of LV
and LA pressures producing a shortened DT. Atrial contraction increases LA
pressure, but A velocity and duration are shortened because LV pressure
increases even more rapidly. When LV diastolic pressure is markedly increased,
there may be diastolic mitral regurgitation during mid-diastole or with atrial
relaxation. Therefore restrictive filling with severe diastolic dysfunction is
characterized by increased E velocity, decreased A velocity (<<E) and
shortened and Systolic forward flow velocity in the pulmonary vein is decreased
because of increased LA pressure and decreased LA compliance.
Doppler features are (Fig. 7):
o E/A
ratio greater than 2
o DT
(<160 ms)
o IVRT
(<70 ms).
o AR
velocity:>35cm
o S/D
ratio:<1
The Valsalva maneuver may reverse the restrictive
filling pattern to grade 1 to 2 patterns, indicating the reversibility of high
filling pressure (grade 3 diastolic filling). However, even if the restrictive
filling pattern does not change with the Valsalva maneuver, reversibility
cannot be excluded because the Valsalva maneuver may not be adequate or filling
pressure is too high to be altered by the Valsalva maneuver.
The transmitral pressure gradient or the
relationship between LA and LV pressures is accurately reflected by mitral
inflow Doppler velocities.Oh JK et al 2006). Diastolic filling is usually
classified initially on the basis of the peak mitral flow velocity of the early
rapid filling wave (E), peak velocity of the late filling wave caused by atrial
contraction (A), the E/A ratio, and deceleration time (DT), which is the time
interval for the peak E velocity to reach zero baseline ( Fig.7 ).
Fig. 7: Summary of the Doppler flow patterns
across the mitral inflow, pulmonary venous flow in normal and different
diastolic dysfunction, also relation with NYHA classes of heart failure (Garcia
MJ et al, 1996).
3.3 Natriuretic Peptide:
3.3.1 General consideration
Natriuretic peptides, atrial
natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type
natriuretic peptide (CNP) produced in the heart are a family of endogenous
polypeptide mediators mainly of cardiac origin with natriuretic with
vasodilator effects. They are sometimes named cardiac hormones (Yamamoto et al,
1996).It constitutes a complex system involving the regulation of sodium
balance and blood pressure (Betowski J et al, 2002).B-type natriuretic peptide
(BNP) was first identified in the porcin brain in 1988, but was subsequently
found to be present in ventricular myocardium, the main source of circulating BNP
(Omland T, 2004).
Other member of this family such
as A-type natriuretic peptides (ANP) C-type natriuretic peptides (CNP),
Dendroaspis natriuretic peptides (DNP) and urodilation (ularitide) discovered.
They are involved in cardiovascular homeostasis, cell-proliferation,
reproductive biology and immune response. Plasma BNP level significantly
increases in systolic heart failure, diastolic heart heart failure, acute
coronary syndrome, right ventricular dysfunction, mitral regurgitation, Age,
renal dysfunction(Troughton R et al, 2004). Koitabashi et al, (2005) found that
BNP level also increases in atrial fibrillation. The higher BNP levels in older
women and men probably reflect diastolic dysfunction (Massie BM, 2003).
The discovery of ANP results from
histological observation of ‘dense bodies’ in atrium explaining its
denomination atrial whose volume increased in animals receiving a sodium
overload. The injection of extracts of these ‘dense bodies’ induced diuresis
and natriuresis and responds to various hypertrophic agonists such as
endothelin-1 (Kerkela R et al, 2002).
ANP is a 28-amino acid
polypeptide secreted by atrial myocytes in response to distension. BNP, thus
named because it was first discovered in brain, is a 32-amino acid mainly
secreted by ventricles in response in response to stretc. B-type natriuretic
peptide (BNP) is a cardiac neuro hormone secreted from the ventricles in
response to ventricular volume expansion and pressure overload. The synthesis
of nBNP occurs through a preprohormone (Elin RJ, 2004). CNP is a 22-amino acid
polypeptide formed in brain and in vascular endothelium. It is a newly
discovered factor that stimulates vasorelaxation and inhibits cell
proliferation (Potter LR et al, 1998). The chemical structure of ANP, BNP and
CNP presents a ring formed by a disulfide bond between 2 cysteine residues.
3.3.2 Biochemistry and molecular Biology:
The natriuretic peptide family
consists of three peptides: atrial nanatriuretic peptide, brain natriuretic
peptide, and c-type natriuretic peptide. The precursor prohormone for each is
encoded by a separate gene. The tissue specific and regulation of each peptide
are unique.
Brain natriuretic peptide was
originally identified in extracts of porcine brain. It is present in human
brain, but there is considerably more in the cardiac ventricles. Human
pro-brain natriuretic peptide contains 108 aminoacids; processing releases a
mature 32-amino-molecule and an amino-terminal fragment (Fig.8). Both circulate
in the plasma, and the concentrations are high in patients with ventricular
hypertrophy or congestive heart failure. (Vesely D et al, 1994). N-terminal
probrain natriuretic peptide has proven to be a powerful tool in the diagnostic
assaesment of dyspnoea as a result of its ability to confirm or exclude the
presence of acute congestive heart failure (Baggish et al, 2004).
Fig .8: Structure of BNP (Processing
of a 108-Amino Acid proBNP Into an Active Form of C-Terminal 32-Amino Acid BNP ,Goetze
JP, 2004)
BNP is a useful biochemical
marker in diagnosis, prognosis, assessment of severity and guide to therapy of
heart failure.
3.3.4 Distribution:
Research about an endocrine
/paracrine role for the heart was started from 1956; it was mainly through the
works that the principle of the arterial extract responsible for diuresis and
natriuresis was identified to be ANP. This was followed by a period of active
research where more members of the family, such as BNP, was isolated from the
venom of the snake Dendroaspis
angusticeps and later identified in
human by researches in the Mayo Clinic, Rochester, USA.Anp and BNP (first
identified in brain) are predominantly produced and secreted by the cardiac
monocytes hence collectively called cardiac Natriuretic peptides. The largest
sector of ANP in humanis left atrium. The ability of other chambers to secret
ANP is the right atrium, right ventricle and left ventricle.
3.3.3 .Table.III Natriuretic peptides discovered to date:
However extra cardiac ANP
secretion is too small to make
significant changes to the plasma levels of ANP. (Nohria A et al., 2006).
BNP on the other hand, is principally secreted
from cardiac ventricles. Apart from ventricles, amniotic tissue produces large
amount of BNP. CNP is largely produced from extra cardiac site such as brain,
vascular endothelium, kidney, testis, ovary, uterus etc. CNP mRNA in heart was
detected by reverse transcriptase-polymerase chain reaction (RT-PCR) but not
with northern blotting, indicating that the CNP gene expression in the heart is
meager. Studies on urodilation are limited. Little is known about their tissue
specific expression except that is highly secreted from renal tubules and
abundant in urine. (Nohria A et al., 2006).
3.3.5 Elimination
Metabolism by neutral endopeptidase:
Neutral endopeptidase a
metaloendopeptidase with zinc at its active centre, serves as the key enzyme
responsible for Natriuretic Peptidase metabolism. This enzyme is maximally
found in the brush border of the proximal convoluted tubule and is also found
in the lungs, heart, intestine, seminal vesicle and neutrophils. NEP degrades
the natriuretic peptides in the rank order of CNP>ANP>BNP. Urodilatin can
also be metabolized by NEP in vitro but this is not physiologically relevant as
the majority of the urodilatin is locally produced in the kidney and excreted
through urine. ANP is also metabolized to certain other enzymes, such as
insulin degrading enzyme. (Nohria A et al., 2006).
Lysosomal degradation:
Natriuretic peptides receptor-C
represents >90% of all the natriuretic peptides receptors in the body and
binds to ANP, BNP and CNP. Apart from the G1 mediated cell signaling roles,
NPR-C facilitates the lisosomal degradation of all known natriuretic peptides.
Although the precise molecular mechanisms are not known.
Urinary excretion:
Urodilatin is an exception as it
is mostly produced in the kidneys and other elimination pathways do not get
much opportunity to metabolize them before they are micturated.
3.3.6 Functions of natriuretic peptides:
The natriuretic peptides can affect
systemic blood pressure by several mechanisms, modification of renal function
and vascular tone, counteracting the renin angiotensin aldosterone system and
action on brain regulatory sites. These systems maintain a condition which
ensures relative constancy of blood electrolytes and water content and
circulating homeostasis.
Main biologic of natriuretic
peptide is as follows:
#Cause natriuresis
#Cause vasodilatation
#Suppression of rennin action
#Suppression of aldosterone action
#Suppression of sympathetic activity
#Inhibition of growth of vascular smooth
muscle (Nohria A et al., 2006).
Recent studies have
demonstrated that BNP levels in patients with diastolic dysfunction are higher
than that in normal controls (Bettencourt P et al, 1999),
but it was less than that in patients with systolic dysfunction (Maisel A et al, 2001).The
sensitivity and specificity of elevated BNP in detecting prolonged isovolumic
relaxation time and increased left end-diastolic pressure were 0.63–0.85 and
0.70–0.76, respectively (Yamamoto et al, 1996).
Recent study by Motrram et al,2003 on a small
patient population has indicated that, although the plasma level of BNP in
patients with hypertension-caused diastolic dysfunction was higher than those
with normal diastolic function, more than 70% patients with diastolic
dysfunction had BNP levels within the normal range.
Lubien and
colleagues measured plasma BNP levels in patients referred for echocardiography
other than for assessment of abnormal systolic function, valve disease,
possible endocarditis, or possible intracardiac thrombus (Lubein E et al,
2002). Those patients with abnormal LV diastolic function, had a mean plasma
BNP concentration of 286±31pg/ml while the normal LV group had a mean BNP
concentration of 33±3pg/ml. Plasma concentrations were particularly elevated in
patients with restrictive filling patterns and in those with symptoms .A BNP
value of 62pg/ml (18pmol/l) gave a sensitivity of 85%, specificity of 83% and
an accuracy of 84% for detecting isolated diastolic dysfunction.
Therefore, in patients with normal systolic left
ventricular function and no valve disease, an elevated plasma BNP concentration
is highly suggestive of clinically significant diastolic dysfunction. This
suspicion should be even stronger if the Doppler examination is also abnormal.
3.3.8 Role of plasma BNP in diagnosing heart failure:
The plasma concentrations of both
ANP and BNP are increased in patient with asymptomatic and symptomatic left
ventricular dysfunction, permitting their use in reaching diagnosis of heart
failure. The value of rapid bedside measurement of plasma BNP for
distinguishing between CHF and a pulmonary cause of dyspnoea has been best
evaluated in a seven-centre, multinationational study of 1586 patients
presenting to the emergency room with a major complaint of acute dyspnoea(.Maisel
As et al ,2002).
In the B-Type Natriuretic Peptide
for Acute Shortness of Breath Evaluation study (Mueller et al, 2006), patients
presenting to the emergency department with acute dyspnea were randomly
assigned to undergo either a single measurement of BNP or not. Based largely on
the findings of the BNP Multinational Study, clinicians were advised that a
plasma BNP concentration <100 pg/mL made the diagnosis of congestive heart
failure unlikely, whereas a level >500 pg/mL made it highly likely. For BNP
levels between 100 pg/mL and 500 pg/mL, the use of clinical judgment and
additional testing was encouraged. The decision cut-points recommended in
Europe for NT-proBNP are 100pg/ml for males and 150pg/ml for women, and in the
USA 125pg/ml for both genders (The Task Force for the Diagnosis and
Treatment of Chronic Heart Failure, European Society of Cardiology. Guidelines for the diagnosis
and treatment of chronic heart failure. Eur Heart J. 2001).
BNP has been suggested as a means of identifying
those heart failure patients at high risk of death or hospitalization, in order
to target therapy and enable selection for tertiary or quaternary services.
Plasma BNP concentrations are higher in patients
with more severe symptoms and in those with more severe cardiac damage. (Valli
N et al, 2001).
A raised BNP is able to differentiate between
moderate and severe impairment of left ventricular function. (Krugers et
al.2001). In addition, BNP also correlates well with cardiopulmonary exercise
capacity and with composite measures of heart failure severity, such as the
Heart Failure Survival Score. (Koglin J et al, 2001).
BNP is an independent predictor of death in
patients with chronic heart failure, and is superior to atrial natriuretic
peptide (ANP) for predicting mortality (Tsutamoto T et al, 1997). In this
study, each 10pg/ml increase in plasma BNP was associated with a 3% increase in
the risk of cardiac death over the follow-up period. BNP is also an independent
predictor of all-cause mortality in patients with asymptomatic or minimally
symptomatic left ventricular dysfunction, being superior to norepinephrine and
left ventricular volumes (Tsutamoso T et al, 1999).
In patients with acute heart failure, BNP has
been shown to be an independent predictor of cardiovascular mortality, (YuCM et
al, 1999) and is also predictive of outcome in patients hospitalized with
decompensated heart failure. (Cheng V et al, 2001) Importantly, this last study
suggested that measuring plasma BNP concentrations before discharge may help to
identify patients with heart failure who are at a low risk of re-admission
within the next month.
BNP may have a role in selecting patients with
advanced heart failure for transplantation. One recent study looked at patients
with severe left ventricular function and heart failure. BNP concentrations
were the strongest predictor of mortality at four years of follow-up. (Stanck B
et al, 2001). In an ambulant heart failure clinic population, plasma BNP was at
least equivalent to the Heart Failure Survival Score (which is commonly used
for assessing patients for transplantation) in risk stratification (Koglin J et
al, 2001).
A recent study looking at 452 ambulatory patients
with left ventricular dysfunction in whom there was a high rate of sudden death
found that the BNP concentration was the only independent predictor of sudden
death (Berger R et al, 2002).
Plasma BNP concentrations are known to fall
rapidly on treatment of patients with heart failure. (Richards AM et al, 1993; MaiseI A et al, 2001). In the
clinic setting, patients whose functional status improved between visits showed
a statistically significant reduction in plasma BNP concentration of about 50%;
other variables such as NT-proANP and ANP or ejection fraction showed no
statistically significant change (Lee SC et al, 2002). However, the monitoring
of therapy by measuring plasma BNP concentration is complicated by the wide
variation of plasma BNP levels reported in patients with symptomatic heart
failure, which may make titration to a ‘target’ dose of BNP difficult.
Furthermore, recent data show a progressive rise in a variety of natriuretic
peptides as patients’ renal function deteriorates (Cattakotti A et al, 2001). As
yet it is unclear what reduction in creatinine clearance is necessary for this
effect appear; it may be relatively modest but nevertheless has implications
for targeting of therapy. Reducing the plasma BNP concentration in the clinical
setting by stepping up the diuretic dose may result in the patient developing
worsening renal function, which may offset the expected reduction in BNP.
Therefore, to titrate drugs against BNP is therefore not as simple an idea as
it first appears.
Nevertheless, there is some evidence of the
possible benefit of a BNP-guided approach to therapy (with diuretics and ACE
inhibitors) from a randomized trial conducted in 69 patients with symptomatic
heart failure due to left ventricular systolic dysfunction (Troughton RW et al,
2000).
BNP may also find a role in guiding introduction
of therapy for patients with heart failure. One study conducted in patients
with chronic stable heart failure due to left ventricular systolic dysfunction
suggested that the beta-blocker carvedilol was most efficacious in patients
with higher pre-treatment BNP concentrations (82.5pg/ml)(Richards AM et al,
1999). This hypothesis has not been examined in a prospective randomized trial.
However, a similar finding for NT-proBNP has also been reported. (Richards AM
et al, 2001). Further work is required before BNP measurement can have a role
in guiding the introduction of beta-blockade (and other therapies) in heart
failure.
3.3.11 Recombinant human BNP (Nesiritide) therapy in heart
Failure
Nesirtide is the newest drug that has been
approved to treat patients with ADHF. Nesiritide is a recombinant formulation
of endogenous B-type natriuretic peptide (BNP. BNP has vasodilatory properties
and is helpful for relieving signs and symptoms and improving the markedly
abnormal homodynamic changes that occur with ADHF. BNP is secreted by the left
ventricle in response to stretching of the myocytes that occurs when left
ventricular end-diastolic pressure (preload) is increased.
In addition to its vasodilatory properties, BNP
has natriuretic effects and neurohormonal antagonism (Abraham WT et al, 1998).
In fact, in contrast to neurohormones such as norepinephrine, aldosterone, and
angiotensin II, which can lead to harmful changes, BNP is a useful
counter-regulatory hormone that plays an important role in cardiovascular
hemostasis. As the severity of heart failure increases, greater amounts of BNP
are secreted by the ventricles in response to greater preload in an attempt to
unload the heart and improve function. Unfortunately, the physiological
activity of BNP is “overwhelmed” by the vasoconstrictive and
fluid-retaining properties of other hormones (angiotensin, aldosterone, and nor-epinephrine).
This increase in the level of BNP is the basis for the point-of-care test for
BNP that has been used to diagnose heart failure in an emergent setting (Maisel
AS et al, 2002). Homodynamic changes that occur with the use of nesiritide
include reduction in pulmonary artery pressures and left ventricular pressures
(pulmonary capillary wedge pressure [PCWP], which is a measure of preload). In
the patient in the case study, nesiritide was chosen because of its
effectiveness in alleviating signs and symptoms and improving homodynamic
status, its ease of administration, its lack of toxicity, and its mild
diuretic/natriuretic properties. Inotropic agents were not indicated because
the patient’s condition was relatively stable, with a good blood pressure and
no indications of hypo perfusion or cardiogenic shock.
The role of nesiritide in the treatment of acute
heart failure has been investigated in several trials. In a 2-part trial,
Colucci et al, 2000, studied patients with acute heart failure: one part was an
efficacy trial (nesiritide vs. placebo); the other part was a comparative trial
(nesiritide vs. standard of care, which could include the administration of
dobutamine, milrinone, nitroglycerin, or nitroprusside at the discretion of the
investigator). In the efficacy trial, a bolus of 0.3 or 0.6 µg/kg was given and
then nesiritide was infused at 2 different doses, either 0.015 µg/kg per minute
or 0.03 µg/kg per minute. In the comparative trial, the bolus and maintenance
doses of nesiritide were the same; however, nesiritide was compared with
standard care as just described. In both trials, the end points were reduction
in PCWP and improvement in signs and symptoms of heart failure, as measured by
using a global clinical assessment scale. Patients included in the trial had
marked homodynamic dysfunction as indicated by a baseline mean PCWP of 28 mm
Hg, a mean cardiac index (calculated as cardiac output in liters per minute
divided by body surface area in square meters) of 1.8, and a mean left
ventricular ejection fraction of 0.22. In the efficacy trial, compared with
placebo, nesiritide improved homodynamic function and global clinical
assessment scores. In the comparative trial, treatment with nesiritide and
standard therapy resulted in similar improvements in signs and symptoms. The
most common adverse effect of nesiritide was hypotension, both asymptomatic and
symptomatic.
The Vasodilatation in the Management of Acute
Congestive Heart Failure (VMAC) trial was done to compare the effects of
nesiritide with the effects of another vasodilator, nitroglycerin. In this
large trial, patients with ADHF and resting dyspnea were randomized to receive
intravenous nitroglycerin (dosage adjusted by investigator), intravenous
nesiritide (either in a fixed dosage of a 2 µg/kg bolus followed by an infusion
at 0.01 µg/kg per minute or an adjustable dose), or placebo in addition to
standard therapy for heart failure. The investigators decided whether to
monitor each patient invasively with a pulmonary artery catheter. This
pulmonary artery catheter was used for monitoring in about half of the patients
(60 of 143 patients receiving nitroglycerin, 124 of 204 patients receiving
nesiritide, and 62 of 142 receiving placebo). This predetermined stratification
and the dosing strategy were an attempt to replicate actual common practice in
managing patients with heart failure without the aid of homodynamic monitoring.
Although both nesiritide and nitroglycerin
decreased PCWP, nesiritide reduced PCWP significantly more than standard care
plus intravenous nitroglycerin or standard care plus placebo reduced PCWP in
the first 3 hours of therapy. The superior reduction of PCWP with nesiritide
was largely sustained for 24 hours during the infusion. After 3 hours, patients
in the nesiritide groups experienced a significant improvement in dyspneic
symptoms compared with the patients who received the placebo but did not show
any improvement compared with patients who received nitroglycerin. After 24
hours, both patients treated with nitroglycerin and patients treated with
nesiritide had similar improvements in dyspneic symptoms.
Significantly more patients treated with
nitroglycerin than patients treated with nesiritide experienced adverse effects
during the first 24 hours of drug infusion. The most common adverse effect (in
both groups) was headache, which occurred to a greater extent in the
nitroglycerin group (20%) than in the nesiritide group (8%). Additionally, more
patients treated with nitroglycerin (5%) than patients treated with nesiritide
(1%) experienced abdominal and catheter-associated pain. Hypotension occurred
in both groups. During the first 24 hours after administration of the drug, 8%
of patients receiving nesiritide had asymptomatic hypotension and 4% had
symptomatic hypotension. Similarly, among patients treated with nitroglycerin,
8% had asymptomatic hypotension and 5% had symptomatic hypotension, although
the duration of the hypotension was longer in the group that received
nesiritide therapy. Thirty-day readmission rates and 6-month mortality rates
did not differ significantly between the 2 groups.
The VMAC trial provides the evidence to support
the currently recommended initial dose of nesiritide, a bolus of 2 µg/kg followed
by a maintenance infusion of 0.01 µg/kg per minute. This study indicates a role
for nesiritide in the treatment of ADHF.
In the Prospective Randomized Evaluation of
Cardiac Ectopy with Dobutamine or Natrecor Therapy (PRECEDENT) study (Burger AJ
et al, 2002); the incidence of ventricular tachycardia was compared between
patients with ADHF receiving dobutamine and patients with ADHF receiving
nesiritide. In that study, 24-hour Holter monitors were used to detect
arrhythmias during infusions of dobutamine and nesiritide. Patients given
dobutamine infusions experienced significantly more episodes of ventricular
ectopy (tachycardia, premature ventricular contractions, couplets, triplets)
than did patients given nesiritide infusions. The occurrence of ventricular
arrhythmias can be a problem in patients with acute heart failure because
potentially lethal arrhythmias may occur. The commonly used inotropic agents,
dobutamine and milrinone, increase the incidence of both atrial and ventricular
arrhythmias (Califf R et al, 2002).
3.4. Heart Failure:
A pathophysiological state in
which an abnormality of cardiac function is responsible for the failure of the
heart to pump blood at a rate commensurate with the requirements of the metabolizing
tissues (Gary S et al, 2008).
3.4.1. Systolic versus Diastolic Heart Failure (Gary S et al, 2008)
A more contemporary distinction
in patients with heart failure is to characterize the particular structural
abnormalities with cardiac imaging techniques, and the majority of clinical
studies in heart failure have used this phenotype. Systolic dysfunction
describes a large, dilated, and often eccentrically hypertrophied ventricle in
which output is limited by impaired ejection during systole, whereas diastolic
dysfunction refers to a thickened, small cavity ventricle in which filling is
limited because of abnormalities during diastole (Table -IV).
These terms are most appropriately defined in
terms of altered ventricular performance and geometry rather than systemic homodynamic
or overt symptoms as they can manifest with almost identical symptomatology. It
is also clear that systolic and diastolic dysfunction frequently coexist in
patients with heart failure because systolic dysfunction, notably on exercise,
can directly influence diastolic function. Systemic symptoms may not correlate
with the degree of ventricular dysfunction as assessed by contraction during
systole at rest.
Table V showed the risk factors
for heart failure ( Abraham. et al, 2008).
3.4.2 Clinical
features
of diastolic heart failure (Redfield et al, 2008)
Patients with HFnlEF were shown to have similar
pathophysiological characteristics compared with HF patients with a reduced EF
including severely reduced exercise capacity, neuroendocrine activation, and
impaired quality of life despite normal EF, normal left ventricular (LV)
volume, and an increased LV mass-to-volume ratio(Kitzman DW et
al,.2002).(TableVI)
Table- VI Clinical Features of Heart
Failure with Normal Ejection Fraction (Framingham criteria for
diagnosis of heart failure*)( Redfield M,2008)
Major criteria Paroxysmal
nocturnal dyspnea or orthopnea
Jugular venous distention (or CVP > 16 mm Hg)
Rales or acute pulmonary edema
Cardiomegaly
Hepatojugular reflex
Response to diuretic (weight loss >4.5 kg in 5 days)
Minor criteria : Ankle
edema
Nocturnal
cough
Exert ional dyspnea
Pleural effusion
Vital capacity < two thirds
of normal
Hepatomegaly
Tachycardia (>120 bpm)
Demographic features: Elderly; female > male
Underlying CV disease: Hypertension, coronary
disease, diabetes,
Atrial fibrillation
Co morbidities: Obesity, renal dysfunction
Doppler echocardiography results:
LV size ————— Normal
to ? (small subset with?) LV mass
LV mass ————— LVH
common but frequently absent;
? Relative
wall thickness (> 0.45)
Left atrium —————- Enlarged
Diastolic dysfunction —— Grade
I-IV (? diastolic dysfunction severity, BP,
Volume
status)
Other features
————– PH, wall motion abnormality, RV enlargement
Pertinent negatives ——– Rule
out valve disease, pericardial disease, ASD
BNP or NT-proBNP: ? but HFnlEF < HFrEF
Exercise testing : ? VO2 peak
Exaggerated hypertensive response in
many
Chronotropic incompetence in subset
Chest radiogram: Similar
to HFrEF, cardiomegaly, pulmonary venous
Hypertension, edema, pleural effusion
Electrocardiogram:
Variable
*Two major or
one major and two minor criteria
3.4.3 Prevalence of
diastolic heart failure
The studies performed until now have assessed the
prevalence of HF with normal EF, using standard echocardiography without
Doppler. In a first meta-analysis of 1995, the investigators of the Framingham
Heart Study (Vasan RS et al,1995) showed wide variability in the prevalence of
this kind of HF (range = 13–74%) while a subsequent study involving the
Framingham offspring cohort pointed out a 51% prevalence of overall HF(Vasan RS,
1999). Very recently, Hogg et al collected ten “cross-sectional”
studies on population, in the United States as in several European countries,
and found very high variability of HF with normal EF. The explanation of this
variability is related mostly to different age and gender of participants. It
has to be considered that this kind of HF is particularly frequent in the
elderly population, occurs more often in the female gender and is associated
much more with arterial hypertension and atrial fibrillation than to coronary
heart disease (Hogg K et al, 2004).
3.4.4 Prognosis of
diastolic heart failure
3.4.5 Management of diastolic dysfunction & diastolic heart failure
Primary prevention of diastolic heart failure
includes smoking cessation and aggressive control of hypertension,
hypercholesterolemia, and coronary artery disease. Lifestyle modifications such
as weight loss, smoking cessation, dietary changes, limiting alcohol intake,
and exercise are equally effective in preventing diastolic and systolic heart
failure. Diastolic dysfunction may be present for several years before it is
clinically evident.
Early diagnosis and treatment is important in
preventing irreversible structural alterations and systolic dysfunction.
However, no single drug has pure lusitropic properties (i.e., selective
enhancement of myocardial relaxation without inhibiting left ventricular
contractility or function). Therefore, medical therapies for diastolic
dysfunction and diastolic heart failure often are empirical and not as well
defined as therapies for systolic heart failure. On the surface, it appears
that the pharmacologic treatments of diastolic and systolic heart failure do
not differ dramatically; however, the treatment of diastolic heart failure is
limited by the lack of large and conclusive randomized control trials. (Hunt SA
et al, 2001). Furthermore, the optimal treatment for systolic heart failure may
exacerbate diastolic heart failure. Most clinical trials to date have focused
exclusively on patients with systolic heart failure; only recently have trials
addressed the treatment of diastolic heart failure.
Although conclusive data on specific therapies
for diastolic heart failure are lacking, the American College of Cardiology and
the American Heart Association joint guidelines (Hunt SA et al, 2001) recommend
that physicians address blood pressure control, heart rate control, central
blood volume reduction, and alleviation of myocardial ischemia when treating
patients with diastolic heart failure. These guidelines target underlying
causes and are likely to improve left ventricular function and optimize
hemodynamics.Table VII lists treatment goals for diastolic heart failure.
TABLE VII.Goals for Treating
diastolic dysfunction & Diastolic Heart
Failure (Hunt SA et al, 2001) .
ACE =
angiotensin-converting enzyme; ARB = angiotensin receptor blocker.
·
IMPROVING
LEFT VENTRICULAR FUNCTION
When treating a patient with diastolic
dysfunction, it is important to control the heart rate and prevent tachycardia
to maximize the diastolic filling period. Beta blockers are particularly useful
for this purpose; however, they do not directly affect myocardial relaxation.
In addition to slowing heart rate, beta blockers have proven benefits in
reducing blood pressure and myocardial ischemia, promoting regression of left
ventricular hypertrophy, and antagonizing the excessive adrenergic stimulation
during heart failure. Beta blockers have been independently associated with
improved survival in patients with diastolic heart failure. (Chen HH et al,
2000). These medications should be used to treat diastolic heart failure,
especially if hypertension, coronary artery disease, or arrhythmia is present.
·
OPTIMIZING
HEMODYNAMICS
Optimizing homodynamic primarily is achieved by
reducing cardiac preload and after load. Angiotensin-converting enzyme (ACE)
inhibitors and angiotensin receptor blockers (ARBs) directly affect myocardial
relaxation and compliance by inhibiting production of or blocking angiotensin
II receptors, thereby reducing interstitial collagen deposition and fibrosis. (Aggomachalelis
N 1996; Mitsunami K,1998). The indirect benefits of optimizing homodynamic
include improving left ventricular filling and reducing blood pressure. More
importantly, there is improvement in exercise capacity and quality of life (Warner
JG et al, 1999). One retrospective study (Philbin EF et al, 2000) showed that
improved survival was associated with ACE inhibitor therapy in patients with
diastolic heart failure. One arm of the CHARM (Candesartan in Heart Failure
Assessment of Reduction in Morbidity and Mortality) trial, (Yusuf S et al, 2003)
which studied the effect of candesartan (Atacand) in patients with normal
ejection fraction for 36.6 months, did not show a significant mortality
benefit. However, it reduced the incidence of hospitalization for CHF
exacerbation.
Diuretics are effective in managing optimal
intravascular volume, and they minimize dyspnea and prevent acute heart failure
in patients with diastolic dysfunction. Although diuretics control blood
pressure, reverse left ventricular hypertrophy, and reduce left ventricular
stiffness, some patients with diastolic heart failure are sensitive to the
preload reduction and may develop hypotension or severe prerenal azotemia.
Intravenous diuretics should only be used to relieve acute symptoms.
The hormone aldosterone promotes fibrosis in the
heart and contributes to diastolic stiffness. The aldosterone antagonist
spironolactone (Aldactone) has been studied in a large clinical trial of
systolic heart failure, (Pitt B et al, 1999), which showed a reduction in
mortality related to heart failure. However, the specific effects of
spironolactone on diastolic dysfunction are unclear.
Calcium channel blockers have been shown to
improve diastolic function directly by decreasing cytoplasmic calcium
concentration and causing myocardial relaxation or indirectly by reducing blood
pressure, reducing or preventing myocardial ischemia, promoting regression of
left ventricular hypertrophy, and by slowing the heart rate. However,
nondihydropyridine calcium channel blockers (e.g., diltiazem [Cardizem]) and
verapamil (Calan) should not be used in patients with bradycardia, conduction
defects, or severe heart failure caused by left ventricular systolic dysfunction
(Gutierrez C et al, 2004). Instead, nondihydropyridines, such as diltiazem and
verapamil, should be used for rate control and angina when beta blockers are
contraindicated or ineffective. Finally, large randomized controlled trials
have not proved that calcium channel blockers reduce mortality in patients with
isolated diastolic dysfunction.
Vasodilators (e.g., nitrates, hydralazine
[Apresoline]) may be useful because of their preload-reducing and anti-ischemic
effects, particularly when ACE inhibitors cannot be used. The Vasodilator Heart
Failure Trial, (Cohn JN et al, 1990), however, did not show significant
survival benefit in patients with diastolic heart failure. Vasodilators should
be used cautiously because decreasing preload may worsen cardiac output. Unlike
other medications used for diastolic heart failure, vasodilators have no effect
on left ventricular regression.
The exact role of digoxin for treating patients
with diastolic heart failure remains unclear. Digoxin can be deleterious in
older patients with left ventricular hypertrophy and hypertrophic obstructive
cardiomyopathy; therefore, digoxin is only appropriate for patients with
diastolic heart failure and atrial fibrillation. (Digitalis investigation group,
1997).
4.
MATERIALS AND METHOD
4.1 Place & Period of Study:
It was a Cross sectional study
and carried out in the department of cardiology, Sir Salimullah Medical College,
Dhaka, from September 2009 to august 2010.
4.2 Study population:
100 total consecuative patients were selected from the department
of cardiology, having history of the risk factors for diastolic dysfunction such
as ischemic heart disease, hypertension, diabetics, and hyperlipidemia without
definite features of overt heart failure on the basis of inclusion and
exclusion criteria. Patients of acute myocardial
infarction were excluded by ECG and biomarkers.
4.2.1 Inclusion criteria:
Patients of
both sexes.
Patients of ?
18 years.
Patients
having risk factors for diastolic dysfunction.
eg. IHD,Hypertension, Diabetes,
Hyperlipidemia,
etc. (having clinically
Suspected
diastolic dysfunction)
4.2.2Exclusion criteria:
Patients with
EF<50%.
Patients with
LVED dimension >55mm.
Heart failure.
Patients with ACS.
Valvular heart
diseases.
Cardiomyopathies.
Pericardial
diseases.
Cardiac cause
of stroke.
Poor echo
window.
Patients with
renal failure, hepatic failure.
Hyperthyroidism,
undue tachycardia.
4.2.3 Grouping of patients:
The selected Patients were
grouped into two-Group-I having diastolic dysfunction and Group–II without
diastolic dysfunction on the basis of Doppler echocardiographic findings.
Plasma BNP level was done in both Groups.
4.2.4 Ethical
Issue:
The study protocol
was approved by Institutional ethical committee.
4.3 Study Methods:
4.3.1 Informed written consents
were taken from all patients included in
The study. (Appendix-I).
After taking History and clinical examination,
echocardiography was done by two cardiologists .Blood was send for plasma BNP
level and for other needed investigations in all 100 selected
patients.Cardiologists who done the echocardiography were blinded to plasma
level of BNP. All findings were recorded in the structured questionnaire (Appendix-I1).
4.3.2 Clinical evaluation:
a) History
Proper history regarding risk
factors of diastolic dysfunction was taken and previous documented history,
investigations were evaluated carefully to exclude heart failure.
I) Ischemic heart disease:
Patients were considered having ischemic heart
disease documented by history, ECG, echocardiography.
II) Hypertension:
Patients were considered as hypertensive having systolic blood pressure
>140 mm hg and diastolic >90 mm hg (JNC’7) with or without treatment.
III) Diabetes:
Patients were considered as
diabetic having fasting blood sugar ?7 mmol/L (WHO diabetes criteria 2009).
IV) Hyperlipidemia:
Patients were considered
hyperlipidemic having—lipid profile above normal.
TCL: ?160 mg/dl,
LDL: ?130 mg/dl, TG: ?200mg/dl (NCEP,2002).
b) Clinical examination:
During clinical examination, emphasis
was given on pulse, blood pressure, jugular
venous pressure, 3rd and 4th heart sounds ,and basal crepitations to
exclude heart failure.
4.3.3 Laboratory investigations:
Following cardiac and biochemical
tests were carried out in all subjects.
I)
ECG:
12 lead electrocardiogram
was
performed to observe any previous evidence of IHD, MI, LVH.
II) Echocardiography:
Echocardiographic instrument:
Echocardiographic machine which were used for the study had conventional (2D
and M mode) with Doppler and color flow imaging facility. At SSMC it was VIVID
7 Dimension. Version 7.x.x (2007) and Philips (i.E. 33 Ultrasound System) 2007,
and the system was equipped with 2.5 and 3.5 MHZ transducers. All patients first underwent 2D & M mode
echocardiography and analyzed for chamber enlargement, ventricular hypertrophy,
wall motion abnormalities, and systolic function. Wall motion abnormalities
were graded from normal to dyskinesia.
Doppler assessment was performed,
by apical four chamber view to assess transmitral flow and pulmonary flow patterns.
Pulsed Doppler sample volume was placed on the tips of mitral valve leaflets,
whereas sample volume was placed 1-
cm
pulmonary venous flow. Flow patterns across the mitral inflow i.e. E and A wave
velocities, E/A ratio, decelaration time (DT) of E wave, isovolumetric
relaxation time (IVRT).Similarly flow patterns across the pulmonary inflow i.e.
and D wave velocities, S/D ratio, atrial reversal (AR) were measured .Normal values
for Doppler parameters were already mentioned. (page-40). As per values of
transmitral and transpulmonary venous inflow parameters, different types/grades
of diastolic dysfunction were classified.
They were absent, abnormal relaxation, pseudonormal, and restrictive patterns
(definitions on page-42-44). All Doppler values were recorded. Flow spectral
was also printed on Polaroid paper with a printer.
Working Definitions of diastolic dysfunction parameters:
Normal
ventricular function:
Defined by normal LV end-diastolic (35-55mm)
and end-systolic (25-36mm) dimensions, no major wall motion abnormalities, an
ejection fraction>55%, no evidence of impaired or restrictive relaxation
abnormalities.
Diastolic dysfunction:
Impaired relaxation:
Defined as an E/A ratio of<1
or DT>240ms in patients<55 years of age, and E/A<0.8 and DT>240ms
in patients >55years age or.IVRT >100ms .with abnormal E/A ratio. And /or
DT>240ms.
Pseudo-normal:
Defined as E/A ratio 1 to 1.5 and
DT>240ms.Confirmation included
Pvd/Pvs>1.5 or IVRT <100ms or by
reversal of the E/A ratio <1 by valslva when possible.
Restrictive like:
Defined as DT<160ms with ?1 of the
followings: left atrial size>50mm, E/A ratio>1.5 or IVRT<70ms, Pvd/Pvs>1.5,
and pulmonary A” reversal >35cm/sec.
Chamber Abnormalities: Left atrial enlargement defined as atrial size
±50mm..LV hypertrophy defined as mean LV thickness of septum and posterior wall
±12mm. patients with HOCM was excluded.
III) Estimation of plasma BNP
level:
Collection Blood sample:
With full aseptic precaution, 3
ml of blood from anticubital vein was taken from each study subject collected in a plastic
test tube containing EDTA(axis shield diagnostic 2003).Plasma was separated by
centrifuging the blood at 3000 rpm for 10 minutes and 1.8 ml of plasma was
collected in a ependroffs tube and preserved at -35?C,until analysis.
Estimation was done by micro particle enzyme
immune assay (MEIA) principle in AxSYM system (Axis-Shield diagnostics, 2003), in
the biochemistry lab, BSMMU.
IV) Fasting blood sugar .
V) Lipid profile: after overnight
fasting (8-10 hours) morning venous blood was taken for plasma lipid
estimation.
VI) Serum creatinine label was
done for exclusion of renal impairment.
4.3.4 Measurement of accuracy of plasma BNP for diagnosis of diastolic
dysfunction (Park K, 2005):
The present study was intended to
find out the accuracy or validity of plasma BNP level as a screening test in
detecting diastolic dysfunction. Before going to the test findings; it would be
worthwhile to interpret the components of accuracy of a screening test. In the
following table, the letter ‘a’ denotes those individuals found positive on
test who have the disease being studied (i.e. true positive), while ‘b’
includes those who exhibit a positive test result but who do not have the disease
(i.e. false positive).The letter ‘c’ is the number of negative test results
having disease (i.e. false negative) and the letter‘d’ is the number of negative
results who do not have the disease (i.e. true negative).
Table: measurement of accuracy
plasma BNP for diagnosis of diastolic dysfunction:
Established diagnosis
Screening Test Total
Diseased Non-diseased
Positive a b
(a+b)
Negative c d
(c+d)
Total (a+c) (b+d)
(a+b+c+d)
The following measures are used to evaluate a screening test:
1. Sensitivity= a/(a+c)×100
2. Specificity= d/(b+d)×100
3. Positive predictive valueof
the test (PPV) =a/ (a+b) ×100
4. Negative predictive value of
the test (NPV) =d/(c+d) ×100
5. Percentage of false+ve=b/ (a+b)
×100
6. Percentage of false—ve=c/(c+d)
×100
Diagnostic accuracy= (a+d)/ (a+b+c+d)
×100
7. Positive likelihood ratio (LR+
)
Probability of positive test
result in a person with the disease
=
Probability of positive test result in a person without the disease
a/(a+c) SEN TP
rate
=
= =
b/(b+d) 1-SPE FP
rate
(LR+ )=1: has no
diagnostic value
(LR+ ) >1: persons
with diseas are more likely to have a positive test result
Than non diseased.
(LR+ ) >10: test
has high diagnostic value.
8. Negative likelihood ratio (LR–)
Probability of negative test result in a
person with the disease
=
Probability of negative test result in a person without the disease
c/(a+c) 1- SEN FN rate
=
= =
d/(b+d) SPE TN
rate
((LR–)=1: has no
diagnostic value
((LR–) <1: persons
with disease are less likely to have a negative test result
Than persons without disease.
((LR–) ?0.1: test has
high diagnostic value.
4.3.5Data processing and statistical analysis:
Data were processed and analyzed
using SPSS (Statistical Packages for Social Sciences), version 11.5. Test
statistics used to analyze the data were Chi-square (?2) Probability
Test (For comparison of data presented on categorical scale) and Student’s
t-Test (for data presented on continuous scale). Risk of developing diastolic
dysfunction was estimated using Odds Ratio (with 95% confidence interval for
Odds Ratio). ANOVA statistics was employed to compare the plasma BNP among the
three types of diastolic dysfunction. Receiver operating characteristic curve
was analyzed to determine the best cut-off point at which optimum sensitivity,
specificity, PPV and NPV can be obtained in diagnosing diastolic dysfunction
using plasma BNP. Level of significance was set at 0.05 and p-value < 0.05
was considered significant.
STUDY FLOW CHART
100 selected Patients on the basis of
inclusion & exclusion criteria attending to the cardiology department (September
2009-auguest 2010),SSMC, Dhaka.
Doppler
Echocardiography
—————————————————————————–
Group -I
Group-II
Patients having
patients without
Diastolic dysfunction (no-76) Diastolic dysfunction
(no-24)
Impaired relaxation Pseudonormal Restrictive
(n=58)
(n=7) (n=11)
BNP level BNPlevel
Results
5. RESULTS
In total 100 selected patients on
the basis of inclusion & exclusion criteria for the study,76 patients with diastolic
dysfunction were screened out by Doppler echocardiography,and 24 had no diastolic dysfunction.Plasma BNP level was done in all .
5.1 Age distribution between groups:
Table I demonstrates that the subjects of the
diastolic dysfunction (group-I) were relatively older than those of without
diastolic dysfunction (group-II). With 61.8% subjects in the former Group being
50 or > 50 years old as opposed to
16.7% in the later group. The mean ages of the subjects in the study and the
control groups were 53.1±1.3 years and 44.5±1.4 years respectively (p <
0.001).
# Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
s*** = significant at p
value<0.001
n=total number of patients.
5.2 Sex distribution between groups:
In diastolic dysfunction group females were
predominant (over 72.4%) but the result is not statically significant of sex (p
= 0.884).Male: Female ratio was 2:1 in group with diastolic dysfunction.
# Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
Ns= not significant
5.3 Age distribution among different types of diastolic dysfunction:
Age distribution among diastolic
dysfunction groups demonstrates that 62.1% patients in impaired relaxation,
85.7% in pseudonormal and 54.5% in restrictive groups were < 60 years old.
The rest of the respective groups (37.9% in impaired relaxation, 14.3% in
pseudonormal and 45.5% in restrictive groups) were 60 or > 60 years old
(Figure 9).
Fig.9: Comparison of age among different
types of diastolic dysfunction.
5.4 Comparison of sex among Different diastolic dysfunction groups :
About 22% of patients, 57.1% in
pseudonormal and 36.4% in restrictive groups were male. Female predominance was
observed in impaired relaxation and restrictive group, while the pseudonormal
group had no significant difference with respect to sex (Figure 10).
Fig.10: Comparison of sex among different
types of diastolic dysfunction.
5.5. Echocardiographic
characteristics among different types of diastolic dysfunction :
Of the 76 patients with diastolic
dysfunction, 58 had impaired relaxation, 7 pseudonormal and 11 restrictive
like. Diastolic function indicators calculated by Doppler echocardiography are
shown in table X. Majority (89.7%) of the subjects with impaired relaxation had
impaired DT (> 220 msec), 100% with pseudonormal <220msec and 100% of
restrictive variety have <160msec. Majority (96.6%) of the impaired group
had E/A ratio < 1, 85.7% of the pseudonormal had E/A ratio 1 – 1.5 and all
of the restrictive-like had E/A ratio > 1.5. IVRT was found impaired
(>100 ms) in 86.2% of impaired relaxation, 80-100ms in 100% of pseudonormal
and <70ms 100% of restrictive types of diastolic dysfunction. However, all
patients in pseudonormal group exhibited abnormal S/D ratio<1 and peak
AR>35cm/sec as compared to 100% and 81.8% in restrictive group respectively.
Table X. Echocardiographic findings among diastolic dysfunction groups :
DT=deceleration time; IVRT=
isovolumetric relaxation time; AR=atrial
reversal velocity.
5.6 Comparison of risk
factors between diastolic dysfunction group and group
without diastolic dysfunction:
Table XI demonstrates Risk factors
profile between groups. No statistically significant difference in proportion
were observed between groups in relation to diabetes, hypertension, smoking
habit, dyslipidemia and coronary artery disease was observed. However, all
these risk factors were higher in diastolic dysfunction group than without
diastolic dysfunction.
# Chi-square (c2)
Test was employed to analyze the data;
* Fisher Exact Test was done to
analyze the Data;
Figures in the
parenthesis denote corresponding percentage.
Ns=not
significant
5.7 Clinical characteristics indifferent type of diastolic dysfunction
groups:
Table XII compares the symptoms
and signs those who developed diastolic dysfunction. Majority of the patients
among the three groups exhibited dyspnoea (86.2% in impaired relaxation, 85.7%
in pseudonormal and 100% in restrictive group)
and chest pain (89.5% in impaired relaxation, 100% in pseudonormal and
90% in restrictive group). In terms of signs, abnormal systolic and diastolic
blood pressure was found in patients among impaired relaxation, pseudonormal
and restrictive group. The groups were identically distributed in terms of
clinical symptoms and signs.
#Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
ns =not significant
5.8 2D & M-mode
echocardiographic characteristics of patients with DD:
The 2D & M-mode
echocardiography findings of patients demonstrate that LA, LVIDd and LVIDs were
significantly lowest in impaired relaxation group compared to pseudonormal and
restrictive groups (p = 0.027, p = 0.012 and p = 0.002 respectively), while,
ejection fraction was significantly highest in impaired relaxation group that
those in pseudonormal and restrictive groups (p = 0.027) (Table XIII).
# Data were analyzed using ANOVA
statistics and were presented as Mean ± SD. S=significant
5.9 2D & M-mode echocardiographic findings between groups:
Table XIV compares the 2D &
M-mode echocardiography findings between those who developed diastolic
dysfunction and those who did not.. The mean LA, LVIDd, LVIDs were almost same
both the groups (35.1 ± 4.7 vs. 33.5 ± 4.0 mm, p = 0.118; 46.4 ± 6.1 vs. 46.1 ±
6.2 mm, p = 0.853 and 30.9 ± 5.7 vs. 31.7 ± 6.3 mm, p = 0.581 respectively).
However, ejection fraction was significantly higher in the former group than
that in later group (63.8 ± 7.5 vs. 60.7 ± 4.2, p = 0.014).
# Student t Test was employed to analyze
the data; presented as Mean ± SD.
5.10. Plasma BNP level between groups:
Majority (97.4%) of the subjects with
diastolic dysfunction had plasma BNP 60 or > 60 pg/ml as opposed to 12.5% of
subjects without diastolic dysfunction. The ability of plasma BNP (at cut-off
value of 60 pg/ml) to predict diastolic dysfunction in patients with normal
systolic function is 255 times higher than that
with plasma BNP ? 60 pg/ml (p
<0.001) (Table XVI).
#Chi-square (c2)
Test was employed to analyze the data;
Figures in the parenthesis denote
corresponding percentage.
S***=highly
significant
5.11 Plasma BNP level in different types of diastolic dysfunctions:
From table XVI it appears that
mean plasma BNP increases with the severity of diastolic dysfunction (from
impaired relaxation to restrictive like filling), though the differences among
the groups were not statistically significant (p = 0.417). But plasma BNP
gradually rises from impaired relaxation
variety to restrictive variety.
(Fig 11)
Data were
analyzed using ANOVA statistics and were presented as mean ± SD.
Fig.11: Level of plasma BNP in different
types of diastolic dysfunction
5.12. Accuracy of plasma BNP level in
diagnosing diastolic dysfunction:
Table
XVII – XX & Figure 12 showed the ability of BNP to detect diastolic
dysfunction. At different cut off value.
The area under the curve (AUC) for the receiver-operating characteristics (ROC)
curve with BNP used to detect any abnormal diastolic dysfunction was 0.98 (95%
confidence interval, 0.953 to 1.002; p < 0.001). A BNP level of 60 pg/ml had
a higher sensitivity of 97.4%, a specificity of 87.5%, a positive predictive value
of 96.1% and an accuracy of 95% for detecting diastolic dysfunction.
Table
XVIII. Accuracy of plasma BNP at cut-off value of 75 in detecting diastolic
dysfunction
XX. Accuracy of BNP level in diagnosing diastolic dysfunction:
cut-off values of plasma BNP from 60 to 75 and 85 pg/ml, the specificities and
PPVs (positive predictive values) increase to their highest compromising with
their sensitivities and NPVs (negative predictive values).
contribution of diastolic dysfunction to the signs snd symptoms of heart
failure. Brain natriuretic peptide, a marker of neurohormonal activation
secreted by cardiomyocytes in response to ventricular wall stretch, has a basic
role in cardiovascular remodeling and volume homeostasis (Maeda K et al, 1998).
cardiovascular diseases. Especially in heart failure it is used for diagnosis, risk stratification or prognosis,
and treatment monitoring (Mueller C et al, 2007).
diastolic dysfunction contributes to plasma BNP level and thus it is useful for
diagnosis of diastolic dysfunction (Tschope C et al, 2005).
patients with risk factors for diastolic dysfunction before features of overt
heart failure, also its validity as a screening test to early diagnose and
detect severity diastolic dysfunction.
type and other 83(87%) included impaired
relaxation and pseudonormal.Poulsen(1999) found 38% impaired relaxation
& other varieties included 24%.
98(57%) had diastolic dysfunction by echocardiography whose 35 were impaired
relaxation variety,21 pseudonormal and 14 had restrictive patterns.
by Doppler echocardiography.Majority were impaired relaxation variety (n=58), then
restrictive variety (n=11), only 7 patients were pseudonormal (Table –X).Impaired
relaxation variety and restrictive variety were more common in female than male(77.6%
vs.22.4%and 63.6%vs.36.4% respectively)(Fig.10), whereas pseudonormal was more
in male (57%vs.42.9%).
the prevalence of diastolic dysfunction increases with age. Its incidence is
reported to be 15-25% in patients <60 years of age, 35-40% between 60-70
years and above 50% over 70 years (Luchi RJ et el, 1982; Wong WF et al, 1989; Wei
I et al, 2005).
50 years (61.8%), mean age was 53.1±1.3 years (Table-VIII) and most of patients
were female (72.4%) (Table-IX), it is similar like other studies.
artery disease26(34.2%), diabetes21(27.6%)(Table-XI) were more prevalent in
patients with diastolic dysfunction, having similarities with the study of
Lubien BS et al, 2001, who found hypertension in 58%,diabetes in 35%,coronary
artery disease in 26% patients. Aziz(2001) found smoking as the commonest risk factor (67%) followed
by hypertenstion(38%), dyslipidemia(31%) and diabetes (20%).
were significantly poor in restrictive than impaired relaxation group (LA:
38.3±5.7vs. 34.3±4.3 mm, p value<0.02; LVIDd: 50.5±5.3 vs.45.3±5.9 mm, p
value<0.01; LVIDs: 35.4±5.6 vs.29.7±5.2 mm, p value<0.002; EF: 59.5±5.9
vs. 65.1±7.2% p value<0.02).This findings were consistent with that of
Nijland et al, 1997. So, restrictive variety of diastolic dysfunction is
associated with poor echocardiographic characteristics.
activation secreted by cardiomyocytes in response to ventricular wall stretch,
has a basic role in cardiovascular remodeling and volume homeostasis (Maeda K
et al, 1998).
cardiovascular diseases. Especially in heart failure it is used for diagnosis, risk stratification or prognosis, and
treatment monitoring (Mueller C et al, 2007).
diastolic dysfunction contributes to plasma BNP level and thus it is useful for
diagnosis of diastolic dysfunction (Tschope C et al, 2005).
have demonstrated that BNP levels in patients with diastolic dysfunction are
higher than that in normal controls but it was less than that in patients with
systolic dysfunction (Maisel A et
al ,2001).
abnormal LV diastolic function had a mean plasma BNP concentration of
286±31pg/ml while the normal LV group had a mean BNP concentration of
33±3pg/ml. Plasma concentrations were particularly elevated in patients with
restrictive filling patterns and in those with symptoms.Karaca et al, 2007
showed raised plasma BNP(66.17±17.56pg/ml) in asymptomatic diastolic
dysfunction, but BNP level
12.0±4.97pg/ml with normal filling pattern.
individuals with isolated diastolic dysfunction group(Table.XV) than without diastolic dysfunction group (
mean 225.8±41.1 pg/ml vs. 38.7±4.8 pg/ml, p value <0.001),which is highly
significant and consistent with other studies.
variety of diastolic dysfunction, we
found that, plasma BNP level was gradually
increased(Table.XVI) & Fig.11, from impaired relaxation variety(211.4pg/ml)
to restrictive variety (351.opg/ml) that
was similar to findings found by Lubien et al,2002,wereas But the
differences among the groups were not as much
as in other studies. The cause may be due to the fact ,that our
patients had no features of overt heart
failure, asymptomatic or only mildly symptomatic.
significantly higher in patients with severe diastolic dysfunction than in
those without (459±462pg/mL vs. 142±166pg/mL, p<0.001) and a
level?138pg/mL appeared to be the best limit for severe diastolic dysfunction,
with accuracy, 70%, sensitivity, 72%, and specificity, 70% ). Alternatively, a
brain natriuretic peptide level?402pg/mL had the highest sensitivity (93%) and
positive predictive value (85%), but the specificity was low (38%). Finally, a
?46pg/ml level, with a 93% negative predictive value, reliably identified
patients free of severe diastolic dysfunction
diagnosis of left ventricular diastolic dysfunction in hypertensive patients.
The results showed that BNP, when rapidly tested at bedside, has a moderate
sensitivity but an excellent specificity in detecting ventricular diastolic
dysfunction.
that, it is a very useful tool to confirm the diagnosis prompted by other
diagnostic means, such as echocardiography.
showed a BNP cut off value of 37.0 pg/ml had a sensitivity of 80%,specificity of 100%,PPV
of 100%, a NPV of 23% and accuracy of 88% in asymptomatic hypertensive patients
with impaired relaxation variety.
79% sensitivity and 92% specificity in diagnosing LV diastolic dysfunction.
sensitivity of 85%, specificity of 83% and an accuracy of 84% for detecting
isolated diastolic dysfunction..Suziki M et al, 2000, showed BNP cut off value
as 41 pg/ml.
study , at different cut off value (60pg/ml,75pg/ml, 85pg/ml)(Table XVII-XX,
& Fig.12 )of plasma BNP, we found different sensitivity (97.4%, 90.8%,89.5%
respectively), different specificity (87.5%,95.8%,100.0% respectively),and
different diagnostic accuracy (95%,92%,92% respectively). The area under the
curve (AUC) for the receiver-operating characteristics (ROC) curve with BNP
used to detect any abnormal diastolic dysfunction was 0.98 (95% confidence
interval, 0.953 to 1.002; p < 0.001). A BNP level of 60 pg/ml had a higher
sensitivity of 97.4%, a specificity of 87.5%, a positive predictive value of
96.1% and an accuracy of 95% for detecting diastolic dysfunction, which was
nearly similar to that found by Lubien et al, 2002.
preclinical diastolic dysfunction in the community is common and is
independently predictive of the future development of heart failure and cardiac
death. So it is necessary to diagnose diastolic dysfunction at early stage
before overt heart failure.
diastolic function requires simultaneous
measurement of LV pressure and volume to
generate pressure-volume curve, but it is an invasive procedure and not fesible
to everywhere. Also Doppler echocardiographic characteristics varies with heart
rate, contractility,preload,afterload,valvular regurgitation and position of
the sample volume(Grodecki PV et al, 1993).So, a simple blood test that reflects diastolic dysfunction with
normal systolic function would be of clinical benefit.
study, it can be assumed that plasma BNP level not only increase in
high risk patients with diastolic dysfunction, but also
rises gradually as the severity of diastolic dysfunction incrases.So it offers
a simple tool for assessing patients at high risk of diastolic dysfunction and,
consequently, of worse outcome in the first-step screening of large
populations or in patients with technically inadequate Doppler echocardiography.
that a rapid assay of plasma can accurately rule out abnormal echocardiographic
findings, either systolic or diastolic.
done regarding plasma BNP and heart failure by Hoque, m.m.(2010), and
Alam,M.S.(2006) but no work was done in relation to isolated diastolic
dysfunction.We think this is the first work done in Bangladesh.
plasma BNP level can accurately predict diastolic dysfunction and clinical
grading of diastolic dysfunction seen on echocardiography. Although plasma BNP
level cannot differentiate between systolic and diastolic dysfunction, a low
level of plasma BNP in the setting of normal systolic function by
echocardiography may be able to rule out clinically suspected diastolic
dysfunction in high risk patients seen on echocardiograpgy.
BNP to diagnose diastolic dysfunction on the basis of Doppler echocardiography,
in patients who had no documented features of heart failure but had risk
factors for diastolic dysfunction like IHD, hypertension, diabetes, dyslipidemia.These
patients were defined as high risk patients for development of heart failure.
Salimullah Medical College, Mitford Hospital, Dhaka and measurement of plasma
BNP was done in the Biochemistry department of BSMMU , Dhaka from September
2008 to August 2010.100 patients were selected on the basis of inclusion and
exclusion criteria.
two cardiologists who were blinded to BNP report. On the basis of Doppler findings,
76 patients had diastolic dysfunction, 24 patients had no diastolic
dysfunction. Plasma BNP level was measured by AxSYMsystem in both groups.
impaired lexation variety, 7 were pseudonormal and 11 patients were restrictive
type. Majority of the subjects with diastolic dysfunction were older than 50
years and female 55(72.4%), the mean age was 53.1±1.3 years. Male: female ratio
was 2:1. Impaired relaxation variety and restrictive variety were more common
in female than male (77.6% vs.22.4%and 63.6%vs.36.4% respectively), whereas
pseudonormal was more in male (57%vs.42.9%).Risk factors were common in both
groups so no significant defference regarding risk factors were found, but Ischemic
heart disease(34.2%vs.25.0%),hypertension(96.1% vs. 91.7%), diabetes (27.6%
vs.6.7%) and dyslipidemia(14.5% vs.4.2%) were slightly higher in diastolic
dysfunction group than other without diastolic dysfunction. Most of the patients
with diastolic dysfunction were hypertensive 73(96.1%),were
ischemic26(34.2%) and 21(27.6%) were
diabetic.2D & M mode echocardiographic findings were poorer in restrictive
variety than impaired relaxation variety(LA
38.3±5.7mm vs.34.3±4.3mm;LVIDd 50.5±5.3 vs.45.3±5.9 mm;LVIDs 35.4±5.6
vs.29.7±5.2mm;EF% 59.5±5.9 vs. 65.1±7.2 respectively).
significantly raised in diastolic dysfunction group than
;p value<0.001).
or>60 pg/ml
dysfunction.
with the severity of diastolic dysfunction (211.4pg/ml in impaired relaxation;
247 pg/ml in pseudonormal; 351pg/ml in restrictive), though the
differences among types of diastolic
dysfunction were not statistically significant(p value<0.417).
showed at different cut off value (60pg/ml,75pg/ml, 85pg/ml) of plasma BNP,
different sensitivity (97.4%, 90.8%,89.5% respectively) ,different specificity
(87.5%,95.8%,100.0% respectively),and different diagnostic accuracy
(95%,92%,92% respectively). The area under the curve (AUC) for the
receiver-operating characteristics (ROC) curve with BNP used to detect any
abnormal diastolic dysfunction was 0.98 (95% confidence interval, 0.953 to
1.002; p < 0.001). A BNP level of 60 pg/ml had a higher sensitivity of 97.4%, a
specificity of 87.5%, a positive predictive value of 96.1% and an accuracy of
95% for detecting diastolic dysfunction,
as promising biomarker for early diagnosis and assessment of severity of diastolic dysfunction in clinically suspected
patients.
with coronary artery disease, hypertension, diabetes and dyslipidemia.Recent
studies have demonstrated that 40% to 50% of heart failure patients have normal
ejection function and diastolic dysfunction is the presumed cause of symptoms
in these individuals. So early recognition is needed. In this respect, raised
plasma BNP play an important role in early diagnosis of diastolic dysfunction
and also recognition of its severity.
echocardiography may lead to a more accurate early diagnosis of diastolic dysfunction.
But further evalution is needed to establish BNP as a ‘gold standard’ for early
diagnosis of diastolic dysfunction.
value in the diagnosis of symptomatic
heart failure.
for diagnostic accuracy of diastolic
dysfunction, so it is necessary to determine new cut off value for early
diagnosis of diastolic dysfunction.
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