Cardiovascular Diseases: Mechanism of Diastolic Functions

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Cardiovascular Diseases: Mechanism of Diastolic Functions


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 LVdiastolic wall stress consistent with stretch-mediated BNP secretion (Tschope C et al, 2005).

BNP levels increase with greater severity ofoverall diastolic dysfunction, independent of LVEF, age, sex,body mass index, and renal function, and the highest levelsare 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 fillingpressure—including transmitral early filling velocity(E)—aswell as with indexes of compliance and myocardial relaxation.In subjects with normal LVEF, BNP (>100 pg/ml) are the strongest independentpredictor 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.


Raised Plasma BNP level is useful for diagnosis of LV diastolic dysfunction.


General Objective:

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..



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:

1. isovolumic relaxation

2. rapid filling

3. slow filling (diastasis)

4. 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).



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).


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

Passive stiffness.

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

isovolumic left ventricular pressure decay

• Filling abnormalities by changes in the filling rate and the time-to-peak


• Changes in passive elastic properties by changes in the diastolic pressure-

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:

  1. 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.

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

Diastolic dysfunction:

Pulmonary venous pressure

Wall tension


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).


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. 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)

Cardiac ischemia





Myocardial disorders

Infiltrative disease (e.g., amyloidosis, sarcoidosis, fatty infiltration)

Noninfiltrative diseases (e.g., idiopathic and hypertrophic cardiomyopathy)

Endomyocardial diseases

Hypereosinophilic syndrome

Storage diseases

Glycogen storage disease


Pericardial disorders

Constrictive pericarditis

Effusive-constrictive pericarditis

Pericardial effusion

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). Chronic Myocardial Ischemia & left ventricular diastolic dysfunction:

One of the most common cardiac diseases associated with abnormalLV diastolic function is myocardial ischemia. The slowing orfailure of myocyte relaxation causes a fraction of actin-myosincross bridges to continue to generate tension throughout diastole—especiallyin early diastole—creating a state of “partial persistentsystole.” Two kinds of ischemia can alter diastolic function:(1) demand ischemia, created by an increase in energy use andoxygen demand that outweighs the necessary myocardial supply,and (2) supply ischemia, caused by a decrease in myocardialblood flow and oxygen demand without a change in energy use.

During demand ischemia, diastolic dysfunction may be relatedto myocardial ATP depletion with a concomitant increase in adenosinediphosphate, resulting in rigor bond formation. (Eberli et al , 2000). Consequently,LV pressure decay is impaired and the left ventricle is stiffer thannormal during diastole. Although ischemia is also associatedwith persistence of an increased intracellular calcium concentrationduring diastole, it is not clear if elevated calcium levelscontribute directly to diastolic dysfunction. (Eberli et al , 2000).

Supply ischemia results from a marked reduction in coronaryflow. The net effect is inadequate coronary perfusion even inthe resting state. Acute supply ischemia causes an initial transientdownward and rightward shift of the diastolic pressure-volumecurve such that end-diastolic volume increases relative to end-diastolicpressure, creating a “paradoxical” increase in diastolic compliance (Apstein et al, 1987).By contrast, diastolic compliance substantially falls duringdemand ischemia. (Varma et al, 2000; Varma et al, 2001).

These opposite initial compliance changes with demand and supplyischemia may be explained by differences in pressure and volumewithin the coronary vasculature, by the mechanical effects ofthe normal myocardium adjacent to the ischemic region, and bytissue metabolic factors. However, the differences between supplyand demand ischemia are transient: after more than 30 minutes ofsustained ischemia, both types of ischemia result in decreaseddiastolic compliance. (Varma et al, 2000; Varma et al, 2001). 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). 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). 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).

A. Normal transmitral Doppler flow velocity pattern

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)

B. Normal Pulmonary vein Doppler Flow velocity pattern

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.


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

Fig.5. Left ventricular (LV) and left atrial (LA) pressure relationship and corresponding mitral inflow velocities in three different diastolic filling patterns: impaired relaxation, normal, and restrictive. Actual Doppler recordings of mitral inflow velocities, representing impaired relaxation (left), normal (center), and restrictive filling (right) patterns. A=late diastolic filling; DT=deceleration time; E=early diastolic filling (Oh JK et al, 2006).

.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).

  • 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

· 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)


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):

  • E/A ratio:<1.0
  • Deceleration time(DT):>240ms
  • IVRT :> 110 sec.
  • Pulmonary venous AR velocity :<25cm
  • S/D ratio :> 1.


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.


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 i