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Cardiovascular Diseases: Mechanism of Diastolic Functions

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.

2. OBJECTIVES:

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..

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:

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).

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 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 Filling

  • 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:

a. 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 tensionCompliance

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)

Cardiac ischemia

Hypertension

Aging

Obesity

Diabetes

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

Hemochromatosis

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).

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).

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.

ECGo 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

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).

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)

o Peak E wave velocity: 53-105cm/sec

o Peak A wave velocity: 26-70 cm/sec

o E/A ratio :>1

o E Deceleration time(DT): 160-220 cm/sec

o 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)

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):

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

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 1.5o 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 2o 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:

ANP BNP CNP UrodilatinNames Atrial natriuretic

peptide(ANP)/natriuretic factor(ANF)

Brain natriuretic peptide/B-type natriuretic peptide

C-type natriuretic peptide

Occurrenc-e Atrium of mammals dependent on pressure in heart

Mostly in ventricle, but is also in brain

Mostly in vascular tissue

Formed in the kidneys and excreted with urine

Number of amino acids

28 32 22 to 53 32(ANP+4)

Properties/Function

Regulation of salt and water balance, effects on blood pressure(natriuresis,vasodilation, rennin and aldosterone antagonism)

Vasodilatation

Regulateon ofwater and Na+ reassertion in the renal collecting ducts

Discovery 1985, de Bold 1988,Sudoh 1990, Sudoh et al.

1986,Frossmann

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).

3.3.7 Role of 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.

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).

3.3 9 BNP as prognostic indicators in heart failure

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).

3.3.10 BNP in monitoring of patients with heart failure

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 IV. Difference between systolic and diastolic heart failure(Gary S et al, 2008).

Systolic Heart Failure Diastolic Heart Failure

Large, dilated heart Small LV cavity, Concentric LV hypertrophy

Normal or low blood pressure Systolic hypertension Broad age group; more Common in men Elderly women more common

Low ejection fraction Normal or increased ejection fraction

S3 gallop S4 gallop 

Table V.Risk factors for heart failure (Abraham W.Tet al, 2008).

Hypertension Rheumatic fever

Diabetes Mediastinal irradiation

Dyslipidemia Sleep disordered breathing

Coronary artery disease Collag. Vascular disease

Valvular heart disease Tgyroid disorders

Obesity cardiotoxic agents

Metabolic syndrome F/H of cardiomyopathy

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 ---------------- EnlargedDiastolic dysfunction ------ Grade I-IV (∞ diastolic dysfunction severity, BP, Volume status)Other features -------------- PH, wall motion abnormality, RV enlargementPertinent negatives -------- Rule out valve disease, pericardial disease, ASDBNP or NT-proBNP: ↑ but HFnlEF < HFrEFExercise testing : ↓ VO2 peak  Exaggerated hypertensive response in many  Chronotropic incompetence in subsetChest radiogram: Similar to HFrEF, cardiomegaly, pulmonary venous Hypertension, edema, pleural effusionElectrocardiogram: 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

Great heterogeneity exists also for results in prognosis of diastolic HF. By the Framingham meta-analysis the annual mortality varies from 1.3% to 17.5% (Vasan RS et al, 1995). This wide variability depends by several factors including first of all, the modality used to classify this kind of HF – mostly according to the evidence of normal EF – but also age and follow-up duration. In a study by registry on 1291 hospitalized patients (70) the mortality was lower in patients with EF ≥ 50% than in those with EF ≤ 39% (OR = 0.69 95% CI 0.49–0.98, p = 0.04). The Framingham offspring cohort informed that the rate of death after 5 years is 68% in patients with HF and normal EF in comparison with 82% of systolic HF, with mortality, however, four times greater than that presented by healthy subjects (Vasan RS et al, 1999).

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) .

Treat precipitating factors and underlying disease.

Prevent and treat hypertension and ischemic heart disease.

Surgically remove diseased pericardium.

Improve left ventricular relaxation.

ACE inhibitors Calcium channel blockers

Regress left ventricular hypertrophy (decrease wall thickness and remove excess collagen).

ACE inhibitors and ARBs Aldosterone antagonists Beta blockers Calcium channel blockers

Maintain atrioventricular synchrony by managing tachycardia (tachyarrhythmia).

Beta blockers (preferred) Calcium channel blockers (second-line agents) Digoxin (controversial) Atrioventricular node ablation (rare cases)

Optimize circulating volume (homodynamic).

ACE inhibitors Aldosterone antagonists (theoretical benefit) Salt and water restriction Diuresis, dialysis, or plasmapheresis

Improve survival.

Beta blocker ACE inhibitors

Prevent relapse by intensifying outpatient follow-up.

Control blood pressure. Dietary counseling (sodium) Monitoring volume status (daily weights and diuretic adjustment) Institute exercise program.

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 (χ2) 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).

Table VIII. Age distribution between diastolic dysfunction group

And without diastolic dysfunction group

Age (years)Diastolic dysfunction

p-value

Present (Group-I)(n = 76)

Absent (Group-II)(n = 24)

<5029(38.2) 20(83.3) <0.001S***

≥5047(61.8) 4(16.7)

Mean ± SD53.1 ± 1.3 44.5 ± 1.4 <0.001S***

# Chi-square (2) Test was employed to analyze the data;Figures in the parenthesis denote corresponding percentage.s*** = significant at p value<0.001n=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.

Table IX. Sex distribution between groups:

Diastolic dysfunction

Sex

P-value

Present(n = 76)

Absent(n = 24)

Male21(27.6) 7(29.2)

0.884ns

Female55(72.4) 17(70.8)

# Chi-square (2) 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).

62.1

85.7

54.5

37.9

14.3

45.5

0102030405060708090

Impaired relaxation Pseudonormal Restrictive

Diastolic dysfunction

Perc

enta

ge

<60 =>60

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).

22.4

57.1

36.4

77.6

42.9

63.6

0

10

20

30

40

50

60

70

80

90

Impaired relaxation Pseudonormal Restrictive

Diastolic dysfunction

Perc

enta

ge

Male Female

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 :

FindingsGroupImpaired 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< 1.01 – 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 flowS/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)

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.

Table. XI. Comparison of risk factors between groups:

Risk factorsDiastolic 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

# Chi-square (2) 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.

Table XII. Comparison of clinical characteristics in different types of diastolic dysfunction

Clinical characteristics

Types of diastolic dysfunction

P-valueImpaired 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

#Chi-square (2) 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).

Table XIII. Comparison of 2D & M-mode echocardiographic characteristics among three types of diastolic dysfunction

2D & M-mode Types of diastolic dysfunction

Echocardiographyp-value

Impaired relaxation(n = 58)

Pseudonormal(n = 7)

Restrictive(n = 11)

LA (mm) 34.3 ± 4.3 36.4 ± 4.5 38.3 ± 5.70.027S

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 ± 5.90.027S

# 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).

Table XIV. 2D & M-mode echocardiography between groups

2D & M-mode Echocardiography findings

Diastolic dysfunction

p-valuePresent(n = 76)

Absent(n = 24)

LA (mm) 35.1 ± 4.7 33.5 ± 4.00.118ns

LVIDd (mm) 46.4 ± 6.1 46.1 ± 6.20.853ns

LVIDs (mm) 30.9 ± 5.7 31.7 ± 6.30.581ns

Ejection fraction (%) 63.8 ± 7.5 60.7 ± 4.20.014s

# Student t Test was employed to analyze the data; presented as Mean ± SD.

ns =not significant; s=significant

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).

Table XV. Comparison of plasma BNP level between groups:

Plasma BNP level (pg/ml)

Diastolic dysfunctionOdds Ratio(95% of CI)

p-valuePresent(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)

#Chi-square (2) 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)

Table XVI. Plasma BNP level in different types of diastolic dysfunction

GroupPlasma BNP (pg/ml)

p-valueMean SEM

Impaired relaxation (n = 58) 211.4 50.6

Pseudonormal (n = 7) 247 15.8 0.417

Restrictive (n = 11) 351 90.6

Data were analyzed using ANOVA statistics and were presented as mean ± SD.

351

247

211.4

0

50

100

150

200

250

300

350

400

Impaired relaxation Pseudonormal Restrictivelike

Types of diastolic dysfunction

Mea

n pl

asm

a BN

P (p

g/m

l)

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 XVII. Accuracy of plasma BNP at cut-off value of 60 in detecting diastolic dysfunction

Plasma BNP level (pg/ml)Diastolic dysfunction

TotalPresent Absent

> 60 73 03 76

≤ 60 03 21 23

Total 75 24 99

Table XVIII. Accuracy of plasma BNP at cut-off value of 75 in detecting diastolic dysfunction

Plasma BNP level (pg/ml)Diastolic dysfunction

TotalPresent 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

TotalPresent Absent

> 85 67 00 67

≤ 85 08 24 32

Total 75 24 99

Table XX. Accuracy of BNP level in diagnosing diastolic dysfunction:

BNP level

Components of accuracy

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

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.

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