INTRODUCTION
Heart failure is a common clinical syndrome which can be caused by many pathophysiologic conditions. It can be caused by valvular, myocardial, and pericardial diseases. It can be acute and of recent onset or chronic and may be present for several months or years. It can be caused by primarily by left ventricular systolic or diastolic dysfunction. In this chapter, heart failure due to myocardial disease has been discussed. Heart failure resulting from left ventricular myocardial systolic dysfunction is referred as systolic heart failure (SHF). It is also called heart failure with reduced ejection fraction (HFREF). When it is primarily due to diastolic dysfunction, it is termed diastolic heart failure (DHF). It is also called heart failure with normal ejection fraction (HFNEF). In this chapter, primarily the pathophysiology of systolic and diastolic heart failure has been discussed. The epidemiology has been briefly discussed.
INCIDENCE, PREVALENCE, AND RISK FACTORS
The incidence of heart failure caused by myocardial disease is high. The lifetime risk of developing heart failure due to myocardial disease is about 20% at all ages older than 40 years.1 In the United States, the prevalence of heart failure is approximately 2.4% of the adult population. It was estimated that in 2011, 5.7 million people had established diagnosis of heart failure.2 By the year 2040, it is expected that 10 million people will have heart failure in the United States of America. Approximately, 23 millions of people have heart failure worldwide. The estimated incidence of heart failure in the United States presently is approaching 10 per 1,000 population older than 65 years of age.3
The prevalence of DHF is very similar to that of SHF. Heart failure due to diastolic dysfunction (HFNEF) is diagnosed in approximately 50% of patients with heart failure.4 DHF is more frequent in women than in men. In the cardiovascular health study, the prevalence of DHF was 67% in women and 42% in men.5–72
The risk factors for developing SHF and DHF are also similar.6 In both SHF and DHF, older age, hypertension, diabetes and obesity are the major risk factors. The incidence of coronary artery disease appears to be higher in SHF than in DHF. However, the incidence of coronary artery disease in DHF is still considerable, about 54% as compared to 63% in SHF. The patients with SHF are relatively younger than patients with DHF. The average age of patients with SHF is 70 years and with DHF, 74 years.6
COST OF MANAGEMENT
The management of established symptomatic heart failure is expensive. In many developed countries, the cost of management of heart failure is 1–2% of the health care budget. In 2007, the cost of management of heart failure exceeded 35 billion dollars in the United States. Presently, it remains unknown about the cost of management of heart failure in underdeveloped countries.
PATHOPHYSIOLOGY OF HEART FAILURE
During the last two decades, there have been considerable advances in the understanding of the pathophysiology of both SHF and DHF. Our knowledge of left ventricular morphology, remodeling, and molecular features in SHF and DHF has improved.
Morphologic Changes in Systolic and Diastolic Heart Failure
In SHF, there is eccentric left ventricular hypertrophy with left ventricular dilatation. There is a substantial increase in left ventricular end-diastolic volumes (LVEDV) and left ventricular end-systolic volumes (LVESV).8,9 The magnitude of increase in end-systolic volume is greater than that of end-diastolic volume. Thus, left ventricular ejection fraction declines. Left ventricular ejection fraction is the ratio of left ventricular total stroke volume (LVTSV) and LVEDV. LVTSV is the difference between LVEDV and LVESV. In patients with SHF, ejection fraction can be reduced due to disproportionate increase in LVEDV with unchanged LVTSV. Left ventricular ejection fraction may also decline when there is marked decrease in LVTSV without any increase in LVEDV. In SHF, there is usually both decrease in LVTSV and an increase in LVEDV.
Left ventricular cavity size is markedly increased in SHF. Left ventricular mass is also increased. However, as the cavity size increases by a greater magnitude than the mass, the cavity/mass ratio is increased. Left ventricular wall thickness remains normal or even decreases despite myocyte hypertrophy. Increased cavity size with normal or decreased wall thickness is associated with increased wall stress (La Place Relation). As wall stress represents left ventricular afterload, increased wall stress is associated with decreased ejection fraction. There is also an increase in myocardial oxygen consumption due to increased wall stress.3
In SHF, there are considerable changes in left ventricular shape and geometry. Normally, left ventricle is ellipsoidal. In SHF, left ventricle becomes globular and spherical. The transverse diameter of left ventricle increases by greater magnitude than the longitudinal diameter. The distance between anterolateral and postero-medial papillary muscles increases causing misalignment of the papillary muscles, chordae, and mitral valve leaflets which produces secondary mitral regurgitation.
In patients with advanced SHF, dyssynchrony of left ventricular wall motion is observed in over one-third of patients. Normally, left ventricular septum contracts and relaxes before the lateral and posterior walls. In SHF, lateral and posterior walls contract and relaxes before interventricular septum. Mechanical dyssynchrony is frequently associated with electrical dyssynchrony, particularly left bundle branch block (LBBB). The morphologic changes in systolic heart failure are summarized in table 1.
In DHF, there is concentric left ventricular hypertrophy without any cavity dilatation. LVEDV and LVEDVs remain normal. There is increased wall thickness. As the cavity size remains normal, wall stress decreases which contributes to maintain normal ejection fraction. Left ventricular mass is increased but as the cavity size remains normal, left ventricular cavity/mass ratio is increased. In DHF, there is little or no change in left ventricular shape and geometry. Left ventricular shape remains ellipsoidal and the transverse axis is shorter than the long axis. There is little or no secondary mitral regurgitation. In approximately one-third of patients with DHF, there is mechanical dyssynchrony.10 The morphologic changes in DHF are summarized in table 2.
Hemodynamic Abnormalities in Systolic and Diastolic Abnormalities
In SHF, the primary hemodynamic abnormality is reduced ejection fraction. Reduced ejection fraction is associated with reduced stroke volume and an increase in LVEDV and LVESV. Increased left ventricular diastolic volumes is associated with increased left ventricular diastolic pressures, a passive increase in left atrial and pulmonary venous pressure.4
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Increased pulmonary venous pressure causes symptoms and signs of pulmonary venous congestion. When there is increased pulmonary venous pressure, there is also an obligatory increase in pulmonary artery pressure which is right ventricular afterload. This secondary pulmonary hypertension may precipitate right ventricular failure. Right ventricular failure is manifested by elevated systemic venous pressure and dependent edema. In advanced SHF, stroke volume decreases; but reflex increase in heart rate may maintain normal cardiac output.
In DHF, the primary functional abnormality is increased left ventricular stiffness which is associated with increased left ventricular diastolic pressure, a passive increase in left atrial and pulmonary venous pressure which causes signs and symptoms of pulmonary venous congestion. There is also an obligatory increase in pulmonary artery pressure when there is increase in pulmonary venous pressure. This secondary pulmonary hypertension may precipitate right ventricular failure manifested by elevated systemic venous pressure and peripheral edema. When there is marked impairment of left ventricular filling, stroke volume is decreased. However, a reflex increase in heart rate may maintain normal cardiac output.
Functional Changes in Systolic and Diastolic Heart Failure
In SHF, the major functional abnormality is impaired contractile function. The indices of contractile function, such as left ventricular dP/dt is decreased. The velocity of contraction is also dereased. When left ventricular pressure volume loops are constructed and end-systolic pressure volume relation is determined, in SHF the end-systolic pressure-volume line shifts downwards and to the right (Fig. 1). End-systolic pressure volume relation is a reliable index of contractile function. Left ventricular stroke volume declines resulting from decreased contractility. In SHF, diastolic pressure volume relation remains unchanged. However, in patients with advanced SHF, left ventricular filling may be abnormal.5
Figure 1: Schematic illustration of pressure-volume loops in normal, systolic, and diastolic dysfunction. SV, stroke volume.
In DHF, left ventricular contractile function remains normal. Diastolic dysfunction is the primary functional abnormality in DHF. Diastolic pressure volume relation shifts upwards and to the left. As discussed earlier, left ventricular stiffness is increased which is the primary mechanism for this shift of diastolic pressure volume curve. Left ventricular end-diastolic pressure increases. If there is a further upward shift of the diastolic pressure volume curve, there is a reduction in stroke volume resulting from marked impairment of left ventricular filling (Fig. 1).
Long-term follow-up studies have demonstrated that, in patients with DHF without coronary artery disease, left ventricular dilatation does not occur. Ejection fraction remains normal. Left ventricular stiffness increases.11
Myocyte and Myocardial Structure in Systolic and Diastolic Heart Failure
In SHF, myocyte length is increased without any change in myocyte diameter. There is increased myosine degradation. There is myocyte hypertrophy, apoptosis and necrosis. Myocardial architecure is abnormal. There is disruption of extracellular matrix. There is disintegration of collagen fibers. The collagen bundles are thinner than normal. The collagen cross links are decreased. There is increased myocardial fibrosis (Table 3).
Calcium regulation is abnormal in SHF. The ratio of matrix metalloproteinases and tissue inhibitor of metalloproteinases is increased in SHF. The ratio of titin isoforms N2BA/N2B is increased in SHF.6
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In DHF, myocyte is thicker than normal and there is no change in myocyte length. In DHF, there is increased synthesis of myosin.
As in SHF, there is myocyte hypertrophy, apoptosis, and necrosis. There is also disorganized extracellular matrix. The collagen bundles are thicker than normal. The collagen volume is increased. The collagen cross links are increased.
In DHF, there is also calcium dysregulation. The ratio of matrix metalloproteinases and tissue inhibitor of metalloproteinases is decreased. The ratio of titin isoforms N2BA/N2B is decreased in DHF.12,13
The solid line represents end-systolic pressure-volume line which shifts downwards and to the right in SHF. Diastolic pressure-volume relation is also illustrated. In DHF, there is an upward and leftward shift.
Neurohormonal Changes in Systolic and Diastolic Heart Failure
In both SHF and DHF, a significant neurohormonal abnormalities occur.14 There is increased norepinephrine levels which reflect activation of sympathetic activity. There is also increased in muscle sympathetic nerve activity. There is also increased renal sympathetic activity which is associated with renal vascular constriction and deterioration of renal function. Increased sympathetic activity promotes myocyte and vascular remodeling. There is also increased systemic vascular resistance which increases left ventricular afterload which contributes to adverse ventricular remodeling. Increased adrenergic activity is associated with vascular remodeling as well. There is hyperplasia of vascular smooth muscle cells. There is also enhanced inflammatory responses which also promote atherothrombosis.
In SHF, there is activation of renin-angiotensin system. Activation of renin-angiotensin also produces ventricular, myocyte, and vascular remodeling. 7Ventricular remodeling is characterized by ventricular dilatation and reduction of left ventricular ejection fraction. There is an increase in both end-diastolic and end-systolic volumes as has been discussed earlier. Angiotensin II increases renal efferent arteriolar tone which initially can maintain glomerular filtration rate.
The myocyte remodeling is characterized by increase in myocyte length without an increase in myocyte width. There is increased myosin degradation. Vascular remodeling is associated with smooth muscle cell hyperplasia, thickening of internal, and external elastic lamina.
There is also activation of aldosterone system as evident from increased serum levels of aldosterone. Stimulation of aldosterone system also promotes ventricular and vascular adverse remodeling. There is increased myocardial fibrosis, increased collagen synthesis, and decreased collagen break down.
In SHF, arginine vasopressin levels are increased.14 The level of vasopressin is higher in symptomatic patients than in asymptomatic patients with left ventricular dysfunction. Vasopressin is released from pituitary glands. Vasopressin stimulates both vasopressin 1 and 2 receptors.15 Vasopressin 2 receptors are primarily concentrated in renal collecting ducts. Normally, the major stimulus for vasopressin release is increased plasma osmolality. However, in heart failure, vasopressin is released irrespective of changes in plasma osmolality. Stimulation of renal vasopressin 2 receptors is associated with inappropriate release of vasopressin and hyponatremia. Activation of vasopressin 1 receptors is associated with myocyte hypertrophy, myocardial fibrosis, and coronary vasoconstriction. It also increases systemic vascular resistance which increases left ventricular afterload and produces adverse remodeling.
In SHF, endothelins are also increased.16 Endothelins are produced by vascular smooth muscle cells and they are potent vasoconstrictors. Endothelin is produced by conversion of big endothelin-1 by a converting enzyme. Endothelin synthesis and release are promoted by norepinephrine, angiotensin II, and oxidized low density lipoproteins.17
In DHF, plasma norepinephrine levels are increased indicating activated adrenergic system. It is not clear whether renin-angiotensin-aldosterone system is activated or not in DHF. However, it appears that neurohormonal abnormalities are very similar in DHF and SHF. Characteristics of ventricular remodeling in SHF and DHF are different. Adverse effects of neurohormonal abnormalities in SHF are summarized in table 4.
Counter-regulatory vasodilating and antimitogenic neurohormones are also elevated both in systolic and diastolic heart failure. Plasma brain natriuretic peptide levels and vasodilating prostacyclins are also increased. However, the effects of these hormones in attenuation of ventricular remodeling appear inadequate.8
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CONCLUSIONS
In this chapter, the pathophysiology of SHF and DHF is discussed. The functional, morphologic, and remodeling features are discussed. Features of ventricular remodeling are distinctly different in SHF and DHF. Changes in myocyte and myocardial architecture are also described, and the differences in SHF and DHF are discussed. Abnormalities in neurohormonal profile in these two clinical subsets are also discussed in details.
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