Heart failure is a state wherein the cardiac output is inadequate to meet the perfusion to support normal tissue metabolism and exercise capacity is limited. It is a progressive disorder of left ventricular remodeling that culminates in a clinical syndrome characterized by impaired cardiac function and circulatory congestion. The heart changes its size and shape in response to a number of mechanical, biochemical, and molecular signals. These changes in myocardial size and shape are referred to as "LV remodeling." The pathophysiology involves structural changes, apoptosis, disorganization of the cytoskeleton, disturbances in calcium homeostasis, alteration in receptor density, signal transduction, and collagen synthesis.
Regardless of the cause, a decrease in ventricular function causes congestive heart failure by chronically decreasing cardiac output and arterial blood pressure. As blood pressure falls, a series of neurohumoral responses are activated to restore normal pressure. Increase in sympathetic tone causes vasoconstriction and tachycardia, whereas renin-angiotensin-aldosterone system (RAS) contributes to vasoconstriction, and causes sodium and water retention. A common characteristic of all compensatory responses is that their short-term effects are helpful, but the long-term effects are deleterious. Vasoconstriction helps to maintain arterial pressure, but increases afterload decreasing stroke volume. Increases in afterload raise myocardial oxygen consumption (MVO2). Sodium and water retention expands circulating volume and preload, helping to maintain cardiac filling pressures and cardiac output. Retention of sodium and water, however, increases venous pressure leading to development of edema and cavitary effusions.
Cardiomyopathy of overload
The heart and the myocardial cells also undergo changes to adapt to ventricular dysfunction. Sympathetic activation increases cardiac output by raising heart rate, inotropy, and lusitropy. Sympathetic activation also increases MVO2 contributing to myocardial remodeling. Increases in preload, afterload, sympathetic activation, and growth hormone activityinduce myocardial growth, whereas activation of RAS, prostaglandin E2, TGF-beta1, and insulin growth factor-1 induce remodeling of cardiac interstitium. All these substances induce expression of proto-oncogens and growth regulating genes that play an important role in mediating hypertrophy (Fig 1). Hypertrophy decreases the load in individual cells and increases cardiac output. Long-term overload-hypertrophy however, is accompanied by myocardial cell death and cardiac fibrosis. This progressive, and eventually lethal growth abnormality, has been called cardiomyopathy of overload. In embryonic hearts, growth factors induce protein synthesis leading to normal cell division. Early after the animal is born, cardiac myocytes withdraw from cell cycle and can no longer divide, whereas protein synthesis is slowed to rates appropriate to maintain and repair the cells. Stimulation of growth factors by chronic overload leads to an increase in protein synthesis. The cell cycle, however, remains blocked and the end result is not normal cell division, but abnormal hypertrophy. Increases in angiotensin II, a peptide that is not only a vasoconstrictor, but also a mitogen, appear to be an important mediator of reversal of inhibition of protein synthesis in the adult heart.
Figure 1 - Causes of Myocardial Cell Death during Heart Failure
Overload-induced hypertrophy leads to a state of chronic energy starvation by the heart. The increase in cardiac mass is not accompanied by an increase in capillary vessels. The hypertrophied ventricle therefore, outstrips its blood supply. The cell volume occupied by sarcomeres increases, leading to an increase ratio of mitochondria to myofibrils, which can exacerbate the energy deficit. The net result is a decrease in capillary density and coronary reserve with the myocardium becoming prone to ischemia, especially in the subendocardium. The relative decrease in oxygen delivery complicates the increased needs of oxygen of the failing heart. There is a close link between hypertrophy and increasing systolic dysfunction. The ischemia resulting from hypertrophy leads to development of focal fibrosis which increases myocardial collagen content. With progression of the myocardial hypertrophy, the early interstitial fibrosis progresses to perimuscular fibrosis impairing both systolic and diastolic function. Myocardial cell necrosis occurs in overloaded hearts in transition to heart failure. Activation of proto-oncogenes and increased concentrations of TGF-beta, IGF-1, and PGE2 induce apoptosis. Cardiomyopathy of overload therefore, represents an unnatural growth of the adult heart leading to a vicious cycle of myocardial cell death and progression of myocardial failure, which culminates in patient death.
Why is Heart Failure a Progressive Disease?
Compensatory mechanisms activated during heart failure have the paradoxical role of serving simultaneously as adaptive, compensatory changes, and as major contributing elements to the progression of CHF by causing myocardial cell death. Cell death in an overloaded heart will add further to the overload on survival myocytes in a vicious cycle.
Increased Afterload: Vasoconstriction, increase in cardiac contractility, and heart rate help maintain blood pressure, but also increase MVO2 accelerating myocardial cell death. Wall stress (a function of afterload), contractility, and heart rate are the main determinants of MVO2. Hypertrophy decreases myocardial oxygen consumption by decreasing wall stress during ejection, but sets the stage for myocardial death. Increase in afterload further decreases left ventricular function leading the organism into a new, decreased steady-state level, where the cardiac output is lower and vasoconstriction higher than would be optimal for the patient.
LV Remodeling: Stretching of myocardium resulting from overload seems to be the initiating signal for adaptive process in the myocardium to begin. This leads to hypertrophy due to growth factor and proto-oncogen stimulation. Hypertrophy unloads the cells of the failing heart by adding new sarcomeres, and also increases contractility and cardiac output. Unfortunately, hypertrophy ultimately leads to cellular abnormalities that result in mitochondrial DNA abnormalities, apoptosis, hastening myocardial cell death. Chronic neurohumoral activation, especially increases in angiotensin II and norepinephrine, and increases in afterload lead to left ventricular and vascular remodeling. Globally, the remodeling process in the ventricle is characterized by progressive left ventricular enlargement and increased chamber sphericity. At the cellular level, the remodeling process is associated with myocyte slippage, hypertrophy, and accumulation of collagen in the interstitial compartment. The final result of this process is the so-called cardiomyopathy of overload. Angiotensin II also causes vascular remodeling leading to hypertrophy of smooth muscle cell of the vessel walls. Vascular remodeling decreases vessel compliance and therefore, increases ventricular afterload.
Figure 2 - Mechanisms of Heart Failure progression
Heart failure is a progressive disease, because the compensatory mechanisms activated to maintain blood pressure and cardiac output during heart failure will ultimately lead to myocardial cell death, further compromising myocardial function. Thus, once a certain point of myocardial dysfunction is reached, CHF becomes a progressive, irreversible disease.
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