The pathophysiology of advanced heart failure☆,☆☆,★
Section snippets
Remodeling
The failing heart is accompanied by a change in ventricular shape and dimension, a process known as remodeling. Remodeling may be regional or global, depending on the type of insult to ventricular function (i.e., regional infarction vs cardiomyopathy) and is brought about by an increase in myocardial mass, an increase in ventricular volume, a change in ventricular shape, and interstitial growth. The dysfunctioning heart compromises stroke volume, and one adaptive compensatory mechanism to
Mechanical Considerations
Patients with advanced heart failure have for the most part enlarged ventricles, which place them at several mechanical disadvantages. The increased radius increases wall stress by Laplace's law, which is incompletely compensated for by the increase in wall thickness that occurs. In addition, the heart operates in a flat portion of the Starling mechanism. Although cardiac output and ventricular performance may be normal at rest, during exercise a marked elevation in pulmonary pressure may occur
Coronary Artery Disease
Heart failure in the setting of coronary artery disease is a heterogeneous condition with several factors contributing to left ventricular dysfunction and heart failure. These include AMI with loss of functional myocytes, development of myocardial fibrosis, and ventricular remodeling. In addition, the presence of coronary disease gives rise to the conditions of stunning and hibernation.
Myocardial stunning is defined as delayed recovery of myocardial function despite restoration of coronary
Arrhythmogenesis
Sudden death accounts for 28% to 68% of all deaths in patients with advanced heart failure treated with angiotensin-converting enzyme inhibitors.47, 48 In patients with relatively well-compensated heart failure, ventricular fibrillation may occur as a primary electrical event such as reentry in a chronic infarct scar; it can also occur in patients with very severe left ventricular dysfunction and hemodynamics in whom preventing or promptly terminating the arrhythmia is unlikely to alter the
Subendocardial Ischemia
Unverferth et al.52 raised the hypothesis that patients with primary cardiomyopathy are stranded in a self-perpetuating course of advancing heart failure. Among other factors, the progressive deterioration is caused by insufficient coronary blood flow to the subendocardium with a resultant loss of the area's ability to contribute to the work of the heart, initiating a vicious cycle that worsens the heart failure and further decreases coronary blood flow.56 Myocardial oxygen demand in patients
Molecular Changes
In advanced heart failure several molecular abnormalities have been identified, affecting in particular contractile protein function and excitation-contraction coupling. These have been demonstrated to be caused by a variety of mechanical, neurohumoral, and autocrine forces. Changes in contractile protein function appear to comprise an initial increase in protein production in response to ventricular overload, accompanied by a reversion to more fetal forms and an eventual reduction in protein
Myocyte Loss
In advanced cardiac failure ongoing myocyte loss is a feature of the myopathic process6, 68 and may occur by either necrosis or apoptosis. β-adrenergic stimulation including cardiac norepinephrine release and exposure to angiotensin II14can produce myocyte necrosis in model systems. In addition, aldosterone69, 70 has been shown to produce myocyte necrosis in rats after prolonged therapy (3 weeks). In this model spironolactone was protective, as were potassium supplements, indicating that the
Endothelial Dysfunction, Skeletal Muscle Dysfunction, and Cardiac Cathexia
In severe heart failure factors other than activity of the sympathetic nervous system and the RAS contribute to peripheral vasoconstriction. α-blockade and angiotensin-converting enzyme inhibition do not restore normal blood flow during exercise.78 Processes that depend on nitrous oxide (NO) such as acetylcholine-mediated vasodilatation and flow-dependent vasodilatation have been shown to be impaired.79, 80 In addition, response to glyceryl trinitrate is impaired. Endothelial dysfunction of
Neurohumoral Changes
Several complementary mechanistic pathways contribute to the physiological adjustments necessary for optimum cardiac function in health and disease. After an insult to cardiac function occurs, however, these mechanisms may cause a paradoxical worsening of cardiac function.
The sympathetic nervous system and the renin-angiotensin system constitute the primary neurohumoral systems for compensating a failing heart, causing largely an increase in afterload and preload. Many other pathways, presently
Role of Cellular Immune Activation
Cytokines are small polypeptides produced by a variety of immune cells and essentially represent an intercellular signaling system. The system is complicated; individual cytokines may be produced by more than one type of cell and may stimulate or inhibit more than one type of cell (Table I).91, 92Often one episode of cytokine release will have multiple effects, but most of the effect is in the locality of release, so that these molecules are largely a paracrine signaling system.
Role of Neurohumoral Pathways
A myriad of peptide signaling systems exist within the body, but in recent years attention has focused on two systems that have been demonstrated to be intimate with the appearance of congestive heart failure: the natriuretic peptides and the endothelins (Figure 3).
Conclusions
Severe heart failure causes the activation of compensatory immunologic and neurohumoral mechanisms. Although perhaps designed to be physiologically beneficial, these mechanisms may be wholly insufficient or, indeed, may paradoxically worsen the cardiac decompensation, creating opportunities for new therapeutic interventions. Simultaneously, the new identification of these plasma constituents may allow more accurate risk stratification of individuals at risk of ventricular dysfunction and
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Cited by (0)
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From the aDepartment of Cardiological Sciences, St. George's Hospital Medical School, London; the bDivision of Cardiology, Northwestern University Medical School, Chicago; and the cDepartment of Cardiology, Cleveland Clinic Foundation.
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Reprint requests: M. Kamran Baig, MD, Department of Cardiological Sciences, St. George's Hospital Medical School, Cranmer Terrace, London, UK SW17 ORE.
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