Many conditions and different heart diseases can progress into heart failure. Regardless of the cause, there is an initial fall in cardiac output that lowers arterial pressure. Clinical signs observed in heart failure are mainly the result of chronic activation of compensatory mechanisms to restore and maintain blood pressure. The cardiovascular system is part of a biologic control system that works in co-operation with the central nervous, renal, and endocrine systems to keep cardiovascular variables at physiologic levels. Maintenance of arterial blood pressure and effective plasma volume are the main priorities of this integrated system. Changes are sensed by high-pressure baroreceptors in the aortic arch and carotid sinus, by mechanoreceptors in the ventricular myocardium, by volume receptors in the atria and great veins, and by the juxtaglomerular apparatus in the kidneys. During episodes of low blood pressure, a reactive neuroendocrine activation occurs to re-establish normal blood pressure. The immediate response is a decrease in parasympathetic drive and an increase in sympathetic drive, causing vasoconstriction (increasing arterial impedance) and tachycardia (increasing cardiac output). Vagal responses tend to be immediate and short-lived, whereas sympathetic responses are slower but last longer. A decrease in renal blood flow causes the release of renin and activation of the renin-angiotensin-aldosterone system (RAS), contributing to vasoconstriction and causing sodium and water retention, which increases the circulating volume. Compensatory mechanisms are acute responses that evolved to maintain an animal’s life during and immediately after an episode of bleeding. During heart failure, however, compensatory mechanisms are chronically activated. In an effort to maintain blood pressure, the cardiovascular system allows the venous pressure to increase and redistributes cardiac output, maintaining blood flow mosdy to essential organs. Compensation cannot be viewed as an isolated response of the circulation. The heart and the myocardial cells undergo changes to adapt to ventricular dysfunction. A common characteristic of all compensatory responses is that the short-term effects are helpful, but the long-term effects are deleterious. In acute injuries to the heart, cardiac output decreases and acute heart failure may occur; this phase, known as transient breakdown, initiates activation of the compensatory mechanisms. In small animals, heart failure is usually a chronic problem, and the transient breakdown phase merges with the following phase. As compensation occurs, cardiac output and clinical signs steadily improve, because the heart and circulation are performing extra work; this compensated phase is known as stable hyperfunction. Chronic hyperfunction leads to progression of left ventricular dysfunction, myocardial cell death, the development of clinical signs, and death, the exhaustion and progressive cardiosclerosis phase.
Central Compensation (the Heart)
The heart participates actively in the compensation for the decrease in cardiac output. Sympathetic activation leads to an increase in the heart rate, inotropy, and lusitropy, all of which increase cardiac output. In addition, hypertrophy helps normalize cardiac output by increasing the stroke volume. Compensatory mechanisms that act on the heart are shown in Central (Cardiac) Compensatory Mechanisms in Heart Failure.
Central (Cardiac) Compensatory Mechanisms in Heart Failure
|Response||Mechanism||Potential Benefit||Potential Harm||Manifestations||Correlates|
|Sympathetic desensitization||Downregulation of beta2 adrenoreceptors, uncoupling of beta2 adrenoreceptors, depletion of myocardial norepinephrine||Energy sparing||Decreased contractility||Low-output signs (e.g., depression, lethargy, hypotension)||Beta-adrenoreceptor blockade may reverse sympathetic desensitization.|
|Tachycardia||Sympathetic activation, parasympathetic withdrawal||Increased cardiac output||Increased MVO2||Tachycardia, decreased heart rate variability||Decrease in heart rate variability correlates with mortality.
Increase in heart rate correlates with sympathetic activation and severity of congestive heart failure.
|Increased inotropy||Sympathetic activation||Increased stroke volume||Increased MVO2||—||—|
|Increased relaxation||Sympathetic activation||Improved diastolic function (lusitropy)||Increased MVO2|
|Appearance of slow myosin in the atria||Changes in isogene expression||Decreased cost to achieve normal tension, energy sparing, increased atrial kick||Atrial failure||Changes do not occur in the ventricles of dogs and cats.|
|Reduced myocardial ATPase activity||Unknown (altered isoenzymes?)||Facilitation of high-pressure, low-speed work; energy sparing||Slowed
ATPase activity is increased in high-output congestive heart failure (e.g.. thyrotoxicosis).
|Pressure overload (concentric hypertrophy)||Increased afterload, renin-angiotensin-aldosterone system activation, increased levels of TNF-alpha and other cytokines||Unloading of individual muscle fibers, decreased wall stress and MVO2||Imbalance in energy demand and supply, focal necrosis, fibrosis, increased collagen formation, diastolic dysfunction||Cardiomegaly, increased diastolic dysfunction and venous congestion||Pressure overload induces cardiomy-opathy of overload.
Growth-inhibitory drugs (e.g., angiotensin-converting enzyme inhibitors, nitrates) may delay development of cardiomyopathy of overload.
|Volume overload (eccentric hypertrophy)||Fiber slippage, increased tension||Increased
compliance(?); increased stroke volume with same ejection fraction (dilatation)
|Increased wall stress and MVO2; pressure hypertrophy||Cardiomegaly||Increased wall stress leads to pressure hypertrophy.|
ACE, Angiotensin-converting enzyme; ATPase, adenosine triphosphatase; CHF, congestive heart failure; MVO2, myocardial oxygen consumption; TNF-alpha, tumor necrosis factor alpha.
During heart failure, sympathetic tone increases (increasing the heart rate) and parasympathetic tone decreases, a combination that leads to tachycardia. It is usually believed that sinus rates above 160 beats/min imply not only parasympathetic withdrawal but also sympathetic activation. The end result is an increase in the heart rate and a decrease in heart rate variability. The increase in the heart rate helps normalize arterial pressure, but at a high price: an increase in MVO2. A decrease in heart rate variability is a negative prognostic factor for overall mortality in human patients with myocardial infarct. In dogs with chronic mitral valve disease, a decrease in heart rate variability correlates with the severity of congestive heart failure Patients with decreased heart rate variability are also less likely to respond to vasodilator infusion. The increase in the heart rate in patients with heart failure parallels sympathetic activation, which in turn correlates with the severity of the heart failure.
Increased Inotropy and Lusitropy
Beta-adrenergic stimulation caused by increased sympathetic tone during heart failure increases calcium entry in the atrial and ventricular cells, calcium release from the sarcoplasmic reticulum, and the interaction between contractile proteins. All these actions increase contractility. Beta-adrenergic stimulation also increases lusitropy by increasing calcium efflux from the cell and calcium uptake by the sarcoplasmic reticulum. The increase in calcium entry is largely responsible for the positive inotropic effect; the facilitated dissociation from troponin and increased calcium uptake by the sarcoplasmic reticulum are the key factors in causing a positive lusitropic effect. Beta-adrenergic stimulation increases cardiac output, but also increases MVO2 and contributes to myocardial remodeling.
Cardiac mass is increased in patients with heart failure, apparently as a result of a combination of reactive fibrosis and myocyte hypertrophy, along with alterations in the cytoskeletal structure in the myocyte. An increase in afterload and neuroendocrine activation lead to left ventricular hypertrophy. Hypertrophy reduces the load in individual cells and increases cardiac output. Hypertrophy causes growth of myocyte and nonmyocyte cells in the extracellular matrix of the myocardium. The growth of myocytes and nonmyocyte cells occurs independent of each other. Chronic anemia and thyrotoxicoses cause myocyte growth without the involvement of fibroblasts, whereas hypertrophy secondary to pressure overload is accompanied by reactive fibrosis that is not secondary to myocyte necrosis. Increases in preload, afterload, sympathetic activation, and growth hormone induce myocardial growth, whereas activation of the RAS, prostaglandin E2, transforming growth factor-beta] (TGF-beta|), and insulinlike growth factor-1 (IGF-1) induce remodeling of the cardiac interstitium. All these substances induce expression of proto-oncogenes and growth-regulating genes that play an important role in the mediation of hypertrophy. Structural remodeling of myocardial collagen matrix contributes to the progression of heart failure.
Hypertrophy in patients with congestive heart failure results in a ventricle that is not normal. Morphologic, biochemical, and genetic changes cause ventricular remodeling, leading to progression of the left ventricular dysfunction. The appearance of a “slow” myosin, a more efficient myosin that spares energy in the heart, has been detected in the atria but not the ventricles of dogs with congestive heart failure. Pressure-induced hypertrophy unloads the individual myocardial cells and decreases wall stress and MVO2. However, hypertrophied ventricles have a capillary deficit and a decreased number of mitochondria, leading to a state of energy starvation. The chronic energy starvation leads to necrosis, fibrosis, an increase in the collagen concentration, and diastolic dysfunction. Volume-induced hypertrophy decreases wall stress and MVO2 and helps maintain stroke volume, probably by increasing compliance. Fiber slippage, however, causes further dilatation of the heart, again increasing wall stress and MVO2 and favoring progression of the left ventricular dysfunction.