Heart Failure
Signs and symptoms of heart failure include tachycardia and manifestations of venous congestion (eg, edema) and low cardiac output (eg, fatigue). Breathlessness, a cardinal symptom of left ventricular (LV) failure, may manifest with progressively increasing severity. (See Clinical Presentation.)
Heart failure can be classified according to a variety of factors. The New York Heart Association (NYHA) classification for heart failure is based on the relation between symptoms and the amount of effort required to provoke them, and The American College of Cardiology/American Heart Association (ACC/AHA) heart failure guidelines complement the NYHA classification to reflect the progression of disease.
Pathophysiology
The common pathophysiologic state that perpetuates the progression of heart failure is extremely complex, regardless of the precipitating event. Compensatory mechanisms exist on every level of organization, from subcellular all the way through organ-to-organ interactions. Only when this network of adaptations becomes overwhelmed does heart failure ensue.
Most important among the adaptations are the Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; alterations in myocyte regeneration and death; myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; and activation of neurohumoral systems. The release of norepinephrine by adrenergic cardiac nerves augments myocardial contractility and includes activation of the renin-angiotensin-aldosterone system [RAAS], the sympathetic nervous system [SNS], and other neurohumoral adjustments that act to maintain arterial pressure and perfusion of vital organs.
In acute heart failure, the finite adaptive mechanisms that may be adequate to maintain the overall contractile performance of the heart at relatively normal levels become maladaptive when trying to sustain adequate cardiac performance.
The primary myocardial response to chronic increased wall stress is myocyte hypertrophy, death/apoptosis, and regeneration.[1] This process eventually leads to remodeling, usually the eccentric type. Eccentric remodeling further worsens the loading conditions on the remaining myocytes and perpetuates the deleterious cycle. The idea of lowering wall stress to slow the process of remodeling has long been exploited in treating heart failure patients.[2]
The reduction of cardiac output following myocardial injury sets into motion a cascade of hemodynamic and neurohormonal derangements that provoke activation of neuroendocrine systems, most notably the above-mentioned adrenergic systems and RAAS.
The release of epinephrine and norepinephrine, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin, causes vasoconstriction, which increases afterload and, via an increase in cyclic adenosine monophosphate (cAMP), causes an increase in cytosolic calcium entry. The increased calcium entry into the myocytes augments myocardial contractility and impairs myocardial relaxation (lusitropy).
The calcium overload may induce arrhythmias and lead to sudden death. The increase in afterload and myocardial contractility (known as inotropy) and the impairment in myocardial lusitropy lead to an increase in myocardial energy expenditure and a further decrease in cardiac output. The increase in myocardial energy expenditure leads to myocardial cell death/apoptosis, which results in heart failure and further reduction in cardiac output, perpetuating a cycle of further increased neurohumoral stimulation and further adverse hemodynamic and myocardial responses.
In addition, the activation of the RAAS leads to salt and water retention, resulting in increased preload and further increases in myocardial energy expenditure. Increases in renin, mediated by decreased stretch of the glomerular afferent arteriole, reduce delivery of chloride to the macula densa and increase beta1-adrenergic activity as a response to decreased cardiac output. This results in an increase in angiotensin II (Ang II) levels and, in turn, aldosterone levels, causing stimulation of the release of aldosterone. Ang II, along with ET-1, is crucial in maintaining effective intravascular homeostasis mediated by vasoconstriction and aldosterone-induced salt and water retention.
The concept of the heart as a self-renewing organ is a relatively recent development.[3] This new paradigm for myocyte biology has created an entire field of research aimed directly at augmenting myocardial regeneration.
The rate of myocyte turnover has been shown to increase during times of pathologic stress.[1] In heart failure, this mechanism for replacement becomes overwhelmed by an even faster increase in the rate of myocyte loss. This imbalance of hypertrophy and death over regeneration is the final common pathway at the cellular level for the progression of remodeling and heart failure.
Ang II also mediates myocardial cellular hypertrophy and may promote progressive loss of myocardial function. The neurohumoral factors above lead to myocyte hypertrophy and interstitial fibrosis, resulting in increased myocardial volume and increased myocardial mass, as well as myocyte loss. As a result, the cardiac architecture changes, which, in turn, leads to further increase in myocardial volume and mass.
As heart failure advances, there is a relative decline in the counterregulatory effects of endogenous vasodilators, including nitric oxide (NO), prostaglandins (PGs), bradykinin (BK), atrial natriuretic peptide (ANP), and B-type natriuretic peptide (BNP). This occurs simultaneously with the increase in vasoconstrictor substances from the RAAS and the adrenergic system. This fosters further increases in vasoconstriction and thus preload and afterload, leading to cellular proliferation, adverse myocardial remodeling, and antinatriuresis, with total body fluid excess and worsening heart failure (HF) symptoms.
For more information, see Natriuretic Peptides in Congestive Heart Failure.
TNF-alpha has been implicated in response to various infectious and inflammatory conditions. Elevations in TNF-alpha levels have been consistently observed in heart failure and seem to correlate with the degree of myocardial dysfunction. Experimental studies suggest that local production of TNF-alpha may have toxic effects on the myocardium, thus worsening myocardial systolic and diastolic function.
Thus, in individuals with systolic dysfunction, the neurohormonal responses to decreased stroke volume result in temporary improvement in systolic blood pressure and tissue perfusion. However, in all circumstances, the existing data support the notion that these neurohormonal responses contribute to the progression of myocardial dysfunction in the long term.
In HFNEF, altered relaxation, and increased stiffness of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occur in response to an increase in ventricular afterload (pressure overload). The impaired relaxation of the ventricle leads to impaired diastolic filling of the left ventricle (LV).
A shift to a steeper ventricular pressure-volume curve results most commonly not only from increased ventricular mass and wall thickness, as observed in aortic stenosis and long-standing hypertension, but also from infiltrative disorders (eg, amyloidosis), endomyocardial fibrosis, and myocardial ischemia.
Parallel upward displacement of the diastolic pressure-volume curve is generally referred to as a decrease in ventricular distensibility. This is usually caused by extrinsic compression of the ventricles.
Heart failure can be classified according to a variety of factors. The New York Heart Association (NYHA) classification for heart failure is based on the relation between symptoms and the amount of effort required to provoke them, and The American College of Cardiology/American Heart Association (ACC/AHA) heart failure guidelines complement the NYHA classification to reflect the progression of disease.
Pathophysiology
The common pathophysiologic state that perpetuates the progression of heart failure is extremely complex, regardless of the precipitating event. Compensatory mechanisms exist on every level of organization, from subcellular all the way through organ-to-organ interactions. Only when this network of adaptations becomes overwhelmed does heart failure ensue.
Most important among the adaptations are the Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; alterations in myocyte regeneration and death; myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; and activation of neurohumoral systems. The release of norepinephrine by adrenergic cardiac nerves augments myocardial contractility and includes activation of the renin-angiotensin-aldosterone system [RAAS], the sympathetic nervous system [SNS], and other neurohumoral adjustments that act to maintain arterial pressure and perfusion of vital organs.
In acute heart failure, the finite adaptive mechanisms that may be adequate to maintain the overall contractile performance of the heart at relatively normal levels become maladaptive when trying to sustain adequate cardiac performance.
The primary myocardial response to chronic increased wall stress is myocyte hypertrophy, death/apoptosis, and regeneration.[1] This process eventually leads to remodeling, usually the eccentric type. Eccentric remodeling further worsens the loading conditions on the remaining myocytes and perpetuates the deleterious cycle. The idea of lowering wall stress to slow the process of remodeling has long been exploited in treating heart failure patients.[2]
The reduction of cardiac output following myocardial injury sets into motion a cascade of hemodynamic and neurohormonal derangements that provoke activation of neuroendocrine systems, most notably the above-mentioned adrenergic systems and RAAS.
The release of epinephrine and norepinephrine, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin, causes vasoconstriction, which increases afterload and, via an increase in cyclic adenosine monophosphate (cAMP), causes an increase in cytosolic calcium entry. The increased calcium entry into the myocytes augments myocardial contractility and impairs myocardial relaxation (lusitropy).
The calcium overload may induce arrhythmias and lead to sudden death. The increase in afterload and myocardial contractility (known as inotropy) and the impairment in myocardial lusitropy lead to an increase in myocardial energy expenditure and a further decrease in cardiac output. The increase in myocardial energy expenditure leads to myocardial cell death/apoptosis, which results in heart failure and further reduction in cardiac output, perpetuating a cycle of further increased neurohumoral stimulation and further adverse hemodynamic and myocardial responses.
In addition, the activation of the RAAS leads to salt and water retention, resulting in increased preload and further increases in myocardial energy expenditure. Increases in renin, mediated by decreased stretch of the glomerular afferent arteriole, reduce delivery of chloride to the macula densa and increase beta1-adrenergic activity as a response to decreased cardiac output. This results in an increase in angiotensin II (Ang II) levels and, in turn, aldosterone levels, causing stimulation of the release of aldosterone. Ang II, along with ET-1, is crucial in maintaining effective intravascular homeostasis mediated by vasoconstriction and aldosterone-induced salt and water retention.
The concept of the heart as a self-renewing organ is a relatively recent development.[3] This new paradigm for myocyte biology has created an entire field of research aimed directly at augmenting myocardial regeneration.
The rate of myocyte turnover has been shown to increase during times of pathologic stress.[1] In heart failure, this mechanism for replacement becomes overwhelmed by an even faster increase in the rate of myocyte loss. This imbalance of hypertrophy and death over regeneration is the final common pathway at the cellular level for the progression of remodeling and heart failure.
Ang II
Research indicates that local cardiac Ang II production (which decreases lusitropy, increases inotropy, and increases afterload) leads to increased myocardial energy expenditure. Ang II has also been shown in vitro and in vivo to increase the rate of myocyte apoptosis.[4] In this fashion, Ang II has similar actions to norepinephrine in heart failure.Ang II also mediates myocardial cellular hypertrophy and may promote progressive loss of myocardial function. The neurohumoral factors above lead to myocyte hypertrophy and interstitial fibrosis, resulting in increased myocardial volume and increased myocardial mass, as well as myocyte loss. As a result, the cardiac architecture changes, which, in turn, leads to further increase in myocardial volume and mass.
Myocytes and myocardial remodeling
In the failing heart, increased myocardial volume is characterized by larger myocytes approaching the end of their life cycle. As more myocytes drop out, an increased load is placed on the remaining myocardium, and this unfavorable environment is transmitted to the progenitor cells responsible for replacing lost myocytes. Progenitor cells become progressively less effective as the underlying pathologic process worsens and myocardial failure accelerates. These features, namely the increased myocardial volume and mass, along with a net loss of myocytes, are the hallmark of myocardial remodeling. This remodeling process leads to early adaptive mechanisms, such as augmentation of stroke volume (Starling mechanism) and decreased wall stress (Laplace mechanism), and later, to maladaptive mechanisms, such as increased myocardial oxygen demand, myocardial ischemia, impaired contractility, and arrhythmogenesis.As heart failure advances, there is a relative decline in the counterregulatory effects of endogenous vasodilators, including nitric oxide (NO), prostaglandins (PGs), bradykinin (BK), atrial natriuretic peptide (ANP), and B-type natriuretic peptide (BNP). This occurs simultaneously with the increase in vasoconstrictor substances from the RAAS and the adrenergic system. This fosters further increases in vasoconstriction and thus preload and afterload, leading to cellular proliferation, adverse myocardial remodeling, and antinatriuresis, with total body fluid excess and worsening heart failure (HF) symptoms.
Systolic and diastolic failure
Systolic and diastolic heart failure each result in a decrease in stroke volume. This leads to activation of peripheral and central baroreflexes and chemoreflexes that are capable of eliciting marked increases in sympathetic nerve traffic. While there are commonalities in the neurohormonal responses to decreased stroke volume, the neurohormone-mediated events that follow have been most clearly elucidated for individuals with systolic heart failure. The ensuing elevation in plasma norepinephrine directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. Norepinephrine, while directly toxic to cardiac myocytes, is also responsible for a variety of signal-transduction abnormalities, such as down-regulation of beta1-adrenergic receptors, uncoupling of beta2-adrenergic receptors, and increased activity of inhibitory G-protein. Changes in beta1-adrenergic receptors result in overexpression and promote myocardial hypertrophy.ANP and BNP
ANP and BNP are endogenously generated peptides activated in response to atrial and ventricular volume/pressure expansion. ANP and BNP are released from the atria and ventricles, respectively, and both promote vasodilation and natriuresis. Their hemodynamic effects are mediated by decreases in ventricular filling pressures, owing to reductions in cardiac preload and afterload. BNP, in particular, produces selective afferent arteriolar vasodilation and inhibits sodium reabsorption in the proximal convoluted tubule. BNP inhibits renin and aldosterone release and, therefore, adrenergic activation as well. ANP and BNP are elevated in chronic heart failure. BNP, in particular, has potentially important diagnostic, therapeutic, and prognostic implications.For more information, see Natriuretic Peptides in Congestive Heart Failure.
Other vasoactive systems
Other vasoactive systems that play a role in the pathogenesis of heart failure include the ET receptor system, the adenosine receptor system, vasopressin, and tumor necrosis factor-alpha (TNF-alpha). ET, a substance produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in heart failure. Elevated levels of ET-1 closely correlate with the severity of heart failure. ET-1 is a potent vasoconstrictor and has exaggerated vasoconstrictor effects in the renal vasculature, reducing renal plasma blood flow, glomerular filtration rate (GFR), and sodium excretion.TNF-alpha has been implicated in response to various infectious and inflammatory conditions. Elevations in TNF-alpha levels have been consistently observed in heart failure and seem to correlate with the degree of myocardial dysfunction. Experimental studies suggest that local production of TNF-alpha may have toxic effects on the myocardium, thus worsening myocardial systolic and diastolic function.
Thus, in individuals with systolic dysfunction, the neurohormonal responses to decreased stroke volume result in temporary improvement in systolic blood pressure and tissue perfusion. However, in all circumstances, the existing data support the notion that these neurohormonal responses contribute to the progression of myocardial dysfunction in the long term.
Heart failure with normal ejection fraction
In diastolic heart failure (heart failure with normal ejection fraction [HFNEF]), the same pathophysiologic processes leading to decreased cardiac output that occur in systolic heart failure also occur, but they do so in response to a different set of hemodynamic and circulatory environmental factors that depress cardiac output.In HFNEF, altered relaxation, and increased stiffness of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occur in response to an increase in ventricular afterload (pressure overload). The impaired relaxation of the ventricle leads to impaired diastolic filling of the left ventricle (LV).
LV chamber stiffness
An increase in LV chamber stiffness occurs secondary to any one of the following 3 mechanisms or to a combination thereof:- Rise in filling pressure
- Shift to a steeper ventricular pressure-volume curve
- Decrease in ventricular distensibility
A shift to a steeper ventricular pressure-volume curve results most commonly not only from increased ventricular mass and wall thickness, as observed in aortic stenosis and long-standing hypertension, but also from infiltrative disorders (eg, amyloidosis), endomyocardial fibrosis, and myocardial ischemia.
Parallel upward displacement of the diastolic pressure-volume curve is generally referred to as a decrease in ventricular distensibility. This is usually caused by extrinsic compression of the ventricles.
Concentric LV hypertrophy
Whereas volume overload, as observed in chronic aortic and/or mitral valvular regurgitant disease, shifts the entire diastolic pressure-volume curve to the right, indicating increased chamber stiffness, pressure overload that leads to concentric LV hypertrophy (LVH, as occurs in aortic stenosis, hypertension, and hypertrophic cardiomyopathy) shifts the diastolic pressure-volume curve to the left along its volume axis so that at any diastolic volume ventricular diastolic pressure is abnormally elevated, although chamber stiffness may or may not be altered. Increases in diastolic pressure lead to increased myocardial energy expenditure, remodeling of the ventricle, increased myocardial oxygen demand, myocardial ischemia, and eventual progression of the maladaptive mechanisms of the heart that lead to decompensated heart failure.Arrhythmias
While life-threatening rhythms are more common in ischemic versus nonischemic cardiomyopathy, arrhythmia imparts a significant burden in all forms of heart failure. In fact, some arrhythmias even perpetuate heart failure. The most significant of all rhythms associated with heart failure are the life-threatening ventricular arrhythmias. Structural substrates for ventricular arrhythmias common in heart failure, regardless of the underlying cause, include the following:- Ventricular dilatation
- Myocardial hypertrophy
- Myocardial fibrosis
source : emedicine.medscape.com
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