Pathophysiology
Advances in the management of heart failure (HF) over the past 20 years have been informed by a better understanding of its pathophysiology. There are few situations in cardiology where treatment has been as closely linked to an appreciation of the underlying science.
Vicious cycle of heart failure. HF is a disease of inappropriate adaptation to injury. The body has a limited range of compensatory responses to circulatory impairment, mainly vasoconstriction and sodium and water retention (see below). In general, however, these adjustments to hypovolemia are poorly suited to pump failure, and increases in the preload and afterload of the failing heart lead to worsening HF (Figure 2.1).
Figure 2.1 The vicious cycle of heart failure. RAAS, renin–angiotensin–aldosterone system.
Neurohormonal pathways activated in HF include the sympathetic nervous system (SNS), the renin–angiotensin–aldosterone system (RAAS) and the natriuretic peptide (NP) system. They play a significant role in the pathophysiology of HF, and pharmacological interventions have been developed accordingly (see Chapter 7).
Sympathetic nervous system. Sympathetic activation of the adrenergic system leads to vasoconstriction, which increases the resistance to blood flow and helps to maintain arterial pressure in the early stages of HF when cardiac output is reduced. However, vasoconstriction also increases the afterload on the heart, leading to a worsening of HF (see Figure 2.1).
Renin–angiotensin–aldosterone system. Enhanced sympathetic outflow also activates the RAAS (Figure 2.2). Renin release from the kidneys causes increased formation of angiotensin I from angiotensinogen and, via the action of angiotensin-converting enzyme (ACE), angiotensin II. Angiotensin II causes systemic vasoconstriction and acts on the adrenal cortex to produce aldosterone, leading to sodium and water retention. In addition, aldosterone (which may be released even in the setting of ACE inhibition) contributes to myocardial and vascular fibrosis. Sympathetic stimulation also releases antidiuretic hormone, which leads to retention of free water and contributes to dilutional hyponatremia.
Figure 2.2 Neurohormonal pathways in heart failure. ACE, angiotensin-converting enzyme; ADH, antidiuretic hormone; AI/AII, angiotensin I/II.
Natriuretic peptide system. The natriuretic peptide family consists of A (atrial) and B (brain) type natriuretic peptides (ANP and BNP), which are produced by cardiomyocytes in response to atrial and ventricular stretch, and C type natriuretic peptide, which is secreted by endothelial and renal cells. NPs, mainly BNP, lead to increased sodium excretion and vasodilation, especially in the early phases of HF. BNP also has anti-remodeling properties. The biological action of BNP is mediated through membrane-bound natriuretic peptide receptors (NPRs) and the peptide is degraded by neutral endopeptidase (including neprilysin). It is postulated that HF is a state of relative BNP deficiency caused by both lack of biologically active peptide and resistance at a receptor level. In end-stage HF, the peptides may not be released because of myocyte loss.
Other pathways also reflect an inappropriate response to injury. Cytokine release is increased in HF, leading to a variety of consequences including apoptosis. The role of these as contributors to the progression of HF, rather than a correlate, is debated. Certainly, the failure of tumor necrosis factor (TNF) inhibitors to improve outcome argues against a causative role.
Remodeling of the myocardium. Global and local responses to maladaptive stimuli lead to myocardial remodeling, namely increased myocardial volume and mass and a net loss of myocytes. The heart has the ability to change the force of contraction, and therefore stroke volume, in response to changes in venous return (the Frank–Starling mechanism). A reduction in stroke volume due to myocardial injury can be overcome by left ventricular (LV) enlargement. This is not a response that can keep occurring indefinitely – eventually a loss of LV function will occur due to reduced interaction between contractile elements, caused by their separation.
LV hypertrophy (LVH) maintains wall stress as the LV enlarges. However, it is also eventually maladaptive as the hypertrophied myocardium exceeds the growth of its blood supply.
Autonomic reflexes. The increase of sympathetic tone associated with HF leads to disturbance of the autonomic reflexes. Persistent elevation of the heart rate is maladaptive in the ventricle: disturbances of LV relaxation are common, so the shortening of diastole that occurs with tachycardia (the duration of systole remains stable) is not well tolerated.
Peripheral vasoconstriction, as described above, symptomatically may contribute to cold sensitivity.
Loss of skeletal muscle is an important manifestation of HF, reflecting inactivity, consequences of circulating substances such as tumor growth factor (TGF)-β and reduced cardiac output. In its most advanced manifestation, loss of skeletal muscle may lead to cachexia. The consequences of this process include contributions to insulin resistance as well as loss of the skeletal muscle circulatory bed. The loss of this vasculature represents an additional decrement in the amount of vasculature that can undergo vasodilation (and therefore unload the LV).
Cardiorenal interactions. Reduced renal perfusion in HF (due to reduced stroke volume and vasoconstriction) is an important contributor to sodium and fluid overload. The exact links between cardiac and renal function have yet to be resolved. More marked disturbances of renal function, leading to coexisting renal failure, may also occur and pose problems for volume control.
Clinical stages and functional classes
The clinical syndrome of HF represents the final manifestation of advanced disease. Although progress has been made in the management of this entity, the greatest hope of avoiding the adverse outcome of HF is to intervene at an earlier subclinical stage, when there is more likelihood of reversing the process. The American Cardiology Association (ACC)/American Heart Association (AHA) guidelines divide progression of the disease into four preclinical and clinical stages (Table 2.1).
TABLE 2.1 The clinical stages and functional classes of heart failure | |||
ACC/AHA stage | Clinical status | NYHA class | Functional status |
A | Preclinical: risk factors for HF but no structural heart disease or symptoms | I | No limitation in any activities; no symptoms from ordinary activities |
B | Preclinical: structural evidence of heart disease, but no symptoms | I | No limitation in any activities; no symptoms from ordinary activities |
C | Clinical: structural evidence of heart disease, and symptoms or signs of HF | I, II, III | No, slight (e.g. mild shortness of breath) or marked limitation of any activity due to symptoms; comfortable only at rest |
D | Clinical: structural evidence of advanced heart disease, and marked symptoms and signs of HF | II, III, IV | Slight or marked limitation of any activity; symptoms at rest |
Adapted from the American College of Cardiology (ACC)/American Heart Association (AHA) 2001 guidelines and The Criteria Committee of the New York Heart Association (NYHA), Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels, 9th edn. Boston: Little, Brown & Co, 1994:253–6. | |||
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