Florian LangEncyclopedia of Molecular Mechanisms of Disease10.1007/978-3-540-29676-8_750
© Springer-Verlag GmbH Berlin Heidelberg 2009
Gohar Azhar1 and Jeanne Y. Wei1
University of Arkansas for Medical Sciences, GRECC and CAVHS, Little Rock, AR, USA
Cardiac insufficiency; Congestive cardiac failure; CCF; Systolic heart failure; SHF; Diastolic heart failure; DHF; Systolic ventricular dysfunction; Diastolic ventricular dysfunction
Definition and Characteristics
Heart failure is a clinical syndrome characterized by the inability of the heart to pump blood commensurate with the requirements of the body [1,2]. Two functional subsets of heart failure that are commonly encountered are diastolic heart failure (DHF) and systolic heart Failure (SHF). SHF is associated with reduced cardiac contractile function and an ejection fraction of 40% or less. DHF can occur in the presence or absence of systolic dysfunction, and is characterized by impaired cardiac relaxation [3–5]. Moderately severe left heart failure can result in secondary right heart failure or biventricular failure. Right heart failure can occur generally in conditions of severe tricuspid regurgitation, severe pulmonary disease or pulmonary hypertension, and in extreme cases, can also result in secondary left heart failure or biventricular failure. Morphologically, heart failure can be the end result of hypertrophic or dilated cardiomyopathy and/or valvular heart disease [1–5]. Familial gene mutations comprise about 20–50% of idiopathic dilated cardiomypathies.
Over 5 million patients in the United States have CHF, and there are 1 million hospitalizations for CHF each year. The incidence is 500,000 new cases each year. The prevalence of heart failure rises dramatically from <1% in individuals under 60 years to over 10% in those older than 80 years.
Familial dilated cardiomyopathy has been linked to mutations in the following genes: lamin A/C; troponin T; α-actinin; titin; desmin; troponin C; cardiac sodium channel α subunit, SCN5A; δ-sarcoglycan; phospholamban; metavinculin; cypher/ZASP; myosin-binding protein-C; LIM protein gene, thympoietin; β myosin heavy chain; cardiac actin; α tropomyosin; telethonin; troponin I; dystrophin; tafazzin. Other causes of cardiomyopathies, including the familial hypertrophic variety, are associated with β myosin heavy chain, myosin light chain, α tropomyosin, troponin T and I, cardiac actin, nkx2.5 and presenilin, PSEN1 and PSEN2 gene mutations [1,2].
Molecular and Systemic Pathophysiology
Common causes of CHF include ischemic, hypertensive heart disease and valvular heart diseases, resulting in cardiomyopathy. Other less common causes include alcoholic cardiomyopathy, viral myocarditis, infiltrative diseases (sarcoidosis, amyloidosis), metabolic disorders (thyroid), cardiotoxins, and drug toxicity. Progressive CHF usually results in reduced cardiac output and a clinical syndrome of left heart failure with pulmonary edema, which might be followed by right heart failure with peripheral edema and hepatic congestion and abdominal ascites. In certain systemic diseases CHF can occur with supra-normal cardiac function, when the metabolic body demand significantly exceeds the supply such as in thyrotoxicosis, severe anemia, arteriovenous shunting, Paget’s disease, and thiamine deficiency. Most patients with end-stage heart failure experience fatigue and weight loss and develop progressive loss of skeletal muscle resulting in cardiac cachexia . In the initial stages of compensated CHF, there is elevation of atrial naturetic peptide, (ANP) brain naturetic peptide (BNP), which helps vasodilate and cause naturesis, thus reducing fluid over-load. Elevation of other cytokines such as angiotensin, TNFα, interleukins 1 and 6 can depress cardiac function and have a negative feed-back effect. The molecular etiology of familial dilated cardiomyopathy can be divided mechanistically into mutations in genes that interfere with transmission of force (e.g. actin, dystrophin) generation of force (e.g., β myosin heavy chain, troponin C), with alteration of nuclear structure (e.g., lamin A/C), with alteration of stretch function (e.g., LIM protein), and genes causing abnormalities in calcium regulation that impact contractile function (e.g., phospholamban). Interestingly, Glu54Lys and Glu40Lys in α tropomyosin gene cause dilated cardiomyopathy whereas Glu62Gln, Ala63Val, Lys70Thr and Val95Ala mutations in the same gene result in hypertrophic cardiomyopathy .
One of the genes that have recently been associated with both cardiomyopathy and CHF in rodents and humans is serum response factor (SRF). SRF has also been demonstrated to be increased with normal aging and might predispose the heart to the development of CHF by reducing cardiac reserve capacity [3,5].
Diagnosis of CHF is clinical, based on severity of symptoms and signs of heart failure on examination [1,2]. Further substantiating evidence can be obtained with chest X rays, EKGs, echocardiogram and/or radionuclide scintigraphy for ejection fraction and regional wall motion analysis. Scintigraphy is useful when echocardiography is technically suboptimal, such as in patients with severe pulmonary disease.
Correction of reversible causes such as uncontrolled hypertension, myocardial ischemia and treatment of underlying disease states as hypo or hyperthyroidism. Diuretic treatment to reduce fluid overload, ACE inhibitors and β-blockers are cornerstones of treatment [1–5]. Carvedilol a nonselective β1- and β2-receptor blocker has been shown to reduce mortality by 30–35%. Vasodilators such as nitrates are useful in pre-load reduction in reducing symptoms of pulmonary congestion. Certain conditions might require antiarrhythmic therapy, and in certain medically refractory cases, cardiac transplantation or cardiomyoplasty may be beneficial.
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