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Aetiology, Pathophysiology and Molecular Pathology of Heart Failure

Updated on August 8, 2011

Heart failure is a complex syndrome that develops when the heart fails to maintain an adequate cardiac output to provide all organs with blood supply appropriate to the demand or the heart manages to maintain an adequate cardiac output only at an expense of an elevated filling pressure, occurring due to any structural or functional cardiac disorder. The aim of this article is to update the knowledge on the aetiology and the pathophysiology of heart failure among professionals and medical students.

Although the aetiology of heart failure is multiple and complex, it can be basically classified into six groups:

1.       Reduced ventricular contractility

2.       Ventricular outflow obstruction (pressure overload)

3.       Ventricular inflow obstruction

4.       Ventricular volume overload

5.       Arrhythmia

6.       Diastolic dysfunction

Reduced contractility of the ventricles is the commonest cause for heart failure, which is precipitated by myocardial infarctions (in 35-40% of the cases), cardiomyopathy (out of which dilated cardiomyopathy is the commonest) and myocarditis. Obstruction of the outflow tracts of the ventricles may also precipitate heart failure. Thus, left heart failure may occur following chronic or sever hypertension, accounting for 10-15% of the cases of heart failure. Aortic stenosis and hypertrophic obstructive cardiomyopathy are also important causes of left ventricular outflow tract obstruction precipitating heart failure. Similarly right heart failure can be precipitated by pulmonary hypertension and pulmonary stenosis. Ventricular inflow obstruction, due to mitral and tricuspid stenosis for left and right hearts respectively, can be the cause of heart failure especially when the demand is high. Ventricular volume overload due to any cause can lead to heart failure. The left ventricle may be overloaded by aortic and mitral regurgitation, arterio-venous fistulae and a ventricular septal defect (VSD) while the right ventricle may be over loaded by an atrial septal defect (ASD). Other causes of systemic volume overload include thyrotoxicosis, beri-beri , pregnancy, anaemia , haemochromatosis  and the Paget’s disease. Arrhythmias can also be a cause for heart failure with the commonest arrhythmias responsible being atrial fibrillation, sick sinus syndrome and complete heart block. Diastolic dysfunction of the heart, i.e. the inability of the heart to dilate adequately to accommodate the venous return, may be the aetiology. Examples for diastolic dysfunction are constrictive pericarditis and pericardial effusion, restrictive cardiomyopathy, left ventricular fibrosis and cardiac tamponade.

Pathophysiology of cardiac failure can be understood as a sequence of events. Initially as the heart fails to maintain an adequate output to meet the functional demand, several compensatory mechanisms are activated. They include the sympathetic nervous system, rennin-angiotensin-aldosterone axis, ADH system and the endothelin system. As a result of the activation of the above compensatory mechanisms salts and water are retained more than before leading to an increased venous return and therefore an increased pre-load. This is also contributed by the increased tone in venous smooth muscles. Increased tone in arteriolar smooth muscle results in an increased after-load. The contractility of the heart as well as the heart rate is increased.

These compensatory mechanisms are initially beneficial but with further deterioration they become counter productive and initiate a vicious cycle. Increased pre-load increases the stretching of cardiac muscle and increases the contractility of the heart as described by the Frank-Starling law. However, over-stretching of cardiac muscle leads to dysfunction. Similarly increased after-load increases the demand on the heart. Increased cardiac contractility increases the demand for oxygen and makes the myocardium more susceptible to ischaemic damage. Increased heart rate reduces the perfusion time to the myocardium as well as the filling time to the ventricles. All these lead to rapid deterioration once the compensatory reserves are exceeded.

Though the above pathophysiological mechanisms explain the decompensation of heart failure, the picture is more complex at the molecular level. Expression of Na+/K+ ATPase, Ca+2 ATPase and the β1-receptor is increased in heart failure. Collagen synthesis is increased with reduced myosin gene expression. Apoptosis of myocardial cells is triggered by free radicals and cytokines. The levels of natriuretic peptides [ANP (formed in atria); BNP (formed by the ventricles, brain); C-type peptide (synthesized by the endothelium)] increase in blood resulting in diuresis, natriuresis, vasodilatation and suppression of RAA axis. The resulting hyponatraemia is a good indicator of very poor prognosis. Peripheral endothelium dependent vasodilatation is impaired as a result of the increased release of endothelin (vasoconstrictor) enhanced by hypoxia, angiotensin-2 and noradrenaline. Action of NO and the release of NO (vasodilator) are blunted aggravating the impairment of vasodilatation. Plasma level of TNF is also increased.

Although the aetiology, pathophysiology and the molecular pathology of heart failure are complex, a good understanding of the above is important to understand the depth of heart failure and the basis and rationale of the pharmacological as well as non-pharmacological management.


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