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Heart failure, also known as congestive heart failure or CHF, is an inability of the heart to pump sufficient blood around the body.
Heart failure typically occurs secondary to an existing pathology that alters cardiac function. Examples of syndromes that can precede heart failure include myocardial infarction, arrhythmia or infection. These can also cause dilated cardiomyopathy, a condition which accounts for approximately one third of all cases of heart failure.
The pathogenesis of heart failure is cyclical and progressive; endogenous mechanisms, which are activated during heart failure in an attempt to counteract the symptoms, actually worsen cardiac function. Cardiac dysfunction, either systolic or diastolic, triggers a decrease in stroke volume and a resultant increase in cardiac output. In healthy individuals the body responds to decreases in cardiac output by initiating the renin-angiotensin-aldosterone system (RAAS) to promote fluid retention, and also by activating the sympathetic nervous system to cause peripheral vasoconstriction. Under normal circumstances this counteracts the imbalance in stroke volume, restoring cardiac output to normal levels.
In patients with heart failure the increase in blood volume, together with the heightened peripheral resistance and elevated levels of circulating catecholamines, causes an increased load on the already weakened ventricles with each contraction, and the stroke volume does not return to normal levels. Repeated cycles of this process further weaken the ventricle walls, prompting ventricular hypertrophy and a decreased force of contraction.
The two most common therapeutic strategies for heart failure are to increase intracellular calcium concentration within myocytes by activating second messenger signaling pathways, and also to block or counteract the neurohormonal compensatory reflexes through the inhibition of the RAAS. Pharmacological agents which trigger a rise in intracellular calcium include positive inotropes, α adrenergic receptor agonists, and phosphodiesterase inhibitors.
However, indirectly targeting the signaling pathways involved in cardiac contractility also induces mechanism-related adverse effects. More recent therapy using small molecule drugs looks to be a promising and more effective strategy for improving contractility in patients with heart failure. Additionally, blocking the neurohormonal reflexes in the failing heart is a more efficacious therapeutic strategy for heart failure compared to increasing contractility, and can be achieved using angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs). The administration of diuretics reduces symptoms associated with heart failure, such as peripheral edema, but it does not reverse or halt the disease pathology.
In addition to the existing compounds, future therapeutic targets include the matrix metalloproteinase enzymes MMP-2 and MMP-9. The expression of these collagenases is increased in heart failure whilst the expression of their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been shown to be downregulated in the same tissue. In support of this, experimental inhibition of MMP-9 reduces ventricular dilatation in a model of heart failure.