If the neurohormonal compensatory mechanisms are activated for sustained periods of time, adaptive changes in the heart and circulation ensue which tip the balance away from compensation towards uncontrolled salt and water retention, vasoconstriction, and the detrimental consequences which lead Co clinical congestive heart failure.
Prolonged ventricular distension leads to a loss of the ability of the heart to increase its output in response to increases in ventricular volume. The sarcomeres are stretched to their limits and further increases in venous return have no more benefit in terms of force of subsequent contraction- In short, the Starling curve becomes depressed and flattened. Further stretch can compromise the function of the atrioventricular valves, further reducing cardiac output. In humans it has been shown that prolonged stretch of the atria leads to depletion of ANP and reduced release in response to stretch. Neural reflexes in response to atrial stretch also become blunted such that atrial baroreceptors are no longer able to moderate sympathetic outflow from the vasomotor centre. Chronic stimulation of heart muscle by the sympathetic nervous system leads to a reduction in density of beta1-adrenoceptors and a decrease in the efficiency of coupling between the remaining receptors and adenylate cyclase (so-called Mown regulation of beta1-adrenoceptors). Thus, one of the main neurohormonal mechanisms increasing the force of contraction of the heart becomes less effective.
As the work load on the heart increases so too does myocardial oxygen consumption. Although cardiac muscle hypertrophy, initially at least, can be regarded as a beneficial compensatory mechanism, with time, the hypertrophied muscle becomes deprived of oxygen as the blood supply fails to keep pace with muscle growth. The development of pulmonary venous congestion and oedema may result in hypoxia and further embarrassment of left ventricular function. An ischaemic myocardium is more susceptible to arrhythmias which may also adversely affect cardiac output.
Vascular adaptation to sustained neurohormonal activation in heart failure includes an increase in the responsiveness of systemic blood vessels to alpha1-adrenoceptor stimulation. Structural changes in the walls of the blood vessels (due to sodium and water retention) occur in chronic heart failure and lead to a non-specific lack of response to vasodilator agents. More specifically. ANP production is reduced as described above and once released, it loses its ability to vasodilate peripheral vessels and reduce aldosterone release. In addition, release of endothelium-derived relaxing factor is reduced in human heart failure patients. Thus, the mutual amplification which occurs between neurohormonal mechanisms of RAAS and the sympathetic nervous system can occur virtually unopposed resulting in vasoconstriction. In humans, heart failure results in increased circulating levels of endothelin, a locally active peptide mediator If produced in excess it is thought that endothelin may have widespread vasoconstrictor effects. Similar increases have been documented in dogs with heart failure, the highest levels occurring in dogs with atrial fibrillation.
With the decrease in ANP production and the loss of sensitivity of the kidney to its effects, the salt-retaining activities of the RAAS proceed unopposed.