Pathophysiology of heart failure.

1 The pathophysiological definition of heart failure states that " cardiac failure is an inability of the heart to deliver blood (and therefore oxygen) at a rate commensurate with the requirements of the metabolising tissues at rest or during light exercise. This leads to characteristic systemic pathophysiological responses (neural, hormonal, renal and others), symptoms and signs.'' However, there is now good agreement that heart failure is not simply associated with a loss of contractile cardiac muscle, but that it is more importantly the consequence of alterations of signal transduction and of defects in regulation of force of contraction. Alterations of β adrenergic regulation of cardiac contraction The loss of pump function in the early stages of heart failure results in neurosympathetic activation characterised by increased concentrations of noradrenaline and angiotensin II in the blood. The resulting vasoconstriction increases afterload, and their neuroendocrine effects on the kidney increases preload (fig 1). Within the myocardial cells themselves, sympathetic activation downregulates β adrenoceptors, it increases G proteins and thereby reduces intracellular cAMP concentrations. 2 Recent investigations have shown that these effects are accompanied by decreased concentrations of the mRNA that forms β 1 adrenoceptors, and by increased concentrations of the mRNA that forms β adreno-ceptor kinase (fig 2). At the biochemical level there is a reduced density of β 1 adrenoceptors in the myocardial cell membrane, and a twofold increase in the concentration of β adrenocep-tor kinase. 3 The net outcome is that the β adrenoceptor adenyl cyclase system is changed in a way that protects the cell from constant stimulation by noradrenaline. It has long been recognised that therapeutic interventions that increase intracellular cAMP long term, such as the β adrenoceptor agonists (dobutamine), partial agonists (xamoterol) or phosphodiesterase inhibitors (milrinone), are associated with a poor prognosis. It is therefore possible to speculate that the most appropriate treatment might be to administer positive inotropic agents in an attempt to overcome the defects in myocyte signal transduc-tion, and that drugs that increase intracellular cAMP should be avoided. Alterations of intracellular calcium homeostasis Beuckelmann et al have reported that the action potential duration is increased in human heart failure. 4 5 This is the consequence of a slower reuptake of calcium by the sar-coplasmic reticulum (SR) during diastole. Recent studies have demonstrated that patients with heart failure have normal protein concentrations of SERCA II and phospholam-ban, but myocardial calcium uptake and calcium ATPase activity within …