Roche

Abstract

T Lüscher

Thomas F Lüscher is Head of Cardiology at the University Hospital, Zürich, Switzerland, and Professor of Cardiology at the same university. Professor Lüscher leads a research group with special interest in vascular disease, endothelial factors and atherosclerosis. He is a prolific author, and has published many research papers and review articles in peer-reviewed journals.

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The role of peripheral resistance

T Lüscher (Zürich, Switzerland)

Cardiovascular homeostasis is regulated by the adrenergic nervous system, which is instrumental in determining systemic vascular tone, heart rate and myocardial contractility. Norepinephrine, the major neurotransmitter of the adrenergic nervous system, acts on a family of G-protein-coupled adrenergic receptors that couple to a number of signalling pathways. Norepinephrine stimulation of a₁, ß₁ and ß₂ adrenergic receptors in the myocardium influences cell growth, gene expression and apoptosis, and therefore exerts profound effects on the structure and function of the heart. It also importantly acts on peripheral vasculature, mediating increases in peripheral vascular resistance and changes in organ blood flow.

Although the primary defect in heart failure is systolic and/or diastolic dysfunction of the left ventricle with reduced cardiac output, increased peripheral vascular resistance is increasingly being recognised as a crucial factor in the pathophysiology of heart failure and as a target for therapy. These increases in resistance are mediated by neurohormonal adaptive mechanisms involving an increased activity of the sympathetic nervous system, as well as endothelin, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Increased peripheral resistance augments cardiac afterload, placing further strain on the failing left ventricle and enhancing the process of cardiac remodelling. Furthermore, decreased renal perfusion as a result of sympathetically-mediated vasoconstriction results in a reduction in glomerular filtration rate, enhancing salt and water retention and leading to worsening heart failure and in turn to peripheral and pulmonary congestion and oedema. This issue is particularly pertinent given the frequency of renal dysfunction and significant renovascular disease in patients with heart failure, many of whom are elderly. ¹

In addition to these haemodynamic effects, increases in peripheral resistance have also been implicated in negative effects on glucose and lipid metabolism seen in patients with hypertension and heart failure. ^2,3 Decreases in peripheral blood flow lead to a decrease in glucose uptake by the skeletal muscle, resulting in raised blood glucose levels. This creates a hyperinsulinaemic state, resulting in downregulation of insulin receptors and increased insulin resistance. ² The independent vasodilatory effect induced by insulin is also blunted in the insulin-resistant state. ³

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