Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of primary, spontaneous cardiac pacemaker activity of the sinoatrial node (SAN) has extensively been studied in several animal species, but is virtually unexplored in man. Understanding the mechanisms of human SAN pacemaker activity is important for developing new therapeutic approaches for controlling the heart rate in the sick sinus syndrome and in diseased myocardium. Here we review the functional role of the hyperpolarization-activated 'funny' current, I(f), in human SAN pacemaker activity. Despite the many animal studies performed over the years, the contribution of I(f) to pacemaker activity is still controversial and not fully established. However, recent clinical data on mutations in the I(f) encoding HCN4 gene, which is thought to be the most abundant isoform of the HCN gene family in SAN, suggest a functional role of I(f) in human pacemaker activity. These clinical findings are supported by recent experimental data from single isolated human SAN cells that provide direct evidence that I(f) contributes to human SAN pacemaker activity. Therefore, controlling heart rate in clinical practice via I(f) blockers offers a valuable approach to lowering heart rate and provides an attractive alternative to conventional treatment for a wide range of patients with confirmed stable angina, while upregulation or artificial expression of I(f) may relieve disease-causing bradycardias.
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PMID:Pacemaker activity of the human sinoatrial node: role of the hyperpolarization-activated current, I(f). 1918 6

Hyperpolarization-activated cation channels generate the I(f) current in the heart. In the sino-atrial node (SAN), I(f) is thought to play an essential role in setting the heart rate and mediating its autonomic control. This review focuses on the role of I(f) in pacemaking and non-pacemaking cardiomyocytes and the resulting therapeutic implications. HCN4 represents the principal isoform underlying sino-atrial I(f) , but other isoforms may also be of importance. To examine the functional role of cardiac channels, several mouse mutants, most of them targeting HCN4, have been generated by different groups. Unexpectedly, these lines display greatly different and as yet unexplained phenotypes. We provide an overview about these HCN mutants and suggest an interpretation of the functional significance of I(f) in the SAN in light of these studies. HCN channels are also present in ventricular myocytes, and an up-regulation of I(f) in the hypertrophic and failing heart may contribute to arrhythmogenesis. Inhibition of I(f) by HCN channel blockers is a novel approach in the treatment of cardiac disorders, and ivabradine is approved for treatment of stable angina pectoris. Remarkably, a recent clinical trial assessing this substance in heart failure showed a significantly improved outcome. The mechanism underlying this beneficial effect is not yet clear and might lie beyond heart rate slowing. Thus, the growing knowledge about cardiac HCN channels will undoubtedly promote the development of the promising class of HCN channel blockers.
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PMID:HCN channels in the heart: lessons from mouse mutants. 2214 57