Number 20, 2003
Hibernation preconditioning

Featured research

Abstracts and commentaries

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Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial
Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine Investigators Group. Circulation. 2003;107;817–823.

Heart rate reduction should benefit patients with chronic stable angina by improving myocardial perfusion and reducing myocardial oxygen demand. This study evaluated the antianginal and anti-ischemic effects of ivabradine, a new heart rate-lowering agent that acts specifically on the sinoatrial node. In a double-blind, placebo-controlled trial, 360 patients with a ³3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg bid) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg bid) and a 1-week randomized withdrawal to ivabradine (10 mg bid) or placebo. Primary efficacy criteria were changes in time to 1-mm ST-segment depression and time to limiting angina during bicycle exercise (exercise tolerance tests), performed at trough of drug activity. In the per-protocol population (n = 257), time to 1-mm ST-segment depression increased in the 5- and 10-mg bid groups (P < 0.005); time to limiting angina increased in the 10-mg bid group (P < 0.05). Deterioration in all exercise tolerance test parameters occurred in patients who received placebo during randomized withdrawal (all P < 0.02) but not in those still receiving ivabradine. No rebound phenomena were observed on treatment cessation. Ivabradine produces dose-dependent improvements in exercise tolerance and time to development of ischemia during exercise. These results suggest that ivabradine, representing a novel class of antianginal drugs, is effective and safe during 3 months of use; longer term safety requires additional assessment.

Commentary
Ivabradine is a member of a new class of drugs that selectively act on the sinoatrial node slowing heart rate, which should benefit patients with stable angina by improving diastolic filling and myocardial perfusion. Ivabradine inhibits the hyperpolarization-activated, mixed sodium/potassium inward If current which significantly influences sinoatrial node pacemaker activity. There is no effect on myocardial contractility.
This study of 360 patients with chronic stable angina compared ivabradine 2.5, 5, or 10 mg twice daily with placebo. Bicycle exercise tests allowed comparisons of time to 1-mm ST-segment depression and time to limiting angina. Dose-dependent improvement in exercise tolerance and time to ischemia were recorded and no rebound occurred on drug cessation. b-Blockers, calcium antagonists and long-acting nitrates were discontinued, indicating the stability of the population. Visual adverse effects were the only significant problem, probably due to the presence of retinal ion channels similar to those of If.
Ivabradine is interesting because of its specific action identifying a possible role where b-blockers and calcium antagonists are contraindicated or cause adverse effects. More data are needed regarding long-term safety.

Graham Jackson

Exercise-induced ischemia initiates the second window of protection in humans independent of collateral recruitment
Lambiase PD, Edwards RJ, Cusack MR, Bucknall CA, Redwood SR, Marber MS. J Am Coll Cardiol. 2003;41:1174–1182.
This study was designed to examine whether exercise-induced ischemia initiated late preconditioning in humans that becomes manifest during subsequent exercise and serial balloon occlusion of the LAD. The existence of late preconditioning in humans is controversial. We therefore compared myocardial responses to exercise-induced and intracoronary balloon inflation-induced ischemia in two groups of patients subjected to different temporal patterns of ischemia. Thirty patients with stable angina secondary to single-vessel LAD disease underwent percutaneous coronary intervention (PCI) after two separate exercise tolerance test protocols designed to investigate isolated early preconditioning (IEP) alone or the second window of protection (SWOP). The IEP subjects underwent three sequential exercise tests at least 2 weeks before PCI. The SWOP subjects underwent five sequential exercise tests commencing 24 hours before PCI. During PCI there was no significant difference in intracoronary pressure-derived collateral flow index between groups (IEP = 0.15 ± 0.13, SWOP = 0.19 ± 0.15). In SWOP patients, compared with the initial exercise test, the exercise test performed 24 hours later had a 40% (P < 0.001) increase in time to 0.1-mV ST-segment depression and a 60% (P < 0.05) decrease in ventricular ectopic frequency. During the first balloon inflation, peak ST-segment elevation was reduced by 49% (P < 0.05) in the SWOP versus the IEP group, and the dependence on collateral flow index observed in the IEP group was abolished (analysis of covariance, P < 0.05). The significant attenuation of ST-segment elevation (47%, P < 0.005) seen at the time of the second inflation in the IEP patients was not seen in the SWOP patients. Exercise-induced ischemia triggers late preconditioning in humans, which becomes manifest during exercise and PCI. This is the first evidence that ischemia induced by coronary occlusion is attenuated in humans by a late preconditioning effect induced by exercise.

Commentary
As discussed in this issue of Heart and Metabolism the heart is able to adapt to short episodes of ischemia by a number of different mechanisms. These mechanisms include the growth of myocardial collaterals and preconditioning. Whilst the presence of myocardial collaterals in the human heart has been documented for centuries, preconditioning was only recognized 15 years ago. In addition, this initial observation was made in dogs. Since the recognition of the laboratory phenomenon of preconditioning a number of studies have sought to determine whether similar findings are seen in the human heart. The occurrence of an early form, or first window, of preconditioning in the human heart was recognized by Yellon et al during cardiopulmonary bypass. The manuscript by Lambiase et al is the first demonstration of a similar phenomenon during the short periods of ischemia that accompany percutaneous coronary intervention. These authors used a pressure-sensing coronary guidewire to derive collateral myocardial blood flow from distal coronary balloon occlusion pressure, coronary sinus pressure, and aortic root pressure. Using these measures they showed that for a given collateral flow, chest pain and ST-segment elevation were less pronounced during balloon occlusion that was preceded by five periods of exercise over a 24-hour period. This finding suggests that there is a second window of cardiac protection in the human heart. One drawback of the study design is that it is not certain how long it takes for this form of protection to appear. Similarly it is not known how long the protection lasts. However, the timing of the onset of protection is entirely in keeping with the interval between last angina and improved prognosis during AMI seen in TIMI 4 [1]. This, together with other in vitro models using human cells/tissue, makes it increasingly likely that late preconditioning is clinically relevant.
However, in an analogous manner to early preconditioning, in order to harness the benefits for patients it becomes necessary to understand the underlying mechanisms. Ultimately this knowledge would be required to avoid the need to initiate protection by inducing myocardial ischemia and to prolong protection so that patients are protected during spontaneous acute coronary episodes. Despite almost two decades of intensive research activity into the mechanisms underlying early and late preconditioning, which have resulted in over 2000 full manuscripts, we seem no nearer a consensus as to how these forms of protection are mediated. There is no doubt the phenomena are interesting and clinically relevant, but in my mind there is considerably more doubt as to whether they can be harnessed to benefit patients. Manuscripts such as that by Lambiase et al suggest that it is important not to give up trying.

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