Chronic skeletal muscle ischemia preserves coronary flow in the ischemic rat heart.

Chronic skeletal muscle ischemia confers cytoprotection to the ventricular myocardium during infarction, but the underlying mechanisms remain unclear. Although neovascularization in the left ventricular myocardium has been proposed as a possible mechanism, the functional capacity of such vessels has not been studied. We examined the effects of chronic limb ischemia on infarct size, coronary blood flow, and left ventricular function after ischemia-reperfusion. Hindlimb ischemia was induced in 65 Wistar rats by excision of the left femoral artery, whereas 65 rats were sham operated. After 4 wk, myocardial infarction was generated by permanent coronary artery ligation. Infarct size was measured 24 h postligation. Left ventricular function was evaluated in isolated hearts after ischemia-reperfusion, 4 wk after limb ischemia. Neovascularization was assessed by immunohistochemistry, and coronary flow was measured under maximum vasodilatation at different perfusion pressures before and after coronary ligation. Infarct size was smaller after limb ischemia compared with controls (24.4 ± 8.1% vs. 46.2 ± 9.5% of the ventricle and 47.6 ± 8.7% vs. 80.1 ± 9.3% of the ischemic area, respectively). Indexes of left ventricular function at the end of reperfusion (divided by baseline values) were improved after limb ischemia (developed pressure: 0.68 ± 0.06 vs. 0.59 ± 0.05, P = 0.008; maximum +dP/dt: 0.70 ± 0.08 vs. 0.59 ± 0.04, P = 0.004; and maximum -dP/dt: 0.86 ± 0.14 vs. 0.72 ± 0.10, P = 0.041). Coronary vessel density was markedly higher (P = 0.00021) in limb ischemic rats. In contrast to controls (F = 5.65, P = 0.00182), where coronary flow decreased, it remained unchanged (F = 1.36, P = 0.28) after ligation in limb ischemic rats. In conclusion, chronic hindlimb ischemia decreases infarct size and attenuates left ventricular dysfunction by increasing coronary collateral vessel density and blood flow.

Chronic skeletal muscle ischemia in rats decreases the inducibility of ventricular tachyarrhythmias after myocardial infarction.

BACKGROUND: Chronic hind-limb ischemia confers cytoprotection after coronary occlusion, but it is unclear whether it ameliorates substrate formation for ventricular tachyarrhythmias (VTs). MATERIALS AND METHODS: Chronic hind-limb ischemia was generated by femoral artery excision in 50 rats, while 25 animals were sham-operated. Left coronary artery ligation was performed after 3 weeks and infarct size was measured 24 hours thereafter. The inducibility of VTs was assessed by programmed electrical stimulation (PES) 4 weeks post-ligation. A score was assigned, based on protocol stage and tachyarrhythmia duration. Monophasic action potentials (MAP) were recorded prior to and 4 weeks after ligation. RESULTS: The infarct size was smaller (p=0.000079) in the ischemic rats (25.7±2.1%) than in the controls (41.7±2.2%), accompanied by a lower (p=0.029) arrhythmia score (1.05±0.38 versus 2.70±0.68, respectively). The action potential duration (APD) was shorter (p<0.05) in the ischemic rats prior to ligation and remained stable after 4 weeks. CONCLUSION: Chronic hind limb ischemia limits infarct size and decreases inducible ventricular tachyarrhythmias.

Dose-dependent effects of sildenafil on post-ischaemic left ventricular function in the rat isolated heart.

OBJECTIVES: Sildenafil may be beneficial during myocardial ischaemia/reperfusion, but this effect may be dose-dependent, accounting for previous conflicting results. We have explored the effects of two acute and one chronic administration regimen on left ventricular function. METHODS: The study was conducted on 36 Wistar rats (290 +/- 7 g). Sildenafil was administered 30 min before ischaemia at a low (0.7 mg/kg, n= 8) or high (1.4 mg/kg, n= 8)dosage. The chronic treatment arm (n= 8) consisted of two daily injections of sildenafil (0.7 mg/kg) for three weeks. The control group was formed by 12 rats. Ischaemic contracture, post-ischaemic recovery and hypercontracture were measured in isolated, Langendorff-perfused preparations. KEY FINDINGS: Ischaemic contracture tended to be lower after high-dose sildenafil, while remaining unchanged after low-dose or chronic sildenafil administration. Compared with controls (62.9 +/- 2.0% of baseline developed pressure), post-ischaemic recovery was higher (P= 0.0069) after low dose (75.1 +/- 2.4%), unchanged (P= 0.13) after high dose (69.1 +/- 2.1%), but lower (P < 0.001) after chronic (42.9 +/- 4.5%) sildenafil administration. Compared with controls (71.8 +/- 3.9 mmHg), hypercontracture was higher (P= 0.0052) after chronic sildenafil administration (89.5 +/- 4.1 mmHg), but similar after acute low dose (65.7 +/- 3.3 mmHg, P= 0.33) or high dose (67.1 +/- 4.7 mmHg, P= 0.43). CONCLUSIONS: The effects of sildenafil after ischaemia/reperfusion were strongly dose-dependent. Beneficial actions on left ventricular function were evident after acute pretreatment with a low dosage, but were lost after doubling the dose. Chronic sildenafil administration deteriorated left ventricular function during ischaemia and reperfusion.

Does sildenafil cause myocardial infarction or sudden cardiac death?

Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. In this paper, we review the current knowledge of the effects of sildenafil on myocardial infarction and sudden cardiac death. The first factor we examine is the sexual activity itself. As several studies have shown, the relative risk for an acute coronary syndrome during intercourse is not very high. Several studies examining the effects of sildenafil on mortality have been published during recent years. The great majority of these studies found that sildenafil is not an extra risk factor for an acute coronary syndrome or sudden cardiac death. In 1997, the rate of myocardial infarction in men 55-64 years of age was 1542 per 1,000000 in the US. According to this, the expected number of deaths as a result of myocardial infarction in patients 55-64 years of age receiving sildenafil, in the 24-hour period after use, from late March 1997 to mid November 1998, should have been 52. Instead, the number of reported deaths were only 15. One very optimistic finding was that sildenafil not only does not increase mortality, but in fact 'preconditions' the heart and has a cardioprotective effect. Besides, many studies have shown that sildenafil does not reduce the exercise tolerance in men with known coronary artery disease. As far as BP is concerned, the differences before and after the use of sildenafil are not clinically significant. The only contraindications for sildenafil are co-administration with alpha-adrenoceptor antagonists or with nitric oxide donors. According to the most recent studies, isoform 5 of phosphodiesterase has also been detected in the myocardium and controls the soluble pool of 3', 5'-cyclic guanosine monophosphate (cGMP). Sildenafil is very specific for cGMP but it may increase cyclic adenosine monophosphate in the myocardium indirectly. This does not occur with small therapeutic doses of the drug. There is some dispute regarding the association of sildenafil with arrhythmias, where the available evidence is not clear. However, there are suspicions that sildenafil may cause sympathetic activation. The overall conclusion is that sildenafil is a safe drug and that its appropriate use does not seem to increase the risk for myocardial infarction or sudden cardiac death.

Acute coronary syndromes in the elderly.

The elderly constitute an increasingly important sector of patients with acute coronary syndromes (ACS), although they have been under-represented in many therapeutic trials. Elderly patients with ACS usually have more complex co-morbidities and worse outcomes than their younger counterparts, and they are less likely to undergo revascularisation or to receive short- and long-term evidence-based medications. The most common ACS in the elderly is non-ST-segment elevation myocardial infarction (STEMI), which is associated with high mortality. For this reason, elderly patients with non-STEMI and unstable angina should be treated invasively early in the course of the episode. In elderly patients with STEMI, primary angioplasty seems to be more effective than fibrinolysis, and in patients aged >85 years a more conservative approach to fibrinolysis is also warranted because of the higher risk for cerebral haemorrhage. Therefore, angioplasty should be preferred when feasible, although more trials are needed before this strategy can definitely be documented as the preferred option. Drug-eluting stents afford greater benefit than bare metal stents in elderly patients and are more cost effective. After fibrinolysis, low-molecular-weight heparin appears to be superior to unfractionated heparin in elderly patients with STEMI but major bleeding and intracranial haemorrhages occur more frequently, especially in women aged >75 years. It is very important to understand that the elderly with ACS constitute a subgroup of atherosclerotic patients for whom decision making must be guided by the patients''physiological age' (determined by their physical condition and other co-morbidities) and not strictly by their 'chronological age'.

Cardiac troponin I in patients with acute lower limb ischemia.

The presence, cause, and clinical significance of elevated cardiac troponin I in patients with acute lower limb ischemia is yet unknown. Forty-six patients (20 men [43%]; mean age 72 +/- 10 years, range 42 to 92) with acute lower limb ischemia were enrolled in this study. Serial creatine kinase (CK), CK isoenzyme MB (CK-MB), and troponin I measurements were obtained in all consecutive patients. Peak levels were evaluated for each patient. Twenty-four patients (52%) had elevated peak troponin I levels (>0.2 ng/ml) during their hospitalization. Patients were divided into 3 groups according to their peak troponin I levels: 11 patients (24%) had peak troponin I levels >1 ng/ml (the high troponin I group), 13 (28%) had levels of 0.2 to 1 ng/ml (the intermediate troponin I group), and the remaining 22 (48%) had peak troponin I levels <0.2 ng/ml (the low troponin I group). The peak CK levels were 10,263 +/- 16,513, 1,294 +/- 1,512, and 934 +/- 1,045 IU/ml (p = 0.04) in the 3 different troponin I subgroups, respectively, and the peak CK-MB levels were 143 +/- 170, 38 +/- 31, and 38 +/- 43, respectively (p = 0.04). Troponin I was positively correlated with CK (R = 0.35, p = 0.017) and CK-MB (R = 0.38, p = 0.009). The mean length of hospitalization was 8.3 +/- 6.2 days for the whole study group and did not vary among the 3 troponin I groups (10.5 +/- 10.9 vs 8.6 +/- 4.9 vs 7.2 +/- 4.0 days, p = 0.762). There were no differences in mortality during hospitalization among the 3 groups (4 of 11 vs 1 of 13 vs 4 of 22 patients, p = 0.22). In conclusion, patients with acute lower limb ischemia often have elevated cardiac troponin I levels. Elevated troponin I levels were not associated with the duration of hospitalization or with in-hospital mortality in this group of patients.