Acute neurocardiogenic injury after subarachnoid hemorrhage.

BACKGROUND: Left ventricular (LV) systolic dysfunction has been reported in humans with subarachnoid hemorrhage (SAH), and its underlying pathophysiology remains controversial. Possible mechanisms include myocardial ischemia versus excessive catecholamine release from sympathetic nerve terminals. METHODS AND RESULTS: For 38 months, echocardiography and myocardial scintigraphy with technetium sestamibi (MIBI) and meta-[(123)I]iodobenzylguanidine (MIBG) were performed on 42 patients admitted with SAH to assess myocardial perfusion and sympathetic innervation, respectively. A blinded observer interpreted the scintigraphic images. Cardiac troponin I (cTI) was measured to quantify the degree of myocyte necrosis. Blinded observers calculated the LV ejection fraction and graded each LV segment as normal (score=1), hypokinetic (score=2), or akinetic (score=3). A wall-motion score was calculated by averaging the sum of the 16 segments. All subjects with interpretable scans (N=41) had normal MIBI uptake. Twelve subjects had either global (n=9) or regional (n=3) absence of MIBG uptake. In comparison with patients with normal MIBG uptake, those with evidence of functional denervation were more likely to have LV regional wall-motion abnormalities (92% versus 52%, P=0.030) and cTI levels >1 microg/L (58% versus 21%, P=0.029). CONCLUSIONS: LV systolic dysfunction in humans with SAH is associated with normal myocardial perfusion and abnormal sympathetic innervation. These findings may be explained by excessive release of norepinephrine from myocardial sympathetic nerves, which could damage both myocytes and nerve terminals.

Treating heart failure with enhanced external counterpulsation (EECP): design of the Prospective Evaluation of EECP in Heart Failure (PEECH) trial.

BACKGROUND: Enhanced external counterpulsation (EECP) treatment can improve exercise tolerance in patients with ischemic heart disease; however, the possible benefits of EECP in patients with stable heart failure (HF) and left ventricular dysfunction (LVD) are unclear. An open pilot study showed significant increases in exercise tolerance in HF patients undergoing EECP. Thus a larger, controlled study of EECP in patients with stable HF (New York Heart Association [NYHA] classes II and III) and LVD was undertaken. METHODS AND RESULTS: The PEECH trial is a controlled, randomized, single-blind, parallel-group, multicenter study of 187 patients with symptomatic but stable HF (NYHA classes II and III) and an LV ejection fraction < or =35% was designed to assess the efficiency of EECP in patients with stable HF. Medical therapy is optimized in all patients based on the recommendations of the Heart Failure Society of America ("Usual Care"), and then randomized between 2 treatment groups; UC or EECP (35 hours over 7 weeks). CONCLUSION: Efficacy measures include standard exercise tolerance tests on a treadmill (modified Naughton protocol), with measurements of peak oxygen uptake and exercise duration time; quality of life questionnaires; NYHA classification; and neurohormonal markers of HF.

A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial.

CONTEXT: Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients, safety and efficacy of antihypertensive agents for coronary artery disease (CAD) have been discerned only from subgroup analyses in large trials. OBJECTIVE: To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (CAS) or a non-calcium antagonist strategy (NCAS). DESIGN, SETTING, AND PARTICIPANTS: Randomized, open label, blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older, which was conducted September 1997 to February 2003 at 862 sites in 14 countries. INTERVENTIONS: Patients were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). Strategies specified dose and additional drug regimens. Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of less than 140 mm Hg (systolic) and less than 90 mm Hg (diastolic); and less than 130 mm Hg (systolic) and less than 85 mm Hg (diastolic) if diabetes or renal impairment was present. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. MAIN OUTCOME MEASURES: Primary: first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke; other: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pressure control at 24 months. RESULTS: At 24 months, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release; 4934 (62.9%) were taking trandolapril; and 3430 (43.7%) were taking hydrochlorothiazide. In the NCAS group, 6083 patients (77.5%) were taking atenolol; 4733 (60.3%) were taking hydrochlorothiazide; and 4113 (52.4%) were taking trandolapril. After a follow-up of 61 835 patient-years (mean, 2.7 years per patient), 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90-1.06). Two-year blood pressure control was similar between groups. The JNC VI blood pressure goals were achieved by 65.0% (systolic) and 88.5% (diastolic) of CAS and 64.0% (systolic) and 88.1% (diastolic) of NCAS patients. A total of 71.7% of CAS and 70.7% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg. CONCLUSION: The verapamil-trandolapril-based strategy was as clinically effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients.

Second hand smoke stimulates tumor angiogenesis and growth.

Exposure to second hand smoke (SHS) is believed to cause lung cancer. Pathological angiogenesis is a requisite for tumor growth. Lewis lung cancer cells were injected subcutaneously into mice, which were then exposed to sidestream smoke (SHS) or clean room air and administered vehicle, cerivastatin, or mecamylamine. SHS significantly increased tumor size, weight, capillary density, VEGF and MCP-1 levels, and circulating endothelial progenitor cells (EPC). Cerivastatin (an inhibitor of HMG-coA reductase) or mecamylamine (an inhibitor of nicotinic acetylcholine receptors) suppressed the effect of SHS to increase tumor size and capillary density. Cerivastatin reduced MCP-1 levels, whereas mecamylamine reduced VEGF levels and EPC. These studies reveal that SHS promotes tumor angiogenesis and growth. These effects of SHS are associated with increases in plasma VEGF and MCP-1 levels, and EPC, mediated in part by isoprenylation and nicotinic acetylcholine receptors.

Comparative effects of aspirin with ACE inhibitor or angiotensin receptor blocker on myocardial infarction and vascular function.

OBJECTIVES: We previously showed that an angiotensin-converting enzyme inhibitor (captopril) or an angiotensin receptor blocker (losartan) reduced infarct size and improved endothelial function in a rat model of ischaemia-reperfusion. The present study was undertaken to see if aspirin (ASA) antagonised the beneficial effects of captopril or losartan. METHODS: One hundred and fourteen Sprague-Dawley rats were randomised into six groups; Control, ASA, captopril, losartan, ASA+captopril, and ASA+losartan. ASA, captopril or losartan were given at a concentration of 40 mg/kg/day in drinking water. After six weeks of pre-treatment, the rats were subjected to 17 minutes of left anterior descending coronary artery occlusion and 120 minutes of reperfusion, with haemodynamic and ECG monitoring. During the reperfusion period, the effective refractory period (ERP), ventricular fibrillation threshold (VFT) and bleeding time (BT) were measured. In fresh aortic rings precontracted with phenylephrine, endothelium-dependent and -independent relaxations were assessed using acetylcholine and nitroglycerin. RESULTS: Haemodynamic changes were not different between the groups. Serum ASA concentrations were 0.5, 1.1 and 0.6 mg/dl in the ASA, ASA+captopril and ASA+losartan groups, respectively, and BT was prolonged (p<0.01). ASA alone reduced endothelium-dependent relaxation (-29+8 vs. -69+11%, p<0.01), but did not change endothelium-independent relaxation. ASA did not affect endothelial relaxation induced by acetylcholine in the presence of either captopril or losartan. Angiotensin I and ERP were elevated by captopril and losartan. Angiotensin II and VFT were elevated by losartan. ASA with captopril, captopril and losartan equally reduced infarct size, compared with control (39+3, 39+4, and 39+5 vs. 53+3%, all p<0.05). CONCLUSIONS: Captopril and losartan had similar cardiovascular protective effects in a rat model of ischaemia-reperfusion. Aspirin did not attenuate the cardiovascular protective effects of captopril or losartan.

The renin-angiotensin system does not contribute to the endothelial dysfunction and increased infarct size in rats exposed to second hand smoke.

INTRODUCTION: Both second hand smoke (SHS) and the renin-angiotensin system (RAS) contribute to endothelial dysfunction and increased infarct size in a rat ischaemia-reperfusion model. However, the potential interaction between SHS and the RAS is unknown. METHODS: Eighty-four rats were randomised into four groups: group C was a normal control; L was given 40 mg/kg/day of losartan in drinking water; SC and SL were exposed to SHS (smoking chamber) and given regular water or 40 mg/kg/day of losartan in drinking water, respectively. After six weeks of pre-treatment, rats were subjected to 17 minutes of left coronary artery occlusion and 2 hours of reperfusion with haemodynamic and ECG monitoring. RESULTS: Haemodynamics were not significantly different among the four groups. Losartan increased the threshold for ventricular fibrillation (p=0.0001) and reduced spontaneous ventricular arrhythmias (p=0.002) during ischaemia-reperfusion, while SHS did not (p=0.713, 0.110), and there was no interaction between losartan and SHS. The maximal endothelium-dependent vasorelaxation induced by a calcium ionophore (A23187) was increased by losartan (p=0.007). Myocardial infarct size was smaller in the losartan groups (p=0.032), larger in the SHS groups (p=0.0001), and there was no significant interaction. CONCLUSION: In conclusion, losartan decreased infarct size and increased endothelium-dependent vasorelaxation. SHS exposure impaired endothelial function and increased infarct size. The effects of losartan and SHS were consistently independent of each other. These results suggest that the RAS does not contribute to the adverse effects of SHS.