Evaluation and management of diastolic heart failure.
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Aged↗
Biomedical subjects
William Grossman
Publications and source records attributed to William Grossman.
The alpha(1A/C)- and alpha(1B)-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse.
Catecholamines and alpha(1)-adrenergic receptors (alpha(1)-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main alpha(1)-AR subtypes, alpha(1A/C) and alpha(1B). Here we tested whether alpha(1)-ARs are required for developmental cardiac hypertrophy by generating alpha(1A/C) and alpha(1B) double KO (ABKO) mice, which had no cardiac alpha(1)-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. alpha(1)-AR stimulation did not activate extracellular signal-regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, alpha(1)-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress.
Animals↗
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.
Angiotensin I↗
Left ventricular systolic unloading and augmentation of intracoronary pressure and Doppler flow during enhanced external counterpulsation.
BACKGROUND: Enhanced external counterpulsation (EECP) is a noninvasive, pneumatic technique that provides beneficial effects for patients with chronic, symptomatic angina pectoris. However, the physiological effects of EECP have not been studied directly. We examined intracoronary and left ventricular hemodynamics in the cardiac catheterization laboratory during EECP. METHODS AND RESULTS: Ten patients referred for diagnostic evaluation underwent left heart catheterization and coronary angiography from the radial artery. At baseline and then during EECP, central aortic pressure, intracoronary pressure, and intracoronary Doppler flow velocity were measured using a coronary catheter, a sensor-tipped high-fidelity pressure guidewire, and a Doppler flow guidewire, respectively. Similar to changes in aortic pressure, EECP resulted in a dramatic increase in diastolic (71+/-10 mm Hg at baseline to 137+/-21 mm Hg during EECP; +93%; P<0.0001) and mean intracoronary pressures (88+/-9 to 102+/-16 mm Hg; +16%; P=0.006) with a decrease in systolic pressure (116+/-20 to 99+/-26 mm Hg; -15%; P=0.002). The intracoronary Doppler measure of average peak velocity increased from 11+/-5 cm/s at baseline to 23+/-5 cm/s during EECP (+109%; P=0.001). The TIMI frame count, a quantitative angiographic measure of coronary flow, showed a 28% increase in coronary flow during EECP compared with baseline (P=0.001). CONCLUSIONS: EECP unequivocally and significantly increases diastolic and mean pressures and reduces systolic pressure in the central aorta and the coronary artery. Coronary artery flow, determined by both Doppler and angiographic techniques, is increased during EECP. The combined effects of systolic unloading and increased coronary perfusion pressure provide evidence that EECP may serve as a potential mechanical assist device.
Adult↗
Angiogenesis.
Several clinical trials of therapeutic angiogenesis in patients with coronary artery disease have shown clinical improvement and provided some objective evidence of improved perfusion and left ventricular function. Larger-scale, placebo-controlled trials, as well as studies of combinations of growth factors and the use of endothelial progenitor-cell or stem-cell supplementation, are in progress. Revascularization of ischemic myocardium with angiogenic compounds and without the mechanical manipulation of atherosclerotic vessels has great potential in the treatment of coronary artery disease. If it is proven to be both safe and efficacious, the revascularization of tissue biologically via medical or gene therapy will be a major advance in the treatment of patients with a diffuse disease that is not amenable to conventional therapy and in the augmentation of revascularization in patients undergoing traditional surgical therapies.
Coronary Artery Disease↗