Background: The effect of spironolactone on clinical outcomes in patients with mild heart failure is unclear.Methods and Results: We performed a retrospective analysis of 482 consecutive patients with left ventricular ejection fraction <= 40% and New York Heart Association I-II symptoms. Major cardiac event (MCE) was defined as death, left ventricular assist device implantation, or United Network of Organ Sharing 1 cardiac transplantation. Proportional hazards analysis was used to determine predictors of MCE and to derive an adjusted hazard for spironolactone therapy. Spironolactone was prescribed to 279 (58%) patients and mean follow-up was 1029 days. After controlling for predictors of clinical events, spironolactone treatment was associated with a trend for lower risk of MCE or heart failure rehospitalization (HR, 0.68; 95% CI, 0.43-1.07; P = .095). Exploration of interaction terms between medications revealed that treatment with the combination of spironolactone and thiazide diuretics was associated with lower risk of clinical events (HR, 0.32; 95% CI, 0.12-0.89; P = .029).Conclusion: In subjects with mild heart failure treated with a thiazide diuretic, the use of spironolactone is associated with reduced risk of MCE or heart failure rehospitalization. A randomized controlled trial is necessary to accurately define the clinical effects of spironolactone in patients with mild heart failure.

BACKGROUND:Pravastatin and simvastatin prolong survival and reduce transplant-related coronary vasculopathy, although low-density lipoprotein (LDL) lowering with these agents is only modest. The objective of this study was to assess the safety of moderate dose atorvastatin and its efficacy when prior treatment with another statin had failed to lower LDL to < 100 mg/dl.METHODS:Data from 185 patients were retrospectively evaluated for adverse events, duration of exposure (person-days), and the mean atorvastatin dose exposure. Changes in lipid parameters, and prednisone and cyclosporine doses were determined.RESULTS:SAFETY:48 patients received atorvastatin for 24,240 person-days at a mean dose exposure of 21 +/- 10 mg. Rhabdomyolysis, myositis, myalgias, and hepatotoxicity occurred in 0, 2, 2, and 0 patients, respectively. All events occurred at the 10-mg dose, within the first 3 months, and were rapidly reversible with atorvastatin discontinuation.EFFICACY:Thirty-four patients evaluable for efficacy analyses had a pre-atorvastatin LDL of 145 +/- 38 mg/dl on the following statins: pravastatin (n = 30, 40 +/- 0mg), fluvastatin (n = 3, 33 +/- 12 mg), simvastatin (n = 1, 40 mg). After atorvastatin (21 +/- 9 mg/day) for 133 +/- 67 days, LDL was reduced to 97 +/- 24 mg/dl (relative reduction 31 +/- 20%, p < 0.0001). At the end of the observation period (418 +/- 229 days, atorvastatin final dose 24 +/- 14 mg/day), LDL was further decreased to 88 +/- 23 mg (relative reduction 37 +/- 17%, p < 0.0001).CONCLUSION:Atorvastatin, when used at moderate doses and with close biochemical and clinical monitoring, appears to be safe and is effective in aggressively lowering LDL in heart transplant recipients when treatment with other statins has failed to achieve LDL goals.

Neuregulins are a family of growth-promoting peptides known to be important in neural and mesenchymal tissue development. Targeted disruption of neuregulin (NRG)-1 or one of two of its cognate receptors, ErbB2 or ErbB4, results in embryonic lethality because of failure of the heart to develop. Although expression of NRGs and their receptors declines after midembryogenesis, both ErbB2 and ErbB4 are present in cardiac myocytes, and NRG-1 expression remains inducible in primary cultures of coronary microvascular endothelial cells from adult rat ventricular muscle. In neonatal rat ventricular myocytes, a soluble NRG-1, recombinant human glial growth factor-2, increased [3H]phenylalanine uptake and induced expression of atrial natriuretic factor (ANF) and sarcomeric F-actin polymerization. The effect of NRG-1 on [3H]phenylalanine uptake and sarcomeric F-actin polymerization was maximal at 20 ng/ml but declined at higher concentrations. NRG-1 activated p42/p44 mitogen-activated protein kinase (MAPK) [extracellular signal-regulated kinase (ERK)-2/ERK1] and ribosomal S6 kinase (RSK)-2 (90-kDa ribosomal S6 kinase), both of which could be inhibited by the MAPK/ERK kinase-1 antagonist PD-098059. NRG-1 also activated 70-kDa ribosomal S6 kinase, which was inhibited by either rapamycin or wortmannin. Activation of these pathways exhibited the same "biphasic" response to increasing NRG-1 concentrations. Wortmannin and LY-294002 blocked sarcomeric F-actin polymerization but not [3H]phenylalanine uptake or ANF expression, whereas PD-098059 consistently blocked both [3H]phenylalanine uptake and ANF expression but not actin polymerization. In contrast, rapamycin inhibited [3H]phenylalanine uptake and F-actin polymerization but not ANF expression. Thus NRG-ErbB signaling triggers multiple nonredundant pathways in postnatal ventricular myocytes.

BACKGROUND:Postprandial angina pectoris has been recognized for more than two centuries and can be identified in up to 10% of patients with chronic ischemic heart disease. Redistribution of myocardial blood flow, from a region supplied by a severely stenotic coronary artery to those supplied by less diseased or normal vessels, is a potential mechanism of postprandial angina.METHODS AND RESULTS:To test this hypothesis, we have determined the effects of a standard liquid meal on whole heart and regional myocardial blood flow, measured by means of dynamic positron emission tomography (PET) with 15O-labeled water in 14 patients with a reproducible history of postprandial angina and 7 matched control subjects. The standard liquid meal precipitated angina pectoris in all patients. Baseline whole heart blood flow was similar and increased normally after the meal in patients (0.97+/-0.14 to 1.14+/-0.25 mL.min(-1).g(-1), P<.04) as in control subjects (0.92+/-0.12 to 1.02+/-0.13 mL.min(-1).g(-1), P<.02). In contrast, the coefficient of variation of blood flow increased significantly after the standard liquid meal in patients (34+/-9%, P<.05 versus baseline) but not in control subjects (17+/-7%, P=NS versus baseline). In patients, analysis of regional myocardial blood flow demonstrated decreased myocardial blood flow in territories supplied by stenotic arteries (1.01+/-0.35 to 0.76+/-0.27 mL.min(-1).g(-1), P<.03), but there was an increase in blood flow in territories supplied by normal arteries (0.89+/-0.16 to 1.34+/-0.25 mL.min(-1).g(-1), P<.001) after the meal.CONCLUSIONS:The standard liquid meal induced angina pectoris in patients with coronary artery disease. Although whole heart blood flow increased appropriately for the greater cardiac work, there was a redistribution of regional blood flow from territories supplied by severely stenosed coronary arteries to those supplied by less diseased or normal arteries. This redistribution may be the cause of myocardial ischemia in postprandial angina.

Neuregulins (i.e. neuregulin-1 (NRG1), also called neu differentiation factor, heregulin, glial growth factor, and acetylcholine receptor-inducing activity) are known to induce growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells. Unexpectedly, mice with loss of function mutations of NRG1 or of either of two of their cognate receptors, ErbB2 and ErbB4, die during midembryogenesis due to the aborted development of myocardial trabeculae in ventricular muscle. To examine the role of NRG and their receptors in developing and postnatal myocardium, we studied the ability of a soluble NRG1 (recombinant human glial growth factor 2) to promote proliferation, survival, and growth of isolated neonatal and adult rat cardiac myocytes. Both ErbB2 and ErbB4 receptors were found to be expressed by neonatal and adult ventricular myocytes and activated by rhGGF2. rhGGF2 (30 ng/ml) provoked an approximate 2-fold increase in embryonic cardiac myocyte proliferation, rhGGF2 also promoted survival and inhibited apoptosis of subconfluent, serum-deprived myocyte primary cultures and also induced hypertrophic growth in both neonatal and adult ventricular myocytes, which was accompanied by enhanced expression of prepro-atrial natriuretic factor and skeletal cu-actin. Moreover, NRG1 mRNA could be detected in coronary microvascular endothelial cell primary cultures prepared from adult rat ventricular muscle. NRG1 expression in these cells was increased by endothelin-l, another locally acting cardiotropic peptide within the heart. The persistent expression of both a neuregulin and its cognate receptors in the postnatal and adult heart suggests a continuing role for neuregulins in the myocardial adaption to physiologic stress or injury.

British Indian Asian men aged <40 years have a twofold to threefold increased risk of death from coronary heart disease (CHD) compared with British whites. Epidemiological studies have suggested an association between glucose intolerance and hyperinsulinemia with premature CHD in Indian Asians. We tested the association of insulin action with myocardial infarction (MI) by using the hyperinsulinemic-euglycemic clamp in 17 MI patients: 8 Punjabi Sikhs (PSMIs), 9 British whites (BWMIs), and 17 control subjects (9 PSCs and 8 BWCs). Metabolic factors associated with insulin resistance were investigated in 51 MI patients (24 PSMIs and 27 BWMIs) and 53 control subjects (28 PSCs and 25 BWCs). Familial aggregation of defective insulin action was examined by studying five pedigrees of Sikh survivors of MI. Sikh survivors of premature MI demonstrated impaired insulin-mediated glucose uptake (P<.001) by use of the clamp technique and nonesterified fatty acid (NEFA) suppression (P<.05) by using both clamp techniques and the oral glucose tolerance test, as compared with Sikh control subjects. White patients had impaired insulin-mediated glucose uptake but normal NEFA suppression. Metabolic factors usually associated with insulin resistance, including increased 2-hour post-oral glucose tolerance test triglycerides, smaller low density lipoprotein particle size, and increased plasminogen activator inhibitor-1, were present in white (all P<.05) but surprisingly absent in Sikh (all P>.05) MI patients compared with respective ethnic control subjects. Fasting glucose and total cholesterol levels did not differ between patients and control subjects. Abdominal obesity, impaired NEFA suppression after oral glucose, and fasting hyperinsulinemia were present in Sikh MI patients and their nondiabetic first-degree relatives compared with Sikh control subjects. PS survivors of premature MI demonstrated impaired insulin-mediated glucose disposal and NEFA suppression compared with ethnic control subjects. BWMI patients showed abnormalities of carbohydrate, but not of NEFA, metabolism compared with white control subjects. Defects of insulin action manifested as abdominal obesity, impaired NEFA suppression, and fasting hyperinsulinemia are present in Sikh MI patients and their asymptomatic, nondiabetic, first-degree relatives. We suggest that these defects may be early metabolic markers that predict risk of premature MI among PSs.

We have shown that unlike fat, protein, xylose, or water, the carbohydrate component of the meal accelerates myocardial ischemia, reduces exercise capacity, and is associated with a more rapid increase in the determinants of myocardial oxygen consumption than exercise in the fasting state. Our results suggest a role for a larger increase in sympathetic nervous activity and/or release of vasoactive gastrointestinal peptides after carbohydrate, but not fat or protein, meals in postprandial angina.

In sympathetic denervation due to primary autonomic failure, ingestion of food causes a fall in blood pressure (BP) and exacerbates postural hypotension. It is not known whether these responses occur in tetraplegics with physiologically complete cervical spinal cord transection, who also have sympathetic dysfunction because of disruption of descending spinal sympathetic pathways. We, therefore, studied the effect of a liquid meal on BP, heart rate (HR) and neurohormonal levels in tetraplegics. Paraplegics with low lesions and without sympathetic dysfunction served as controls. After food ingestion, there was no fall in BP in tetraplegics or in controls. HR did not change in either group. After food, plasma noradrenaline was unchanged in tetraplegics, but rose in controls, while plasma renin activity (PRA) rose in tetraplegics but not in controls. The fall in BP and rise in HR on head-up tilt after the meal in tetraplegics was similar to that before the meal. There was no change in PRA following pre-prandial tilt in either group; postpprandial tilt raised levels in the tetraplegics, unlike in controls. Thus there is considerable variance in the responses to food between tetraplegics and paraplegic controls, and even greater differences when compared with published data in other autonomic disorders with sympathetic dysfunction; this may relate to the site and the nature of the sympathetic lesion and the ability to activate compensatory mechanism.

Patients with coronary artery disease or heart failure have been shown to be insulin resistant. Whether in these patients heart muscle participates in the insulin resistance, and whether reduced blood flow is a mechanism for such resistance is not known. We measured heart and skeletal muscle blood flow and glucose uptake during euglycemic hyperinsulinemia (insulin clamp) in 15 male patients with angiographically proven coronary artery disease and chronic regional wall motion abnormalities. Six age- and weight-matched healthy subjects served as controls. Regional glucose uptake was measured by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose (FDG), blood flow was measured by the H2(15)O method. Myocardial glucose utilization was measured in regions with normal perfusion and wall motion as assessed by radionuclide ventriculography. Whole-body glucose uptake was 37+/-4 micromol x min(-1) x kg(-1) in controls and 14+/-2 mciromol x min(-1) x kg(-1) in patients (P = 0.001). Myocardial blood flow (1.09+/-0.06 vs. 0.97+/-0.04 ml x min(-1) x g(-1), controls vs. patients) and skeletal muscle (arm) blood flow (0.046+/-0.012 vs. 0.043+/-0.006 ml x min(-1) x g(-1)) were similar in the two groups (P = NS for both). In contrast, in patients both myocardial (0.38+/-0.03 vs. 0.70+/-0.03 micromol x min(-1) x g(-1), P = 0.0005) and muscle glucose uptake (0.026+/-0.004 vs. 0.056+/-0.006 micromol x min(-1) x g(-1), P = 0.005) were markedly reduced in comparison with controls. In the whole dataset, a direct relationship existed between insulin-stimulated glucose uptake in heart and skeletal muscle. Patients with a history of myocardial infarction and a low ejection fraction are insulin resistant. This insulin resistance affects both the myocardium and skeletal muscle and is independent of blood flow.

We have investigated the haemodynamic and hormonal responses to angiotensin converting enzyme inhibition in 12 patients with primary autonomic failure (AF, 5 pure autonomic failure, 7 multiple system atrophy) and 7 normal subjects. Measurements of blood pressure (BP), heart rate (HR), stroke distance (SO) and cardiac index (CI, continuous wave Doppler, forearm blood flow (FBF, strain gauge plethysmography) and digital skin blood flow (DSBF, laser Doppler flowmetry) were made non-invasively. Plasma renin activity (PRA) and noradrenaline (NGRAD) were measured before and at 30 min intervals after captopril (50 mg, oral). Basal supine BP was higher in AF compared to normals (p < 0.05). After captopril, mean BP fell in AF (117 ± 6 to 103 ± 5 mmHg, p < 0.05). but not in normals (99 ± 4 to 97 ± 5 mmHg, ns). HR was unchanged after captopril in both groups. The depressor response in AF was accompanied by a fall in SD (9.6 ± 1.2 to 7.6 ± 0.7 cm, p < 0.05) and in CI (676 ± 79 to 536 ± 65 cm/min, p < 0.05). SD and CI were unchanged after captopril in normals (SD, 7.7 ± 1.3 to 7.4 ± 0.6 cm; CI. 579 ± 117 to 571 ± 69 cm/min, both ns). There was no reduction in forearm or digital skin vascular resistance after captopril in either group. Basal PRA in AF was similar to normals, but did not rise after captopril (691 ± 217 to 681 ± 221 pg/ml/hr, ns), unlike normals (813 ± 103 to 1360 ± 290 pg/ml/hr, p < 0.05). NORAO was unchanged after captopril in both groups. We conclude that. captopril lowers blood pressure in AF, unlike normals. The depressor response in AF occurs independently of plasma renin levels and sympathetic nervous activity, suggesting that alternative mechanisms, including accumulation of bradykinin and prostaglandins, may be responsible.