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M A Pfeffer

Publications and source records attributed to M A Pfeffer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Endothelin-A receptor antagonism during acute myocardial infarction in rats.

Endothelin levels are increased in rats with experimentally induced myocardial infarction. The purpose of this study was to determine whether endothelin-A (ET(A)) receptor antagonism alters ventricular remodeling and the development of heart failure after myocardial infarction (MI). We administered 10 mg/kg/day of A-127722 to rats post-MI for 6 weeks. A hemodynamic study was performed and passive pressure-volume curves obtained. In rats without infarcts, ET(A) receptor antagonist (n = 8; vehicle, n = 5) had no effect. However, in rats with infarcts ET(A) antagonism (n=14, MI = 35%; vehicle: n = 19, MI = 32%) reduced systemic arterial and LV systolic (but not end-diastolic) pressures and shifted the pressure-volume relationship to the right. Because LV mass was not changed, the volume-to-mass ratio was increased and was correlated inversely with the ability of the LV to maximally develop pressure. This increase in volume at low distending pressures was also coupled with a tendency (P < 0.06) for reduced scar thickness, suggesting that early initiation of an ET(A) receptor antagonism increased infarct expansion. The reduction in blood pressure offset the increase in volume such that wall stresses were unchanged, as was LV mass. The early use of ET(A) receptor antagonism in the rat model of myocardial infarction did not beneficially alter LV remodeling.

Animals↗
PubMed2000

Enhancing cardiac protection after myocardial infarction: rationale for newer clinical trials of angiotensin receptor blockers.

Treatment of acute myocardial infarction (MI) has been advanced considerably in the past 20 years with the advent of acute reperfusion strategies such as thrombolytic therapy or primary angioplasty and the use of adjunctive medical therapies such as aspirin, beta-blockers, and HMG-CoA reductase inhibitors (statins); each has been proven to reduce morbidity and mortality rates after MI. Angiotensin-converting enzyme (ACE) inhibitors have earned an important place in this list of winners, particularly in patients clinically assessed as being at higher risk for cardiovascular death. The benefits of treating such patients with an ACE inhibitor have clearly shown significant improvements in survival that are both complementary and additive to the other proven therapies. However, a significant subset of patients treated with ACE inhibitors will die or have worsening congestive heart failure despite adequate therapy. Appropriate risk stratification can help guide the clinician in identifying patients at greatest risk for cardiovascular events after MI. Fortunately, investigators are currently exploring the potential benefits of more specific and selective blockade of the renin-angiotensin system with AT(1) receptor blockers (ARBs) in the hope of enhancing survival beyond that evidenced with ACE inhibition alone. These agents pharmacologically inhibit the renin-angiotensin system at the angiotensin (Ang) II type 1 receptor level. Although there are theories postulating why blocking the harmful effects of Ang II at this receptor would be more effective than inhibiting ACE-mediated conversion from inactive Ang I to Ang II, extrapolation to the clinical setting remains highly speculative. These hypotheses can only be tested by direct comparisons of ACE inhibitors and ARBs in the appropriate patient populations. The VALIANT (Valsartan in Acute Myocardial Infarction) trial is testing the hypothesis that interruption of the renin-angiotensin pathway by using the ARB valsartan alone or in combination with an ACE inhibitor will be more effective in saving lives than an ACE inhibitor alone in treating patients at high risk. This trial will enroll patients with symptoms of congestive heart failure or depressed left ventricular ejection fraction and randomly assign them to either captopril, valsartan, or the combination. Other proven conventional post-MI therapies are encouraged. This study will definitively determine whether the use of valsartan offers additional benefits over those achieved with ACE inhibitor monotherapy in patients at high risk after MI.

Angiotensin II↗
PubMed2000

Valsartan in acute myocardial infarction trial (VALIANT): rationale and design.

BACKGROUND: Survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. METHODS: Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. CONCLUSION: VALIANT is a large international investigative effort that will evaluate the role of valsartan in the management of patients with MI associated with heart failure and/or left ventricular dysfunction. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors.

Angiotensin II↗
PubMed2000

Will more complete inhibition of the RAAS with angiotensin receptor blockade improve survival following myocardial infarction?

Angiotensin-converting enzyme (ACE) inhibitors have a well-established role in the management of patients with hypertension, diabetes, heart failure and myocardial infarction (MI). ACE inhibitors have been particularly well studied in acute and chronic MI with consistent and substantial survival benefits demonstrated, particularly in the higher risk groups. The recent development of angiotensin II (Ang II) receptor blockers (ARBs) as a well tolerated pharmacological therapy to more completely inhibit the actions of Ang II at the AT1-receptor level raises questions concerning comparative efficacy with the proven ACE inhibitor experience. Two major trials will provide a direct comparison of ARBs with an ACE inhibitor. The Valsartan in Acute Myocardial Infarction (VALIANT) trial is specifically designed to compare and contrast the ARB, valsartan, used both alone as well as in combination with a proven ACE inhibitor regimen, in a high risk MI population. VALIANT, with its three arms targetting 14,500 patients, is uniquely poised to determine whether the pharmacological advance in the development of ARBs confers additional clinical (survival) value in high risk MI patients.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1999

Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators.

BACKGROUND: Elevated plasma concentrations of C-reactive protein (CRP) are associated with increased cardiovascular risk. We evaluated whether long-term therapy with pravastatin, an agent that reduces cardiovascular risk, might alter levels of this inflammatory parameter. METHODS AND RESULTS: CRP levels were measured at baseline and at 5 years in 472 randomly selected participants in the Cholesterol and Recurrent Events (CARE) trial who remained free of recurrent coronary events during follow-up. Overall, CRP levels at baseline and at 5 years were highly correlated (r=0.60, P<0.001). However, among those allocated to placebo, median CRP levels and the mean change in CRP tended to increase over time (median change, +4. 2%; P=0.2 and mean change, +0.07 mg/dL; P=0.04). By contrast, median CRP levels and the mean change in CRP decreased over time among those allocated to pravastatin (median change, -17.4%; P=0.004 and mean change, -0.07 mg/dL; P=0.002). Thus, statistically significant differences were observed at 5 years between the pravastatin and placebo groups in terms of median CRP levels (difference, -21.6%; P=0.007), mean CRP levels (difference, -37.8%; P=0.002), and absolute mean change in CRP (difference, -0.137 mg/dL; P=0.003). These effects persisted in analyses stratified by age, body mass index, smoking status, blood pressure, and baseline lipid levels. Attempts to relate the magnitude of change in CRP to the magnitude of change in lipids in both the pravastatin and placebo groups did not reveal any obvious relationships. CONCLUSIONS: Among survivors of myocardial infarction on standard therapy plus placebo, CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin resulted in significant reductions in this inflammatory marker that were not related to the magnitude of lipid alterations observed. Thus, these data further support the potential for nonlipid effects of this agent.

Adult↗
PubMed1999

Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction. BACKGROUND: Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction. METHODS: Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials. RESULTS: Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001). CONCLUSIONS: One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.

Adult↗
PubMed1999

Increased pulse pressure and risk of heart failure in the elderly.

CONTEXT: Arterial stiffness increases with age. Thus, pulse pressure, an index of arterial stiffening, may predict congestive heart failure (CHF) in the elderly. OBJECTIVE: To study prospectively the association between pulse pressure and risk of CHF. DESIGN: Prospective cohort study. SETTING: The community-based East Boston Senior Health Project, East Boston, Mass. PATIENTS: A total of 1621 men and women (mean [SD] age, 77.9 [5.0] years) free of CHF who had blood pressure measurements taken in 1988-1989 and were followed up for 3.8 years. MAIN OUTCOME MEASURE: Incidence of CHF as ascertained by hospital discharge diagnosis (n = 208) and death certificates (n = 13). RESULTS: After controlling for age, sex, mean arterial pressure, history of coronary heart disease, diabetes mellitus, atrial fibrillation, valvular heart disease, and antihypertensive medication use, pulse pressure was an independent predictor of CHF. For each 10-mm Hg elevation in pulse pressure, there was a 14% increase in risk of CHF (95% confidence interval, 1.05-1.24; P = .003). Those in the highest tertile of pulse pressure (>67 mm Hg) had a 55% increased risk of CHF (P=.02) compared with those in the lowest (<54 mm Hg). Pulse pressure was more predictive than systolic blood pressure alone and was independent of diastolic blood pressure. CONCLUSION: Pulse pressure, an easily measurable correlate of pulsatile hemodynamic load, is an independent predictor of risk of CHF in this elderly cohort.

Aged↗
PubMed1999

Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators.

BACKGROUND: The role of lipid modification in stroke prevention is controversial, although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease. METHODS AND RESULTS: To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infarction, we followed 4159 subjects with average total and LDL serum cholesterol levels (mean, 209 and 139 mg/dL, respectively) who had sustained an infarction an average of 10 months before study entry and who were randomized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events (CARE) trial. Using prospectively defined criteria, we assessed the incidence of stroke, a prespecified secondary end point, and transient ischemic attack (TIA) over a median 5-year follow-up period. Patients were well matched for stroke risk factors and the use of antiplatelet agents (85% of subjects in each group). Compared with placebo, pravastatin lowered total serum cholesterol by 20%, LDL cholesterol by 32%, and triglycerides by 14% and raised HDL cholesterol by 5% over the course of the trial. A total of 128 strokes (52 on pravastatin, 76 on placebo) and 216 strokes or TIAs (92 on pravastatin, 124 on placebo) were observed, representing a 32% reduction (95% CI, 4% to 52%, P=0.03) in all-cause stroke and 27% reduction in stroke or TIA (95% CI, 4% to 44%, P=0.02). All categories of strokes were reduced, and treatment effect was similar when adjusted for age, sex, history of hypertension, cigarette smoking, diabetes, left ventricular ejection fraction, and baseline total, HDL, and LDL cholesterol and triglyceride levels. There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo (2 versus 6, respectively). CONCLUSIONS: Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infarction in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy.

Aged↗
PubMed1999

Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.

OBJECTIVES: We sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study. BACKGROUND: The CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values. METHODS: There were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels). RESULTS: Quartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI). CONCLUSIONS: Within the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.

Adult↗
PubMed1999

Ejection fraction by radionuclide ventriculography and contrast left ventriculogram. A tale of two techniques. SAVE Investigators. Survival and Ventricular Enlargement.

OBJECTIVES: We assessed the abilities of two methods to measure ejection fraction (EF)-radionuclide ventriculography (RVG) and contrast left ventriculography (Cath-EFa) to predict cardiovascular events. BACKGROUND: Both RVG and Cath-EFa are commonly used methods to measure left ventricular performance and assess prognosis. Their comparative abilities to predict clinical events have not been reported. METHODS: Both RVG EF and Cath-EFa were measured within 16 days of myocardial infarction (MI) in 688 patients. The results were divided into terciles. Prognosis by terciles was assessed for each technique. A multivariate analysis was performed to determine which EF measurement was a better predictor of prognosis. RESULTS: Average RVG-EF was 32%+/-7, while Cath-EFa was 42%+/-10. Both RVG and Cath-EFa were poorly correlated (R=0.42). Event rate declined across terciles with increasing EF for both techniques (events in lowest to highest tercile of Cath-EFa 40.7%, 25.9%, 11.6%, p < 0.001; and RVG-EF 39.9%, 26.1%, 15.6%, p < 0.001). There was concordance of terciles in 303 of 688 patients (44%). When patients in the highest RVG terciles were in the highest Cath-EFa tercile, the event rate was 7%. However, when patients in the highest RVG terciles were in the lowest Cath-EFa tercile, the event rate was 19%. Both Cath-EFa (p < 0.001) and RVG-EF (p < 0.001) were independent predictors of cardiovascular events. CONCLUSIONS: Ejection fraction measured by RVG or during catheterization is a valuable tool in the risk stratification of postinfarct patients. When disagreement is present between clinical impression and measurement by either method, the use of an alternative measurement is warranted and complementary.

Adult↗
PubMed1999

Echocardiography-derived left ventricular end-systolic regional wall stress and matrix remodeling after experimental myocardial infarction.

OBJECTIVES: We tested the hypothesis that regional end-systolic left ventricular (ESLV) wall stress is associated with extracellular matrix remodeling activity after myocardial infarction (MI). BACKGROUND: Increased left ventricular (LV) wall stress is a stimulus for LV enlargement, and echocardiography can be used to estimate regional wall stress. A powerful validation of a noninvasive method of estimating wall stress would be predicting cellular responses after a MI. METHODS: Echocardiographic images were obtained in rats 1, 7, 14 or 21 days after coronary ligation (n = 11) or sham surgery (n = 5). End-systolic left ventricular wall stress was calculated by finite element analysis in three regions (infarcted, noninfarcted and border) from short-axis images. Matrix metalloproteinase-9 (MMP-9) and macrophage density were determined by immunohistochemistry, and positive cells were counted in high power fields (hpf). RESULTS: Average ESLV wall stress was higher in rats with MI when compared to shams irrespective of time point (p < 0.01), and ESLV wall stress in the infarcted regions increased with time (25.1 +/- 5.9 vs. 69.9 +/- 4.4 kdyn/cm2, day 1 vs. 21; p < 0.01). Matrix metalloproteinase-9 expression was higher in infarcted and border regions when compared to noninfarcted regions (22.1 vs. 25.7 vs. 0.10 cells/hpf, respectively; p < 0.01). Over all regions, ESLV wall stress was associated with MMP-9 (r = 0.76; p < 0.001), macrophage density (r = 0.72; p < 0.001) and collagen content (r = 0.67; p < 0.001). End-systolic left ventricular wall stress was significantly higher when MMP-9 positive cell density was greater than 10 cells/hpf (45+/-20 vs. 14+/-10 kdyn/cm2; p < 0.001). CONCLUSIONS: Regional increases in ESLV wall stress determined by echocardiography-based structural analysis are associated with extracellular matrix degradation activity.

Animals↗
PubMed1999

Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials.

UNLABELLED: Estimate the effect of angiotensin converting enzyme (ACE) inhibitors on the risk of sudden cardiac death (SCD) following myocardial infarction (MI). BACKGROUND: Trials in post-MI patients have shown that ACE inhibitor therapy reduces mortality. However, the effect on SCD as a mechanism has not been clarified. METHODS: Trials of ACE inhibitor therapy following MI reported between January, 1978 and August, 1997 were identified. Studies were included if they met the following criteria: 1) randomized comparison of ACE inhibitor to placebo within 14 days of MI; 2) study duration/blinded follow-up of > or =6 weeks; 3) the number of deaths and modes of death were reported or could be obtained from the investigators. RESULTS: We identified 374 candidate articles, of which 15 met the inclusion criteria. The 15 trials included 15,104 patients, 2,356 of whom died. Most (87%) fatalities were cardiovascular and 900 were SCDs. A significant reduction in SCD risk or a trend towards this was observed in all of the larger (N > 500) trials. Overall, ACE inhibitor therapy resulted in significant reductions in risk of death (random effects odds ratio [OR] = 0.83; 95% confidence interval [CI] 0.71-0.97), cardiovascular death (OR = 0.82; 95% CI 0.69-0.97) and SCD (OR = 0.80; 95% CI 0.70-0.92). CONCLUSIONS: This analysis is consistent with prior reports showing that ACE inhibitors decrease the risk of death following a recent MI by reducing cardiovascular mortality. Moreover, this analysis suggests that a reduction in SCD risk with ACE inhibitors is an important component of this survival benefit.

Aged↗
PubMed1999

Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators.

OBJECTIVES: This analysis was carried out to determine if revascularized patients derive benefit from the 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin. BACKGROUND: The HMG-CoA reductase inhibitors result in substantial reductions in serum cholesterol and stabilization of atherosclerotic plaques in patients with coronary artery disease. METHODS: Pravastatin was found to reduce clinical cardiovascular events in the Cholesterol and Recurrent Events (CARE) trial consisting of 4,159 patients with a documented myocardial infarction and an average cholesterol level (mean 209 mg/dl and all <240 mg/dl). A total of 2,245 patients underwent coronary revascularization before randomization including 1,154 patients with percutaneous transluminal coronary angioplasty (PTCA) alone, 876 patients with coronary artery bypass graft (CABG) alone, and 215 patients with both procedures. Clinical events in revascularized patients were compared between patients on placebo and on pravastatin. RESULTS: In the 2,245 patients who had undergone revascularization, the primary endpoint of coronary heart disease death or nonfatal myocardial infarction (MI) was reduced by 4.1% with pravastatin (relative risk [RR] reduction 36%, 95% confidence interval [CI] 17 to 51, p = 0.001). Fatal or nonfatal MI was reduced by 3.3% (RR reduction 39%, 95% CI 16 to 55, p = 0.002), postrandomization repeat revascularization was reduced by 2.6% (RR reduction 18%, 95% CI 1 to 33, p = 0.068) and stroke was reduced by 1.5% (RR reduction 39%, 95% CI 3 to 62, p = 0.037) with pravastatin. Pravastatin was beneficial in both the 1,154 PTCA patients and in the 1,091 CABG patients who had undergone revascularization before randomization. CONCLUSIONS: Pravastatin reduced clinical events in revascularized postinfarction patients with average cholesterol levels. This therapy was well tolerated and its use should be considered in most patients following coronary revascularization.

Angioplasty, Balloon, Coronary↗
PubMed1999

Temporal dissociation of left ventricular function and remodeling following experimental myocardial infarction in rats.

BACKGROUND: Left ventricular function early after myocardial infarction (MI) predicts subsequent clinical outcome. Nevertheless, the relationship between early changes in left ventricular function and subsequent left ventricular remodeling has not been well defined. METHODS AND RESULTS: To explore the temporal relationship between left ventricular function and remodeling after MI, rats (n = 63) underwent coronary artery ligation with and without reperfusion at 45 or 180 minutes or a sham operation. All animals were followed up by serial echocardiography preligation; 4, 24, and 48 hours; and 1, 2, 3, 4, 6, and 9 weeks after MI. Measures of global left ventricular size and function and regional wall motion were obtained at physiological heart rates. Histological infarct sizes (range, 0% to 52%) were determined in all animals. Within 4 hours of MI, fractional area change (FAC) decreased dramatically in association with an increase in left ventricular systolic cavity area, whereas diastolic area increased more gradually. Early FAC was related to infarct size (r = -0.82; P < .000), predicted the extent of left ventricular enlargement (P = .0001), and remained depressed throughout the duration of follow-up. Regional wall motion excursion and systolic wall thickness decreased in the infarcted and noninfarcted regions in animals with large infarctions. CONCLUSIONS: The rate of left ventricular dilatation after MI in rats is proportional to initial left ventricular function, although left ventricular function remains relatively constant as the ventricle progressively enlarges. Regional myocardial function after a large MI is abnormal in noninfarcted as well as infarcted regions.

Animals↗
PubMed1999

Inducible nitric oxide synthase and tumor necrosis factor in animal models of myocardial necrosis induced by coronary artery ligation or isoproterenol injection.

BACKGROUND: Increased expression of inducible nitric oxide synthase (iNOS) has been described in humans with cardiomyopathies. Most animal models of ischemia-induced heart failure use the surgical ligation of coronary arteries. However, studies of iNOS expression in these models may be confounded by a robust immune response because of the surgical procedure itself leading to iNOS expression in the heart, as well as in other tissues. METHODS AND RESULTS: iNOS expression was studied in adult male rats injected subcutaneously with either 250 mg/kg of isoproterenol (ISO) or vehicle on 2 consecutive days. This approach induces diffuse myocardial necrosis and leads to the development of a dilated cardiomyopathy. Hearts from ISO-injected animals harvested at 6 weeks had evidence of apical and subendocardial scarring. These hearts showed a 9.6-fold (left ventricle [LV], P = .004) and an 11.9-fold (right ventricle, P = .002) increase in the expression of tumor necrosis factor (TNF), and a 6.8-fold increase (LV, P = .0183) in iNOS messenger RNA compared with vehicle-injected controls. iNOS protein also was detectable by immmunoprecipitation in left ventricular muscle from ISO-injected animals, as well as by immunohistochemical analysis. CONCLUSION: Expression of TNF and iNOS in the heart is increased in an experimental model of dilated cardiomyopathy that minimizes the confounding effects of surgery, supporting a role for the activation of innate immunity signaling pathways in the pathogenesis of heart failure.

Animals↗
PubMed1999

Contemporary management of patients with left ventricular systolic dysfunction. Results from the Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry.

AIMS: The reported prevalence of angiotensin-converting enzyme (ACE) inhibitor use in patients with heart failure varies considerably. Recent reports suggest that many patients who could benefit from such therapy are not receiving ACE inhibitors. The Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry was established to understand better the demographics, characteristics, and contemporary use of ACE inhibitors in an international registry. METHODS AND RESULTS: Between August 1996 and April 1997, each of 105 study centres from eight countries in North America and Europe was invited to review retrospectively the medical records of 100 consecutive patients with left ventricular ejection fractions </=35%. The median age of the 9580 Registry patients was 66 years, 26% were women, the median ejection fraction was 27%, and the primary aetiology of left ventricular dysfunction was ischaemic (63%). Eighty percent of patients were receiving ACE inhibitors. The most common reason for non-use of ACE inhibitors was intolerance (9%). CONCLUSION: The SPICE Registry provides a contemporary description of the demographics and management of patients with documented left ventricular systolic dysfunction. The contemporary use of ACE inhibitors (80%) appears to be higher than previously reported and the main reason for non-use is perceived intolerance (9%).

Aged↗