Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial.

AIMS: To investigate whether the degree of albuminuria reduction observed in the ALTITUDE trial is associated with renal and cardiovascular protection, and secondly, whether the reduction in albuminuria was too small to afford clinical benefit. METHODS: In a post hoc analysis of the ALTITUDE trial in 8561 patients with type 2 diabetes and chronic kidney disease or cardiovascular disease we examined the effect of albuminuria changes at 6 months on renal and cardiovascular outcomes using Cox proportional hazard regression. RESULTS: The median change in albuminuria in the first 6 months in the aliskiren arm of the trial was -12% (25th to 75th percentile: -48.7_to_ +41.9%) and 0.0% (25th to 75th percentile: -40.2_to_55%) in the placebo arm. Changes in albuminuria in the first 6 months were linearly associated with renal and cardiovascular endpoints: a >30% reduction in albuminuria in the first 6 months was associated with a 62% reduction in renal risk and a 25% reduction in cardiovascular risk compared with an increase in albuminuria. The association between changes at 6 months in albuminuria and renal or cardiovascular endpoints was similar in the two treatment groups (p for interaction >0.1 for both endpoints). CONCLUSIONS: The addition of aliskiren to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy resulted in albuminuria changes that were associated with renal and cardiovascular risk changes. This did not translate into renal or cardiovascular protection because the overall reduction in albuminuria in the aliskiren arm was too small and nearly similar to that in the placebo arm.

Atrial natriuretic factor gene expression in ventricles of rats with spontaneous biventricular hypertrophy.

A subset of Wistar-Kyoto (WKY) rats that spontaneously develops biventricular hypertrophy (BVH) in response to increased cardiac output was evaluated for ventricular expression of the atrial natriuretic factor (ANF) gene. Normal WKY rats had low levels of left ventricular ANF mRNA and minimally detectable ANF transcripts in the right ventricle. In contrast, BVH rats showed a sixfold greater ANF mRNA concentration in the left ventricle than age-matched WKY controls. BVH right ventricular ANF mRNA levels equaled those found in BVH left ventricles and were dramatically greater than WKY right ventricular controls. Unlike experimental models of hypertrophy, both left and right ventricles significantly increase ANF gene transcripts in the natural development of BVH. The left and right ventricles can concordantly respond to hypertrophy and increase ANF gene transcription.

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.

VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial.

BACKGROUND: Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma. METHODS AND RESULTS: We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL-apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P:=0.04), apoCIII in VLDL+LDL (RR 2.3, P:=0.04), and apoE in HDL (RR 1.8, P:=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P:=0.03), was not related to coronary events (RR 1.3, P:=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results. CONCLUSIONS: The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.

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.

Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape.

Infarct expansion after myocardial infarction results in early ventricular enlargement and distortion of ventricular geometry. To characterize the components of late volume enlargement, biplane left ventriculography was performed in 52 patients 3 weeks and 1 year after a first anterior myocardial infarction. Biplane diastolic circumference and contractile and noncontractile segment lengths were measured. Global geometry was evaluated by using a sphericity index (angiographic volume of the ventricle divided by the volume of a sphere with the same circumference). Regional geometry was assessed by measurement of endocardial curvature, an important determinant of wall tension. End-diastolic volume was enlarged at baseline and increased at 1 year (230 +/- 42 to 244 +/- 55 ml, p = 0.01) as a result of increases in contractile segment length (34 +/- 5 to 37 +/- 5 cm, p less than 0.001) and sphericity index (0.74 +/- 0.07 to 0.76 +/- 0.08, p less than 0.001), whereas the noncontractile segment length decreased (15 +/- 6 to 12 +/- 6 cm, p less than 0.005). Curvature analysis revealed a flattening of presumably high tension concavity at the anterobasal (-6.0 +/- 4.0 to -4.5 +/- 3.7, p less than 0.01) and inferior (-4.5 +/- 2.0 to -3.6 +/- 2.1, p less than 0.005) margins of the infarct and less bulging of the anterior wall (9.4 +/- 2.5 to 8.2 +/- 2.3, p less than 0.001). Patients selected for late enlargement (diastolic volume increase greater than 20 ml, n = 19) had an increase in sphericity (0.75 +/- 0.05 to 0.80 +/- 0.08, p less than 0.005) and in diastolic circumference (54 +/- 3 to 56 +/- 4 cm, p less than 0.001) secondary to elongation of the contractile segment (32 +/- 4 to 36 +/- 4 cm, p = 0.001) at 1 year. Thus, late ventricular enlargement after anterior infarction results from an increase in contractile segment length and a change in ventricular geometry and is not a result of progressive infarct expansion. In the group of patients at high risk for late ventricular enlargement because of persistent occlusion of the infarct-related vessel, captopril therapy attenuated late volume enlargement by preventing these changes in contractile segment length and chamber geometry.

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.

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.

Effects of reperfusion on arrhythmias and death after coronary artery occlusion in the rat: increased electrical stability independent of myocardial salvage.

OBJECTIVES: This study sought to delineate salvage-dependent from salvage-independent coronary reperfusion in acute myocardial infarction and the effects on spontaneously occurring arrhythmias and arrhythmic death in rats. BACKGROUND: Reperfusion of the infarct-related artery might increase electrical stability independently of salvage of ischemic myocardium. METHODS: In 98 conscious rats the electrocardiogram was monitored by telemetry for 48 h after MI, and all episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analyzed. Reperfusion at 45 min (RP45) (n = 15), 90 min (RP90) (n = 18) and 180 min (RP180) (n = 30) min was compared with permanent coronary artery occlusion (CAO) (n = 35) with respect to the post-reperfusion periods. RESULTS: RP45, RP90 and RP180 reduced the incidence of VT by 93%, 98% and 88% and VF by 89%, 97% and 92%, respectively (all p < 0.01 vs. CAO). The all-cause mortality rate was reduced from 47% (CAO) to 8% (RP45, p < 0.05) and 0% (RP90, p < 0.01); after RP180 it was 17% (CAO 42%, p = 0.08). All reperfusion regimens reduced arrhythmic deaths: 47% to 8% (RP45, p < 0.05), 47% to 0% (RP90, p < 0.01) and 42% to 8% (RP180, p < 0.05). Infarct size was identical to that during CAO (49 +/- 10% [mean +/- SD]) and RP180 (49 +/- 10%), whereas preferentially epicardial salvage occurred at RP45 (36 +/- 8%, p < 0.001) and RP90 (38 < 10%, p < 0.001). CONCLUSIONS: Early and late reperfusion reduce the incidence and duration of VT and VF in conscious rats with acute MI. Thereby, arrhythmia-related mortality is improved through the prevention of fatal VF episodes. Thus, reperfusion increases the electrical stability of the heart independently of myocyte salvage, as proposed by the open artery hypothesis.

Cost-effectiveness of captopril therapy after myocardial infarction.

OBJECTIVES: This study sought to assess the cost-effectiveness of captopril therapy for survivors of myocardial infarction. BACKGROUND: The recent randomized, controlled Survival and Ventricular Enlargement (SAVE) trial showed that captopril therapy improves survival in survivors of myocardial infarction with an ejection fraction < or = 40%. The present ancillary study was designed to determine how the costs required to achieve this increase in survival compared with those of other medical interventions. METHODS: We developed a decision-analytic model to assess the cost-effectiveness of captopril therapy in 50- to 80-year old survivors of myocardial infarction with an ejection fraction < or = 40%. Data on costs, utilities (health-related quality of life weights) and 4-year survival were obtained directly from the SAVE trial, and long-term survival was estimated using a Markov model. In one set of analyses, we assumed that the survival benefit associated with captopril therapy would persist beyond 4 years (persistent-benefit analyses), whereas in another set we assumed that captopril therapy incurred costs but no survival benefit beyond 4 years (limited-benefit analyses). RESULTS: In the limited-benefit analyses, the incremental cost-effectiveness of captopril therapy ranged from $3,600/quality-adjusted life-year for 80-year old patients to $60,800/quality-adjusted life-year for 50-year old patients. In the persistent-benefit analyses, incremental cost-effectiveness ratios ranged from $3,700 to $10,400/quality-adjusted life-year, depending on age. The outcome was generally not sensitive to changes in estimates of variables when they were varied individually over wide ranges. In a "worst-case" analysis, incremental cost-effectiveness ratios for captopril therapy remained favorable ($8,700 to $29,200/quality-adjusted life-year) for 60- to 80-year old patients but were higher ($217,600/quality-adjusted life-year) for 50-year old patients. CONCLUSIONS: We conclude that the cost-effectiveness of captopril therapy for 50- to 80-year old survivors of myocardial infarction with a low ejection fraction compares favorably with other interventions for survivors of myocardial infarction.

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.

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.

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.

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.

Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial.

OBJECTIVES: We sought to determine the effect of pravastatin on recurrent cardiovascular events in women with average cholesterol levels after myocardial infarction (MI). BACKGROUND: Little information is available on the effectiveness of lipid lowering in secondary prevention of coronary heart disease (CHD) in women; in particular, those with CHD and average cholesterol levels. METHODS: In the Cholesterol and Recurrent Events (CARE) trial, 576 postmenopausal women, between 3 and 20 months after MI, with a total cholesterol level <240 mg/dl and a low density lipoprotein cholesterol level 115 to 174 mg/dl, were randomized to receive pravastatin 40 mg/day or matching placebo for a median follow-up period of 5 years. The main outcome measures were combined coronary events (coronary death, nonfatal MI, percutaneous transluminal coronary angioplasty [PTCA] or coronary artery bypass graft surgery [CABG]), the primary trial end point (coronary death or nonfatal MI) and stroke. RESULTS: Women treated with pravastatin had a risk reduction of 43% for the primary end point (p = 0.035), 46% for combined coronary events (p = 0.001), 48% for PTCA (p = 0.025), 40% for CABG (p = 0.14) and 56% for stroke (p = 0.07). The 3,583 men in the CARE trial also showed a reduction in risk, but the magnitude tended to be less. Pravastatin improved plasma lipids similarly in men and women. There were no differences in risk of coronary events in the placebo group between men and women. Minor differences between men and women were present in baseline characteristics and treatment for MI, in general, conferring a higher risk status and a lower incidence of CABG in the women. CONCLUSIONS: Pravastatin led to significant early reduction of a wide range of cardiovascular events in post-MI women with average cholesterol levels.

Angiotensin converting enzyme inhibitors and cardiovascular remodelling.

Regional alterations in left ventricular function are generally present in patients who sustain an acute myocardial infarction. Segmental wall motion abnormalities in left ventricular systolic function can be identified in the hyperacute period and generally persist in patients with myocardial infarction. Through the process of infarct expansion, the infarcted territory may thin and lengthen in the short term following a myocardial infarction. Some infarct survivors are also prone to further progressive alterations in the shape and size of the left ventricle, a process that has been termed "postinfarction ventricular remodelling". Although a component of left ventricular remodelling appears to represent an adaptive process serving to preserve stroke volume and cardiac output following myocardial injury, the enlargement process may have undesirable long term effects on global left ventricular function and on clinical prognosis. Fortunately, recent experimental and clinical evidence shows that ventricular remodelling and its deleterious consequences may be preventable.

Mechanism of the negative inotropic action of leukotrienes C4 and D4 on isolated rat heart.

Leukotrienes C4 and D4 (LTC4 and LTD4), possible mediators of cardiac dysfunction during inflammatory injury, may depress cardiac function by reducing coronary flow or by exerting a negative effect directly on the myocardium. We used an isovolumic rat heart preparation perfused at constant pressure and measured left ventricular developed pressure (mmHg), coronary flow (ml.min-1), oxygen extraction, and myocardial oxygen consumption and delivery (mumol O2.[gramme dry weight]-1.min-1) during infusion of five doses of angiotensin II, LTC4, LTD4 (approximately 10 to approximately 300 pmol.min-1), and noradrenaline (400 to 2000 pmol.min-1), or perfusion with medium which contained calcium at half-concentration. LTC4 and LTD4 were equipotent with angiotensin. At low effective doses, increased oxygen extraction offset the decrease in oxygen delivery, maintaining a stable level of oxygen consumption and left ventricular developed pressure. At the highest doses, angiotensin, LTC4 and LTD4 reduced coronary flow from 21 to 15, 21 to 13, and 21 to 13 ml.min-1, respectively. And, despite greater oxygen extraction of 59%, 58% and 65% for angiotensin, LTC4 and LTD4, left ventricular developed pressure fell from a baseline of 120 mmHg to 113, 106 and 92, respectively. In contrast, low calcium perfusion reduced left ventricular developed pressure (126 to 92) and oxygen extraction (46 to 30%) without changing coronary flow or oxygen delivery. These results suggest that LTC4 and LTD4 are potent coronary vasoconstricting agents which depress cardiac function by limiting oxygen delivery.

Cardiac hypertrophy and performance of Dahl hypertensive rats on graded salt diets.

The relationship between arterial pressure and left ventricular (LV) functional capacity and LV mass during the natural development of cardiac hypertrophy was assessed in Dahl-resistant (R) and -sensitive (S) hypertensive rats maintained on three dietary NaCl regimens (0.4%, 4.0%, and 8.0% for 9 weeks, then 4.0%) from 5 until 20 weeks of age. In R rats, arterial pressure and LV mass were unaffected by diet. In contrast, S rats demonstrated levels of arterial pressure and LV hypertrophy that were graded according to dietary NaCl. Hemodynamic studies on rats under ether anesthesia demonstrated that the graded pressure elevation in S rats was produced by corresponding increases in total peripheral resistance, as cardiac output did not vary. During acute volume loading, the S rats on all diets achieved the same maximum stroke volume as did R rats, despite the marked increase in the arterial pressure of S rats. An analysis of the ejection fraction/afterload relationship demonstrated preserved contractile state. The ability of the left ventricle to generate pressure was increased in S rats in direct proportion to the degree of LV hypertrophy. Thus, in young adult S rats, cardiac performance was well compensated since pump and contractile functions were maintained and pressure-generating capacity was increased in relation to the degree of LV hypertrophy.

Isolated systolic hypertension : prognostic information provided by pulse pressure.

Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension.