Peer Grande

Genetically Elevated C-Reactive Protein and Ischemic Vascular Disease

BACKGROUND Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association. METHODS We studied 10,276 persons from a general population cohort, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms. RESULTS The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease. CONCLUSIONS Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.

Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction Result of the Double-Blind, Randomized, Placebo-Controlled Stem Cells in Myocardial Infarction (STEMMI) Trial

Background— Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction. Methods and Results— Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention <12 hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 &mgr;g/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core laboratory analyzed all MRI examinations. Systolic wall thickening improved 17% in the infarct area in the G-CSF group and 17% in the placebo group (P=1.0). Comparable results were found in infarct border and noninfarcted myocardium. Left ventricular ejection fraction improved similarly in the 2 groups measured by both MRI (8.5 versus 8.0; P=0.9) and echocardiography (5.7 versus 3.7; P=0.7). The risk of severe clinical adverse events was not increased by G-CSF. In addition, in-stent late lumen loss and target vessel revascularization rate in the follow-up period were similar in the 2 groups. Conclusions— Bone marrow stem cell mobilization with subcutaneous G-CSF is safe but did not lead to further improvement in ventricular function after acute myocardial infarction compared with the recovery observed in the placebo group.

Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease

CONTEXT Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. OBJECTIVE To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD). DESIGN, SETTING, AND PARTICIPANTS Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. MAIN OUTCOME MEASURES Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. RESULTS Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62). CONCLUSION Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.

PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

OBJECTIVES The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. BACKGROUND The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. METHODS We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). RESULTS In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). CONCLUSIONS The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life.

Use of initial ST-segment deviation for prediction of final electrocardiographic size of acute myocardial infarcts

The decision to administer thrombolytic therapy for limitation of acute myocardial infarction (AMI) size must occur when only the history, physical examination and 12-lead electrocardiogram of a patient are available. A method that could quickly assess the amount of jeopardized myocardium would greatly aid the physician. This study developed formulas from 68 anterior and 80 inferior AMI patients using the extent of initial ST-segment deviation (ST delta) to predict the final AMI size estimated by the Selvester QRS score in a population not receiving reperfusion therapy. Inclusion required: initial anterior or inferior AMI; admission electrocardiogram less than or equal to 8 hours after the onset of symptoms with evidence of epicardial injury; elevated creatine kinase-MB; a predischarge electrocardiogram taken greater than or equal to 72 hours after admission; and no AMI extension before the predischarge electrocardiogram. The extent of epicardial injury was quantified by counting the number of leads with greater than or equal to 0.1 mm ST delta, by the sum (sigma) of ST delta in all leads and by the sigma ST delta in the lead groups associated with each AMI location. These results were compared to the AMI size estimated from the predischarge electrocardiogram. Univariable and multivariable analyses generated these formulas for AMI size: anterior = 3[1.5 (number leads ST increases) - 0.4]; inferior = 3[0.6 (sigma ST increases II, III, aVF) + 2.0]. Thus, formulas based on quantitative measurements of ST delta on the admission electrocardiogram are predictive of final QRS-estimated AMI size, and may be useful in determining the efficacy of acute reperfusion therapy.

Effects of Statin Therapy According to Plasma High-Sensitivity C-Reactive Protein Concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) A Retrospective Analysis

Background— We examined whether the antiinflammatory action of statins may be of benefit in heart failure, a state characterized by inflammation in which low cholesterol is associated with worse outcomes. Methods and Results— We compared 10 mg rosuvastatin daily with placebo in patients with ischemic systolic heart failure according to baseline high sensitivity-C reactive protein (hs-CRP) <2.0 mg/L (placebo, n=779; rosuvastatin, n=777) or ≥2.0 mg/L (placebo, n=1694; rosuvastatin, n=1711). The primary outcome was cardiovascular death, myocardial infarction, or stroke. Baseline low-density lipoprotein was the same, and rosuvastatin reduced low-density lipoprotein by 47% in both hs-CRP groups. Median hs-CRP was 1.10 mg/L in the lower and 5.60 mg/L in the higher hs-CRP group, with higher hs-CRP associated with worse outcomes. The change in hs-CRP with rosuvastatin from baseline to 3 months was −6% in the low hs-CRP group (27% with placebo) and −33.3% in the high hs-CRP group (−11.1% with placebo). In the high hs-CRP group, 548 placebo-treated (14.0 per 100 patient-years of follow-up) and 498 rosuvastatin-treated (12.2 per 100 patient-years of follow-up) patients had a primary end point (hazard ratio of placebo to rosuvastatin, 0.87; 95% confidence interval, 0.77 to 0.98; P=0.024). In the low hs-CRP group, 175 placebo-treated (8.9 per 100 patient-years of follow-up) and 188 rosuvastatin-treated (9.8 per 100 patient-years of follow-up) patients experienced this outcome (hazard ratio, 1.09; 95% confidence interval, 0.89 to 1.34; P>0.2; P for interaction=0.062). The numbers of deaths were as follows: 581 placebo-treated (14.1 per 100 patient-years of follow-up) and 532 rosuvastatin-treated (12.6 per 100 patient-years) patients in the high hs-CRP group (hazard ratio, 0.89; 95% confidence interval, 0.79 to 1.00; P=0.050) and 170 placebo-treated (8.3 per 100 patient-years) and 192 rosuvastatin-treated (9.7 per 100 patient-years) patients in the low hs-CRP group (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43; P=0.14; P for interaction=0.026). Conclusion— In this retrospective hypothesis-generating study, we found a significant interaction between hs-CRP and the effect of rosuvastatin for most end points whereby rosuvastatin treatment was associated with better outcomes in patients with hs-CRP ≥2.0 mg/L. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction

AIMS Elevated non-fasting triglycerides mark elevated levels of remnant cholesterol. Using a Mendelian randomization approach, we tested whether genetically increased remnant cholesterol in hypertriglyceridaemia due to genetic variation in the apolipoprotein A5 gene (APOA5) associates with an increased risk of myocardial infarction (MI). METHODS AND RESULTS We resequenced the core promoter and coding regions of APOA5 in individuals with the lowest 1% (n = 95) and highest 2% (n = 190) triglyceride levels in the Copenhagen City Heart Study (CCHS, n = 10 391). Genetic variants which differed in frequency between the two extreme triglyceride groups (c.-1131T > C, S19W, and c.*31C > T; P-value: 0.06 to <0.001), thus suggesting an effect on triglyceride levels, were genotyped in the Copenhagen General Population Study (CGPS), the CCHS, and the Copenhagen Ischemic Heart Disease Study (CIHDS), comprising a total of 5705 MI cases and 54 408 controls. Genotype combinations of these common variants associated with increases in non-fasting triglycerides and calculated remnant cholesterol of, respectively, up to 68% (1.10 mmol/L) and 56% (0.40 mmol/L) (P < 0.001), and with a corresponding odds ratio for MI of 1.87 (95% confidence interval: 1.25-2.81). Using APOA5 genotypes in instrumental variable analysis, the observational hazard ratio for a doubling in non-fasting triglycerides was 1.57 (1.32-2.68) compared with a causal genetic odds ratio of 1.94 (1.40-1.85) (P for comparison = 0.28). For calculated remnant cholesterol, the corresponding values were 1.67(1.38-2.02) observational and 2.23(1.48-3.35) causal (P for comparison = 0.21). CONCLUSION These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.

Estimation of acute myocardial infarct size in man by serum CK-MB measurements.

This study was performed to determine the relationship between myocardial infarct size estimated by serum CK-MB methods and the extent of irreversible injury in acute myocardial infarction. In 321 consecutive patients, infarct size was estimated by different mathematical models, and in 22 patients who died in hospital, the extent of myocardial necrosis was determined by autopsy. We also investigated the depletion of CK-MB in infarcted tissue, the recovery of CK-MB in the plasma volume, and the elimination of CK-MB from plasma. Myocardial CK-MB depletion was relatively greater in the larger infarcts, whereas the recovery of enzyme in plasma was independent of the infarct size. Correction of serum CK-MB for changes in plasma volume improved the estimate significantly (p < 0.05). The correlation between the measured infarct size (g) and the estimated infarct size (units per liter and gram-equivalents) was highly significant (r = 0.85–0.89, SEE = 23–27%, p < 0.001). Thus, a semiquantitative expression of the extent of myocardial necrosis can be determined in vivo.

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

BACKGROUND The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. TRIAL DESIGN TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. CONCLUSION TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

The Angiotensin-converting Enzyme Inhibition Post Revascularization Study (APRES).

OBJECTIVE This study was performed to assess the effect of treatment with ramipril on the incidence of cardiac events after invasive revascularization in patients with asymptomatic moderate left ventricular dysfunction. BACKGROUND In patients with angina pectoris and left ventricular dysfunction, both invasive revascularization and treatment with angiotensin-converting enzyme inhibitors reduce cardiac mortality and morbidity. Whether there is a benefit from combining the two treatment strategies has never been evaluated prospectively. METHODS After invasive revascularization, 159 patients with preoperative chronic stable angina pectoris, left ventricular ejection fraction between 0.30 and 0.50 and no clinical heart failure were randomly assigned to receive double-blind treatment with either ramipril or placebo and subsequently followed for a median of 33 months. RESULTS Ramipril reduced the incidence of the triple-composite end point of cardiac death, acute myocardial infarction or clinical heart failure (risk reduction 58%; 95% confidence interval 7% to 80%, p = 0.031). The incidence of the quadruple-composite end point of cardiac death, acute myocardial infarction, clinical heart failure or recurrent angina pectoris was not altered with ramipril. These findings were consistent across subgroups with respect to left ventricular ejection fraction below or above 0.40, and whether coronary artery bypass grafting or percutaneous transluminal coronary angioplasty was performed. CONCLUSIONS In patients with angina pectoris and asymptomatic moderate left ventricular dysfunction, long-term treatment with ramipril after invasive revascularization significantly reduced the incidence of the composite end point of cardiac death, acute myocardial infarction or clinical heart failure, indicating that the beneficial effects of angiotensin-converting enzyme inhibitor treatment may be extended to include treatment of this patient group.