Long-term survival and causes of death in patients with ST-elevation acute coronary syndrome without obstructive coronary artery disease.

Aims: We aimed to study survival and causes of death in patients with ST-elevation acute coronary syndrome (STE-ACS) with and without obstructive coronary artery disease (CAD). Methods and results: We included 4793 consecutive patients with STE-ACS triaged for acute coronary angiography at a large cardiac invasive centre (2009-2014). Of these, 88% had obstructive CAD (stenosis ≥50%), 6% had non-obstructive CAD (stenosis 1-49%), and 5% had normal coronary arteries. Patients without obstructive CAD were younger and more often female with fewer cardiovascular risk factors. Median follow-up time was 2.6 years. Compared with patients with obstructive CAD, the short-term hazard of death (≤30 days) was lower in both patients with non-obstructive CAD [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.27-0.89, P = 0.018] and normal coronary arteries (HR 0.31, 95% CI 0.11-0.83, P = 0.021). In contrast, the long-term hazard of death (>30 days) was similar in patients with non-obstructive CAD (HR 1.15, 95% CI 0.77-1.72, P = 0.487) and higher in patients with normal coronary arteries (HR 2.44, 95% CI 1.58-3.76, P < 0.001), regardless of troponin levels. Causes of death were cardiovascular in 70% of patients with obstructive CAD, 38% with non-obstructive CAD, and 32% with normal coronary arteries. Finally, patients without obstructive CAD had lower survival compared with an age and sex matched general population. Conclusions: STE-ACS patients without obstructive CAD had a long-term risk of death similar to or higher than patients with obstructive CAD. Causes of death were less often cardiovascular. This suggests that STE-ACS patients without obstructive CAD warrant medical attention and close follow-up.

Deferred versus conventional stent implantation in patients with ST-segment elevation myocardial infarction (DANAMI 3-DEFER): an open-label, randomised controlled trial.

BACKGROUND: Despite successful treatment of the culprit artery lesion by primary percutaneous coronary intervention (PCI) with stent implantation, thrombotic embolisation occurs in some cases, which impairs the prognosis of patients with ST-segment elevation myocardial infarction (STEMI). We aimed to assess the clinical outcomes of deferred stent implantation versus standard PCI in patients with STEMI. METHODS: We did this open-label, randomised controlled trial at four primary PCI centres in Denmark. Eligible patients (aged >18 years) had acute onset symptoms lasting 12 h or less, and ST-segment elevation of 0·1 mV or more in at least two or more contiguous electrocardiographic leads or newly developed left bundle branch block. Patients were randomly assigned (1:1), via an electronic web-based system with permuted block sizes of two to six, to receive either standard primary PCI with immediate stent implantation or deferred stent implantation 48 h after the index procedure if a stabilised flow could be obtained in the infarct-related artery. The primary endpoint was a composite of all-cause mortality, hospital admission for heart failure, recurrent infarction, and any unplanned revascularisation of the target vessel within 2 years' follow-up. Patients, investigators, and treating clinicians were not masked to treatment allocation. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01435408. FINDINGS: Between March 1, 2011, and Feb 28, 2014, we randomly assigned 1215 patients to receive either standard PCI (n=612) or deferred stent implantation (n=603). Median follow-up time was 42 months (IQR 33-49). Events comprising the primary endpoint occurred in 109 (18%) patients who had standard PCI and in 105 (17%) patients who had deferred stent implantation (hazard ratio 0·99, 95% CI 0·76-1·29; p=0·92). Procedure-related myocardial infarction, bleeding requiring transfusion or surgery, contrast-induced nephopathy, or stroke occurred in 28 (5%) patients in the conventional PCI group versus 27 (4%) patients in the deferred stent implantation group, with no significant differences between groups. INTERPRETATION: In patients with STEMI, routine deferred stent implantation did not reduce the occurrence of death, heart failure, myocardial infarction, or repeat revascularisation compared with conventional PCI. Results from ongoing randomised trials might shed further light on the concept of deferred stenting in this patient population. FUNDING: Danish Agency for Science, Technology and Innovation, and Danish Council for Strategic Research.

Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: a placebo-controlled, randomized study.

BACKGROUND: In patients with severe aortic stenosis (AS), treatment with angiotensin-converting enzyme inhibitors has previously been considered contraindicated. However, there is a lack of clinical evidence to confirm these potential hemodynamic risks and benefits. METHODS: Forty-four patients with severe AS (aortic valve area <1 cm(2)) were randomized to treatment with trandolapril 22 mg daily/placebo (1:1). Right heart catheterization and echocardiography were performed at rest and during exercise at baseline and on day 3. Follow-up was performed before valve replacement or after a maximum of 8 weeks, when exercise echocardiography was repeated. RESULTS: Compared with placebo, systolic blood pressure and systemic arterial compliance significantly changed at day 3 (-14 ± 11 vs -5 ± 13 mm Hg, P = .02, and 0.08 ± 0.16 vs -0.05 ± 0.86 mL/m(2) per mm Hg, P = .03, respectively). Changes in left ventricular end systolic volume (LVESV) was nonsignificant (-8 ± 9 vs -3 ± 11 mL, P = .17). At a median of 49 days of follow-up, changes in LVESV and N-terminal pro-brain natriuretic peptide were even lower revealing significant differences between the groups (-7.8 ± 2.6 vs -0.5 ± 2.5 mL, P = .04, and -19 ± 7 vs 0.8 ± 6 pmol/L, P = .04, respectively). No episodes of symptomatic hypotension were noted, and other hemodynamic parameters remained unchanged. CONCLUSION: Angiotensin-converting enzyme inhibition in severe AS caused a decrease in LVESV and N-terminal pro-brain natriuretic peptide with other hemodynamic parameters preserved both at rest and during exercise implying hemodynamic improvement with left ventricular unloading.

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.

Genetic variation in ABCG1 and risk of myocardial infarction and ischemic heart disease.

OBJECTIVE: ATP binding cassette transporter G1 (ABCG1) facilitates cholesterol efflux from macrophages to mature high-density lipoprotein particles. Whether genetic variation in ABCG1 affects risk of atherosclerosis in humans remains to be determined. METHODS AND RESULTS: We resequenced the core promoter and coding regions of ABCG1 in 380 individuals from the general population. Next, we genotyped 10 237 individuals from the Copenhagen City Heart Study for the identified variants and determined the effect on lipid and lipoprotein levels and on risk of myocardial infarction (MI) and ischemic heart disease (IHD). g.-376C>T, g.-311T>A, and Ser630Leu predicted risk of MI in the Copenhagen City Heart Study, with hazard ratios of 2.2 (95% confidence interval: 1.2-4.3), 1.7 (1.0-2.9), and 7.5 (1.9-30), respectively. These results were confirmed for g.-376C>T in a case-control study comprising 4983 independently ascertained IHD cases and 7489 controls. Expression levels of ABCG1 mRNA were decreased by approximately 40% in g.-376C>T heterozygotes versus noncarriers (probability values: 0.005-0.009). Finally, in vitro specificity protein 1 (Sp1) bound specifically to a putative Sp1 binding site at position -382 to -373 in the ABCG1 promoter, and the presence of the -376 T allele reduced binding and transactivation of the promoter by Sp1. CONCLUSIONS: This is the first report of a functional variant in ABCG1 that associates with increased risk of MI and IHD in the general population.

TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.

OBJECTIVE: The goal of this study was to test whether TRIB1-rs2954029 and GCKR-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population. METHODS AND RESULTS: We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally. Risk of IHD and MI was examined prospectively, cross-sectionally, and in a case-control study, and a metaanalysis was performed. TRIB1 TA (50%) and AA (27%) versus TT (23%) genotypes were associated with increased levels of triglycerides (total increase, +0.16 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), apolipoprotein B (+5.7 mg/dL; P<0.001), and low-density lipoprotein cholesterol (+0.11 mmol/L; P<0.001) and with decreased levels of high-density lipoprotein cholesterol (-0.04 mmol/L; P<0.001). In metaanalyses of the 3 studies combined, TRIB1 TA and AA versus TT genotypes were associated with 13% (95% CI, 5% to 20%) and 15% (7% to 23%) increased risk of IHD, and 11% (1% to 21%) and 17% (6% to 30%) increased risk of MI, respectively. Although GCKR CT (46%) and TT (14%) versus CC (40%) genotypes had effects on triglycerides (+0.17 mmol/L; trend, P<0.001), remnant cholesterol (+0.07 mmol/L; P<0.001), and apolipoprotein B (+4.6 mg/dL; P<0.001) similar to those of TRIB1, GCKR did not influence low-density lipoprotein cholesterol levels or risk of IHD or MI. Risks of IHD were similar after stratification for gender, age, body mass index, hypertension, diabetes mellitus, smoking, statin use, alcohol intake, and physical activity. CONCLUSIONS: In the general population, both TRIB1-rs2954029 and GCKR-rs1260326 were associated with lipid levels, whereas TRIB1 was also associated with increased risk of IHD and MI.

Surgical treatment of acute pulmonary embolism--a 12-year retrospective analysis.

OBJECTIVES: Surgical embolectomy for acute pulmonary embolism (PE) is considered to be a high risk procedure and therefore a last treatment option. We wanted to evaluate the procedures role in modern treatment of acute PE. DESIGN: All data on patients treated with surgical embolectomy for acute PE were retrieved from our clinical database. The mortality was extracted from the Danish mortality register. RESULTS: From October 1998 to July 2010, 33 patients underwent surgical embolectomy. All procedures were done through a median sternotomy and extracorporeal circulation. Twenty-six patients were diagnosed with a high risk PE and 7 with an intermediate risk PE and intracardial pathology. Six patients had been insufficiently treated with thrombolysis. Thirteen patients had contraindication for thrombolysis. Six patients were brought to the operating theatre in cardiogenic shock, 8 needed ventilator support, and 1 was in cardiac arrest. The postoperative 30-day mortality was 6% and during the 12-year follow-up the cumulative survival was 80% with 4 late deaths. CONCLUSION: Surgical pulmonary embolectomy can be performed with low mortality although the treated patients belong to the most compromised part of the PE population. The results support surgical embolectomy as a vital part of the treatment algorithm for acute PE.

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.

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 > 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). CONCLUSIONS: 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 > or = 2.0 mg/L. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Genetically reduced soluble epoxide hydrolase activity and risk of stroke and other cardiovascular disease.

BACKGROUND AND PURPOSE: The development of stroke has been linked to lowered levels of epoxyeicosatrienoic acids in the cerebral microvasculature. These substances are metabolized by the enzyme-soluble epoxide hydrolase encoded by the EPHX2 gene. We tested whether genetically reduced soluble epoxide hydrolase activity is associated with risk of ischemic stroke, myocardial infarction, and ischemic heart disease. METHODS: We genotyped participants from the Copenhagen City Heart Study (n=10 352), the Copenhagen General Population Study (n=26 042), the Copenhagen Carotid Stroke Study (n=398 cases+796 control subjects), and the Copenhagen Ischemic Heart Disease Study (n=4901 cases+9798 control subjects) for the R103C, R287Q, and Arg(402-403ins) variants in the EPHX2 gene and recorded hospital admissions due to ischemic stroke, myocardial infarction, and ischemic heart disease. RESULTS: The hazard/odds ratio for ischemic stroke did not differ from 1.0 for any of the EPHX2 genotypes or genotype combinations in the Copenhagen City Heart Study (P for trend=0.15 to 0.76), in the Copenhagen General Population Study (P for trend=0.75 to 0.95), and the Copenhagen Carotid Stroke Study (P for trend=0.08 to 1.00). Similar results were obtained for myocardial infarction and ischemic heart disease in the 3 studies. CONCLUSIONS: Our results show with significant power that genetically reduced soluble epoxide hydrolase activity is not a major risk factor for ischemic stroke, myocardial infarction, or ischemic heart disease in the Danish population. This suggests that the relationship between the EPHX2 gene and risk of ischemic stroke and other cardiovascular disease does not exist or its effect size is likely to be quite small.

Rosuvastatin in older patients with systolic heart failure.

BACKGROUND: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients. METHODS: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations. RESULTS: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group. CONCLUSIONS: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.)

Predictors of exercise capacity and symptoms in severe aortic stenosis.

AIMS: This study investigated the association between invasive and non-invasive estimates of left ventricular (LV) filling pressure and exercise capacity, in order to find new potential candidates for risk markers in severe aortic valve stenosis (AS). METHODS AND RESULTS: Twenty-nine patients with AS, aortic valve area (AVA) < 1 cm(2), performed a symptom-limited multistage supine bicycle exercise test. Immediately before the exercise test, the pulmonary capillary wedge pressure (PCWP), Doppler index for LV filling (E/e'), and left atrial (LA) volume were measured. Symptomatic status was determined by senior staff doctors blinded to the results of this study. All patients terminated the exercise test because of dyspnoea. There were no significant differences in AVA between asymptomatic patients (n = 9) and symptomatic patients (n = 20), and AVA did not correlate with exercise capacity (r = -0.16, P = NS). In contrast, PCWP, LA volume, and E/e' were significantly increased in the symptomatic group and they all correlated with exercise capacity (r = -0.66, -0.75, and -0.62, respectively, P < 0.001). Receiver operating characteristic curve analysis confirmed that PCWP, LA volume index, and E/e' all provided incremental information [area under the curve (AUC) = 0.90, 0.92, and 0.90, respectively, P < 0.05] over AVA index (AUC = 0.66, NS) in predicting symptomatic status. CONCLUSION: PCWP, LA volume, or E/e' is closely related to exercise capacity and symptomatic status, and may therefore be important markers of disease severity in AS. Clinical Trials.gov Identifier: NCT00252317 (http://clinicaltrials.gov/ct2/results?term=NCT00252317).

Long-term effects of invasive treatment in patients with a post-thrombolytic Q-wave myocardial infarction.

OBJECTIVES: The aim of the present study was to assess the effect of a deferred invasive treatment strategy on long-term outcome in patients with a post-thrombolytic Q-wave myocardial infarction and inducible myocardial ischemia. DESIGN: Patients (N=751) with post-thrombolytic Q-wave myocardial infarction and inducible ischemia (angina pectoris or silent myocardial ischemia) were randomized to a deferred invasive treatment (balloon angioplasty or coronary bypass surgery) or medical treatment. Vital status and non-fatal cardiac events defined as hospitalization caused by acute cardiac events were recorded for a median of 11.4 years. RESULTS: Survival was significantly improved in patients receiving invasive treatment compared to patients treated medically (hazard ratio 0.85 (95% confidence limits 0.73-0.99), p=0.034). Subgroup analysis showed a reduction of non-fatal cardiac events and improved survival among the patients with post-infarction angina pectoris and not among the patients with silent myocardial ischemia. CONCLUSIONS: A deferred invasive treatment strategy improves survival compared to medical treatment in patients with inducible myocardial ischemia after a post-thrombolytic Q-wave myocardial infarction.

Leukotriene C4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals.

Ischemic cardiovascular disease and obstructive pulmonary disease involve inflammation. Leukotrienes may be important pro-inflammatory mediators. We tested the hypothesis that the (-1072)G > A and (-444)A > C promoter polymorphisms of leukotriene C4 synthase confer risk of transient ischemic attack (TIA), ischemic stroke, ischemic heart disease (IHD), asthma, and chronic obstructive pulmonary disease (COPD). We genotyped individuals from the Danish general population, the Copenhagen City Heart Study, and Danish patients with IHD/coronary atherosclerosis, the Copenhagen Ischemic Heart Disease Study. We used prospective (n = 10,386), cross-sectional (n = 10,386), and case-control (n = 2392 + 5012) designs. Allele frequency was 0.07 for (-1072)A and 0.29 for (-444)C. Cumulative incidence for TIA was higher for (-1072)AA versus GG genotype (log-rank: p < 0.001), and lower for (-444)CC versus AA genotype (log-rank: p = 0.03). Cumulative incidence for ischemic stroke was also lower for (-444)CC versus AA genotype (log-rank: p = 0.04). Multifactorially adjusted hazard ratios for TIA were 5.2(95% CI:1.9-14) for (-1072)AA versus GG genotype, and 0.4(0.2-1.0) for (-444)CC versus AA genotype. Corresponding values were 1.9 (0.7-5.2) and 0.7 (0.5-1.0) for ischemic stroke, and 0.8 (0.4-1.6) and 1.0 (0.9-1.2) for IHD. In the case-control study, corresponding multifactorially adjusted odds ratios for IHD/coronary atherosclerosis were 0.5 (0.2-1.3) and 1.2 (1.0-1.5). These genotypes were not associated with risk of asthma or COPD. Leukotriene C4 synthase promoter genotypes influence risk of TIA and ischemic stroke, but not risk of IHD/coronary atherosclerosis, asthma, or COPD.

Cardiac troponin I degradation in serum of patients with hypertrophic obstructive cardiomyopathy undergoing percutaneous septal ablation.

INTRODUCTION: Troponin has become the most important marker for diagnosing acute myocardial infarction, yet knowledge is scarce regarding appearance of specific degradation fragments in the blood. We have recently described the appearance of intact cardiac troponin I (cTnI) and 7 degradation products in patients suffering from ST-elevation myocardial infarction (STEMI) using Western blot analysis. However, the time resolution in STEMI patients is hampered by the rather vague time point 'onset of pain'. We therefore sought to utilize a time-wise more reliable model of human myocardial necrosis: percutaneous transluminal septal myocardial ablation (PTSMA) of hypertrophic obstructive cardiomyopathy (HOCM). Here the iatrogenic induction of myocardial necrosis occurs in vivo, allowing us to investigate degradation of cTnI by the second. METHODS: Blood samples were obtained from 8 patients with HOCM just prior to initiation of PTSMA and up to 50 h following the procedure. Western blot analysis was performed with subsequent analysis of relative intensities of the bands as compared to the degradation of cTnI in STEMI patients from the ASSENT-2 troponin substudy. RESULTS: We demonstrate intact cTnI and 9 degradation products [molecular weight (MW) 12.0-23.5 kDa]. The bands were comparable in MW to degradation fragments in STEMI. Their early rise in intensity, occurring within few minutes after the alcohol injection, emphasizes how susceptible troponin bands are to chemical/ischemic insults. Moreover, two additional bands were visible in the PTSMA population. CONCLUSION: This work describes the degradation products of troponin I in HOCM patients undergoing PTSMA. The detected bands appear fast and are similar to degradations following STEMI. This model contributes to our knowledge of the degradation patterns of troponin in disease states, and may thus play a role in the interpretation of elevated troponin levels.

Release patterns of pregnancy-associated plasma protein A in patients with acute coronary syndromes assessed by an optimized monoclonal antibody assay.

OBJECTIVE: Pregnancy-associated plasma protein A (PAPP-A) is expressed in eroded and ruptured atheromatous plaques, and circulating levels are elevated in acute coronary syndromes (ACS). Our objective was to investigate release patterns of PAPP-A in ACS and whether they differ among different types of ACS. METHODS: In 40 patients, PAPP-A concentrations were measured in serially collected samples assessed by a novel ELISA technique. The patients were grouped according to type of ACS. RESULTS: Release patterns for ST elevation myocardial infarction (STEMI) patients who underwent primary percutaneous coronary intervention (pPCI) showed a single substantial PAPP-A increase shortly after pPCI, followed by an abrupt return to normal levels without secondary peaks. STEMI, high-risk and low-risk non-ST elevation myocardial infarction/unstable angina pectoris (NSTEMI/UAP) patients without pPCI showed highly variable patterns with primary peaks followed by secondary PAPP-A increases. All patients with elevated PAPP-A levels reached the upper reference level within 24 h. There was a significant difference in median peak levels between STEMI (23.2 mIU/L) and low-risk ACS patients (6.35 mIU/L) (p = 0.004) and between high-risk (median = 15.3 mIU/L) and low-risk ACS patients (p = 0.01). Among high-risk ACS patients, NSTEMI patients had significantly higher peak levels than UAP patients (p = 0.003). CONCLUSION: PAPP-A serum levels increase above normal values within 24 h after onset of symptoms in ACS. There are significant differences in PAPP-A peak levels and release patterns across the spectrum of ACS patients.

Estrogen receptor alpha polymorphism and risk of cardiovascular disease, cancer, and hip fracture: cross-sectional, cohort, and case-control studies and a meta-analysis.

BACKGROUND: We hypothesized that the estrogen receptor alpha (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture. METHODS AND RESULTS: We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case-control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12,190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21). CONCLUSIONS: ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.

Pregnancy associated plasma protein A, a novel, quick, and sensitive marker in ST-elevation myocardial infarction.

Traditional biomarkers in acute coronary syndromes reflect myocardial necrosis but not the underlying arteriosclerotic disease. Pregnancy-associated plasma protein A (PAPP-A) is a new biomarker in acute coronary syndromes that detects vulnerable plaques in arteriosclerotic disease and identifies acute coronary syndromes earlier than traditionally used biomarkers. Information regarding circulating PAPP-A levels in patients with ST elevation myocardial infarctions (STEMIs) is limited and contradictory. The aim of the present study was to describe the presence and time-related pattern of circulating PAPP-A levels in patients with STEMIs. Consecutive patients (n = 354) referred for primary percutaneous intervention because of STEMI were included in the study. Blood samples for the analysis of PAPP-A, creatine kinase-MB (CKMB), and troponin T were drawn at admission and every 6 to 8 hours until biomarkers of myocardial necrosis were consistently decreasing. PAPP-A was measured using a newly developed sandwich enzyme-linked immunosorbent assay technique based on 2 monoclonal antibodies. In total, 1,091 PAPP-A, 1,049 troponin T, and 1,016 CKMB samples were analyzed. Mean PAPP-A values at admission were significantly higher in patients with STEMIs than in those with non-ST elevation myocardial infarctions or unstable angina pectoris (27.6 vs 12.2 mIU/L, p <0.01). In samples drawn <2 hours after admission, the sensitivity of PAPP-A was superior (93%) to that of CKMB (60%) and troponin T (61%). In conclusion, PAPP-A levels are elevated in >90% of patients presenting with STEMIs if measured <6 hours after the onset of symptoms or <2 hours of primary percutaneous coronary intervention. In the early stages of STEMI, PAPP-A seems to be a more sensitive marker of myocardial infarction than CKMB and troponin T.

Pre-discharge exercise test for evaluation of patients with complete or incomplete revascularization following primary percutaneous coronary intervention: a DANAMI-2 sub-study.

OBJECTIVES: It is unclear whether the completeness of revascularization impacts on the prognostic value of an exercise test after primary percutaneous coronary intervention (PCI). METHODS: The DANAMI-2 trial included patients with ST elevation acute myocardial infarction randomized to primary PCI or fibrinolysis. Of the 790 patients randomized to primary PCI, 572 performed an exercise test. Prospectively, 310 patients were classified as having complete and 216 as having incomplete revascularization. Primary endpoint was a composite of reinfarction and/or death. RESULTS: Patients with incomplete revascularization had lower exercise capacity [6.5 (95% CI: 1.9-12.8) vs. 7.0 (95% CI: 2.1-14.0) METs, p = 0.004] and more frequently ST depression [43 (20%) vs. 39 (13%), p = 0.02] compared to patients with complete revascularization. ST depression was not predictive of outcome in either groups, while multivariable analyses showed that exercise capacity was predictive of reinfarction and/or death in patients with incomplete revascularization [hazard ratio = 0.71 (95% CI: 0.54-0.93), p = 0.012] or of death alone [hazard ratio = 0.56 (95% CI: 0.41-0.77), p = 0.0003], which was not found in patients with complete revascularization. CONCLUSIONS: Exercise capacity was prognostic of reinfarction and/or death in patients with incomplete revascularization, but not in completely revascularized patients. ST segment depression alone did not predict residual coronary stenosis or dismal prognosis.