Robert Zweiker

Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

CONTEXT Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

Influence of beta-blockers on melatonin release.

AbstractObjective: Melatonin is a mediator in the establishment of the circadian rhythm of biological processes. It is produced in the pineal gland mainly during the night by stimulation of adrenergic beta1- and alpha1-receptors. Sleep disturbances are common side-effects of beta-blockers. The influence of specific beta-blockade as well as that of combined alpha-and beta-blockade on melatonin production has not been investigated in humans before. Methods: We performed a randomized, double-blind, placebo-controlled, cross-over study in 15 healthy volunteers. Subjects received single oral doses of 40 mg (R)-propranolol, 40 mg (S)-propranolol, 50 mg (R)-atenolol, 50 mg (S)-atenolol, 25 mg (R,S)-carvedilol, 120 mg (R,S)-verapamil or placebo at 1800 hours. Urine was collected between 2200 hours and 0600 hours, and 6-sulfatoxy-melatonin (aMT6s), the main metabolite of melatonin which is almost completely eliminated in urine, was determined by radioimmunoassay (RIA). Results: Mean nocturnal excretion of aMT6s in urine after intake of the drugs was as follows (in μg): placebo 26; (R)-propranolol 24 (−7%, NS); (S)-propranolol 5 (−80%, P < 0.001); (R)-atenolol 27 (+7%, NS); (S)-atenolol 4 (−86%, P < 0.01); (R,S)-carvedilol 23 (−10%, NS); (R,S)-verapamil 29 (+14%, NS). These data show that only the specifically beta-blocking (S)-enantiomers of propranolol and atenolol decrease the nocturnal production of melatonin whereas the non-beta-blocking (R)-enantiomers have no effect. Unexpectedly, (R,S)-carvedilol which inhibits both alpha- and beta-adrenoceptors does not decrease melatonin production. Conclusion: These findings indicate that beta-blockers decrease melatonin release via specific inhibition of adrenergic beta1-receptors. Since lower nocturnal melatonin levels might be the reason for sleep disturbances, further clinical studies should investigate whether or not oral administration of melatonin might avoid this well-known side-effect of beta-blockers. The reason why (R,S)-carvedilol does not influence melatonin production remains to be determined.

Increased Neopterin in Patients With Chronic and Acute Coronary Syndromes

OBJECTIVES The aim of our study was to determine neopterin levels in patients with chronic and acute coronary syndromes. BACKGROUND In chronic and acute coronary syndromes the release of different cytokines activates cellular defense. Infiltration of neutrophils and monocytes/macrophages is detected in the vessel wall as well as in the myocardium. Neopterin, which is a by-product of the guanosine triphosphate-biopterin pathway, is a marker for those activated macrophages. METHODS We studied 123 subjects: 1) 21 consecutive patients (17 men, 4 women; mean age +/- SD 66 +/- 15 years, range 31 to 87) with acute myocardial infarction (AMI); 2) 62 consecutive patients (50 men, 12 women; mean age 61 +/- 8 years, range 43 to 81) with signs and symptoms of clinically stable coronary artery disease (CAD); and 3) 40 healthy blood donors (28 men, 12 women; mean age 35 +/- 13 years). Neopterin levels were determined with a commercially available enzyme-linked immunosorbent assay method. RESULTS In patients with AMI before thrombolytic therapy, neopterin levels were significantly higher than levels in patients with CAD and control subjects (13.7 vs. 8.6 and vs. 6.8 nmol/liter, p < 0.0001). Values also differed significantly between patients with CAD and control subjects (p < 0.0001). Neopterin levels in patients with AMI were measured seven times during a 72-h period. Within-group comparison showed significant differences over this period (p < 0.00001). The lowest value (11.4 nmol/liter) was observed after 4 h and differed significantly from the initial value and values after 24 and 72 h (p < 0.05). After 72 h, neopterin increased to 14.9 nmol/liter, a value significantly different from all values other than the initial one. There was no correlation between neopterin and creatine kinase (CK); CK, MB isoenzyme; or lactate dehydrogenase as markers for the extent of the myocardial infarction during the observation period. CONCLUSIONS Our data support the hypothesis of an activation of monocytes and macrophages in patients with an acute or chronic coronary syndrome. Neopterin as a marker for macrophage activation is significantly increased in patients with chronic CAD and more pronounced in patients with AMI shortly after the onset of symptoms.

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): A randomised, open-label, multicentre trial

BACKGROUND Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti-ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT). METHODS In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step-down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22. FINDINGS Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI 0·62-1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group (42 patients [3%]; pnon-inferiority=0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59-1·13]; p=0·23). INTERPRETATION Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI. FUNDING Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Changes in thyroid hormone parameters after acute myocardial infarction

Abnormalities in circulating thyroid hormone levels are very common in systemic nonthyroidal illnesses, such as acute myocardial infarction. In this study, thyroid parameters were determined in a series of 16 consecutive infarction patients treated by thrombolysis. Blood samples were taken before therapy as well as 2, 4, 6, 8, 12 and 72 h following admission. Total and free serum thyroxin and triiodothyronine decreased and reverse T3 increased significantly showing no major variations up to 72 h, whereas thyroid-stimulating hormone values remained almost unchanged during the observation period. Subjects with CK-MB levels of more than 150 ng/ml (n = 10) revealed similar changes in thyroid parameters in comparison to those with lower values (n = 6; NS). Thus, although hormone modifications very often occur following acute infarction, thyroid status may not serve as a marker for the extent of left ventricular dysfunction in the early phase of myocardial infarction.

Transient reduction of autoantibodies against oxidized ldl in patients with acute myocardial infarction

Fifteen consecutive patients (mean age 66 +/- 14, range 31-82) with an acute myocardial infarction (MI) suitable for thrombolytic therapy were included in this study. Autoantibodies against oxidized low-density lipoprotein (LDL) were determined by enzyme-linked immunosorbent assay (ELISA). Patients (n = 10) with marked elevation of the MB isoenzyme of creatinine kinase (CK-MB)-mass had significant decreases of oLDL-Ab during the acute phase, with a minimum after 8 h following the onset of thrombolytic therapy (within-group significance: p < .001; between groups: p = .01). Patients (n = 5) with CK-MB-mass values less than 70 ng/ml did not show this phenomenon. Furthermore, significant correlations existed between CK-MB-mass and oLDL-Ab after 6 and 8 h (n = 15; r = .72; p = .003) and the time of the highest CK-MB-mass values (after 12 h) and the time of the maximal decrease of oLDL-Ab (after 8 h) (r = .74; p = .003). Our observations provide further evidence for the release of free radicals and for increased lipid peroxidation during reperfusion after prolonged ischemia. The decrease of oLDL-Ab appears to be a marker for the severity of MI.

Key role of postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: An angiographic study

BACKGROUND The associations between impaired glucose tolerance (IGT) and postchallenge diabetes with the presence and extent of angiographically characterized coronary atherosclerosis are unclear. MATERIALS AND METHODS We enrolled 1040 consecutive Caucasian patients undergoing coronary angiography for the evaluation of coronary artery disease (CAD). An oral 75-g glucose tolerance test was performed in patients without previously diagnosed diabetes. RESULTS From our patients, 394 had normal glucose tolerance (NGT), 190 impaired glucose tolerance (IGT), 90 isolated postchallenge diabetes (postchallenge glucose >or=200 mg/dl), and 366 type 2 diabetes previously established or newly diagnosed on the basis of fasting glucose (conventional diabetes). Coronary atherosclerosis was more frequent in patients with IGT, isolated postchallenge diabetes, or conventional diabetes when compared to NGT subjects (87.9, 95.6, 89.1 versus 80.7%; p=0.030, 0.001, 0.043, respectively). The prevalence of significant coronary stenoses >or=50%, compared to NGT subjects (57.4%), was similar in IGT patients (59.5%; p=0.628), but significantly higher in patients with isolated postchallenge diabetes (77.8%; p=0.001) or conventional diabetes (68.0%; p=0.002). Also the number of significant stenoses compared to NGT subjects was similar in IGT patients, but significantly higher in those with isolated postchallenge or conventional diabetes. These results were confirmed after multivariate adjustment. CONCLUSIONS Abnormal glucose tolerance is strongly and independently associated with angiographically characterized coronary atherosclerosis. In IGT, non-significant coronary atherosclerosis is more frequent than in NGT; the prevalence and number of significant stenoses increases when postchallenge diabetes evolves.

Syncope in Dilated Cardiomyopathy Is a Predictor of Sudden Cardiac Death

Fifty percent of patients with dilated cardiomyopathy die within 5 years of diagnosis. Syncope is known to be a predictor of poor outcome in patients with advanced heart failure. To assess the risk of patients with dilated cardiomyopathy with a history of syncope during standard medical treatment we compared this group to similar patients without syncope. Twenty-three patients with angiographically proven dilated cardiomyopathy and syncope were followed prospectively and compared to 201 patients without history of syncope. All patients showed a left-ventricular ejection fraction of less than 45%. Both groups did not differ in left-ventricular ejection fraction at baseline (30 +/- 7% in the syncope group, 30 +/- 8% in the no syncope group). Mean follow-up was 2.6 years in the syncope group and 2.4 years in the no syncope group. At baseline, syncope patients used more often amiodarone (p < 0.04), while there was no statistically significant difference between the two groups regarding the intake of digitalis, diuretics and angiotensin-converting enzyme inhibitors. Twenty-six percent of patients in the syncope group and 20% in the no syncope group died during follow-up (non significant). The striking difference, however, was the type of death: 5 out of 6 patients in the syncope group died suddenly compared to 13 of 41 patients in the no syncope group (p < 0.025). Patients with dilated cardiomyopathy and a history of syncope are at high risk of sudden death.

Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients

AIMS The prevalence of post-challenge hyperglycaemia in coronary patients is high. Until now, it is unclear whether post-challenge hyperglycaemia is associated with an increased risk for future macrovascular events in this clinically important patient population. METHODS AND RESULTS We enrolled 1040 patients undergoing coronary angiography for the evaluation of suspected or established coronary artery disease. In patients without previously established diabetes mellitus, an oral glucose tolerance test (oGTT) was performed. Prospectively, mortality and macrovascular events were recorded over a mean follow-up period of 3.8 years. From our patients, 394 had normal glucose tolerance (NGT), 280 post-challenge hyperglycaemia (this subgroup includes both impaired glucose tolerance and post-challenge diabetes) and 366 had conventional diabetes. The incidence of macrovascular events was significantly higher in patients with post-challenge hyperglycaemia as well as in patients with conventional diabetes than in subjects with NGT (23.6 and 29.5% vs. 18.5%; P = 0.013 and P < 0.001, respectively). Adjusted hazard ratios were 1.46 (95% CI 1.03-2.07, P = 0.033) for patients with post-challenge hyperglycaemia and 1.73 (1.25-2.37, P = 0.001) for patients with conventional diabetes. CONCLUSION Post-challenge hyperglycaemia is associated with future macrovascular events in patients undergoing coronary angiography for the evaluation of stable coronary artery disease (CAD). Oral glucose tolerance tests in this high-risk population thus identify patients with a particularly unfavourable prognosis.

Human Paraoxonase1 Gene Polymorphisms and the Risk of Coronary Heart Disease: A Community-Based Study

Published data on the association between paraoxonase1 (PON1) polymorphisms and coronary heart disease (CHD) have yielded controversial results. The objective of this study was to determine the possible relationship between the two human PON1 amino acid variants, the Leu55Met and the Gln192Arg polymorphism, and the risk of CHD in a community-dwelling cohort of European ancestry. PON1 genotypes of 152 women and 151 men out of 1,998 randomly selected individuals aged 44–75 years were determined by polymerase chain reaction-based restriction enzyme digestion. Study participants underwent cardiological examination including a structured clinical interview, resting ECG, exercise testing and echocardiography. The diagnosis of CHD was based on history and/or appropriate findings during cardiac examination. Evidence for CHD was found in 43 (14.2%) study participants. The Leu/Leu (LL), Leu/Met (LM) and Met/Met (MM) genotypes at position 55 were noted in 131 (43.2%), 128 (42.2%) and 44 (14.5%) subjects; the Gln/Gln (QQ), Gln/Arg (QR) and Arg/Arg (RR) genotypes at codon 192 occurred in 167 (55.1%), 118 (38.9%) and 18 (5.9%) individuals, respectively. Homozygosity for the 55L-allele was significantly associated with CHD (p = 0.02), while the Gln192Arg polymorphism had no effect (p = 0.16). Logistic regression analysis demonstrated age (odds ratio 1.06/year), smoking (odds ratio 2.86), HDL cholesterol (odds ratio 0.94/mg/dl) and the paraoxonase LL genotype (odds ratio 2.25) to be significant predictors of CHD. These data suggest that the paraoxonase LL genotype at position 55 may present a risk factor for CHD.