Light to Moderate Alcohol Consumption Is Associated With Lower Risk of Aortic Valve Sclerosis: The Study of Health in Pomerania (SHIP).

OBJECTIVE: In developed countries, sclerotic and calcific degeneration of the aortic valve is a common disorder showing pathophysiologic similarities with atherothrombotic coronary disease. Light to moderate alcohol consumption has been associated with a lower risk for atherothrombotic coronary disease and mortality. Whether alcohol consumption affects the development of aortic valve sclerosis (AVS) is not well known. In the present study, we aim to analyze the cross-sectional association between average daily alcohol consumption and AVS in the general population. APPROACH AND RESULTS: We analyzed cross-sectional data from 2022 men and women, aged 45 to 81 years, from the population-based Study of Health in Pomerania. We used a computer-assisted interview that included beverage-specific questions about quantity and frequency of alcohol over the last 30 days to calculate the average quantity of alcohol consumption (in grams of ethanol per day). AVS was ascertained by echocardiography. The prevalence of AVS was 32.3%. Average daily alcohol intake displayed a J-type relation with AVS (fully adjusted P value: 0.005). Compared with individuals with an average consumption of 10 g of alcohol per day, multivariable-adjusted odds ratios were 1.60 (95% confidence interval, 1.19-2.14) among current abstainers and 1.56 (95% confidence interval, 1.01-2.41) among individuals with an average consumption of 60 g per day. CONCLUSIONS: Our findings indicate that light to moderate alcohol consumption was associated with a lower odd of having AVS. Prospective data need to address whether alcohol consumption and related changes over time in several biological markers affect the progression of AVS.

Hepatic steatosis is associated with aortic valve sclerosis in the general population: the Study of Health in Pomerania (SHIP).

OBJECTIVE: We aimed to analyze the association between hepatic steatosis and aortic valve sclerosis in the general population. APPROACH AND RESULTS: Cross-sectional data of 2212 men and women, aged 45 to 81 years, from the baseline examination of the population-based Study of Health in Pomerania (SHIP-0) were analyzed. Hepatic steatosis was primarily defined as the presence of a hyperechogenic ultrasound pattern of the liver. Aortic valve sclerosis was determined by echocardiography. In our sample, hepatic steatosis was present in 877 (39.7%) individuals. Among participants with hepatic steatosis, aortic valve sclerosis was more common (n=323; 36.8%) compared with participants without hepatic steatosis (n=379; 28.4%; P<0.001). After adjustment for potential confounders, individuals with hepatic steatosis had 33% higher odds of aortic valve sclerosis compared with those without hepatic steatosis (95% confidence interval, 6%-66%; P=0.014). Additional adjustment for high-sensitive C-reactive protein, serum ferritin levels, and white blood cells slightly reduced the association to 32% (95% confidence interval, 4%-66%; P=0.021). CONCLUSIONS: Our findings add evidence that hepatic steatosis and aortic valve sclerosis are interrelated after adjustment for major confounders. The release of proatherogenic substances by the steatotic liver or its contribution to insulin resistance and dyslipidemia may contribute to the development of calcification and sclerosis of the aortic valve.

Association between degenerative aortic valve disease and long-term exposure to cardiovascular risk factors: results of the longitudinal population-based KORA/MONICA survey.

AIMS: Degenerative aortic valve disease (DAVD), a common finding in the elderly, is associated with an increased risk of death due to cardiovascular causes. Taking advantage of its longitudinal design, this study evaluates the prevalence of DAVD and its temporal associations with long-term exposure to cardiovascular risk factors in the general population. METHODS AND RESULTS: We studied 953 subjects (aged 25-74 years) from a random sample of German residents. Risk factors had been determined at a baseline investigation in 1994/95. At a follow-up investigation, 10 years later, standardized echocardiography determined aortic valve morphology and aortic valve area (AVA) as well as left ventricular geometry and function. At the follow-up study, the overall prevalence of DAVD was 28%. In logistic regression models adjusting for traditional cardiovascular risk factors at baseline age (OR 2.0 [1.7-2.3] per 10 years, P < 0.001), active smoking (OR 1.7 [1.1-2.4], P = 0.009) and elevated total cholesterol levels (OR 1.2 [1.1-1.3] per increase of 20 mg/dL, P < 0.001) were significantly related to DAVD at follow-up. Furthermore, age, baseline status of smoking, and total cholesterol level were significant predictors of a smaller AVA at follow-up study. In contrast, hypertension and obesity had no detectable relationship with long-term changes of aortic valve structure. CONCLUSIONS: In the general population we observed a high prevalence of DAVD that is associated with long-term exposure to elevated cholesterol levels and active smoking. These findings strengthen the notion that smoking cessation and cholesterol lowering are promising treatment targets for prevention of DAVD.

Ticagrelor-based antiplatelet regimens in patients treated with coronary artery bypass grafting: a meta-analysis of randomized controlled trials.

OBJECTIVES: The optimal antiplatelet strategy in patients undergoing CABG remains unclear. This is the first meta-analysis investigating the clinical outcomes associated with ticagrelor-based antiplatelet regimens in patients receiving CABG. METHODS: Relevant scientific databases were searched for studies investigating antiplatelet regimens after CABG from inception until April 1, 2019. Studies which randomly assigned CABG patients to either ticagrelor-based or control antiplatelet regimens were eligible. The primary outcome of this analysis was all-cause death. The main secondary outcome was MI. Other outcomes of interest were cardiac death, major adverse cardiac events, stroke and bleeding. This study is registered with PROSPERO, number CRD42019122192. RESULTS: Five trials comprising 3996 patients (2002 assigned to ticagrelor-based and 1994 to control antiplatelet regimens) were eligible for quantitative synthesis. The median follow-up was 12 months. Control antiplatelet regimens consisted of either aspirin or clopidogrel or both. As compared to control, ticagrelor-based regimens reduced the risk of all-cause death [0.61 (0.43-0.87); P = 0.007], cardiac death [0.58 (0.39-0.86); P = 0.007] and major adverse cardiac events [0.79 (0.63-0.98); P = 0.03], without difference in the risk of MI [0.76 (0.50-1.18); P = 0.22], stroke [0.99 (0.56-1.78); P = 0.98] or bleeding [1.04 (0.95-1.14); P = 0.41]. There was a treatment effect modification for the primary outcome associated with trials enrolling predominantly patients with acute coronary syndrome (P for interaction = 0.038). CONCLUSIONS: In patients receiving CABG, ticagrelor-based regimens reduce mortality and major adverse cardiac events without excess bleeding risk as compared with aspirin monotherapy or the combination of aspirin and clopidogrel. The benefit of ticagrelor-based regimens is more relevant in those studies enrolling predominantly patients with acute coronary syndrome. These findings require further confirmation in randomized trials focused on this subset of patients and powered for clinical outcomes.

Ticagrelor monotherapy versus aspirin in patients undergoing multiple arterial or single arterial coronary artery bypass grafting: insights from the TiCAB trial.

OBJECTIVES: We evaluated the effect of ticagrelor monotherapy on outcomes after multiple arterial grafting (MAG) or single arterial grafting (SAG) in coronary artery bypass grafting (CABG). METHODS: In a post hoc, non-randomized analysis of the TiCAB (Ticagrelor in CABG; ClinicalTrials.gov NCT01755520) trial, we compared event rates for ticagrelor versus aspirin in patients undergoing MAG and SAG. Primary outcome was the composite of cardiovascular death, non-fatal myocardial infarction (MI), stroke or repeat revascularization 1 year after CABG. Secondary outcomes included individual components of the primary end point, all-cause death and bleeding. RESULTS: Among 1753 patients, 998 patients underwent MAG and 755 patients underwent SAG. There was no significant difference in the 1-year primary composite outcome for ticagrelor versus aspirin with MAG [7.2% vs 7.9%; hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.57-1.43; P = 0.66] or SAG (12.3% vs 8.6%; HR 1.47, 95% CI 0.93-2.31; P = 0.10). Event rates for cardiovascular death, MI, stroke, repeat revascularization and all-cause death were similar for both treatment groups with MAG and SAG. No significant difference in major bleeding was observed for ticagrelor versus aspirin with MAG (2.6% vs 2.7%; HR 0.95, 95% CI 0.44-2.05; P = 0.90) or SAG (5.8% vs 4.0%; HR 1.49, 95% CI 0.77-2.89; P = 0.24). CONCLUSIONS: In patients undergoing either MAG or SAG in the TiCAB trial, ticagrelor monotherapy compared with aspirin did not affect the rate of cardiovascular death, non-fatal MI, stroke or repeat revascularization, or the rate of bleeding, at 1 year after CABG.

Clinical outcomes of complete versus incomplete revascularization in patients treated with coronary artery bypass grafting: insights from the TiCAB trial.

OBJECTIVES: In this post hoc analysis of the Ticagrelor in coronary artery bypass grafting (CABG) trial, we aimed to analyse patients treated with CABG receiving either complete revascularization (CR) or incomplete revascularization (ICR) independent from random allocation to either ticagrelor or aspirin. METHODS: Of 1859 patients enrolled in the Ticagrelor in CABG trial, 1550 patients (83.4%) received CR and 309 patients (16.6%) ICR. Outcomes were evaluated regarding all-cause mortality, cardiovascular death, myocardial infarction (MI), repeat revascularization, stroke and bleeding within 12 months after CABG. RESULTS: Baseline parameters revealed significant differences regarding clinical presentation (stable angina pectoris: CR 68.9% vs ICR 71.2%, instable angina pectoris: 14.1% vs 7.8%, non-ST elevation MI: 17.0% vs 21.0%, P ˂ 0.01), lesion characteristics (chronic total occlusion: CR 91.3% vs ICR 96.8%, P ˂ 0.01), operative technique [off-pump coronary artery bypass surgery (OPCAB): CR 3.0% vs ICR 6.1%, P ˂ 0.01] and number of utilized grafts (total number of grafts: 2.69/patient vs 2.49/patient, P ˂ 0.001). ICR patients displayed a significantly increased risk of repeat revascularization [hazard ratio (HR) 1.91, 95% confidence interval (CI) 1.16-3.16; P < 0.01] and percutaneous coronary intervention (HR 1.95, 95% CI 1.13-3.35; P < 0.05) within 12 months after CABG. Higher risk for repeat revascularization in ICR patients was independent from random allocation to either ticagrelor or aspirin and persisted after adjustment for baseline imbalances. CONCLUSIONS: Patients with ICR presented more stable at the time of admission, but received less grafts, highly likely due to a higher rate of chronic total occlusion lesions and performed OPCAB. Although mortality presented no difference between groups, our results suggest that patients benefit from CR with regard to prevention of repeat revascularization.

Polymorphisms in the promoter region of the dimethylarginine dimethylaminohydrolase 2 gene are associated with prevalence of hypertension.

UNLABELLED: Infusion of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) causes an elevation of blood pressure and depression of cardiac output. Polymorphisms in the promoter region of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase 2 (DDAH2) gene have been associated with elevated ADMA concentrations and adverse outcomes in critically ill patients. We hypothesized that two DDAH2 promoter -1151 A/C and -449 G/C polymorphisms (rs805304 and rs805305) will be associated with blood pressure levels, hypertension prevalence and measures of cardiac structure and function in the general population. METHODS AND RESULTS: We genotyped rs805304 and rs805305 in 783 participants of the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg S3 study. Plasma ADMA concentrations did not differ by rs805304 and rs805305 genotypes. Both polymorphisms were associated with a higher prevalence of hypertension. The odds ratio (adjusted for age, gender and body mass index) for hypertension was 1.70 (95%CI: 1.22-2.36: p=0.002) for those homozygous (n=348) for the -1151A allele and 1.80 (95%CI: 1.29-2.49, p<0.001) for individuals homozygous for the -449G allele (n=350). However, both polymorphisms were not related to measures of cardiac structure and function (left ventricular [LV] mass, LV wall thickness, LV end-diastolic diameter, ejection fraction, E/A ratio, isovolumetric relaxation time) in multivariable-adjusted models. CONCLUSION: The present study indicates that the -1151 A/C and -449 G/C polymorphisms in the DDAH2 promoter region are not related to plasma ADMA levels or measures of cardiac structure and function but are associated with an increased prevalence of hypertension. The mechanisms of this association need further investigation.

Regional differences in the prevalence of left ventricular hypertrophy within Germany.

BACKGROUND: There are considerable regional disparities in the prevalence of cardiovascular risk factors within Germany. We undertook this study to investigate differences in the prevalence of left ventricular hypertrophy (LVH) between northeast and southwest Germany. METHODS: Data from two population-based studies, Kooperative Gesundheitsforschung im Raum Augsburg (KORA) conducted in southwest and Study of Health in Pomerania (SHIP) conducted in northeast Germany, were utilized. The study population comprised 2,516 women and men (835 from KORA and 1,681 from SHIP) aged 45-74 years who had no history of myocardial infarction. Echocardiograms were obtained according to standard protocols. Left ventricular mass (LVM), left ventricular mass indexed for body height, and left ventricular hypertrophy were used as dependent variables in multivariable analyses. RESULTS: SHIP participants had higher LVM and left ventricular mass index values compared with KORA participants. These differences remained after analyses were adjusted for major confounders including obesity and hypertension. Consequently, there were higher proportions of LVH in SHIP compared with KORA across all 10-year age groups. Multivariable logistic regression revealed that the odds for LVH in participants living in northeast Germany were higher in women and men, respectively, by 1.57 (95% confidence interval: 1.18-2.09) and 1.68 (95% confidence interval: 1.25-2.27) than in participants living in southwest Germany. Potential methodological differences between studies do not seem to account for these findings. CONCLUSION: There is a higher prevalence of LVH in northeast compared with southwest Germany. Regional disparities in hypertension and overweight only partly explain this difference.

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.

Implications of persistent prehypertension for ageing-related changes in left ventricular geometry and function: the MONICA/KORA Augsburg study.

BACKGROUND: It is unclear whether persistent prehypertension causes structural or functional alterations of the heart. METHODS: We examined echocardiographic data of 1005 adults from a population-based survey at baseline in 1994/1995 and at follow-up in 2004/2005. We compared individuals who had either persistently normal (<120 mmHg systolic and <80 mmHg diastolic, n = 142) or prehypertensive blood pressure (120-139 mmHg or 80-89 mmHg, n = 119) at both examinations using multivariate regression modeling. RESULTS: Over 10 years, left ventricular end-diastolic diameters were stable and did not differ between the two groups. However, the prehypertensive blood pressure group displayed more pronounced ageing-related increases of left ventricular wall thickness (+4.7 versus +11.9%, P < 0.001) and left ventricular mass (+8.6 versus +15.7%, P = 0.006). Prehypertension was associated with a raised incidence of left ventricular concentric remodeling (adjusted odds ratio 10.7, 95% confidence interval 2.82-40.4) and left ventricular hypertrophy (adjusted odds ratio 5.33, 1.58-17.9). The ratio of early and late diastolic peak transmitral flow velocities (E/A) decreased by 7.7% in the normal blood pressure versus 15.7% in the prehypertensive blood pressure group (P = 0.003) and at follow-up the ratio of early diastolic peak transmitral flow and early diastolic peak myocardial relaxation velocities (E/EM) was higher (9.1 versus 8.5, P = 0.031) and left atrial size was larger (36.5 versus 35.3 mm, P = 0.024) in the prehypertensive blood pressure group. Finally, the adjusted odds ratio for incident diastolic dysfunction was 2.52 (1.01-6.31) for the prehypertensive blood pressure group. CONCLUSIONS: Persistent prehypertension accelerates the development of hypertrophy and diastolic dysfunction of the heart.

Haematocrit levels and left ventricular geometry: results of the MONICA Augsburg Echocardiographic Substudy.

BACKGROUND: Extreme alterations in blood count such as anaemia or polycythemia are known to cause circulatory changes and, if these alterations persist, adaptations of cardiac geometry. OBJECTIVES: To investigate further the association between haematocrit levels and left ventricular geometry in a population-based sample. METHODS: We examined 687 women and 648 men, aged 25-74 years, participating in the third population-based MONICA Augsburg study. Anthropometry, blood pressure, laboratory measurements and M-mode echocardiography were obtained using standardized methods. RESULTS: Haematocrit levels were inversely related to end-diastolic diameters (P < 0.001). By contrast, septal and posterior wall thickness displayed parabolic association curves with nadirs at physiological haematocrit levels (P < 0.001). These associations remained significant after adjustment for age, sex, body fat, hypertension, diabetes mellitus, cardiovascular disease, heart failure, serum creatinine, and were likewise found for haemoglobin levels or numbers of erythrocytes. These correlations appeared to be secondary to changes in blood pressure and stroke volume that correlated either positively (blood pressure) or inversely (stroke volume) with haematocrit levels. Consequently, a concentric pattern of left ventricular hypertrophy, i.e. a relative wall thickness of 0.45 or greater, was significantly more prevalent in subjects with high haematocrit levels than in those with intermediate haematocrit levels. By contrast, an eccentric left ventricular hypertrophy, i.e. relative wall thickness less than 0.45, was more common in subjects with low haematocrit levels. CONCLUSION: In the general population, the variability of haematocrit levels and its haemodynamic consequences translates to distinct patterns of left ventricular geometry.

Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP.

Activation of BNP and IL-6 are hallmarks of left ventricular (LV) dysfunction and congestive heart failure (CHF). To assess the relative activation of BNP and IL-6 in clinical and experimental heart failure, we performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 were measured in a large group of patients in the chronic phase after myocardial infarction (MI) and an animal study in which LV gene expression of BNP and IL-6 was assessed in rapid ventricular pacing-induced heart failure. In the human study, NT-proBNP and IL-6 were measured by non-extracted, enzyme-linked immunoassay in 845 subjects (n=468 outpatients after MI, MONICA MI register Augsburg; and 377 siblings without MI, control). NT-proBNP (295+/-23pg/mL vs. CTRL 84+/-8, P<0.05) and IL-6 (2.7+/-0.1pg/mL vs. CTRL 2.1+/-0.1, P<0.05) were both elevated in subjects with MI. These increases were particularly pronounced in the presence of concomitant CHF (both P<0.01 vs. CTRL) and LV dysfunction (EF<45%, both P<0.05 vs. CTRL). However, NT-proBNP was significantly correlated with several cardiac structural and functional parameters (EF, LVMI, history of MI, CHF symptoms; all P<0.05) upon regression analysis whereas IL-6 was only correlated with history of MI (P<0.001). Accordingly, MI subjects with symptomatic LV dysfunction were detected by NT-proBNP with a greater sensitivity, specificity, and ROC-area (85%, 88%, and 0.87, respectively) as compared to IL-6 (69%, 53%, and 0.67, respectively). In the animal study, IL-6 and BNP expression were both significantly elevated in CHF (both P<0.05) but with a much greater absolute activation of BNP. In addition, BNP mRNA expression displayed a stronger inverse correlation with LV function (r=-0.74; P<0.001) than IL-6 (r=-0.53; P=0.001) and was a markedly more sensitive and specific molecular marker of LV dysfunction (sensitivity 91%, specificity 100%, ROC-area 0.94) than IL-6 (sensitivity 74%, specificity 83%, ROC-area 0.87). Our animal study provides evidence that IL-6 expression is activated in heart failure but to a significantly lesser degree than that of BNP. Both the stronger expression of BNP and the better correlation with LV function provide the molecular basis for a diagnostic superiority of NT-proBNP in clinical LV dysfunction and heart failure.

Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy.

Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5'-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8+/-1.52 vs non-TGGC 94.8+/-0.99 g/m(2), p=0.027; SWT: TGGC 11.5+/-0.14 vs non-TGGC 11.1+/-0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men.

Long-term pattern of brain natriuretic peptide and N-terminal pro brain natriuretic peptide and its determinants in the general population: contribution of age, gender, and cardiac and extra-cardiac factors.

AIMS: The natriuretic peptides BNP and NT-proBNP are potent cardiac markers, but knowledge of long-term changes is sparse. We thus quantified determinants of change in BNP and NT-proBNP in a study of south German residents (KORA). METHODS AND RESULTS: A total of 1005 men and women (age 25-74 years, mean 48 years) underwent physical examination and echocardiography at baseline and at follow-up after 10 years. The current analysis comprised 877 subjects with dual measurements of BNP and NT-proBNP. Both markers increased in both sexes (P < 0.001) during the 10-year follow-up, and higher levels in women persisted across time (P for sex difference <0.001). Among baseline covariates, predictors for 10-year change of NT-proBNP, BNP, or both were age, sex, diabetes status, and heart rate (multivariable regression analysis, each P < 0.05). However, changes of covariates over the 10-year follow-up were much stronger determinants. Specifically, incident myocardial infarction, new beta-blocker medication, and increased cardiac parameters (left atrial diameter, LV end-diastolic diameter, and LV mass index) were associated with increasing BNP, NT-proBNP, or both, whereas increased heart rate, haematocrit, and body mass index (BMI) were associated with decreasing BNP and NT-proBNP (all P < 0.05). CONCLUSION: Next to ageing and sex, a variety of changes in covariates reflecting the sequelae of cardiac remodelling as well as myocardial infarction and diabetes influence long-term changes of BNP and NT-proBNP. Of note, diabetes and increased BMI exert opposite effects. For interpretation of individual marker concentrations, a host of covariates needs to be considered, especially in subjects without prevalent or incident cardiac disease.

Effects of smoking on arterial distensibility, central aortic pressures and left ventricular mass.

BACKGROUND: The effects of smoking on central aortic pressures and the age-related increase in left ventricular mass (LVM) are largely unknown. We studied the relationship between smoking, arterial distensibility, central aortic pressures and left ventricular mass in two population-based studies. METHODS: Data was obtained from two German population-based studies (KORA and SHIP, participants' ages 25-84 years). We identified 114 normotensive current smokers and 185 normotensive all-time non-smokers in KORA as well as 400 and 588 such individuals in SHIP. Echocardiographic LVM was obtained at baseline (T0) and follow-up after ten years (T1) in KORA and at follow-up (T1) in SHIP. Additionally, pulse-wave analysis-based central aortic pressure and augmentation index (AIx) were measured at T1 in KORA. RESULTS: Cross-sectional analysis, using KORA T0 and SHIP T1, revealed in both studies a higher covariate-adjusted LVM and left ventricular mass index (LVMI) in smokers as compared with non-smokers. Moreover, in the KORA T1 examination, the smokers demonstrated a more pronounced increase, relative to baseline, of LVM (+13.5%) and LVMI (+13.4%) compared to non-smokers (+8.59% and +8.65%; p=0.036 and 0.042, respectively). Additionally, at KORA T1 smokers had a higher central systolic blood pressure and higher AIx than non-smokers (p=0.012 and p=0.001, respectively). CONCLUSIONS: The difference in central aortic pressure due to enhanced and more prolonged wave reflection may explain our finding of a further pronounced increase in left ventricular wall thickness and mass over time in smokers.

Genetic markers enhance coronary risk prediction in men: the MORGAM prospective cohorts.

BACKGROUND: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. METHODS: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. RESULTS: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. CONCLUSIONS: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

Variation in body composition determines long-term blood pressure changes in pre-hypertension: the MONICA/KORA (Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Research in the Region of Augsburg) cohort study.

OBJECTIVES: We studied the relationship between changes in body composition and changes in blood pressure levels. BACKGROUND: The mechanisms underlying the frequently observed progression from pre-hypertension to hypertension are poorly understood. METHODS: We examined 1,145 subjects from a population-based survey at baseline in 1994/1995 and at follow-up in 2004/2005. First, we studied individuals pre-hypertensive at baseline who, during 10 years of follow-up, either had normalized blood pressure (PreNorm, n = 48), persistently had pre-hypertension (PrePre, n = 134), or showed progression to hypertension (PreHyp, n = 183). In parallel, we studied predictors for changes in blood pressure category in individuals hypertensive at baseline (n = 429). RESULTS: After 10 years, the PreHyp group was characterized by a marked increase in body weight (+5.71% [95% confidence interval (CI): 4.60% to 6.83%]) that was largely the result of an increase in fat mass (+17.8% [95% CI: 14.5% to 21.0%]). In the PrePre group, both the increases in body weight (+1.95% [95% CI: 0.68% to 3.22%]) and fat mass (+8.09% [95% CI: 4.42% to 11.7%]) were significantly less pronounced than in the PreHyp group (p < 0.001 for both). The PreNorm group showed no significant change in body weight (-1.55% [95% CI: -3.70% to 0.61%]) and fat mass (+0.20% [95% CI: -6.13% to 6.52%], p < 0.05 for both, vs. the PrePre group). CONCLUSIONS: After 10 years of follow-up, hypertension developed in 50.1% of individuals with pre-hypertension and only 6.76% went from hypertensive to pre-hypertensive blood pressure levels. An increase in body weight and fat mass was a risk factor for the development of sustained hypertension, whereas a decrease was predictive of a decrease in blood pressure.

The aging process of the heart: obesity is the main risk factor for left atrial enlargement during aging the MONICA/KORA (monitoring of trends and determinations in cardiovascular disease/cooperative research in the region of Augsburg) study.

OBJECTIVES: This prospective study evaluated the association of obesity and hypertension with left atrial (LA) volume over 10 years. BACKGROUND: Although left atrial enlargement (LAE) is an independent risk factor for atrial fibrillation, stroke, and death, little information is available about determinants of LA size in the general population. METHODS: Participants (1,212 men and women, age 25 to 74 years) originated from a sex- and age-stratified random sample of German residents of the Augsburg area (MONICA S3). Left atrial volume was determined by standardized echocardiography at baseline and again after 10 years. Left atrial volume was indexed to body height (iLA). Left atrial enlargement was defined as iLA > or =35.7 and > or =33.7 ml/m in men and women, respectively. RESULTS: At baseline, the prevalence of LAE was 9.8%. Both obesity and hypertension were independent predictors of LAE, obesity (odds ratio [OR]: 2.4; p < 0.001) being numerically stronger than hypertension (OR: 2.2; p < 0.001). Adjusted mean values for iLA were significantly lower in normal-weight hypertensive patients (25.4 ml/m) than in obese normotensive individuals (27.3 ml/m; p = 0.016). The highest iLA was found in the obese hypertensive subgroup (30.0 ml/m; p < 0.001 vs. all other groups). This group also presented with the highest increase in iLA (+6.0 ml/m) and the highest incidence (31.6%) of LAE upon follow-up. CONCLUSIONS: In the general population, obesity appears to be the most important risk factor for LAE. Given the increasing prevalence of obesity, early interventions, especially in young obese individuals, are essential to prevent premature onset of cardiac remodeling at the atrial level.

Left atrial size by planimetry is superior to M-mode diameter: biochemical calibration by atrial and brain natriuretic peptide.

BACKGROUND: Left atrial (LA) size is routinely assessed by M-mode on echocardiography. Recently, a superiority of apical measures of LA size has been suggested, but no biochemical calibration has been attempted yet. The aim of the current study was to compare echocardiographic parameters of LA size through biochemical calibration with the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). METHODS: A total of 610 middle-aged (50-67 years) subjects from a population-based sample (MONICA Augsburg, Germany) were characterized with respect to LA area and volume from the apical two-chamber (2C) and four-chamber (4C) views in addition to M-mode echocardiography. ANP and BNP concentrations were determined by radioimmunoassay. RESULTS: A significant correlation to ANP and BNP was present with all measures on LA size. The univariate correlation was lowest with M-mode diameter (r = 0.11 with ANP; r = 0.09 with BNP, both P < .03), whereas 2C volume displayed the closest correlation (r = 0.20 with ANP and r = 0.28 with BNP, both P < .001) and even slightly exceeded 2C area, 4C volume, and 4C area. 2C volume further displaced LV systolic function, mass index, and heart rate as statistically significant predictors of ANP (P < .001) and BNP (P < .001) on adjusted regression analysis, whereas M-mode diameter was displaced as a significant predictor of ANP and BNP (P = not significant). CONCLUSIONS: The current population-based echocardiographic study allows new insight into the value of different measures of LA size. The closer association between natriuretic peptide concentrations and parameters derived from planimetry and volumetry suggests a superiority of these parameters LA diameter. LA volumetry should be included in routine echocardiography for optimized assessment of LA size.