Jan Stritzke

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.

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.

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.

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.

BNP as a marker of diastolic dysfunction in the general population: Importance of left ventricular hypertrophy

BNP is a marker of systolic left ventricular dysfunction (LVSD) and heart failure. To assess BNP for the detection of diastolic dysfunction in the general population, we examined 1678 subjects within an age‐ and sex‐stratified survey (MONICA Augsburg). BNP was measured using a commercially available RIA (Shionogi).

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.

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).

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.

Hepatic Steatosis Is Associated With Aortic Valve Sclerosis in the General Population The Study of Health in Pomerania (SHIP)

ObjectiveWe aimed to analyze the association between hepatic steatosis and aortic valve sclerosis in the general population. Approach and ResultsCross-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). ConclusionsOur 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.

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.

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.