Bernhard Kuch

Common variants in myocardial Ion channel genes modify the QT interval in the general population : Results from the KORA study

Altered myocardial repolarization is one of the important substrates of ventricular tachycardia and fibrillation. The influence of rare gene variants on repolarization is evident in familial long QT syndrome. To investigate the influence of common gene variants on the QT interval we performed a linkage disequilibrium based SNP association study of four candidate genes. Using a two-step design we analyzed 174 SNPs from the KCNQ1, KCNH2, KCNE1, and KCNE2 genes in 689 individuals from the population-based KORA study and 14 SNPs with results suggestive of association in a confirmatory sample of 3277 individuals from the same survey. We detected association to a gene variant in intron 1 of the KCNQ1 gene (rs757092, +1.7 ms/allele, P=0.0002) and observed weaker association to a variant upstream of the KCNE1 gene (rs727957, +1.2 ms/allele, P=0.0051). In addition we detected association to two SNPs in the KCNH2 gene, the previously described K897T variant (rs1805123, −1.9 ms/allele, P=0.0006) and a gene variant that tags a different haplotype in the same block (rs3815459, +1.7 ms/allele, P=0.0004). The analysis of additive effects by an allelic score explained a 10.5 ms difference in corrected QT interval length between extreme score groups and 0.951 of trait variance (P<0.00005). These results confirm previous heritability studies indicating that repolarization is a complex trait with a significant heritable component and demonstrate that high-resolution SNP-mapping in large population samples can detect and fine map quantitative trait loci even if locus specific heritabilities are small.

The associations of body size and body composition with left ventricular mass: impacts for indexation in adults ☆

OBJECTIVES We investigated the relationship between body size, body composition and left ventricular mass (LVM) in adults, and assessed the impact of different indexations of LVM on its associations with gender, adiposity and blood pressure. BACKGROUND The best way to normalize LVM for body size to appropriately distinguish physiologic adaptation from morbid heart morphology was discussed. METHODS We undertook a community survey of 653 men and 718 women, aged 25 to 74 years. Lean body mass (LBM) was determined by bioelectric impedance analyses and LVM was assessed by two-dimensional guided M-mode echocardiography. RESULTS After traditional indexations to body height, body height2.7, or body surface area, men had higher LVM than women (p < 0.001). These gender differences disappeared (p > 0.05) when LVM was indexed to LBM. The type of indexation also modified the strength of the association between adiposity and LVM. The estimated impact of body fat on LVM indexed to LBM was less than half that obtained with traditional indexations. In contrast, the magnitude of the associations of blood pressure with LVM was entirely independent of the type of indexation. CONCLUSIONS This study showed the prominent influence of body composition on adult heart size. Indexation for LBM removed gender differences for LVM and reduced the impact of adiposity, but left the effects of blood pressure unchanged. We suggest that this approach be used for clinical and research applications.

Body Composition and Prevalence of Left Ventricular Hypertrophy

BACKGROUND Fat-free mass (FFM) has been proposed as an optimal normalization of left ventricular (LV) mass to body size. We sought to evaluate the novel FFM-based criteria of LV hypertrophy (LVH). METHODS AND RESULTS A population sample of 1371 men and women aged 25 to 74 years was examined by echocardiography and bioelectrical impedance analysis. Internal partition values for LVH were generated in a healthy population subgroup on the basis of LV mass divided by FFM and by the traditional indexations to body height, height(2.7), and body surface area. In contrast to the sex-specific criteria required by traditional indexations, the value of LV mass/FFM that divided individuals with and without LVH was identical for men and women (4.1 g/kg). Estimates of LVH prevalence varied significantly by type of indexation used, internally or externally derived cut points, and by population subgroups. Differences were pronounced among hypertensives and the obese. Thus, the application of LV mass/FFM more than halved the risk of LVH in obese versus nonobese women (odds ratio, 2.5; 95% confidence interval, 1.6 to 4.0) compared with criteria based on LV mass/height(2.7) (odds ratio, 5.5; 95% confidence interval, 3.6 to 8.3). Implications among hypertensives were less marked. CONCLUSIONS Indexation of LV mass to FFM eliminates sex-specific LVH criteria. The proportion of individuals defined as having LVH using the new criteria deviate markedly from traditional indexations. Prospective investigations will be needed to identify the prognostic implications of different indexations, especially in subgroups such as the obese.

Neurohormonal activity and left ventricular geometry in patients with essential arterial hypertension

The purpose of this study was to investigate whether the basal activity of the renin-angiotensin-aldosterone system or the basal levels of the atrial natriuretic peptide (ANP) are related to distinct patterns of left ventricular (LV) geometry in patients with essential hypertension. The left ventricle of patients with arterial hypertension may be exposed to a variety of growth-regulating mechanisms, including pressure overload and humoral activation. The interaction of such growth stimuli may be involved in the modulation of LV geometry. LV geometry was determined echocardiographically in 104 patients with mild to moderate essential hypertension. The same number of age- and sex-matched normotensive subjects served as controls. Plasma renin activity (PRA) and serum concentrations of aldosterone and ANP were measured by radioimmunoassay. Correlation analyses revealed that PRA was significantly associated with septal wall thickness and LV mass index (r = 0.25; p < 0.005 each). In addition, as compared with normal subjects (1.0 +/- 0.7 ng/ml/hr), PRA was significantly increased in patients with concentric LV hypertrophy (LVH) (3.4 +/- 6.6 ng/ml/hr, p < 0.01). Aldosterone displayed a close correlation with septal, posterior, and relative wall thickness (r > 0.27, p < 0.005 each). Compared with normal subjects (74 +/- 27 pg/ml), patients with hypertension and pathologic patterns of LV geometry were characterized by elevations of aldosterone (LV remodeling 203 +/- 93 pg/ml, concentric LVH 123 +/- 67 pg/ml; eccentric LVH 199 +/- 89 pg/ml; p < 0.05 each). ANP was significantly associated with septal wall thickness, left ventricular dimension, and LV mass index (r > 0.22, p < 0.005 each). Furthermore, compared with normal subjects (50 +/- 17 pg/ml), ANP values were significantly increased in patients with hypertension and concentric LVH (80 +/- 44 pg/ml, p < 0.005) and eccentric LVH (88 +/- 24 pg/ml, p < 0.001). Multivariate analysis adjusting for systolic blood pressure, body mass index, and age revealed that renin and ANP were independently associated with LV mass index (p < 0.05 each). Interestingly, adjusted PRA levels were not related to any specific pattern of LV geometry. In contrast, adjusted ANP levels were associated with concentric and eccentric LVH, whereas adjusted aldosterone levels were significantly elevated in subjects with LV remodeling and eccentric LVH (p < 0.005). Thus elevated levels of renin and ANP may be found in patients with hypertension and elevated LV mass index. In addition, ANP and aldosterone are related to specific geometric patterns of the left ventricle. The data may further stimulate the discussion on the mechanisms that account for alterations of LV geometry in hypertension.

Determinants of Short-Period Heart Rate Variability in the General Population

Decreased heart rate variability (HRV) is associated with a worse prognosis in a variety of diseases and disorders. We evaluated the determinants of short-period HRV in a random sample of 149 middle-aged men and 137 women from the general population. Spectral analysis was used to compute low-frequency (LF), high-frequency (HF) and total-frequency power. HRV showed a strong inverse association with age and heart rate in both sexes with a more pronounced effect of heart rate on HRV in women. Age and heart rate-adjusted LF was significantly higher in men and HF higher in women. Significant negative correlations of BMI, triglycerides, insulin and positive correlations of HDL cholesterol with LF and total power occurred only in men. In multivariate analyses, heart rate and age persisted as prominent independent predictors of HRV. In addition, BMI was strongly negatively associated with LF in men but not in women. We conclude that the more pronounced vagal influence in cardiac regulation in middle-aged women and the gender-different influence of heart rate and metabolic factors on HRV may help to explain the lower susceptibility of women for cardiac arrhythmias.

Familial predisposition of Left ventricular hypertrophy

OBJECTIVES The study evaluated the contribution of familial predisposition to the risk of left ventricular hypertrophy (LVH). BACKGROUND Left ventricular hypertrophy is a multifactorial condition that serves as an important predictor of cardiovascular mortality. At present it is unclear whether familial predisposition contributes to the manifestation of LVH. Thus, we determined whether siblings of subjects with LVH are at increased risk to present with an elevation of LV mass or an abnormal LV geometry. METHODS Echocardiographic and anthropometric measurements were performed in 2,293 individuals who participated in the echocardiographic substudies of population-based MONICA Augsburg surveys. In addition, a total of 319 siblings of survey participants with echocardiographic evidence of LVH were evaluated. The risk of these siblings to present with LVH or abnormal LV geometry was estimated by comparison with 636 subjects matched for gender and age that were selected from the entire echocardiography study base. RESULTS Blood pressure, body mass index, age, and gender (i.e., known determinants of LV mass) were comparable in LVH-siblings and the matched comparison group. However, septal and posterior wall thicknesses, relative wall thickness as well as LV mass index were significantly elevated in LVH-siblings (p < 0.001, each) whereas LV dimensions did not differ. Likewise, the prevalence of LVH was raised in LVH-siblings, as was the relative risk of LVH after adjustment for confounders (p < 0.05). More specifically, LVH-siblings displayed increased prevalences of concentric remodeling and concentric LVH (p < 0.05) but not of eccentric LVH. CONCLUSIONS Familial predisposition appears to contribute to increased LV wall thickness, to the development of LV hypertrophy and abnormal LV geometry.

20-year trends in clinical characteristics, therapy and short-term prognosis in acute myocardial infarction according to presenting electrocardiogram: the MONICA/KORA AMI Registry (1985-2004).

Objectives.  To examine the extent to which evidence‐based beneficial therapy is applied in practice, whether this is changing over time and is associated with improved outcomes.

Sex Differences in Patient-Reported Symptoms Associated With Myocardial Infarction (from the Population-Based MONICA/KORA Myocardial Infarction Registry)

Many studies have examined gender-related differences in symptoms of acute myocardial infarction (AMI). However, findings have been inconsistent, largely because of different study populations and different methods of symptom assessment and data analysis. This study was based on 568 women and 1,710 men 25 to 74 years old hospitalized with a first-ever AMI from January 2001 through December 2006 recruited from a population-based AMI registry. Occurrence of 13 AMI symptoms was recorded using standardized patient interview. After controlling for age, migration status, body mass index, smoking, some co-morbidities including diabetes, and type and location of AMI through logistic regression modeling, women were significantly more likely to complain of pain in the left shoulder/arm/hand (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.10 to 1.69), pain in the throat/jaw (OR 1.78, 95% CI 1.43 to 2.21), pain in the upper abdomen (OR 1.39, 95% CI 1.02 to 1.91), pain between the shoulder blades (OR 2.22, 95% CI 1.78 to 2.77), vomiting (OR 2.23, 95% CI 1.67 to 2.97), nausea (OR 1.94, 95% CI 1.56 to 2.39), dyspnea (OR 1.45, 95% CI 1.17 to 1.78), fear of death (OR 2.17, 95% CI 1.73 to 2.72), and dizziness (OR 1.49, 95% CI 1.16 to 1.91) than men. Furthermore, women were more likely to report >4 symptoms (OR 2.14, 95% CI 1.72 to 2.66). No significant gender differences were found in chest pain, feelings of pressure or tightness, diaphoresis, pain in the right shoulder/arm/hand, and syncope. In conclusion, women and men did not differ regarding the chief AMI symptoms of chest pain or feelings of tightness or pressure and diaphoresis. However, women were more likely to have additional symptoms.

Sex and age specific time patterns and long term time trends of pre-hospital delay of patients presenting with acute ST-segment elevation myocardial infarction.

BACKGROUND Prompt initiation of treatment after symptom onset of ST-elevation myocardial infarction (STEMI) is a central goal in limiting myocardial damage because of the time-dependent nature of reperfusion therapies. We examined time patterns and long term time trends of pre-hospital delay time (PHDT) of STEMI patients. METHODS PHDT from 3093 STEMI patients derived from the Augsburg Myocardial Infarction Registry (1985-2004) surviving >24h after admission was obtained by a standardized bedside interview. Patients with in-hospital MI (n=140) and resuscitation (n=157) were excluded. Linear regression models were used to examine monthly median PHDT and individual PHDT over time. RESULTS Female sex was associated with longer PHDT (189 (98-542quartiles) min vs. 154 (85-497) min; p<0.0003). Median PHDT in the youngest male subgroup (25-54 years) was 128 (73-458) min and mounted to 205 (107-600) min in the oldest female subgroup (65-74 years). A minority of 12.4% of patients reached hospital within 1h of delay ranging from 8.7% (in oldest women) to 15.9% (in youngest men). The age-adjusted linear regression model for monthly PHDT revealed no significant change over 20-year time in both sexes. The corresponding average annual percentage change estimates were -0.45 (95% CI: -1.40 to 0.54) for men and -0.08 (95% CI: -1.80 to 1.67) for women. Emergency ambulance use increased over time, however transportation time remained stable. CONCLUSIONS PHDT in STEMI patients is constantly high over a 20-year observation period. Room for improvement especially in older women was evidenced. Preventive strategies with focused efforts on this subgroup are warranted.

Triggering of acute myocardial infarction by different means of transportation.

Background: Prior studies have reported an association between traffic-related air pollution in urban areas and exacerbation of cardiovascular disease. We assess here whether time spent in different modes of transportation can trigger the onset of acute myocardial infarction (AMI). Design: We performed a case-crossover study. We interviewed consecutive cases of AMI in the KORA Myocardial Infarction Registry in Augsburg, Southern Germany between February 1999 and December 2003 eliciting data on potential triggers in the four days preceding myocardial infarction onset. Results: A total of 1459 cases with known date and time of AMI symptom onset, who had survived 24 hours after the onset, completed the registry’s standard interview on potential triggers of AMI. An association between exposure to traffic and AMI onset 1 hour later was observed (odds ratio: 3.2; 95% confidence interval [CI]: 2.7–3.9, p < 0.001). Using a car was the most common source of traffic exposure; nevertheless, times spent in public transport or on a bicycle were similarly associated with AMI onset 1 hour later. While the highest risk for AMI onset was within 1 hour of exposure to traffic, the elevated risk persisted for up to 6 hours. Women, patients aged 65 years or older, patients not part of the workforce, and those with a history of angina or diabetes exhibited the largest associations between times spent in traffic and AMI onset 1 hour later. Conclusion: The data suggest that transient exposure to traffic regardless of the means of transportation may increase the risk of AMI transiently.