Andrea Baessler

Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample.

AIMS The prevalence of left ventricular diastolic abnormalities in the general population is largely unclear. Thus, the aim of this study was, firstly, to identify abnormal diastolic function by echocardiography in an age-stratified population-based European sample (MONICA Augsburg, n=1274, 25 to 75 years, mean 51+/-14) and, secondly, to analyse clinical and anthropometric parameters associated with diastolic abnormalities. METHODS AND RESULTS The overall prevalence of diastolic abnormalities, as defined by the European Study Group on Diastolic Heart Failure (i.e. age dependent isovolumic relaxation time (92-105 ms) and early (E-wave) and late (A-wave) left ventricular filling (E/A-ratio, 1-0.5)) was 11.1%. When only subjects treated with diuretics or with left atrial enlargement were considered (suggesting diastolic dysfunction) the prevalence was 3.1%. The prevalence of diastolic abnormalities varied according to age: from 2.8% in individuals aged 25-35 years to 15.8% among those older than 65 years (P<0.01). Significantly higher rates of diastolic abnormalities were observed in men as compared to women (13.8% vs 8.6%, P<0.01). Independent predictors of diastolic abnormalities were arterial hypertension, evidence of left ventricular (LV) hypertrophy, and coronary artery disease. Interestingly, in the absence of these predisposing conditions, diastolic abnormalities (4.3%) or diastolic dysfunction (1.1%) were rare, even in subjects older than 50 years of age (4.6%) and (1.2%), respectively. In addition to these factors, diastolic dysfunction was related to high body mass index, high body fat mass, and diabetes mellitus. CONCLUSION The prevalences of diastolic abnormalities and diastolic dysfunction are higher than that of systolic dysfunction and are increased (despite age-dependent diagnostic criteria) in the elderly. However, in the absence of risk factors for diastolic abnormalities or diastolic dysfunction, namely LV hypertrophy, arterial hypertension, coronary artery disease, obesity and diabetes the condition is rare even in elderly subjects. These data allow speculation on whether diastolic heart failure may be prevented by improved implementation of measures directed against predisposing conditions.

Renin angiotensin system and gender differences in the cardiovascular system

In the effort to explain gender-related differences of the cardiovascular system, the renin-angiotensin system experienced intensive exploration. Indeed, the development of hypertension as well as the progression of coronary artery disease and heart failure have two factors in common: (1) display distinct gender specific characteristics and (2) are enhanced by the renin-angiotensin system. It is therefore interesting to note that data from experimental animals, epidemiological surveys, and clinical investigations suggest that the components of the circulating as well as tissue-based renin-angiotensin system are markedly affected by gender. However, the issue is complicated by counter-regulatory effects of estrogen on the system with the substrate, on one hand, and the processing enzymes as well as the chief receptor, on the other hand. In fact, angiotensinogen is up-regulated particularly by oral administration of estrogen, whereas renin, angiotensin-converting enzyme (ACE), and AT-1 receptor are down-regulated by the hormone. While under well-defined experimental conditions the net effect of estrogen appears to result in suppression of the renin-angiotensin system, the clinical situation may be more complex. The judgment is further complicated by the difficulty in precisely measuring the activity of the system at the tissue level. Moreover, clinically relevant read-outs for the activity of the renin-angiotensin system may be regulated multifactorially or only indirectly affected by the system. Nevertheless, the undisputable, profound biochemical changes in the renin-angiotensin system related to the estrogen status allow speculation that such interaction explains some of the differences in the cardiovascular system of men and women.

Distinct Heritable Patterns of Angiographic Coronary Artery Disease in Families With Myocardial Infarction

Background—Coronary artery disease (CAD) and myocardial infarction (MI) are significantly determined by genetic background. Whether distinct angiographic features of CAD are affected by inherited factors has never been investigated. Thus, we analyzed comprehensively the extent to which various aspects of CAD, including disease severity, distribution of lesions, presence of coronary calcification, morphology of stenoses, and anatomic characteristics, are under genetic control. Methods and Results—We retrospectively studied the coronary angiograms of 882 siblings with CAD from 401 families. These families were ascertained through index patients defined by MI before the age of 60 years and at least 1 sibling with MI or coronary revascularization procedures. Heritability calculations were performed with variance-component analysis. Additionally, recurrence risks to siblings were analyzed. Traditional cardiovascular risk factors and age at the first coronary event displayed significant heritable components. After adjustment for age and sex, significant heritabilities were identified for proximal stenoses, in particular, left main CAD (h2=0.49±0.12; P=0.01), coronary calcification (h2=0.51±0.17; P=0.001), and ectatic coronary lesions (h2=0.52±0.07; P=0.001). In contrast, no heritability was found for distal disease (h2=0.05±0.19; NS), the pattern of coronary arterial blood supply, or the number of diseased vessels. Calculation of recurrence risks in siblings largely confirmed the heritability estimates. Conclusions—Distinct morphological characteristics associated with CAD show different degrees of heritability. Notably, the most hazardous localizations, like left main or proximal disease, display a high heritability. In contrast, some features of coronary morphology, such as distal disease, do not appear to be markedly influenced by heritable factors.

Association of common polymorphisms in GLUT9 gene with gout but not with coronary artery disease in a large case-control study.

Background Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study. Methods and Findings First, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52–0.75; p  =  3.2*10−7). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region. Conclusion Thus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population.

Genetic variants within the LPIN1 gene, encoding lipin, are influencing phenotypes of the metabolic syndrome in humans

OBJECTIVE— Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within LPIN1 are associated with traits of the metabolic syndrome. RESEARCH DESIGN AND METHODS— A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age- and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome was defined via the sum of its core components and, additionally, by a factor score derived from factor analysis. Permutation-based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance. RESULTS— Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the metabolic syndrome (odds ratio 1.6 [95% CI 1.2–2.2]), while the other two, being less common (5.7 and 4.0%), are strongly associated with lower blood pressure levels (systolic blood pressure 127 ± 18 vs. 135 ± 20 mmHg; P = 0.0001), a lower BMI (24.6 ± 3.6 vs. 26.9 ± 4.1 kg/m2; P = 3.7 × 10−7) and waist circumference (82 ± 12 vs. 90 ± 12 cm; P = 3.2 × 10−8), lower A1C levels (5.1 ± 0.7 vs. 5.3 ± 0.9%; P = 0.0002), as well as a lower metabolic syndrome factor score (−0.67 ± 1.00 vs. 0.04 ± 1.24; P = 1.4 × 10−7). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%; P = 0.00001), obesity (12.9 vs. 30.8%; P = 0.0003), diabetes (2.2 vs. 8.2%; P = 0.041), and the presence of three or more metabolic syndrome components (3.3 vs. 13.7%; P = 0.002) were significantly lower than in subjects not carrying one of these protective haplotypes. Strong associations were also observed in the replication sample using the same haplotypes but with effects in the opposite direction. CONCLUSIONS— These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome.

Alterations of plasma lysophosphatidylcholine species in obesity and weight loss.

Background Obesity and related diseases of the metabolic syndrome contribute to the major health problems in industrialized countries. Alterations in the metabolism of lipid classes and lipid species may significantly be involved in these metabolic overload diseases. However, little is known about specific lipid species in this syndrome and existing data are contradictive. Methods In this study, we quantified plasma lipid species by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in obese subjects before and after 3 month weight loss as well as in a control group. Results The comparison of obese subjects with control subjects before weight loss revealed significantly lower lysophosphatidylcholine (LPC) concentrations in obesity. LPC concentrations did not significantly increase during the observed period in the weight loss group. Analysis of LPC species revealed a decrease of most species in obesity and negative correlations with C-reactive protein (CRP) and body mass index (BMI). Correlating BMI ratio before and after weight loss with the ratio of total LPC and individual LPC species revealed significant negative relationships of LPC ratios with BMI ratio. Conclusions Our findings contribute to the contradictive discussion of the role of LPC in obesity and related chronic inflammation strongly supporting pre-existing data in the literature that show a decrease of LPC species in plasma of obese and a potentially anti-inflammatory role in these subjects.

Genetic variation in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is associated with myocardial infarction in the German population

Genetic variation in the genes ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) and stroke in Icelandic and Scottish populations. Both genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in a large study of German MI patients. Two previously described four SNP (single nucleotide polymorphism) haplotypes of the ALOX5AP gene (termed haplotype A and B) and one SNP (rs2660899) of the LTA4H gene conferring the greatest risk of MI in previous studies were genotyped in 1211 unrelated MI cases from the German MI Family Study and in 1015 healthy married-in spouses serving as controls. Haplotype B in the ALOX5AP gene was associated with an increased risk of MI in the German population, confirming previously reported associations of this haplotype with CAD (coronary artery disease) in populations from Scotland and Italy. No association with the risk of MI was detected for haplotype A of the ALOX5AP gene or for SNP rs2660899 representing the LTA4H gene. In conclusion, haplotype B of the ALOX5AP gene is associated with an increased risk of MI in a large German study. The present study is the third independent report from a European population describing an increased risk of CAD for carriers of haplotype B of the ALOX5AP gene, which substantiates further a role of this gene in the pathogenesis of CAD in Europeans.

The lipoprotein subfraction profile: heritability and identification of quantitative trait loci.

The HDL and LDL subclass profile is an emerging cardiovascular risk factor. Yet, the biological and genetic mechanisms controlling the lipoprotein subclass distribution are unclear. Therefore, we aimed 1) to determine the heritability of the entire spectrum of LDL and HDL subclass features and 2) to identify gene loci influencing the lipoprotein subfraction pattern. Using NMR spectroscopy, we analyzed the lipoprotein subclass distribution in 1,275 coronary artery disease patients derived from the Regensburg Myocardial Infarction Family Study. We calculated heritabilities, performed a microsatellite genome scan, and calculated linkage. HDL and LDL subclass profiles showed heritabilities ranging from 23% to 67% (all P < 10−3) of traits using univariate calculation. After multivariate adjustment, we found heritabilities of 27–48% (all P < 0.05) for HDL and 21–44% for LDL traits. The linkage analysis revealed a significant logarithm of the odds (LOD) score (3.3) for HDL particle concentration on chromosome 18 and a highly suggestive signal for HDL particle size on chromosome 12 (2.9). After multivariate adjustment, we found a significant maximum LOD score of 3.7 for HDL size. Our study is the first to analyze heritability and linkage for the entire spectrum of LDL and HDL subclass features. Our findings may lead to the identification of genes controlling the lipoprotein subclass distribution.

Association of the Ghrelin Receptor Gene Region With Left Ventricular Hypertrophy in the General Population Results of the MONICA/KORA Augsburg Echocardiographic Substudy

Growth hormone (GH) can influence left ventricular myocardial growth, structure, and function. The GH secretagogue receptor (GHSR, ghrelin receptor) is known to be involved in GH release and is expressed in the myocardium. We hypothesized that genetic variants within the GHSR are associated with parameters of left ventricular mass (LVM) and geometry. Ten single-nucleotide polymorphisms (SNPs) covering the gene region were genotyped in 1230 members of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Augsburg Echocardiographic Substudy). Linkage disequilibrium analysis revealed a linkage disequilibrium block consisting of 5 SNPs forming 2 common haplotypes. One haplotype was found significantly more often in subjects without left ventricular hypertrophy ([LVH] 69% versus 59%; permutated P=0.0015), whereas the second haplotype was significantly more frequent in individuals with LVH (32% versus 26%; P=0.019). Homozygous subjects presented with an increase of risk with respect to all heart size parameters. A significantly increasing frequency of the risk haplotype could be observed from the lowest (20.9%) to the highest quintile (31.0%) of gender-specific LVM distributions (P=0.0096). We found association of the minor alleles of individual single nucleotide polymorphisms contributing to the haplotypes with higher LVM indices, septal wall thickness, and different LVH criteria consistent in men and women in matched cases and controls (LVM, women: 144.8±30.9 [noncarrier] versus 171.3±36.0 [homozygous], P=0.001; men: 186.7±42.4 versus 236.3±64.5, P=0.002). These data suggest that common variants in the GHSR region are associated with parameters of LVM and geometry independent of blood pressure and body mass in the general population and, thus, may be involved in the pathogenesis of LVH.

The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors

Recently, the genetic variant Y402H in the CFH (complement factor H) gene was associated with an increased risk for MI (myocardial infarction) in a prospective Caucasian cohort. In another nested case-control study, however, the CFH-Y402H variant did not carry susceptibility to MI. The aim of the present study was to test for an association between the CFH-Y402H variant and MI in a large case-control sample with a familial background for CAD (coronary artery disease). A total of 2161 individuals from the German MI family study were studied by questionnaire, physical examination and biochemical analyses. MI patients (n=1188; 51.4+/-8.6 years at first MI) were recruited from families with at least two members affected by MI and/or severe CAD. Spouses, sisters-in-law and brothers-in-law respectively, without MI/CAD were included as unaffected controls (n=973; 56.9+/-9.8 years). Genotyping was performed using a TaqMan assay. The common Y402H variant in the CFH gene was not associated with classical cardiovascular risk factors (diabetes, hypercholesterolaemia, hypertension, obesity, smoking and C-reactive protein serum levels). No association was found between the CFH-Y402H variant and susceptibility to MI. Separate analyses in both men and women revealed no gender-specific influence of the gene variant on cardiovascular risk factors or MI. This investigation was unable to replicate the association between the common CFH-Y402H variant and susceptibility to MI in our large Caucasian population which is enriched for genetic factors. We conclude that the CFH-Y402H variant has no relevant risk-modifying effect in our population.