Guenter Riegger

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.

The Benefits of Early Combination Treatment of Carvedilol and an ACE-Inhibitor in Mild Heart Failure and Left Ventricular Systolic Dysfunction. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure Evaluation Trial (CARMEN)

AbstractAims: Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and β-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination. Methods: In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril. Results: In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates. Conclusion: CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of β-blockade should not be delayed.

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.

Globular and full-length adiponectin induce NO-dependent vasodilation in resistance arteries of Zucker lean but not Zucker diabetic fatty rats.

BACKGROUND Adiponectin increases nitric oxide (NO) production in endothelial cell cultures and is reduced in the circulation of obese and diabetic patients, but its functional effect on resistance arteries is not yet studied in detail. METHODS We assessed the direct vasodilatory response of isolated mesenteric resistance arteries of Zucker diabetic fatty (ZDF) rats and Zucker lean (ZL) rats to globular adiponectin (gAd) and full-length adiponectin (fAd) and tested the effect of additional reactive oxygen species (ROS) inhibitors in vitro. Serum adiponectin and insulin levels were measured by ELISA. The mRNA expressions of the adiponectin receptors and the downstream signaling molecules adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1), adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 2 (APPL2), and endothelial NO synthase (eNOS) in mesenteric resistance arteries were quantified by real-time reverse transcriptase PCR. RESULTS Both gAd and fAd induced a relevant dose-dependent vasodilation in ZL, but not in hypoadiponectinemic ZDF rats. This effect was totally blunted by L-nitroarginine-methyl-ester indicating NO dependency. The addition of ROS inhibitors could not improve the vasodilatory effect of adiponectin. Vasodilatory response to acetylcholine was reduced in ZDF rats, which could not be enhanced by low-dose adiponectin. Adiponectin receptor 1 (AdipoR1) was higher expressed than adiponectin receptor 2 (AdipoR2) with no significant differences between both animal groups, but APPL1 was significantly decreased in ZDF rats. The eNOS expression was not significantly different between ZL and ZDF rats. CONCLUSIONS Adiponectin exerts a NO-dependent vasodilation in resistance arteries of normoglycemic ZL rats, but not diabetic ZDF rats. This may contribute to endothelial dysfunction in ZDF rats. Alterations in the expression of APPL1 may be involved in the observed insensitivity to adiponectin in ZDF rats.

Electrocardiographic diagnosis of left ventricular hypertrophy in aortic valve disease: evaluation of ECG criteria by cardiovascular magnetic resonance

BackgroundLeft ventricular hypertrophy (LVH) is a hallmark of chronic pressure or volume overload of the left ventricle and is associated with risk of cardiovascular morbidity and mortality. The purpose was to evaluate different electrocardiographic criteria for LVH as determined by cardiovascular magnetic resonance (CMR). Additionally, the effects of concentric and eccentric LVH on depolarization and repolarization were assessed.Methods120 patients with aortic valve disease and 30 healthy volunteers were analysed. As ECG criteria for LVH, we assessed the Sokolow-Lyon voltage/product, Gubner-Ungerleider voltage, Cornell voltage/product, Perugia-score and Romhilt-Estes score.ResultsAll ECG criteria demonstrated a significant correlation with LV mass and chamber size. The highest predictive values were achieved by the Romhilt-Estes score 4 points with a sensitivity of 86% and specificity of 81%. There was no difference in all ECG criteria between concentric and eccentric LVH. However, the intrinsicoid deflection (V6 37 ± 1.0 ms vs. 43 ± 1.6 ms, p < 0.05) was shorter in concentric LVH than in eccentric LVH and amplitudes of ST-segment (V5 -0.06 ± 0.01 vs. -0.02 ± 0.01) and T-wave (V5 -0.03 ± 0.04 vs. 0.18 ± 0.05) in the anterolateral leads (p < 0.05) were deeper.ConclusionBy calibration with CMR, a wide range of predictive values was found for the various ECG criteria for LVH with the most favourable results for the Romhilt-Estes score. As electrocardiographic correlate for concentric LVH as compared with eccentric LVH, a shorter intrinsicoid deflection and a significant ST-segment and T-wave depression in the anterolateral leads was noted.

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.

Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations

Recent data provided strong evidence for the association of single nucleotide polymorphisms (SNPs) in the lymphotoxin-α (LTA) and galectin-2 (LGALS2) genes with myocardial infarction (MI) in a Japanese population. For populations of other genetic background, the relevance of these polymorphisms in the pathogenesis of MI remains controversial. We aimed to define the role of LTA and LGALS2 SNPs in two German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. In the first population, MI patients were ascertained by a strong family history of MI (n = 1214). Controls were unrelated disease-free participants of the study (n = 1080). The second population included patients suffering from sporadic (nonfamilial) MI from the German KORA register (n = 607). The control group consisted of participants of the WHO MONICA survey in Germany (n = 1492). TaqMan assays were used to determine the genotypes of 4 SNPs in the LTA genomic region and 1 SNP in the LGALS2 gene. Single SNPs in both genomic regions as well as haplotypes in the LTA genomic region were tested for association in various models of inheritance. No association with MI could be found for any of the examined SNPs in the LTA genomic region and LGALS2 gene, or for haplotypes spanning the LTA genomic region. In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI. These variants are unlikely to play a significant role in populations of European origin.

High-sensitive Troponin I in acute cardiac conditions: Implications of baseline and sequential measurements for diagnosis of myocardial infarction

BACKGROUND High-sensitive Troponin I (hsTnI) facilitates the early diagnosis of myocardial infarction (MI). However, since hsTnI has not been well characterized in non-ischemic cardiac conditions, the predictive value of hsTnI for MI remains unclear. METHODS hsTnI (ADVIA Centaur, Siemens) on admission was analyzed in 929 patients with acute cardiac condition and invasive ascertainment of coronary status by catheterization. RESULTS Hs-TnI upon presentation was higher in patients with STEMI (median 1.27 ng/mL, IQR 0.13-14.5 ng/mL) as compared to patients with Non-STEMI (0.66 ng/mL, IQR 0.10-4.0 ng/mL, p<0.001) whereas it did not differ from STEMI in Tako-Tsubo cardiomyopathy (2.57 ng/mL, IQR 0.17-8.4 ng/mL) and myocarditis (9.76 ng/mL, IQR 2.0-27.0 ng/mL). In patients with resuscitation of non-ischemic cause (0.31 ng/mL, IQR 0.06-1.3 ng/mL), acute heart failure (0.088 ng/mL, IQR 0.035-0.30 ng/mL) and hypertensive emergency (0.066 ng/mL, IQR 0.032-0.34 ng/mL), hs-TnI was elevated above the recommended threshold of 0.04 ng/mL. At this cutpoint of 0.04 ng/mL, hsTnI indicated acute MI (STEMI or Non-STEMI) with a sensitivity of 88% and a specificity of 45% (ROC-AUC 0.748). When patients with STEMI were excluded, hsTnI indicated Non-STEMI with a sensitivity of 87% and a specificity of 45% (ROC-AUC 0.725). When sequential measurements were taken into account in a restricted cohort, a maximum hsTnI of ≥0.40 ng/mL provided a sensitivity of 89% and a specificity of 85% (ROC-AUC 0.909) for Non-STEMI. CONCLUSIONS HsTnI is a sensitive, albeit unspecific marker of MI. In patients with mildly elevated hsTnI and without evidence for STEMI, we suggest serial assessment of hsTnI and a 10-fold higher cutpoint of 0.40 ng/mL before Non-STEMI is assumed.

Evidence for a Possible Inhibitory Interaction between the HO-1/CO- and Akt/NO-Pathways in Human Endothelial Cells

ObjectiveThe protective properties of heme oxygenase 1 (HO-1) give reason to study this mechanism as a potential therapeutic target for inflammatory and cardiovascular diseases. Recent evidence suggests a possible interaction between the HO-1/CO- and the protein kinase Akt/NO-pathway. This study was designed to examine the effects of continuous HO-1 overexpression in endothelial cells.MethodsOncoretroviral vectors were constructed to achieve constitutive overexpression of HO-1, Akt, and green fluorescence protein in human umbilical vein endothelial cells. [3H]thymidine-incorporation and lipid-peroxidation were measured following exposure to heme and H2O2. Expression of HO-1, Akt and its downstream-target endothelial NO-synthase were quantified by Western blot analysis. NO-synthase-activity was measured using the citrulline-conversion-assay.ResultsHO-1-overexpression reduced proliferative rates and DNA-synthesis of HUVEC, but provided potent protection from oxidative stress induced by heme and H2O2. Phosphorylated-Akt and eNOS was downregulated in HO-1-HUVEC. eNOS-activity was reduced in HO-1-HUVEC. Co-infection with the Akt-retrovirus restored proliferative rates and eNOS-expression and -activity.ConclusionContinuously elevated HO-1-activity protects EC from oxidative stress but inhibits Akt-mediated proliferation and eNOS-expression. This inhibitory feedback mechanism could be a limitation of HO-1 as a target for the treatment of vascular disease.