A genetic variant of the atrial natriuretic peptide gene is associated with left ventricular hypertrophy in a non-diabetic population - the Malmo preventive project study

Background: Epidemiological studies have shown considerable heritability of blood pressure, thus suggesting a role for genetic factors. Previous studies have shown an association of a single nucleotide polymorphism rs5068 in the NPPA locus gene with higher levels of circulating atrial natriuretic peptide as well as with lower intra individual blood pressure, but up to date, no association between rs5068 and cardiac organ damage, i.e. left ventricular hypertrophy, has been accounted for in humans. We sought to explore if rs5068 is associated with left ventricular hypertrophy as measured by echocardiographic examination in a non-diabetic population. Methods: 968 non-diabetic individuals from the Malmo Preventive Project (mean age 67 years; 31% women) were genotyped and examined with echocardiography. Logistic regression was used to adjust for covariates. Results: The minor allele of rs5068 was associated with decreased prevalence of left ventricular hypertrophy (p = 0.021) after adjustment for sex and age. In the multivariate logistic analysis including; age, sex, systolic blood pressure, antihypertensive and/or cardioprotective treatment, body mass index and fasting plasma glucose, the association of rs5068 with left ventricular hypertrophy was, as expected, attenuated (p = 0.061). Conclusion: In a non-diabetic population, the minor allele of rs5068 was associated with lower left ventricular mass. These findings suggest that rs5068, or genetic variants in linkage disequilibrium, might affect susceptibility to left ventricular hypertrophy and support the possible protective role of natriuretic peptides

The Early-Onset Myocardial Infarction Associated PHACTR1 Gene Regulates Skeletal and Cardiac Alpha-Actin Gene Expression.

The phosphatase and actin regulator 1 (PHACTR1) locus is a very commonly identified hit in genome-wide association studies investigating coronary artery disease and myocardial infarction (MI). However, the function of PHACTR1 in the heart is still unknown. We characterized the mechanisms regulating Phactr1 expression in the heart, used adenoviral gene delivery to investigate the effects of Phactr1 on cardiac function, and analyzed the relationship between MI associated PHACTR1 allele and cardiac function in human subjects. Phactr1 mRNA and protein levels were markedly reduced (60%, P<0.01 and 90%, P<0.001, respectively) at 1 day after MI in rats. When the direct myocardial effects of Phactr1 were studied, the skeletal α-actin to cardiac α-actin isoform ratio was significantly higher (1.5-fold, P<0.05) at 3 days but 40% lower (P<0.05) at 2 weeks after adenovirus-mediated Phactr1 gene delivery into the anterior wall of the left ventricle. Similarly, the skeletal α-actin to cardiac α-actin ratio was lower at 2 weeks in infarcted hearts overexpressing Phactr1. In cultured neonatal cardiac myocytes, adenovirus-mediated Phactr1 overexpression for 48 hours markedly increased the skeletal α-actin to cardiac α-actin ratio, this being associated with an enhanced DNA binding activity of serum response factor. Phactr1 overexpression exerted no major effects on the expression of other cardiac genes or LV structure and function in normal and infarcted hearts during 2 weeks' follow-up period. In human subjects, MI associated PHACTR1 allele was not associated significantly with cardiac function (n = 1550). Phactr1 seems to regulate the skeletal to cardiac α-actin isoform ratio

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.This work was supported by a grant from the US National Heart, Lung, and Blood Institute (N01-HL-25195; R01HL 093328 to RSV), a MAIFOR grant from the University Medical Center Mainz, Germany (to PSW), the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, and the Federal Ministry of Research and Education, Germany (BMBF 01EO1003 to PSW). This work was also supported by the research project Greifswald Approach to Individualized Medicine (GANI_MED). GANI_MED was funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (contract 03IS2061A). We thank all study participants, and the colleagues and coworkers from all cohorts and sites who were involved in the generation of data or in the analysis. We especially thank Andrew Johnson (FHS) for generation of the gene annotation database used for analysis. We thank the German Center for Cardiovascular Research (DZHK e.V.) for supporting the analysis and publication of this project. RSV is a member of the Scientific Advisory Board of the DZHK. Data on CAD and MI were contributed by CARDIoGRAMplusC4D investigators. See Supplemental Acknowledgments for consortium details. PSW, JFF, AS, AT, TZ, RSV, and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

Age and gender differences in risk factor burden, myocardial dysfunction and cardiovascular events in relation to glucose metabolism

The risk of cardiovascular disease (CVD) and heart failure (HF) among individuals with diabetes is at least two times greater than in non-diabetic subjects. However, the excess risk of CVD in diabetic subjects seems to decrease with age. As the majority of patients with diabetes, CVD and HF are elderly it is important to establish the extent to which the associations between these conditions differ from those in younger populations. The overall aim of the work presented in this thesis was to study gender-related associations between glucose metabolism and myocardial dysfunction, risk factor burden and CVD events in middle-aged and elderly subjects. The hypothesis tested was that similar associations would be observed in elderly as in younger populations, although the associations would be weaker with advancing age. Data from two population-based cohort studies were used: MPP-RES (Sweden: n=18,238, mean age 69+/-6 years, range 57-86 years) and AGES-RS (Iceland: n=5,764, mean age 76+/-6 years, range 67-95). In Paper I the associations between echocardiographic indices of left ventricular diastolic dysfunction (LVDD), LV mass index (LVMI) and glucometabolic status were studied in echocardiography subcohorts from the two cohort studies (MPP-RES n=1,792; AGES-RS n=841). The MPP-RES cohort was divided into two age groups: middle-aged (57-69 years) and elderly subjects (70-80 years). All subjects were grouped according to fasting glucose level (FG, mmol/l): ==7.0 (new-onset diabetes) and established diabetes, and trends between the groups were assessed. Few and inconsistent associations were observed in the AGES-RS cohort and in the elderly group in the MPP-RES cohort between increasing glucometabolic impairment and measures of LVDD. These observations are in contrast to previous findings in younger subjects as well as the present findings in the middle-aged group in the MPP-RES cohort, where a significant association was found between increasing LVDD and increasing glucometabolic impairment. It was concluded that changes in LV diastolic function may be more related to age than glucose metabolism in elderly subjects. In Paper II possible associations between N-terminal pro-B-type natriuretic peptide (Nt-proBNP) and FG as a continuous variable and in FG groups (as in Paper I) were assessed in the MPP-RES echocardiography subcohort. A positive correlation was found between Nt-proBNP and FG among middle-aged men. A positive correlation was also observed among elderly men, albeit non-significant. A non-significant negative correlation was observed among women in both age groups. The results indicate that caution should probably be exercised when interpreting Nt-proBNP values in subjects with impaired glucose metabolism. In Paper III the strength of the correlation between glucometabolic impairment, CVD risk factor burden and self-rated health (SRH), in middle-aged and elderly groups in the whole MPP-RES cohort (n=18,238) was compared. Correlations between increasing glucometabolic impairment and CVD risk factor burden and the proportion of subjects reporting poor SRH increased for both men and women in both age groups (p-trend <0.0001 for all). The slope of the trend curve with increasing CVD risk factor burden was significantly steeper for elderly women than for elderly men (p-interaction=0.002). The slope of the trend curve for poor SRH was significantly steeper for middle-aged than for elderly men (p-interaction=0.005), while no difference was observed between the age groups in the women. These results indicate lifelong CVD risk factor clustering and poorer SRH with increased glucometabolic impairment, being somewhat more pronounced in elderly women than in elderly men. Finally, in Paper IV we examined whether the previously observed age-related reduction in excess CVD risk for diabetic compared to non-diabetic subjects also applies to pre-diabetic conditions. The MPP-RES cohort was followed for 4.1+/-1.3 years during which 1,296 CVD events occurred. Subjects were grouped by FG, gender and age, as previously. The hazard ratios for CVD events increased with increasing FG among middle-aged men and women. No comparable increase was observed among elderly subjects, where men with FG =<5.0-6.9 and women with FG =<5.0-6.0 had HRs close to 1.0. The B-coefficients for interaction between age groups and intergroup trends were -0.17 (unadjusted p=0.01) and -0.15 (fully adjusted p=0.03) for men, and -0.13 (p=0.27) for women (irrespective of adjustment). It was concluded that FG values within the upper pre-diabetic range conveyed less excess risk of CVD events among elderly than middle-aged men and women

Telomeres and cardiovascular disease risk: an update 2013.

Leukocyte telomere length (LTL) has been regarded as a potential marker of biologic aging because it usually shortens in a predictable way with age. Recently, a growing interest in cardiovascular aging has led to a number of new epidemiologic studies investigating LTL in various disease conditions. Some methodological problems exist because there are different methods available to determine LTL, and standardization is much needed. For example, in the majority of studies, patients with early-onset coronary heart disease have been shown to have shorter LTL. In addition, patients with diabetes mellitus complications tend to have shorter LTL than control subjects. On the other hand, increased left ventricular hypertrophy or mass is associated with longer LTL, and studies investigating hypertension have reported both shorter and longer LTL than found in normotensive control subjects. There is, therefore, a need for longitudinal studies to elucidate these complicated relationships further, to provide estimations of telomere attrition rates, and to overcome analytical problems when only cross-sectional studies are used. The understanding of cardiovascular aging and telomere biology may open up new avenues for interventions, such as stem cell therapy or agents that could retard this aging process over and beyond conventional risk factor control

Self-rated health and classical risk factors for coronary heart disease predict development of erectile dysfunction 25 years later.

Aim: To investigate the impact of classical coronary heart disease (CHD) risk factors on the development of future erectile dysfunction (ED). Methods and results: A total of 830 randomly selected subjects were included. Baseline CHD risk factors were evaluated in relation to ED (evaluated by the International Index of Erectile Function-5 questionnaire) 25 years later. At follow-up, 499 men (60%) had some degree of ED. In age-adjusted logistic regression analysis, self-rated health [odds ratio (OR) 1.59, 95% confidence interval (CI): 1.09-2.31], family history of CHD (OR 1.75, CI: 1.17-2.61), fasting blood glucose (OR 1.52, CI: 1.14-2.02), triglycerides (OR 1.25, CI: 1.01-1.54), systolic blood pressure (SBP) (OR 1.19, CI: 1.04-1.35), body mass index (OR 1.08, CI: 1.03-1.13) and serum glutamyl transferase (GT) (OR 1.81, CI: 1.23-2.68), predicted ED. Independent predictors were higher age, low self-rated health, higher blood glucose, higher GT and a family history of CHD. Higher SBP was borderline significantly independent (p = 0.05). Furthermore, baseline age-adjusted Framingham risk score for CHD, also predicted future ED (OR 1.20, CI: 1.03-1.38). Conclusions: Our study supports and expands previous findings that ED and CHD share many risk factors, further underscoring the close link between ED and CHD. Men presenting with ED should be evaluated for the presence of other CHD risk factors

Cardiovascular event risk in relation to dietary fat intake in middle-aged individuals: data from The Malmo Diet and Cancer Study

BACKGROUND AND DESIGN: The hypothesis that diets rich in total and saturated fat and poor in unsaturated fats increase the risk for cardiovascular disease is still vividly debated. The aim of this study was to examine whether total fat, saturated fat, or unsaturated fat intakes are independent risk factors for cardiovascular events in a large population-based cohort. METHODS: 28 098 middle-aged individuals (61% women) participated in the Malmo Diet and Cancer Study between 1991 and 1996. In this analysis, individuals with an earlier history of cardiovascular disease were excluded. With adjustments made for confounding by age and various anthropometric, social, dietary, and life-style factors, hazard ratios (HR) were estimated for individuals categorized by quartiles of fat intake [HR (95% confidence interval, CI), Cox's regression model]. RESULTS: No trend towards higher cardiovascular event risk for women or men with higher total or saturated fat intakes, was observed. Total fat: HR (95% CI) for fourth quartile was 0.98 (0.77-1.25) for women, 1.02 (0.84-1.23) for men; saturated fat: 0.98 (0.71-1.33) for women and 1.05 (0.83-1.34) for men. Inverse associations between unsaturated fat intake and cardiovascular event risk were not observed. CONCLUSIONS: In relation to risks of cardiovascular events, our results do not suggest any benefit from a limited total or saturated fat intake, nor from relatively high intake of unsaturated fat