Arterial stiffness and Vitamin D levels: the Baltimore Longitudinal Study of Aging

CONTEXT: The importance of vitamin D for bone health has long been acknowledged. Recent evidence suggests that vitamin D can also play a role in reducing the risk of several other diseases, including cardiovascular disease. OBJECTIVE: The aim of this study is to test the hypothesis that 25-hydroxyvitamin D (25-OH D) is an independent cross-sectional correlate of central arterial stiffness in a normative aging study population. DESIGN AND SETTINGS: We conducted a cross-sectional analysis. SUBJECTS: We studied 1228 healthy volunteers (50% males; age, 70\ub112 yr) of the Baltimore Longitudinal Study of Aging. MAIN OUTCOME MEASURES: We measured carotid-femoral pulse wave velocity (PWV) and 25-OH D levels. RESULTS: We found a significant inverse association between PWV and 25-OH D levels (adjusted r2=0.27; \u3b2=-0.43; P=0.001). After adjusting for age, gender, ethnicity, season of blood draw, estimated glomerular filtration rate, physical activity level, cardiovascular risk factors score (smoking, visceral obesity, hypercholesterolemia, hypertension, and diabetes), calcium/vitamin D supplementation, serum calcium, and PTH levels, the association between PWV and 25-OH D levels was only slightly reduced and remained statistically significant (adjusted r2=0.34; \u3b2=-0.34; P=0.04). CONCLUSIONS: Vitamin D levels are inversely associated with increased arterial stiffness in a normative aging population, irrespective of traditional risk factor burden. Further research is needed to understand the mechanism of this association and to test the hypothesis that vitamin D supplementation can reduce arterial stiffness

Identification of New SRF Binding Sites in Genes Modulated by SRF Over-Expression in Mouse Hearts

Background To identify in vivo new cardiac binding sites of serum response factor (SRF) in genes and to study the response of these genes to mild over-expression of SRF, we employed a cardiac-specific, transgenic mouse model, with mild over-expression of SRF (Mild-O SRF Tg). Methodology Microarray experiments were performed on hearts of Mild-O-SRF Tg at 6 months of age. We identified 207 genes that are important for cardiac function that were differentially expressed in vivo. Among them the promoter region of 192 genes had SRF binding motifs, the classic CArG or CArG-like (CArG-L) elements. Fifty-one of the 56 genes with classic SRF binding sites had not been previously reported. These SRF-modulated genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes was significantly increased. Using public databases of mouse models of hemodynamic stress (GEO database), we also found that similar altered expression of the SRF-modulated genes occurred in these hearts with cardiac ischemia or aortic constriction as well. Conclusion and significance SRF-modulated genes are actively regulated under various physiological and pathological conditions. We have discovered that a large number of cardiac genes have classic SRF binding sites and were significantly modulated in the Mild-O-SRF Tg mouse hearts. Hence, the mild elevation of SRF protein in the heart that is observed during typical adult aging may have a major impact on many SRF-modulated genes, thereby affecting Cardiac structure and performance. The results from our study could help to enhance our understanding of SRF regulation of cellular processes in the aged heart

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

What keeps us ticking: a funny current, a calcium clock, or both?

On the basis of prolific experimental evidence supported by novel numerical modeling, it is reasonable to conclude that the tightly coupled system of SR Ca 2+ cycling and surface membrane proteins is the clock that controls SANC normal automaticity, leading to their mutual functional entrainment [115]. The clock is robust because the same factors that regulate SR Ca 2+ cycling, i.e., Ca 2+ and PKA and CaMKII-dependent protein phosphorylation, also regulate sarcolemmal ion channel function and thereby couple SR Ca 2+ cycling to the surface membrane. G protein-coupled receptor signaling ensures pacemaker flexibility by affecting rate regulation by impacting on the very same factors that ensure pacemaker fail-safe operation or robustness in a given steady state. Intimately intertwined robustness and flexibility of the heart's pacemaker ensure a wide range of stable heart rates. Rebuttal: DiFrancesco. Ed, you concentrate on the existence of a complex cellular machinery underlying Ca 2+ cycling. I have no problem with this, but we are discussing here the function of Ca 2+ cycling and that of the funny current. Clearly, none of the mechanisms working in a pacemaker cell can be functionally removed without major impact on the whole behaviour of the cell. Normal physiological pacemaking depends on the integrity of all participating cellular processes, and pointing out that one mechanism is essential for rate control does not mean that mechanism is responsible for that control. The questions we need to address here are simpler ones: which is the physiological process selected to generate spontaneous activity (or, better, discriminating between pacing and silent cardiomyocytes)? Also, when a change in rate is required, which is the physiological process selected, typically by the autonomic nervous system, to produce it? A change in the rate of Ca 2+ fluctuations, or a change in I f