Background-After myocardial infarction (MI), extensive remodeling of extracellular matrix contributes to scar formation and preservation of hemodynamic function. On the other hand, adverse and excessive extracellular matrix remodeling leads to fibrosis and impaired function. The present study investigates the role of the small leucine-rich proteoglycan biglycan during cardiac extracellular matrix remodeling and cardiac hemodynamics after MI. Methods and Results-Experimental MI was induced in wild-type (WT) and bgn Ϫ/0 mice by permanent ligation of the left anterior descending coronary artery. Biglycan expression was strongly increased at 3, 7, and 14 days after MI in WT mice. bgn Ϫ/0 mice showed increased mortality rates after MI as a result of frequent left ventricular (LV) ruptures. Furthermore, tensile strength of the LV derived from bgn Ϫ/0 mice 21 days after MI was reduced as measured ex vivo. Collagen matrix organization was severely impaired in bgn Ϫ/0 mice, as shown by birefringence analysis of Sirius red staining and electron microscopy of collagen fibrils. At 21 days after MI, LV hemodynamic parameters were assessed by pressure-volume measurements in vivo to obtain LV end-diastolic pressure, end-diastolic volume, and end-systolic volume. bgn Ϫ/0 mice were characterized by aggravated LV dilation evidenced by increased LV end-diastolic volume (bgn

Background-In the European Project On Genes in Hypertension (EPOGH), we investigated in 3 populations to whatextent left ventricular mass (LVM) was associated with genetic variation in the angiotensin II receptors type 1 (AGTR1 A1166C) and type 2 (AGTR2 G1675A) while accounting for possible gene-gene interactions with the angiotensinconverting enzyme (ACE D/I) and angiotensinogen (AGT Ϫ532C/T) polymorphisms. Methods and Results-We randomly recruited 221 nuclear families (384 parents, 431 offspring) in Cracow (Poland), Novosibirsk (Russia), and Mirano (Italy). Echocardiographic LVM was indexed to body surface area, adjusted for covariates, and subjected to multivariate analyses using generalized estimating equations and quantitative transmission disequilibrium tests in a population-based and family-based approach, respectively. For AGTR1 and AGTR2, there was no heterogeneity in the phenotype-genotype relations across populations. LVM index was unrelated to the AGTR1 A1166C polymorphism. In men, in the population-and family-based analyses, the allelic effects of the AGTR2 polymorphism on LVM index differed (Pϭ0.01) according to sodium excretion. In women, this gene-environment interaction did not reach statistical significance. In untreated men, LVM index (4.2 g/m 2 per 100 mmol) and left ventricular internal diameter (0.73 mm/100 mmol) increased (PϽ0.02) with higher sodium excretion in the presence of the G allele with an opposite tendency in A allele carriers. The ACE D/I polymorphism, together with the ACE genotype-by-sodium interaction term, significantly and independently improved the models relating LVM index to the AGTR2 polymorphism and the AGTR2 genotype-by-sodium interaction. Conclusions-The present findings support the hypothesis that in men the AGTR2 G1675A and the ACE D/I polymorphisms independently influence LVM and that salt intake modulates these genetic effects.

Abstract-Activation of type-1 dopamine receptors (DRD1) reduces renal sodium reabsorption. In a family-based random sample of 611 untreated whites (women, 45.0%; mean age, 38.6 years), we measured blood pressure (BP). We used the endogenous lithium clearance to assess fractional sodium excretion (FE Na ) and proximal (RNa prox ) and distal (RNa dist ) tubular sodium reabsorption. We investigated multivariate-adjusted associations with the DRD1 promoter (AϪ48G, GϪ94A, and CϪ800T) and GRK4 (Ala142Val Key Words: blood pressure Ⅲ clinical genetics Ⅲ dopamine receptor gene Ⅲ GRK4 Ⅲ lithium clearance Ⅲ population science Ⅲ tubular transport D opamine reduces sodium reabsorption in the proximal renal tubules via activation of dopamine type-1 (DRD1) receptors, which leads to inhibition of sodium transporters, including the Na,H-exchanger and Na,K-ATPase. 1 The DRD1 promoter harbors several single-nucleotide polymorphisms (SNPs), 2 which influence the expression of the gene. Dopamine exerts its actions via G protein-coupled receptors, which in turn are under control of G protein-coupled receptor kinases (GRKs). 1 Amino-acid changing polymorphisms in one particular member of this family, GRK4, cause hyperphosphorylation, desensitization, and internalization of the DRD1 receptor and enhance the expression of the angiotensin II type-1 receptor. 1 The genes encoding DRD1 and GRK4 localize to chromosomes 5q35.1 3 and 4p16.3, 4 respectively. The GRK4 gene locus is embedded in a cluster on chromosome 4p16, which is associated with hypertension 5,6 and also includes ␣-adducin (ADD1). To our knowledge, there are no studies showing significant genome-wide linkage of hypertension with the DRD1 locus, although a genome-scan meta-analysis 7 identified 5q as a suggestive region.Measuring the clearance of endogenous lithium provides a way of estimating sodium handling in the proximal and postproximal nephron. 8,9 Expressing the renal clearance of endogenous lithium as a fraction of creatinine clearance provides a measure of tubular sodium reabsorption that is standardized for the glomerular filtration rate. 8,9 The fractional excretion of lithium (FE Li ) is a noninvasive marker of proximal tubular sodium handling and the proportion of sodium escaping reabsorption in the proximal segment of the nephron. FE Li also allows the calculation of the fractional distal reabsorption of sodium (RNa dist ). To our knowledge, no prior study addressed the possible association of these renal