Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

<p>Abstract</p> <p>Background</p> <p>Angiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).</p> <p>Methods</p> <p>We genotyped five polymorphisms of the <it>AGT</it>, <it>ACE</it>, <it>AT1R</it>, <it>5-HT2A</it>, and <it>5-HTT </it>genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.</p> <p>Results</p> <p>We found a significantly higher frequency of <it>AT1R </it>1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The <it>AT1R </it>1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.</p> <p>Conclusions</p> <p>The 1166 C <it>AT1R </it>allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the <it>AGT</it>, <it>ACE</it>, <it>5-HT2A </it>and <it>5-HTT </it>did not contribute to the risk of cardiac hypertrophy.</p

Selective Serotonin Reuptake Inhibitor Use Is Associated with Right Ventricular Structure and Function: The MESA-Right Ventricle Study

PURPOSE:Serotonin and the serotonin transporter have been implicated in the development of pulmonary hypertension (PH). Selective serotonin reuptake inhibitors (SSRIs) may have a role in PH treatment, but the effects of SSRI use on right ventricular (RV) structure and function are unknown. We hypothesized that SSRI use would be associated with RV morphology in a large cohort without cardiovascular disease (N = 4114). METHODS:SSRI use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were assessed via cardiac magnetic resonance imaging. The cross-sectional relationship between SSRI use and each RV measure was assessed using multivariable linear regression; analyses for RV mass and end-diastolic volume (RVEDV) were stratified by sex. RESULTS:After adjustment for multiple covariates including depression and left ventricular measures, SSRI use was associated with larger RV stroke volume (RVSV) (2.75 mL, 95% confidence interval [CI] 0.48-5.02 mL, p = 0.02). Among men only, SSRI use was associated with greater RV mass (1.08 g, 95% CI 0.19-1.97 g, p = 0.02) and larger RVEDV (7.71 mL, 95% 3.02-12.40 mL, p = 0.001). SSRI use may have been associated with larger RVEDV among women and larger RV end-systolic volume in both sexes. CONCLUSIONS:SSRI use was associated with higher RVSV in cardiovascular disease-free individuals and, among men, greater RV mass and larger RVEDV. The effects of SSRI use in patients with (or at risk for) RV dysfunction and the role of sex in modifying this relationship warrant further study

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

Heights And Weights Of Primary School Children Of Different Social Background In Ankara, Turkey

A cross-sectional anthropometric survey was carried out in a low socio-economic and high socioeconomic region of Ankara, Turkey, to measure the weights and heights of school children, The study group consisted of 5289 children between the ages of 5 and 11 years, Both boys and girls from the high socio-economic group had superior body measurements compared to those of the low socio-economic group, The difference between the mean weight for age values of two groups was statistically significant (P < 0.05), whereas no statistically significant difference was found on the basis of height for age values among all age groups, To make a comparison both with National Centre for Health Statistics and World Health Organisation (NCHS-WHO) standards and Turkish standards we used the data from high socio-economic group only, Our results showed that the mean height and weight values of boys and girls were higher than the 50th centile height and weight values of NCHS-WHO standards, Almost 25 years have passed since the measurements of Turkish standards were taken, The height differences were in the range of 0.24-1.51 cm/decade, with a mean value of 0.96 cm/decade, These results led us to conclude that, local/regional standards for height and weight are needed, and repeated assessments are useful for follow-up of populations.WoSScopu

The comparison of vascular reactivities of arterial and venous grafts to vasodilators: Management of graft spasm

Graft spasm in the perioperative or postoperative period increases the risk of morbidity and mortality after coronary revascularization and hence necessitates urgent treatment. We have studied the effects of various vasodilators against noradrenaline- and endothelin-1-induced spasms in saphenous vein, internal mammary artery and gastroepiploic artery. In internal mammary and gastroepiploic arteries, the nitrovasodilators, sodium nitroprusside and glyceryl trinitrate, effectively reversed the spasms induced either with noradrenaline (for sodium nitroprusside; internal mammary artery: 101.07% +/- 1.63%; gastroepiploic artery: 94.10% +/- 2.07%) or endothelin-1 (for sodium nitroprusside; internal mammary artery: 97.67% +/- 4.94%; gastroepiploic artery: 90.69% +/- 2.61%). However, in saphenous vein contracted with endothelin-1, the responsiveness to nitrovasodilators was significantly blunted (for sodium nitroprusside: 52.33% +/- 5.19%) than that of rings contracted with noradrenaline (for sodium nitroprusside: 95.04% +/- 1.94%). Both arterial and venous grafts exhibited moderate beta-receptor function in response to isoproterenol, Isoproterenol was less effective in inhibiting the contractions of endothelin-1 in saphenous vein and gastroepiploic artery but not in internal mammary artery. On the other hand, nifedipine and papaverine were fully effective in reversing all the spasms in three of the graft materials. From these results, it can be deduced that saphenous vein is refractory against cyclic guanidine monophosphate (cGMP)-dependent and beta-receptor mediated relaxations when endothelin-1 was used as the spasmogenic agent. Internal mammary artery is the most responsive graft material to the vasodilators regardless of the nature of spasmogenic stimulus. Gastroepiploic artery exhibits functional similarity with internal mammary artery, with the exception of beta-receptor responsiveness