Novel quantitative trait locus is mapped to chromosome 12p11 for left ventricular mass in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease. The genetic basis of LVM is unclear although a high heritability has been suggested. We sought to map quantitative trait loci (QTL) for LVM using large Dominican families.</p> <p>Methods</p> <p>Probands were selected from Dominican subjects of the population-based Northern Manhattan Study (NOMAS). LVM was measured by transthoracic echocardiography. A set of 405 microsatellite markers was used to screen the whole genome among 1360 subjects from 100 Dominican families who had complete phenotype data and DNA available. A polygenic covariate screening was run to identify the significant covariates. Variance components analysis was used to estimate heritability and to detect evidence for linkage, after adjusting for significant risk factors. Ordered-subset Analysis (OSA) was conducted to identify a more homogeneous subset for stratification analysis.</p> <p>Results</p> <p>LVM had a heritability of 0.58 in the studied population (p < 0.0001). The most significant evidence for linkage was found at chromosome 12p11 (MLOD = 3.11, empirical p = 0.0003) with peak marker at D12S1042. This linkage was significantly increased in a subset of families with the high average waist circumference (MLOD = 4.45, p = 0.0045 for increase in evidence for linkage).</p> <p>Conclusion</p> <p>We mapped a novel QTL near D12S1042 for LVM in Dominicans. Enhanced linkage evidence in families with larger waist circumference suggests that gene(s) residing within the QTL interact(s) with abdominal obesity to contribute to phenotypic variation of LVM. Suggestive evidence for linkage (LOD = 1.99) has been reported at the same peak marker for left ventricular geometry in a White population from the HyperGEN study, underscoring the importance of this QTL for left ventricular phenotype. Further fine mapping and validation studies are warranted to identify the underpinning genes.</p

A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes

<p>Abstract</p> <p>Background</p> <p>Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM.</p> <p>Methods</p> <p>Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets.</p> <p>Results</p> <p>In the overall analysis, the most significant association was found to rs10743465, downstream of the <it>SOX5 </it>gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p < 0.001. In the subset analysis, the most significant difference in genetic effect between those with high and low WC occurred with rs1157480 (p = 1.37E-04 for the difference in β coefficients), located upstream of <it>TMTC1</it>. Twelve additional SNPs in or near 6 genes had p < 0.001.</p> <p>Conclusions</p> <p>The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. <it>SOX5 </it>may play an important role in the regulation of LVM. An interaction of <it>TMTC1 </it>with abdominal obesity may contribute to phenotypic variation of LVM.</p

Left atrioventricular remodeling in the assessment of the left ventricle diastolic function in patients with heart failure: a review of the currently studied echocardiographic variables

Multiparametric echocardiographic imaging of the failing heart is now increasingly used and useful in decision making in heart failure. The reasons for this, relies on the need of different strategies of handling these patients, as differentiation of systolic or diastolic dysfunction, as well as on the gamma of approaches available, such as percutaneous and surgical revascularization, devices implantations, and valvular regurgitations and stenosis corrections. Congestive heart failure in patients with normal left ventricular diameters or preserved left ventricular ejection fraction had been pointed out recently as present in a proportion so high as 40 to 50 percent of cases of heart failure, mainly due to the epidemics in well developed countries, as is the problem of not well controlled metabolic states (such as obesity and diabetes), but also due to the real word in developing countries, as is the case of hypertension epidemics and its lack of adequate control. As a matter of public utility, the guidelines in the diagnosis and treatment of such patients will have to be cheap, available, easily reproducible, and ideally will furnish answers for the clinician questions not in a binary "black or white" manner, but with graduations, so if possible it has to be quantitative. The present paper aim to focus on the current clinical applications of tissue Doppler and of left atrial function and remodeling, and its pathophysiologic relationship with the left ventricle, as will be cleared in the documented review of echocardiography that follows, considering that the need of universal data on the syndrome of the failing heart does not mean, unfortunately, that all patients and clinicians in developing countries have at their own health facilities the same imaging tools, since they are, as a general rule, expensive

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Effects of pulmonary balloon valvuloplasty on right coronary artery blood flow in pulmonary valve stenosis

Pulmonary balloon valvuloplasty results in improvement in the right coronary artery blood flow velocity pattern and the volumetric flow in patients with pulmonary valve stenosis. These changes are closely related to concomitant changes in right ventricular systolic pressure

Exaggerated carotid sinus massage responses are related to severe coronary artery disease in patients being evaluated for chest pain

Background: Previous studies have reported that carotid sinus massage responses are associated with advancing age and carotid or coronary artery disease. Hypothesis: This study was undertaken to investigate the potential role of carotid sinus hypersensitivity as a marker for the presence of coronary artery disease, and especially left main stein disease, in patients who were referred for evaluation of chest pain. Methods: Toward this end, carotid sinus stimulation with simultaneous recordings of the electrocardiogram and aortic pressure was performed before coronary arteriography in 150 selected consecutive patients (mean age 59.4 +/- 9 years) who were referred for evaluation of chest pain. Results: Coronary artery disease was present in 118 patients (78.7%); of these, 35 had single-vessel disease, 35 had double-vessel disease, 33 had triple-vessel disease, and 15 had left main stem with or without such vessel disease. Carotid sinus hypersensitivity was found in 40 patients (26.6%). The incidence of hypersensitivity in patients with single-, double-, or triple-vessel disease and left main stem disease was 8.5, 14.2. 57.5. and 73.3%. respectively. Stepwise multiple logistic regression analysis revealed that left main stem disease was significantly and independently related to the presence of carotid sinus hypersensitivity (p &lt; 0.05). In addition, the presence of hypersensitivity had 73.3% sensitivity, 86.2% specificity, and 96.3% negative predictive value for the presence of left main stem disease. Conclusion: In patients being evaluated for suspected ischemic heart disease, carotid sinus massage responses are related to severe coronary disease. The absence of hypersensitivity may reflect absence of left main stem disease