Citations

BackgroundSystemic hypertension is a common characteristic in acute heart failure (HF). This increasingly recognized phenotype is commonly associated with renal dysfunction and there is an unmet need for renal enhancing therapies. In a canine model ofHFand acute vasoconstrictive hypertension we characterized and compared the cardiorenal actions ofM‐atrial natriuretic peptide (M‐ANP), a novel particulate guanylyl cyclase (pGC) activator, and nitroglycerin, a soluble guanylyl cyclase (sGC) activator.Methods and ResultsHFwas induced by rapid RV pacing (180 beats per minute) for 10 days. On day 11, hypertension was induced by continuous angiotensin II infusion. We characterized the cardiorenal and humoral actions prior to, during, and following intravenousM‐ANP(n=7), nitroglycerin (n=7), and vehicle (n=7) infusion. Mean arterial pressure (MAP) was reduced byM‐ANP(139±4 to 118±3 mm Hg,P<0.05) and nitroglycerin (137±3 to 116±4 mm Hg,P<0.05); similar findings were recorded for pulmonary wedge pressure (PCWP) withM‐ANP(12±2 to 6±2 mm Hg,P<0.05) and nitroglycerin (12±1 to 6±1 mm Hg,P<0.05).M‐ANPenhanced renal function with significant increases (P<0.05) in glomerular filtration rate (38±4 to 53±5 mL/min), renal blood flow (132±18 to 236±23 mL/min), and natriuresis (11±4 to 689±37 mEq/min) and also inhibited aldosterone activation (32±3 to 23±2 ng/dL,P<0.05), whereas nitroglycerin had no significant (P>0.05) effects on these renal parameters or aldosterone activation.ConclusionsOur results advance the differential cardiorenal actions ofpGC(M‐ANP) andsGC(nitroglycerin) mediatedcGMPactivation. These distinct renal and aldosterone modulating actions makeM‐ANPan attractive therapeutic forHFwith concomitant hypertension, where renal protection is a key therapeutic goal.

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency &lt; 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

We analyzed the phenotype associated with the atrial natriuretic peptide (ANP) genetic variant rs5065 in a random community-based sample. We also assessed and compared the biological action of 2 concentrations (10 −10 mol/L, 10 –8 mol/L) of ANP and ANP-RR, the protein variant encoded by the minor allele of rs5065, on activation of the guanylyl cyclase (GC)-A and GC-B receptors, production of the second messenger 3′,5′-cGMP in endothelial cells, and endothelial permeability. rs5065 genotypes were determined in a cross-sectional adult cohort from Olmsted County, MN (n=1623). Genotype frequencies for rs5065 were 75%, 24%, and 1% for TT, TC, and CC, respectively. Multivariate analysis showed that the C allele was associated with increased risk of cerebrovascular accident (hazard ratio, 1.43; 95% confidence interval, 1.09–1.86; P =0.009) and higher prevalence of myocardial infarction (odds ratio, 1.82; 95% confidence interval, 1.07–3.09; P =0.026). ANP-RR 10 −8 mol/L activated the GC-A receptor (83.07±8.31 versus no treatment 0.18±0.04 per 6 wells; P =0.006), whereas ANP-RR 10 −10 mol/L did not. Neither 10 −8 mol/L nor 10 −10 mol/L ANP-RR activated GC-B receptor ( P =0.10, P =0.35). ANP 10 −8 mol/L and ANP-RR 10 −8 mol/L stimulated 3′,5′-cGMP production in endothelial cells similarly ( P =0.58). Both concentrations of ANP-RR significantly enhanced human aortic endothelial cell permeability (69 versus 29 relative fluorescence units [RFUs], P =0.012; 58 versus 39 RFUs, P =0.015) compared with ANP. The minor allele of rs5065 was associated with increased cardiovascular risk. ANP-RR activated the GC-A receptor, increased 3′,5′-cGMP in endothelial cells, and when compared with ANP, augmented endothelial cell permeability.

Background Neurohormonal dysregulation contributes to heart failure (HF) progression. We sought to determine the effect of cardiac resynchronisation therapy (CRT) on the nerve growth factor (NGF), a biomarker that promotes the maturation, and survival of sympathetic nerve endings, and amino-terminal propeptide of type III procollagen (PIIINP), a marker of type III collagen synthesis. Methods This prospective study enrolled 20 healthy age-matched controls and 45 consecutive patients (pts) who received CRT-D. NYHA class, distance of 6-min walk and echocardiography and plasma concentrations of NGF, PIIINP, b-type natriuretic peptide (BNP), norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were measured before and 6 month after CRT. Response to CRT was defined as ≥15% reduction in left ventricular end-systolic volume index (LVESVI) at 6-month follow-up. Results The baseline BNP (557±692 vs 47±35, p<0.01) and PIIINP (8.22±3.76 vs 5.36±1.47, p<0.01) were elevated in HF compared to controls, while NGF, NE, EPI and DA levels were not different. Twenty two of 45 pts (49%) responded to CRT. The responder group demonstrated significant decrease only in BNP level (p=0.04) at 6-month follow-up, parallelling with the clinical improvements (table 1). The baseline PIIINP was lower in CRT responders than non-responders (p=0.04), and it correlated with the reduction of LVESVI (p=0.01, r=−0.50) after CRT. The further multivariate analysis showed only the plasma PIIINP level among clinic characters and all the biomarkers can predict the improvement of LVESV index (OR=8.33, P=0.01). Conclusion The low PIIINP level, which is consistent with possible less cardiac fibrosis and a more plastic ventricle at baseline, is associated with CRT responsiveness. Contrary to previous reports, the NGF levels were not reduced during HF and that there was no NGF rebound in CRT responders.

OBJECTIVE We hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population. RESEARCH DESIGN AND METHODS We genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068. RESULTS Genotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%. All subsequent analyses are AA versus AG+GG. After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: −1.7 kg/m2 [0.8], P = 0.04). In the AG+GG group, males with HDL cholesterol levels &lt;40 mg/dL are less frequent (P = 0.05) and obesity tends to be less prevalent (P = 0.07). Importantly, the G allele is associated with a lower prevalence of metabolic syndrome (P = 0.02). After adjusting for BMI, the above associations were attenuated. Independently of age, sex, and BMI, the minor allele is also associated with lower systolic blood pressure (−6.0 mmHg [2.5], P = 0.02) and lower prevalence of hypertension (odds ratio 0.41 [95% CI 0.20–0.83], P = 0.01). CONCLUSIONS The association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome. These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome.

BACKGROUND High-sensitivity cardiac troponin (hs-cTn) assays are now available that can detect measurable troponin in significantly more individuals in the general population than conventional assays. The clinical use of these hs-cTn assays depends on the development of proper reference values. Therefore, our objective was to define hs-cTnI reference values and determinants in the general community, in a healthy reference cohort, and in subsets with diseases. MATERIALS AND METHODS A well-characterized community-based cohort of 2042 study participants underwent clinical assessment and echocardiographic evaluation. Baseline hs-cTnI measurements were obtained in 1843 individuals. A healthy reference cohort (n = 565) without cardiac, renal, or echocardiographic abnormalities was identified. RESULTS Measurable hs-cTnI was identified in 1716 (93%) of the community-based study cohort and 499 (88%) of the healthy reference cohort. Parameters that significantly contributed to higher hs-cTnI concentrations in the healthy reference cohort included age, male sex, systolic blood pressure, and left ventricular mass. Glomerular filtration rate and body mass index were not independently associated with hs-cTnI in the healthy reference cohort. Individuals with diastolic and systolic dysfunction, hypertension, and coronary artery disease (but not impaired renal function) had significantly higher hs-cTnI values than the healthy reference cohort. CONCLUSIONS We assessed an hs-cTnI assay with the aid of echocardiographic imaging in a large, well-characterized community-based cohort. hs-cTnI is remarkably sensitive in the general population, and there are important sex and age differences among healthy reference individuals. These results have important implications for defining hs-cTnI reference values and identifying disease.