Citations

Background Cyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure ( HF ) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular ( LV ) function. Methods and Results We assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW ) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II ‐dependent respiratory control, was present in both HF and tadalafil‐treated animals. Conclusions Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

Abstract Aims We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. Methods and results We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (−39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. Conclusion Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

Background We recently reported that normal aldosterone levels are associated with cardiovascular, renal, and metabolic disease in a sample of the US general community (Visit 1). For the current analyses we used the same cohort in a new 4‐year follow‐up study (Visit 2). Methods and Results We measured aldosterone at Visit 1 and analyzed its predictive role for new diseases at Visit 2 (n=1140). We measured aldosterone at Visit 2 and investigated its associations with disease at Visit 2 (n=1368). We analyzed aldosterone continuously and we also dichotomized the variable as whether subjects were in the third tertile versus second and first tertiles. As continuous variable at Visit 1, aldosterone predicted new onset hypertension ( HTN ) ( OR =1.36, CI =1.13–1.63, P =0.001), central obesity ( OR =1.36, CI =1.07–1.73, P =0.011), and use of lipid‐lowering drugs ( OR =1.25, CI =1.05–1.48, P =0.012) at Visit 2, after adjustment for age, sex, and body mass index. When in the third tertile (8.5–88.6 ng/dL), aldosterone predicted type 2 diabetes (T2 DM , OR =1.96, CI =1.03–3.70, P =0.039). At Visit 2, aldosterone remained associated with HTN , obesity, and chronic kidney disease ( CKD ), as reported for Visit 1. However, aldosterone was not associated with heart failure ( HF ) at Visit 1 and 2, nor was aldosterone a predictor of HF between visits. Conclusions Aldosterone predicts new HTN , central obesity, T2 DM , and use of lipid‐lowering drugs in the general community and remains associated with HTN , obesity, and CKD over 4 years. Aldosterone is not associated nor predicts HF . Further studies are warranted to evaluate aldosterone as therapeutic target in the general community.

1.A family of structurally related but genetically distinct natriuretic peptides exist which include atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of myocardial cell origin and C-type natriuretic peptide (CNP) of endothelial and renal epithelial cell origin. All three exert actions via cGMP, with ANP and BNP functioning via the natriuretic peptide A receptor and CNP via the natriuretic peptide B receptor. 2.Circulating and urinary natriuretic peptides were determined in response to acute intravascular volume overload (AVO). Additionally, their functional role in cardiorenal regulation during AVO was investigated by utilizing the natriuretic peptide receptor antagonist HS-142-1. Control (n = 5) and study dogs (HS-142-1, n = 9) underwent AVO with normal saline equal to 10% of body weight over 1 ;h. Both groups demonstrated similar significant increases in right atrial pressure, pulmonary capillary wedge pressure, pulmonary artery pressure and cardiac output. Circulating ANP paralleled increases in right atrial pressure and pulmonary capillary wedge pressure, with no changes in plasma BNP or CNP. At peak AVO, urinary CNP excretion was increased compared with baseline (7.0±4.2 versus 62±8.0 ;pg/min, P< 0.05). 3.In the HS-142-1-treated group, plasma cGMP was decreased compared with the control group (9.6±1.1 to 5.0±1.2 ;pmol/ml, P< 0.05). A significant attenuation of natriuresis (566±91 versus 1241±198 ;μEq/min, P< 0.05) and diuresis (4.8±0.7 versus 10.1±2.0 ;ml/min, P< 0.05) was also observed at peak AVO in the HS-142-1 treated group. 4.These findings support differential and selective responses of the three natriuretic peptides to AVO, in which plasma ANP and urinary CNP are markers for AVO. Secondly, these studies confirm the role of ANP and CNP but not BNP in the natriuretic and diuretic response to acute volume overload.

1. While the natriuretic peptides (atrial, brain and C-type) mediate potent endothelium-independent vasorelaxing actions in vitro, the role of the endogenous natriuretic peptide system in vascular regulation in vivo remains unclear. 2. HS-142-1 is a novel natriuretic peptide receptor antagonist derived from a fungus named Aureobasidium sp. which selectively blocks particulate guanylate cyclase-linked natriuretic peptide A and B receptors that bind atrial, brain and C-type natriuretic peptide, and thus attenuates the generation of cGMP. 3. To characterize the vascular actions of the endogenous natriuretic peptide system in the control of basal coronary and systemic haemodynamics, six normal male mongrel anaesthetized dogs were studied while a second group of five dogs served as a control. HS-142-1 was given as an intravenous bolus at 3 mg/kg and was studied over five 20 min periods. 4. No significant difference after HS-142-1 was observed in mean arterial pressure, heart rate, cardiac output, right atrial pressure, pulmonary capillary wedge pressure or systemic vascular resistance compared with control. In contrast, a significant increase in coronary vascular resistance and decrease in coronary blood flow were observed which were different from the baseline values and the responses of the control group. 5. These studies demonstrate that HS-142-1 produces vasoconstriction in the coronary circulation. We conclude that the endogenous natriuretic peptide system, which is of cardiac and endothelial cell origin, is an important regulator of basal coronary vascular tone.

Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end-organ damage in adulthood.

Abstract To identify genetic variants that contribute to colorectal cancer (CRC) susceptibility, we performed a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, followed by a replication of genome-wide statistically significant associations (P &lt; 5E-8) in 16,823 cases and 18,211 controls of European ancestry. This study revealed a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.5E-9), providing additional insight into the etiology of CRC and highlighting the value of association mapping in diverse populations. Citation Format: Hansong Wang, Terrilea Burnett, Suminori Kono, Christopher Haiman, Motoki Iwasaki, Lynne Wilkens, Lenora Loo, David Van Den Berg, Laurence Kolonel, Brian Henderson, Temitope Keku, Robert Sandler, Lisa Signorello, William Blot, Polly Newcomb, Mala Pande, Christopher Amos, Dee West, Stéphane Bézieau, Sonja Berndt, Brent Zanke, Li Hsu, Noralane Lindor, Robert Haile, John Hopper, Mark Jenkins, Steven Gallinger, Graham Casey, Stephanie Stenzel, Fredrick Schumacher, Ulrike Peters, Stephen Gruber, Shoichiro Tsugane, Dan Stram, Loic Le Marchand. Transethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-282. doi:10.1158/1538-7445.AM2014-LB-282

C-type natriuretic peptide (CNP) is an endothelium-derived peptide that is released as a protective mechanism in response cardiovascular injury or disease. However, no studies have investigated circulating CNP, identifying clinical factors that may influence CNP and its relationship to cardiovascular disease in the general population. We studied 1841 randomly selected subjects from Olmsted County, MN (mean age, 63±11 years; 48% men). Plasma CNP was measured by a well-established radioimmunoassay and echocardiography, clinical characterization, and detailed medical record review were performed. We report that CNP circulates at various concentrations (median, 13 pg/mL), was unaffected by sex, was weakly associated by age, and that highest quartile of CNP identified a high-risk phenotype. Subjects with CNP in the highest quartile were associated with increased risk of myocardial infarction (multivariable-adjusted hazard ratio, 1.51; 95% confidence interval, 1.09–2.09; P =0.01) but not heart failure, cerebrovascular accidents, or death during a follow-up of 12 years. Addition of the highest quartile of CNP to clinical variables led to a modest increase in the integrated discrimination improvement for risk of myocardial infarction. In a large community-based cohort, elevated circulating CNP identified a high-risk phenotype that included cardiovascular comorbidities and left ventricular dysfunction, and provided evidence that highest concentrations of CNP potentially has prognostic value in predicting future risk of myocardial infarction. Together, these data from the general population highlight the potential value of CNP and support the need for additional studies to evaluate whether mechanisms regulating CNP could improve outcomes.

Although effective in relieving symptoms of edema in congestive heart failure (CHF), diuretic-induced natriuresis may be associated with reductions in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), which subsequently may reduce the duration of natriuresis. Moreover, recent studies have reported that the preservation of GFR is an important predictor of survival in human CHF. We hypothesized that the acute detrimental renal hemodynamic and tubular responses to furosemide in symptomatic human CHF will be attenuated by AT1 receptor blockade with losartan. We defined the renal hemodynamic and tubular actions and aldosterone responses to furosemide (40 mg, orally) in the presence of acute AT1 receptor antagonism (losartan, MSD, 50 mg orally) vs. placebo in 10 subjects with CHF (New York Heart Association II-III) in a double-blind, placebo-controlled crossover study. Furosemide with placebo increased sodium excretion and reduced ERPF and GFR ( P < 0.05 vs. baseline). After 4 h, sodium excretion compared with baseline was decreased ( P < 0.05). In contrast, furosemide with losartan resulted in a greater increase in sodium excretion but without reductions in ERPF and GFR ( P < 0.05 vs. placebo). After 4 h, sodium excretion was greater compared with the placebo group. Importantly, plasma aldosterone tended to increase in the placebo group, whereas it was decreased ( P < 0.05 vs. baseline) only in the losartan group. These studies underscore the pathophysiological role of the AT1 receptor in mediating detrimental renal and adrenal properties of diuretics in human CHF. AT1 receptor antagonism preserves GFR and renal blood flow and enhances sodium excretion during acute diuretic therapy in addition to inhibiting aldosterone secretion. These findings support the use of AT1 receptor blockade for human CHF requiring acute diuretics to improve renal hemodynamic and tubular function and to suppress aldosterone.