BACKGROUND Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. METHODS In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro–brain natriuretic peptide (NT-proBNP). RESULTS In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (−381 accelerometer units; 95% confidence interval [CI], −780 to 17; P = 0.06) and a significant decrease in hours of activity per day (−0.30 hours; 95% CI, −0.55 to −0.05; P = 0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (−439 accelerometer units; 95% CI, −792 to −86; P = 0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. CONCLUSIONS Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo.

Myocardial aging is characterized by LV fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent anti-fibrotic and anti-proliferative properties of C-type natriuretic peptide (CNP), however the relationship between circulating CNP, LV fibrosis and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2, 11 and 20 month old male Fischer rats. Further in vitro, we establish the anti-proliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis which precedes impairment of diastolic and systolic function. Additionally we demonstrate in cultured adult human cardiac fibroblasts that the direct anti-proliferative actions of high dose CNP may involve a non-cGMP pathway via the clearance receptor. Taken together these studies provide new insights into myocardial aging and the relationship to the anti-fibrotic and anti-proliferative peptide CNP.

Background-Neutral endopeptidase 24.11 (NEP) is a metalloprotease that is localized in the greatest abundance in the kidney and degrades natriuretic peptides, such as atrial natriuretic peptide (ANP). Mild congestive heart failure (CHF) is characterized by increases in circulating ANP without activation of the renin-angiotensin-aldosterone system (RAAS) or sodium retention. In contrast, severe CHF is characterized by sodium retention and coactivation of both ANP and the RAAS. Methods and Results-We defined the acute cardiorenal actions of the NEP inhibitor candoxatrilat (8 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) in 4 groups of anesthetized dogs (normal, nϭ8; mild CHF, nϭ6; severe CHF, nϭ5; and severe CHF with chronic AT 1 receptor antagonism, nϭ5). Mild CHF was produced by rapid ventricular pacing at 180 bpm for 10 days and severe CHF at 245 bpm for 10 days. In mild CHF, urinary sodium excretion and glomerular filtration rate were greatest in response to acute NEP inhibition compared with the response in either control animals or those with severe CHF. Furthermore, an increase in glomerular filtration rate was observed only in mild CHF in association with increases in renal blood flow and decreases in renal vascular resistance and distal tubular sodium reabsorption. Urinary ANP and cGMP excretion, markers for renal biological actions of ANP, were greatest in mild CHF. The renal actions observed in mild CHF were attenuated in severe CHF and not restored by chronic AT 1 receptor antagonism. Conclusions-The results of the present study demonstrate that acute NEP inhibition in mild CHF results in marked increases in renal hemodynamics and sodium excretion that exceed that observed in control animals and severe CHF. These studies underscore the potential therapeutic role for NEP inhibition to enhance renal function in mild CHF, an important phase of CHF that is marked by selective activation of endogenous ANP in the absence of an activated RAAS.

C-type natriuretic peptide (CNP) is an endothelium-derived peptide that is released as a protective mechanism in response cardiovascular injury and/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 1,841 randomly selected subjects from Olmsted County, Minnesota, USA (mean age 63 ± 11 years; 48% male). 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 gender, 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 (multi-variable adjusted hazard ratio, 1.51; 95% confidence interval, 1.09–2.09; P= 0.01) but not heart failure, cerebrovascular accidents or death over 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 highlights the potential value of CNP and supports the need for additional studies to evaluate whether mechanisms regulating CNP could improve outcomes.

Despite the success that drug eluting stents (DES) have achieved for minimizing in-stent restenosis (ISR), the anti-restenotic agents used in DES have been implicated in delayed endothelial healing and impairment of endothelial functions. Cenderitide (CD-NP) is a novel anti-proliferation chimeric peptide of semi-endothelial origin, thus this paper aims to demonstrate the selectivity aspect of this new peptide via in vitro evaluation on key players in ISR—smooth muscle cells (SMCs) and endothelial cells (ECs). The micro-bicinchoninic acid (BCA) protein assay was used to investigate the CD-NP release from films and stents. Cenderitide-contained films blended with poly(ethylene glycol) and its copolymer exhibited higher release kinetics compared to neat PCL formulation. Cenderitide-eluting stents (CES) was produced by coating bare metallic stents with CD-NP entrapped poly(ε-caprolactone) using an ultrasonic spray coater. The investigation of CD-NP on in vitro cells revealed that CD-NP inhibits HCaSMCs proliferation but exhibits no effects on HUVECs proliferation. Moreover, CD-NP released up to 7 days displayed inhibitory effects on SMCs proliferation. The CES produced in this work shows that the released CD-NP inhibits HCaSMCs proliferation but did not hamper HUVECs proliferation in vitro, suggesting that it has potential to reduce ISR without retarding the endothelialisation healing in vivo.

The use of drug-eluting coronary stents has led to significant reduction in in-stent restenosis (ISR), but led to delayed endothelialization, necessitating the prolonged use of expensive anti-thrombotic drugs with their side-effects. Cenderitide (CD-NP) is a novel anti-proliferative chimeric peptide of semi-endothelial origin. Our previous work in vitro has demonstrated; that the smooth muscle cells (SMCs) were inhibited significantly more than endothelial cells (ECs) which is the desirable feature of an anti-restenosis drug. This work reports the effects of implantation of a centeritide-eluting stent (CES) on in-stent restenosis and endothelialization in an in vivo model. cenderitide-eluting stents were produced by coating bare metallic stents with CD-NP entrapped in biodegradable poly(ε-caprolactone) using an ultrasonic spray coater. A total of 32 stents were successfully implanted into 16 pigs, and all animal survived for 28 days. The plasma levels of CD-NP were significantly higher in the CES group than in the control group (bare metal stents and polymer coated stent) at post-stenting, indicating the successful release of CD-NP into blood stream in vivo. Furthermore, SEM analysis results showed the greater endothelial coverage of the stent struts, as well as between the struts in CES group. Moreover, histological results showed mild inflammation, and low fibrin score at 28 days. However, plasma cGMP (second messenger, cyclic 3′,5′ guanosine monophosphate) does not show a significant difference, and the CES is also unable to show significant difference in terms on neointimal area and stenosis, in comparison to BMS at 28 days.

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The renin-angiotensin-aldosterone axis is an integral component linking the renal-humoral system to the cardiovascular system. It is involved in the normal control of blood pressure and intravascular volume. Its activity is also enhanced in pathologic states, namely congestive heart failure, in which stimulation of the axis leads to further deleterious effects on the heart. The well-established dogma that the renin-angiotensin-aldosterone system (RAAS) is a linear cascade is evolving into a vision of this system as a more complex process. It is now known that angiotensin has several subtypes. Each subtype is a ligand at several receptor subtypes and these interactions are not mutually exclusive. The aim of this review is to discuss the different angiotensin subtypes, their receptor interactions and their pathophysiological roles in humoral and renal functions in congestive heart failure. In addition, we will also review the different therapeutic approaches that interrupt the RAAS and the evidence that supports their utility in congestive heart failure (CHF).