Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression. METHODS AND RESULTS: Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1ß, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort. CONCLUSIONS: Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.

Combination Sodium Nitrite and Hydralazine Therapy Attenuates Heart Failure With Preserved Ejection Fraction Severity in a "2-Hit" Murine Model.

Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia.

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis, consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress, and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis showed that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure.

BACKGROUND: Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine γ-lyase (CSE), 1 of 3 hydrogen-sulfide-producing enzyme, is predominantly localized in the vascular endothelium. The interaction between the endothelial CSE-hydrogen sulfide axis and endothelial-mesenchymal transition, an important pathological process contributing to the formation of fibrosis, has yet to be investigated. METHODS: Endothelial-cell-specific CSE knockout and Endothelial cell-CSE overexpressing mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. Cardiac function, vascular reactivity, and treadmill exercise capacity were measured to determine the severity of heart failure. Histological and gene expression analyses were performed to investigate changes in cardiac fibrosis and the activation of endothelial-mesenchymal transition. RESULTS: Endothelial-cell-specific CSE knockout mice exhibited increased endothelial-mesenchymal transition and reduced nitric oxide bioavailability in the myocardium, which was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and worsened exercise performance. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased endothelial-mesenchymal transition and cardiac fibrosis, preserved cardiac and endothelial function, and improved exercise capacity. CONCLUSIONS: Our data demonstrate that endothelial CSE modulates endothelial-mesenchymal transition and ameliorate the severity of pressure-overload-induced heart failure, in part, through nitric oxide-related mechanisms. These data further suggest that endothelium-derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.

Soluble urokinase plasminogen activator receptor: from biomarker to active participant in atherosclerosis and cardiovascular disease.

Atherosclerosis contributes to the majority of deaths related to cardiovascular disease (CVD). Recently, the nonspecific inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) has shown prognostic value in patients with CVD; however, it remains unclear whether suPAR participates in the disease process. In this issue of the JCI, Hindy and colleagues report on their evaluation of a multi-ethnic cohort of over 5,000 participants without known CVD. High suPAR levels correlated with incident CVD and atherosclerosis. Genetic analysis revealed two variants associated with the suPAR-encoding gene (PLAUR) with higher plasma suPAR levels. Notably, a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that seen in atherogenesis. These findings suggest a causal relationship between suPAR and coronary artery calcification and have clinical implications that extend to inflammatory disorders beyond CVD.

Serum Metabolomics Reveals Distinct Profiles during Ischemia and Reperfusion in a Porcine Model of Myocardial Ischemia-Reperfusion.

Acute myocardial infarction (MI) is one of the leading causes of death worldwide. Early identification of ischemia and establishing reperfusion remain cornerstones in the treatment of MI, as mortality and morbidity can be significantly reduced by establishing reperfusion to the affected areas. The aim of the current study was to investigate the metabolomic changes in the serum in a swine model of MI induced by ischemia and reperfusion (I/R) injury, and to identify circulating metabolomic biomarkers for myocardial injury at different phases. Female Yucatan minipigs were subjected to 60 min of ischemia followed by reperfusion, and serum samples were collected at baseline, 60 min of ischemia, 4 h of reperfusion, and 24 h of reperfusion. Circulating metabolites were analyzed using an untargeted metabolomic approach. A bioinformatic approach revealed that serum metabolites show distinct profiles during ischemia and during early and late reperfusion. Some notable changes during ischemia include accumulation of metabolites that indicate impaired mitochondrial function and N-terminally modified amino acids. Changes in branched-chain amino-acid metabolites were noted during early reperfusion, while bile acid pathway derivatives and intermediates predominated in the late reperfusion phases. This indicates a potential for such an approach toward identification of the distinct phases of ischemia and reperfusion in clinical situations.

Mitochondrial H2S Regulates BCAA Catabolism in Heart Failure.

BACKGROUND: Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure. METHODS: Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency. RESULTS: Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction. CONCLUSIONS: Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.

Use of Polyvinyl Alcohol-Porcine Small Intestine Submucosa Stent in the Prevention of Anastomotic Leaks in the Porcine Colon.

INTRODUCTION: Gastrointestinal anastomoses are performed millions of times per year worldwide. The major complication they share is anastomotic leak. We describe the development and initial safety/efficacy of a novel luminal stent which aims to address this clinical issue. MATERIALS AND METHODS: The stent was created out of two materials, a polyvinyl alcohol core and outer layer of acellular porcine small intestine submucosa. Ten healthy pigs underwent laparotomy, a portion of the colon was transected, and the stent was placed within the colonic lumen at the site of resection. Pigs were sacrificed at the end of postoperative week 2, and postoperative week 4. A portion of the descending colon was resected, and tissue samples from the anastomosis, intentional defect scar, and normal bowel overlying the stent were sent for histopathologic examination. RESULTS: All ten animals survived the study. None developed any clinical signs of obstruction, infection, leakage, fistula, wound complications, or bleeding. No evidence of colonic leak or luminal stenosis/stricture was noted. CONCLUSIONS: The results of this study show that a polyvinyl alcohol/acellular porcine small intestine submucosa stent sewn underneath a colonic anastomosis with a 2 cm intentional defect will result in no anastomotic complications. There were also no complications from placing this stent in any pigs. Additional studies with a control group should be conducted to see if this same stent can be built in different diameters, lengths, and configurations to prevent leaks in other organs. These encouraging results will hopefully lead to decreased leaks and the need for temporary ostomies in humans.

Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities.

A lack of preclinical large animal models of heart failure with preserved ejection fraction (HFpEF) that recapitulate this comorbid-laden syndrome has led to the inability to tease out mechanistic insights and to test novel therapeutic strategies. This study developed a large animal model that integrated multiple comorbid determinants of HFpEF in a miniswine breed that exhibited sensitivity to obesity, metabolic syndrome, and vascular disease with overt clinical signs of heart failure. The combination of a Western diet and 11-deoxycorticosterone acetate salt-induced hypertension in the Göttingen miniswine led to the development of a novel large animal model of HFpEF that exhibited multiorgan involvement and a full spectrum of comorbidities associated with human HFpEF.

Efficacy of a Novel Mitochondrial-Derived Peptide in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

With the complexities that surround myocardial ischemia/reperfusion (MI/R) injury, therapies adjunctive to reperfusion that elicit beneficial pleiotropic effects and do not overlap with standard of care are necessary. This study found that the mitochondrial-derived peptide S14G-humanin (HNG) (2 mg/kg), an analogue of humanin, reduced infarct size in a large animal model of MI/R. However, when ischemic time was increased, the infarct-sparing effects were abolished with the same dose of HNG. Thus, although the 60-min MI/R study showed that HNG cardioprotection translates beyond small animal models, further studies are needed to optimize HNG therapy for longer, more patient-relevant periods of cardiac ischemia.

Nonlethal Inhibition of Gut Microbial Trimethylamine N-oxide Production Improves Cardiac Function and Remodeling in a Murine Model of Heart Failure.

Background Patients at increased risk for coronary artery disease and adverse prognosis during heart failure exhibit increased levels of circulating trimethylamine N-oxide (TMAO), a metabolite formed in the metabolism of dietary phosphatidylcholine. We investigated the efficacy of dietary withdrawal of TMAO as well as use of a gut microbe-targeted inhibitor of TMAO production, on cardiac function and structure during heart failure. Methods and Results Male C57BLK/6J mice were fed either control diet, a diet containing TMAO (0.12% wt/wt), a diet containing choline (1% wt/wt), or a diet containing choline (1% wt/wt) plus a microbial choline trimethylamine lyase inhibitor, iodomethylcholine (0.06% wt/wt), starting 3 weeks before transverse aortic constriction. At 6 weeks after transverse aortic constriction, a subset of animals in the TMAO group were switched to a control diet for the remainder of the study. Left ventricular structure and function were monitored at 3-week intervals. Withdrawal of TMAO from the diet attenuated adverse ventricular remodeling and improved cardiac function compared with the TMAO group. Similarly, inhibiting gut microbial conversion of choline to TMAO with a choline trimethylamine lyase inhibitor, iodomethylcholine, improved remodeling and cardiac function compared with the choline-fed group. Conclusions These experimental findings are clinically relevant, and they demonstrate that TMAO levels are modifiable following long-term exposure periods with either dietary withdrawal of TMAO or gut microbial blockade of TMAO generation. Furthermore, these therapeutic strategies to reduce circulating TMAO levels mitigate the negative effects of dietary choline and TMAO in heart failure.

Effects of a novel hydrogen sulfide prodrug in a porcine model of acute limb ischemia.

OBJECTIVE: Previous studies have shown that hydrogen sulfide (H2S) exerts potent proangiogenic properties under in vitro conditions and in rodent models. We sought to determine whether a novel H2S prodrug promotes peripheral revascularization in a swine model of acute limb ischemia (ALI). METHODS: ALI was induced in 17 female miniswine via intravascular occlusion of the external iliac. At day 7 after ALI induction, miniswine (n = 17) were randomized to received placebo or the H2S prodrug, SG-1002 (800 mg per os twice a day), for 35 days. At day 35 SG-1002 increased circulating levels of H2S (5.0 ± 1.2 µmol/L vs 1.8 ± 0.50 µmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 µmol/L vs 2.6 ± 0.8 µmol/L; P < .05), and nitrite (0.5 ± 0.05 µmol/L vs 0.3 ± 0.03 µmol/L; P < .005) compared with placebo. SG-1002 therapy increased angiographic scoring in ischemic limb vessel number (27.6 ± 1.6 vs 22.2 ± 1.8; P < .05) compared with placebo. Treatment with SG-1002 preserved existing capillaries in ischemic limbs (128.3 ± 18.7 capillaries/mm2 vs 79.0 ± 9.8 capillaries/mm2; P < .05) compared with placebo. Interestingly, treatment with SG-1002 also improved coronary vasorelaxation responses to bradykinin and substance P in miniswine with ALI. CONCLUSIONS: Our results suggest that daily administration of the H2S prodrug, SG-1002, leads to an increase in circulating H2S and nitric oxide signaling and preserves vessel number and density in ischemic limbs. Furthermore, SG-1002 therapy improved endothelial-dependent coronary artery vasorelaxation in the setting of ALI. Our data demonstrate that SG-1002 preserves the vascular architecture in ischemic limbs and exerts vascular protective effects in the coronary vasculature in a model of peripheral vascular disease.

Repeated cell transplantation and adjunct renal denervation in ischemic heart failure: exploring modalities for improving cell therapy efficacy.

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar-Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45 min of coronary artery ligation followed by reperfusion for 12-14 weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20 min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8 weeks. In the second arm, at 4 weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20 min following reperfusion and RDN or a sham at 4 weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.

Renal Denervation Prevents Heart Failure Progression Via Inhibition of the Renin-Angiotensin System.

BACKGROUND: Previously, we have shown that radiofrequency (RF) renal denervation (RDN) reduces myocardial infarct size in a rat model of acute myocardial infarction (MI) and improves left ventricular (LV) function and vascular reactivity in the setting of heart failure following MI. OBJECTIVES: The authors investigated the therapeutic efficacy of RF-RDN in a clinically relevant normotensive swine model of heart failure with reduced ejection fraction (HFrEF). METHODS: Yucatan miniswine underwent 75 min of left anterior descending coronary artery balloon occlusion to induce MI followed by reperfusion (R) for 18 weeks. Cardiac function was assessed pre- and post-MI/R by transthoracic echocardiography and every 3 weeks for 18 weeks. HFrEF was classified by an LV ejection fraction <40%. Animals who met inclusion criteria were randomized to receive bilateral RF-RDN (n = 10) treatment or sham-RDN (n = 11) at 6 weeks post-MI/R using an RF-RDN catheter. RESULTS: RF-RDN therapy resulted in significant reductions in renal norepinephrine content and circulating angiotensin I and II. RF-RDN significantly increased circulating B-type natriuretic peptide levels. Following RF-RDN, LV end-systolic volume was significantly reduced when compared with sham-treated animals, leading to a marked and sustained improvement in LV ejection fraction. Furthermore, RF-RDN improved LV longitudinal strain. Simultaneously, RF-RDN reduced LV fibrosis and improved coronary artery responses to vasodilators. CONCLUSIONS: RF-RDN provides a novel therapeutic strategy to reduce renal sympathetic activity, inhibit the renin-angiotensin system, increase circulating B-type natriuretic peptide levels, attenuate LV fibrosis, and improve left ventricular performance and coronary vascular function. These cardioprotective mechanisms synergize to halt the progression of HFrEF following MI/R in a clinically relevant model system.

A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure.

Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-ß. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

Combined Angiotensin Receptor-Neprilysin Inhibitors Improve Cardiac and Vascular Function Via Increased NO Bioavailability in Heart Failure.

BACKGROUND: There is a paucity of data about the mechanisms by which sacubitril/valsartan (also known as LCZ696) improves outcomes in patients with heart failure. Specifically, the effects of sacubitril/valsartan on vascular function and NO bioavailability have not been investigated. We hypothesized that sacubitril/valsartan therapy increases circulating NO levels and improves vascular function in the setting of heart failure. METHODS AND RESULTS: Male spontaneously hypertensive rats underwent myocardial ischemia/reperfusion surgery to induce heart failure and were followed for up to 12 weeks with serial echocardiography. Rats received sacubitril/valsartan (68 mg/kg), valsartan (31 mg/kg), or vehicle starting at 4 weeks after reperfusion. At 8 or 12 weeks of reperfusion, animals were euthanized and tissues were collected for ex vivo analyses of NO bioavailability, aortic vascular reactivity, myocardial and vascular histology, and cardiac molecular assays. Left ventricular structure and function were improved by both valsartan and sacubitril/valsartan compared with vehicle. Sacubitril/valsartan resulted in superior cardiovascular benefits, as evidenced by sustained improvements in left ventricular ejection fraction and end-diastolic pressure. Ex vivo vascular function, as measured by aortic vasorelaxation responses to acetylcholine and sodium nitroprusside, was significantly improved by valsartan and sacubitril/valsartan, with more sustained improvements afforded by sacubitril/valsartan. Furthermore, myocardial NO bioavailability was significantly enhanced in animals receiving sacubitril/valsartan therapy. CONCLUSIONS: Sacubitril/valsartan offers superior cardiovascular protection in heart failure and improves vascular function to a greater extent than valsartan alone. Sacubitril/valsartan-mediated improvements in cardiac and vascular function are likely related to increases in NO bioavailability and explain, in part, the benefits beyond angiotensin receptor blockade.

Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney.

BACKGROUND: Sustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF). OBJECTIVES: This study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism. METHODS: Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN. RESULTS: Following RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta1 antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF. CONCLUSIONS: This study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.