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• Hyperkalemia associated with increased RAASI down-titration in real-world cohort of over 77,000. • Advanced age, renal dysfunction, elevated potassium, and prior hospitalizations are risk factors of RAASI downtitration. • RAASI dose reduction/interruption was associated with heightened risks of hospitalization (HR 1.16) and mortality (HR 1.69) compared to RAASI continuation. • Findings underscore importance of averting RAASI down-titration attributable to hyperkalemia. Renin-angiotensin-aldosterone system inhibitors (RAASIs) play a crucial role in the treatment of several chronic cardiovascular conditions. Nonetheless, hyperkalemia, a frequent side effect, often leads to the discontinuation of RAASIs. The implications of hyperkalemia-driven changes in RAASI medications are poorly understood. Population-based, observational, retrospective cohort study. Two large healthcare databases were utilized to identify 77,089 individuals aged 55 years and older with chronic conditions who were prescribed RAASIs between 2015 and 2017 in Southern Barcelona, Spain. We assessed the interplay between serum potassium abnormalities, RAASI management, and their associations with clinical outcomes, adjusting for potential confounders including socioeconomic factors, medical conditions, and potassium levels. The one-year prevalence of hyperkalemia (defined as serum potassium, K+ >5.0 mmol/L) was 17.8 %. RAASI were down-titrated in 16.1 % of these 13,673 patients with K+ levels. Factors linked to a higher likelihood of reducing/discontinuing RAASI after developing hyperkalemia included older age, impaired kidney function, higher potassium levels, and previous hospitalizations. Dose reduction/discontinuation of RAASI after developing hyperkalemia was associated with an increased risk of hospitalization (adjusted hazard ratio [HR] 1.16, 95 % confidence interval [CI] 1.10–1.21) and with increased mortality (HR 1.60, 95 % CI 1.56–1.84). In this large, observational study, hyperkalemia was linked to a greater likelihood of discontinuing RAASIs. Down-titration of RAASI was independently associated with unfavorable clinical outcomes such as hospitalization and specially mortality. Although the observational nature of the study, these findings underscore the importance of preventing circumstances that may lead to RAASI down-titration, such as hyperkalemia, as well as preventing hospitalizations and mortality, to ensure RAASI benefits. [ABSTRACT FROM AUTHOR]

It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT—in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)—at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up. [ABSTRACT FROM AUTHOR]

• The impact of hyperkalemia in the down-titration or reduction of HF therapy is well known. • Patiromer and sodium zirconium cyclosilicate are new treatment available for hyperkalemia. • Patiromer and sodium zirconium cyclosilicate were significantly associated with heart failure therapy optimization, reduction of hyperkalemia events and reduction of mean potassium levels, albeit with a higher rate of hypokalemia events. • Trials evaluating whether this heart failure therapy optimization results in a lower incidence of major adverse cardiovascular events are now needed. Hyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. PubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4–26%), decreased hyperkalemia events by 29% (95% CI: 55–92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18–0.44) compared to placebo, maintaining a good safety profile. NPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. CRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811 NPB in HF: A new therapeutic approach for an old problem Caption: CI, confidence interval; GI, gastrointestinal; HF, heart failure; NPB, novel potassium binders; RAASi, RAAS inhibitors; RCT, randomized controlled trial; RR, relative risk; SZC, sodium zirconium cyclosilicate. [Display omitted] [ABSTRACT FROM AUTHOR]

Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension. The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort. Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively. Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65). Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes. [Display omitted] [ABSTRACT FROM AUTHOR]

Few interventions have shown improved prognosis in patients with heart failure and preserved ejection fraction (HFpEF). Serum chloride levels, which are affected by serum renin secretion, are associated with the prognosis of HFpEF patients. However, the relationship between serum chloride levels and the effects of renin-angiotensin system inhibitors (RASi) in HFpEF patients remains unclear. We investigated whether the prognostic benefit of RASi depends on baseline serum chloride levels in HFpEF patients. This observational study included 506 hospitalized patients with HFpEF (ejection fraction ≥50%) who were discharged. They were divided into two categories based on serum chloride levels at admission (cutoff level: 101 mEq/L) according to previous reports. In each chloride category, all-cause mortality, the primary endpoint, was compared between patients who received RASi and those who did not. Patients who received RASi had a significantly lower mortality rate after discharge than those who did not, but only in the lower chloride category (log-rank, P = 0.001). Multivariable Cox regression analysis confirmed the effect of risk reduction by RASi on all-cause mortality in the lower chloride category (adjusted hazard ratio: 0.31, 95% confidence interval: 0.11–0.84). The prognostic advantages of RASi were evident in the lower chloride category, but not in the higher chloride category, at admission (P for interaction = 0.027). RASi administration was associated with an improved prognosis only in HFpEF patients with a low baseline serum chloride level. Clinicians should consider RASi administration if patients' serum chloride levels are low, to improve the long-term prognosis of HFpEF patients. • Serum chloride level affects renin-angiotensin-aldosterone system (RAS) in HFpEF patients. • Patients with low chloride level receiving RAS inhibitor had lower mortality rates. • Prognostic benefit of RAS inhibitor in HFpEF patients depended on baseline serum chloride levels. [ABSTRACT FROM AUTHOR]

This study was conducted to investigate the safety and effectiveness of sacubitril/valsartan (sac/val) for elderly patients with hypertension and heart failure in the real-world setting. Patients with established hypertension complicated with structural or functional impairment of ventricular fillings [New York Heart Association (NYHA) functional class II–IV)] were enrolled. The effectiveness of sac/val in terms of BP reduction and improvement in frailty and echocardiographic evaluation of cardiac function were examined from baseline to 6-month administration. Overall, 241 patients were treated with sac/val and 227 with renin angiotensin aldosterone system inhibitor (RAASi) for hypertension control. There were significant difference in the degree of systolic blood pressure reduction between two groups. Echocardiography showed that sac/val significantly improved left ventricular ejection fraction [4.0% (95% CI: 2.0–7.5) vs −1.0 (95% CI: −4.0–2.0), P = 0.001] during the follow-up visits. Significant improvements in NYHA function class and FRAIL scores post sac/val were observed after 3 and 6 month treatment. The rate of primary cardiovascular composite outcome was higher in patients in the RAASi group (26.9%; 95% CI: 19.6–34.0) than in the sac/val group (22.0%; 95% CI: 16.7–27.3). Sac/val may be useful not only for reducing BP, but also for improving the structural and functional parameters of echocardiography, eventually resulting in a significant improvement of the overall symptomatic status, a significant reduction in NYHA class, and functional improvement. • Sac/val could significantly reduced BP and serum NT-proBNP levels, as well as contribute to higher EF and lower LV mass by its impact on cardiovascular hemodynamics. • Participants receiving sac/val exhibited a significant improvement of overall symptomatic status with a significant reduction in NYHA-class and functional improvement evaluated by questionnaire-based measures of patientlevel activity in real-world settings. • Sac/val reduced the risks of composite cardiovascular events occurrence and of hospitalization of heart failure, as compared with RAASi. • The safety profile of sac/val was favorable in the balance of serum potassium. [ABSTRACT FROM AUTHOR]

The prognostic role of moderate hyperkalemia in reduced ejection fraction (HFrEF) patients is still controversial. Despite this, it affects the use of renin–angiotensin–aldosterone system inhibitors (RAASi) with therapy down-titration or discontinuation. Aim of the study was to assess the prognostic impact of moderate hyperkalemia in chronic HFrEF optimally treated patients. We retrospectively analyzed MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes) database, with median follow-up of 4.2 [IQR 1.9–7.5] years. Data on K+ levels were available in 7087 cases. Patients with K+ plasma level ≥ 5.6 mEq/L and < 4 mEq/L were excluded. Remaining patients were categorized into normal >4 and < 5 mEq/L (n = 4826, 68%) and moderately high ≥5.0 and ≤ 5.5 mEq/L (n = 496, 7%) K+. Then patients were matched by propensity score in 484 couplets of patients. MECKI score value was 7% [IQR 3.1–14.1%] and 7.3% [IQR 3.4–15%] (p = 0.678) in patients with normal and moderately high K+ values while cardiovascular mortality events at two years follow-up were 41 (4.2%) and 33 (3.4%) (p = 0.333) in each group respectively. Moderate hyperkalemia does not influence patients' outcome in a large cohort of ambulatory HFrEF patients. • Hyperkalemia affects up to 18% of HFrEF patients leading to therapy down-titration. • The prognostic role of moderate hyperkalemia is still controversial. • We discovered that moderate hyperkalemia in HF is not associated to worst outcome. [ABSTRACT FROM AUTHOR]

Renin-angiotensin system inhibitor (RASi) and β-blocker provide prognostic benefits as guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). However, there is limited data for the favorable effects in such patients receiving regular hemodialysis. We aimed to evaluate the prognostic impact of RASi and β-blocker in patients with HFrEF who receive regular hemodialysis. In this retrospective, single-center, observational study, from 2110 consecutive patients hospitalized for HF and who survived to discharge, 97 with HFrEF who received regular hemodialysis were included for analysis. They were classified into three groups according to prescribed medication at discharge following index hospitalization: both RASi and β-blocker (Dual-GDMT group: n = 55), either RASi or β-blocker (Mono-GDMT group: n = 34), and neither RASi nor β-blocker (No-GDMT group: n = 8). The primary endpoint was a composite of all-cause death and rehospitalization for heart failure. The mean age was 66 years and 79% of the patients were men. During the median follow-up of 501 days, the primary endpoint occurred in 43 patients (44%). Kaplan-Meier analysis revealed that the Dual-GDMT group had the lowest rates of the primary endpoint (log-rank test for trend: p < 0.001). Even after adjustment for diverse covariates (multivariate Cox regression), the Dual-GDMT (hazard ratio [HR]: 0.04, 95% confidence interval (CI): 0.005–0.32) and Mono-GDMT (HR: 0.08, 95% CI: 0.01–0.50) groups had better prognoses than the No-GDMT group. The prescription of RASi and/or β-blocker was associated with a lower adverse-event rate after discharge in patients with HFrEF who were on regular hemodialysis. • Patients on regular hemodialysis were generally excluded from randomized outcome studies of heart failure. • Prognostic effect of guideline-directed medical therapy in patients with heart failure on regular hemodialysis is unknown. • RAS inhibitor and/or β-blocker therapy was associated with better clinical outcomes of HFrEF patients on hemodialysis. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) presenting with low blood pressure (BP) have been underrepresented in large-scale clinical trials. We investigated the characteristics and implementation of conventional guideline-directed medical therapy (GDMT; renin-angiotensin system inhibitors and β-blockers) in patients with low BP hospitalized for HF with systolic dysfunction. Conventional GDMT was evaluated by discharge BP among 2043 consecutive patients with HF and left ventricular ejection fraction (LVEF) < 50% in the WET-HF registry. Among the 708 (34.7%) patients with lower discharge BP (≤ 100 mmHg; the lower tertiles), exploratory subgroups included patients with previous HF hospitalization, inotrope use, New York Heart Association (NYHA) III–IV class, and lower estimated glomerular filtration rate (eGFR) and LVEF (lower than median value). We evaluated the risk-adjusted association between GDMT implementation and 2-year adverse events (all-cause mortality or HF rehospitalization). Among the 2043 patients (age 74 [63–82] years), the median systolic BP was 108 (98–120) mmHg. Among patients with lower BP, GDMT prescription rate was 62.7%, and GDMT use was associated with decreased adverse events (HR:0.74, 95%CI:0.58–0.94). GDMT prescription rates were lower among higher-NYHA class and lower-eGFR subgroups compared with their reference subgroups, and directionally similar outcomes were noted in all subgroups (favoring GDMT use); however, this association was somewhat attenuated in the lower-eGFR group (HR:0.87, 95%CI:0.64–1.17). Conventional GDMT use was associated with decreased adverse outcomes in most patients with HF compounded by systolic dysfunction and low BP, albeit caution is warranted in patients with renal dysfunction. • ≈60% of HF patients with systolic dysfunction and low BP received conventional GDMT. • Low BP was associated with worse long-term clinical outcomes. • Conventional GDMT use was associated with better clinical outcomes in low BP group. • The favorable prognostic effect of GDMT was consistent across all high-risk subgroups. • This association was somewhat attenuated in the lower-eGFR subgroup. [ABSTRACT FROM AUTHOR]

• Cancer incidence and cancer-related mortality of patients with heart failure are higher than those expected for the general population. • Increased sympathetic activity, renin-angiotensin-aldosterone system activation, chronic inflammation and oxidative stress are proposed biological mechanisms to explain the increased risk of cancer in patients with heart failure. • Prognosis of patients with heart failure and co-existing malignancies is poor, with mortality rates that exceed 40% during the first year after cancer diagnosis. To assess the incidence of cancer diagnosis and cancer-related mortality in patients with heart failure (HF). Observational study based in a prospective cohort of patients with HF referred to a specialized Spanish clinic between 2010 and 2019. The observed incidence of malignancies (excluding non-melanoma skin cancer) was compared to that expected for the general Spanish population according to the Global Cancer Observatory. We studied 1909 consecutive patients with HF. Over a median follow-up of 4.07 years, 165 new cases of malignancy were diagnosed. Observed age-standardized incidence rates of cancer were 861 (95% CI 618.4–2159.4) cases per 100,000 patients-years in men and 728.5 (95% CI 451.1–4308.7) cases per 100,000 patients-years in women; while age-standardized incidence rates of cancer expected for the general Spanish population were 479.4 cases per 100,000 patients-years in men (risk ratio = 1.80) and 295.5 cases per 100,000 patients-years in women (risk ratio = 2.46). Both a history of pre-existing malignancy at baseline and the development of new malignancies during follow-up were associated with reduced survival. Observed age-standardized cancer-related mortality was 344.1 (95% CI 202.1–1675) deaths per 100,000 patient-years in men and 217.0 (95% CI 32.8–3949.3) deaths per 100,000 patient-years in women; while age-standardized cancer-related mortality expected for the general Spanish population was 201.4 deaths per 100,000 patients-years in men (risk ratio = 1.71) and 96.2 deaths per 100,000 patients-years in women (risk ratio = 2.26). Patients with HF showed higher incidence rates of cancer diagnosis and cancer-related mortality than those expected for the general population. [Display omitted] [ABSTRACT FROM AUTHOR]

Renin-angiotensin system inhibitors (RASI) reduce adverse cardiovascular events in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤40% and mild or moderate chronic kidney disease (CKD). However, RASI administration rate and its association with long-term outcomes in patients with CKD complicated by HF with LVEF >40% remain unclear. We analyzed 1923 consecutive patients with LVEF >40% registered within the multicenter database for hospitalized HF. We assessed RASI administration rate and its association with all-cause mortality among patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR]: 30–60 mL/min/1.73 m2). Exploratory subgroups included patients grouped by age (<80, ≥80 years), sex, previous HF hospitalization, B-type natriuretic peptide (higher, lower than median), eGFR (30–44, 45–59 mL/min/1.73 m2), systolic blood pressure (<120, ≥120 mmHg), LVEF (41–49, ≥50%), and mineralocorticoid receptor antagonists (MRA) use. Among patients with LVEF >40%, 980 (51.0%) had mild or moderate CKD (age: 81 [74–86] years; male, 52.6%; hypertension, 69.7%; diabetes, 25.9%), and 370 (37.8%) did not receive RASI. RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use. After multivariable adjustments, RASI use was independently associated with lower all-cause mortality over a 2-year median follow-up (hazard ratio: 0.58, 95% confidence interval: 0.43–0.79, P = 0.001), and the mortality rate difference was predominantly due to cardiac death, consistent in all subgroups. Approximately one-third of HF patients with mild or moderate CKD and LVEF >40% were discharged without RASI administration and demonstrated relatively guarded outcomes. • CKD is one of the most important comorbidities in HF patients with preserved EF. • In mild or moderate CKD, the cardiovascular benefits of RASI are demonstrated. • Non-use of RASI was common in HF patients with mild or moderate CKD and LVEF >40%. • RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use in mild/moderate CKD. • RASI use was associated with lower all-cause death and cardiac-related death. [ABSTRACT FROM AUTHOR]

• RAAS inhibition is a mainstay of the pharmacological treatment of HFrEF • In HFrEF, whenever possible, the use of ARNI should be preferred over ACE inhibitor • ARNI should be considered as first line therapy in de novo HFrEF patients • ARNI should be considered in HFmrEF, no definitive evidence support them in HFpEF Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community. [ABSTRACT FROM AUTHOR]

• Transforming growth factor (TGF)-α is upregulated in the PVN in heart failure (HF). • Angiotensin II and cytokines stimulate TNF-α converting enzyme to release TGF-α. • TGF-α activates EGFR to induce extracellular signal-regulated kinase (ERK) 1/2 signaling. • ERK1/2 in PVN upregulates excitatory mediators to drive sympathetic excitation in HF. • The elevated TGF-α in PVN promotes neuroinflammation and autonomic activation in HF. Activation of epidermal growth factor receptor (EGFR) tyrosine kinase is associated with increased extracellular signal-regulated kinase (ERK) 1/2 signaling in the hypothalamic paraventricular nucleus (PVN), which contributes to the sympathetic excitation in heart failure (HF). Transforming growth factor (TGF)-α is a major endogenous ligand for EGFR. The present study sought to determine whether TGF-α increases in the PVN in HF and promotes the activation of EGFR to increase ERK1/2 activity. Male rats received bilateral PVN microinjections of an EGFR siRNA or a scrambled siRNA followed by an intracerebroventricular (ICV) injection of TGF-α or vehicle one week later. In rats pretreated with the scrambled siRNA, ICV TGF-α increased phosphorylated (p-) EGFR and upregulated the expression of p-ERK1/2 and mRNA levels of proinflammatory cytokines (PICs) and renin-angiotensin system (RAS) components in the PVN, when compared with the untreated age-matched control rats. These responses to ICV TGF-α were significantly attenuated in rats pretreated with the EGFR siRNA. Furthermore, bilateral PVN microinjection of a TGF-α siRNA in HF rats significantly decreased the elevated levels of TGF-α, p-EGFR, p-ERK1/2 and the mRNA expression of PICs and RAS components in the PVN, compared with the HF rats treated with a scrambled siRNA. The TGF-α siRNA-treated HF rats also exhibited lower plasma norepinephrine levels and improved peripheral manifestations of HF. These data suggest that TGF-α expression is upregulated in the PVN in HF and induces the activation of EGFR-mediated ERK1/2 signaling to augment the inflammation and RAS activity that drives sympathetic excitation in HF. [ABSTRACT FROM AUTHOR]

Background: Although renin-angiotensin-aldosterone system (RAAS) activation is believed to be the major driver of acute heart failure (AHF) episodes our understanding of its prevalence and clinical relevance in contemporary settings is incomplete. Methods: Serum renin and aldosterone were measured at day-1 and at discharge in patients (n = 211) that were hospitalized between 2016 and 2017 for AHF in a single cardiology center. The population was profiled based on upper limits of normal (ULN) of both biomarkers assessed at day-1 and linked with the clinical course and outcomes. Results: The study population constituted of three profiles: RAAS−/− (n = 121 [57%]); RAAS+/− (n = 60 [28%]); and RAAS+/+ (n = 30 [14%]). The RAAS+/+ profile had the lowest blood pressure and serum sodium at admission, day-2 and discharge compared to the other profiles (p < 0.001). The RAAS+/+ patients had significantly lower urine Na+ at admission (57.8 ± 36.7 vs 97.3 ± 31.3 and 86.4 ± 35.0), day-1 (52.7 ± 32.7 vs 85.3 ± 36.3 and 75.5 ± 33.9) mmol/l, vs RAAS−/− and RAAS+/− profiles, respectively, all p < 0.001. There was also a gradual decrease of renal function across increasing RAAS profiles. The RAAS+/+ profile received higher dose of furosemide at discharge 120 [80–160] vs the other profiles 80 [40–120] mg, p < 0.01. The risks of one year mortality or HF rehospitalization increased across the RAAS profiles (p < 0.001). The trajectory of renin or aldosterone change during hospitalization was not related to outcomes. Conclusions: The RAAS overactivity is not essential for development of AHF. However, elevated RAAS is a marker of more advanced stages of heart failure, is related to low natriuresis and adverse clinical outcomes. [Display omitted] • In contemporary population, the RAAS overactivity is not essential for development of clinical picture of acute heart failure • There appear to be differential phenotypes of water/sodium handling disabilities among patients hospitalized for AHF • RAAS overactivity is related with low natriuresis, high diuretic demand and poor outcome in AHF. • The trajectory of renin during hospitalization as a result of reduction of extracellular volume did not impact the prognosis. [ABSTRACT FROM AUTHOR]

Inhibition of the renin angiotensin aldosterone system (RAAS) improves survival and reduces adverse cardiac events in heart failure with reduced ejection fraction, but the benefit is not well-defined following left ventricular assist device (LVAD). We analyzed the ISHLT IMACS registry for adults with a primary, continuous-flow LVAD from January 2013 to September 2017 who were alive at postoperative month 3 without a major adverse event, and categorized patients according to treatment an angiotensin converting enzyme inhibitor (ACEI/ARB) or mineralocorticoid receptor antagonist (MRA). Propensity score matching was performed separately for ACEI/ARB vs none (n = 4,118 each) and MRA vs none (n = 3,892 each). Of 11,494 patients included, 50% were treated with ACEI/ARB and 38% with MRA. Kaplan-Meier survival was significantly better for patients receiving ACEI/ARB (p < 0.001) but not MRA (p = 0.31). In Cox proportional hazards analyses adjusted for known predictors of mortality following LVAD, ACEI/ARB use (hazard ratio 0.81 [95% confidence interval 0.71-0.93], p < 0.0001) but not MRA use (hazard ratio 1.03 [95% confidence interval 0.88-1.21], p = 0.69) was independently associated with lower mortality. Among patients treated with an ACEI/ARB, there was a significantly lower unadjusted risk of cardiovascular death (p < 0.001), risk of gastrointestinal bleeding (p = 0.01), and creatinine level (p < 0.001). MRA therapy was associated with lower risk of gastrointestinal bleeding (p = 0.01) but higher risk of hemolysis (p < 0.01). Potential limitations include residual confounding and therapy crossover. These findings suggest a benefit for ACEI/ARB therapy in patients with heart failure after LVAD implantation. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) have shown antiarrhythmic effects that are useful as part of the upstream therapy for atrial fibrillation (AF), both for primary and secondary prevention. Nevertheless, the potential prognosis value of these drugs in terms of mortality and major cardiovascular events is unclear, especially in older population with AF. Scientific evidence is scarce in this population and shows contradictory results. The aim of this study was to assess the potential benefit of ACEi and ARB in terms of mortality and major cardiovascular outcomes (hospitalization for heart failure, acute myocardial infarction and stroke) in older patients with AF, based on a real-world data analysis. Observational: analysis of a retrospective registry. The study included 9365 patients of 75 years or older diagnosed with AF, from CardioCHUVI-AF_75 registry: ClinicalTrials.gov Identifier: NCT04364516. Date of registration: November 26, 2018. We performed propensity score matching techniques to obtain 2 comparable groups of 3601 patients with and without ACEi or ARB treatment. We compared survival and cardiovascular outcomes in both groups of patients using Cox proportional hazards models. We did not find significant differences in terms of survival between using or not using ACEi or ARB for the older population (hazard ratio for mortality: 0.959, 95% confidence interval 0.872–1.054). There were no significant differences regarding cardiovascular major events between the 2 groups. Treatment with ACEi or ARB did not improve outcomes in terms of survival and cardiovascular events in older patients with AF. These results should prompt the conduct of randomized clinical trials specifically in the older AF patient population to robustly address this issue. [ABSTRACT FROM AUTHOR]

Introduction: Heart failure patients have poor outcomes comparable to some malignancies; however, the modern guideline directed medical therapy (GDMT) has improved its outcomes. The clinical characteristics and prescribers' compliance with GDMT for heart failure patients have not been studied in the Mackay region.Methods: A retrospective cohort study of 115 consecutive adult heart failure patients was conducted at our institution.Results: The study cohort consisted of 80% (n=92) males. Ischaemia was the leading cause accounting for 54% (n=62) of the cohort, followed by idiopathic cardiomyopathy at 32% (n=37). Drug-induced and Takotsubo cardiomyopathies were responsible for 11% and 1% respectively. Two (2) patients (2%) had valvular heart disease. Hypertension was present in 57% while diabetes and atrial fibrillation were present in 32% and 43% of patients. Fifty-nine per cent (59%) had a smoking history. All, except four patients, had reduced left ventricular ejection fraction (LVEF <50%) at diagnosis. Among patients with coronary ischaemia, 37% and 31% were revascularised with percutaneous coronary interventions and bypass graft surgeries, respectively. Renin-angiotensin-aldosterone system inhibitors and beta blockers were prescribed in 94% and 95% of the patients, respectively. Mineralocorticoid inhibitors were used in 25% while ivabradine was given to 8% of patients. Nine per cent (9%) of patients received cardiac resynchronisation therapy. Most patients had improvement in functional class and LVEF during follow-up. There were very few mortalities at 3% (n=3) at the median follow-up of 403 (IQR 239-896) days.Conclusion: Our study has shed light on heart failure epidemiology in the Mackay region. We found excellent compliance with GDMT and good prognosis for most patients in terms of both symptom and survival. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

• The hypothalamic paraventricular nucleus (PVN) is a source of augmented sympathetic nerve activity in heart failure (HF). • Epidermal growth factor receptor (EGFR) activates extracellular signal-related kinase 1 and 2 (ERK1/2) in PVN of HF rats. • ERK1/2 upregulates PVN expression of excitatory mediators that drive sympathetic activity in HF rats. • siRNA knockdown of EGFR in the PVN reduces sympathetic activity and improves the peripheral manifestations of HF. • Brain EGFR is a potential target for therapeutic intervention in the augmented sympathetic activity that promotes HF progression. Activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling in cardiovascular regulatory regions of the brain contributes to sympathetic excitation in myocardial infarction (MI)-induced heart failure (HF) by increasing brain renin-angiotensin system (RAS) activity, neuroinflammation, and endoplasmic reticulum (ER) stress. The mechanisms eliciting brain ERK1/2 signaling in HF are still poorly understood. We tested the involvement of the epidermal growth factor receptor (EGFR) which, upon activation, stimulates ERK1/2 activity. Adult male Sprague-Dawley rats received bilateral microinjections of a lentiviral vector encoding a small interfering RNA (siRNA) for EGFR, or a scrambled siRNA, into the hypothalamic paraventricular nucleus (PVN), a recognized source of sympathetic overactivity in HF. One week later, coronary artery ligation was performed to induce HF. Four weeks later, the EGFR siRNA-treated HF rats, compared with the scrambled siRNA-treated HF rats, had lower mRNA and protein levels of EGFR, lower levels of phosphorylated (p-) EGFR and p-ERK1/2 and lower mRNA levels of the inflammatory mediators TNF-α, IL-1β and cyclooxygenase-2, the RAS components angiotensin-converting enzyme and angiotensin II type 1a receptor and the ER stress markers BIP and ATF4 in the PVN. They also had lower plasma and urinary norepinephrine levels and improved peripheral manifestations of HF. Additional studies revealed that p-EGFR was increased in the PVN of HF rats, compared with sham-operated control rats. These results suggest that activation of EGFR in the PVN triggers ERK1/2 signaling, along with ER stress, neuroinflammation and RAS activity, in MI-induced HF. Brain EGFR may be a novel target for therapeutic intervention in MI-induced HF. [ABSTRACT FROM AUTHOR]

Hyperkalemia is a potentially life-threatening condition associated with the use of heart failure (HF) medications, which can lead to increased morbidity and mortality. Novel approaches for hyperkalemia prevention are needed, especially in limited-resource settings. Despite multiple studies showing the beneficial impact of pharmaceutical-counseling in several outcomes, there is a knowledge-gap regarding its impact on hyperkalemia prevention. A case-control study was performed in patients from the Adult Heart Failure Clinic Registry in our institution. Cases were selected using a definition of serum potassium K+ ≥5.5 mmol/L. To study the association between hyperkalemia and relevant risk factors, we performed a multivariate logistic regression analysis using the Least Absolute Shrinkage and Selection Operator (LASSO) method for variable selection. We also fitted a Classification and Regression Tree (CART) to establish complex interactions and effect modifiers between the selected variables. We matched 483 controls (eligible HF patients without hyperkalemia) to 132 cases (eligible HF patients with hyperkalemia based on age and calendar, yielding a total sample size of 615 patients (270 females) for this study. Cases had statistically significant lower odds of receiving a pharmacist-based multidimensional intervention (PBMI) (OR 0.57; 95% CI, 0.43–0.80) or having HF with reduced ejection fraction (OR 0.56; 95% CI, 0.18–0.72). On the other hand, patients who presented hyperkalemia had statistically significant higher odds of having a history of chronic kidney disease stage 4 (OR 4.97; 95% CI, 2.24–11.01) or 5 (OR 6.73; 95% CI, 1.69–26.84) and being on enalapril at doses =40 mg/day (OR, 9.90; 95% CI 5.81–16.87). PBMI is a practical approach to prevent hyperkalemia in HF patients in a limited-resource setting. However, clinical trials are needed to assess its effectiveness. Unlabelled Image • Hyperkalemia is a potentially life-threatening condition associated with the use of heart failure medications. • Hyperkalemia directly impacts clinical outcomes by increasing morbidity and mortality. • Hyperkalemia limits the usage of Guideline directed medical therapy and promoting suboptimal dose-titration. • Novel approaches for hyperkalemia prevention are needed, especially in limited-resource settings. • A pharmacist-based multidimensional intervention seems to be an efficient approach that could significantly improve HF patients' management in limited-resource heart centers. [ABSTRACT FROM AUTHOR]

Background: The myocardium exhibits an adaptive tissue-specific renin-angiotensin system (RAS), and local dysbalance may circumvent the desired effects of pharmacologic RAS inhibition, a mainstay of heart failure with reduced ejection fraction (HFrEF) therapy.Objectives: This study sought to investigate human myocardial tissue RAS regulation of the failing heart in the light of current therapy.Methods: Fifty-two end-stage HFrEF patients undergoing heart transplantation (no RAS inhibitor: n = 9; angiotensin-converting enzyme [ACE] inhibitor: n = 28; angiotensin receptor blocker [ARB]: n = 8; angiotensin receptor neprilysin-inhibitor [ARNi]: n = 7) were enrolled. Myocardial angiotensin metabolites and enzymatic activities involved in the metabolism of the key angiotensin peptides angiotensin 1-8 (AngII) and Ang1-7 were determined in left ventricular samples by mass spectrometry. Circulating angiotensin concentrations were assessed for a subgroup of patients.Results: AngII and Ang2-8 (AngIII) were the dominant peptides in the failing heart, while other metabolites, especially Ang1-7, were below the detection limit. Patients receiving an ARB component (i.e., ARB or ARNi) had significantly higher levels of cardiac AngII and AngIII (AngII: 242 [interquartile range (IQR): 145.7 to 409.9] fmol/g vs 63.0 [IQR: 19.9 to 124.1] fmol/g; p < 0.001; and AngIII: 87.4 [IQR: 46.5 to 165.3] fmol/g vs 23.0 [IQR: <5.0 to 59.3] fmol/g; p = 0.002). Myocardial AngII concentrations were strongly related to circulating AngII levels. Myocardial RAS enzyme regulation was independent from the class of RAS inhibitor used, particularly, a comparable myocardial neprilysin activity was observed for patients with or without ARNi. Tissue chymase, but not ACE, is the main enzyme for cardiac AngII generation, whereas AngII is metabolized to Ang1-7 by prolyl carboxypeptidase but not to ACE2. There was no trace of cardiac ACE2 activity.Conclusions: The failing heart contains considerable levels of classical RAS metabolites, whereas AngIII might be an unrecognized mediator of detrimental effects on cardiovascular structure. The results underline the importance of pharmacologic interventions reducing circulating AngII actions, yet offer room for cardiac tissue-specific RAS drugs aiming to limit myocardial AngII/AngIII peptide accumulation and actions. [ABSTRACT FROM AUTHOR]

The suppression of adrenergic and renin-angiotensin-aldosterone system (RAAS) activity, exaggerated due to hypoperfusion-related hypoxia and/or sodium retention, is crucial for drugs' efficacy in heart failure (HF). Both, insufficient oxygenation and excess sodium impair the glycocalyx-dependent microcroperfusion and peripheral metabolism, therefore enhancing the adrenergic and RAAS activity. The local renal and pulmonary RAAS activity and hypoxia increase sodium retention. Interstitial sodium accumulation activates interstitial inflammation and coagulation disorders that further diminish glycocalyx-supported microperfusion and peripheral metabolism. The main trigger of glycocalyx damage in reduced ejection fraction (EF) HF is hypoxia; whereas, in HF preserved EF sodium retention prevails; both stimulate left ventricular (LV) cardiac output (CO), however, impair microperfusion and metabolic heat production. Infrared-dependent, surface-induced flow (SIF) and diamagnetic properties of oxygenated haemoglobin; both improve non-Newtonian blood flow. Therefore, the temperature-driven SIF augments the deoxygenated erythrocytes' flow, while the pulmonary oxygenation of haemoglobin, by diamagnetic properties, enables frictionless erythrocytes' flow in the oxygenated blood compartments complementing the cardiac function in HF. [ABSTRACT FROM AUTHOR]

Heart failure (HF) has emerged as an important and increasing disease burden in India. We present the 5-year outcomes of patients hospitalized for HF in India. The Trivandrum Heart Failure Registry (THFR) recruited consecutive patients admitted for acute HF among 16 hospitals in Trivandrum, Kerala in 2013. Guideline-directed medical therapy (GDMT) was defined as the combination of beta-blockers (BB), renin angiotensin system blockers (RAS), and mineralocorticoid receptor antagonists (MRA) in patients with HF with reduced ejection fraction (HFrEF, EF < 40%) at discharge. We used Cox proportional hazards models and Kaplan-Meier survival plots for analysis. The MAGGIC risk score variables were included as exposure variables. Among 1205 patients [69% male, mean (SD) age = 61.2 (13.7) years], HFrEF constituted 62% of patients and among them, 25% received GDMT. The 5-year mortality rate was 59% (n = 709 deaths), and median survival was 3.1 years. Sudden cardiac death and pump failure caused 46% and 49% of the deaths, respectively. In the multivariate Cox model, components of GDMT associated with lower 5-year mortality risks were discharge prescription of BB, RAS blocker, and MRA. Older age, lower systolic blood pressure, NYHA class III or IV, and higher serum creatinine were also associated with higher 5-year mortality. Three out of every 5 patients had died during 5-years of follow-up with a median survival of approximately 3 years. Lack of GDMT in patients with HFrEF and frequent readmissions were associated with higher 5-year mortality. Quality improvement programmes with strategies to improve adherence to GDMT and reduction in readmissions may improve HF outcomes in this region. • The THFR is the first heart failure registry in India with 5-year follow-up and low attrition rate. • Median survival time of HF patients in the Trivandrum Heart Failure Registry(THFR) is 3.1 years. • In this relatively younger cohort of HF patients, 3 out of 5 patients had died at 5-years. • Those who received guideline directed medical therapy at discharge from index hospitalization(25%) had better survival. • Interventions aimed at increasing guideline directed medical therapy may improve HF outcomes in India. [ABSTRACT FROM AUTHOR]

• Rheumatoid arthritis patients have high risk of heart failure. Age, cardiovascular risk factors, and rheumatoid arthritis duration increase the heart failure risk. • Patients with rheumatoid arthritis and heart failure largely share similar mechanistic pathways with patients with heart failure without rheumatoid arthritis. These include a higher expression of biomarkers associated with congestion, inflammation, fibrosis and RAAS activation. • Treatments that prolong the event-free survival of heart failure patients without rheumatoid arthritis should also be formally tested in patients with concomitant heart failure and rheumatoid arthritis. Rheumatoid arthritis (RA) patients have high risk of heart failure (HF). Identifying the risk factors and mechanistic pathways associated with HF in patients with RA. Cohort study enrolling 355 RA patients. HF was defined according to the ESC criteria. 93 circulating protein-biomarkers (91CVDIIOlink®+troponin-T+c-reactive protein) were measured. Regression modeling (multivariate and multivariable) were built and network analyses were performed - based on the identified relevant protein biomarkers. 115 (32.4%) patients fulfilled the ESC criteria for HF, but only 24 (6.8%) had a prior HF diagnosis. Patients with HF were older (67 vs. 55yr), had a longer RA duration (10 vs. 14yr), had more frequently diabetes, hypertension, obesity, dyslipidemia, atrial fibrillation, and ischemic arterial disease. Several protein-biomarkers remained independently associated with HF, the top (FDR1%) were adrenomedullin, placenta-growth-factor, TNF-receptor-11A, and angiotensin-converting-enzyme-2. The networks underlying the expression of these biomarkers pointed towards congestion, apoptosis, inflammation, immune system signaling and RAAS activation as central determinants of HF in RA. Similar HF-associated biomarker-pathways were externally found in patients without RA. Having RA plus HF increased the risk of cardiovascular events compared to RA patients without RF; adjusted-HR (95%CI)=2.37 (1.07-5.30), p=0.034 Age, cardiovascular risk factors, and RA duration increase the HF odds in patients with RA. Few RA patients had a correct prior HF diagnosis, but the presence of HF increased the patients' risk. RA patients with HF largely share the mechanistic pathways of HF patients without RA. Randomized HF trials should include patients with RA. NCT03960515 Image, graphical abstract Legend: RAAS, renin-angiotensin aldosterone system. [ABSTRACT FROM AUTHOR]

Although individual studies failed to demonstrate significant benefits with neurohormonal inhibitors in patients affected by heart failure (HF) with preserved ejection fraction (HFpEF), an evident trend towards a reduction in hospitalization and mortality has been previously documented in most cases. We aimed to conduct an updated meta-analysis on the effect of neurohormonal inhibitors [renin-angiotensin-aldosterone system (RAAS) inhibitors and angiotensin receptor neprilysin inhibitors (ARNi)] on the primary composite outcome of mortality and hospitalizations for HF and on the secondary outcomes of mortality and hospitalizations separately analyzed. The extended literature search ended up with the identification of a total of 12 studies cumulatively including 30,882 patients, 16,540 in the treatment and 14,432 in the control groups. Eleven studies explored the outcome of death, 9 studies reported data about HF hospitalizations and 8 studies explored the composite outcome of death and HF hospitalizations. Our meta-analysis showed that treatment with neurohormonal inhibitors was significantly associated with a reduced risk of the primary composite outcome (OR 0.87, 95%CI: 0.82–0.93, p <.001; I2 = 2.2.) and with a decreased risk of HF hospitalizations (OR 0.84, 95%CI: 0.75–0.94, p =.002; I2 = 63%). In contrast, no significant effect on death was found (OR 0.79, 95%CI: 0.55–1.12, p =.184; I2 = 96.4%). Results remained substantially unchanged in the leave-one-out sensitivity analysis. Our current work supports a beneficial effect of neurohormonal inhibitors (RAAS blockers and ARNi) on the primary composite outcome of death and HF hospitalizations and on the secondary outcome of HF hospitalizations in HFpEF patients. This finding provides support to the current prevalent clinical approach and to level of evidence reported in the Guidelines. • RAAS blockers and ARNi reduce the outcome of mortality and/or HF hospitalizations. • RAAS blockers and ARNi reduce the outcome of HF hospitalizations. • RAAS blockers and ARNi do not significantly reduce the outcome of mortality. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are considered a promising cell type for the treatment of heart failure (HF). In particular, MSCs in adipose tissue are being evaluated as an effective therapeutic tool. However, adipose MSCs are a major source of adipocyte generation and linked to obesity, which is an independent risk factor for HF. MSCs express all of the components of the renin–angiotensin system (RAS), which plays a pivotal role in the pathophysiology of HF. The local RAS also regulates MSC adipogenesis, indicating a connection between MSC–adipogenesis–obesity and HF. This review examines evidence of the complex relationship between HF and adipose MSCs and discusses how to explore this association for favorable therapeutic outcomes for HF. Current therapeutic options for advanced heart failure (HF) are limited and the development of alternative therapies for this critical clinical condition is eagerly awaited. Cell therapy offers a promising new alternative for HF treatment, with mesenchymal stem cells (MSCs) in adipose tissue considered one of the most promising cell types for HF cell therapy. However, MSCs in adipose tissue are a major source of adipocyte generation and obesity is known as an independent risk factor for HF, while MSCs might be related to the enigmatic obesity paradox. Emerging evidence suggests an important link between MSC–adipogenesis–obesity and HF. The therapeutic efficacy of adipose MSCs in clinical trials has not been established; however, preconditioning or genetic modification to improve the therapeutic effects of MSCs showed encouraging results. [ABSTRACT FROM AUTHOR]

Background: The necessity of neurohumoral blockers in patients with heart failure who demonstrate normalized ejection fractions after cardiac resynchronization therapy remains unclear.Objectives: The aim of this study was to investigate the feasibility and safety of neurohumoral blocker withdrawal in patients with normalized ejection fractions after cardiac resynchronization therapy.Methods: In this prospective, open-label, randomized controlled pilot trial with a 2 × 2 factorial design, subjects were randomized to withdrawal of renin-angiotensin-aldosterone system inhibitors and/or beta-blockers versus continuation of treatment. The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular end-systolic volume index of >15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure-related hospitalizations, and incidence of sustained ventricular arrhythmias at 24 months.Results: Eighty subjects were consecutively enrolled and randomized among 4 groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). Of the 80 subjects, 6 (7.5%) met the primary and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 subjects because of hypertension or supraventricular arrhythmias.Conclusions: The incidence of the primary and secondary endpoints over a follow-up period of 2 years was low in both the control group and in the groups in which neurohumoral blockers were discontinued. However, neurohumoral blocker withdrawal was hampered by cardiac comorbidities. (Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients [STOP-CRT]; NCT02200822). [ABSTRACT FROM AUTHOR]

Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF). Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death. Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995–5666 vs 575 ng/L, 205–1714; PRA 1.7 ng/mL/h, 0.4–5.6 vs 0.6 ng/mL/h, 0.2–2.6; aldosterone 153 ng/L, 85–246 vs 113 ng/L, 72–177; norepinephrine 517 ng/L, 343–844 vs 430 ng/L, 259–624; all p < 0.001, epinephrine 31 ng/L, 10–63 vs 25 ng/L, 10–44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044). Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population. • Neurohormonal activation has been well documented in HFrEF. • There is limited evidence on neurohormonal activation in HFpEF and HFmrEF. • Sympathetic and RAAS activation is present only in a group of HFpEF/HFmrEF patients. • Neurohormonal blockade may be useful only in a subset of HFpEF/HFmrEF patients. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) is the most common cause of hospital admission in adults >=65 years and represents a global public health crisis [1]. The 5-year mortality rate was considerably higher in patients with history of HF readmissions compared to patients without HF readmissions (69% vs 50%) confirming the prognostic significance of the history of previous hospitalization [5],[6]. [Extracted from the article]

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Background: Recent data suggest that beta blockers are associated with increased perioperative risk in hypertensive patients. We investigated whether beta blockers were associated with an increased risk in elderly patients with raised preoperative arterial blood pressure.Methods: We conducted a propensity-score-matched cohort study of primary care data from the UK Clinical Practice Research Datalink (2004-13), including 84 633 patients aged 65 yr or over. Conditional logistic regression models, including factors that were significantly associated with the outcome, were constructed for 30-day mortality after elective noncardiac surgery. The effects of beta blockers (primary outcome), renin-angiotensin system (RAS) inhibitors, calcium-channel blockers, thiazides, loop diuretics, and statins were investigated at systolic and diastolic arterial pressure thresholds.Results: Beta blockers were associated with increased odds of postoperative 30-day mortality in patients with systolic hypertension (defined as systolic BP >140 mm Hg; adjusted odds ratio [aOR]: 1.92; 95% confidence interval [CI]: 1.05-3.51). After excluding patients for whom prior data suggest benefit from perioperative beta blockade (patients with prior myocardial infarction or heart failure), rather than adjusting for them, the point estimate shifted slightly (aOR: 2.06; 95% CI: 1.09-3.89). Compared with no use, statins (aOR: 0.35; 95% CI: 0.17-0.75) and thiazides (aOR: 0.28; 95% CI: 0.10-0.78) were associated with lower mortality in patients with systolic hypertension.Conclusions: These data suggest that the safety of perioperative beta blockers may be influenced by preoperative blood pressure thresholds. A randomised controlled trial of beta-blocker withdrawal, in select populations, is required to identify a causal relationship. [ABSTRACT FROM AUTHOR]

Endotrophin, a type VI collagen cleavage product, has fibrosis, and insulin resistance effects. Type VI collagen also plays a role in cardiac fibrosis. In this study, we aimed to investigate the role of endotrophin in the pathogenesis of cardiac fibrosis by determining its levels in patients with heart failure with reduced and mid-range ejection fraction (EF). We also aimed to determine the possible association between endotrophin and treatment that prevents ventricular fibrosis. Sixty patients with heart failure with reduced and mid-range EF and 27 volunteers with no cardiac failure were included in this study. In both groups, biochemical tests, EF, and endotrophin levels were measured. ELISA was performed for the determination of endotrophin levels. When compared with the control group, there was no significant difference for endotrophin levels in the patient group (p =.35). Participants in the study were divided into two groups according to their EFs, 40% and less, and 40–49%. They were classified according to their use of renin-angiotensin-aldosterone system (RAAS) blocking drugs. Endotrophin levels were significantly lower in patients with mid-range EFs between 40 and 49% (p =.03) using RAAS blockers. This study is the first to evaluate the relationship between endotrophin and heart failure. Endotrophin levels were found to be low in patients with heart failure with mid-range EF who were using RAAS blockers. This suggests that RAAS blockers may influence endotrophin levels and thus could have a role in the prevention of remodelling. • Determination of fibrosis-associated biomarkers will help to understand the pathophysiology of heart failure. • Endotrophin is a by-product produced by matrix metalloproteinases in the synthesis of the alpha 3 chain of type VI collagen. • Endotrophin levels were significantly lower in RAAS-blocker users of the mid-range heart failure group. • This suggests that there may be a possible association between endotrophin release and RAAS. [ABSTRACT FROM AUTHOR]

The optimal medical treatment in patients with chronic obstructive pulmonary disease (COPD) and right-sided heart failure (RHF) is unknown. We aimed to estimate the risks of all-cause mortality associated with the current clinical use of various cardiovascular drugs in this patient-group. We followed all patients with registered COPD and RHF (defined as a diagnosis of pulmonary hypertension plus use of loop-diuretics) for the risk of all-cause mortality (Jan 1, 1995 to Dec 31, 2015) using the Danish nationwide administrative registries. The association between mortality and claimed prescriptions for cardiovascular drugs was assessed by multivariable Cox regression models. 5991 patients (mean age 74 ± standard deviation 10 years, 51% women) were included. Of these, 1440 (24%) used beta-blockers, 2149 (36%) renin-angiotensin system inhibitors [RASi], 1340 (22%) oral anticoagulants, 1376 (23%) calcium channel blockers, 1194 (20%) statins, 1824 (30%) spironolactone, and 2099 (35%) low-dose aspirin. During an average follow-up of 2.2 years (±standard deviation 2.8, min-max 0–19.6 years), 5071 (85%) died, corresponding to a mortality rate of 38 per 100 person-years (95% confidence interval 37–39). Compared to no use, beta-blockers were associated with adjusted hazards ratio 0.90 (95% confidence interval 0.84–0.98), RASi 0.92 (0.86–0.98), calcium channel blockers 0.86 (0.80–0.92), spironolactone 1.17 (1.10–1.24), statins 0.85 (0.78–0.92), oral anticoagulants 0.87 (0.79–0.95), and aspirin 0.99 (0.93–1.05). Propensity-score matched analyses and inverse-probability-weighted models yielded similar results. Several cardiovascular drugs may be associated with lowered mortality in COPD and RHF. Given the grave prognosis, randomized clinical trials are warranted to test this hypothesis. • Patients with COPD and right heart failure have a very poor prognosis. • The outcomes of cardiovascular pharmacotherapies are unknown. • In our observational study, several medications were associated with lowered mortality. • Randomized studies are warranted to confirm our observations. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is a common, costly condition with an increasing burden on Australian health care system resources. Knowledge of the burden of HF on patients and on the health system is important for resource allocation. This study is the first systematic review to estimate the mortality and readmission rates after hospitalisation for HF in the Australian population.Methods: We searched for studies of HF hospitalisation in Australia published between January 1990 and May 2016, using a systematic search of PubMed, Medline, Scopus, Web of Science, EMBASE and Cochrane Library databases. Studies reporting 30-day and/or 1-year outcomes for mortality or readmission following hospitalisation were eligible and included in this study.Results: Out of 2889 articles matching the initial search criteria, a total of 13 studies representing 67,255 patients were included in the final analysis. The pooled mean age of heart failure patients was 76.3 years and 51% were male (n=34,271). The pooled estimated 30-day and 1-year all-cause mortality were 8% and 25% respectively. The pooled estimated 30-day and 1-year all-cause readmission rates were 20% and 56% respectively. There is a high prevalence of comorbidities in heart failure patients. There were limited data on readmission and mortality in rural patients and Indigenous people.Conclusions: Heart failure hospitalisations in Australia are followed by substantial readmission and mortality rates. [ABSTRACT FROM AUTHOR]

It has recently been established that carotid bodies play a significant role in the regulation of activities of the cardiovascular system as well as in the pathogenesis of arterial hypertension, heart failure and diabetes. Aim of study was to determinate the influence of polymorphisms within genes of the renin-angiotensin-aldosterone system (RAAS) on the volume of the carotid bodies (CB) in patients with hypertension (HTA). The study group consisted of 77 patients with HTA. All patients were genotyped for single-nucleotide polymorphisms of genes coding for: angiotensinogen: rs4762, rs5049, rs5051 and rs699; angiotensin-converting enzyme: rs4343; angiotensin receptor type 1 gene (AGTR1): rs5182 and rs5186; and the aldosterone synthase: rs1799998. The estimation of volumes of CB (V rCB+lCB ) was based on computed tomography angiography. Among individuals with essential hypertension certain relationships were documented between rs5182 and rs5186 polymorphisms of AGTR1 gene and rs1799998 polymorphism of CYP11B2 gene on one hand and the volume of carotid bodies on one other. Patients carrying the C alleles within the rs5182 and rs5186 of AGTR1 gene was associated with higher values of V rCB+lCB . The carriage of the T allele in the rs5182 locus of the AGTR1 gene determine lower values of V rCB+lCB . In summary, in patients with HTA a higher volume of CB may be resulted from the presence of specific genotypes in RAAS. [ABSTRACT FROM AUTHOR]

Inflammation in the hypothalamic paraventricular nucleus (PVN) contributes to neurohumoral excitation and its adverse consequences in systolic heart failure (HF). The stimuli that trigger inflammation in the PVN in HF are not well understood. Angiotensin II (AngII) has pro-inflammatory effects, and circulating levels of AngII increase in HF. The subfornical organ (SFO), a circumventricular structure that lacks an effective blood–brain barrier and senses circulating AngII, contains PVN-projecting neurons. We hypothesized that activation of AngII type 1a receptors (AT 1a R) in the SFO induces neuroinflammation downstream in the PVN. Male rats received SFO microinjections of an adeno-associated virus carrying shRNA for AT 1a R, a scrambled shRNA, or vehicle. One week later, some rats were euthanized to confirm the transfection potential and knockdown efficiency of the shRNA. Others underwent coronary artery ligation to induce HF or a sham coronary artery ligation (Sham). Four weeks later, HF rats that received the scrambled shRNA had increased mRNA in SFO and PVN for AT 1a R, inflammatory mediators and indicators of neuronal and glial activation, increased plasma levels of AngII, tumor necrosis factor-α, norepinephrine and arginine vasopressin, and impaired cardiac function, compared with Sham rats that received scrambled shRNA. The central abnormalities were ameliorated in HF rats that received AT 1a R shRNA, as were plasma norepinephrine and vasopressin. Sham rats that received AT 1a R shRNA had reduced SFO AT 1a R mRNA but no other changes compared with Sham rats that received scrambled shRNA. The results suggest that activation of AT 1a R in the SFO upregulates the neuroinflammation in the PVN that contributes to neurohumoral excitation in HF. [ABSTRACT FROM AUTHOR]

Body fluid volume regulation is a complex process involving the interaction of various afferent (sensory) and neurohumoral efferent (effector) mechanisms. Historically, most studies focused on the body fluid dynamics in heart failure (HF) status through control of the balance of sodium, potassium, and water in the body, and maintaining arterial circulatory integrity is central to a unifying hypothesis of body fluid regulation in HF pathophysiology. The pathophysiologic background of the biochemical determinants of vascular volume in HF status, however, has not been known. I recently demonstrated that changes in vascular and red blood cell volumes are independently associated with the serum chloride concentration, but not the serum sodium concentration, during worsening HF and its recovery. Based on these observations and the established central role of chloride in the renin-angiotensin-aldosterone system, I propose a unifying hypothesis of the "chloride theory" for HF pathophysiology, which states that changes in the serum chloride concentration are the primary determinant of changes in plasma volume and the renin-angiotensin-aldosterone system under worsening HF and therapeutic resolution of worsening HF. [ABSTRACT FROM AUTHOR]

It is commonly accepted that the renin–angiotensin–aldosterone system (RAAS) is a cardiovascular circulating hormonal system that plays also an important role in the modulation of several patterns in the brain. The pathway of the RAAS can be divided into two classes: the traditional pathway of RAAS, also named classic RAAS, and the non-classic RAAS. Both pathways play a role in both cardiovascular and neurological diseases through a peripheral or central control. In this regard, renewed interest is growing in the last years for the consideration that the brain RAAS could represent a new important therapeutic target to regulate not only the blood pressure via central nervous control, but also neurological diseases. However, the development of compounds able to cross the blood–brain barrier and to act on the brain RAAS is challenging, especially if the metabolic stability and the half-life are taken into consideration. To date, two drug classes (aminopeptidase type A inhibitors and angiotensin IV analogues) acting on the brain RAAS are in development in pre-clinical or clinical stages. In this article, we will present an overview of the biological functions played by peripheral and brain classic and non-classic pathways of the RAAS in several clinical conditions, focusing on the brain RAAS and on the new pharmacological targets of the RAAS. [ABSTRACT FROM AUTHOR]

The use of renin–angiotensin–aldosterone system (RAAS) inhibitors in the treatment of chronic heart failure (HF) and arterial hypertension is recommended by the European Society of Cardiology Guidelines on the basis of consolidated evidence supporting their efficacy in the development of such a disease. However, the high incidence of re-hospitalization and mortality in patients undergoing chronic HF, leads to the need for the development of novel RAAS inhibitors possessing a better pharmacokinetic/pharmacodynamics profile in approaching hemodynamic imbalance and myocardial dysfunction associated with the development of chronic HF. Here we summarize some of the recent advances in the area of RAAS-modulators, including novel renin inhibitors, mineralcorticoid receptor antagonists and novel AT1 and AT2-receptor modulators. In addition, the pharmacology of a new class of compounds which display both AT1-receptor blocking properties combined with inhibition of neprilysin, the vasopeptidase enzyme degradating natriuretic peptide (ARNi), will be reviewed, alongside with their impact in the pathophysiology of chronic HF. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the leading causes for hospitalization in the United States and Europe, and is accompanied by high mortality. Current pharmacological therapy of chronic heart failure with reduced ejection fraction is largely based on compounds that inhibit the detrimental action of the adrenergic and the renin–angiotensin–aldosterone systems on the heart. More than one decade after spironolactone, two novel therapeutic principles have been added to the very recently released guidelines on heart failure therapy: the HCN-channel inhibitor ivabradine and the combined angiotensin and neprilysin inhibitor valsartan/sacubitril. New compounds that are in phase II or III clinical evaluation include novel non-steroidal mineralocorticoid receptor antagonists, guanylate cyclase activators or myosine activators. A variety of novel candidate targets have been identified and the availability of gene transfer has just begun to accelerate translation from basic science to clinical application. This review provides an overview of current pharmacology and pharmacotherapy in chronic heart failure at three stages: the updated clinical guidelines of the American Heart Association and the European Society of Cardiology, new drugs which are in clinical development, and finally innovative drug targets and their mechanisms in heart failure which are emerging from preclinical studies will be discussed. [ABSTRACT FROM AUTHOR]

Neprilysin is a zinc-dependent endopeptidase. It is ubiquitous in distribution and promiscuous in function, with >50 putative peptide substrates with varying levels of in vitro and/or in vivo evidence of functional relevance. In the first part of this review, we discuss the genetic, structural, substrate, and pathophysiological aspects of neprilysin. We incorporate information provided by genetically modified models, as well as pre-clinical and clinical data from investigations of synthetic neprilysin inhibitors. We next highlight the value of neprilysin as a biotarget and weigh the clinical benefits of synthetic neprilysin inhibitors, either alone or in combination with antagonists of the renin-angiotensin system. Finally, we provide evidence about soluble neprilysin as a biomarker surrogate in patients with heart failure and identify important gaps that require further research before soluble neprilysin is used clinically. In sum, neprilysin is a versatile, veteran player returning yet again to center stage after an eventful career spanning >40 years. [ABSTRACT FROM AUTHOR]

Renal dysfunction and heart failure commonly co-exist; it is termed the cardiorenal syndrome (CRS). This combination of renal and cardiac impairment presents a substantial clinical challenge and is associated with adverse prognosis. The pathogenesis of the CRS is complex, including chronic activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, together with reduced renal perfusion. Chronic activation of the RAAS can impair mitochondrial function, and increase mitochondrial derived oxidative stress which in turn can lead to renal injury and sodium and water retention. For example, it has been shown that exogenous Ang II augments renal mitochondrial oxidative stress, reduces GFR and induces albuminuria in rats with heart failure. Administration of Ang II also augmented renal mitochondrial dysfunction in aged mice. Current treatments for CRS, including angiotensin-converting enzyme inhibitors, exert limited renal protection if any at all. Therefore, novel treatments particularly those that can target renal mechanisms downstream to chronic activation of the renal renin-angiotensin system are likely to exert renoprotection in the setting of CRS. [ABSTRACT FROM AUTHOR]

Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications. [ABSTRACT FROM AUTHOR]

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. [ABSTRACT FROM AUTHOR]

Background Renin–angiotensin–aldosterone system (RAAS) blockers are effective therapies for heart failure and reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVD). We aimed to assess the efficacy and safety of RAAS blockers in these patients. Methods We searched MEDLINE, EMBASE, and Cochrane Library in May 2015. Twenty-one double-blind randomized controlled trials (RCTs) with 69,229 patients were included this network meta-analysis. Results Compared with placebo, an angiotensin receptor–neprilysin inhibitor (ARNI) had the highest probability of reducing all-cause mortality (odds ratio [OR] = 0.67, 95% credible interval [CrI]: 0.48–0.86), followed by an aldosterone receptor antagonist (ARA, OR = 0.74, 95% CrI: 0.62–0.88) and an angiotensin-converting enzyme inhibitor (ACEI, OR = 0.80, 95% CrI: 0.71–0.89). The most efficacious therapy for preventing heart failure hospitalization was ARNI (OR = 0.55, 95% CrI: 0.40–0.71), followed by combination therapy with an angiotensin II receptor blocker (ARB) plus an ACEI (OR = 0.61, 95% CrI: 0.49–0.75), then an ACEI alone (OR = 0.69, 95% CrI: 0.61–0.77). Sensitivity analysis restricted to nine RCTs with a high background use of ACEI and/or ARB (> 80%) indicated that adding an ARA to current standard therapy significantly reduced mortality (OR = 0.73, 95% CrI: 0.51–0.95) and hospitalization risk (OR = 0.67, 95% CrI: 0.47–0.87), but did not significantly increase the discontinuation risk (OR = 1.29, 95% CrI: 0.83–2.31). Conclusions ARNI has the highest probability of being the most efficacious therapy for HFrEF in reducing death and hospitalization for heart failure. ARA has the most favorable benefit–risk profile as an adjunct to background ACEI and/or ARB therapy. [ABSTRACT FROM AUTHOR]

Background Adults with single ventricle physiology palliated with a Fontan circulation experience high mortality due to circulatory failure. Renin-angiotensin-aldosterone system (RAAS) genotype contributes to adverse cardiovascular outcomes in acquired heart failure. This study evaluated associations between RAAS genotype, ventricular mass and function in a contemporary cohort of adults with a Fontan circulation. Methods This single-center prospective study included adults (n = 106) seen after the Fontan operation (mean age 27 ± 9 years). Patients were genotyped for 5 pro-hypertrophic RAAS gene polymorphisms. Serum BNP, ventricular mass and function, and clinical events were compared between those with ≥ 2 homozygous risk genotypes (“high-risk”, n = 31) versus those with ≤ 1 homozygous risk genotypes (“low risk”, n = 75). Results “High-risk” genotype was associated with diastolic dysfunction and higher serum BNP levels. There was no association between RAAS genotype and either ventricular mass or systolic function. During a mean follow-up duration of 9.5 ± 7.6 years, late Fontan failure occurred in 20% (n = 21) of patients, including 7 deaths. Serum BNP emerged as an independent predictor of late Fontan failure (HR 1.11 [CI 1.01–1.23] for each 50 unit increase in BNP, p = 0.04) and death alone (HR 1.25 [CI 1.07–1.47] for each 50 unit increase in BNP, p = 0.006). RAAS genotype was not associated with adverse clinical events. Conclusions Fontan failure is common among adults with single ventricle physiology. RAAS genotype is not associated with increased ventricular mass but does appear to influence diastolic function late after the Fontan operation. Elevated BNP is an independent predictor of Fontan failure and mortality in adulthood. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. Vildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. Vildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]