Drugs For Treatment Of Heart Failure Research Articles

Assessing the practicality of a novel heart failure therapeutic score (QUAD Score) for drug optimisation in heart failure with a reduced ejection fraction

Abstract Introduction The 4 pillars of drug treatment for heart failure with a reduced ejection fraction (HFrEF) [Angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin receptor–neprilysin inhibitors (ARNi), β-blockers (BB), Mineralocorticoid receptor antagonists (MRA), and Sodium-glucose cotransporter 2 inhibitors (SGLT2i)], are recommended by international HF guidelines to improve patient outcomes. Treatment inertia remains a challenge with non-prescription or sub-optimal dosing of these therapies. We developed a pragmatic HFrEF treatment score (QUAD score) (Figure 1) to prompt initiation and/or titration of sub-optimally dosed foundational therapies. Patients are categorized as poor (<8), good (8-14), and excellent (15-24) based on the dose and number of foundational drugs prescribed. This study aims to assess the practical utility of the QUAD score and its influence on treatment optimization. Methods Unwarned prescribing HCPs were approached consecutively in person, within clinical settings. Participants were told the questions were part of a research project and they provided verbal consent. Responses were anonymous and no patients were involved; therefore, verbal consent was considered proportionate and reasonable. HCPs were given an information sheet describing the QUAD score (Figure 1). They were then presented with 3 hypothetical clinical scenarios of haemodynamically stable and uncomplicated HFrEF patients with uncalculated poor, good and excellent QUAD scores. They were asked to calculate the QUAD score and if they proposed any changes to treatment. Time was recorded using a stopwatch and proposed changes were recorded. They were then invited to answer a series of follow-on questions. Results Between September 2023 and February 2024, there were 70 respondents. 71% (50) were doctors and 29% (20) allied HCPs. 83% (58) placed patients in the correct treatment grade in at least one scenario. 62.9% (44) did so for all three scenarios (Figure 2) with numerically more HCPs compared to doctors (80% vs 56% p=0.06).The median (IQR) time in seconds required to calculate the QUAD score for clinical scenarios 1,2 and 3 was 158 (100-234), 86 (54-122) and 83 (53-119) respectively. In response to the calculated QUAD score, 94.3% (66), recommended drug treatment optimisations. On a 5-point Likert scale (1 -poor, 5- excellent), 77.1% of participants rated the QUAD score ≥3 for ease of use, and 88.6% rated ≥3 as an incentive for treatment optimization. Conclusion We demonstrated the rapid clinical usability of the QUAD Score in a cohort of unselected prescribing HCPs, with a decremental calculation time with each presented clinical scenario. HCPs were also motivated to achieve further HF drug therapy optimization based on the calculated score. We conclude that the QUAD Score as a HFrEF drug therapy score may have a role in addressing treatment inertia however, it needs validation against clinically relevant outcomes in a larger cohort of HFrEF patients.

Prognostic value of gut microbe-generated metabolite phenylacetylglutamine in patients with heart failure.

Phenylacetylglutamine (PAGln) is a phenylalanine-derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)-relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Fasting plasma PAGln levels were measured by stable-isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patients with stable HF from two large cohorts. All-cause mortality was assessed at 5-year follow-up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3-year follow-up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4-6.9) μM. Highest quartile of PAGln was associated with 3.09-fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5-year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07-2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0-4.8] μM), and PAGln levels were associated with a 1.92-fold increase in 3-year HF hospitalization or all-cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02-3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N-oxide levels. High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio-renal risk markers.

3. How to Use New Drugs for Heart Failure Treatment

3. How to Use New Drugs for Heart Failure Treatment

Actualization of Positions of Gliflozins in Treatment Algorithms for Patients with Heart Failure: Chronology of Success

INTRODUCTION: Despite the efforts of the cardiologic communities to introduce approaches to treatment of heart failure (HF) based on the highest level of evidence, HF remains one of the least satisfied demands in the therapy of cardiovascular diseases due to high prevalence, poor prognosis and insufficient use of treatment methods with clinically proven effectiveness. The article considers chronology of study and introduction of sodium-glucose cotransporter 2 inhibitors (syn.: gliflozins; SGLT2is) in clinical practice from the moment of creation of the first drug of this group ― florizin ― and further, stepwise with the change of the therapeutic paradigm as the result of performed clinical trials. Thus, EMPAREG OUTCOME, CANVAS, DECLARE-TIMI 58 studies demonstrated that SGLT2is not only produce a glucosuric effect, but also reduce the development and progression of HF and increase the life expectancy of patients with type 2 diabetes mellitus (DM2) and with reduced left ventricular ejection fraction (LFEF). DAPA-HF, EMPEROR-Reduced studies proved a possibility of improving the outcomes for patients with HF with reduced LVEF irrespective of the presence or absence of DM2, thereby significantly expanding the potential target group for SGLT2is. EMPEROR-Preserved study is the only study of SGLT2is to date (the study drug ― empagliflozin) that has demonstrated high effectiveness of the drug in prevention of cardiovascular mortality and hospitalizations for HF, probably irrespective of LVEF and the existence of DM2. In result, on September 9, 2021, FDA (Food and Drug Administration, USА) assigned the breakthrough therapy status to Jardiance (empagliflozin) drug for treatment of HF with preserved LFEF. EMPA-REG OUTCOME, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DAPA-CKD studies have shown SGLT2is to slow down the development of the terminal stage of chronic kidney disease. Finally, the main result of EMPULSE study completed in 2022, was the proven clinical benefit of empagliflozin in hospitalized and stabilized patients with acute HF decompensation irrespective of HF status and existence of DM2.
 CONCLUSION: From the moment SGLT2is have been introduced in the clinical practice, they rapidly and successfully passed the way from the second-line antidiabetic drugs for which it was just enough not to worsen the prognosis for serious cardiovascular complications, to independent and effective class of drugs for treatment of HF (with class I and IIa recommendations). The totality of clinical trials of empagliflozin showed that empaflorizin is so far the only drug of the SGLT2is group with the proven safety and clinical effectiveness including the influence on the prognosis, in patients with HF irrespective of the LVEF status, presence or absence of DM2, for use in outpatient treatment and in stabilized patients in hospital.

Construction of a Non-Mutually Exclusive Decision Tree for Medication Recommendation of Chronic Heart Failure.

Objective: Although guidelines have recommended standardized drug treatment for heart failure (HF), there are still many challenges in making the correct clinical decisions due to the complicated clinical situations of HF patients. Each patient would satisfy several recommendations, meaning the decision tree of HF treatment should be nonmutually exclusive, and the same patient would be allocated to several leaf nodes in the decision tree. In the current study, we aim to propose a way to ensemble a nonmutually exclusive decision tree for recommendation system for complicated diseases, such as HF. Methods: The nonmutually exclusive decision tree was constructed via knowledge rules summarized from the HF clinical guidelines. Then similar patients were defined as those who followed the same pattern of leaf node allocation according to the decision tree. The frequent medication patterns for each similar patient were mined using the Apriori algorithms, and we also carried out the outcome prognosis analyses to show the capability for the evidence-based medication recommendations of our nonmutually exclusive decision tree. Results: Based on a large database that included 29,689 patients with 84,705 admissions, we tested the framework for HF treatment recommendation. In the constructed decision tree, the HF treatment recommendations were grouped into two independent parts. The first part was recommendations for new cases, and the second part was recommendations when patients had different historical medication. There are 14 leaf nodes in our decision tree, and most of the leaf nodes had a guideline adherence of around 90%. We reported the top 10 popular similar patients, which accounted for 32.84% of the whole population. In addition, the multiple outcome prognosis analyses were carried out to assess the medications for one of the subgroups of similar patients. Our results showed even for the subgroup of the same similar patients that no one medication pattern would benefit all outcomes. Conclusion: In the present study, the methodology to construct a nonmutually exclusive decision tree for medication recommendations for HF and its application in CDSS was proposed. Our framework is universal for most diseases and could be generally applied in developing the CDSS for treatment.

Drug Treatment of Heart Failure in Children: Gaps and Opportunities.

Medical therapy for pediatric heart failure is based on a detailed mechanistic understanding of the underlying causes, which are diverse and unlike those encountered in most adult patients. Diuresis and improved perfusion are the immediate goals of care in the child with acute decompensated heart failure. Conversion to maintenance oral therapy for heart failure is based on the results of landmark studies in adults, as well as recent pediatric clinical trials and heart failure guidelines. There will continue to be an important role for newer drugs, some of which are in active trials in adults, and some of which are already approved for use in children. The need to plan for clinical trials in children during drug development for heart failure is emphasized.

Fatal pulmonary tumour thrombotic microangiopathy in patient with ovarian adenocarcinoma: review and a case report

BackgroundPulmonary tumour thrombotic microangiopathy (PTTM) is a fatal disease in which tumour cells embolize to the pulmonary vasculature leading to pulmonary hypertension and right heart failure. Early diagnosis is essential for timely treatment which can reduce intimal pulmonary vascular proliferation and prolong survival, improve the symptoms. Due to rare occurrences and no clear diagnostic guidelines the disorder usually is found post-mortem. We present a review of this rare disease and a case of post-mortem diagnosed pulmonary tumour thrombotic microangiopathy in a young female.Case presentation51 years old woman presented with progressively worsening dyspnea, right ventricular failure signs and symptoms. Computerized tomography denied pulmonary embolism. 2D transthoracic echocardiography demonstrated right ventricle dilatation and dysfunction, severely increased systolic pulmonary pressure. Right heart catheterization revealed pre-capillary pulmonary hypertension with mean pulmonary artery pressure of 78 mmHg, pulmonary wedge pressure of 15 mmHg, reduced cardiac output to 1.78 L/min with a calculated pulmonary vascular resistance of 35 Wood units, and extremely low oxygen saturation (26%) in pulmonary artery. Because of worsening ascites, pelvic magnetic resonance imaging was performed, tumours in both ovaries were diagnosed. Due to the high operative risk, detailed tumour diagnosis surgically was not established. The patient developed progressive cardiorespiratory failure, unresponsive to optimal heart failure drug treatment. A postmortem morphology analyses revealed tumorous masses in pre-capillary lung vessels, right ventricle hypertrophy, ovary adenocarcinoma.ConclusionsAn early diagnosis of PTTM is essential. Most cases are lethal due to respiratory failure progressing rapidly. Patients with a history of malignancy, symptoms and signs implying of PH should be considered of having PTTM. If detected early enough, combination of chemotherapy with specific PH therapy is believed to be beneficial in reducing intimal proliferation and prolonging survival, along with improving the symptoms.

A year in heart failure: an update of recent findings.

Major changes have occurred in these last years in heart failure (HF) management. Landmark trials and the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of HF have established four classes of drugs for treatment of HF with reduced ejection fraction: angiotensin‐converting enzyme inhibitors or an angiotensin receptor‐neprilysin inhibitor, beta‐blockers, mineralocorticoid receptor antagonists, and sodium‐glucose co‐transporter 2 inhibitors, namely, dapagliflozin or empagliflozin. These drugs consistently showed benefits on mortality, HF hospitalizations, and quality of life. Correction of iron deficiency is indicated to improve symptoms and reduce HF hospitalizations. AFFIRM‐AHF showed 26% reduction in total HF hospitalizations with ferric carboxymaltose vs. placebo in patients hospitalized for acute HF (P = 0.013). The guanylate cyclase activator vericiguat and the myosin activator omecamtiv mecarbil improved outcomes in randomized placebo‐controlled trials, and vericiguat is now approved for clinical practice. Treatment of HF with preserved ejection fraction (HFpEF) was a major unmet clinical need until this year when the results of EMPEROR‐Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic HFpEF) were issued. Compared with placebo, empagliflozin reduced by 21% (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P < 0.001), the primary outcome of cardiovascular death or HF hospitalization. Advances in the treatment of specific phenotypes of HF, including atrial fibrillation, valvular heart disease, cardiomyopathies, cardiac amyloidosis, and cancer‐related HF, also occurred. Coronavirus disease 2019 (COVID‐19) pandemic still plays a major role in HF epidemiology and management. All these aspects are highlighted in this review.

Sex Differences and Regulatory Actions of Estrogen in Cardiovascular System.

Great progress has been made in the understanding of the pathophysiology of cardiovascular diseases (CVDs), and this has improved the prevention and prognosis of CVDs. However, while sex differences in CVDs have been well documented and studied for decades, their full extent remains unclear. Results of the latest clinical studies provide strong evidence of sex differences in the efficacy of drug treatment for heart failure, thereby possibly providing new mechanistic insights into sex differences in CVDs. In this review, we discuss the significance of sex differences, as rediscovered by recent studies, in the pathogenesis of CVDs. First, we provide an overview of the results of clinical trials to date regarding sex differences and hormone replacement therapy. Then, we discuss the role of sex differences in the maintenance and disruption of cardiovascular tissue homeostasis.

The 'diamond' approach to personalized drug treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is a complex clinical syndrome with symptoms and signs due to cardiac dysfunction, leading to high hospitalization and morbidity. HF treatment has rapidly developed in recent decades, and breakthroughs have been made. Although conventional neurohormonal blockade therapies, including β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), significantly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), mortality and rehospitalization remain high. Therefore, new therapies are needed. Previous studies demonstrated that ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT2) inhibitor, vericiguat, and omecamtiv mecarbil (OM) are beneficial for HFrEF. However, there is a lack of systematic review of the most optimal manner to use under various clinical conditions. This review summarizes the current knowledge regarding these therapies to give suggestions regarding clinical use timing, application scope, and optimal therapies under various conditions. Most importantly, we propose the HF diamond approach to express the necessity of conjunction of therapies. Different from the current guidelines, we suggest to use the diamond approach in an early and comprehensive manner at the beginning of ventricular remodeling in HFrEF to prevent further deterioration of HF and maximize the prognosis of patients.

The Role of Adherence to Basic Pharmacotherapy of Heart Failure for Prevention of Late Adverse Events in Patients with Coronary Artery Disease and Left Ventricular Dysfunction After Surgical Revascularization of Myocardium

Aim. To determine the role of adherence to the basic drug treatment of heart failure (HF) in prevention of late major adverse events (MAEs) after isolated coronary artery bypass grafting (CABG) in patients with stable coronary artery disease (CAD) and left ventricular (LV) dysfunction at three-year follow-up.Material and methods. A prospective non-controlled single-center study included 125 consecutive patients with stable CAD and LV EF&lt;50% (62±8 years; 114 [91.2%] males), after isolated CABG. At three-year follow-up MAЕs occurred in 40 (32.0%) patients. The data on pharmacotherapy at followup were obtained in 124 patients: 85 (68.6%) patients without MAEs and 39 (31.4%) patients with MAEs.Results. The enrolled sample of patients was characterized by high discharge prescription rate of renin-angiotensin system (RAS; 86.3%) blockers (angiotensin-converting enzyme inhibitors or angiotensin-II receptors blockers), beta-blockers (BBs; 97.6%) and mineralocorticoid receptors antagonists (MRAs; 79.0%), being comparable in MAEs and non-MAEs groups. The total coverage of basic HF pharmacotherapy (the combination of RAS blockers, BBs and MRAs) at discharge was 66.1%. At follow-up, about one third of patients in both groups withheld previously prescribed triple HF therapy. The MAEs were associated with more frequent withhold of previously prescribed RAS blockers, as opposed to patients without MAEs (20.5% and 7.1%, respectively; р=0.009). The majority of patients in both groups continued BBs therapy at follow-up (95.0% and 92.9%, respectively; p=0.187). Additionally, we observed the decline of MRAs intake frequency at follow-up (to 43.6% and 49.4%, respectively; p=0.547).Conclusion. During 3-year follow-up after isolated CABG, about one third of patients with stable CAD and baseline LVEF&lt;50% interrupted triple basic HF therapy (including RAS blockers, BBs and MRAs), mainly due to decrease of RAS blockers and MRAs usage. MAEs in patients with stable CAD and baseline LVEF&lt;50% after CABG were associated with suboptimal use and more frequent interruption of RAS blockers.

TAC induced cardiac hypertrophy leads to increased levels of circulating microvesicles

Abstract Introduction Cardiac hypertrophy and heart failure are wide spread diseases of elderly patients in the industrialised world and drive a majority of healthcare costs in these countries. Therefore, there is a high urgency to understand the development and progress of heart failure to find new therapeutic strategies especially in early stages. Microvesicles are involved in the development and propagation of almost all cardiac diseases and increased levels of circulating microvesicles can be found in blood of patients with chronic heart failure. To point out the underlying mechanisms and to provide a new animal model based approach, we investigated microvesicle (MV)-release in mice that underwent Transverse Aortic Constriction (TAC). TAC is a common method to induce cardiac hypertrophy and heart failure in mice by inducing pressure overload. We hypothesized that TAC leads to upregulation of total MV and MV of specific origin. Methods and results Wildtype C57BL/6 mice underwent TAC to induce cardiac hypertrophy and heart failure. After TAC, mice developed cardiac hypertrophy as determined by altered heart weight/ bodyweight ratio, end-diastolic and end-systolic diameter and decreased fractional shortening. Total numbers of circulating microvesicles were detected 1, 4 and 12 weeks after TAC. We found that total numbers of circulating macrovesicles raised in a time dependent manner. Similar observations could be done with samples stained for annexin V, although results were not significant. Moreover, microvesicles were stained with specific surface markers for lymphocyte (CD3), monocyte (CD14), endothelial cells (CD31), thrombocytes (CD41), B-cells (CD45) and neutrophils (Lys6). One week after TAC increased numbers of specific microvesicles could be detected which in the course declined rapidly. Only microvesicles subgroup of lymphocyte origin showed significant increase one week after TAC-OP. Conclusion In this study, we show that total number of circulating microvesicles raise after TAC over an observation period of 12 weeks. Furthermore, we found that increased numbers of circulating microvesicles of specific origin like lymphocytes, monocytes, endothelial cells, thrombocytes, B-cells and neutrophils showed a trend towards increased levels one week after TAC with a rapid decline in subsequent detection. To our knowledge this is the first time that the impact of TAC on number of circulating microvesicles in mice was investigated. Future studies should characterize the content and effects of these MV on recipient cells to elucidate possible contributions to heart failure progression or protective effects. Detecting new harmful or protective effects of heart failure triggered by circulating microvesicles could offer new highly needed approaches to suppress heart failure development or deliver the possibility to develop new drugs for heart failure treatment. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Else Kröner-Fresenius

Training general practitioners to improve evidence-based drug treatment of patients with heart failure: acluster randomised controlled trial.

AimsTo assess whether a single training session for general practitioners (GPs) improves the evidence-based drug treatment of heart failure (HF) patients, especially of those with HF with reduced ejection fraction (HFrEF).Methods and resultsA cluster randomised controlled trial was performed for which patients with established HF were eligible. Primary care practices (PCPs) were randomised to care-as-usual or to the intervention group in which GPs received a half-day training session on HF management. Changes in HF medication, health status, hospitalisation and survival were compared between the two groups. Fifteen PCPs with 200 HF patients were randomised to the intervention group and 15 PCPs with 198 HF patients to the control group. Mean age was 76.9 (SD 10.8) years; 52.5% were female. On average, the patients had been diagnosed with HF 3.0 (SD 3.0) years previously. In total, 204 had HFrEF and 194 HF with preserved ejection fraction (HFpEF). In participants with HFrEF, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased in 6 months in both groups [5.2%; (95% confidence interval (CI) 2.0–10.0)] and 5.6% (95% CI 2.8–13.4)], respectively [baseline-corrected odds ratio (OR) 1.07 (95% CI 0.55–2.08)], while beta-blocker use increased in both groups by 5.2% (95% CI 2.0–10.0) and 1.1% (95% CI 0.2–6.3), respectively [baseline-corrected OR 0.82 (95% CI 0.42–1.61)]. For health status, hospitalisations or survival after 12–28 months there were no significant differences between the two groups, also not when separately analysed for HFrEF and HFpEF.ConclusionA half-day training session for GPs does not improve drug treatment of HF in patients with established HF.Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01487-x) contains supplementary material, which is available to authorized users.

Highlights in heart failure.

Heart failure (HF) remains a major cause of mortality, morbidity, and poor quality of life. It is an area of active research. This article is aimed to give an update on recent advances in all aspects of this syndrome. Major changes occurred in drug treatment of HF with reduced ejection fraction (HFrEF). Sacubitril/valsartan is indicated as a substitute to ACEi/ARBs after PARADIGM‐HF (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73 to 0.87 for sacubitril/valsartan vs. enalapril for the primary endpoint and Wei, Lin and Weissfeld HR 0.79, 95% CI 0.71–0.89 for recurrent events). Its initiation was then shown as safe and potentially useful in recent studies in patients hospitalized for acute HF. More recently, dapagliflozin and prevention of adverse‐outcomes in DAPA‐HF trial showed the beneficial effects of the sodium–glucose transporter type 2 inhibitor dapaglifozin vs. placebo, added to optimal standard therapy [HR, 0.74; 95% CI, 0.65 to 0.85;0.74; 95% CI, 0.65 to 0.85 for the primary endpoint]. Trials with other SGLT 2 inhibitors and in other patients, such as those with HF with preserved ejection fraction (HFpEF) or with recent decompensation, are ongoing. Multiple studies showed the unfavourable prognostic significance of abnormalities in serum potassium levels. Potassium lowering agents may allow initiation and titration of mineralocorticoid antagonists in a larger proportion of patients. Meta‐analyses suggest better outcomes with ferric carboxymaltose in patients with iron deficiency. Drugs effective in HFrEF may be useful also in HF with mid‐range ejection fraction. Better diagnosis and phenotype characterization seem warranted in HF with preserved ejection fraction. These and other burning aspects of HF research are summarized and reviewed in this article.

Research into glucose-lowering drugs for heart failure treatment.

British Journal of Community NursingVol. 24, No. 11 TreatmentsResearch into glucose-lowering drugs for heart failure treatmentAysha MendesAysha MendesE-mail Address: [email protected]Freelance journalist specialising in healthcare and psychologySearch for more papers by this authorAysha MendesPublished Online:1 Nov 2019https://doi.org/10.12968/bjcn.2019.24.11.560AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article References National Institute for Health and Care Excellence. Chronic heart failure in adults: diagnosis and management [NG106]. 2018. www.nice.org.uk/guidance/ng106 (accessed 24 October 2019) Google ScholarNeal B, Perkovic V, Mahaffey KW et al.; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:644–657. https://doi.org/10.1056/NEJMoa1611925 Crossref, Medline, Google ScholarNHS. Overview: heart failure. 2018. https://www.nhs.uk/conditions/heartfailure/ (accessed 18 October 2019) Google ScholarPasternak B, Ueda P, Eliasson et al. Use of sodium glucose cotransporter 2 inhibitors and risk of major cardiovascular events and heart failure: Scandinavian register based cohort study. BMJ. 2019; 366:l4772. https://doi.org/10.1136/bmj.l4772 Crossref, Medline, Google ScholarRushton CA, Kadam UT. Polypharmacy in heart failure: a growing challenge. Br J Cardiac Nurs. 2011; 6(5):214–220. https://doi.org/10.12968/bjca.2011.6.5.214 Link, Google ScholarSharp J, McCowat M. Depression in heart failure. Br J Cardiac Nurs. 2019; 14(6):1–11. https://doi.org/10.12968/bjca.2019.0011 Link, Google ScholarWiviott SD, Raz I, Bonaca MP et al.; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–357. https://doi.org/10.1056/NEJMoa1812389 Crossref, Medline, Google ScholarZelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019; 393:31–39. https://doi.org/10.1016/S0140-6736(18)32590-X Crossref, Medline, Google ScholarZinman B, Wanner C, Lachin JM et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128. https://doi.org/10.1056/NEJMoa1504720 Crossref, Medline, Google Scholar FiguresReferencesRelatedDetails 2 November 2019Volume 24Issue 11ISSN (print): 1462-4753ISSN (online): 2052-2215 Metrics History Published online 1 November 2019 Published in print 2 November 2019 Information© MA Healthcare LimitedPDF download

P6342Subcutaneous delivery of NPA7, first-in-class novel bispecific designer peptide: enhances cardiorenal function and suppresses renin and aldosterone in vivo and in vitro

Abstract Introduction The rapid increase of patients of heart failure (HF) is a major health burden worldwide. Most importantly is the need to develop innovative new drugs for treatment of HF, such as sacubitril/valsartan which in part functions by enhancing the natriuretic peptides (NPs). We engineered NPA7 as a novel 30 amino acid bispecific designer peptide which activates the particulate guanylyl cyclase A receptor (pGC-A)/cGMP and for which the NPs both ANP and BNP are ligands and the Mas-receptor (MasR)/cAMP pathways for Angiotensin 1–7 (Ang1–7) is the endogenous ligand. We previously reported that acute intravenous (IV) administration of NPA7 shows cardiorenal protective and renin-aldosterone suppressing actions that go beyond the native peptides, BNP or Ang 1–7, which may have therapeutic potential for HF. Purpose To support the clinical development of NPA7 as a potential therapy in HF which promotes NP and MasR pathways, we investigated the actions and stability of subcutaneous (SQ) administration of NPA7 in normal canines. We also defined NPA7's peptide stability and metabolites in canine plasma. Methods Plasma and urinary cGMP, cardiorenal and renin-aldosterone responses to SQ injection (10μg/kg) were determined over 4 hours in normal canines (n=5) in vivo. Ex vivo, we established stability of NPA7 and key metabolites in canine serum using liquid chromatography-mass spectrometry (LC-MS). Data are expressed as mean ± SEM. * P&lt;0.05 vs. BL. Results In vivo, SQ NPA7 resulted in a sustained increase at 2 hours in plasma (BL: 10±3; 120 min: 30±6* pmol/ml) and urinary (BL: 1033±198; 120 min: 5792±857* pmol/min) cGMP, GFR (BL: 29±6; 120 min: 70±12* ml/min) and sodium excretion (BL: 18±10; 120 min: 144±33* ueq/min). We observed a gradual reduction in BP at 60 min (BL: 109±4; 60 min: 99±7* mmHg) with a sustained decrease in PCWP at 4 hours (BL: 5±0.9; 240 min: 3.1±0.6* mmHg). SQ NPA7 also suppressed plasma renin and aldosterone up to 3 hours after SQ injection. LC-MS revealed that NPA7 was highly stable with both the pGC-A and MasR activating moieties intact ex vivo in canine serum with a disappearance time of 2 hours. We also identified 2 major NPA7 metabolites NPA71–27 and NPA71–28. Conclusions SQ NPA7 possesses cGMP activating, cardiac unloading, diuretic, natriuretic, and renin-aldosterone suppressing actions in normal canines. NPA7 is also highly stable in serum. These studies support SQ administration as an effective delivery strategy for NPA7, a first-in-class innovative bispecific dual pGC-A/MasR activator now in preclinical development for HF.

New therapies for the treatment of heart failure: a summary of recent accomplishments.

Despite continuous efforts to prevent cardiovascular diseases (CVDs), heart failure prevails as the number one cause of death in developed countries. To properly treat CVDs, scientists had to take a closer look at the factors that contribute to their pathogenesis and either modernize current pharmaceuticals or develop brand new treatments. Enhancement of current drugs, such as tolvaptan and omecamtiv mecarbil, sheds new light on already-known therapies. Tolvaptan, a vasopressin antagonist, could be adopted in heart failure therapy as it reduces pre- and afterload by decreasing systolic blood pressure and blood volume. Omecamtiv mecarbil, which is a myosin binding peptide, could aid cardiac contractility. The next generation vasodilators, serelaxin and ularitide, are based on naturally occurring peptides and they reduce peripheral vascular resistance and increase the cardiac index. In combination with their anti-inflammatory properties, they could turn out to be extremely potent drugs for heart failure treatment. Cardiotrophin has exceeded many researchers’ expectations, as evidence suggests that it could cause sarcomere hypertrophy without excessive proliferation of connective tissue. Rapid progress in gene therapy has caused it to finally be considered as one of the viable options for the treatment of CVDs. This novel therapeutic approach could restore stable heart function either by restoring depleted membrane proteins or by balancing the intracellular calcium concentration. Although it has been set back by problems concerning its long-term effects, it is still highly likely to succeed.

New trends in drug treatment of heart failure in old age

Heart failure (HF) is a complex clinical syndrome, with high prevalence in the elderly. The World Heath Organization (WHO) predicts that by 2050 the population aged over 80 years will account around 400 million, reflecting that HF will still represent a major public health concern. Improved management of cardiovascular diseases and HF, together with the increased life expectancy explains, at least in part, the high prevalence of HF especially in the elderly. Beside the canonical therapy for HF failure, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers and aldosterone antagonists, new potential and promising therapies, such as sacubitril/valsartan, iron deficiency treatment and serelaxine, are emerging also in elderly HF patients. In this review we focus on the classical recommended HF therapy and the possible application of new trends in elderly.

Drug treatment of heart failure in the elderly.

The prevalence of heart failure increases with age. Changes in the age distribution and growing life expectancy will lead to a further rise. However, data concerning drug treatment of heart failure especially in the elderly are scarce. Subgroup analyses of the heart failure trials suggest that drug therapy in older patients should follow the recommendations in the current guidelines. In doing so, several common comorbidities in these patients (e. g., impaired renal function) have to be considered and may have an influence on the therapy (e. g., drug dose, choice of active pharmaceutical ingredient, etc.). Especially in old, multimorbid patients, possible interaction of drugs might play a substantial role. In many cases the main goal of the therapy, especially in the very elderly, is to improve symptoms and quality of life.

Phenotype mapping of heart failure with preserved ejection fraction

Abstract Heart failure with preserved ejection fraction (HFPEF) has become the main phenotypic model of heart failure (HF) in community and referral patients in Brazil and in the world. Despite advances in the development of new drugs for HF treatment, there has been no significant improvement in mortality of this condition. According to many studies, this can be explained by the heterogeneous nature of HF physiopathology, whose basic mechanisms may result in different clinical presentations, culminating in the emerging of different phenogroups in this syndrome. In this context, phenotype mapping of HFPEF has emerged as a possible solution, since it enables the development of clinical trials that establish specific therapeutic strategies for each phenotypic profile. New technologies in the field of artificial intelligence have enabled the assessment of a large volume of data and infer intrinsic patterns and different outcomes. Thereby, it is possible to obtain mutually exclusive categories of HFPEF, with a phenotype mapping of the syndrome and grouping of patients according to their phenotypic features. Besides, other diseases can have the same clinical phenotype but different pathophysiological basis, the so called “phenocopies”. These tools enable the analysis and categorization of the wide spectrum of heart failure, contributing to solve the dilemmas of the treatment of this syndrome.