{"title":"Phosphodiesterase Inhibitors","authors":"R. Plácido, M. Lainščak","doi":"10.17987/icfj.v17i0.607","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.607","url":null,"abstract":"Phosphodiesterases (PDEs) comprise a superfamily with 11 subfamilies. Within these families, more than 40 isoforms are expressed. Phosphodiesterase-3 inhibitors (PDE3i) are used as inotrope/vasodilators for acute heart failure (HF), and PDE5i for pulmonary hypertension and erectile dysfunction. Despite being studied for chronic HF, none of the PDEis have been presently approved for such an indication itself. The PDE3is milrinone (the PROMISE trial and OPTIME-CHF), raised safety concerns. Although low-dose intravenous milrinone with a beta-blocker is till proposed by some. Enoximone failed to show significant benefits in patients with severe chronic HF in a series of phase 3 clinical trials (ESSENTIAL 1, ESSENTIAL II, EMOTE, EMPOWER). Of the PDE5is, Sildenafil is the most extensively investigated, with proven efficacy in treating erectile dysfunction and pulmonary arterial hypertension, but it has only been tested in relatively small trials in the field of HFrEF, but shows some promise in HFpEF and in pulmonary hypertension complicating HF. Elucidation of the potential clinical role of PDEis on across the spectrum of HF phenotypes will require more definitive evidence from large-scale clinical trials.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90222430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical Trial Design, Endpoints and Regulatory Considerations in Heart Failure","authors":"G. Rosano","doi":"10.17987/icfj.v17i0.595","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.595","url":null,"abstract":"After the withdrawal of flosequinan in the early 1990’s, because of an increased risk of mortality and fatal arrhythmias, the bar for the approval of new drugs in heart failure has been raised and regulatory agencies have requested evidence for the efficacy of new treatments on mortality and morbidity end-points. However, more recently, regulatory agencies have become more open to include the assessment of functional capacity as an efficacy endpoint, at least in selected subgroups of patients. Therefore, a new therapy for the treatment of heart failure can be approved if it improves survival and/or reduces hospitalisations or if it safely improves functional capacity. This article reviews clinical trial design, trial endpoints and regulatory issues in Heart Failure trials.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86085237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Vasopressin Receptor Antagonists (Vaptans) in Heart Failure","authors":"P. Lipiec, M. Metra","doi":"10.17987/icfj.v17i0.605","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.605","url":null,"abstract":"Arginine vasopressin (a peptide neuroendocrine hormone) levels are elevated in patients with HF. Acting through 3 receptor subtypes, it can cause vasoconstriction and cardiac remodelling (receptors V1a), adrenocorticotropic hormone release (receptors V1b) and water reabsorption (receptors V2), thereby increasing preload and afterload. Vasopressin-receptor antagonists (vaptans), induce hypotonic diuresis and have been proposed as a treatment option for hyponatraemia, a known complication of HF. Three vaptans have been so tested; tolvaptan, conivaptan and lixivaptan, and two (tolvaptan and conivaptan) have been approved for clinical use in hyponatraemia (in the USA). The EVEREST trial studied tolvaptan in over 4100 patients hospitalized with an exacerbation of chronic HF with reduced LVEF. No effect was seen on long-term mortality or HF-related morbidity, but there was greater weight loss and better dyspnoea and oedema relief over the short-term. Similar results were seen in the AQUAMARINE study. The 2016 European HF guidelines, therefore gave the limited recommendation: “Tolvaptan may be used to treat patients with volume overload and resistant hyponatraemia”. Despite targeting an attractive therapeutic target, vasopressin receptor antagonists (vaptans) have to date played only a minor role in our management of HF.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"382 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74948254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hypoglycaemic Agents in Patients with Heart Failure","authors":"G. Rosano, P. Seferovic","doi":"10.17987/icfj.v18i0.623","DOIUrl":"https://doi.org/10.17987/icfj.v18i0.623","url":null,"abstract":"No Abstract","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76397845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"sGC Stimulators and Activators","authors":"H. Tolppanen, P. Ponikowski","doi":"10.17987/icfj.v18i0.609","DOIUrl":"https://doi.org/10.17987/icfj.v18i0.609","url":null,"abstract":"Nitric oxide (NO)-soluble guanylate cyclase(sGC)-cGMP signalling is impaired in HF syndromes, which could predispose to vascular oxidative stress. Nitrates directly stimulate cGMP, but are limited by tolerance. Therapeutic targets that aim at increasing cGMP concentrations have therefore been explored. Recently, two classes of drugs have been discovered, the sGC activators and the sGC stimulators, which target two different redox states of sGC: the NO-sensitive reduced (ferrous) sGC and NO-insensitive oxidized (ferric) sGC, respectively. Cinaciguat is an activator and riociguat and vericiguat are sGC stimulators. Vericiguat is the most advanced agent in its clinical trial programme with two completed phase IIb studies, SOCRATES -REDUCED in HFrEF and SOCRATES-PRESERVED in HFpEF, with mixed results on NT-proBNP. The ongoing VICTORIA trial in HFrEF will study 4,872 participants with a mortality/morbidity end-point and VITALITY HFpEF trial will study 735 participants, with a quality of life end-point.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86648042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Clinical Problem: Heart Failure Syndromes and their Epidemiology","authors":"M. Kałużna-Oleksy, E. Jankowska","doi":"10.17987/icfj.v17i0.591","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.591","url":null,"abstract":"Heart failure (HF) is increasing in incidence and is a growing health care burden. HF is responsible for a large proportion of deaths as well as for diverse associated morbidities. Both in-hospital and 1-year outcomes of patients admitted for acute HF (AHF) remain poor. HF can be classified by LVEF, by the time course of its presentation and by its associated symptoms and triggering factors. The population of patients with HF is huge, and prognosis remains poor.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91120986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Adenosine Receptor Agonists","authors":"M. Wallner, P. Ponikowski","doi":"10.17987/icfj.v18i0.613","DOIUrl":"https://doi.org/10.17987/icfj.v18i0.613","url":null,"abstract":"Adenosine is a purine nucleoside that binds to adenosine cell surface receptors, which are widely expressed in heart and blood vessel cells as well as in the brain, kidney and adipose tissue.There are 4 subtypes of P1 (adenosine) G protein-coupled receptors (GPCR), named A1, A2A, A2B, and A3, which mediate a variety of cardioprotective and regenerative effects. In the heart, these effects are predominantly mediated through A1 receptors (A1R), which are expressed in atrial and ventricular cardiomyocytes and smooth muscle cells. Pre-clinical studies have reported multiple potential benefits achievable by modulation of adenyl cyclase with beneficial effects in a variety of pre-clinical models of cardiovascular disease including chronic heart failure (HF). A1R blockade (e.g. rolofylline) was however not successful in the PROTECT trial, where 2033 patients with acute HF and renal dysfunction were randomized to rolofylline or placebo, showed no benefit on renal function, symptoms, rehospitalization, or mortality. Following this attention turned to partial adenosine agonists, capadenoson and neladenoson bialanate hydrochloride, which has two phase II studies underway, PANACHE (HFpEF) and PANTHEON (HFrEF).","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"116 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79189628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Combined RAAS and NEP Inhibition","authors":"G. Vergaro, M. Metra","doi":"10.17987/icfj.v17i0.601","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.601","url":null,"abstract":"The neurohormonal model of HF has provided the rationale for the use of drug classes blocking the effectors of both the RAAS and SNS at different sites, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA), and beta-blockers. Combined NEP and ACE blockade although unsuccessful with omapatrilat in the OVERTURE trial, found success with sacubitril/valsartan in the Paradigm-HF trial. The results of PARADIGM-HF trial represent one of the most significant breakthroughs in the management of HF of the last decade, representing a shift from neurohomonal antagonism to neurohormonal modulation.","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80930872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolving Targets for Heart Failure: the Journey so far","authors":"G. Rosano","doi":"10.17987/icfj.v17i0.589","DOIUrl":"https://doi.org/10.17987/icfj.v17i0.589","url":null,"abstract":"The treatment of heart failure has included vasodilators, positive inotropes and most successfully neuro-hormonal blockade. Recent research has looked at metabolic and immune modulatory approaches, and implantable, mainly electrical devices. The near future in pharmacological research for heart failure remains focussed on classic methodologies and small molecules, but despite significant improvements we still know relatively little of the complex interactions in HF particularly for HFpEF.. Pharmacotherapy will in future be combined with advances in biotechnology, nanotechnology and devices and a digital revolution will help us to monitor patients at a distance, using wireless devices. Heart failure research has achieved much over the last 4 decades but the pace of innovation and research has not abated and future advances in this disabling condition are indeed likely. ","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83359583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Jankowska, M. Drozd, M. Tkaczyszyn, P. Ponikowski
{"title":"Iron Therapy","authors":"E. Jankowska, M. Drozd, M. Tkaczyszyn, P. Ponikowski","doi":"10.17987/icfj.v18i0.625","DOIUrl":"https://doi.org/10.17987/icfj.v18i0.625","url":null,"abstract":"No abstract","PeriodicalId":32119,"journal":{"name":"International Cardiovascular Forum Journal","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90173291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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