[New perspectives in the diagnosis and treatment of heart failure with preserved ejection fraction (HFpEF)]. / Avancées dans le diagnostic et traitement de l'insuffisance cardiaque à fraction d'éjection préservée.

Heart failure with preserved ejection fraction (HFpEF), defined as ≥50 %, affects 1 to 3 % of the population and represents a diagnostic challenge. Clinical scores have been developed to facilitate the diagnosis of affected patients, who can now benefit from new treatments. Recent studies have shown a reduction in cardiovascular morbidity and mortality with sodium-glucose cotransporter-2 (SGLT-2) inhibitors in this population. Other promising drugs, currently in the study phase, could potentially change the management approach in the near future. Finally, controlling symptoms, signs of congestion and the frequently encountered comorbidities in this population remain crucial.

L'insuffisance cardiaque à fraction d'éjection préservée (HFpEF), soit ≥ 50 %, touche 1 à 3 % de la population et représente un défi diagnostique. Des scores cliniques ont été développés pour faciliter l'identification des patients concernés qui peuvent désormais bénéficier de nouveaux traitements. Des études récentes ont en effet montré une diminution de la morbimortalité cardiovasculaire grâce aux inhibiteurs du cotransporteur sodium-glucose de type 2 (iSGLT2) dans cette population. D'autres médicaments prometteurs actuellement en phase d'étude pourraient aussi changer la prise en charge dans un futur proche. Enfin, le contrôle des symptômes et signes de congestion ainsi que le traitement des comorbidités fréquemment rencontrées dans cette population restent essentiels.

Practical outpatient management of worsening chronic heart failure.

Management of worsening heart failure (WHF) has traditionally been hospital-based, but with the rising burden of heart failure (HF), the pressure on healthcare systems exerted by this disease necessitates a different strategy than long (and costly) hospital stays. A strategy for outpatient intravenous (IV) diuretic treatment of WHF has been developed in certain American centres in the past 10 years, whereas European centres have been mostly favouring 'classic' in-hospital management of WHF. Embracing novel, outpatient approaches for treating WHF could substantially reduce the burden on healthcare systems while improving patient's satisfaction and quality of life. The present article is intended to provide essential knowledge and practical guidelines aimed at helping clinicians implement these new ambulatory approaches using day hospital and/or at-home hospitalization. The topics addressed by our group of HF experts include the pathophysiological background of diuretic therapy, the most suitable profile of WHF that may be managed in an ambulatory setting, the pharmacological protocols that can be used, as well as a detailed description of healthcare structures that can be proposed to deliver these ambulatory care interventions. The practical aspects of day hospital and hospital-at-home IV diuretic administration are specifically emphasized. The algorithm provided along with the practical IV diuretic protocols should assist HF clinicians in implementing this new approach in their local clinical setting.

Overexpression of endothelial ß3 -adrenergic receptor induces diastolic dysfunction in rats.

AIMS: Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide (• NO) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tgß3 ) that overexpresses the human ß3 -adrenoceptor (hß3 -AR) in the endothelium with the underlying rationale that the • NO pathway should be stimulated in the endothelium. METHODS AND RESULTS: Transgenic rats (Tgß3 ) that express hß3 -AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45-week-old rats. Among all altered genes, we focus on • NO synthase expression and endothelial function with arterial reactivity and evaluation of • NO and O2 •- production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the hß3 -AR overexpression. Overexpression of hß3 -AR leads to a reduction of Nos3 mRNA expression (-72%; P < 0.05) associated with a decrease in protein expression (-19%; P < 0.05). Concentration-dependent vasodilation to isoproterenol was significantly reduced in Tgß3 aorta (-10%; P < 0.05), while • NO and O2 •- production was increased. In the same time, Tgß3 rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 ± 0.01 (wild type, WT) vs. 1.33 ± 0.04 (Tgß3 ); P < 0.05] and in left ventricular end-diastolic pressure [5.57 ± 1.23 mmHg (WT) vs. 11.68 ± 1.11 mmHg (Tgß3 ); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 ± 1.9 mL/min (WT) vs. 45.8 ± 2.5 mL/min (Tgß3 ); P < 0.05]. CONCLUSIONS: The Tgß3 rat model displays the expected increase in • NO production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.

Familial screening in case of acute myocarditis reveals inherited arrhythmogenic left ventricular cardiomyopathies.

AIMS: Several data suggest that acute myocarditis could be related to genetic variants involved in familial cardiomyopathies, particularly arrhythmogenic cardiomyopathy, but the management of patients with acute myocarditis and their families regarding their risk for having an associated inherited cardiomyopathy is unclear. METHODS AND RESULTS: Families with at least one individual with a documented episode of acute myocarditis and at least one individual with a cardiomyopathy or a history of sudden death were included in the study. Comprehensive pedigree, including genetic testing, and history of these families were analysed. Six families were included. Genetic analysis revealed a variant in desmosomal proteins genes in all the probands [five in desmoplakin (DSP) gene and one in desmoglein 2 gene]. In the five families identified with a DSP variant, genetic testing was triggered by the association of an acute myocarditis with a single case of apparently isolated dilated cardiomyopathy or sudden death. Familial screening identified 28 DSP variant carriers; 39% had an arrhythmogenic left ventricular (LV) cardiomyopathy phenotype. Familial histories of sudden death were frequent, and a remarkable phenotype of isolated LV late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance without any other structural abnormality was found in 38% of asymptomatic mutation carriers. None of the DSP variant carriers had imaging characteristics of right ventricle involvement meeting current Task Force criteria for arrhythmogenic right ventricular cardiomyopathy. CONCLUSIONS: Comprehensive familial screening including genetic testing in case of acute myocarditis associated with a family history of cardiomyopathy or sudden death revealed unknown or misdiagnosed arrhythmogenic variant carriers with left-dominant phenotypes that frequently evade arrhythmogenic right ventricular cardiomyopathy Task Force criteria. In view of our results, acute myocarditis should be considered as an additional criterion for arrhythmogenic cardiomyopathy, and genetic testing should be advised in patients who experience acute myocarditis and have a family history of cardiomyopathy or sudden death.

ß1-Adrenergic cardiac contractility is increased during early endotoxemic shock: Involvement of cyclooxygenases.

AIMS: Endothelial dysfunction is one of the earliest symptoms in septic patients and plays an important role in the cardiovascular alterations. However, the endothelial mechanisms involved in the impaired sympathetic regulation of the cardiovascular system are not clear. This study aimed to determine the role of the endocardial endothelium (EE) in the cardiac ß-adrenergic (ß-AR) remodeling at the early phase of endotoxemic shock. MAIN METHODS: Rats received either lipopolysaccharide (LPS) or saline (control) intravenously. Three hours later, ß-AR cardiac contractility was evaluated on papillary muscles with or without a functional EE. KEY FINDINGS: Isoproterenol-induced contractility was strongly increased in papillary muscles from LPS rats. A similar increase was observed with a ß1-AR stimulation, whereas ß2-AR and ß3-AR produced similar contractility in control and LPS treatments. The removal of the EE did not modify ß1-AR-induced contractility in controls, whereas it abolished the increased ß1-AR response in LPS-treated muscles. In LPS-treated papillary muscle, the increased ß1-AR-induced contractility was not modified by pretreatment with a NOS inhibitor or an endothelin receptor antagonist. Conversely, the increased ß1-AR-induced contractility was abolished by indomethacin, a non-selective cyclooxygenase (COX) inhibitor, as well as by selective inhibitors of COX1 and COX2. An early treatment with indomethacin improved the survival of LPS rat. SIGNIFICANCE: Our results suggest that the EE is involved in the increased cardiac ß1-AR contractility in the early phase of endotoxemic shock. This effect is mediated through the activation of COX1 and COX2 and suggests these may be novel putative therapeutic targets during endotoxemic shock.

Pulmonary hypertension in chronic heart failure: definitions, advances, and unanswered issues.

Pulmonary hypertension (PH) is a common and severe complication of heart failure (HF). Consequently, HF is the leading cause of PH. For many years, specialists have attempted to better understand the pathophysiology of PH in HF, to define its prevalence and its impact on prognosis in order to improve the therapeutic management of these patients. Nowadays, despite the recent guidelines published on the subject, several points remain unclear or debated, and until now, no study has demonstrated the efficacy of any treatment. The aim of this review is to report the evolution of the concepts on post-capillary PH (diagnosis, prevalence, prognosis, and therapeutics). The main issues are raised, focusing especially on the link between structural alterations and haemodynamic abnormalities, to discuss the possible reasons for treatment failures and future potential targets.