Frank Edelmann

Effect of Escitalopram on All-Cause Mortality and Hospitalization in Patients With Heart Failure and Depression: The MOOD-HF Randomized Clinical Trial.

IMPORTANCE Depression is frequent in patients with heart failure and is associated with adverse clinical outcomes. Long-term efficacy and safety of selective serotonin reuptake inhibitors in these patients are unknown. OBJECTIVE To determine whether 24 months of treatment with escitalopram improves mortality, morbidity, and mood in patients with chronic systolic heart failure and depression. DESIGN, SETTING, AND PARTICIPANTS The Effects of Selective Serotonin Re-Uptake Inhibition on Morbidity, Mortality, and Mood in Depressed Heart Failure Patients (MOOD-HF) study was a double-blind, placebo-controlled randomized clinical trial conducted at 16 tertiary medical centers in Germany. Between March 2009 and February 2014, patients at outpatient clinics with New York Heart Association class II-IV heart failure and reduced left ventricular ejection fraction (<45%) were screened for depression using the 9-item Patient Health Questionnaire. Patients with suspected depression were then invited to undergo a Structured Clinical Interview based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) to establish the diagnosis. INTERVENTIONS Patients were randomized 1:1 to receive escitalopram (10-20 mg) or matching placebo in addition to optimal heart failure therapy. Study duration was 24 months. MAIN OUTCOMES AND MEASURES The composite primary outcome was time to all-cause death or hospitalization. Prespecified secondary outcomes included safety and depression severity at 12 weeks of treatment (including the titration period), which were determined using the 10-item Montgomery-Åsberg Depression Rating Scale (total possible score, 0 to 60; higher scores indicate more severe depression). RESULTS A total of 372 patients (mean age, 62 years; 24% female) were randomized and had taken at least 1 dose of study medication when the data and safety monitoring committee recommended the trial be stopped early. During a median participation time of 18.4 months (n = 185) for the escitalopram group and 18.7 months (n = 187) for the placebo group, the primary outcome of death or hospitalization occurred in 116 (63%) patients and 119 (64%) patients, respectively (hazard ratio, 0.99 [95% CI, 0.76 to 1.27]; P = .92). The mean Montgomery-Åsberg Depression Rating Scale sum score changed from 20.2 at baseline to 11.2 at 12 weeks in the escitalopram group and from 21.4 to 12.5 in the placebo group (between-group difference, -0.9 [95% CI,-2.6 to 0.7]; P = .26). Safety parameters were comparable between groups. CONCLUSIONS AND RELEVANCE In patients with chronic heart failure with reduced ejection fraction and depression, 18 months of treatment with escitalopram compared with placebo did not significantly reduce all-cause mortality or hospitalization, and there was no significant improvement in depression. These findings do not support the use of escitalopram in patients with chronic systolic heart failure and depression. TRIAL REGISTRATION isrctn.com Identifier: ISRCTN33128015.

Myocardial Hypertrophy and Its Role in Heart Failure with Preserved Ejection Fraction

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load, and cytokines associated with arterial hypertension, chronic kidney disease, diabetes, and other comorbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood, but may include extracellular matrix changes, vascular dysfunction, as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca(2+) turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound comorbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training, on the other hand, in clinical trials improved exercise tolerance and diastolic function, but did not reduce LVH. Thus current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF.

Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study

Aims The aim of the present multicentre study was to analyse a large cohort of healthy subjects and patients with a common condition such as heart failure (HF) with the purpose of determining the normal range and the usefulness of right ventricular (RV) systolic strain to detect subtle RV systolic abnormalities using 2D speckle-tracking echocardiography. Methods and results We analysed 238 healthy subjects and a cohort of 642 patients characterized by asymptomatic patients (n = 216) and patients with HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (n = 218 and n = 208, respectively) prospectively included in 10 centres. The normal range of RV systolic strain analysing the healthy subjects was as follows: RV global strain −24.5 ± 3.8 and RV free wall strain −28.5 ± 4.8 (lowest expected value −17 and −19%, respectively). Concerning the ability of these myocardial parameters to detect subtle RV systolic abnormalities, RV global and free wall systolic strain were able to detect subtle RV longitudinal systolic abnormalities in a significant proportion of patients with HFrEF and to a lesser extent in HFpEF despite preserved tricuspid annular plane systolic excursion, tricuspid lateral annular peak systolic velocity by pulsed tissue Doppler imaging, and RV fractional area change. In addition, RV global and free wall systolic strain were significantly linked to the symptomatic status of the patients. Conclusions The findings from this study provide important data regarding the normal range of RV global and free wall systolic strain and highlight the clinical relevance of these RV myocardial parameters to detect subtle RV systolic abnormalities in patients with HF.

Exercise training in heart failure

Exercise training in patients with chronic stable heart failure (HF) is a recommended and broadly accepted treatment strategy that is an integral part of an evidence-based management involving pharmacological and non-pharmacological therapies. There is ample scientific evidence that exercise training in HF with reduced (HFrEF) and with preserved ejection fraction (HFpEF) improves exercise capacity, HF symptoms and quality of life. This is due to an improvement of central hemodynamics, endothelial function, neurohumoral activation, skeletal muscle structure and function as well as a decrease in inflammatory markers. The largest randomized, controlled HF-ACTION study (Heart Failure-A Controlled Trial Investigating Outcomes of exercise TraiNing) demonstrated that exercise training results in a modest improvement of all-cause mortality and hospitalizations in HFrEF, depending on adequate compliance. Outcome data in HFpEF are lacking. Besides compliance, efficacy of exercise training is dependent on the intensity and type of exercise. Resistance and high intensity endurance training in addition to a standard aerobic exercise seem to be superior in improving the clinical status of HF patients. In the future, individualized exercise programs will help to improve long-term adherence to exercise training.ZusammenfassungKörperliches Training bei stabiler chronischer Herzinsuffizienz ist neben pharmakologischen und nichtpharmakologischen Behandlungskonzepten eine in den aktuellen Leitlinien empfohlene und besonders bei eingeschränkter linksventrikulärer (LV) Funktion [“heart failure with reduced ejection fraction“ (HFrEF)] breit akzeptierte Therapieoption. Eine Vielzahl randomisierter Studien zu körperlichem Training bei HFrEF und eine wachsende Zahl von Studien zu Herzinsuffizienz mit erhaltener LV-Funktion [“heart failure with preserved ejection fraction“ (HFpEF)] belegen, dass die Belastungstoleranz, Symptomatik und Lebensqualität signifikant verbessert werden können. Ursächlich hierfür sind durch körperliches Training induzierte Verbesserungen der zentralen Hämodynamik, der Endothelfunktion, der Inflammation, der neurohumoralen Aktivierung, aber auch der Skelettmuskulatur. HF-ACTION, die größte randomisierte, kontrollierte Studie zu körperlichem Training, zeigte für Patienten mit HFrEF in Abhängigkeit von der Compliance einen positiven Effekt auf Mortalität und Hospitalisierungen. Bei HFpEF fehlen Studien zu den prognostischen Effekten von Training bislang. Neben der Compliance beeinflussen auch die gewählte Trainingsintensität und -modalität die Wirksamkeit von körperlichem Training. So scheinen eine höhere Intensität und ein zusätzlich zum aeroben Ausdauertraining durchgeführtes Krafttraining vorteilhaft zu sein. Individualisierte Trainingskonzepte sollten zukünftig dazu beitragen, eine langfristige Motivation zum körperlichen Training bei Herzinsuffizienz aufrechtzuerhalten.AbstractExercise training in patients with chronic stable heart failure (HF) is a recommended and broadly accepted treatment strategy that is an integral part of an evidence-based management involving pharmacological and non-pharmacological therapies. There is ample scientific evidence that exercise training in HF with reduced (HFrEF) and with preserved ejection fraction (HFpEF) improves exercise capacity, HF symptoms and quality of life. This is due to an improvement of central hemodynamics, endothelial function, neurohumoral activation, skeletal muscle structure and function as well as a decrease in inflammatory markers. The largest randomized, controlled HF-ACTION study (Heart Failure-A Controlled Trial Investigating Outcomes of exercise TraiNing) demonstrated that exercise training results in a modest improvement of all-cause mortality and hospitalizations in HFrEF, depending on adequate compliance. Outcome data in HFpEF are lacking. Besides compliance, efficacy of exercise training is dependent on the intensity and type of exercise. Resistance and high intensity endurance training in addition to a standard aerobic exercise seem to be superior in improving the clinical status of HF patients. In the future, individualized exercise programs will help to improve long-term adherence to exercise training.

Left ventricular longitudinal systolic function analysed by 2D speckle-tracking echocardiography in heart failure with preserved ejection fraction: a meta-analysis

Background The purpose of this meta-analysis was to confirm if the global longitudinal systolic function of the left ventricle (LV) is altered in patients with heart failure with preserved ejection fraction (HFpEF). Methods We searched in different databases (Medline, Embase and Cochrane) studies that analysed LV global longitudinal systolic strain (GLS) in patients with HFpEF and in controls (such as healthy subjects or asymptomatic patients with arterial hypertension, diabetes mellitus or coronary artery disease). Results Twenty-two studies (2284 patients with HFpEF and 2302 controls) were included in the final analysis. Patients with HFpEF had significantly lower GLS than healthy subjects (mean −15.7% (range −12% to −18.9%) vs mean −19.9% (range −17.1% to −21.5%), weighted mean difference −4.2% (95% CI −3.3% to −5.0%), p < 0.001, respectively). In addition, patients with HFpEF had also significantly lower GLS than asymptomatic patients (mean −15.5% (range −13.4% to −18.4%) vs mean −18.3% (range −15.1% to −20.4%), weighted mean difference −2.8%(95% CI −1.9% to −3.6%), p < 0.001, respectively). In line, 10 studies showed that the rate of abnormal GLS was significantly higher in patients with HFpEF (mean 65.4% (range 37%–95%)) than in asymptomatic subjects (mean 13% (range 0%–29.6%)). Regarding the prognostic relevance of abnormal GLS in HFpEF, two multicentre studies with large sample size (447 and 348) and high number of events (115 and 177) showed that patients with abnormal GLS had worse cardiovascular (CV) outcomes than those with normal GLS (HR for CV mortality and HF hospitalisation 2.14 (95% CI 1.26 to 3.66) and 1.94 (95% CI 1.22 to 3.07)), even adjusting these analyses for multiples clinical and echocardiographic variables. Conclusion The present meta-analysis analysing 2284 patients with HFpEF and 2302 controls confirms that the longitudinal systolic function of the LV is significantly altered in high proportion of patients with HFpEF. Further large multicentre studies with the aim to confirm the prognostic role of abnormal GLS in HFpEF are warranted.

Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial

BACKGROUND Remote patient management in patients with heart failure might help to detect early signs and symptoms of cardiac decompensation, thus enabling a prompt initiation of the appropriate treatment and care before a full manifestation of a heart failure decompensation. We aimed to investigate the efficacy of our remote patient management intervention on mortality and morbidity in a well defined heart failure population. METHODS The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial was a prospective, randomised, controlled, parallel-group, unmasked (with randomisation concealment), multicentre trial with pragmatic elements introduced for data collection. The trial was done in Germany, and patients were recruited from hospitals and cardiology practices. Eligible patients had heart failure, were in New York Heart Association class II or III, had been admitted to hospital for heart failure within 12 months before randomisation, and had a left ventricular ejection fraction (LVEF) of 45% or lower (or if higher than 45%, oral diuretics were being prescribed). Patients with major depression were excluded. Patients were randomly assigned (1:1) using a secure web-based system to either remote patient management plus usual care or to usual care only and were followed up for a maximum of 393 days. The primary outcome was percentage of days lost due to unplanned cardiovascular hospital admissions or all-cause death, analysed in the full analysis set. Key secondary outcomes were all-cause and cardiovascular mortality. This study is registered with ClinicalTrials.gov, number NCT01878630, and has now been completed. FINDINGS Between Aug 13, 2013, and May 12, 2017, 1571 patients were randomly assigned to remote patient management (n=796) or usual care (n=775). Of these 1571 patients, 765 in the remote patient management group and 773 in the usual care group started their assigned care, and were included in the full analysis set. The percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause death was 4·88% (95% CI 4·55-5·23) in the remote patient management group and 6·64% (6·19-7·13) in the usual care group (ratio 0·80, 95% CI 0·65-1·00; p=0·0460). Patients assigned to remote patient management lost a mean of 17·8 days (95% CI 16·6-19·1) per year compared with 24·2 days (22·6-26·0) per year for patients assigned to usual care. The all-cause death rate was 7·86 (95% CI 6·14-10·10) per 100 person-years of follow-up in the remote patient management group compared with 11·34 (9·21-13·95) per 100 person-years of follow-up in the usual care group (hazard ratio [HR] 0·70, 95% CI 0·50-0·96; p=0·0280). Cardiovascular mortality was not significantly different between the two groups (HR 0·671, 95% CI 0·45-1·01; p=0·0560). INTERPRETATION The TIM-HF2 trial suggests that a structured remote patient management intervention, when used in a well defined heart failure population, could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. FUNDING German Federal Ministry of Education and Research.

Investigating a biomarker‐driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide vs. furosemide on serum C‐terminal propeptide of procollagen type I (DROP‐PIP trial)

Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro‐fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C‐terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels.

Amount or intensity? Potential targets of exercise interventions in patients with heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) remains a common condition with no pharmacological treatment. Physical activity (PA) improves symptoms and quality of life (QoL), but no clear recommendations exist on PA in HFpEF patients. We investigated the association of PA (amount/intensity) on clinical phenotype in HFpEF.

[Recommendations for the treatment of heart failure : What's new?].

Treatment escalation of chronic systolic heart failure depends on left ventricular function and symptoms of the patients. In symptomatic patients with severely reduced left ventricular function (ejection fraction ≤ 30 %), the following therapeutic approaches are recommended: (1) angiotensin-converting enzyme (ACE) inhibitors (angiotensin receptor blocker in case of ACE inhibitor intolerance); (2) β-blockers; (3) mineralocorticoid receptor antagonists; (4) diuretics in case of signs and symptoms of congestion; (5) digitalis, in particular in patients with atrial fibrillation; (6) ivabradine in patients with sinus rhythm and a heart rate ≥ 75/min; (7) an implantable cardioverter defibrillator (ICD); (8) in case of left bundle branch block or wide QRS complex, cardiac resynchronization therapy (CRT; in most cases in combination with an implantable cardioverter defibrillator); (9) intravenous administration of iron in case of iron deficiency; (10) exercise training should be strongly recommended in patients with stable heart failure.

Rationale and design of a multicentre, randomized, placebo-controlled trial of mirabegron, a Beta3-adrenergic receptor agonist on left ventricular mass and diastolic function in patients with structural heart disease Beta3-left ventricular hypertrophy (Be: A multicentre, randomized, placebo-controlled trial of mirabegron

Progressive left ventricular (LV) remodelling with cardiac myocyte hypertrophy, myocardial fibrosis, and endothelial dysfunction plays a key role in the onset and progression of heart failure with preserved ejection fraction. The Beta3‐LVH trial will test the hypothesis that the β3 adrenergic receptor agonist mirabegron will improve LV hypertrophy and diastolic function in patients with hypertensive structural heart disease at high risk for developing heart failure with preserved ejection fraction.