Background There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF). Objectives The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria. Methods In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria. Results The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria). Conclusions Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951).

T1* ratio mapping was introduced and validated for motion-corrected myocardial tissue characterization in cardiac MRI, demonstrating diagnostic value across cardiomyopathies and improved detection of myocardial involvement compared with late gadolinium enhancement.

BackgroundPatients with chronic heart failure (CHF) frequently suffer from depressive comorbidity. CHF and depressive comorbidity can cause somatic symptoms. The correct attribution of somatic symptoms is important. Thus, we aimed to assess potential differences in somatic symptom severity between CHF patients with and without depressive comorbidity.MethodsWe evaluated depressive comorbidity using the Patient Health Questionnaire-9 (PHQ-9), somatic symptom severity with the Patient Health Questionnaire-15 (PHQ-15), and sociodemographic and medical variables in 308 CHF outpatients. To compare somatic symptom severity between CHF patients with and without depressive comorbidity, we conducted item-level analyses of covariance.ResultsOf the 308 participating patients, 93 (30.3%) met the PHQ-9 criteria for depressive comorbidity. These patients did not differ from those without depressive comorbidity with regard to age, sex, left ventricular function, and multimorbidity. Patients with depressive comorbidity scored significantly higher on ten out of thirteen PHQ-15 items than patients without depressive comorbidity. The largest effect sizes (0.71-0.80) were shown for symptoms of headache, chest pain, shortness of breath, and palpitations, and the latter three were potentially attributable to heart failure.ConclusionsAmong patients with CHF, somatic symptoms are more pronounced in those with depressive comorbidity than those without depressive comorbidity. This finding is especially true for cardiac symptoms independent of CHF severity. The potential interpretation of somatic symptoms as correlates of depressive comorbidity must be recognized in clinical practice.

Community-based interventions may promote awareness and adherence to atrial fibrillation (AF)-related therapies, potentially reducing adverse events. The ARENA project investigated the health status, therapies and events in AF patients in the Rhein–Neckar Region, Germany. The subproject “ARENA intervention” studied the effect of community-based interventions on AF-associated outcomes. From 2016 onward, patients with diagnosed AF were recruited for the observational ARENA registry. In 2018, an intervention period was initiated involving population-based information campaigns on AF diagnosis and therapies. The “control group” was recruited prior to initiation, and the “intervention group” afterward. Patients underwent standardized follow-up > 1 year after recruitment. Clinical outcomes, therapy and quality of life were compared between the two groups. A total of 2769 patients were included. This real-world cohort showed high adherence to oral anticoagulation therapy (OAC) and an increased use of NOACs over vitamin K antagonists over time. In the intervention group (n = 1362), more patients continued OAC at follow-up (87.1

Objective: Atrial fibrillation (AF) is associated with impaired health-related quality of life (HRQoL), an increased risk of morbidity, and mortality. Traditional AF-related outcomes (e.g., AF recurrence) primarily demonstrate the physiological benefits of AF management but do not focus on the benefits experienced subjectively by the patient (i.e., patient-reported outcomes), which have been suggested as optimal endpoints in AF intervention studies. The aim of this study is to identify medical and psychological factors associated with impaired HRQoL at 1-year follow-up. Methods: Using data from the prospective observational multicenter ARENA study in patients with AF, we analyzed associations between medical factors, anxiety, and HRQoL at 1-year follow-up assessed using 5-level EuroQoL-5D. Results: In 1353 AF patients (mean age 71.4 +/- 10.3 years, 33.8% female), none of the medical predictors (e.g., heart disease) or history of cardioversion were associated with HRQoL at the 1-year follow-up. Higher generalized anxiety (beta = -0.114, p < .001) but not cardiac anxiety (beta = -0.006, p = .809) at baseline predicted decreased HRQoL, independent of confounding variables and patients' medical status. Furthermore, the worsening of patients' generalized anxiety was associated with decreased HRQoL (beta =-0.091, p < .001). In contrast, the improvement of generalized anxiety over time predicted higher HRQoL (beta = 0.097, p < .001). Finally, the worsening of patients' cardiac anxiety over time was associated with decreased HRQoL (beta =-0.081, p < .001). Conclusion: Our results highlight the importance of anxiety as a predictor of future HRQoL in patients with AF. Additional studies to examine the impact of anxiety treatment on HRQoL in this population are needed.

AimsEpidemiological surveillance has raised safety concerns for mRNA SARS-CoV-2-vaccination-related myocarditis. We aimed to analyze epidemiological, clinical and imaging findings associated with clinical outcomes in these patients in an international multi-center registry (NCT05268458).Methods and resultsPatients with clinical and CMR diagnosis of acute myocarditis within 30 days after mRNA SARS-CoV-2-vaccination were included from five centers in Canada and Germany between 05/21 and 01/22. Clinical follow-up on persistent symptoms was collected. We enrolled 59 patients (80% males, mean age 29 years) with CMR-derived mild myocarditis (hs-Troponin-T 552 [249-1,193] ng/L, CRP 28 [13-51] mg/L; LVEF 57 & PLUSMN; 7%, LGE 3 [2-5] segments). Most common symptoms at baseline were chest pain (92%) and dyspnea (37%). Follow-up data from 50 patients showed overall symptomatic burden improvement. However, 12/50 patients (24%, 75% females, mean age 37 years) reported persisting symptoms (median interval 228 days) of chest pain (n = 8/12, 67%), dyspnea (n = 7/12, 58%), with increasing occurrence of fatigue (n = 5/12, 42%) and palpitations (n = 2/12, 17%). These patients had initial lower CRP, lower cardiac involvement in CMR, and fewer ECG changes. Significant predictors of persisting symptoms were female sex and dyspnea at initial presentation. Initial severity of myocarditis was not associated with persisting complaints.ConclusionA relevant proportion of patients with mRNA SARS-CoV-2-vaccination-related myocarditis report persisting complaints. While young males are usually affected, patients with persisting symptoms were predominantly females and older. The severity of the initial cardiac involvement not predicting these symptoms may suggest an extracardiac origin.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with impaired health-related quality of life (HRQoL), high symptom severity, and poor cardiovascular outcomes. Both clinical and psychological factors may contribute to symptom severity and HRQoL in AF. Methods: Using data from the observational Atrial Fibrillation Rhine-Neckar Region (ARENA) trial, we identified medical and psychosocial factors associated with AF-related symptom severity using European Heart Rhythm Association symptom classification and HRQoL using 5-level EuroQoL- 5D. Results: In 1218 AF patients (mean age 71.1 ± 10.5 years, 34.5% female), female sex (OR 3.7, p < 0.001), preexisting coronary artery disease (CAD) (OR 1.7, p = 0.020), a history of cardioversion (OR 1.4, p = 0.041), cardiac anxiety (OR 1.2; p < 0.001), stress from noise (OR 1.4, p = 0.005), work-related stress (OR 1.3, p = 0.026), and sleep disturbance (OR 1.2, p = 0.016) were associated with higher AF-related symptom severity. CAD (β = −0.23, p = 0.001), diabetes mellitus (β = −0.25, p < 0.001), generalized anxiety (β = −0.30, p < 0.001), cardiac anxiety (β = −0.16, p < 0.001), financial stress (β = −0.11, p < 0.001), and sleep disturbance (β = 0.11, p < 0.001) were associated with impaired HRQoL. Conclusions: Psychological characteristics, preexisting CAD, and diabetes may play an important role in the identification of individuals at highest risk for impaired HRQoL and high symptom severity in patients with AF.

During the worldwide ongoing immunization campaign against SARS-CoV-2, growing data on very rare but potentially harmful side effects of such vaccines arise since approval trials have not been adequately powered to detect those events. Besides the already reported vaccine-related myocarditis, which primarily occurs in young male individuals, our attention was recently drawn to a series of older male and female patients, who were referred to our institutions with isolated acute pericarditis without myocardial damage, shortly after SARS-CoV-2 vaccination. We describe a series of five adult patients presenting with chest pain, shortness of breath and isolated pericarditis with and without pericardial effusion after SARS-CoV-2 vaccination. All patients underwent echocardiography and cardiac magnetic resonance, and the corresponding findings, including late gadolinium enhancement (LGE) and T1 and T2 mapping are reported herein. To our knowledge, such cases have not been systematically reported in the current literature so far.

Background: Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, with or without diabetes, but additional data are needed about the effect of the drug on inpatient and outpatient events that reflect worsening heart failure. Methods: We randomly assigned 3730 patients with class II to IV heart failure with an ejection fraction of ≤40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to recommended treatments for heart failure, for a median of 16 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. Results: Empagliflozin reduced the combined risk of death, hospitalization for heart failure or an emergent/urgent heart failure visit requiring intravenous treatment (415 versus 519 patients; empagliflozin versus placebo, respectively; hazard ratio [HR], 0.76; 95% CI, 0.67–0.87; P <0.0001). This benefit reached statistical significance at 12 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (HR, 0.67; 95% CI, 0.50–0.90; P =0.008) and that required a vasopressor or positive inotropic drug or mechanical or surgical intervention (HR, 0.64; 95% CI, 0.47–0.87; P =0.005). As compared with placebo, fewer patients in the empagliflozin group reported intensification of diuretics (297 versus 414 [HR, 0.67; 95% CI, 0.56–0.78; P <0.0001]). Additionally, patients assigned to empagliflozin were 20% to 40% more likely to experience an improvement in New York Heart Association functional class and were 20% to 40% less likely to experience worsening of New York Heart Association functional class, with statistically significant effects that were apparent 28 days after randomization and maintained during long-term follow-up. The risk of any inpatient or outpatient worsening heart failure event in the placebo group was high (48.1 per 100 patient-years of follow-up), and it was reduced by empagliflozin (HR, 0.70; 95% CI, 0.63–0.78; P <0.0001). Conclusions: In patients with heart failure and a reduced ejection fraction, empagliflozin reduced the risk and total number of inpatient and outpatient worsening heart failure events, with benefits seen early after initiation of treatment and sustained for the duration of double-blind therapy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03057977.

Myocardial strain is a convenient parameter to quantify left ventricular (LV) function. Fast strain-encoding (fSENC) enables the acquisition of cardiovascular magnetic resonance images for strain-measurement within a few heartbeats during free-breathing. It is necessary to analyze inter-vendor agreement of techniques to determine strain, such as fSENC, in order to compare existing studies and plan multi-center studies. Therefore, the aim of this study was to investigate inter-vendor agreement and test-retest reproducibility of fSENC for three major MRI-vendors. fSENC-images were acquired three times in the same group of 15 healthy volunteers using 3 Tesla scanners from three different vendors: at the German Heart Institute Berlin, the Charité University Medicine Berlin-Campus Buch and the Theresien-Hospital Mannheim. Volunteers were scanned using the same imaging protocol composed of two fSENC-acquisitions, a 15-min break and another two fSENC-acquisitions. LV global longitudinal and circumferential strain (GLS, GCS) were analyzed by a trained observer (Myostrain 5.0, Myocardial Solutions) and for nine volunteers repeatedly by another observer. Inter-vendor agreement was determined using Bland-Altman analysis. Test-retest reproducibility and intra- and inter-observer reproducibility were analyzed using intraclass correlation coefficient (ICC) and coefficients of variation (CoV). Inter-vendor agreement between all three sites was good for GLS and GCS, with biases of 0.01–1.88%. Test-retest reproducibility of scans before and after the break was high, shown by ICC- and CoV values of 0.63–0.97 and 3–9% for GLS and 0.69–0.82 and 4–7% for GCS, respectively. Intra- and inter-observer reproducibility were excellent for both parameters (ICC of 0.77–0.99, CoV of 2–5%). This trial demonstrates good inter-vendor agreement and test–retest reproducibility of GLS and GCS measurements, acquired at three different scanners from three different vendors using fSENC. The results indicate that it is necessary to account for a possible bias (< 2%) when comparing strain measurements of different scanners. Technical differences between scanners, which impact inter-vendor agreement, should be further analyzed and minimized. DRKS Registration Number: 00013253. Universal Trial Number (UTN): U1111-1207-5874.

Background Psychosocial factors in cardiovascular diseases are increasingly acknowledged by patients, health care providers and payer organizations. Due to the rapidly increasing body of evidence, the German Cardiac Society has commissioned an update of its 2013 position paper on this topic. The German version was published in 2018 and the current manuscript is an extended translation of the original version. Methods This position paper provides a synopsis of the state of knowledge regarding psychosocial factors in the most relevant cardiovascular diseases and gives recommendations with respect to their consideration in clinical practice. Results Psychosocial factors such as low socioeconomic status, acute and chronic stress, depression, anxiety and low social support are associated with an unfavorable prognosis. Psychosocial problems and mental comorbidities should be assessed routinely to initiate targeted diagnostics and treatment. For all patients, treatment should consider age and gender differences as well as individual patient preferences. Multimodal treatment concepts should comprise education, physical exercise, motivational counseling and relaxation training or stress management. In cases of mental comorbidities, brief psychosocial interventions by primary care providers or cardiologists, regular psychotherapy and/or medications should be offered. While these interventions have positive effects on psychological symptoms, robust evidence for possible effects on cardiac outcomes is still lacking. Conclusions For coronary heart disease, chronic heart failure, arterial hypertension, and some arrhythmias, there is robust evidence supporting the relevance of psychosocial factors, pointing to a need for considering them in cardiological care. However, there are still shortcomings in implementing psychosocial treatment, and prognostic effects of psychotherapy and psychotropic drugs remain uncertain. There is a need for enhanced provider education and more treatment trials.

AimsDespite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT‐HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF).MethodsPatients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double‐blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all‐cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all‐cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF.ConclusionThe DIGIT‐HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all‐cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.

Psychosoziale Faktoren bei Herz-Kreislauferkrankungen sind zunehmend in das Bewusstsein von Patienten, Leistungserbringern und Kostenträgern gerückt. Aufgrund der rasch anwachsenden Evidenz hat die Deutsche Gesellschaft für Kardiologie ein Update des gleichnamigen Positionspapiers aus dem Jahr 2013 in Auftrag gegeben.

In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.

Background: While comprehensive evidence exists regarding negative effects of depression on self-care behaviours in patients with chronic heart failure (CHF), the relation between anxiety and self-care behaviours in patients with CHF is not clear. The aim of this study was to analyse the interactions between anxiety, depression and self-care behaviours in patients with CHF. Methods: The self-care behaviour of CHF outpatients was measured using the European Heart Failure Self-care Behaviour Scale (EHFScBS). The Patient Health Questionnaire (PHQ) was used to assess anxiety, the PHQ-9 was used to measure depression severity. Differences between patients with and without anxiety were assessed with the respective tests. Associations between anxiety, self-care and other predictors were analysed using linear regressions. Results: Of the 308 participating patients, 35 (11.4%) fulfilled the PHQ criteria for an anxiety disorder. These patients took antidepressants more frequently (11.8% versus 2.3%, p = .02), had had more contacts with their general practitioner within the last year (11.8 ± 16.1 versus 6.7 ± 8.6, p = .02), and had a higher PHQ-9 depression score (12.9 ± 5.7 versus 6.5 ± 4.7, p < .01) than patients without anxiety disorder. Anxiety and self-care were negatively associated (ß = −0.144, r2 = 0.021, p = 0.015). The explanation of variance was augmented in a multivariate regression with the predictors age, sex, education, living with a partner, and New York Heart Association (NYHA) class (r2 = 0.098) when anxiety was added (r2 = 0.112). Depression further increased the explanation of variance (ß = −0.161, r2 = 0.131, p = 0.019). Conclusions: Anxiety is negatively associated with self-care behaviour in patients with CHF. However, this effect disappears behind the stronger influence of depression on self-care. The consideration of mental comorbidities in patients with CHF is important.

Evaluation of the heart failure (HF) incidence in Olmsted County (Minnesota/USA) revealed a decline from 316 per 100,000 in 2000 to 219 per 100,000 in 2010 equating to a relative reduction of 37.5 %. The decline in HF incidence was greater for HFrEF than for HFpEF (– 45 % vs. – 28 %) und smaller in men than in women (-29 % vs. – 43 %). Notebly, it was independent from age. The 1-year mortality rate was 20.2 %. Noncardiovascular causes were the predominent reasons for both mortality and hospitalizations. Neither mortality nor hospitalization rate declined over time. Sound data on the HF incidence are currently not available for Germany. However, the total number of HF-related hospitalizations increased during the period from 2000 to 2014. This phenomenon is most likely due to an increased prevalence secondary to optimized HF therapy and changes in demography with a higher HF hospitalization rate in elderly patients.

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.