Aims: Clinical studies suggest beneficial effects of renin–angiotensin system blockade for prevention of left ventricular (LV) dysfunction after chemotherapy. However, the efficacy of this strategy as primary prevention has been poorly studied. This study aimed at identifying the pathophysiological mechanisms by which mineralocorticoid receptor antagonism (MRA) or angiotensin converting enzyme inhibition (ACEi) provide protection against doxorubicin-induced cardiotoxicity (DIC) in mouse models of acute and chronic toxicity. Methods and results: Acute DIC was induced by a single injection of Dox at 15 mg/kg and chronic DIC applied 5 injections of Dox at 4 mg/kg/week. MRA was achieved using eplerenone or cardiomyocyte-specific ablation of the MR gene in transgenic mice and ACEi using enalapril. Drugs were provided with the first dose of Dox and applied until the end of the study. In both model of DIC, Dox induced cardiac atrophy with decreased LV volume, reduced cardiomyocyte cell size, and cardiac dysfunction. In the acute model, neither MRA nor ACEi protected against these manifestations of DIC. In the chronic model, concomitant treatment with eplerenone did not protect against DIC and drastically increased plasma aldosterone levels and cardiac levels of angiotensin II type 1 receptor and of connective tissue growth factor (CTGF), as observed in acute DIC. Enalapril treatment in the chronic model, however, protected against cardiac dysfunction and cardiomyocyte atrophy and was associated with increased activation of the PI3K/AKT/mTOR pathway along with normal levels of CTGF. Conclusion: Enalapril and eplerenone disparately impact on cellular signalling in DIC. Eplerenone, on top of Dox treatment was not protective and associated with increased levels of plasma aldosterone and of cardiac CTGF. In contrast, we show that primary prevention with enalapril preserves LV morphology and function in a clinically relevant model of chronic DIC, with increased stimulation of the PI3K/AKT/mTOR axis and normal CTGF levels suggesting potential therapeutic implications.

Background Elevated red blood cell distribution width (RDW) is a valid predictor of outcome in acute heart failure (AHF). It is unknown whether elevated RDW remains predictive in AHF patients with either preserved left ventricular ejection fraction (LVEF) ≥50% or reduced LVEF (<50%). Methods and results Prospective local registry including 402 consecutive hospitalized AHF patients without acute coronary syndrome or need of intensive care. The primary outcome was all-cause mortality (ACM) at 1 year after admission. Demographic and clinical data derive from admission, echocardiographic examinations (n = 269; 67%) from hospitalization. The Cox proportional hazard model including all patients (P < 0.001) was adjusted for age, gender, and RDW quartiles. Independent predictors of 1-year ACM were cardiogenic shock (HR 2.86; CI: 1.3–6.4), male sex (HR 1.9; CI: 1.2–2.9), high RDW quartile (HR 1.66; CI: 1.02–2.8), chronic HF (HR 1.61; CI: 1.05–2.5), valvular heart disease (HR 1.61; CI: 1.09–2.4), increased diastolic blood pressure (HR 1.02 per mmHg; CI: 1.01–1.03), increasing age (HR 1.04 by year; CI: 1.02–1.07), platelet count (HR 1.002 per G/l; CI: 1.0–1.004), systolic blood pressure (HR 0.99 per mmHg; CI: 0.98–0.99), and weight (HR 0.98 per kg; CI: 0.97–0.99). A total of 114 patients (28.4%) died within the first year; ACM of all patients increased with quartiles of rising RDW (χ² 18; P < 0.001). ACM was not different between RDW quartiles of patients with reduced LVEF (n = 153; χ² 6.6; P = 0.084). In AHF with LVEF ≥50% the probability of ACM increased with rising RDW (n = 116; χ² 9.9; P = 0.0195). Conclusions High RDW is associated with increased ACM in AHF patients with preserved but not with reduced LVEF in this study population.

Symptom perception in heart failure has recently been described as essential in the self-care process bridging self-care maintenance and self-care management. Accordingly, symptom perception appears to be critical for improving patient outcomes such as decreased hospital readmission and increased survival. To explore what interventions have been reported on heart failure symptom perception and to describe outcomes responsive to symptom perception. We conducted a scoping review using PRISMA Extension for Scoping Reviews. Structured searches of Medline, PubMed, Embase, CINAHL, PsychINFO, Web of Science, Cochrane, Joanna Briggs Institute and Grey literature databases. Two authors independently screened references for eligibility. Eligible articles were written in English, French, German, Swedish, Italian or Spanish and concerned symptom perception in adults with heart failure. Data were extracted and charted in tables by three reviewers. Results were narratively summarized. We identified 99 eligible studies from 3055 references. Seven interventional studies targeted symptom perception as the single intervention component. Mixed results have been found: while some reported decreased symptom frequency, intensity and distress, enhanced health-related quality of life, improved heart failure self-care maintenance and management as well as a greater ability to mention heart failure symptoms, others found more contacts with healthcare providers or no impact on anxiety, heart failure self-care nor a number of diary reported symptoms. Additional interventional studies included symptom perception as one component of a multi-faceted intervention. Outcomes responsive to symptom perception were improved general and physical health, decreased mortality, heart failure decompensation, as hospital/emergency visits, shorter delays in seeking care, more consistent weight monitoring, improved symptom recognition as well as self-care management, decreased hospital length of stay and decreased costs. While many studies allowed to map a comprehensive overview of interventions supporting symptom perception in heart failure as well as responsiveness to outcomes, only a few single component intervention studies targeting symptom perception have been reported and study designs preclude assessing intervention effectiveness. With regard to multiple component interventions, the specific impact of symptom perception interventions on outcomes remains uncertain to date. Well-designed studies are needed to test the effectiveness of symptom perception interventions and to elucidate relationships with outcomes.

A 35-year-old woman (body mass index, 16 kg/m 2 ; height, 140 cm) presented to the emergency ward with severe dyspnea of acute onset. The medical history was noteworthy for bilateral hypacusis treated with a hearing aid. On admission, the laboratory results revealed an N-terminal prohormone of brain natriuretic peptide level of 10 219 ng/L (normal Ͻ200 ng/L). Thoracic CT scan excluded pulmonary embolism but showed cardiomegaly with pericardial and bilateral pleural effusion suggesting the presence of acute heart failure. Cardiac MRI (CMR) demonstrated a severely reduced left ventricular ejection fraction (LVEF, 13%) and severe right ventricular dysfunction (Figure 1A and 1B, baseline); LV mass index was normal. Late gadolinium enhancement images demonstrated extensive subepicardial lesions in inferior and lateral LV segments (Figure 1C, baseline). The angiogram excluded a coronary pathology, and myocardial histology was without histological signs of infiltrative or active inflammatory disease. The ECG was noteworthy for a shortened PQ interval, but supraventricular tachycardia was not revealed during long-term ECG monitoring. Otherwise, the patient showed a hyperglycemic fasting glucose level (7.5 mmol/L; normal Ͻ5.6 mmol/L), and, whereas lactate level was normal at rest (2 mmol/L; normal Ͻ2.4 mmol/L), a rapid increase to 4.3 mmol/L was noteworthy after 150 seconds of bicycle exercise at 35 W. Cerebral MRI showed cerebellar atrophy (Figure 2) in the absence of a clinically relevant neurological disorder, and ophthalmologic examination revealed bilateral ocular maculopathy. With standard heart failure therapy including low-dose ␤-blockade, angiotensin-converting enzyme inhibition, aldosterone blockade, and loop diuretics, the patient recovered to New York Heart Association class II; in parallel, the NT-proBNP-level decreased to 391 ng/L. After 18 months, CMR showed significant improvement of systolic biventricular function (LVEF, 48%; minor right ventricular dysfunction) (Figure 1D and 1E), whereas volume and pattern of the myocardial lesions remained unchanged (Figure 1F).

Ventricular assist devices (VAD) are valuable options for patients with heart failure awaiting cardiac transplantation. We assessed the impact of pre-transplant VAD implantation on the incidence of post-transplant infections in a nationwide cohort of heart transplant recipients. Heart transplant recipients included in the Swiss Transplant Cohort Study between May 2008 and December 2012 were analyzed. Cumulative incidence curves were used to calculate the incidence of bacterial or Candida infections (primary endpoint) and of other infections (secondary endpoint) after transplant. Cox regression models treating death as a competing risk were used to identify risk factors for the development of infection after transplant. Overall, 119 patients were included in the study, 35 with a VAD and 84 without VAD. Cumulative incidences of post-transplant bacterial or Candida infections were 37.7 % in VAD patients and 40.4 % in non-VAD patients. In multivariate analysis, the use of cotrimoxazole prophylaxis was the only variable associated with bacterial/Candida infections after transplant (HR 0.29 [95 % CI 0.15-0.57], p < 0.001), but presence of a VAD was not (HR 0.94, [95 % CI 0.38-2.32], p = 0.89, for continuous-flow devices, and HR 0.45 [0.15 – 1.34], p = 0.15, for other devices). Risk for post-transplant viral and all fungal infections was not increased in patients with VAD. One-year survival was 82.9 % (29/35) in the VAD group and 82.1 % (69/84) in the non-VAD group. All 6 patients in the VAD group that died after transplant had a history of pre-transplant VAD infection. In this nationwide cohort of heart transplant recipients, the presence of VAD at the time of transplant had no influence on the development of post-transplant infections.