December 2018 at a Glance: New Imaging Methods, Translational Cardiology and Non-Medical Treatment

A position statement by the Heart Failure Association of the European Society of Cardiology describes new imaging modalities for diagnostic and prognostic evaluation, as well as to guide treatment, in patients with heart failure (HF).1 New imaging modalities with potential major impact on HF management include assessment of myocardial deformation by speckle imaging, three-dimensional ultrasound imaging, stress tests for the evaluation of contractile and filling function and the diagnosis of HF with preserved ejection fraction (HFpEF), the progress of magnetic resonance techniques, molecular imaging and other innovations.1-4 This progress is driving major changes in the assessment of HF patients such as switching from two-dimensional to three-dimensional imaging, better tissue characterization through cardiac magnetic resonance, assessment of cardiac function not only at rest but also during stress, novel non-invasive hybrid techniques for the simultaneous assessment of coronary anatomy and myocardial perfusion and, lastly, functional imaging with the assessment of pathophysiologic processes such as inflammation and apoptosis.1 Abnormalities in calcium homeostasis are key mechanisms of cardiac dysfunction in HF.5, 6 The role of protein phosphatase 1 (PP1) and 2A (PP2A) is still unsettled. Fischer et al.7 analysed phosphatase activity in human myocardium from healthy controls and patients with compensated hypertrophy and patients with end-stage HF. Compared with normal hearts, PP1 expression was unchanged in the heart of patients with compensated hypertrophy but greater in failing hearts, and this was attended by lower activity of PP1 endogenous inhibitor-1. In contrast, PP2A expression was lower in both the hypertrophied and the failing hearts. Calcium homeostasis was severely disturbed in failing hearts, compared to those with hypertrophy, as shown by higher sarcoplasmic reticulum calcium leak, lower systolic calcium transients and decreased sarcoplasmic reticulum calcium load. Inhibition of PP1/PP2A by okadaic acid increased calcium load and calcium transients but worsened diastolic sarcoplasmic reticulum calcium leak and caused arrhythmias. Conversely, selective activation of PP1 by a PP1-disrupting peptide markedly reduced sarcoplasmic reticulum calcium leak as well as arrhythmias without worsening the other mechanisms related with calcium homeostasis.7 Empagliflozin reduced HF events and mortality in diabetic patients at high risk of cardiovascular events.8 The mechanisms of these beneficial effects are still unsettled. Pabel et al.9 studied the direct myocardial effects of empagliflozin in isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension without any change in contractility, calcium transient amplitude, or diastolic calcium level. These results were confirmed in a murine model. The mechanisms of these favourable effects of empagliflozin were further evaluated using myofilaments from skinned myocytes from non-failing or HFpEF subjects and rat experimental models. The main mechanism of action of empagliflozin was increased phosphorylation of the myofilament regulatory proteins.9 Growth differentiation factor-15 (GDF-15) is associated with adverse prognosis in HF.10 Bouabdallaoui et al.11 assessed the association of GDF-15 with outcomes in patients enrolled in PARADIGM-HF. GDF-15 values were increased in patients with HF and reduced ejection fraction (HFrEF). Age, diabetes, creatinine, high-sensitive troponin T, N-terminal pro-B-type natriuretic peptide, and New York Heart Association (NYHA) class III/IV were the variables most strongly associated with elevated GDF-15 values. Baseline GDF-15 and its changes during follow-up were associated with subsequent mortality and cardiovascular events. No interaction with treatment and no relation with assigned therapy were found. Fussner et al.12 analysed 91 patients with cardiac sarcoidosis followed in 1994–2014 at two large U.S. academic medical centres. Cardiomyopathy was the primary presentation in 47 patients (51.6%). During follow-up, 31 of 47 cardiomyopathy patients had an improvement in left ventricular ejection fraction (LVEF), 23 had a decline in LVEF or a clinical exacerbation, and 15 of 22 patients presenting with ventricular arrhythmia had recurrences. These results did not differ by treatment group: prednisone alone, alternate immunosuppression with or without prednisone, or no immunosuppression. During a median follow-up of 44 months, 14 patients reached the composite endpoint of left ventricular (LV) assist device placement, heart transplant, or death. Event-free survival did not differ by treatment group, but was worse among patients presenting with cardiomyopathy. Pareek et al.13 described the 5-year activity and outcomes of 535 patients of a cardio-oncology service in the United Kingdom. Rates of cardiotoxicity for anthracyclines, anti-HER2 agents and tyrosine kinase inhibitors were 75.8%, 69.8% and 62.1%, respectively. Patients with LV systolic dysfunction (n = 128) were younger, had higher rates of hypertension and previous exposure to chemotherapy/radiotherapy. At a median follow-up of 360 days, 93.8% of patients with LV systolic dysfunction showed improvement in LVEF, from 45% to 53%, and NYHA class. All patients with normal LVEF and biochemical markers and 89% of those with LV dysfunction were considered as suitable to continue cancer therapy. Sixty-seven per cent of patients with LV dysfunction could complete their anti-cancer treatment.13 The impact of exercise-based cardiac rehabilitation on mortality and hospitalizations of HFrEF patients was assessed by individual patient data meta-analysis of randomized trials (18 trials with 3912 patients).14 Compared to control, there was no significant difference in pooled time to event estimates with cardiac rehabilitation, although wide confidence intervals (CIs) were found for all-cause mortality [hazard ratio (HR) 0.83, 95% CI 0.67–1.04]. No difference in HF hospitalizations was found (HR 0.98, 95% CI 0.72–1.35). No strong evidence of differential intervention effects across patient characteristics was found.14 Costanzo et al.15 described the 12-month clinical outcomes of all patients with central sleep apnoea treated for at least 3 months with unilateral transvenous phrenic nerve stimulation in the prospective, multicentre, non-randomized remedē® System pilot study. Sleep metrics and quality of life improved from baseline to 6 and 12 months. HF hospitalizations were lower in treated patients (4.7% vs. 17% in control patients).