Effects of sacubitril-valsartan on remodelling, fibrosis and mitochondria in a murine model of isoproterenol-induced left ventricular dysfunction.

BACKGROUND: Sacubitril/valsartan has been demonstrated to promote left ventricular (LV) reverse remodelling and improve outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. We aimed to evaluate the effects of sacubitril/valsartan on LV remodelling, myocardial fibrosis and mitochondrial biology in a murine model of non-ischaemic LV dysfunction. METHODS: Adult transgenic male mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injections to induce LV systolic dysfunction. After 7 days, mice were randomized to a 2-week treatment with saline (ISO-AS n = 15), valsartan (ISO + V n = 12) or sacubitril/valsartan (ISO + S/V n = 12). Echocardiography was performed at baseline, at day 7, and after each of the 2 weeks of treatment. After sacrifice at day 21, histological and immunochemical assays were performed. A control group of AS mice was also obtained (Ctrl-AS n = 8). RESULTS: Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement in LVEF (p = 0.009 vs ISO-AS) and fractional shortening (p = 0.032 vs ISO-AS) after 2- week treatment. In both ISO + V and ISO + S/V groups, a trend toward reduction of the cardiac collagen 1/3 expression ratio was detected. ISO + V and ISO + S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. CONCLUSION: In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV systolic function, and on cardiac energetics, by improving mitochondrial activity.

Unanticipated subcutaneous ICD end-of-service due to premature battery depletion and occurrence of lead fracture: A single centre experience.

The use of subcutaneous ICDs (S-ICD) is growing over years despite increasing alerts on premature battery depletion (PBD) and lead fractures leading to unanticipated device replacements. In our single-centre study including 192 patients, per year analysis demonstrated that incidence of PBD is higher than previously reported with overall greatest battery replacement requirements around the fifth year of follow-up. The underlying issue appears to be limited to old series devices, but only a longer follow-up will clarify the real impact of this phenomenon on patient outcomes. PBD is an underestimated S-ICDs issue and if the hereby demonstrated trend were to be confirmed in latest device series, this would bring significant concerns to patient safety and huge economic expense to health system.

Use of biomarkers to diagnose and manage cardiac amyloidosis.

Amyloidoses are characterized by the tissue accumulation of misfolded proteins into insoluble fibrils. The two most common types of systemic amyloidosis result from the deposition of immunoglobulin light chains (AL) and wild-type or variant transthyretin (ATTRwt/ATTRv). Cardiac involvement is the main determinant of outcome in both AL and ATTR, and cardiac amyloidosis (CA) is increasingly recognized as a cause of heart failure. In CA, circulating biomarkers are important diagnostic tools, allow to refine risk stratification at baseline and during follow-up, help to tailor the therapeutic strategy and monitor the response to treatment. Among amyloid precursors, free light chains are established biomarkers in AL amyloidosis, while the plasma transthyretin assay is currently being investigated as a tool for supporting the diagnosis of ATTRv amyloidosis, predicting outcome and monitor response to novel tetramer stabilizers or small interfering RNA drugs in ATTR CA. Natriuretic peptides (NPs) and troponins are consistently elevated in patients with AL and ATTR CA. Plasma NPs, troponins and free light chains hold prognostic significance in AL amyloidosis, and are evaluated for therapy decision-making and follow-up, while the value of NPs and troponins in ATTR is less well established. Biomarkers can be usefully integrated with clinical and imaging variables at all levels of the clinical algorithm of systemic amyloidosis, from screening to diagnosis and prognosis, and treatment tailoring.

Prognostic value of cardiopulmonary exercise testing in cardiac amyloidosis.

AIMS: In amyloid patients, cardiac involvement dramatically worsens functional capacity and prognosis. We sought to study how the cardiopulmonary exercise test (CPET) could help in functional assessment and risk stratification of patients with cardiac amyloidosis (CA). METHODS AND RESULTS: We carried out a multicentre study including patients with light chain (AL) or transthyretin (TTR) CA. All patients underwent exhaustive examination including CPET and follow-up. The primary prognostic endpoint was the occurrence of death or heart failure hospitalization. Overall, 150 patients were included (91 AL and 59 TTR CA). Median age, systolic blood pressure, N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin T were 70 (64-78) years, 121 [interquartile range (IQR) 109-139] mmHg, 2806 (IQR 1218-4638) ng/L and 64 (IQR 33-120) ng/L, respectively. New York Heart Association classes were I-II in 64%. Median peak oxygen consumption (VO2 ) and circulatory power were low at 13.0 (10.0-16.9) mL/kg/min and 1730 (1318-2614) mmHg/mL/min, respectively. The minute ventilation/carbon dioxide production slope was increased to 37 (IQR 33-45). A total of 77 patients (51%) had chronotropic insufficiency. After a median follow-up of 20 months, there were 37 deaths and 44 heart failure hospitalizations. At multivariate Cox analysis, peak VO2 ≤13 mL/kg/min [hazard ratio (HR) 2.7, 95% confidence interval (CI) 1.6-4.8], circulatory power ≤1730 mmHg/mL/min (HR 2.4, 95% CI 1.2-4.6) and NT-proBNP ≥1800 ng/L (HR 2.2, 95% CI 1.1-4.3) were found to be associated with the primary outcome. No events occurred in patients with both peak VO2 >13 mL/kg/min and NT-proBNP <1800 ng/L, while the association of VO2 ≤13 mL/kg/min with NT-proBNP ≥1800 ng/L identified a very high-risk subgroup. CONCLUSION: In CA, CPET is helpful in assessing functional capacity, circulatory and chronotropic responses as well as the prognosis of patients along with cardiac biomarkers.