Cardiovascular Toxicity of Immune Checkpoint Inhibitors: Clinical Risk Factors.

PURPOSE OF REVIEW: Immune checkpoint inhibitors, such as monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1, have improved the outcome of many malignancies, but serious immune-related cardiovascular adverse events have been observed. Patients' risk factors for these toxicities are currently being investigated. RECENT FINDINGS: Interfering with the CTLA-4 and PD-1 axes can bring to several immune-related adverse events, including cardiotoxic events such as autoimmune myocarditis, pericarditis, and vasculitis, suggesting that these molecules play an important role in preventing autoimmunity. Risk factors (such as pre-existing cardiovascular conditions, previous and concomitant cardiotoxic treatments, underlying autoimmune diseases, tumor-related factors, simultaneous immune-related toxic effects, and genetic factors) should be always recognized for the correct management of these toxicities.

Validation of "(fr)AGILE": a quick tool to identify multidimensional frailty in the elderly.

BACKGROUND: Several tools have been proposed and validated to operationally define frailty. Recently, the Italian Frailty index (IFi), an Italian modified version of Frailty index, has been validated but its use in clinical practice is limited by long time of administration. Therefore, the aim of this study was to create and validate a quick version of the IFi (AGILE). METHODS: Validation study was performed by administering IFi and AGILE, after a Comprehensive Geriatric Assessment (CGA) in 401 subjects aged 65 or over (77 ± 7 years). AGILE was a 10-items tool created starting from the more predictive items of the four domains of frailty investigated by IFi (mental, physical, socioeconomic and nutritional). AGILE scores were stratified in light, moderate and severe frailty. At 24 months of follow-up, death, disability (taking into account an increase in ADL lost ≥1 from the baseline) and hospitalization were considered. Area under curve (AUC) was evaluated for both IFi and AGILE. RESULTS: Administration time was 9.5 ± 3.8 min for IFi administered after a CGA, and 2.4 ± 1.2 min for AGILE, regardless of CGA (p < 0.001). With increasing degree of frailty, prevalence of mortality increased progressively from 6.5 to 41.8% and from 9.0 to 33.3%, disability from 16.1 to 64.2% and from 22.1 to 59.8% and hospitalization from 17.2 to 58.7% and from 27.0 to 52.2% with AGILE and IFi, respectively (p = NS). Relative Risk for each unit of increase in AGILE was 56, 44 and 24% for mortality, disability and hospitalization, respectively and was lower for IFi (8, 7 and 4% for mortality, disability and hospitalization, respectively). The AUC was higher in AGILE vs. IFi for mortality (0.729 vs. 0.698), disability (0.715 vs. 0.682) and hospitalization (0.645 vs. 0.630). CONCLUSIONS: Our study shows that AGILE is a rapid and effective tool for screening multidimensional frailty, able to predict mortality, disability and hospitalization, especially useful in care settings that require reliable assessment instruments with short administration time.

Type 2 myocardial infarction: is it a geriatric syndrome?

Type 2 myocardial infarctions (T2-MI) is a type of necrosis that results from reduced oxygen supply and/or increased demand secondary to other causes unrelated to acute coronary atherothrombosis. The development and implementation of sensitive and high-sensitivity cardiac necrosis marker and the age-related increase of comorbidity lead to a boost of the frequency of T2-MI. T2-MI is often a complication of a high degree of clinical frailty in older adults, emerging as a "geriatric syndrome". Age-related non-cardiovascular causes may be the triggering factors and are strongly associated with the diagnosis, treatment, and prognosis of T2-MI. To date, there are no guidelines on management of this pathology in advancing age. Patient-centered approach and comprehensive geriatric assessment play a key role in the diagnosis, therapy and prognosis of geriatric patients with T2-MI.

Pulmonary Hypertension Phenotypes in Systemic Sclerosis: The Right Diagnosis for the Right Treatment.

Systemic sclerosis is an auto-immune disease characterized by skin involvement that often affects multiple organ systems. Pulmonary hypertension is a common finding that can significantly impact prognosis. Molecular pathophysiological mechanisms underlying pulmonary hypertension in systemic sclerosis can be extremely heterogeneous, leading to distinct clinical phenotypes. In addition, different causes of pulmonary hypertension may overlap within the same patient. Since pulmonary hypertension treatment is very different for each phenotype, it is fundamental to perform an adequate diagnostic work-up to properly and promptly identify the prevalent mechanism underlying pulmonary hypertension in order to start the right therapies. When pulmonary hypertension is caused by a primary vasculopathy of the small pulmonary arteries, treatment with pulmonary vasodilators, often in an initial double-combination regimen, is indicated, aimed at reducing the mortality risk profile. In this review, we describe the different clinical phenotypes of pulmonary hypertension in the scleroderma population and discuss the utility of clinical tools to identify the presence of pulmonary vascular disease. Furthermore, we focus on systemic sclerosis-associated pulmonary arterial hypertension, highlighting the advances in the knowledge of right ventricular dysfunction in this setting and the latest updates in terms of treatment with pulmonary vasodilator drugs.

Efficacy of a nutraceutical combination on lipid metabolism in patients with metabolic syndrome: a multicenter, double blind, randomized, placebo controlled trial.

BACKGROUND: Nutraceuticals represent a new therapeutic frontier in the treatment of metabolic syndrom (MetS) and related cardiovascular risk factors. The aim of this study was to evaluate the potential beneficial effects of Armolipid Plus (AP) (berberine 500 mg, red yest rice, monacolin K 3 mg and policosanol 10 mg) on insulin resistance, lipid profile, particularly on small and dense LDL cholesterol (sdLDL-C), representing the most atherogenic components, as well as its effects on high sensitivity C-reactive protein, a notable marker of cardiovascular risk, blood pressure and cardiac remodeling in subjects affected by MetS, with left ventricular hypertrophy. METHODS: The study was a prospective, multi-center, randomized, double blind, placebo-controlled trial. One hundred and fifty eight patients, aged between 28 and 76 years old, were enrolled and randomized to receive either one tablet of AP or placebo (PL) once daily for 24 weeks. Anthropometric and vital parameters, total cholesterol (tot-C), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceridemia (TG), non-HDL cholesterol (NHDL-C) and sdLDL-C were evaluated. RESULTS: After 24 weeks of treatment, the analysis performed on 141 subjects (71 in AP arm and 70 in PL arm), showed a significant improvement of lipid profile in the AP group, with reduction in tot-C (- 13.2 mg/dl), LDL-C (- 13.9 mg/dl) and NHDL-C (- 15.3 mg/dl) and increase in HDL-C (+ 2.0 mg/dl). These changes were equally significant compared with placebo (tot-C: AP - 13.2 mg/dL vs PL + 2.7 mg/dL, p < 0.01; LDL-C: AP -13.9 mg/dl vs PL + 1.5 mg/dl, p < 0.01; NHDL-C: AP -15.3 mg/dl vs PL + 2.8 mg/dl, p < 0.01), Although no significant difference was observed between the two arms in the reduction of HDL-C nevertheless it increased significantly in the AP group (AP + 2 mg/dL p < 0.05, PL 0.13 mg/dL). CONCLUSION: The results of this study, applicable to a specific local population show that, in a population of subjects affected by MetS, treatment with AP improves the lipid profile and the most atherogenic factors, thus suggesting a reduction in the risk of development and progression of atherosclerosis, particularly in subjects with high atherogenic risk, due to the presence of sdLDL-C.

Permanent atrial fibrillation and pulmonary embolism in elderly patients without deep vein thrombosis: is there a relationship?

BACKGROUND AND AIM: Permanent Atrial Fibrillation (pAF) is associated with increased risk of embolic complications. The relationship between pAF and pulmonary embolism (PE) has not been extensively investigated in elderly patients. Here, we aim at verifying whether pAF is associated to an increased risk of PE in a cohort of elderly patients with and without Deep Vein Thrombosis (DVT). METHODS: 235 patients older than 65 years with PE with or without pAF were retrospectively enrolled and stratified by the absence or presence of DVT. The diagnosis of PE was performed by computed tomography angiography (CTA). Right echocardiographic parameters were monitored. The severity of PE was evaluated by CTA quantization (PE score = 1, involvement of main branches of pulmonary artery) and by dimer-D (> 3000 µg/L). RESULTS: DVT was identified only in 51 cases of PE (21.7%). pAF prevalence was higher in PE without than in those with DVT (64.9% vs. 35.1%, p < 0.01). PE severity was more evident in pAF patients without than in those with DVT. Multivariate analysis of the role of pAF on PE severity confirms these results (RR = 3.41 for PE score = 1, and 8.55 for dimer-D > 3000 µg/L). CONCLUSIONS: We conclude that in elderly patients with PE, the prevalence of pFA was doubled, in the absence of DVT, and it is associated with a more severe PE in the absence than in the presence of DVT. Thus, in the absence of DVT, pFA should be considered as cause of PE.

Inflammatory, Serological and Vascular Determinants of Cardiovascular Disease in Systemic Lupus Erythematosus Patients.

BACKGROUND AND AIM: Systemic lupus erythematosus (SLE) is associated with increased risk of cardiovascular disease (CVD). Among many mechanisms, accelerated atherosclerosis, endothelial dysfunction, and hypercoagulability play a main role. Here, we investigate whether inflammatory, serological and clinical markers of SLE determine and correlate with arterial stiffness in SLE patients. MATERIALS AND METHODS: Routine blood samples, inflammatory mediators, specific antibodies, and 24 h proteinuria were measured in 43 SLE patients and 43 age and sex-matched controls using routine laboratory assays. We also assessed arterial stiffness by measuring radial artery applanation tonometry-derived augmentation index (AI), normalized AI (AIx@75), aortic pulse pressure, central systolic, diastolic and peripheral blood pressure. RESULTS: SLE patients showed a significantly greater arterial stiffness vs. controls, as demonstrated by the significantly higher AIx@75 and aortic pulse pressure. Interestingly, regression analysis showed that age, systolic pulse pressure, inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), daily dose of glucocorticoids, and cumulative organ damage positively correlated with arterial stiffness. CONCLUSIONS: SLE patients show increased arterial stiffness which correlates with markers of inflammation, that is involved in early alterations in arterial walls. Applanation tonometry can be used to screen SLE patients for subclinical vascular damage to implement prevention strategies for CVD.

The reverse metabolic syndrome in the elderly: Is it a "catabolic" syndrome?

Traditional risk factors of cardiovascular death in the general population, including body mass index (BMI), serum cholesterol, and blood pressure are also found to relate to outcomes in the geriatric population, but in a differing direction. A higher body mass index, hypercholesterolemia and hypertension are not harmful but even permit better survival at advancing age. This phenomenon is called "reverse epidemiology" or "risk factor paradox" and is also detected in a variety of chronic disease states such as chronic heart failure. Accordingly, a low BMI, blood pressure and cholesterol values are associated with a worse prognosis. Several possible causes are hypothesized to explain this elderly paradox, but this phenomenon remains controversial and its underlying reasons are poorly understood. The aim of this review is to recognize the factors behind this intriguing phenomenon and analyse the consequences that it can bring in the management of the cardiovascular therapy in elderly patient. Finally, a new phenotype identified as "catabolic syndrome" has been postulated.

Acute care hospital at different levels of intensity: the role of Geriatrician.

The traditional model of care is based on "disease-centered" management that requires the organization of the hospital in specialized wards, to which the patient is assigned for the main disease. The growing need to optimize economical and human resources and to promote a global approach to the patient has led to the setting up of the intensity of care model. It is a health system based on a "patient-centered" approach, where the hospital is organized in departments dedicated to patients with homogenous needs of care. In Italy, intensity of care model is currently being tested in the hospital organization, where three levels of intensity are proposed: low, medium and high. The purpose of the following review is to describe the role and importance of the Geriatrician in each of these care settings and to highlight the contradiction of a National Health System which promotes the geriatric approach to all types of patients, but does not invest in the formation and integration of the figure of the Geriatrician in clinical practice, condemning it to marginalization or even extinction.

Syncope and Epilepsy coexist in 'possible' and 'drug-resistant' epilepsy (Overlap between Epilepsy and Syncope Study - OESYS).

BACKGROUND: Differential diagnosis between syncope and epilepsy in patients with transient loss of consciousness of uncertain etiology is still unclear. Thus, the aim of the present work is to evaluate the prevalence of syncope in patients with "possible" or "drug-resistant" epilepsy. METHODS: The Overlap between Epilepsy and SYncope Study (OESYS) is a multicenter prospective observational study designed to estimate the prevalence of syncope in patients followed in Epilepsy Centers for "possible" or "drug-resistant" epilepsy and assessed according the European Society of Cardiology (ESC) guidelines of syncope diagnosis. RESULTS: One hundred seven patients were evaluated; 63 (58.9%) had possible and 44 (41.1%) drug-resistant epilepsy. A final diagnosis of isolated syncope was in 45 patients (42.1%), all with possible epilepsy (45/63, 71.4%). Isolated epilepsy was found in 21 patients (19.6%) and it was more frequent in the drug-resistant than in the possible epilepsy group (34.1% vs. 9.5%, p = 0.002). More importantly, syncope and epilepsy coexisted in 37.4% of all patients but the coexistence was more frequent among patients with drug-resistant than possible epilepsy (65.9% vs. 17.5%, p < 0.001). CONCLUSIONS: Isolated syncope was diagnosed in ≈ 70% of patients with possible epilepsy. Syncope and epilepsy coexisted in ≈ 20% of patients with possible and in ≈ 60% of patients with drug-resistant epilepsy. These findings highlight the need of ESC guidelines of syncope approach in patients with possible and drug-resistant epilepsy.

Chronic obstructive pulmonary disease and long-term mortality in elderly subjects with chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) and chronic obstructive pulmonary disease (COPD) are associated with high rates of mortality in elderly subjects. Concurrent CHF and COPD frequently occur, especially in with advancing age. This study examines long-term mortality in community-dwelling elderly subjects affected by CHF alone, COPD alone, and coexistent CHF and COPD. METHODS: The study evaluated 12-years mortality in 1288 subjects stratified for the presence or absence of CHF or COPD alone, and for coexistence of CHF and COPD. RESULTS: Mortality, at 12 year follow-up, was 46.7% overall, 68.6% in the presence of CHF alone (p < 0.001), 56.9% in the presence of COPD alone (p < 0.01); mortality was 86.2% where CHF and COPD coexisted (p < 0.001) and was significantly higher than in CHF or COPD alone (p < 0.05). Multivariate analysis indicates that CHF (Hazard risk = 1.67, 95% confidence interval 1.15-3.27, p < 0.031) and COPD (Hazard risk = 1.27, 95% confidence interval = 1.08-1.85, p < 0.042) were predictive of long-term mortality. When CHF and COPD simultaneously occurred, the risk dramatically increased up to 3.73 (95% confidence interval = 1.19-6.93, p < 0.001). CONCLUSIONS: Long-term follow-up showed higher mortality among elderly subjects affected by CHF or COPD. Simultaneous presence of CHF and COPD significantly increased the risk of death. Therefore, the presence of COPD in CHF patients should be considered a relevant factor in predicting high risk of mortality.

The Italian version of the "frailty index" based on deficits in health: a validation study.

BACKGROUND AND AIM: Several measurements were taken for frailty classification in geriatric population. "Frailty index" is based on "deficits in health," but it is still not available in Italian version. Thus, the aim of the present work was to validate a version of "frailty index" for the Italian geriatric community. METHODS: The validation of Italian frailty index (IFi) is based on a cohort study that enrolled 1077 non-disabled outpatients aged 65 years or older (81.3 ± 6.5 years) in Naples (Italy). IFi has been expressed as a ratio of deficits present/deficits considered after a comprehensive geriatric assessment. IFi was stratified in light, moderate and severe frailty. Mortality, disability (considering an increase in ADL lost ≥1 from the baseline) and hospitalization were considered at 3, 6, 12, 18 and 24 months of follow-up. Area under curve (AUC) was evaluated for both Fried's and IFi frailty index. RESULT: At the end of follow-up, mortality increased from 1.0 to 30.3%, disability from 40.9 to 92.3% and hospitalization from 0.0 to 59.0% (p < 0.001 for trend). Multivariate analysis shows that the relative risk for unit increase in IFi is 1.09 (95% CI = 1.01-1.17, p = 0.013) for mortality, 1.04 (95% CI = 1.01-1.06, p = 0.024) for disability and 1.03 (95% CI = 1.01-1.07, p = 0.041) for hospitalization. AUC is higher in IFi with respect to Fried's frailty index when considering mortality (0.809 vs. 0.658, respectively), disability (0.800 vs. 0.729, respectively) and hospitalization (0.707 vs. 0.646, respectively). CONCLUSIONS: IFi is a valid measure of frailty after the comprehensive geriatric assessment in an Italian cohort of non-institutionalized patients.

Long-term prognostic value of stress myocardial perfusion imaging and coronary computed tomography angiography: A meta-analysis.

BACKGROUND: We conducted a meta-analysis to compare the long-term prognostic value of stress single-photon emission computed tomography myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for adverse cardiovascular events in subjects with suspected or known coronary artery disease. METHODS AND RESULTS: We searched PubMed, Cochrane, Web of Science, and Scopus database between January 2000 and December 2014 for stress MPI and CCTA studies that followed up ≥ 100 subjects for ≥ 2.5 years and provided the unadjusted and/or adjusted hazard ratio (HR) at Cox regression analysis. Summary risk estimates for abnormal perfusion at MPI or ≥ 50% coronary stenosis at CCTA were derived in random effect regression analysis, and causes of heterogeneity were determined in meta-regression analysis. We identified 21 eligible articles (10 MPI and 11 CCTA) including 25,258 participants (13,484 in MPI and 11,774 in CCTA studies) with suspected or known coronary artery disease. Among the included publications, 8 MPI and 8 CCTA studies reported the HR for the occurrence of hard events (death and nonfatal myocardial infarction). The pooled HR was comparable for MPI and CCTA studies. The HR for the occurrence of a combined endpoint including revascularization as event was reported in 4 MPI and 6 CCTA studies. The pooled HR was higher for CCTA compared to MPI (P < .05) also when only MPI and CCTA studies with limited representation of prior CAD were considered. CONCLUSIONS: The long-term prognostic value of MPI and CCTA for the occurrence of hard events is similar. However, the association between event-free survival and CCTA is higher than MPI when coronary revascularization is included in the endpoint.

Prognostic role of lactate on mortality in younger and older patients with cardio-respiratory failure admitted to an acute intensive care unit.

BACKGROUND AND AIM: Acidosis is able to induce negative changes of different organs that increase progressively with aging. At present it is not known whether the levels of lactate may differently influence the prognosis of younger and older patients. Thus, the aim of this study is to evaluate the prognostic value of lactate levels after admission of younger and older patients to an acute intensive care unit. METHODS: Younger (<65 years, n = 118) and older (≥65 years, n = 165) patients admitted to an acute intensive care unit were prospectively enrolled and classified according to diagnosis of acute heart or/and respiratory failure. For each patient, APACHE II score, time of hospitalization and mortality, blood levels of lactate were collected. RESULTS: Both in-hospital mortality and lactate >2.5 mmol/L at the admission was higher in the older than in the younger patients (42.4 vs. 20.3 %, p < 0.01 and 57.8 vs. 31.9 %, p < 0.01, respectively). Lactate level was higher in older than in the younger patients both at admission and after 24 h (3.9 ± 3.4 vs. 2.4 ± 2.2 mmol/L and 2.4 ± 2.0 vs. 1.4 ± 1.3 mmol, p < 0.01, respectively). Accordingly, multivariate analysis shows that lactate was predictive of mortality in younger (OR = 2.65, 95 % CI 1.62-5.24, p = 0.03) and even more in the older (OR = 4.74, 95 % CI 2.10-6.70, p < 0.01) patients. CONCLUSIONS: Lactate concentration increase is associated with increased mortality in younger patients but, even more so, in older patients admitted to an acute intensive care unit. These results confirm the experimental evidence showing acidosis has a greater effect of leading to organ failure and higher mortality with increasing age.

Long-term mortality in frail elderly subjects with osteoarthritis.

OBJECTIVE: Elderly subjects are characterized by a high prevalence of OA and clinical frailty. This study aimed to examine the predictive role of clinical frailty on long-term mortality in elderly subjects with and without OA. METHODS: Mortality was evaluated after a 12-year follow-up in 698 subjects with and 590 subjects without OA recruited in 1992. Clinical frailty was assessed according to the Frailty Staging System and stratified in tertiles. RESULTS: After a 12-year follow-up, mortality was 42.2% in subjects without and 55.8% in subjects with OA (P = 0.256). With increasing frailty, mortality increased by 30.5% (P for trend < 0.001) in subjects without and by 45.6% in subjects with OA (P for trend < 0.001). Multivariate analysis showed that frailty [hazard ratio (HR) = 1.49 for each unit of increase, 95% CI 1.32, 1.94, P < 0.001) but not OA (HR = 1.28, 95% CI 0.987, 1.39, P = 0.412) was predictive of long-term mortality. Moreover, when Cox regression analysis was performed, frailty enhanced the risk of long-term mortality for each unit of increase by 32% (HR = 1.32, 95% CI 1.06, 1.65, P = 0.03) in the absence of OA and by 98% in the presence (HR = 1.98, 95% CI 1.63, 2.95, P < 0.01) of OA. CONCLUSION: Clinical frailty significantly predicts mortality in subjects without OA and even more in those with OA. Thus clinical frailty may be considered a new prognostic factor to identify subjects with OA at high risk of mortality.

Arterial wave reflections and ventricular-vascular interaction in patients with left ventricular systolic dysfunction.

Central aortic pressure waveform (AoPW) is the summation of a forward-traveling wave generated by the left ventricle and a backward-traveling wave caused by the reflection of the forward wave. The aim of this study was to evaluate the effect of ventricular-vascular coupling on the morphology of AoPW in chronic heart failure patients with different degrees of left ventricular systolic dysfunction (LVSD) using pulse wave analysis (PWA). PWA of AoPW and left ventricular (LV) function were evaluated by applanation tonometry in 26 control subjects, in 12 patients with left ventricular ejection fraction (LVEF) ≤ 30%, and in 14 patients with LVEF > 30%. Augmentation pressure, augmentation index, wasted energy, and ejection duration were lower in patients with LVEF ≤ 30% than in those with LVEF > 30% and in control subjects. Furthermore, augmentation index showed an inverse correlation with Doppler mitral E-wave amplitude (r = -0.40; P = 0.04) and E/A ratio (r = -0.42; P = 0.03) and a direct correlation with deceleration time of mitral E-waves (r = 0.39; P = 0.04). In patients with severe LVSD (LVEF ≤ 30%), aortic wave reflections negatively interfere with LV function and induce a shortening of ejection duration. In contrast, AoPW is similar in patients with moderate LVSD (LVEF > 30%) and in control subjects.

Effect of Sacubitril-Valsartan in reducing depression in patients with advanced heart failure.

BACKGROUND: Depression is highly prevalent in Heart Failure (HF). Treatment with sacubitril/valsartan improved quality of life and survival in HF patients. Aim of the study was to investigate prospectively the effect of sacubitril/valsartan on depression in advanced HF patients in waiting list for heart transplant (HT). METHODS: 37 consecutive patients with advanced HF in waiting list for HT were treated with sacubitril/valsartan. We analyzed data derived from the assessment performed the year before the beginning of sacubitril/valsartan, at study entry, and at one year of follow-up. Depression was assessed with Beck Depression Inventory II (BDI) scale. Cognitive function were assessed with Mini-Mental State Examination (MMSE). Functioning was evaluated measuring meters at 6 Minute Walking Test (6MWT) and maximum rate of oxygen consumption (VO2 max). RESULTS: At baseline, 64.9% of HF patients were in NYHA III and 35.1% NYHA IIIB, BDI was 15.2 ± 5.2 with 59.5% of patients with a score > 13. MMSE was 27.8 ± 2.6. After one year of follow-up NYHA class improved significantly, with 56.8% in NYHA II, 40.5% in NYHA III and 2.7% NYHA in IIIB (p < 0.001). VO2 max and 6MWT increased. Notably, BDI was 9.5 ± 3.9 with 21.6% of patients with a score > 13. MMSE remain stable (28.2 ± 2.1) (p = 0.104). No statistical differences are observed between data collected in the evaluation 1-year before and soon before treatment with sacubitril/valsartan. Multivariate regression analysis demonstrate a relationship between reduction in BDI-II score and improvement in six-minute walking test independently by the effect of sex, age, selective serotonin reuptake inhibitors, VO2 max, NT-proBNP, PAPs, NYHA class differences evaluated at follow-up versus baseline. CONCLUSIONS: Our study showed a reduction in depressive symptomatology in heart transplant waiting list patients treated with sacubitril/valsartan. The improvement in depressive symptomatology was paralleled by 6MWT increase in the follow-up.

Bmi1 inhibitor PTC-209 promotes Chemically-induced Direct Cardiac Reprogramming of cardiac fibroblasts into cardiomyocytes.

The development of therapeutic approaches based on direct cardiac reprogramming of fibroblasts into induced-cardiomyocytes (iCM) has emerged as an attractive strategy to repair the injured myocardium. The identification of the mechanisms driving lineage conversion represents a crucial step toward the development of new and more efficient regenerative strategies. To this aim, here we show that pre-treatment with the Bmi1 inhibitor PTC-209 is sufficient to increase the efficiency of Chemical-induced Direct Cardiac Reprogramming both in mouse embryonic fibroblasts and adult cardiac fibroblasts. PTC-209 induces an overall increase of spontaneously beating iCM at end-stage of reprogramming, expressing high levels of late cardiac markers Troponin T and myosin muscle light chain-2v. The inhibition of Bmi1 expression occurring upon PTC-209 pre-treatment was maintained throughout the reprogramming protocol, contributing to a significant gene expression de-regulation. RNA profiling revealed that, upon Bmi1 inhibition a significant down-regulation of genes associated with immune and inflammatory signalling pathways occurred, with repression of different genes involved in interleukin, cytokine and chemokine pathways. Accordingly, we observed the down-regulation of both JAK/STAT3 and MAPK/ERK1-2 pathway activation, highlighting the crucial role of these pathways as a barrier for cardiac reprogramming. These findings have significant implications for the development of new cardiac regenerative therapies.