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Aims The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF). Methods and results We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow‐up visit after 2 years of follow‐up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO2 max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m2, and N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow‐up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO2 max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E′, VE/VCO2 slope, and NT‐pro‐BNP decreased. At right heart catheterization performed after 1 year of follow‐up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow‐up (P < 0.001), with a reduction in all PF domains. Conclusions Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together with an NT‐pro‐BNP reduction constant over the follow‐up.

Anthracyclines are widely used in anticancer protocols, but can induce cardiotoxicity by mechanisms that mainly involve oxidative damage and mitochondrial dysfunction. Radiotherapy can also impair cardiac function by promoting myocardial fibrosis, microvascular damage and decreased density of myocardial capillaries. Hence, we aim at investigating prospectively whether radiotherapy impacts heart function in lymphoma patients who had been already treated with anthracyclines. Twenty-nine consecutive patients with Hodgkin or non-Hodgkin lymphomas underwent echocardiography at baseline (before antineoplastic treatments), and then every two months, until 6 months after treatments completion. Echo evaluation included standard 2D and Speckle Tracking. Twenty-two patients treated with anthracycline-based regimens were eligible. Out of the 22 patients, 8 received chemotherapy only (subgroup 1), while 14 underwent radiotherapy after chemotherapy (subgroup 2). At the end of chemotherapy, ejection fraction was significantly reduced in the whole population. At 6 months after completion of therapies, E/E' increased and Global Longitudinal Strain was compromised in subgroup 2, suggesting additional damage induced by radiotherapy after chemotherapy. On the basis of the data from our small prospective study we can hypothesize that in lymphoma patients anthracyclines can worsen cardiac function, and radiotherapy may have an additional unfavorable myocardial impact.

Despite recent advances in Pulmonary Arterial Hypertension (PAH) treatment, this condition is still characterized by an extremely poor prognosis. In this review, we discuss the use of newly-approved drugs for PAH treatment with already known mechanisms of action (macitentan), innovative targets (riociguat and selexipag), and novel therapeutic approaches with initial up-front combination therapy. Secondly, we describe new potential signaling pathways and investigational drugs with promising role in the treatment of PAH.

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. Summary: 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.

Aims The assessment of frailty in older adults with heart failure (HF) is still debated. Here, we compare the predictive role and the diagnostic accuracy of physical vs. multidimensional frailty assessment on mortality, disability, and hospitalization in older adults with and without HF. Methods and results A total of 1077 elderly (≥65 years) outpatients were evaluated with the physical (phy‐Fi) and multidimensional (m‐Fi) frailty scores and according to the presence or the absence of HF. Mortality, disability, and hospitalizations were assessed at baseline and after a 24 month follow‐up. Cox regression analysis demonstrated that, compared with phy‐Fi score, m‐Fi score was more predictive of mortality [hazard ratio (HR) = 1.05 vs. 0.66], disability (HR = 1.02 vs. 0.89), and hospitalization (HR = 1.03 vs. 0.96) in the absence and even more in the presence of HF (HR = 1.11 vs. 0.63, 1.06 vs. 0.98, and 1.14 vs. 1.03, respectively). The area under the curve indicated a better diagnostic accuracy with m‐Fi score than with phy‐Fi score for mortality, disability, and hospitalizations, both in absence (0.782 vs. 0.649, 0.763 vs. 0.695, and 0.732 vs. 0.666, respectively) and in presence of HF (0.824 vs. 0.625, 0.886 vs. 0.793, and 0.812 vs. 0.688, respectively). Conclusions The m‐Fi score is able to predict mortality, disability, and hospitalizations better than the phy‐Fi score, not only in absence but also in presence of HF. Our data also demonstrate that the m‐Fi score has better diagnostic accuracy than the phy‐Fi score. Thus, the use of the m‐FI score should be considered for the assessment of frailty in older HF adults.

Modifications of lean mass are a frequent critical determinant in the pathophysiology and progression of heart failure (HF). Sarcopenia may be considered one of the most important causes of low physical performance and reduced cardiorespiratory fitness in older patients with HF. Sarcopenia is frequently misdiagnosed as cachexia. However, muscle wasting in HF has different pathogenetic features in sarcopenic and cachectic conditions. HF may induce sarcopenia through common pathogenetic pathways such as hormonal changes, malnutrition, and physical inactivity; mechanisms that influence each other. In the opposite way, sarcopenia may favor HF development by different mechanisms, including pathological ergoreflex. Paradoxically, sarcopenia is not associated with a sarcopenic cardiac muscle, but the cardiac muscle shows a hypertrophy which seems to be “not-functional.” First-line agents for the treatment of HF, physical activity and nutritional interventions, may offer a therapeutic advantage in sarcopenic patients irrespective of HF. Thus, sarcopenia is highly prevalent in patients with HF, contributing to its poor prognosis, and both conditions could benefit from common treatment strategies based on pharmacological, physical activity, and nutritional approaches.

Aims The effects of GRK2 inhibition on myocardial metabolism in heart failure (HF) are unchartered. In this work, we evaluated the impact of pharmacological inhibition of GRK2 by a cyclic peptide, C7, on metabolic, biochemical, and functional phenotypes in experimental HF. Methods and results C7 was initially tested on adult mice ventricular myocyte from wild type and GRK2 myocardial deficient mice (GRK2‐cKO), to assess the selectivity on GRK2 inhibition. Then, chronic infusion of 2 mg/kg/day of C7 was performed in HF mice with cryogenic myocardial infarction. Cardiac function in vivo was assessed by echocardiography and cardiac catheterization. Histological, biochemical, and metabolic studies were performed on heart samples at time points. C7 induces a significant increase of contractility in wild type but not in adult ventricle myocytes from GRK2‐cKO mice, thus confirming C7 selectivity for GRK2. In HF mice, 4 weeks of treatment with C7 improved metabolic features, including mitochondrial organization and function, and restored the biochemical and contractile responses. Conclusions GRK2 is a critical molecule in the physiological regulation of cardiac metabolism. Its alterations in the failing heart can be pharmacologically targeted, leading to the correction of metabolic and functional abnormalities observed in HF.

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 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.

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.

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 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.

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 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.

In the last years, guidelines for the treatment of hypertension recommended individualized blood pressure goals for geriatric population because of elderly susceptibility to adverse outcomes and higher mortality rate deriving from the excessive blood pressure lowering, especially in "frail" elderly. Recent findings from the SPRINT study, which demonstrated that intensive blood pressure lowering was associated with lower rates of cardiovascular events and mortality in both hypertensive fit and frail elderly subjects compared to standard treatment, heavily influenced the recent US guidelines. In SPRINT sub-study analysis of adults aged ≥75 years, the most controversial issue appears the method of blood pressure measurement, the selection of patients and related-frailty degree that appears to be very light. Accordingly, it has been described that light frailty is related to good outcomes in older adults. SPRINT findings in "frail elderly patients" cannot be applied to the clinical practice because this condition has been clearly under-estimated. Thus, frailty status should be routinely and correctly quantified in order to identify the frailty degree and to find the best harms-benefits balance of antihypertensive drug treatment in frail older adults.

Aims SCN5A is a disease-causing gene associated with familial dilated cardiomyopathy (FDC). We examined the possible association between a common polymorphism in the SCN5A gene (c.1673A>G-p.H558R; rs1805124) and the risk of dilated cardiomyopathy (DCM) occurrence. Methods We genotyped 185 DCM cases (familial DCM, idiopathic DCM and postischemic DCM) and 251 controls for the p.H558R polymorphism in the SCN5A gene, to test the association of the molecular epidemiology of the individuals with the presence/absence of various types of DCM. Results Our results showed that the rs1805124 polymorphism was significantly associated with DCM, and the association was more significant in patients with FDC; furthermore, in these individuals, the less frequent GG genotype was associated with a 7.39-fold increased risk of disease [95% confidence interval (95% CI) = 2.88–18.96; P

Ilaria Liguori,1 Gennaro Russo,1 Luisa Aran,1 Giulia Bulli,1 Francesco Curcio,1 David Della-Morte,2,3 Gaetano Gargiulo,4 Gianluca Testa,1,5 Francesco Cacciatore,1,6 Domenico Bonaduce,1 Pasquale Abete1 1Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy; 2Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 3Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, Rome, Italy; 4Division of Internal Medicine, AOU San Giovanni di Dio e Ruggi di Aragona, Salerno, Italy; 5Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy; 6Azienda Ospedaliera dei Colli, Monaldi Hospital, Heart Transplantation Unit, Naples, Italy Abstract: Life expectancy is increasing worldwide, with a resultant increase in the elderly population. Aging is characterized by the progressive loss of skeletal muscle mass and strength – a phenomenon called sarcopenia. Sarcopenia has a complex multifactorial pathogenesis, which involves not only age-related changes in neuromuscular function, muscle protein turnover, and hormone levels and sensitivity, but also a chronic pro-inflammatory state, oxidative stress, and behavioral factors – in particular, nutritional status and degree of physical activity. According to the operational definition by the European Working Group on Sarcopenia in Older People (EWGSOP), the diagnosis of sarcopenia requires the presence of both low muscle mass and low muscle function, which can be defined by low muscle strength or low physical performance. Moreover, biomarkers of sarcopenia have been identified for its early detection and for a detailed identification of the main pathophysiological mechanisms involved in its development. Because sarcopenia is associated with important adverse health outcomes, such as frailty, hospitalization, and mortality, several therapeutic strategies have been identified that involve exercise training, nutritional supplementation, hormonal therapies, and novel strategies and are still under investigation. At the present time, only physical exercise has showed a positive effect in managing and preventing sarcopenia and its adverse health outcomes. Thus, further well-designed and well-conducted studies on sarcopenia are needed. Keywords: sarcopenia, elderly, assessment, therapy

Ilaria Liguori,1 Gennaro Russo,1 Francesco Curcio,1 Giulia Bulli,1 Luisa Aran,1 David Della-Morte,2,3 Gaetano Gargiulo,4 Gianluca Testa,1,5 Francesco Cacciatore,1,6 Domenico Bonaduce,1 Pasquale Abete1 1Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy; 2Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 3San Raffaele Roma Open University, Rome, Italy; 4Division of Internal Medicine, AOU San Giovanni di Dio e Ruggi di Aragona, Salerno, Italy; 5Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy; 6Azienda Ospedaliera dei Colli, Monaldi Hospital, Heart Transplantation Unit, Naples, Italy Abstract: Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest. Keywords: elderly, reactive oxygen species, reactive nitrogen species, antioxidants

Background Treatment with valsartan/sacubitril was found to be associated both with reduction in mortality risk for HF. Purpose To investigate the effect of sacubitril/valsartan on physical frailty (PF) in advanced HF patients in waiting list for heart transplantion (HT) in a two years follow-up study. Methods We enrolled 45 consecutive patients (status 2B UNOs). Patients tolerant to ACE-inhibitor and/or ARBs were treated with valsartan/sacubitril. Patients were required to have left ventricular ejection fraction (LVEF) of ≤35% and to be taking a stable dose of a β-blocker and an ACE inhibitor or an ARB for at least 4 weeks before enrollment. The dosage of sacubitril/valsartan was increased if tolerance was good. Frailty was assessed using an adapted version of Fried's Frailty Phenotype used in advanced HF patients in waiting list for transplantation. Patients were followed up until HT, device (TAH/LVAD) implant, or last follow-up visit. Results Mean NYHA class was 3.1±0.4, with 5.7% NYHA 2, 62.9% NYHA 3 and 31.4% NYHA 3B. LVEF was 25.1±6.4, VO2 max (ml/kg/min) was 10.3±2.3, cardiac index (L/min/m2) was 2.3±0.6, and NT-proBNP (pg/ml) was 4054.8±3977. At 3 months, 31.5% of patients received the target dose of 97/103 mg/BID, 31.6% the half dose (49/51mg BID) and 26.3% the low dose (24/26 mg BID) and 10.5% the half low dose (24/26 mg daily). The baseline mean value of physical frailty was 3.86±0.8, specifically 94.3% showed exhaustion, 91.4% physical inactivity, 88.6% weakness, 85.7% slowness and 28.6% loss of appetite. All patients had a frailty score ≥3. During follow-up there were no deaths. After treatment, NYHA class improved significantly (2.4±0.6 vs 3.1±0.4; p=0.002), with 5.7% NYHA 1, 48.6% NYHA 2, 42.9% NYHA 3 and 2.9% NYHA 3B (p Conclusions Our study shows an improvement in PH in patients with advanced HF in waiting list for HT after therapy with sacubitril/valsartan. These changes seem to appear very early after introduction of the treatment and to be maintained over time. The improvement in all physical domain was paralleled by VO2 max and 6-minute walking test increase. The pro-BNP-NT reduction was significant in the first month of treatment and remain quite stable in the follow-up.

Rationale: Dyspnea and exercise limitation are common symptoms in Systemic Sclerosis (SSc) patients. Multiorgan involvement and disease activity could lead patients to different clinical complications and affect prognosis. Aim of this study was to explore the role of cardiopulmonary exercise test (CPET) in the evaluation of exercise limitation and in the characterization of specific phenotypes of organ involvement in SSc patients. Methods: 24 consecutive patients (23 women, 51.3 ± 2.0 mean age) diagnosed with clinically stable SSc (EULAR 2013) underwent resting echocardiography and maximal symptom-limited incremental CPET. Patients were categorized into three groups: A (interstitial lung disease on CT scan), B (pulmonary vascular diesase), C (left ventricular dysfunction). Results were compared with those of 23 healthy controls and among SSc groups. Results: Compared to controls, SSc patients exhibited a significant reduction in functional capacity, ventilatory limitation and a higher estimated pulmonary pressure at echocardiography. Group A (3 patients) exhibited reduced ventilation, lower VO2max, higher PetCO2, and a worse oxygen uptake efficiency slope. Group B (6 patients) was charaterized by higher VE/VCO2 slope, reduced exercise capacity and a peculiar breathing pattern with the presence of exercise oscillatory ventilation. Group C (15 patients) showed lower ventilation, VO2max and VO2/work slope. Conclusion: CPET can unmask early exercise limitation and can be useful in the identification of different clinical phenotypes in SSc patients.

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.

Sympathetic nervous system hyperactivity has a well-recognized role in the pathophysiology of heart failure with reduced left ventricular ejection fraction. Alterations in sympathetic nervous system have been related to the pathophysiology of pulmonary arterial hypertension, but it is unclear whether cardiac sympathetic nervous system is impaired and how sympathetic dysfunction correlates with hemodynamics and clinical status in pulmonary arterial hypertension patients. The aim of this study was to evaluate the cardiac sympathetic nervous system activity by means of 123 Iodine-metaiodobenzylguanidine nuclear imaging in pulmonary arterial hypertension patients and to explore its possible correlation with markers of disease severity. Twelve consecutive pulmonary arterial hypertension patients (nine women, median age 56.5 (17.8), eight idiopathic and four connective tissue-associated pulmonary arterial hypertension) underwent cardiac 123 Iodine-metaiodobenzylguanidine scintigraphy. The results were compared with those of 12 subjects with a negative history of cardiovascular or pulmonary disease who underwent the same nuclear imaging test because of a suspected paraganglioma or pheochromocytoma, with a negative result (controls), and 12 patients with heart failure with reduced left ventricular ejection fraction. Hemodynamics, echocardiography, six-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro brain natriuretic peptide were collected in pulmonary arterial hypertension patients within one week from 123 Iodine-metaiodobenzylguanidine scintigraphy. Cardiac 123 Iodine-metaiodobenzylguanidine uptake, assessed as early and late heart-to-mediastinum ratio, was significantly lower in pulmonary arterial hypertension compared to controls (p = 0.001), but similar to heart failure with reduced left ventricular ejection fraction. Myocardial 123 Iodine-metaiodobenzylguanidine turnover, expressed as washout rate, was similar in pulmonary arterial hypertension and heart failure with reduced left ventricular ejection fraction and significantly higher compared to controls (p = 0.016). In the pulmonary arterial hypertension group, both early and late heart-to-mediastinum ratios and washout rate correlated with parameters of pulmonary arterial hypertension severity including pulmonary vascular resistance, right atrial pressure, tricuspid annular plane systolic excursion, N-terminal pro brain natriuretic peptide, and peak VO 2 . Although we evaluated a small number of subjects, our study showed a significant impairment in cardiac sympathetic nervous system in pulmonary arterial hypertension, similarly to that observed in heart failure with reduced left ventricular ejection fraction. This impairment correlated with indices of pulmonary arterial hypertension severity. Cardiac sympathetic dysfunction may be a contributing factor to the development of right-sided heart failure in pulmonary arterial hypertension.

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.

Increased left ventricular mass (LVM) is often present in metabolic syndrome (MS), also in the setting of well-controlled blood pressure (BP). Aim of the present study was to evaluate the efficacy of a nutraceutical combination of berberine, red yeast rice extract and policosanol (Armolipid Plus™, AP) in reducing LVM in patients with MS and left ventricular hypertrophy (LVH).In this multicenter, randomized, double-blind, placebo-controlled trial, 158 patients with MS (IDF criteria) and LVH (LVM48 g/mOne-hundred-and-forty-five patients (AP n = 74, placebo n = 71) completed the study. A significant percentage reduction in LVM was observed in AP group vs baseline (-2.7%, p 0.0001), and compared to placebo (-4.1%, p 0.0001), and remained significant after adjustment for age, sex, baseline systolic BP and BMI and their changes during the study period. The proportion of subjects showing LVM reduction was higher in AP group than in the placebo group (57% vs 28%, adjusted p = 0.007). Treatment with AP was associated with improvement of lipid profile.24-week of treatment with AP is associated with a significant reduction in LVM in subjects with MS and LVH, in addition to favourable effects on lipid profile, and could represent an effective strategy aiming at reducing the associated cardiovascular risk. The trial was registered at clinicaltrials.gov with ID NCT02295176.

Chronic heart failure (CHF) is frequently linked to clinical frailty, a complex geriatric condition associated with negative outcomes. However, the full characterization of frailty is still debated. Fried and colleagues focused on a ‘physical phenotype’ of frailty based on the assessment of unintentional weight loss, muscle weakness, slow walking speed, low physical activity, and exhaustion,1 while Rockwood and colleagues fostered a multidimensional concept involving, besides physical impairments, comorbidity, disability, mental, nutritional, and social components (known as the ‘Canadian frailty index’).

Aims Butyric acid (BUT), a short chain fatty acid produced daily by the gut microbiota, has proven beneficial in models of cardiovascular diseases. With advancements in cancer survival, an increasing number of patients are at risk of anticancer drug cardiotoxicity. Here we assess whether the novel BUT derivative phenylalanine-butyramide (FBA) protects from doxorubicin (DOXO) cardiotoxicity, by decreasing oxidative stress and improving mitochondrial function. Methods and results In C57BL6 mice, DOXO produced left ventricular dilatation assessed by echocardiography. FBA prevented left ventricular dilatation, fibrosis and cardiomyocyte apoptosis when co-administered with DOXO. DOXO increased atrial natriuretic peptide, brain natriuretic peptide, connective tissue growth factor, and matrix metalloproteinase-2 mRNAs, which were not elevated on co-treatment with FBA. DOXO, but not FBA + DOXO mice, also showed higher nitrotyrosine levels, and increased inducible nitric oxide synthase expression. Accordingly, DOXO hearts showed lower levels of intracellular catalase vs. sham, while pre-treatment with FBA prevented this decrease. We then assessed for reactive oxygen species (ROS) emission: DOXO induced increased activity of mitochondrial superoxide dismutase and higher production of H2 O2 , which were blunted by FBA pre-treatment. FBA also ameliorated mitochondrial state 3 and state 4 respiration rates that were compromised by DOXO. Furthermore, in DOXO animals, the mitochondrial degree of coupling was significantly increased vs. sham, while FBA was able to prevent such increase, contributing to limit ROS production, Finally, FBA reduced DOXO damage in human cellular models, and increased the tumour-killing action of DOXO. Conclusions Phenylalanine-butyramide protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by reduction in oxidative stress and amelioration of mitochondrial function.

This Registry demonstrated that PAD program is essential to increase the survivors, in particular in regions with densely populated area and with insufficient road network. In these areas it is essential to increase the number of AED installation and the Cardiopulmonary Resuscitation (CPR) training among the general population. Strong positive predictive factors of outcome were a short delay to defibrillation, bystander CPR and place of collapse.

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

Craniosynostosis syndromes are rare and prognosis would benefit from early diagnosis and treatment. We tried to establish a fast molecular diagnosis method to detect craniosynostosis syndromes.One patient aged 6 months was observed and diagnosed at first, and then another 10 patients were included in this study. All of them suffered from congenital hydrocephalus with normal head circumference. Karyotype analysis, chromosome genome microarray analysis and whole exome sequencing were used.The first patient was diagnosed as Apert Syndrome based on his clinical features and whole exome sequencing. The other 10 patients were also detected by the same protocol and one of them was found to be with Crouzon Syndrome. Both of the patients with craniosynostosis syndrome were treated in time and benefited from this new diagnosis protocol.Craniosynostosis syndromes cause hearing loss and deformity. It is worthy to detect mutations on FGFR1, FGFR2 and FGFR3 for children who suffer from congenital hydrocephalus with normal head circumference.

Elderly people are characterized by a high prevalence of falls and sarcopenia. However, the relationship among Tinetti mobility test (TMT) score, a powerful tool to detect elderly people at risk of falls, and sarcopenia is still not thoroughly investigated. Thus, to determine the relationship between TMT score and muscle mass and strength, 337 elderly participants (mean age 77.1 ± 6.9 years) admitted to comprehensive geriatric assessment were enrolled. TMT score, muscle mass by bioimpedentiometer, and muscle strength by grip strength were evaluated. Muscle mass progressively decreased as TMT score decreased (from 15.3 ± 3.7 to 8.8 ± 1.8 kg/m2; p for trend

Rationale: A reduction in heart rate recovery (HRR) has been considered a marker of parasympathetic dysfunction, and it has been shown to be predictive of mortality in different clinical settings. It is unclear whether HRR is impaired in patients with pulmonary arterial hypertension (PAH) and whether it correlates with exercise impairment. Aim of this study was to evaluate the parasympathetic nervous activity by means of HRR after cardiopulmonary exercise testing (CPET) in patients with PAH and to explore its possible correlation with parameters of exercise capacity. Methods: 24 consecutive patients with Group 1 PAH (24 women, mean age 51.0 ± 6.6 years, 15 with idiopathic PAH, 7 with connective tissue-associated PAH, 2 PAH due to congenital heart disease) underwent maximal symptom-limited incremental CPET. HRR was calculated as the difference in heart rate between maximum tolerated exercise and 1 minute later. The results were compared with those of 15 healthy controls, and 15 patients with heart failure due to reduced left ventricular ejection fraction (HFrEF). Results: HRR was significantly lower in PAH compared to controls (11.83 ± 8.0 versus 25.67 ± 13.1, p Conclusions: A significant impairment in parasympathetic nervous activity was observed in our cohort of PAH patients, similar to that of HFrEF, and it was correlated with indices of exercise performance. Parasympathetic function imbalance may be a contributing factor to the reduced exercise tolerance in PAH patients.

Objectives The objective of this study was to evaluate the effect on mortality of self-reported physical activity evaluated by the physical activity scale for the elderly (PASE) in elderly patients with advanced heart failure enrolled in a cardiac rehabilitation unit after heart failure decompensation (NYHA class IIIB). Methods The study prospectively enrolled 314 elderly patients (≥65 years) with heart failure in NYHA class IIIB (symptomatic with a recent history of dyspnoea at rest) consecutively admitted to cardiac rehabilitation between January 2010 and July 2011. Comprehensive geriatric assessment was performed. Physical activity was evaluated by PASE and stratified in tertiles (0–15, 16–75 and >75). Mortality was collected from September to October 2015 in 300 patients. Results The mean age was 74.5 ± 6.1 (range 65–89); 74.7% were men, 132 patients (44.0%) died during the follow-up (44.1 ± 20.7 months). Univariate analysis shows that physical activity level conducted before heart failure decompensation was inversely related to mortality (from 76.0% to 8.2%, P = 0.000). Multivariate analysis confirms that the PASE score predicts mortality independently of several demographic and clinical variables (hazard rate 0.987, 95% confidence interval (CI) 0.980–0.994, P = 0.000). Notably, when considering PASE 0–15 versus 16–75 score and PASE 0–15 versus > 75 score, the hazard rate is 4.06 (95% CI 1.67–9.84, P Conclusions Physical activity level evaluated by the PASE score is inversely related to mortality in elderly patients with advanced heart failure confirming the reduction of mortality exerted by moderate physical activity in such patients.

BACKGROUND: Orthostatic hypotension (OH) has high prevalence in frail older adults. However, its effect on mortality, disability, and hospitalization in frail older adults is poorly investigated. Thus, we assessed the relationship between the prevalence of OH and its effect on mortality, disability, and hospitalization in noninstitutionalized older adults stratified by frailty degree. METHODS: Prospective, observational study of 510 older participants (≥65 years of age) consecutively admitted to a geriatric evaluation unit to perform a geriatric comprehensive assessment. MEASUREMENTS: Clinical frailty was assessed using the Italian frailty index (40 items). Systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), and heart rate (bpm) were evaluated in clinostatic position and after 1, 3, and 5 minutes of orthostatic position. OH was defined with a decrease of 20 mm Hg in systolic blood pressure and/or a decrease of 10 mm Hg in diastolic blood pressure. RESULTS: OH prevalence was 22%, and it increased from 9.0% to 66.0% according to frailty degree (P for trend

BACKGROUND: Malnutrition indices and muscle mass and strength in the elderly are poorly investigated. Moreover, malnutrition seems to be 1 of the more important factors in the cause of sarcopenia. The presence of sarcopenia and its relationship with malnutrition indices were studied in noninstitutionalized elderly people who underwent Comprehensive Geriatric Assessment (CGA). METHODS: A total of 473 elderly subjects (mean age, 80.9 ± 6.6 years) admitted to CGA were studied. Malnutrition risk was evaluated with Mini Nutritional Assessment (MNA) score, whereas muscle mass and muscle strength were evaluated by bioimpedentiometry and hand grip, respectively. Sarcopenia was assessed as indicated in the European Working Group on Sarcopenia in Older People (EWGSOP) consensus. RESULTS: Overall prevalence of sarcopenia was 13.1%, and it increased from 6.1% to 31.4% as MNA decreased (P < .001). MNA score was lower in elderly subjects with sarcopenia (15.4 ± 4.2) than without sarcopenia (22.0 ± 4.0) (P = .024). Linear regression analysis showed that MNA score is linearly related both with muscle mass (r = 0.72; P < .001) and strength (r = 0.42; P < .001). Multivariate analysis, adjusted for several confounding variables including comorbidity and disability, confirmed these results. CONCLUSIONS: MNA score is low in noninstitutionalized elderly subjects with sarcopenia, and it is linearly related to muscle mass and muscle strength. These data indicate that MNA score, when evaluated with muscle mass and strength, may recognize elderly subjects with sarcopenia.