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Manlio Cipriani, Vincenzo De Simone, Luciana D'Angelo, Enrico Perna, Marzia Lilliu, Virginia Bovolo, Fabrizio Oliva, Maria Frigerio Cardiovascular and Thoracic Department, A De Gasperis Niguarda Ca' Granda Hospital, Milan, Italy Abstract: Heart transplantation represents the “gold standard” for the treatment of patients with end-stage heart failure, but remains challenged by inadequate donor supply, finite graft survival, and long-term complications arising from immunosuppressive therapy. In addition, a lot of patients waiting for a heart transplant experience clinical deterioration, and other patients become ineligible to undergo this treatment due to their age or relevant comorbidities. Left ventricular assist devices have emerged as a valid therapeutic option for advanced heart failure. In recent years, we have seen significant advances not only in the technologies available, but also in patient selection, indications for use, and management after implantation. Consequently, there has been an increase in the number of implants and an improvement in the survival rate and quality of life for these patients. At the same time, there are new challenges on the horizon. Patient selection is a difficult process, based on clinical and imaging parameters and risk scores, and more data are needed to refine patient selection criteria and the timing of the implant. Left ventricular assist device-related complications are still a serious problem, causing adverse events and hospital readmissions. Continuous progress in the development of these implantable devices, such as a further reduction in size and hopefully the abolition of the external driveline, will probably make ventricular assist devices an option also for less advanced stages of heart failure. Here, we discuss the current indications for left ventricular assist device implantation, patient selection criteria, and the most frequent complications associated with these devices. Keywords: mechanical circulatory support, heart failure, destination therapy, bridge to transplantation, heart transplant

Imtroduction: The high-risk population of patients with cardiovascular (CV) disease or risk factors (RF) suffering from COVID-19 is heterogeneous. Several predictors for impaired prognosis have been identified. However, with machine learning (ML) approaches, certain phenotypes may be confined to classify the affected population and to predict outcome. This study aimed to phenotype patients using unsupervised ML technique within the International Postgraduate Course Heart Failure Registry for patients hospitalized with COVID-19 and Cardiovascular disease and/or RF (PCHF-COVICAV)., Material and Methods: Patients from the eight centres with follow-up data available from the PCHF-COVICAV registry were included in this ML analysis (K-medoids algorithm)., Results: Out of 617 patients included into the prospective part of the registry, 458 [median age: 76 (IQR:65-84) years, 55% male] were analyzed and 46 baseline variables, including demographics, clinical status, comorbidities and biochemical characteristics were incorporated into the ML. Three clusters were extracted by this ML method. Cluster 1 (n = 181) represents mainly women with the least number of overall comorbidities and cardiovascular RF. Cluster 2 (n = 227) is characterized mainly by men with non-CV conditions and less severe symptoms of infection. Cluster 3 (n=50) mainly represents men with the highest prevalence of cardiac comorbidities and RF, more extensive inflammation and organ dysfunction with the highest 6-month all-cause mortality risk., Conclusions: The ML process has identified three important clinical clusters from hospitalized COVID-19 CV and/or RF patients. The cluster of males with severe CV disease, particularly HF, and multiple RF presenting with increased inflammation had a particularly poor outcome.

Aims: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations., Methods and Results: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001)., Conclusions: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: After the implantation of a left ventricular assist device (LVAD), many patients continue to experience exercise intolerance. VAFRACT trial evaluates the additional benefit of LVAD echo-guided optimization (EO) on functional capacity (FC), measured by cardiopulmonary exercise test (CPET), and quality of life (QoL)., Methods and Results: Twenty-seven patients were randomized in a 1:1 ratio to EO (EO group) vs. standard settings (CONTROL group) at least after 3 months from LVAD implant procedure. The optimal device speed was defined as the one that allows an intermittent aortic valve opening and a neutral position of the interventricular septum without increasing aortic or tricuspid regurgitation and preserving right ventricular function. The primary endpoint was peak oxygen uptake (VO 2 peak) change after 3 months. Echo-guided optimization significantly improves VO 2 peak (from 13.2 ± 2.5 to 14.2 ± 2.5 mL/kg/min; P < 0.001), oxygen pulse (from 9.75 ± 1.46 to 10.75 ± 2.2 mL; P < 0.001), CPET exercise time (from 490 ± 98 to 526 ± 116 s; P = 0.02), 6 min walk distance (from 363 ± 54 to 391 ± 52 m; P = 0.04), and QoL, using EuroQol Five Dimensions 3L (from 0.796 ± 0.1 to 0.85 ± 0.08; P < 0.001) and the Kansas City Cardiomyopathy Questionnaire (from 81.6 ± 6.9 to 84.6 ± 5.6; P = 0.025)., Conclusions: Echo-guided optimization can significantly influence the FC and the QoL of LVAD patients. This procedure should represent a fundamental step in their clinical management, through the establishment of consolidated follow-up protocols. Our study may represent a starting point for a future, adequately powered clinical trial with a longer term follow-up., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

: Improvement in hemodynamic parameters is routinely demonstrated in patients implanted with continuous-flow left ventricular assist devices (CF-LVADs). However, functional capacity assessed by cardiopulmonary exercise test (CPET), following LVAD implantation, remains considerably restricted. In this review, we analyzed the current knowledge on the causes of the persistent limitation in exercise capacity in CF-LVAD patients. Limitation to exercise is multifactorial and involves: LVAD factors (fixed CF-LVAD pump speed), native cardiac factors (residual function of native left ventricle, right ventricular dysfunction, aortic valve abnormalities), comorbidities (abnormal skeletal muscle metabolism, low skeletal muscle mass, anemia), patient's characteristics (age, physical deconditioning). In addition, we emphasize the role of some potential therapeutic strategies like the increase in CF-LVAD pump speed according to the patient's activity, the echo-optimization of the device (paying attention to right ventricular function and aortic valve opening), the implementation of physical rehabilitation and the treatment of potentially reversible extracardiac factors (anemia, muscle deconditioning, obesity).

Background: Previous reports have suggested that despite their dramatic presentation, patients with fulminant myocarditis (FM) might have better outcome than those with acute nonfulminant myocarditis (NFM). In this retrospective study, we report outcome and changes in left ventricular ejection fraction (LVEF) in a large cohort of patients with FM compared with patients with NFM., Methods: The study population consists of 187 consecutive patients admitted between May 2001 and November 2016 with a diagnosis of acute myocarditis (onset of symptoms <1 month) of whom 55 required inotropes and/or mechanical circulatory support (FM) and the remaining 132 were hemodynamically stable (NFM). We also performed a subanalysis in 130 adult patients with acute viral myocarditis and viral prodrome within 2 weeks from the onset, which includes 34 with FM and 96 with NFM. Patients with giant-cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis and those <15 years of age were excluded from the subanalysis., Results: In the whole population (n=187), the rate of in-hospital death or heart transplantation was 25.5% versus 0% in FM versus NFM, respectively ( P <0.0001). Long-term heart transplantation-free survival at 9 years was lower in FM than NFM (64.5% versus 100%, log-rank P <0.0001). Despite greater improvement in LVEF during hospitalization in FM versus NFM forms (median, 32% [interquartile range, 20%-40%] versus 3% [0%-10%], respectively; P <0.0001), the proportion of patients with LVEF <55% at last follow-up was higher in FM versus NFM (29% versus 9%; relative risk, 3.32; 95% confidence interval, 1.45-7.64, P =0.003). Similar results for survival and changes in LVEF in FM versus NFM were observed in the subgroup (n=130) with viral myocarditis. None of the patients with NFM and LVEF ≥55% at discharge had a significant decrease in LVEF at follow-up., Conclusions: Patients with FM have an increased mortality and need for heart transplantation compared with those with NFM. From a functional viewpoint, patients with FM have a more severely impaired LVEF at admission that, despite steep improvement during hospitalization, remains lower than that in patients with NFM at long-term follow-up. These findings also hold true when only the viral forms are considered and are different from previous studies showing better prognosis in FM., (© 2017 American Heart Association, Inc.)

Our recent ultrastructural study of human parotid glands revealed that the melatonin receptors, MT1 and MT2, are localised in the plasma cell membranes of acinar and ductal cells but also, and intriguingly, predominantly in acinar secretory granules, giving rise to the working hypothesis that secretory granules are a part of a transcytotic transport system for melatonin. To put this hypothesis to the test in rat parotid glands, anaesthetised animals were exposed to a high melatonin dose (3 mg/kg per hour), infused intravenously over two hours and aiming to stimulate a glandular melatonin-receptor-dependent intracellular transport system, if any. Thirty minutes later, the right parotids were removed. Pre-stimulation, left parotid gland tissue was removed to serve as (untreated) controls. Gland tissues were processed for the gold post-embedding technique and for western blot analysis. In untreated glands, on transmission electron microscope images, melatonin receptors displayed a distribution pattern similar to that in human parotids, i.e. here, too, the receptors were principally associated with the acinar secretory granules. In melatonin- treated glands, the number of granules associated with the MT1 receptor was twice that in untreated glands, despite the same total granule number in the two glands. Moreover, the density of gold particles showing MT1-receptor immunoreactivity associated with granules in melatonin-treated glands was 2.5 times that in untreated glands. The number of MT1 receptors associated with the granule membrane was about three times higher in melatonin-treated glands than in untreated glands, while the number of MT1 receptors inside the granules was about twice that in untreated glands. The immunoblotting of membrane-enriched samples showed that the MT1-receptor expression was about three times that of untreated glands. When it came to the MT2 receptor, no changes were observed. Melatonin itself thus exerts dynamic effects on its MT1 receptor, which may reflect an adaptive receptor-linked carrier system for melatonin, delivering - upon gland stimulation - melatonin to the saliva by exocytosis.

In vivo animal studies show that pentagastrin, cholecystokinin and melatonin cause the secretion and synthesis of salivary proteins. Melatonin occurs in large amounts in the gut and is released into the blood on food intake. In vitro experiments suggest that pentagastrin exerts secretory activity in human salivary glands, as judged by ultrastructural changes, reflecting secretion, and an actual protein output. Currently, it is hypothesised that melatonin induces secretory exocytotic events in the human parotid gland. Human parotid tissues were exposed to a high single concentration of melatonin in vitro, processed for high resolution scanning electron microscopy and then assessed morphometrically with the emphasis on the membrane of the intercellular canaliculi, a site of protein secretion. Compared with controls and in terms of density, the melatonin-exposed parotid tissues displayed increases in protrusions (signalling anchored granules) and microbuds (signalling membrane recycling and/or vesicle secretion) and decreases in microvilli (signalling cytoskeletal re-arrangement related to exocytosis), phenomena abolished or very largely reduced by the melatonin receptor blocker, luzindole. In conclusion, acinar serous cells of parotid tissue displayed in vitro exocytotic activity to melatonin, signalling protein secretion. Whether, under physiological conditions, melatonin influences the secretion of human parotid glands remains to be explored, however.

Several studies have evidenced high prevalence of myocardial systolic and diastolic dysfunction among patients with systemic sclerosis (SSc). Exercise echocardiography has shown a diagnostic and prognostic role in identifying early left ventricular (LV) dysfunction in several myocardial pathological settings. The aim of our study was to evaluate early signs of LV impairment under exercise and their correlation to patient's exercise tolerance. Forty-five patients (age 60.4 ± 10.3 years) with SSc and 20 age and sex comparable controls were enrolled in the study. All patients underwent clinical evaluation, 2D echocardiography associated with Tissue Doppler and speckle tracking to evaluate LV deformation indexes, and an exercise echocardiography to evaluate left ventricle contractile reserve (LVCR) and exercise pulmonary pressures. Finally, a 6-minute walking test (6MWT) to evaluate exercise tolerance was also performed. Compared to controls, SSc patients showed an impaired diastolic function (E/E' 10.9 ± 3.7 vs 8.36 ± 2.01; p < 0.01) associated with larger left atrial dimensions (LAVI 28.4 ± 8.7 vs 19.3 ± 4.6 mL/m(2); p < 0.01). During exercise echocardiography, a reduced global longitudinal strain at peak exercise (S-GLS) was highlighted compared to controls (15.7 ± 3.6 vs 18.2 ± 2.2; p = 0.001). A S-GLS cutoff <18%, identified by ROC analysis, identified SSc patients with a reduced diastolic function, exercise tolerance at the 6MWT and higher pulmonary pressures. Our data show that in SSc patients a reduced LVCR characterizes the patients with a more extensive cardiovascular impairment in terms of LV diastolic function, pulmonary pressures and exercise tolerance. These data underline the importance of exercise echocardiography for the preclinical screening of the LV impairment in this population.