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Although decades of the reductionist approach achieved great milestones in optimizing the immunosuppres-sion therapy, traditional clinical parameters still fail in predicting both acute and chronic (mainly) rejection events leading to higher rates across all solid organ transplants. To clarify the underlying immune-related cel-lular and molecular mechanisms, current biomedical research is increasingly focusing on "transplantomics" which relies on a huge quantity of big data deriving from genomics, transcriptomics, epigenomics, proteomics, and metabolomics platforms. The AlloMap (gene expression) and the AlloSure (donor-derived cell-free DNA) tests represent two successful examples of how omics and liquid biopsy can really improve the precision med-icine of heart and kidney transplantation. One of the major challenges in translating big data in clinically useful biomarkers is the integration and interpretation of the different layers of omics datasets. Network Medicine offers advanced bioinformatic-molecular strategies which were widely used to integrate large omics datasets and clinical information in end-stage patients to prioritize potential biomarkers and drug targets. The applica-tion of network-oriented approaches to clarify the complex nature of graft rejection is still in its infancy. Here, we briefly discuss the real-life clinical applications derived from omics datasets as well as novel opportunities for establishing predictive tests in solid organ transplantation. Also, we provide an original "graft rejection interactome" and propose network-oriented strategies which can be useful to improve precision medicine of solid organ transplantation.

Ventricular septal rupture (VSR) is a mechanical complication of acute myocardial infarction (MI). VSR and early surgical repair is associated with a high mortality rate and suboptimal results with frequent postoperative residual shunt. Rapid diagnosis and proper management are critical. We present the case of a 73-year-old patient who came to our Emercency Room (ER) reporting oppressive chest pain and profuse sweating . The physical examination showed a 4/6 L rude holosystolic murmur in right parasternal location. Electrocardiogram (ECG) showed inferior MI. Hematochemicals tests detected an increase of myocardial necrosis markers. Two-dimensional and three-dimensional transthoracic echocardiography (TTE) showed normal-sized left ventricle with akinesia of inferior and posterolateral walls and akinesia of posterior basal septum with ventricular septal rupture at this level. Coronary angiography showed total occlusion in mid right coronary artery (RCA). An intra-aortic balloon pump (IABP) was inserted to promote hemodynamic stability of the patient and as a bridge. Afterload was reduced using vasodilatators. A preoperative transesophageal echocardiography (TOE) showed the presence of an additional septal rupture into middle posterior interventricular septum. The role of echocardiographic assessment in VSR, therapeutic management, IABP use and timing of surgery are discussed.

Introduction Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates. Objective The objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system. Methods We retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs. Results A total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01–1.18). Conclusions Immune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01086-8.

We present the case of a giant distal aortic pseudoaneurysm 35 years after a classic mechanical Bentall operation. Computed tomography and coronary angiography showed that this originated from the distal suture line. The proximal suture and coronary ostia appeared to be intact. At reoperation, we found a complete dehiscence of distal suture line: the graft was floating in the pseudoaneurysm, mimicking an “elephant trunk” procedure. This complication suggested a systematic and accurate follow-up of patients who underwent an original Bentall procedure.

One of the major challenges of cardiovascular primary prevention approach is the absence of early biomarkers of endothelial dysfunction which may be useful for identifying at-risk subjects. Endothelial dysfunction is a systemic disorder in which traditional cardiovascular risk factors, such as aging, gender, hypertension, smoking, hyperglycemia, and dyslipidemia, as well as emerging risk determinants, such as fetal factors, gut microbiome alteration, clonal hematopoiesis, air pollution, and sleep disorders act synergistically to tip the endothelial balance in favor of vasoconstrictive, pro-inflammatory, and pro-thrombotic phenotypes. Endothelial dysfunction can start already in fetal life and may be regained once detrimental stimuli are removed. The hallmark of endothelial dysfunction is a marked reduction of nitric oxide (NO) bioavailability owing to epigenetic-sensitive dysregulation of the endothelial nitric oxide synthase (eNOS) gene and upregulation of reactive oxygen species (ROS) in endothelial cells (ECs). Advance in liquid-based assays and molecular biology tools are providing novel potential EC-specific biomarkers for prediction and diagnosis of endothelial dysfunction. Significant associations between clinically useful indexes of endothelial dysfunction, mainly brachial artery flow-mediated dilation (FMD), and increased number of endothelial microparticles (EMPs), increased levels of endoglin and endocan, as well as reduced levels of irisin were observed in subjects with one or more traditional risk factors. However, none entered in clinical practice yet. Smoking cessation, weight loss, physical exercise, and diet control are the milestones of cardiovascular primary prevention, and they may restore endothelial function via epigenetic-sensitive pathways able to reduce inflammation and oxidative stress and increase NO production . We briefly summarize well-known and novel molecular routes driving early endothelial dysfunction mainly in human ECs and related potential biomarkers which may add predictive or diagnostic value to the traditional non-invasive techniques. Also, we focus on clinical trials investigating lifestyle modifications and their impact on molecular routes involved in restoring endothelial function.

The coronavirus disease 2019 (COVID-19) pandemic has profoundly affected all health care professionals. The outbreak required a thorough reorganization of the Italian regional local health care system to preserve resources such as ventilators, beds in intensive care units and surgical and anaesthesiological staff. Levels of priority were created, together with a rigorous triage procedure for patients with COVID-19, which led to postponement of all elective procedures. Urgent cases were discussed with the local heart team and percutaneous approaches were selected as the first treatment option to reduce hospital stay. COVID-19 and COVID-19-free pathways were created, including adequate preparation of the operating room, management of anaesthesiological procedures, transportation of patients and disinfection. It was determined that patients with chronic diseases were at increased risk of adverse outcomes. Systemic inflammation, cytokine storm and hypercoagulability associated with COVID-19 increased the risk of heart failure and cardiac death. In this regard, the early use of extracorporeal membrane oxygenation could be life-saving in patients with severe forms of acute respiratory distress syndrome or refractory heart failure. The goal of this paper was to report the Italian experience during the COVID-19 pandemic in the setting of cardiovascular surgery., Coronavirus disease 2019 (COVID-19) is a new pandemic infectious disease caused by a novel beta-coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].

After mitral valve replacement in an 81-year-old woman, there was evidence of an important communication between the esophagus and the right pleura. Diagnosis was confirmed with Oral Gastrografin radiography and esophagoscopy. Thoracic computed tomography scans better indicated fistula location and extension, but also showed the close relationship and the compression of huge left atrium on the oesophagus. Our hypothesis was that the lesion was induced by transoesophageal echocardiography probe in a favourable setting. An enlarged left atrium should be recognized as a risk factor for TEE-induced esophageal perforation, especially in fragile patients, with marked esophagus distortion.

Mast cells are multifunctional immune cells with complex roles in tissue homeostasis and disease. Cardiac mast cells (HCMCs) are strategically located within the human myocardium, in atherosclerotic plaques, in proximity to nerves, and in the aortic valve. HCMCs express the high-affinity receptor (FcεRI) for IgE and can be activated by anti-IgE and anti-FcεRI. Autoantibodies to IgE and/or FcεRI have been found in the serum of patients with a variety of immune disorders. We have compared the effects of different preparations of IgG anti-IgE obtained from patients with atopic dermatitis (AD) with rabbit IgG anti-IgE on the release of preformed (histamine and tryptase) and lipid mediators [prostaglandin D2(PGD2) and cysteinyl leukotriene C4(LTC4)] from HCMCs. Functional human IgG anti-IgE from one out of six AD donors and rabbit IgG anti-IgE induced the release of preformed (histamine, tryptase) and de novo synthesized mediators (PGD2and LTC4) from HCMCs. Human IgG anti-IgE was more potent than rabbit IgG anti-IgE in inducing proinflammatory mediators from HCMCs. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Although functional anti-IgE autoantibodies rarely occur in patients with AD, when present, they can powerfully activate the release of proinflammatory and vasoactive mediators from HCMCs.

This study aims to identify baseline medications that, as a proxy for the diseases they are dispensed for, are associated with increased risk of mortality in COVID-19 patients from two regions in Spain and Italy using real-world data. We conducted a cross-country, retrospective, observational study including 8570 individuals from both regions with confirmed SARS-CoV-2 infection between 4 March and 17 April 2020, and followed them for a minimum of 30 days to allow sufficient time for the studied event, in this case death, to occur. Baseline demographic variables and all drugs dispensed in community pharmacies three months prior to infection were extracted from the PRECOVID Study cohort (Aragon, Spain) and the Campania Region Database (Campania, Italy) and analyzed using logistic regression models. Results show that the presence at baseline of potassium-sparing agents, antipsychotics, vasodilators, high-ceiling diuretics, antithrombotic agents, vitamin B12, folic acid, and antiepileptics were systematically associated with mortality in COVID-19 patients from both countries. Treatments for chronic cardiovascular and metabolic diseases, systemic inflammation, and processes with increased risk of thrombosis as proxies for the conditions they are intended for can serve as timely indicators of an increased likelihood of mortality after the infection, and the assessment of pharmacological profiles can be an additional approach to the identification of at-risk individuals in clinical practice.

We describe the case of a patient with an ascending aorta and aortic root aneurysm who underwent aortic valve replacement, 14 years earlier, with a mechanical prosthesis, which was normally functioning at time of reoperation. We describe the "completion Bentall" technique - a modified Bentall technique -, a procedure for prosthesis-sparing aortic root replacement. This technique simplifies the original procedure in reinterventions, reducing complication rates and aortic cross-clamping and cardiopulmonary bypass times, with a good surgical result.

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir, therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.

After Italy's first national restriction measures in 2020, a robust approach was needed to monitor the emerging epidemic of coronavirus disease 2019 (COVID-19) at subnational level and provide data to inform the strengthening or easing of epidemic control measures.We adapted the European Centre for Disease Prevention and Control rapid risk assessment tool by including quantitative and qualitative indicators from existing national surveillance systems. We defined COVID-19 risk as a combination of the probability of uncontrolled transmission of severe acute respiratory syndrome coronavirus 2 and of an unsustainable impact of COVID-19 cases on hospital services, adjusted in relation to the health system's resilience. The monitoring system was implemented with no additional cost in May 2020.The infectious diseases surveillance system in Italy uses consistent data collection methods across the country's decentralized regions and autonomous provinces.Weekly risk assessments using this approach were sustainable in monitoring the epidemic at regional level from 4 May 2020 to 24 September 2021. The tool provided reliable assessments of when and where a rapid increase in demand for health-care services would occur if control or mitigation measures were not increased in the following 3 weeks.Although the system worked well, framing the risk assessment tool in a legal decree hampered its flexibility, as indicators could not be changed without changing the law. The relative complexity of the tool, the impossibility of real-time validation and its use for the definition of restrictions posed communication challenges.Après avoir pris ses premières mesures de restriction nationales en 2020, l'Italie avait besoin d'une approche solide pour surveiller l'épidémie naissante de maladie à coronavirus 2019 (COVID-19) au niveau régional, et fournir les données permettant de renforcer ou d'alléger les mesures destinées à l'endiguer.Nous avons adapté l'outil d'évaluation rapide des risques du Centre européen de prévention et de contrôle des maladies en y intégrant des indicateurs quantitatifs et qualitatifs issus des systèmes de surveillance nationaux existants. Pour définir le risque lié à la COVID-19, nous avons associé la probabilité d'une transmission incontrôlée du coronavirus 2 du syndrome respiratoire aigu sévère, à l'impact immédiat des cas de COVID-19 sur les services hospitaliers, en procédant à des ajustements selon la résilience du système de soins de santé. Le dispositif de surveillance a été mis en œuvre en mai 2020 sans entraîner de coûts supplémentaires.En Italie, le système de surveillance des maladies infectieuses repose sur des méthodes uniformes de collecte de données dans les provinces autonomes et régions décentralisées à travers le pays.Les évaluations des risques réalisées toutes les semaines avec cette approche ont permis de surveiller l'épidémie à l'échelle régionale du 4 mai 2020 au 24 septembre 2021. L'outil a identifié les dates et lieux susceptibles de connaître une augmentation rapide de la demande en services de soins de santé si aucune mesure supplémentaire de contrôle et de lutte n'était prise dans les trois semaines.Bien que le système ait fonctionné, inscrire l'outil d'évaluation des risques dans un décret législatif a réduit sa flexibilité, car les indicateurs ne pouvaient être modifiés sans réformer la loi. La relative complexité de l'outil, l'impossibilité de procéder à une validation en temps réel et son usage pour imposer des restrictions ont posé des problèmes de communication.Tras las primeras medidas nacionales de restricción en Italia en 2020, se necesitaba un enfoque sólido para supervisar la epidemia emergente de la coronavirosis de 2019 (COVID-19) a nivel subnacional y proporcionar datos que informaran sobre el refuerzo o la flexibilización de las medidas de contención de la epidemia.Se adaptó la herramienta de valoración rápida de riesgos del Centro Europeo para la Prevención y el Control de las Enfermedades, al incluir indicadores cuantitativos y cualitativos de los sistemas nacionales de vigilancia existentes. Se definió el riesgo de la COVID-19 como una combinación de la probabilidad de transmisión descontrolada del coronavirus del síndrome respiratorio agudo grave de tipo 2 y de un efecto no sostenible de los casos de la COVID-19 en los servicios hospitalarios, y se ajustó en relación con la capacidad de recuperación del sistema sanitario. El sistema de supervisión se aplicó sin costes adicionales en mayo de 2020.El sistema de vigilancia de las enfermedades infecciosas en Italia aplica métodos de recopilación de datos coherentes en todas las regiones y provincias autónomas descentralizadas del país.Las valoraciones semanales de los riesgos mediante este enfoque fueron sostenibles en la supervisión de la epidemia a nivel regional entre el 4 de mayo de 2020 y el 24 de septiembre de 2021. La herramienta proporcionó valoraciones fiables de cuándo y dónde se produciría un rápido aumento de la demanda de servicios sanitarios si no se incrementaban las medidas de contención o mitigación en las tres semanas siguientes.Aunque el sistema funcionó bien, el hecho de enmarcar la herramienta de valoración de los riesgos en un decreto legal dificultó su flexibilidad, ya que los indicadores no se podían modificar sin cambiar la ley. La relativa complejidad de la herramienta, la imposibilidad de validación en tiempo real y su uso para la definición de las restricciones plantearon problemas de comunicación.المشكلة بعد إجراءات التقييد الوطنية الأولى بإيطاليا في عام 2020، كانت هناك حاجة إلى أسلوب فعّال لرصد الوباء المستجد لمرض فيروس كورونا 2019 (كوفيد 19) على المستوى دون الوطني، وتوفير البيانات لدراسة إمكانية تعزيز أو تخفيف تدابير مكافحة الوباء. الأسلوب قمنا بتكييف أداة لتقييم المخاطر السريعة تابعة للمركز الأوروبي للوقاية من الأمراض ومكافحتها، وذلك من خلال تضمين مؤشرات كمية ونوعية من أنظمة المراقبة الوطنية الحالية. كذلك قمنا بتعريف مخاطر كوفيد 19 على أنها مزيج من احتمالية الانتقال غير المُقيد لمتلازمة الجهاز التنفسي الحادة الشديدة لفيروس كورونا 2، والتأثير غير المستدام لحالات كوفيد 19 على خدمات المستشفيات، مع تعديلها فيما يتعلق بمرونة النظام الصحي. تم تنفيذ نظام المراقبة دون تكلفة إضافية في مايو/أيار 2020. المواقع المحلية يستخدم نظام مراقبة الأمراض المعدية في إيطاليا طرقًا متسقة لجمع البيانات عبر المناطق اللامركزية في البلد والمقاطعات المستقلة. التغيّرات ذات الصلة كانت تقييمات المخاطر الأسبوعية باستخدام هذا الأسلوب مستدامة في رصد الوباء على المستوى الإقليمي، طوال الفترة من 4 مايو/أيار 2020 إلى 24 سبتمبر/أيلول 2021. قدمت الأداة تقييمات موثوقة حول توقيت ومكان حدوث زيادة سريعة في الطلب على خدمات الرعاية الصحية في حالة السيطرة، أو إذا لم يتم زيادة تدابير التخفيف في الأسابيع الثلاثة التالية. الدروس المستفادة على الرغم من أن النظام قد عمل بشكل جيد، إلا أن صياغة أداة تقييم المخاطر في مرسوم قانوني أعاقت مرونته، حيث لا يمكن تغيير المؤشرات دون تغيير القانون. أدى التعقيد النسبي للأداة، واستحالة التحقق من فعاليتها في الوقت الفعلي، واستخدامها لتعريف القيود، إلى ظهور تحديات في التواصل.问题 2020 年意大利首次实施全国性限制措施后，需要采取可靠方法以监测新型冠状病毒肺炎（新冠肺炎）疫情在地方层面的蔓延情况，并提供数据以表明是否需要加强或放松疫情控制措施。方法 通过纳入现有国家监测系统的定量和定性指标，我们调整了欧洲疾病预防和控制中心的快速风险评估工具。我们将新型冠状病毒肺炎风险综合定义为严重急性呼吸系统综合症冠状病毒 2 不受控制传播的可能性以及新型冠状病毒肺炎病例对医院服务的非持续性影响，并根据卫生系统的顺应力进行了调整。2020 年 5 月，在没有产生额外成本的前提下实施了监测系统。当地状况 意大利传染病监测系统在全国各个分散的地区和自治省统一使用相同的数据收集方法。相关变化 在 2020 年 5 月 4 日至 2021 年 9 月 24 日期间，使用这种方法开展的每周风险评估在监测区域层面疫情情况方面具有可持续性。该工具能够可靠地评估，如果在接下来的 3 周内没有加强控制或缓解措施，何时何地医疗保健服务需求会迅速增加。经验教训 尽管该系统运作良好，但将风险评估工具纳入法令范畴限制了其灵活性，因为若不更改法律，则无法变更指标。该工具的相对复杂性、实时验证的不可能性及其在法规限定方面的用途导致产生了沟通挑战。.После первых национальных ограничительных мер в Италии в 2020 году потребовался активный подход для мониторинга зарождающейся эпидемии коронавирусной инфекции 2019 года (COVID-19) на субнациональном уровне и для предоставления данных для обоснования усиления или ослабления мер по борьбе с эпидемией.Авторы адаптировали инструмент для оперативных оценок рисков Европейского центра по контролю и профилактике заболеваний, включив в него количественные и качественные показатели из существующих национальных систем эпиднадзора. Авторы определили риск COVID-19 как комбинацию вероятности неконтролируемой передачи тяжелого острого респираторного синдрома, вызванного коронавирусом-2, и разрушительного воздействия случаев COVID-19 на больничное обслуживание, которая скорректирована с учетом устойчивости системы здравоохранения. Система мониторинга была внедрена без каких-либо дополнительных затрат в мае 2020 года.В системе эпиднадзора за инфекционными заболеваниями в Италии используются последовательные методы сбора данных по децентрализованным регионам и автономным провинциям страны.Еженедельные оценки рисков с использованием данного подхода регулярно применялись при мониторинге эпидемии на региональном уровне с 4 мая 2020 года по 24 сентября 2021 года. Инструмент обеспечил надежную оценку того, когда и где может произойти быстрое увеличение спроса на медицинские услуги, если меры по борьбе или смягчению последствий не будут усилены в течение следующих 3 недель.Несмотря на то что система работала эффективно, включение инструмента для оценок рисков в юридические постановления ограничивало его гибкость, поскольку показатели не могли быть изменены без изменения закона. Относительная сложность инструмента, невозможность проверки в реальном времени и его использование для определения ограничений создают проблемы коммуникации.

Coronavirus disease 2019 (COVID-19) has substantially challenged healthcare systems worldwide. By investigating population characteristics and prescribing profiles, it is possible to generate hypotheses about the associations between specific drug-utilisation profiles and susceptibility to COVID-19 infection. A retrospective drug-utilisation study was carried out using routinely collected information from a healthcare database in Campania (Southern Italy). We aimed to discover the prevalence of drug utilisation (monotherapy and polytherapy) in COVID-19 versus non-COVID-19 patients in Campania (~ 6 million inhabitants). The study cohort comprised 1532 individuals who tested positive for COVID-19. Drugs were grouped according to the Anatomical Therapeutic Chemical (ATC) classification system. We noted higher prevalence rates of the use of drugs in the ATC categories C01, B01 and M04, which was probably linked to related comorbidities (i.e., cardiovascular and metabolic). Nevertheless, the prevalence of the use of drugs acting on the renin-angiotensin system, such as antihypertensive drugs, was not higher in COVID-19 patients than in non-COVID-19 patients after adjustments for age and sex. These results highlight the need for further case–control studies to define the effects of medications and comorbidities on susceptibility to and associated mortality from COVID-19.

COVID-19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated and evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real-life context is strongly needed. LINKED ARTICLES: This article is part of a themed issue on The second wave: are we any closer to efficacious pharmacotherapy for COVID 19? (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.10/issuetoc.

Claudio Napoli,1 Paola Bontempo,2 Vittorio Palmieri,3 Enrico Coscioni,4 Ciro Maiello,5 Francesco Donatelli,6 Giuditta Benincasa1 1Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, 80138, Italy; 2Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, 80138, Italy; 3Department of Cardiac Surgery and Transplantation, Heart Transplantation Unit in Adults of the ‘Ospedali dei Colli Monaldi-Cotugno-CTO’, Naples, Italy; 4Department of Cardiac Surgery, Azienda Ospedaliera Universitaria San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy; 5Department of Cardiovascular Surgery and Transplants, Monaldi Hospital, Azienda dei Colli, Naples, Italy; 6Chair of Cardiac Surgery, Department of Cardiothoracic Center, Istituto Clinico Sant’Ambrogio, University of Milan, Milan, ItalyCorrespondence: Giuditta BenincasaDepartment of Advanced Medical and Surgical Sciences (DAMSS), University of Campania “Luigi Vanvitelli”, Naples, ItalyTel +390815667916Email giuditta.benincasa@unicampania.itAbstract: Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy (“epidrugs”) is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials isevaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.Keywords: heart failure, personalized therapy, epidrugs

Heart transplantation (HTx) is considered the gold-standard therapy for the treatment of advanced heart failure (HF). The long-term survival in HTx is hindered by graft failure which represents one of the major limitations of the long-term efficacy of HTx. Endomyocardial biopsy (EMB) and the evaluation of donor-specific antibodies (DSA) are currently considered the essential diagnostic tools for surveillance of graft rejection. Recently, new molecular biomarkers (including cell-free DeoxyriboNucleic Acid, exosomes, gene profiling microarray, nanostring, reverse transcriptase multiplex ligation-dependent probe amplification, proteomics and immune profiling by quantitative multiplex immunofluorescence) provide useful information on mechanisms of graft rejection. The ambitious role of a similar change of perspective is aimed at a better and longer graft preservation.

Purpose of review Cardiovascular diseases (CVDs) are typically caused by multifactorial events including mutations in a large number of genes. Epigenetic-derived modifications in the cells are normal but can be amended by aging, lifestyle, and exposure to toxic substances. Major epigenetic modifications are DNA methylation, histone modification, chromatin remodeling as well as the noncoding RNAs. These pivotal players are involved in the epigenetic-induced modifications observed during CVDs. Nevertheless, despite impressive efforts capitalized in epigenetic research in the last 50 years, clinical applications are still not satisfactory. Recent findings Briefly, we present some of the recent steps forward in the epigenetic studies of CVDs. There is an increased appreciation for the contribution of epigenetic alterations in the development of CVDs. Now, we have novel epigenetic biomarkers and therapeutic trials with the use of statins, metformin, and some compounds affecting epigenetic pathways including a BET inhibitor apabetalone. The new knowledge of epigenetic regulation is also discussed in the light of precision medicine of CVDs. Summary Epigenetic studies of CVDs have the promise to yield both mechanistic insights as well as adjunct treatments (repurposed drugs and apabetalone). The overall concept of precision medicine is not widely recognized in routine medical practice and the so-called reductionist approach remains the most used way to treat CVD patients.

Background The novel coronavirus (SARS-CoV-2) pandemic spread rapidly worldwide increasing exponentially in Italy. To date, there is lack of studies describing clinical characteristics of the people at high risk of infection. Hence, we aimed (i) to identify clinical predictors of SARS-CoV-2 infection risk, (ii) to develop and validate a score predicting SARS-CoV-2 infection risk, and (iii) to compare it with unspecific scores. Methods Retrospective case-control study using administrative health-related database was carried out in Southern Italy (Campania region) among beneficiaries of Regional Health Service aged over than 30 years. For each person with SARS-CoV-2 confirmed infection (case), up to five controls were randomly matched for gender, age and municipality of residence. Odds ratios and 90% confidence intervals for associations between candidate predictors and risk of infection were estimated by means of conditional logistic regression. SARS-CoV-2 Infection Score (SIS) was developed by generating a total aggregate score obtained from assignment of a weight at each selected covariate using coefficients estimated from the model. Finally, the score was categorized by assigning increasing values from 1 to 4. Discriminant power was used to compare SIS performance with that of other comorbidity scores. Results Subjects suffering from diabetes, anaemias, Parkinson’s disease, mental disorders, cardiovascular and inflammatory bowel and kidney diseases showed increased risk of SARS-CoV-2 infection. Similar estimates were recorded for men and women and younger and older than 65 years. Fifteen conditions significantly contributed to the SIS. As SIS value increases, risk progressively increases, being odds of SARS-CoV-2 infection among people with the highest SIS value (SIS = 4) 1.74 times higher than those unaffected by any SIS contributing conditions (SIS = 1). Conclusion Conditions and diseases making people more vulnerable to SARS-CoV-2 infection were identified by the current study. Our results support decision-makers in identifying high-risk people and adopting of preventive measures to minimize the spread of further epidemic waves.

AIMS: Chronic kidney disease (CKD) is associated with increased thrombotic events and seems to influence platelet reactivity. Conflicting results have been published on platelet response in CKD patients with stable coronary artery disease. The aim of our study was to investigate the impact of CKD on platelet aggregation in acute coronary syndrome (ACS) patients receiving dual antiplatelet therapy, included the more potent P2Y12 inhibitors. METHODS: We enrolled 206 patients with ACS, divided in two groups, according to the presence or the absence of moderate/severe CKD. Platelet aggregation was performed with light transmission aggregometry and results are expressed as percentage of maximum platelet aggregation. High residual platelet reactivity (HRPR) was defined as maximum platelet aggregation more than 59%. RESULTS: Patients with CKD [estimate glomerular filtration rate (eGFR)

Background There is an ever-growing number of patients requiring aortic valve replacement (AVR). Limited data is available on the long-term outcomes and structural integrity of bioprosthetic valves in younger patients undergoing surgical AVR. Methods The INSPIRIS RESILIA Durability Registry (INDURE) is a prospective, open-label, multicentre, international registry with a follow-up of 5 years to assess clinical outcomes of patients younger than 60 years who undergo surgical AVR using the INSPIRIS RESILIA aortic valve. INDURE will be conducted across 20–22 sites in Europe and Canada and intends to enrol minimum of 400 patients. Patients will be included if they are scheduled to undergo AVR with or without concomitant root replacement and/or coronary bypass surgery. The primary objectives are to 1) determine VARC-2 defined time-related valve safety at one-year (depicted as freedom from events) and 2) determine freedom from stage 3 structural valve degeneration (SVD) presenting as morphological abnormalities and severe haemodynamic valve degeneration at 5 years. Secondary objectives include the assessment of the haemodynamic performance of the valve, all stages of SVD, potential valve-in-valve procedures, clinical outcomes (in terms of New York Heart Association [NYHA] function class and freedom from valve-related rehospitalisation) and change in patient quality-of-life. Discussion INDURE is a prospective, multicentre registry in Europe and Canada, which will provide much needed data on the long-term performance of bioprosthetic valves in general and the INSPIRIS RESILIA valve in particular. The data may help to gather a deeper understanding of the longevity of bioprosthetic valves and may expand the use of bioprosthetic valves in patients under the age of 60 years. Trial registration ClinicalTrials.gov identifier: NCT03666741 (registration received September, 12th, 2018).

Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (irADRs). Among irADRs, cardiac ones are rare, but also associated with higher mortality rates. Here, we evaluate the occurrence of cardiac ADRs associated with ICIs. Methods: We retrieved Individual Case Safety Reports (ICSRs) on ICIs-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance, EV). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to March 14th, 2020. The Reporting Odds Ratio (ROR) and its’ 95% confidence interval (95%CI) was computed to assess the reporting probability of cardiac ADRs for each ICI compared to all other ICIs. Findings: A total of 2,478 ICSRs with at least one ICI as suspected drug were retrieved from EV, of which 249 (10%) were related to combined treatments. The three most reported ICIs were nivolumab (43 . 2%), pembrolizumab (32 . 5%), and the association nivolumab and ipilimumab (9 . 4%). A total of 3,388 cardiac ADRs were identified. Cardiac ADRs were serious (99%) and associated with a fatal outcome (30 . 1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs (ROR 1 . 09, 95%CI 1 . 01–1 . 18). Interpretation: ICIs-induced cardiac ADRs were serious and associated with unfavorable outcomes. In our study, nivolumab was the only ICI associated with a small increased reporting probability of ICSRs with cardiac ADRs compared to all other ICIs. In this regards, further head-to-head studies are needed. Funding: This research was funded under grant n. 2017NR7W5K_002 (PRIN 2017) from MIUR, Italy. Declaration of Interests: No conflict to declare. Ethics Approval Statement: Safety data deriving from the spontaneous reporting system are anonymous and in compliance with the ethical standard. Therefore, no further ethical measure was required.

Lower extremity arterial disease (LEAD) affects over 200 million people worldwide but, as of today, is not adequately treated and represents an important cause of morbidity, mortality and disability. Although the use of antithrombotic therapy is recommended to prevent cardiovascular adverse events, patients with LEAD often receive inadequate prescription for antithrombotic agents (antiplatelets and anticoagulants). Historically, the inadequate use of antithrombotic drugs in this clinical setting has been ascribed to the lack of high quality scientific data obtained from clinical trials enrolling patients with LEAD. However, the results of more recent clinical trials support the use of antithrombotic drugs for these patients. The aim of this article is to summarize the available evidence supporting the prescription of antithrombotic agents in patients with LEAD.

Different and several public health strategies have been planned to reduce transmission of pandemic due to SARS-CoV-2 since it started. None drugs have been confirmed as able to prevent viral transmission. Hydroxychloroquine with its immunomodulatory properties has been proposed as potential anti-viral drug in particular for prevention once viral exposure has been happen or in first phases of infection. Furthermore, in several immunological systemic disease hydroxychloroquine was able to reduce the number of thrombotic complications. So, because COVID-19 was associated to immunological imbalance and to thrombotic complications, we retrospectively analyzed the rate of infection in those patients being under treatment with this drug during COVID-19 epidemic outbreak from 8 March until 28 April in particular comparing those with pre-exposure to this treatment and those that were not taking this medication before SARS-CoV-2 viral infections.

Adipose-derived mesenchymal stem cells (ASCs) are promising therapeutic tools in regenerative medicine because they possess self-renewal, differentiation and immunomodulatory capacities. After isolation, ASCs are passaged multiple times in vitro passages to obtain a sufficient amount of cells for clinical applications. During this time-consuming procedure, ASCs become senescent and less proliferative, compromising their clinical efficacy. Here, we sought to investigate how in vitro passages impact ASC proliferation/senescence and expression of immune regulatory proteins. MicroRNAs are pivotal regulators of ASC physiology. Particularly, miR-200c is known to maintain pluripotency and targets the immune checkpoint Programmed death-ligand 1 (PD-L1). We therefore investigated its involvement in these critical characteristics of ASCs during in vitro passages. We found that when transiently expressed, miR-200c-3p promotes proliferation, maintains stemness, and contrasts senescence in late passaged ASCs. Additionally, this miRNA modulates PD-L1 and Indoleamine 2,3-Dioxygenase (IDO1) expression, thus most likely interfering with the immunoregulatory capacity of ASCs. Based on our results, we suggest that expression of miR-200c-3p may prime ASC towards a self-renewing phenotype by improving their in vitro expansion. Contrarily, its inhibition is associated with senescence, reduced proliferation and induction of immune regulators. Our data underline the potential use of miR-200c-3p as a switch for ASCs reprogramming and their clinical application.

We hypothesized that the spread of SARS-CoV-2 in urine during a severe COVID-19 infection may be the expression of the worsening disease evolution. Therefore, the aim of this study was to verify if the COVID-19 disease severity is related to the viral presence in urine samples. We evaluated the clinical evolution in acute COVID-19 patients admitted in the sub-intensive care and intensive care units between 28 of December 2020 and 15th of February 2021 and being positive for SARS-CoV-2 RNA in the respiratory tract, including repeated endotracheal aspirates (ETA), sputum, nasopharyngeal swabs (NPS) and urine. We found that those subjects with SARS-COV-2 in the urine at admittance (8 out of 60 eligible patients) had a more severe disease than those with negative SARS-CoV-2 in urine. Further, they showed an increase in fibrinogen and (C-reactive Protein) CRP serum levels, requiring mechanic ventilation. Of those with positive SARS-CoV-2 in the urine, 50% died. According to our preliminary results, it seems that the presence of SARS-CoV-2 in the urine characterizes patients with a more severe disease and is also related to a higher death rate.

Aims Surgical endarterectomy is the therapy of choice for atherosclerotic common femoral artery (CFA) obstruction. Recently, some large single-centre series have shown encouraging results for the percutaneous treatment of CFA obstructions. The purpose of this study was to evaluate the safety, feasibility, and one-year efficacy of the endovascular treatment of CFA obstructions with combined use of directional atherectomy (DA) and a paclitaxel-coated balloon (DCB). Methods and results Between January 2012 and July 2014, 30 consecutive patients with severely calcified obstructions of the common femoral artery were treated in our centre using DA followed by DCB dilatation. Provisional stenting was allowed in the case of a suboptimal result. Twenty cases (66%) were isolated CFA interventions, whereas five (17%) and five (17%) also involved inflow and outflow vessels, respectively. Chronic total CFA occlusions (CTO) were recanalised in six cases (20%). Procedural success was achieved in all cases; stenting was needed in three cases (10%). At one year, restenosis and target lesion revascularisation were observed in two of 30 (6.6%) and one of 30 (3.3%) patients, respectively. The secondary patency rate was 96.7%. Conclusions This single-centre prospective study suggests that the combined use of DA and DCB is a safe and effective alternative to surgery, a treatment option for common femoral artery lesions and provides encouraging results in this setting.

Background: Heart Failure (HF) and cognitive impairment (CI) represent two high incident diseases worldwide, with extremely elevated mortality and morbidity rates. Their prevalence is expected to further increase in the next years due to the aging population, thus they pose enormous clinical, social and economic challenges. Sympathetic nervous system hyperactivity is known to play a pivotal role in HF pathophysiology and progression. In fact, increased cardiac and circulating catecholamine levels are responsible for several molecular and structural abnormalities with detrimental effects on the failing heart. The proof of this latter concept is represented by the clinical success of -Blocker therapy that is able to attenuate HF-related morbidity and mortality. Recently, adrenergic system alterations have been implied also in the pathogenesis of CI and dementia opening the window for new fascinating and promising therapeutic opportunities. Objective: Assess the state of the art on the relationship between cognitive impairment and heart failure. Method: In the present manuscript, we propose an updated review of literature and patent on the role of sympathetic nervous system derangement in the pathogenesis of HF and CI. Conclusion: We have discussed recent findings allowing the identification of new molecular targets that hopefully will contribute to the generation of effective therapeutic strategies for HF and dementia. In this article, the patents US20100048479, US7060871, WO2006052857, US7351401, US5721243, WO1994009155, US5449604, WO1999058981, US5985581, EP2319511, EP2377534, EP2650303, WO2006004939, WO2010132128 and EP1779858 are summarized.