The sGCa Vericiguat Exhibit Cardioprotective and Anti-Sarcopenic Effects through NLRP-3 Pathways: Potential Benefits for Anthracycline-Treated Cancer Patients.

Anthracycline-induced cardiomyopathies and sarcopenia are frequently seen in cancer patients, affecting their overall survival and quality of life; therefore, new cardioprotective and anti-sarcopenic strategies are needed. Vericiguat is a new oral guanylate cyclase activator that reduces heart failure hospitalizations or cardiovascular death. This study highlighted the potential cardioprotective and anti-sarcopenic properties of vericiguat during anthracycline therapy. Human cardiomyocytes and primary skeletal muscle cells were exposed to doxorubicin (DOXO) with or without a pre-treatment with vericiguat. Mitochondrial cell viability, LDH, and Cytochrome C release were performed to study cytoprotective properties. Intracellular Ca++ content, TUNEL assay, cGMP, NLRP-3, Myd-88, and cytokine intracellular levels were quantified through colorimetric and selective ELISA methods. Vericiguat exerts significant cytoprotective and anti-apoptotic effects during exposure to doxorubicin. A drastic increase in cGMP expression and reduction in NLRP-3, MyD-88 levels were also seen in Vericiguat-DOXO groups vs. DOXO groups (p < 0.001) in both cardiomyocytes and human muscle cells. GCa vericiguat reduces cytokines and chemokines involved in heart failure and sarcopenia. The findings that emerged from this study could provide the rationale for further preclinical and clinical investigations aimed at reducing anthracycline cardiotoxicity and sarcopenia in cancer patients.

[ANMCO Position paper - 2023 ANMCO States General: The shortage of healthcare personnel in the cardiology field]. / Position paper ANMCO ­ Stati Generali ANMCO 2023: La carenza del personale sanitario in ambito cardiologico.

Over the latest years, a worrying progressive reduction of medical specialists has been observed in Italy and in other European and non-European countries. This trend is assuming alarming proportions, especially considering the continuous population aging and the concomitant increase in the prevalence of chronic cardiovascular disease. The underlying reasons are complex and multifactorial. The purpose of this document, derived from the collegial discussion held during the 2023 ANMCO States General is to highlight the current critical issues regarding the lack of healthcare personnel in the cardiology field, examining the current and future Italian situation and proposing some potential strategies to counteract this alarming phenomenon.

[Identification and treatment of high-risk coronary atheromatous plaques: towards a shared strategy between the clinical and interventional cardiologist]. / Identificazione e trattamento della placca ateromasica coronarica ad alto rischio: verso una strategia condivisa tra il cardiologo clinico e l'interventista.

Modern coronary diagnostic methods, including cardiac computed tomography and intracoronary imaging, allow the identification of vulnerable coronary plaques with a high probability of complicating and causing acute coronary syndrome. The treatment limited to the plaques responsible for ischemic events could not be enough to prevent major cardiovascular events because most flow-limiting plaques are quiescent or slowly evolving. In several cases the plaques responsible for acute event determine a moderate reduction of the vessel lumen but have well-defined characteristics of vulnerability. The purpose of this review is (i) to describe the characteristics of these plaques based on both the pathological anatomy and computed tomography and intracoronary imaging findings and the associated clinical risk of developing future coronary events; (ii) to evaluate available trials on early treatment of vulnerable plaques by percutaneous revascularization; and (iii) to propose a decision-making algorithm in primary prevention integrating the search for myocardial ischemia and vulnerable plaques.

Use of cangrelor in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Study design and interim analysis of the ARCANGELO study.

BACKGROUND: The itAlian pRospective Study on CANGrELOr (ARCANGELO) was aimed to assess the safety of using cangrelor during percutaneous coronary intervention (PCI) in patients with acute coronary syndromes (ACS) in the daily practice. HYPOTHESIS: The safety of cangrelor after the transition to oral P2Y12 inhibitors was evaluated as the incidence of bleeding outcomes in the 30 days following PCI according to postauthorization safety study guidelines. METHODS: Adults with ACS who were treated with cangrelor in one of the 28 centers involved in the study. Patients who consented to participate were followed in the 30 days following their PCI. Bleedings (Bleeding Academic Research Consortium [BARC] classification), major adverse cardiac events (MACEs), and adverse events were recorded. The interim results at two-thirds of the enrollment period are presented. RESULTS: A total of 17 bleedings were observed in the 320 patients who completed the study at this stage. All bleedings were classified as BARC Type 1-2, except for one case of Type 3a (vessel puncture site hematoma). Four patients experienced MACEs (2 acute myocardial infarctions, 1 sudden cardiac death, 1 noncardiovascular death due to respiratory distress, and multiorgan failure). None of the bleedings was rated as related to cangrelor. CONCLUSIONS: The interim results of the ARCANGELO study provide a preliminary confirmation that the use of cangrelor on patients with ACS undergoing PCI is not associated with severe bleedings.

COMPASS criteria applied to a contemporary cohort of unselected patients with stable coronary artery diseases: insights from the START registry.

AIMS: Recently, the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial demonstrated that dual therapy reduced cardiovascular outcomes compared with aspirin alone in patients with stable atherosclerotic disease. METHODS AND RESULTS: We sought to assess the proportion of patients eligible for the COMPASS trial and to compare the epidemiology and outcome of these patients with those without COMPASS inclusion or with any exclusion criteria in a contemporary, nationwide cohort of patients with stable coronary artery disease. Among the 4068 patients with detailed information allowing evaluation of eligibility, 1416 (34.8%) did not fulfil the inclusion criteria (COMPASS-Not-Included), 841 (20.7%) had exclusion criteria (COMPASS-Excluded), and the remaining 1811 (44.5%) were classified as COMPASS-Like. At 1 year, the incidence of major adverse cardiovascular event (MACE), a composite of cardiovascular death, myocardial infarction, and stroke, was 0.9% in the COMPASS-Not-Included and 2.0% in the COMPASS-Like (P = 0.01), and 5.0% in the COMPASS-Excluded group (P < 0.0001 for all comparisons). Among the COMPASS-Like population, patients with multiple COMPASS enrichment criteria presented a significant increase in the risk of MACE (from 1.0% to 3.3% in those with 1 and ≥3 criteria, respectively; P = 0.012), and a modest absolute increase in major bleeding risk (from 0.2% to 0.4%, respectively; P = 0.46). CONCLUSION: In a contemporary real-world cohort registry of stable coronary artery disease, most patients resulted as eligible for the COMPASS. These patients presented a considerable annual risk of MACE that consistently increases in the presence of multiple risk factors.

The Pharmacological Approach to Oncologic Patients with Acute Coronary Syndrome.

Among acute coronary syndrome (ACS) patients, 15% have concomitant cancer, especially in the first 6 months after their diagnosis, as well as in advanced metastatic stages. Lung, gastric, and pancreatic cancers are the most frequent malignancies associated with ACS. Chemotherapy and radiotherapy exert prothrombotic, vasospastic, and proinflammatory actions. The management of cancer patients with ACS is quite challenging: percutaneous revascularization is often underused, and antiplatelet and anticoagulant pharmacological therapy should be individually tailored to the thrombotic risk and to the bleeding complications. Sometimes oncological patients also show different degrees of thrombocytopenia, which further complicates the pharmacological strategies. The aim of this review is to summarize the current evidence regarding the treatment of ACS in cancer patients and to suggest the optimal management and therapy to reduce the risk of adverse coronary events after ACS in this high-risk population.

[Appropriateness criteria for the management of lipid-lowering therapy with alirocumab in high cardiovascular risk patients. The opinion of a multidisciplinary group of Italian experts]. / Criteri di appropriatezza nella gestione della terapia ipocolesterolemizzante con alirocumab nel paziente ad alto rischio cardiovascolare. L'opinione di un gruppo multidisciplinare di esperti italiani.

High levels of LDL cholesterol (LDL-C) represent a causal factor for cardiovascular diseases on an atherosclerotic basis, with a direct correlation between these and mortality or cardiovascular events, such that the reduction of both is associated proportionally and linearly with the reduction of LDL-C.Statins and ezetimibe are used for LDL-C lowering but may not be sufficient to achieve the targets defined by the ESC/EAS guidelines, which recommend use of PCSK9 inhibitors for further LDL-C reduction in patients not at goal.This project submitted 86 clinical scenarios to a group of experts, cardiologists, internists and lipidologists, collecting their opinion on the appropriateness of different behaviors and decisions. We used the RAND/UCLA method of assessing the appropriateness of clinical interventions, validated to combine the best scientific evidence available with expert judgment. To this end, the benefit-risk ratio was evaluated in the proposed clinical scenarios. Each indication was classified as "appropriate", "uncertain" or "inappropriate" based on the average score given by the participants.This document presents the results of a consensus process that led to the development of recommendations for the management of clinical scenarios on the treatment of patients with dyslipidemia, which cannot always be solved with scientific evidence alone.

ANMCO POSITION PAPER: The role of cardiology in the management of the health needs in the post-Covid-19 era.

At the end of 2019 a new Coronavirus appeared in China and, from there, it spread to the rest of the world. On 24th May, 2020, the confirmed cases in the world were more than 5 million and the deaths almost 350.000. At the end of May, Italy reported more than 27.000 cases among healthcare professionals and 163 deaths among physicians. The National Health Systems from almost all over the world, including Italy's, were unprepared for this pandemic, and this generated important consequences of organizational nature. All elective and urgent specialized activities were completely reorganized, and many hospital units were partially or completely converted to the care of the COVID-19 patients. A significant reduction in hospital admissions for acute heart disease were recorded during the SARS-CoV-2 pandemic and, in order to gradually resume hospital activities, the Italian National Phase 2 Plan for the partial recovery of activities, must necessarily be associated with a Phase 2 Health Plan. In regards to the cardiac outpatient activities we need to identify short term goals, i.e. reschedule the suspended outpatient activities, revise the waiting lists, review the 'timings' of the bookings. This will reduce the number of available examinations compared to the pre-Covid-19 era. The GP's collaboration could represent an important resource, a structured telephone follow-up plan is advisable with the nursing staff's involvement. It is equally important to set medium-long term goals, the pandemic could be an appropriate moment for making a virtue of necessity. It is time to reason on prescriptive appropriateness, telemedicine implementation intended as integration to the traditional management. It is time to restructure the cardiological units related to the issue of structural adjustment to the needs for functional isolation. Moreover, the creation of 'grey zones' with multidisciplinary management according to the intensity of care levels seems to be necessary as well as the identification of Covid dedicated cardiologies. Finally, the pandemic could represent the opportunity for a permanent renovation of the cardiological and territorial medicine activities.

Clinical outcomes, pharmacological treatment, and quality of life of patients with stable coronary artery diseases managed by cardiologists: 1-year results of the START study.

AIMS: We evaluated the 1-year clinical events, pharmacological management, and quality of life in a contemporary cohort of stable coronary artery disease (CAD) patients managed by cardiologists. METHODS AND RESULTS: START (STable Coronary Artery Diseases RegisTry) was a prospective, observational, nationwide study that enrolled 5070 stable CAD patients over 3 months in 183 cardiology centres in Italy. At 1 year, 4790 (94.5%) patients had data on vital status. Death occurred in 107 (2.2%) patients and the cause of death was cardiovascular in 41 (38.3%) of cases. Among the 4775 patients with follow-up data on clinical events available, a hospitalization due to cardiovascular and non-cardiovascular causes occurred in 523 (11.0%) and in 231 (4.8%) of cases, respectively. Over 60% of patients reported as 'no problems' in all domains (61.4-84.5%) of the EuroQoL quality of life 5D-5L questionnaire. Among the 3239 patients with clinical visit/telephone interview at follow-up, in whom optimal medical therapy (OMT; aspirin or thienopyridine, ß-blocker, and statin) was prescribed at enrolment, 2971 (91.7%) were still receiving OMT at follow-up. At multivariable analysis, only increasing age (odds ratio 0.98; 95% confidence interval 0.97-0.99; P = 0.04) resulted as independent negative predictor of OMT persistence at 1 year from enrolment. CONCLUSION: In this large, contemporary registry, stable CAD patients managed by cardiologists presented a high rate of clinical events at 1 year. Nevertheless, the persistence to OMT and quality of life appeared reasonable.

Management of atrial fibrillation in the emergency room and in the cardiology ward: the BLITZ AF study.

AIMS: To assess the number of admissions to the emergency room (ER) of patients with atrial fibrillation (AF) or atrial flutter (af) and their subsequent management. To evaluate the clinical profile and the use of antithrombotics and antiarrhythmic therapy in patients with AF admitted to cardiology wards. METHODS AND RESULTS: BLITZ-AF is a multicentre, observational study conducted in 154 centres on patients with AF/af. In each centre, data were collected, retrospectively for 4 weeks in ER and prospectively for 12 weeks in cardiology wards. In ER, there were 6275 admissions. Atrial fibrillation was the main diagnosis in 52.9% of the cases, af in 5.9%. Atrial fibrillation represented 1.0% of all ER admissions and 1.7% of all hospital admissions. A cardioversion has been performed in nearly 25% of the cases. Out of 4126 patients, 52.2% were admitted in cardiology ward; mean age was 74 ± 11 years, 41% were females. Patients with non-valvular AF were 3848 (93.3%); CHA2DS2-VASc score was ≥2 in 87.4%. Cardioversion was attempted in 38.8% of the patients. In-hospital mortality was 1.2%. At discharge, 42.6% of the patients were treated with vitamin K antagonists, 39.5% with direct oral anticoagulants, 13.6% with other antithrombotic drugs, and 4.2% did not take any antithrombotic agent. Rate control strategy was pursued in 47.2%, rhythm control in 44.0%, 45.6% were discharged in sinus rhythm. CONCLUSION: Atrial fibrillation still represents a significant burden on health care system. Oral anticoagulant use increased over time even if compliance with guidelines, with respect to prevention of the risk of stroke, remains suboptimal.

Safety and feasibility of balloon aortic valvuloplasty in non-TAVI centers: The "BAV for life" experience.

OBJECTIVES: To evaluate the safety and the feasibility of balloon aortic valvuloplasty (BAV) procedure made by trained operators in centers not performing transcatheter aortic valve implantation (TAVI). BACKGROUND: BAV is a valuable therapeutic tool for patients with symptomatic severe aortic valve stenosis (AS) at prohibitive risk for TAVI or surgery. METHODS: Consecutive high-risk AS patients underwent BAV in five non-TAVI centers, where BAV operators had completed a 6-month training period in high-volume TAVI centers (Group A). All clinical, echocardiographic, and procedural data were prospectively collected and compared with data of patients treated in TAVI center (Group B). RESULTS: Between June 2016 and June 2017, 55 patients (83.9 ± 7.0 years) were enrolled: 25 in Group A and 30 in Group B. After BAV, a substantial reduction of the peak-to-peak aortic valve gradient was obtained in both groups (-35.3 ± 15.2 vs -28.8 ± 13.9 mmHg, P =0.25). No major bleeding or vascular complications occurred. In-hospital death was observed in three patients of Group A and two patients of Group B (P =0.493). The mean follow-up time was 303 ± 188 days; no patients were lost. The 1-year survival free from overall death (Group A 75.8% vs Group B 68.8%; P =0.682) and heart failure rehospitalization (Group A 73.0% vs Group B 66.8%; P =0.687) was similar in the two groups. At multivariable analysis, low left ventricular (LV) ejection fraction (HR: 0.943; P = 0.011) and cardiogenic shock (HR: 5.128; P = 0.002) at admission were independent predictors of mortality. CONCLUSIONS: BAV is a safe and effective procedure that can be performed by trained operators in centers not performing TAVI.

[ANMCO position paper on sacubitril/valsartan in the management of patients with heart failure]. / Position paper ANMCO sull'utilizzo della terapia con sacubitril/valsartan nel paziente con scompenso cardiaco.

Sacubitril/valsartan, the first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is the first medication to demonstrate a mortality benefit in patients with chronic heart failure and reduced ejection fraction (HFrEF) since the early 2000s. Sacubitril/valsartan simultaneously suppresses renin-angiotensin-aldosterone system activation through blockade of angiotensin II type 1 receptors and enhances the activity of vasoactive peptides including natriuretic peptides, through inhibition of neprilysin, the enzyme responsible for their degradation. In the landmark PARADIGM-HF trial, patients with HFrEF treated with sacubitril/valsartan had a 20% reduction in the primary composite endpoint of cardiovascular death or heart failure hospitalization, a 20% lower risk of cardiovascular death, a 21% to 20% lower risk of a first heart failure hospitalization, and a 16% to 20% lower risk of death from any cause, compared with subjects allocated to enalapril (all p<0.001).Following the trial, new international guidelines endorsed sacubitril/valsartan as a class I recommendation for the management of patients with HFrEF who remain symptomatic despite optimal medical management. In Italy, sacubitril/valsartan is reimbursed by the National Health Service since March 2017 within criteria set by the Italian Medicines Agency subject to patient inclusion in a dedicated monitoring registry. Although numerous post-hoc analyses of the original trial suggested that the benefits of this innovative medication may extend across a variety of subgroups, many questions do not yet have an evidence-based answer.In this position paper, we discuss the current role of sacubitril/valsartan in the management of chronic HFrEF, treatment eligibility and the modulating role of patients' characteristics. Moreover, we address concerns elicited by the PARADIGM-HF study and shortcomings of this novel drug, to clarify the place of this new therapy in the context of global care of heart failure in Italy. Our aim is to provide clinical cardiologists with a concise and practical guidance on when and how to use sacubitril/valsartan, to assist clinicians in closing the gap between scientific innovation and real-world experience.

Lights and shadows of long-term dual antiplatelet therapy in "real life" clinical scenarios.

Dual antiplatelet therapy (DAPT) is a cornerstone of treatment for patients with acute coronary syndromes (ACS). Mounting evidences have opened the debate about the optimal DAPT duration. Considering the ACS-pathophysiology, the most recent guidelines recommend DAPT in all ACS patients for at least 12 months unless there are contraindications such as excessive risk of bleeding. Thus, it can be considered acceptable earlier discontinuation if the risk of morbidity from bleeding outweighs the anticipated benefit. On the other hand, several studies have clearly indicated that a significant burden of platelet related-events, such as stroke and new ACS might occur after this period, suggesting that potential benefits might derive by prolonging DAPT beyond 12 months (Long DAPT). Indeed, although current guidelines give some indications about patients eligible for Long DAPT, they do not embrace several real-life clinical scenarios. Thus, in such scenarios, how to decide whether a patient is eligible for Long DAPT or not might be still challenging for clinicians. This position paper presents and discusses various "real-life" clinical scenarios in ACS patients, in order to propose several possible recommendations to overcome guidelines potential limitations.

Mitral Prolapse: An Old Mysterious Entity - The Incremental Role of Multimodality Imaging in Sports Eligibility.

Mitral valve prolapse is generally a benign condition characterized by fibromyxomatous changes of the mitral leaflet with displacement into the left atrium and late-systolic regurgitation. Although it is an old clinical entity, it still arouses perplexity in diagnosis and clinical management. Complications, such as mitral regurgitation (MR), atrial fibrillation, congestive heart failure, endocarditis, ventricular arrhythmias, and sudden cardiac death (SCD), have been reported. A large proportion of the overall causes of SCD in young competitive athletes is explained by mitral valve prolapse. Recent studies have shown the fibrosis of the papillary muscles and inferobasal left ventricular wall in mitral valve prolapse, suggesting a possible origin of ventricular fatal arrhythmias. Athletes with mitral valve prolapse and MR should undergo annual evaluations including physical examination, echocardiogram, and exercise stress testing to evaluate the cardiovascular risks of competitive sports and obtain the eligibility. In this setting, multimodality imaging techniques - echocardiography, cardiac magnetic resonance, and cardiac computed tomography - should provide a broad spectrum of information, from diagnosis to clinical management of the major clinical profiles of the disease.

ANMCO/ISS/AMD/ANCE/ARCA/FADOI/GICR-IACPR/SICI-GISE/SIBioC/SIC/SICOA/SID/SIF/SIMEU/SIMG/SIMI/SISA Joint Consensus Document on cholesterol and cardiovascular risk: diagnostic-therapeutic pathway in Italy.

Atherosclerotic cardiovascular disease still represents the leading cause of death in Western countries. A wealth of scientific evidence demonstrates that increased blood cholesterol levels have a major impact on the outbreak and progression of atherosclerotic plaques. Moreover, several cholesterol-lowering pharmacological agents, including statins and ezetimibe, have proved effective in improving clinical outcomes. This document focuses on the clinical management of hypercholesterolaemia and has been conceived by 16 Italian medical associations with the support of the Italian National Institute of Health. The authors discuss in detail the role of hypercholesterolaemia in the genesis of atherosclerotic cardiovascular disease. In addition, the implications for high cholesterol levels in the definition of the individual cardiovascular risk profile have been carefully analysed, while all available therapeutic options for blood cholesterol reduction and cardiovascular risk mitigation have been explored. Finally, this document outlines the diagnostic and therapeutic pathways for the clinical management of patients with hypercholesterolaemia.

Consensus Document of the Italian Association of Hospital Cardiologists (ANMCO), Italian Society of Cardiology (SIC), Italian Association of Interventional Cardiology (SICI-GISE) and Italian Society of Cardiac Surgery (SICCH): clinical approach to pharmacologic pre-treatment for patients undergoing myocardial revascularization procedures.

The wide availability of effective drugs in reducing cardiovascular events together with the use of myocardial revascularization has greatly improved the prognosis of patients with coronary artery disease. The combination of antithrombotic drugs to be administered before the knowledge of the coronary anatomy and before the consequent therapeutic strategies, can allow to anticipate optimal treatment, but can also expose the patients at risk of bleeding that, especially in acute coronary syndromes, can significantly weigh on their prognosis, even more than the expected theoretical benefit. In non ST-elevation acute coronary syndromes patients in particular, we propose a 'selective pre-treatment' with P2Y12 inhibitors, based on the ischaemic risk, on the bleeding risk and on the time scheduled for the execution of coronary angiography. Much of the problems concerning this issue would be resolved by an early access to coronary angiography, particularly for patients at higher ischaemic and bleeding risk.

ANMCO Position Paper: the use of non-vitamin K dependent new oral anticoagulant(s) in pulmonary embolism therapy and prevention.

The new oral anticoagulants (NOACs) have radically changed the approach to the treatment and prevention of thromboembolic pulmonary embolism. The authors of this position paper face, in succession, issues concerning NOACs, including (i) their mechanism of action, pharmacodynamics, and pharmacokinetics; (ii) the use in the acute phase with the 'double drug single dose' approach or with 'single drug double dose'; (iii) the use in the extended phase with demonstrated efficacy and with low incidence of bleeding events; (iv) the encouraging use of NOACs in particular subgroups of patients such as those with cancer, the ones under- or overweight, with renal insufficiency (creatinine clearance > 30 mL/min), the elderly (>75 years); (v) they propose a possible laboratory clinical pathway for follow-up; and (vi) carry out an examination on the main drug interactions, their potential bleeding risk, and the way to deal with some bleeding complications. The authors conclude that the use of NOACs both in the acute phase and in the extended phase is equally effective to conventional therapy and associated with fewer major bleeding events, which make their use in patients at higher risk of recurrences safer.