ANMCO position paper 'Appropriateness of prescribing direct oral anticoagulants in stroke and systemic thromboembolism prevention in adult patients with non-valvular atrial fibrillation'.

The appropriateness of prescribing direct oral anticoagulants [dabigatran, rivaroxaban, apixaban, and edoxaban (DOACs)] is regulated on the criteria established in Phase III trials. These criteria are reported in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of lower doses than those recommended in drug data sheets is not uncommon. Literature data show that the inappropriate prescription of reduced doses causes drug underexposure and up to a three-fold increase in the risk of stroke/ischaemic transient attack, systemic thromboembolism, and hospitalization. Possible causes of the deviation between the dose that should be prescribed and that prescribed in the real world include erroneous prescription, an overstated haemorrhagic risk perception, and the presence of frail and complex patients in clinical practice who were not included in pivotal trials, which makes it difficult to apply study results to the real world. For these reasons, we summarize DOAC indications and contraindications. We also suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory bodies recommend.

Smoking cessation interventions after acute coronary syndromes. Results of a cross-sectional survey in the Lazio Region of Italy.

Given the limited research on Italian hospital smoking care practices, a cross-sectional survey was undertaken in April-May 2011 to describe the current status of smoking cessation interventions for ACS patients in cardiovascular institutions of the Lazio Region of Italy. Lazio is a region of central Italy with a resident population of about 5,600,000. According to the data of the Regional Health Authority, about 10.000 patients are admitted for ACS every year in this region of Italy. Acute cardiac care in the region is currently provided by 33 Cardiology Divisions. All of these units were considered as eligible for the survey. The eligible respondent for each unit was the director. A self-report questionnaire was developed based on previous studies that examined the specific features of smoking cessation care provided to hospitalised patients. Questionnaires were forwarded by the Lazio Regional Section of the Italian National Association of Hospital Cardiologists (ANMCO). Completed questionnaires were received from 22 of the 33 eligible Divisions (66%). These 22 responding units currently provide acute care to about 70% of all ACS patients of the region. Responding units were more likely to represent public non-teaching hospitals (p = 0.002), while non-responders were mostly from private non-teaching institutions (p = 0.04). Response rates were not influenced by the presence of either interventional catheterization laboratory (Cathlab) or cardiac surgery within the hospitals. The survey suggest that most of cardiology units fail to provide recommended smoking care interventions to ACS patients. In particular, brief smoking cessation advice before discharge represents the only systematically implemented approach in clinical practice (22 units; 100%). Smoking cessation counselling is provided only in 9 units (40%). Specific pharmacotherapy is prescribed in selected case only in about one third of units (7 units; 32%), with varenicline being the preferred drug. Structural variables and organizational complexity have no influence on smoking care, as hospitals with Cathlab and cardiac surgery do not implement more effective strategies. Overall, this survey shows that the majority of smoking ACS inpatients may receive inadequate smoking care and that hospitals have considerable opportunity for improvement.

Direct Oral Anticoagulants in Patients with Obesity and Atrial Fibrillation: Position Paper of Italian National Association of Hospital Cardiologists (ANMCO).

The use of the direct oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban (DOACs) offers some major advantages over warfarin and other vitamin K antagonists (VKAs). One advantage is the possibility to use a fixed dose in normal-weight patients, overweight patients and patients with obesity. However, the "one size fits all" strategy raised a concern regarding the possibility to undertreat patients with a high body mass index. No randomized controlled trials (RCTs) have ever compared VKAs and DOACs in this population. We analyzed data from the literature on DOAC pharmacokinetics and pharmacodynamics, results from the four pivotal phase III trials on non-valvular atrial fibrillation, retrospective observational studies and metanalyses. While we are aware of the limitation imposed by the absence of specific RCTs, we propose the position of the Italian Association of Hospital Cardiologists (ANMCO) on the use of DOACs in patients with obesity based on the existing evidence.

[ANMCO Position paper: Prescription appropriateness of direct oral anticoagulants for stroke and systemic thromboembolis with non-valvular atrial fibrillation]. / Position paper ANMCO: Appropriatezza prescrittiva degli anticoagulanti orali diretti nella prevenzione dell'ictus e dell'embolia sistemica nei pazienti adulti affetti da fibrillazione atriale non valvolare.

The prescription appropriateness of direct oral anticoagulants (DOACs [dabigatran, rivaroxaban, apixaban, and edoxaban]) is carefully regulated, taking into account the criteria established in phase III trials and listed in the summary of the product characteristics of the four DOACs. In clinical practice, prescriptions are not always in compliance with established indications. In particular, the use of doses lower than those recommended in drug data sheets is relatively frequent. Literature data show that the inappropriate prescription of DOAC doses causes drug underexposure and an up to three-fold increase in the risk of stroke/transient ischemic attack, systemic thromboembolism, and hospitalizations. Possible causes of the deviation between the dose that should be prescribed and that actually employed may include erroneous prescriptions, an overstated bleeding risk perception, and the presence of frail patients, who were not included in pivotal trials. For these reasons, we summarize DOAC indications and contraindications and suggest the appropriate use of DOACs in common clinical scenarios, in accordance with what international guidelines and national and international health regulatory agencies recommend.

Myocardial infarction induces embryonic reprogramming of epicardial c-kit(+) cells: role of the pericardial fluid.

Stem cells expressing c-kit have been identified in the adult epicardium. In mice, after myocardial infarction, these cells proliferate, migrate to the injury site and differentiate toward myocardial and vascular phenotype. We hypothesized that, acutely after myocardial infarction, pericardial sac integrity and pericardial fluid (PF) may play a role on epicardial cell gene expression, proliferation and differentiation. Microarray analysis indicated that, in the presence of an intact pericardial sac, myocardial infarction modulated 246 genes in epicardial cells most of which were related to cell proliferation, cytoskeletal organization, wound repair and signal transduction. Interestingly, WT1, Tbx18 and RALDH2, notably involved in epicardial embryonic development, were markedly up-regulated. Importantly, coexpression of stem cell antigen c-kit and WT1 and/or Tbx18 was detected by immunohistochemistry in the mouse epicardium during embryogenesis as well as in adult mouse infarcted heart. Injection of human pericardial fluid from patients with acute myocardial ischemia (PFMI) in the pericardial cavity of non-infarcted mouse hearts, enhanced, epicardial cell proliferation and WT1 expression. Further, PFMI supplementation to hypoxic cultured human epicardial c-kit(+) cells increased WT1 and Tbx18 mRNA expression. Finally, insulin-like growth factor 1, hepatocyte growth factor and high mobility group box 1 protein, previously involved in cardiac c-kit(+) cell proliferation and differentiation, were increased in PFMI compared to the pericardial fluid of non ischemic patients. In conclusion, myocardial infarction reactivates an embryonic program in epicardial c-kit(+) cells; soluble factors released in the pericardial fluids following myocardial necrosis may play a role in this process.

Identification of myocardial and vascular precursor cells in human and mouse epicardium.

During cardiac development, the epicardium is the source of multipotent mesenchymal cells, which give rise to endothelial and smooth muscle cells in coronary vessels and also, possibly, to cardiomyocytes. The aim of the present study was to determine whether stem cells are retained in the adult human and murine epicardium and to investigate the regenerative potential of these cells following acute myocardial infarction. We show that c-kit(+) and CD34(+) cells can indeed be detected in human fetal and adult epicardium and that they represent 2 distinct populations. Both subsets of cells were negative for CD45, a cell surface marker that identifies the hematopoietic cell lineage. Immunofluorescence revealed that freshly isolated c-kit(+) and CD34(+) cells expressed early and late cardiac transcription factors and could acquire an endothelial phenotype in vitro. In the murine model of myocardial infarction, there was an increase in the absolute number and proliferation of epicardial c-kit(+) cells 3 days after coronary ligation; at this time point, epicardial c-kit(+) cells were identified in the subepicardial space and expressed GATA4. Furthermore, 1 week after myocardial infarction, cells coexpressing c-kit(+), together with endothelial or smooth muscle cell markers, were identified in the wall of subepicardial blood vessels. In summary, the postnatal epicardium contains a cell population with stem cell characteristics that retains the ability to give rise to myocardial precursors and vascular cells. These cells may play a role in the regenerative response to cardiac damage.

HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells.

High Mobility Box 1 Protein (HMGB1) is a cytokine released into the extracellular space by necrotic cells and activated macrophages in response to injury. We recently demonstrated that HMGB1 administration into the mouse heart during acute myocardial infarction induces cardiac tissue regeneration by activating resident cardiac c-kit+ cells (CSCs) and significantly enhances left ventricular function. In the present study it was analyzed the hypothesis that human cardiac fibroblasts (cFbs) exposed to HMGB1 may exert a paracrine effect on mouse and human CSCs. Human cFbs expressed the HMGB1 receptor RAGE. Luminex technology and ELISA assays revealed that HMGB1 significantly enhanced VEGF, PlGF, Mip-1alpha, IFN-gamma, GM-CSF, Il-10, Il-1beta, Il-4, Il-1ra, Il-9 and TNF-alpha in cFbs cell culture medium. HMGB1-stimulated cFbs conditioned media induced CSC migration and proliferation. These effects were significantly higher to those obtained when HMGB1 was added directly to the culture medium. In conclusion, we provide evidence that HMGB1 may act in a paracrine manner stimulating growth factor, cytokine and chemokine release by cFbs which, in turn, modulate CSC function. Via this mechanism HMGB1 may contribute to cardiac tissue regeneration.

Autologous bone marrow mononuclear cell transplantation in patients undergoing coronary artery bypass grafting.

BACKGROUND: Recent studies have shown that autologous bone marrow mononuclear cell (aBM-MNC) transplantation can be effectively performed in human beings either by the coronary route or by endoventricular injections. However, scanty data are available for patients undergoing coronary artery bypass grafting (CABG). Accordingly, the aim of this study was to evaluate the feasibility and safety of aBM-MNC transplantation in patients with recent myocardial infarction undergoing CABG. METHODS AND RESULTS: The study population included 36 consecutive patients with recent myocardial infarction (< 6 months) undergoing CABG. Eighteen patients (17 men, mean age 64 years) underwent CABG plus aBM-MNC transplantation, whereas 18 subjects undergoing conventional CABG (17 men, mean age 67 years) served as control subjects. Cell transplantation was performed by direct injections in the border zone of the recently infarcted area. An average number of 292 +/- 232 x 10(6) aBM-MNCs was injected in each patient. When compared with control subjects, transplanted patients showed higher values of troponin I peak after CABG (median values of 1.65 ng/mL vs 0.64 ng/mL, P < .001). No major transplant-related adverse event could be detected. During follow-up, transplanted patients had an improvement in left ventricular ejection fraction (from 0.46 to 0.51, P < .05) and wall motion score index (from 1.71 to 1.42, P < .01). The incidence of arrhythmias immediately after CABG and during follow-up was similar in the 2 groups. CONCLUSIONS: Our data support the idea that direct injection of aBM-MNCs in the myocardium during CABG is feasible and safe. Larger studies are needed to assess the efficacy of such an approach in patients undergoing CABG.

Stem cell therapy for cardiac arrhythmias.

Clinical studies suggest that stem cell transplantation (SCT) is feasible and has the potential for beneficial effects in several cardiac affections, including myocardial infarction and advanced heart failure. However, concern exists about the possible occurrence of serious arrhythmias after SCT, even if such complication has been shown only in case of skeletal myoblast transplantation. SCT might induce arrhythmias by several mechanisms, such as electrotonic stimulation of cardiac cells, electrical heterogeneity of action potentials during stem cell differentiation process, increased nerve sprouting, and local tissue injury induced by intramyocardial injection. As a matter of fact, the use of endothelial progenitor cells from the peripheral blood or of stem cells from bone marrow has not been associated with any significant cardiac rhythm disturbance. Recently, a new opportunity for SCT has emerged: the development of a biological cardiac pacemaker. Both gene therapy and cell therapy have been used in this new perspective. In fact, at present, the transformation of a normal cardiomyocyte in a pacemaker cell can be obtained in animal models by the injection of a plasmid or virus, incorporating the gene encoding for specific proteins. This procedure transforms cardiomyocytes in transgenic cells that may show an overexpression of beta2-adrenergic receptors, or abnormal membrane ion channels. As an alternative, genetically modified mesenchymal stem cells can be delivered within the heart and engraft to develop a biological pacemaker. To date, several studies have been performed in different animal models employing both cell and gene therapy. However, complex problems concerning safety and efficacy require a solution before we can move to the step of clinical evaluation in human beings.

A complete atrioventricular block secondary to myocardial metastases of lung cancer. A case report.

A metastatic involvement of the heart is an uncommon phenomenon in clinical practice; it is more frequent in patients with end-stage disease and a wide tumor spread. The clinical diagnosis is very difficult because there are no early symptoms and most often, the presence of metastases in other sites, such as lung and lymph nodes, may determine a misunderstanding of the clinical picture. We report the case of a young male (44 years old) with a complete atrioventricular block due to metastatic myocardial involvement from a primary occult lung cancer. The first symptom of the disease was a syncopal spell. In spite of permanent pacemaker implantation, the patient died suddenly and unexpectedly after 3 days. Autopsy revealed an anaplastic carcinoma of the right lung hilus. The myocardium was invaded by numerous metastatic nodules, particularly in the interventricular septum and in the left ventricular wall.

[Italian cardiologists and tobacco smoking. A survey on the prevalence and knowledge of smoking and strategies for smoking cessation in a cohort of Italian cardiologists]. / Cardiologi italiani e fumo di tabacco. Survey su prevalenza e conoscenza del tabagismo e delle strategie antifumo di una coorte di cardiologi italiani.

BACKGROUND: Tobacco use is the single most preventable cause of death. Its cessation is the most cost-effective strategy for reducing long-term cardiovascular morbidity and mortality. Although both healthcare professionals and the general population are aware of the detrimental effects of smoking on health, more than 25% of Italians are current smokers. Recent surveys showed that almost 50% of smoker patients relapse to smoke after having been discharged for acute coronary syndrome. Physicians who smoke may be a barrier for effective cessation interventions. Thus, it is important to assess cardiologists' attitude toward smoking habits and the implementation of smoking cessation programs. METHODS: The survey "Italian cardiologists and smoking habits" has been held in 2013 during the 44° National Congress of the Italian Association of Hospital Cardiologists (ANMCO) to assess cardiologists' smoking status, their level of knowledge about smoking cessation interventions and their involvement in the management of smoking cessation. Out of more than 1200 cardiologists attending the ANMCO congress, 610 subjects (aged 51 ± 11 years) answered an anonymous 35-item questionnaire; they were asked to declare their smoking status (9.5% current smokers). RESULTS: Among doctors who attended the survey, 58% correctly indicated smoking as an addiction and 45% regularly advised their patients to stop smoking. The majority of cardiologists (93%) reported a positive attitude toward smoking cessation strategies, 62% of them thought that cardiologists themselves should treat smoking dependence, though specific tools (70%) and education for the management of smoking cessation are lacking (66%). Two thirds of the entire sample of ANMCO cardiologists declared their willingness to participate in specialized educational programs. CONCLUSIONS: More than a half of Italian cardiologists are aware that smoking is an addiction. Although they feel themselves yet inadequate toward this approach, they are favorable to implement their own knowledge and skills toward smoking cessation.

Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis.

BACKGROUND: We recently demonstrated that epicardial progenitor cells participate in the regenerative response to myocardial infarction (MI) and factors released in the pericardial fluid (PF) may play a key role in this process. Exosomes are secreted nanovesicles of endocytic origin, identified in most body fluids, which may contain molecules able to modulate a variety of cell functions. Here, we investigated whether exosomes are present in the PF and their potential role in cardiac repair. METHODS AND RESULTS: Early gene expression studies in 3day-infarcted mouse hearts showed that PF induces epithelial-to-mesenchymal transition (EMT) in epicardial cells. Exosomes were identified in PFs from non-infarcted patients (PFC) and patients with acute MI (PFMI). A shotgun proteomics analysis identified clusterin in exosomes isolated from PFMI but not from PFC. Notably, clusterin has a protective effect on cardiomyocytes after acute MI in vivo and is an important mediator of TGFß-induced. Clusterin addition to the pericardial sac determined an increase in epicardial cells expressing the EMT marker α-SMA and, interestingly, an increase in the number of epicardial cells ckit(+)/α-SMA(+), 7days following MI. Importantly, clusterin treatment enhanced arteriolar length density and lowered apoptotic rates in the peri-infarct area. Hemodynamic studies demonstrated an improvement in cardiac function in clusterin-treated compared to untreated infarcted hearts. CONCLUSIONS: Exosomes are present and detectable in the PFs. Clusterin was identified in PFMI-exosomes and might account for an improvement in myocardial performance following MI through a framework including EMT-mediated epicardial activation, arteriogenesis and reduced cardiomyocyte apoptosis.

Effect of smoking relapse on outcome after acute coronary syndromes.

The aim of the present study was to evaluate the smoking relapse rate among smokers who had become abstinent during admission for acute coronary syndromes. The association between smoking relapse and mortality was also analyzed. A cohort of 1,294 consecutive active smokers who had interrupted smoking after admission for acute coronary syndromes (1,018 men and 276 women, mean age 59.7 ± 12.3 years) was followed up for 12 months after the index admission. All patients received a brief in-hospital smoking cessation intervention consisting of repeated counseling sessions. During follow-up, 813 patients (62.8%) resumed regular smoking (median interval to relapse 19 days, interquartile range 9 to 76). Increasing age (hazard ratio [HR] 1.034 per year, 95% confidence interval [CI] 1.028 to 1.039, p = 0.001) and female gender (HR 1.23, 95% CI 1.09 to 1.42, p = 0.03) were independent predictors of smoking relapse. Patients enrolled in a cardiac rehabilitation program (HR 0.74, 95% CI 0.51 to 0.91, p = 0.02) and those with diabetes (HR 0.79, 95% CI 0.68 to 0.94, p = 0.03) were more likely to remain abstinent. During follow-up, 97 patients died (1-year probability of death 0.075, 95% CI 0.061 to 0.090). Multivariate analysis with the Cox proportional hazard regression method, including smoking relapse as a time-dependent covariate, demonstrated that, after adjustment for patient demographics, the clinical history features and variables related to the index event, the resumption of smoking was an independent predictor of total mortality (HR 3.1, 95% CI 1.3 to 5.7, p = 0.004). In conclusion, smoking relapse after acute coronary syndromes is associated with increased mortality, and counseling interventions should be integrated into the postdischarge support to reduce the negative effects of smoking resumption.

Full-dose atorvastatin versus conventional medical therapy after non-ST-elevation acute myocardial infarction in patients with advanced non-revascularisable coronary artery disease.

AIMS: This study tested the hypothesis that the addition of full-dose atorvastatin (80 mg/day) to conventional medical treatment could reduce ischaemic recurrences after non-ST-elevation acute myocardial infarction (NSTE-AMI) in patients with severe and diffuse coronary artery disease (CAD) not amenable to any form of mechanical revascularisation. METHODS AND RESULTS: The study was an open-label, randomised, controlled, blinded end-point classification trial, employing the PROBE (Prospective Open Treatment and Blinded End Point Evaluation) design. A total of 290 patients (mean age 74.6 +/- 9.6 years) with NSTE-AMI and angiographic evidence of severe and diffuse CAD, not amenable to revascularisation by either coronary surgery or angioplasty, were randomised to atorvastatin 80 mg/day (n = 144) or conventional medical treatment (n = 146). A primary end point event (combination of cardiovascular death, non-fatal acute myocardial reinfarction and disabling stroke within 12 months of randomisation) occurred in 16.0% of patients treated with atorvastatin 80 mg/day and in 26.7% of patients receiving conventional treatment (HR 0.56; 95% CI 0.33-0.93, p = 0.027). The study was not blinded. Consequently, a bias in the assessment of clinical outcome cannot be completely excluded. CONCLUSIONS: In conclusion, when compared with a conventional treatment strategy, full-dose therapy with atorvastatin 80 mg/day provides greater protection against ischaemic recurrences after NSTE-AMI in patients with severe, diffuse, non-revascularisable CAD.

[Secondary cardiovascular prevention after acute coronary syndrome in clinical practice]. / Prevenzione cardiovascolare secondaria dopo sindrome coronarica acuta nella pratica clinica.

Secondary prevention after acute coronary syndromes should be aimed at reducing the risk of further adverse cardiovascular events, thereby improving quality of life, and lengthening survival. Despite compelling evidence from large randomized controlled trials, secondary prevention is not fully implemented in most cases after hospitalization for acute coronary syndrome. The Lazio Region (Italy) has about 5.3 million inhabitants (9% of the entire Italian population). Every year about 11 000 patients are admitted for acute coronary syndrome in hospitals of the Lazio Region. Most of these patients receive state-of-the art acute medical and interventional care during hospitalization. However, observational data suggest that after discharge acute coronary syndrome patients are neither properly followed nor receive all evidence-based treatments. This consensus document has been developed by 11 Scientific Societies of Cardiovascular and Internal Medicine in order develop a sustainable and effective clinical approach for secondary cardiovascular prevention after acute coronary syndrome in the local scenario of the Lazio Region. An evidence-based simplified decalogue for secondary cardiovascular prevention is proposed as the cornerstone of clinical intervention, taking into account regional laws and relative shortage of resources. The following appropriate interventions should be consistently applied: smoking cessation, blood pressure control (blood pressure < 130/80 mmHg), optimal lipid management (LDL cholesterol < 80 mmHg), weight and diabetes management, promotion of physical activity and rehabilitation, correct use of antiplatelet agents, beta-blockers, renin-angiotensin-aldosterone system blockers.