[Embolic stroke of undetermined source - ESUS: a new challenge for the cardiologist]. / Ictus embolico di origine indeterminata ­ ESUS: una nuova sfida per il cardiologo.

Embolic stroke of undetermined source (ESUS) is a new clinical entity which requires an accurate diagnostic work-up. The involvement of the cardiologist in this challenge is of paramount importance as in many cases an occult cardioembolic source is detectable. In the absence of subclinical atrial fibrillation detectable by prolonged ECG monitoring, potential causes of ESUS include atrial cardiomyopathy, left ventricular dysfunction or heart failure, aortic plaques and patent foramen ovale. The assessment of a causal relationship between these cardiac abnormalities and ESUS is often a difficult challenge and the randomized clinical trials performed so far failed to demonstrate a superiority of direct oral anticoagulants (DOAC) over aspirin. In selected individual patients with heart failure in sinus rhythm with high CHA2DS2-VASc score, or aortic plaques with thrombotic component, oral anticoagulation with DOAC might be considered even in the absence of evidence from randomized clinical trials.

Mechanical thrombectomy in patients with heart failure: the Italian registry of Endovascular Treatment in Acute Stroke.

BACKGROUND: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF. METHODS: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed. RESULTS: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0-2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24-1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05-1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results. CONCLUSION: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments.

[A strange case of double stroke: Dr. Jekyll and Mr. Hyde]. / Uno strano caso di doppio ictus: Dr. Jekyll e Mr. Hyde.

The etiological diagnosis of ischemic stroke is crucial for secondary prevention, but often complex for the patients' cardiovascular comorbidities, each of which may cause a stroke. We report the case of an 84-year-old patient with severe left ventricular systolic dysfunction due to dilated cardiomyopathy and implantable cardioverter-defibrillator in primary prevention, hospitalized for atherothrombotic ischemic stroke treated conservatively and later by carotid thromboendarterectomy for ulcerated plaque of the right internal carotid artery. A week after discharge, an embolic ischemic stroke occurred due to thrombosis of the left atrial appendage in absence of atrial fibrillation. A careful analysis of the patient's cardiovascular risk factors, clinical signs and neuroimages allowed for the etiological diagnosis of both cerebral ischemic events. The case is also peculiar because of left atrial appendage thrombus formation in the context of severe left ventricular systolic dysfunction in absence of atrial fibrillation. In the same patient, the recurrent stroke was not due to the same cause and, owing to the complexity of the differential diagnosis, a multidisciplinary neurological and cardiological approach is pivotal for the management of these patients.

[Atrial tachycardia degenerating into atrial fibrillation during recurrence of ischemic stroke: prolonged ECG monitoring in appropriately selected patients with embolic stroke of undetermined source]. / Tachicardia atriale che degenera in fibrillazione atriale durante recidiva di ictus ischemico: utilità diagnostica del monitoraggio ECG prolungato in pazienti con ictus embolico ad eziologia indeterminata adeguatamente selezionati.

The search for silent atrial tachyarrhythmias remains one of the cornerstones in patients suffering from embolic stroke of undetermined source. We report the case of a 76-year-old female patient suffering from recurrence of ischemic stroke, adequately selected based on the presence of predictors of atrial fibrillation (AF), to perform prolonged ECG monitoring. This recording allowed to document long-lasting AF triggered by atrial tachycardia. It was also possible to demonstrate a direct correlation between AF and new cerebral stroke.

Use of bempedoic acid for LDL cholesterol lowering and cardiovascular risk reduction: a consensus document from the Italian study group on atherosclerosis, thrombosis and vascular biology.

The clinical benefit of LDL cholesterol (LDL-C) lowering for cardiovascular disease prevention is well documented. This paper from the Italian Study Group on Atherosclerosis, Thrombosis and Vascular Biology summarizes current recommendations for treatment of hypercholesterolemia, barriers to lipid-lowering therapy implementation and tips to overcome them, as well as available evidence on the efficacy and safety of bempedoic acid. We also report an updated therapeutic algorithm for pharmacological LDL-C lowering in view of the introduction of bempedoic acid in clinical practice.

[ANMCO Position paper: Cardiovascular disease in women - prevention, diagnosis, treatment and organization of care]. / Position paper ANMCO: Malattie cardiovascolari nella donna ­ prevenzione, diagnosi, terapia e organizzazione delle cure.

Cardiovascular diseases are still the main cause of death among women despite the improvements in treatment and prognosis achieved in the last 30 years of research. The determinant factors and causes have not been completely identified but the role of "gender" is now recognized. It is well known that women tend to develop cardiovascular disease at an older age than men, and have a high probability of manifesting atypical symptoms not often recognized. Other factors may also co-exist in women, which may favor the onset of specific cardiac diseases such as those with a sex-specific etiology (differential effects of estrogens, pregnancy pathologies, etc.) and those with a different gender expression of specific and prevalent risk factors, inflammatory and autoimmune diseases and cancer. Whether the gender differences observed in cardiovascular outcomes are influenced by real biological differences remains a matter of debate.This ANMCO position paper aims at providing the state of the research on this topic, with particular attention to the diagnostic aspects and to care organization.

[Early detection of cancer after bleeding during oral anticoagulant therapy in patients with atrial fibrillation: a new perspective]. / Identificazione precoce di cancro dopo sanguinamento in corso di terapia anticoagulante orale nei pazienti con fibrillazione atriale: una nuova prospettiva.

Antithrombotic therapy, in particular oral anticoagulation, is associated with an increased risk of bleeding. During anticoagulant treatment bleedings may also be caused by occult cancer, allowing its early diagnosis. The use of direct oral anticoagulants is associated with a lower risk of bleeding compared to vitamin K antagonists, but in the presence of a cancer lesion the risk of bleeding is not inferior. Atrial fibrillation patients with gastrointestinal bleeding during warfarin therapy are 6 times more likely to be diagnosed with cancer than patients without bleeding. In patients with hematuria, the probability of cancer is almost triple if treated with warfarin. With all the four direct oral anticoagulants newly colon cancer diagnoses have been reported in association with bleedings in phase III randomized clinical trials. In the real world, a 4.5% incidence of newly diagnosed cancer has been reported, mainly in the early stage and preceded by a bleeding event. Gastrointestinal bleeding is associated with a 13 times higher risk of newly diagnosed gastrointestinal cancer, genitourinary bleeding with a 18 times higher risk of newly diagnosed genitourinary cancer, and bronchopulmonary bleeding with a 15 times higher risk of newly diagnosed lung cancer. In the presence of bleeding during oral anticoagulant therapy, a diagnostic screening is warranted in order to detect occult cancer. An adverse event such as bleeding can become a favorable opportunity.

Combined neurogenic pulmonary oedema and atypical Takotsubo cardiomyopathy in a patient with ischaemic stroke: a unique case report.

BACKGROUND: Neurogenic pulmonary oedema (NPO) and Takotsubo cardiomyopathy are rare complications of ischaemic stroke. They are considered to be due to an excess catecholamine release after sympathetic nervous stimulation following stroke onset. Among the different types of Takotsubo cardiomyopathy, apical ballooning is recognized as the typical form, but three atypical patterns have been described (midventricular, basal, and focal) which are more commonly observed in patients with neurological disorders. CASE SUMMARY: A 78-year-old woman was treated with intravenous alteplase and underwent mechanical thrombectomy for ischaemic stroke. During the procedure, her respiratory condition quickly worsened requiring invasive mechanical ventilation because of a wide and persistent reduction of the inspiratory oxygen fraction/arterial partial oxygen pressure ratio. Transthoracic echocardiography revealed moderate left ventricular systolic dysfunction with akinesis of the septal-apical and inferior-apical segments. Coronary angiography excluded obstructive lesions and/or evidence of acute plaque rupture. Ventriculography confirmed akinesis/dyskinesis of the inferior segment of the left ventricular apex associated with normal kinesis of the remaining segments. Chest X-ray revealed an infiltrative shadow on both lungs. After 24 h from NPO onset, her respiratory function improved and she was finally discharged on Day 7 without neurological defects. Left ventricular systolic dysfunction was reversible and ejection fraction normalized in 3 months. DISCUSSION: It is a very rare case of simultaneous NPO and Takotsubo cardiomyopathy following ischaemic stroke. Moreover, it is unique in that it is the first observation of NPO associated with an atypical pattern of Takotsubo cardiomyopathy, which is more frequent in patients with neurological disorders. A rapid recognition and treatment are essential for patient survival.

Risk Factors for Intracerebral Hemorrhage in Patients With Atrial Fibrillation on Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention.

[Figure: see text].

Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis.

BACKGROUND: Antithrombotic/anticoagulation effects of direct oral anticoagulants (DOACs) are dose-dependent. However, recent observations suggest that administering lower dose DOACs may better protect against all-cause mortality. We investigated whether, in patients with established atherosclerosis, DOAC dose selection would affect the risk of all-cause mortality. METHODS: We performed a structured literature research for controlled trials allowing random assignment to a lower dose DOAC, a higher dose DOAC, or control therapy in patients with established atherosclerosis. Pooled risk ratios (RRs) of all-cause mortality in lower and higher dose DOACs versus control therapy were estimated using a random-effect model. RESULTS: Atherosclerosis manifested as acute coronary syndrome (n=17,220), stable coronary (CAD) and/or peripheral artery disease (PAD) (n=27,395) or CAD associated with atrial fibrillation (n=4,510). Antithrombotic doses of rivaroxaban (2.5 mg or 5.0 mg BID) or dabigatran (50 mg, 75 mg, 110 mg, or 150 mg, BID) were tested in three trials versus single or dual antiplatelet control therapy, whereas anticoagulation doses of edoxaban (30 mg or 60 OD) were tested versus warfarin in one trial. Compared to control, patients receiving lower dose (RR 0.80, 95% CI 0.73-0.89, p<0.0001, I²=0%), but not those receiving higher dose DOACs (RR 0.95, 95% CI 0.87-1.05, p=0.3074, I²=0%), had a significant reduction of all-cause mortality. Benefit from lower dose DOACs remained after sensitivity analysis or direct comparison with higher dose DOACs (RR 0.84, 95% CI 0.76-0.93, p=0.0009, I²=0%). CONCLUSIONS: Within antithrombotic/anticoagulation regimens of DOAC administration, selection of lower dose appears to protect from all-cause mortality in patients with established atherosclerosis.

Questions and Answers on Practical Thrombotic Issues in SARS-CoV-2 Infection: A Guidance Document from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology.

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk-benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

[Antithrombotic treatments in patients with SARS-CoV-2 infection: from current evidence to reasonable recommendations - A position paper from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology]. / Terapie antitrombotiche in pazienti con infezione da SARS-CoV-2: dalle attuali evidenze alle ragionevoli raccomandazioni ­ Position paper del Gruppo di Studio Aterosclerosi, Trombosi e Biologia Vascolare.

Given the high prevalence of preexisting cardiovascular diseases and the increased incidence of adverse cardiovascular events in patients hospitalized for SARS-CoV-2 infection, the identification of optimal antithrombotic approaches in terms of risk/benefit ratio and outcome improvement appears crucial in this setting. In the present position paper we collected current evidence from the literature to provide practical recommendations on the management of antithrombotic therapies (antiplatelet and anticoagulant) in various clinical contexts prevalent during the SARS-CoV-2 outbreak: in-home management of oral anticoagulant therapy; interactions between drugs used in the SARS-CoV-2 infection and antithrombotic agents; in-hospital management of antithrombotic therapies; diagnosis, risk stratification and treatment of in-hospital thrombotic complications.

[One-year follow-up of Italian patients with atrial fibrillation treated with edoxaban in ETNA-AF Europe]. / Dati di un anno di follow-up dei pazienti italiani con fibrillazione atriale trattati con edoxaban nello studio ETNA-AF Europe.

BACKGROUND: The ongoing prospective, single-arm, observational, phase 4 ETNA-AF Europe study is collecting real-world data about the safety and, secondarily, the effectiveness and therapeutic adherence of newly prescribed edoxaban for non-valvular atrial fibrillation in Europe. METHODS: At the end of enrollment in 2018, 13 980 subjects were included, of whom 3509 were Italian. Of them, 3341 (95.2%) had follow-up data available at 1 year. RESULTS: Their mean age was 75 ± 9.3 years, with 56.9% being ≥75 years old. The CHA2DS2-VASc score was ≥4 in 1380 (41.3%) patients. Overall, 662 patients (19.7%) were judged as "frail" by the investigators. Edoxaban 30 mg/day was given to 1048 (31.4%) subjects, who were older with more comorbidities and a lower estimated creatinine clearance than those prescribed the 60 mg/day dose. Overall, the rates of bleeding and thromboembolic events were low: major bleeding was 1.63%/year, intracranial hemorrhage 0.16%/year, stroke or systemic embolism 0.50%/year and all-cause mortality 3.72%/year. Rates were higher in subjects ≥75 years or with a CHA2DS2-VASc score ≥4 and in frail individuals. Remarkably, there was a trend for no increase in intracranial bleeding with more advanced age. CONCLUSIONS: These findings confirm the favorable safety and effectiveness profile of edoxaban in atrial fibrillation patients in routine clinical care in Italy.

[ETNA-AF study: Italian baseline data and comparison with the European population in atrial fibrillation patients treated with edoxaban]. / Lo studio ETNA-AF: dati basali della popolazione italiana e confronto con la popolazione europea nei pazienti affetti da fibrillazione atriale trattati con edoxaban.

The introduction of direct oral anticoagulants (DOACs) has been the main therapeutic revolution in the last 20 years. Four molecules have been approved for the thromboembolic prophylaxis in patients with non-valvular atrial fibrillation (AF). After the publication of phase 3 clinical trials, many studies evaluating DOAC safety and efficacy in daily clinical practice have been published. Edoxaban is the latest DOAC available on the market, based on the results of the ENGAGE AF-TIMI 48 trial. The phase 4 ETNA-AF (Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation) observational study was designed with the aim to confirm the results of the pivotal clinical trial in routine care in unselected patients with AF. This registry involved several sites and enrolled a large population in Europe and in Italy (13 980 and 3512 patients, respectively). The broad spectrum of patients will allow to have an overview of the characteristics of the AF population and to make a comparison with previous national registries and between different European realities.

[Heart-brain interactions]. / Interazioni cuore-cervello.

Heart-brain interactions are represented by the association of cerebral ischemia with coronary artery disease, cardioembolic cerebral ischemia, and cardiovascular complications due to brain damage. As atherosclerosis is a systemic inflammatory disease, in patients with transient ischemic attack, stroke or asymptomatic carotid artery disease, a previous myocardial infarction, angina or an asymptomatic coronary artery disease are often associated and a correlation between the carotid atherosclerosis and coronary artery disease severity has been reported. Furthermore, the long-term prognosis of patients with stroke is strongly affected by coronary events. At the same time, the prevalence of concomitant cerebrovascular disease is common in patients with coronary artery disease. Other cardiovascular diseases, including left atrial and left atrial appendage thrombosis in atrial fibrillation, thrombi in the left ventricle in acute and chronic coronary artery disease and dilated cardiomyopathies, infective endocarditis with vegetations, cardiac valve prosthesis thrombosis, cardiac tumors, mitral and aortic valve calcifications, aortic plaques and patent foramen ovale, are associated with cardioembolic events. Finally, acute ischemic or hemorrhagic cerebral events, epileptic seizures, cerebral traumas, and brain tumors can be associated with electrocardiographic abnormalities, catecholaminergic myocardial damage, or arrhythmias.

[Edoxaban in patients with atrial fibrillation and cancer]. / Edoxaban nel paziente con fibrillazione atriale e cancro.

Advances in cancer therapy have led to a significant improvement of survival in most types of malignancies over the past few decades. As a result, there is a growing population of cancer survivors, expected to reach 18 million people in 2030 in the US and a similar number in Europe. Interestingly, cancer survivor studies have shown that although about half of these patients eventually die of cancer, one third of them actually die of cardiovascular disease. Arrhythmias represent a significant part of cardiovascular complications and atrial fibrillation is the main arrhythmia occurring in cancer patients.Antithrombotic therapy is a challenge: the optimal international normalized ratio (INR) level in patients on therapy with vitamin K antagonists is achieved in only 12% of them; in these patients, direct oral anticoagulants seem to be effective and safe for the prevention of stroke and systemic embolic events compared to warfarin and have similar risk of major bleeding. Among the trials, ENGAGE AF-TIMI 48 provides more data on the efficacy and safety of edoxaban in cancer patients.

Antithrombotic therapy for patients with an indication for oral anticoagulation undergoing percutaneous coronary intervention with stent: The case of venous thromboembolism.

The management of antithrombotic therapy in patients on oral anticoagulation (OAC) for atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent (PCI) is currently addressed by expert consensus documents and official Guidelines. No specific data, nor management suggestions, are available for OAC patients undergoing PCI in whom the indication for OAC is venous thromboembolism (VTE). In this article, the available evidence on VTE patients undergoing PCI, as obtained from studies where patients with various indications for PCI were included, is evaluated, and an algorithm for the management of antithrombotic therapy in this unique population is proposed.

A handbook for the clinical cardiologist about CRT/ICD. A practical guide about how to survive during an on call shift.

Cardiac resynchronization therapies (CRTs) have been demonstrated to improve the clinical management and prognosis of selected patients with heart failure. CRT devices include both CRT pacemakers (CRT-P) and CRT defibrillators (CRT-D), with the latter being used to treat life-threatening ventricular arrhythmias. A significant advantage of CRTs is the ability to monitor several vital parameters which, thanks to advanced technology, may be remotely assessed. Personalized programming options allow patients to receive the maximum benefit from these treatments. In this review we report the main diagnostic and therapeutic algorithms used in clinical practice.