COVID-19 outbreak had a major impact on the organization of care in Italy, and a survey to evaluate provision of for arrhythmia during COVID-19 outbreak (March-April 2020) was launched. A total of 104 physicians from 84 Italian arrhythmia centres took part in the survey. The vast majority of participating centres (95.2%) reported a significant reduction in the number of elective pacemaker implantations during the outbreak period compared to the corresponding two months of year 2019 (50.0% of centres reported a reduction of > 50%). Similarly, 92.9% of participating centres reported a significant reduction in the number of implantable cardioverter-defibrillator (ICD) implantations for primary prevention, and 72.6% a significant reduction of ICD implantations for secondary prevention (> 50% in 65.5 and 44.0% of the centres, respectively). The majority of participating centres (77.4%) reported a significant reduction in the number of elective ablations (> 50% in 65.5% of the centres). Also the interventional procedures performed in an emergency setting, as well as acute management of atrial fibrillation had a marked reduction, thus leading to the conclusion that the impact of COVID-19 was disrupting the entire organization of health care, with a massive impact on the activities and procedures related to arrhythmia management in Italy.

Summary Patients with SCAD and concomitant COPD are at high risk of cardiovascular adverse events, due to chronic inflammation, responsible of endothelial dysfunction, oxidative stress and heightened platelet reactivity (PR). The objective of this randomised clinical trial was to test if ticagrelor is superior to clopidogrel in improving endothelial function in patients with stable coronary artery disease (SCAD) and concomitant chronic obstructive pulmonary disease (COPD). Forty-six patients with SCAD and COPD undergoing percutaneous coronary intervention (PCI) were randomly assigned to receive clopidogrel (n=23) or ticagrelor (n=23) on top of standard therapy with aspirin. The following parameters were assessed at baseline and after 1 month: i) rate of apoptosis and ii) nitric oxide (NO) levels in human umbilical vein endothelial cells (HUVECs), iii) levels of reactive oxygen species (ROS) in peripheral blood mononuclear cell, iv) 29 cytokines/chemokines, v) on-treatment PR. The primary endpoint of the study was the 1-month rate of HUVECs apoptosis. The rate of apoptosis after 1 month was significantly lower in patients treated with ticagrelor (7.4 ± 1.3% vs 9.3 ± 1.5%, p<0.001), satisfying the pre-specified primary endpoint. In the ticagrelor arm, levels of NO were higher (10.1 ± 2.2 AU vs 8.5 ± 2.6 AU, p=0.03) while those of ROS (4 ± 1.8 AU vs 5.7 ± 2.8 AU, p=0.02) and P2Y 12 reactivity units (52 ± 70 PRU vs 155 ± 62 PRU, p<0.001) were lower. There were no differences in cytokines/chemokines levels and aspirin reactivity units between groups. In patients with SCAD and COPD undergoing PCI, ticagrelor, as compared to clopidogrel is superior in improving surrogate markers of endothelial function and on-treatment PR (ClinicalTrials.gov, NCT02519608). Supplementary Material to this article is available online at www.thrombosis-online.com.

BACKGROUND Recently, tangles and plaque-like aggregates have been identified in certain cases of dilated cardiomyopathy (DCM). This suggests a potential underlying cause for the one-third of cases, traditionally labeled idiopathic (iDCM), where there is no specific diagnostic test or targeted therapy. OBJECTIVE We sought to identify the make-up of myocardial aggregates to understand the molecular mechanisms of these cases of DCM; this strategy has been central to understanding Alzheimer’s disease. METHODS Aggregates were extracted from human iDCM samples with high congophilic reactivity (an indication of plaque presence) and the findings validated in a larger cohort of samples. We tested the expression, distribution, and activity of cofilin in human tissue and generated a cardiac-specific knockout mouse model to investigate the functional impact of the human findings. We also modeled cofilin inactivity in vitro using pharmacological and genetic gain and loss of function approaches. RESULTS Aggregates in the human myocardium were enriched for cofilin-2, an actin-depolymerizing protein known to participate in neurodegenerative diseases and nemaline myopathy. Cofilin-2 was predominantly phosphorylated, rendering it inactive. Cardiac-specific haploinsufficiency of cofilin-2 in mice recapitulated the human disease’s morphological, functional, and structural phenotype. Pharmacological stimulation of cofilin-2 phosphorylation and genetic overexpression of the phosphomimetic protein promoted the accumulation of “stress-like” fibers and severely impaired cardiomyocyte contractility. CONCLUSIONS Our study provides the first biochemical characterization of prefibrillar myocardial aggregates in humans and the first report to link cofilin-2 to cardiomyopathy. The findings suggest a common pathogenetic mechanism between certain iDCMs and other chronic degenerative diseases, laying the groundwork for new therapeutic strategies.

Summary: Given its broad use as a screening tool, the electrocardiogram (ECG) has largely become one of the most common diagnostic tests performed in routine clinical practice. As a result, the finding of left bundle-branch block (LBBB) in the absence of a well-defined clinical setting has become relatively frequent and raises questions and often concerns. While in the absence of clinically detectable heart disease LBBB does not necessarily imply poor outcomes, physicians should be aware of the role of LBBB in stratifying risk of cardiovascular events and death in subjects with both ischemic and nonischemic heart disease. This paper reviews historical landmarks, pathophysiologic features, prognostic implications, and clinical management of LBBB in apparently healthy subjects and those with heart disease. Evolving Concepts, Misunderstandings, and Current Appraisal of Left Bundle-Branch BlockAs early as the beginning of the past century, Eppinger and Tothberger, by means of a rudimental but efficient experimental model, performed experiments destroying pieces of dog myocardium by injecting silver nitrate and then observing the induced electrocardiographic (ECG) changes. 1 By means of a single esophageal-anal lead, these and other investigators found that injuring the left and right bundle branches resulted, respectively, in an upward and a downward QRS deflection on ECG. 2 Ironically, the mere extrapolation of data obtained from this experimental canine model resulted in a 25-year misunderstanding of the real electrical abnormalities. Left bundle-branch block (LBBB) pattern was incorrectly identified as right bundle-branch block (RBBB), and vice versa. In fact, since the esophageal-anal lead was erroneously judged to be "vertical" in the dog, the presence in humans of a wide downward deflection in leads II and III was considered to disclose RBBB. 3 Almost 70 years after elucidation of this long-lasting misinterpretation, the electrogenesis and ECG pattern of LBBB appear to be fully clarified. Under normal conditions, the electrical impulse from the His bundle passes through a narrow anterior fascicle, a broader early branching posterior fascicle, and a third septal segment composed of many branches originating from each of the fascicles. The electrical impulse then spreads through a rich peripheral Purkinje network that couples with individual myocardial cells. 4,5 The simultaneous electrical activation of the right ventricle from its own branch results in the QRS complex, which then represents the "sum" of two parallel and independent electrical phenomena. Left bundle-branch block completely modifies the electrical activation of the left ventricle and QRS complex on ECG. The activation of the interventricular septum, which is left-sided in physiologic conditions, originates on its right side. The electrical impulse propagates then inferiorly, to the left, and slightly anteriorly. This results in a nonhomogeneous and delayed depolarization of the left ventricle, which can be only partially preserved in the presen...

Ischaemic heart disease is a major cause of death and disability worldwide, while angina represents its most common symptom. It is estimated that approximately 9 million patients in the USA suffer from angina and its treatment is challenging, thus the strategy to improve the management of chronic stable angina is a priority. Angina might be the result of different pathologies, ranging from the “classical” obstruction of a large coronary artery to alteration of the microcirculation or coronary artery spasm. Current clinical guidelines recommend antianginal therapy to control symptoms, before considering coronary artery revascularization. In the current guidelines, drugs are classified as being first-choice (beta-blockers, calcium channel blockers, and short-acting nitrates) or second-choice (ivabradine, nicorandil, ranolazine, trimetazidine) treatment, with the recommendation to reserve second-line modifications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. However, such a categorical approach is currently questioned. In addition, current guidelines provide few suggestions to guide the choice of drugs more suitable according to the underlying pathology or the patient comorbidities. Several other questions have recently emerged, such as: is there evidence-based data between first- and second-line treatments in terms of prognosis or symptom relief? Actually, it seems that newer antianginal drugs, which are classified as second choice, have more evidence-based clinical data that are more contemporary to support their use than what is available for the first-choice drugs. It follows that actual guidelines are based more on tradition than on evidence and there is a need for new algorithms that are more individualized to patients, their comorbidities, and pathophysiological mechanism of chronic stable angina.

wrong, an error that was confirmed by a number of completely unsuccessful clinical trials that failed to show the benefits with a range of putative infarct-reducing agents. The main reason for this discrepancy lay in the time of administration of the compounds (i.e., before the onset of ischemia in the experimental setting, after the infarct in the clinical one).It then became apparent that early reperfusion was a prerequisite for the salvage of ischemic tissue. At the same time, it became also evident that reperfusion per se can be, paradoxically, dangerous, increasing rather than reducing the extension of the infarct.The second line of research related to cardiac surgery. Quickly, coronary artery bypass became a standard procedure for patients with angina and, with the time, this was extended, although with poor results, to evolving myocardial infarction (MI). No doubt that the surgeons had the monopoly of reperfusion and indeed they managed to develop techniques such as cardioplegia and hypothermia able to protect against the damage induced by reperfusion. Once again, the success of these techniques relies on their application before induction of ischemia.The third line of research is linked to pharmacologists who, in parallel with surgeons and pathologists, questioned that the thrombus was the result of an infarct. They proved that, actually, it is the cause of the infarct and started to look at measures to dissolve the infarct-initiating thrombi. Medicine has been undergoing constant changes, with cardiology being arguably the fastest changing field of all. The evolution -or should we say the revolution -of reducing the progression of coronary atherosclerosis with aspirin, angiotensin enzyme inhibitors and cholesterol-lowering drugs had a remarkable effect on the treatment of coronary artery disease. But perhaps one of the most important changes in cardiology is the ability to reperfuse the ischemic myocardium and consequently to reduce the deleterious effects of acute ischemia. Interestingly, during the second half of the century, 4 independent and different streams of research were initiated and would culminate in the ability to reperfuse the ischemic human heart.The first line of research related to pathophysiology. The 1960 s witnessed a remarkable increase in the systematic study of (1) the nature of atheroma and thrombosis and (2) the metabolic, contractive, ultrastructural and electrophysiological consequences of myocardial ischemia. Later, in part because of the relative ease of restoring coronary flow, investigators, including the authors of this review, turned their attention to the effects of reperfusion. 1-4 The idea of protecting the ischemic myocardium soon attracted a lot of enthusiasm and a cornucopia of compounds such as β-blockers, calcium antagonists, antiinflammatory drugs, and vasodilators were administered to animals with results that appeared dramatically successful. In the 1970 s and 1980 s, however, it became clear that this approach was Tissue salvage of severely ischemic myocardiu...

Background: Cardiac resynchronization therapy (CRT) has been introduced to treat drug refractory chronic heart failure (CHF). Apelin, the endogenous ligand of the APJ receptor, is under evaluation for its potential role in human CHF pathophysiology. This study aims to assess whether biventricular pacing affects plasma apelin levels in patients with severe CHF. Methods and results: Fourteen patients (9 men, 5 women, mean age 68 ± 13 years) undergoing biventricular pace-maker/ICD implantation were studied. Patients underwent baseline clinical and echocardiographic evaluation, and assessment of plasma apelin and NT-proBNP levels. The evaluation was repeated 48 h and 9 ± 2 months after device implantation to assess the acute and chronic effects of CRT on apelin and NT-proBNP levels. Eight healthy age-and sex-matched subjects served as controls.In CHF patients, baseline apelin levels were reduced and NT-proBNP increased compared to control subjects (apelin: 0.47 ± 0.2 vs. 0.97 ± 0.3 ng/mL, p < 0.001; NT-proBNP: 2007 ± 114 vs. 229 ± 72 pmol/L, p < 0.001). Short-term evaluation did not reveal any effect of CRT on apelin or NT-proBNP levels. By contrast, at 9 ± 2 months follow-up, CRT responders showed left ventricular reverse remodelling and an increase in ejection fraction, together with a significant increase in plasma apelin levels (0.99 ± 0.1 vs. 0.47 ± 0.2 ng/mL, p < 0.001) and decrease in NT-proBNP (938 ± 591 vs. 2007 ± 114 pmol/L, p < 0.05). Conclusions: Long-term CRT increases plasma levels of the endogenous inotrope apelin in patients with CHF.

The FRASER program will fill critical gaps in the knowledge regarding the link between frailty, cardiovascular disease, interventional procedures and outcome and will help physicians in the generation of a more personalized risk assessment and in the identification of potential targets for interventions.