Pathophysiology of Atrial Fibrillation and Approach to Therapy in Subjects Less than 60 Years Old.

Atrial fibrillation (AF) is an arrhythmia that affects the left atrium, cardiac function, and the patients' survival rate. Due to empowered diagnostics, it has become increasingly recognized among young individuals as well, in whom it is influenced by a complex interplay of autoimmune, inflammatory, and electrophysiological mechanisms. Deepening our understanding of these mechanisms could contribute to improving AF management and treatment. Inflammation is a complexly regulated process, with interactions among various immune cell types, signaling molecules, and complement components. Addressing circulating antibodies and designing specific autoantibodies are promising therapeutic options. In cardiomyopathies or channelopathies, the first manifestation could be paroxysmal AF; persistent forms tend not to respond to antiarrhythmic drugs in these conditions. Further research, both in vitro and in vivo, on the use of genomic biotechnology could lead to new therapeutic approaches. Additional triggers that can be encountered in AF patients below 60 years of age are systemic hypertension, overweight, diabetes, and alcohol abuse. The aims of this review are to briefly report evidence from basic science and results of clinical studies that might explain the juvenile burden of the most encountered sustained supraventricular tachyarrhythmias in the general population.

Modern subcutaneous implantable defibrillator therapy in patients with cardiomyopathies and channelopathies: data from a large multicentre registry.

AIMS: Patients with cardiomyopathies and channelopathies are usually younger and have a predominantly arrhythmia-related prognosis; they have nearly normal life expectancy thanks to the protection against sudden cardiac death provided by the implantable cardioverter defibrillator (ICD). The subcutaneous ICD (S-ICD) is an effective alternative to the transvenous ICD and has evolved over the years. This study aimed to evaluate the rate of inappropriate shocks (IS), appropriate therapies, and device-related complications in patients with cardiomyopathies and channelopathies who underwent modern S-ICD implantation. METHODS AND RESULTS: We enrolled consecutive patients with cardiomyopathies and channelopathies who had undergone implantation of a modern S-ICD from January 2016 to December 2020 and who were followed up until December 2022. A total of 1338 S-ICD implantations were performed within the observation period. Of these patients, 628 had cardiomyopathies or channelopathies. The rate of IS at 12 months was 4.6% [95% confidence interval (CI): 2.8-6.9] in patients with cardiomyopathies and 1.1% (95% CI: 0.1-3.8) in patients with channelopathies (P = 0.032). No significant differences were noted over a median follow-up of 43 months [hazard ratio (HR): 0.76; 95% CI: 0.45-1.31; P = 0.351]. The rate of appropriate shocks at 12 months was 2.3% (95% CI: 1.1-4.1) in patients with cardiomyopathies and 2.1% (95% CI: 0.6-5.3) in patients with channelopathies (P = 1.0). The rate of device-related complications was 0.9% (95% CI: 0.3-2.3) and 3.2% (95% CI: 1.2-6.8), respectively (P = 0.074). No significant differences were noted over the entire follow-up. The need for pacing was low, occurring in 0.8% of patients. CONCLUSION: Modern S-ICDs may be a valuable alternative to transvenous ICDs in patients with cardiomyopathies and channelopathies. Our findings suggest that modern S-ICD therapy carries a low rate of IS. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/Identifier: NCT02275637.

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.

AIMS: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). METHODS AND RESULTS: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). CONCLUSION: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

The Brugada Syndrome　- From Gene to Therapy.

It is almost a quarter of century that a pioneering work of 2 researchers named Brugada brought the entire scientific community to understanding the molecular, clinical, and electrophysiological aspects of a distinctive syndrome. It affects mainly young adults with syncope and/or sudden cardiac death caused by polymorphic ventricular tachycardia or ventricular fibrillation in the absence of any sign of cardiac degeneration or alteration. Although the involvement of the epicardial layer of the right ventricular outflow tract, and the requirement of pharmacologic challenge for unveiling concealed forms, have been fully characterized, many areas of uncertainties remain to be elucidated, such as the unpredictable usefulness of programmed ventricular stimulation, the role of radiofrequency catheter ablation for reducing ST-segment elevation, and the value of risk stratification in patients diagnosed with upper displacement of right precordial leads. How much Brugada syndrome is an intense field of research is witnessed by 4 different consensus committees that took place in a relatively short period of time considering the recent discovery of this intricate arrhythmogenic disease. The main focus of this review is to describe the milestones in Brugada syndrome from its first phenotypic and genotypic appraisals to recent achievements in electrical therapies proposed for the management of this fascinating rhythm disturbance that, despite new diagnostic and therapeutic learnings, still predisposes to sudden cardiac death.

Clinical Presentation and Outcome of Brugada Syndrome Diagnosed With the New 2013 Criteria.

INTRODUCTION: The 2013 HRS/EHRA/APHRS consensus statement recommends the use of V1 and V2 leads recorded in the second and third intercostal spaces (High-ICS) for diagnosis of Brugada syndrome (BrS) creating a new category of patients discovered only with modified leads. The clinical presentation and the arrhythmic risk in these patients are ill defined. This study was aimed at assessing the role of High-ICS in the analysis of BrS and the clinical profile of the patients diagnosed only when ECG leads are moved to upper intercostal spaces. METHODS AND RESULTS: We searched our Brugada syndrome registry and identified 300 subjects (age 36 ± 13 years), without a diagnostic coved ST-segment elevation in conventional V1 -V3 leads, both at baseline and after provocative drug challenge. Sixty-four subjects (21.3%, mean age at last follow-up 42 ± 11 years) were diagnosed with High-ICS. Diagnosis was possible at baseline only in 4 subjects while in 60 it was made after drug challenge with sodium channel blockers. Three subjects (4.7%) with spontaneous abnormal ECG experienced cardiac events with an annual event rate (0.11%) superimposable to that of the low risk category of BrS diagnosed in standard leads. CONCLUSION: This study demonstrates that the use of new diagnostic criteria for BrS allows increasing the diagnostic yield by 20% and that the arrhythmic risk is low when BrS can be established only in High-ICS. We also show that the prognostic value of spontaneous ECG pattern is confirmed in this subgroup.

Clinical Usefulness of a Mobile Application for the Appropriate Selection of the Antiarrhythmic Device in Heart Failure.

BACKGROUND: Appropriate selection of implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device can be challenging in patients with left ventricular (LV) dysfunction. In this setting, limited information exists about the role of medical applications in helping physicians to choose the most useful device. METHODS: We developed a medical application that provides guidelines-based algorithms for helping doctors in decision process using the Apache Cordova application programming interface. e-CRTD App was tested in 36 consecutive patients (age 66.4 ± 8.5 years, 31 males) with diagnosis of heart failure (HF) addressed to electrophysiology laboratory for evaluation of ICD (N = 18) or CRT with defibrillator device (CRT-D; N = 18) implantation. Two separate teams evaluated each patient independently: expert electrophysiologists (Group A); cardiologists in training using the App (Group B). RESULTS: The outcomes of the clinical evaluation performed by Groups A and B were similar in 100% of patients in terms of classes of recommendations to device (Class I in eight cases, Class IIa in seven cases, Class III in the remaining 21). Surprisingly, the majority of indications from the general practitioners to cardiac device were inappropriate (N = 17 ICD, and N = 4 CRT-D, Class III); nevertheless, e-CRTD App helped Group B (nonexpert cardiologists) in excluding all these cases. CONCLUSIONS: This study describes and validates a mobile application realized to help the decision-making process in HF patients candidate to ICD/CRT-D. This application supports physicians to assess the eligibility for ICD or CRT-D according to current guidelines in patients with LV dysfunction.

Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection against cardiac arrest, and the use of implantable defibrillators in the pediatric population is limited by side effects. There is therefore a need to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of the calsequestrin 2 (CASQ2) wild-type gene in a catecholaminergic polymorphic ventricular tachycardia knock-in mouse model carrying the CASQ2(R33Q/R33Q) (R33Q) mutation. METHODS AND RESULTS: We engineered an adeno-associated viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild-type (AAV9-CASQ2) plus the green fluorescent protein (GFP) gene to infect newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9, and 12 months to investigate the ability of the infection to prevent the disease and adult R33Q mice studied after 2 months to assess whether the AAV9-CASQ2 delivery could revert the catecholaminergic polymorphic ventricular tachycardia phenotype. In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin; the rescue of electrophysiological and ultrastructural abnormalities in calcium release units present in R33Q mice; and the lack of life-threatening arrhythmias. CONCLUSIONS: Our data demonstrate that viral gene transfer of wild-type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of catecholaminergic polymorphic ventricular tachycardia and that this curative effect lasts for 1 year after a single injection of the vector, thus posing the rationale for the design of a clinical trial.

Clinical significance of non-vitamin K antagonist oral anticoagulants in the management of atrial fibrillation.

Atrial fibrillation (AF) is the most commonly observed rhythm disorder in clinical practice. It is associated with a high risk of thromboembolic stroke and increased cardiovascular mortality. Vitamin K antagonists (VKAs), the only oral anticoagulants used for thromboembolic prophylaxis in AF patients over the past 60 years, have been effective in reducing thromboembolic stroke, compared with placebo and aspirin, in this group of patients. However, VKAs have a very narrow therapeutic window, so regular monitoring of the therapeutic effect is obligatory for their use. The need for regular assessment of blood anticoagulation often causes dissatisfaction and reduces patients' quality of life. Non-VKA oral anticoagulants (NOACs), such as dabigatran, a direct thrombin inhibitor, and 3 factor Xa inhibitors, namely rivaroxaban, apixaban, and edoxaban, have been developed in recent years and have increased the armamentarium available to the physician for thromboprophylaxis in non-valvular AF (NVAF) patients. This review describes the characteristics of NOACs, analyzing aspects related to their use in the thromboprophylaxis of NVAF patients. It also discusses how to optimize NOAC therapy in specific clinical conditions, such as renal or liver impairment, and concomitant assumption of drugs potentially interfering with NOACs action. Finally, it focuses on NOAC-related bleeding management in the setting of non-cardiac surgery or radiofrequency catheter ablation of NVAF.

Emerging role of microRNAs in cardiovascular diseases.

Despite the recent progress in the diagnosis and treatment of cardiovascular diseases, these are still a major source of morbidity and mortality worldwide. For this reason, a large research effort was directed to the identification of the underlying pathophysiological aspects of cardiovascular diseases. Nevertheless, many mechanisms still need to be more deeply investigated, limiting the development of efficient diagnostic and therapeutic strategies for a relevant number of patients. Recently, microRNAs (miRs) emerged as powerful regulators of biological processes, offering a further opportunity to better understand the biological mechanisms responsible for the development of cardiovascular diseases, including cellular function and cell-to-cell communication. At the same time, the recent demonstration that cell-derived circulating miRs can be measured in the blood opens up their use as powerful biomarkers. The present review summarizes the most relevant experimental evidences on the involvement of miRs in cardiovascular diseases, including vascular remodeling, coronary artery disease, heart failure and ischemic stroke, thus highlighting potential targets for novel therapeutic strategies.

The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods.

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to the regulation of various biological processes. Thus, HDACs play pivotal roles in various diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews the structure and function of the four classes of human HDACs. While four HDAC inhibitors are currently available for treating hematological malignancies, numerous others are undergoing clinical trials. However, their non-selective toxicity necessitates ongoing research into safer and more efficient class-selective or isoform-selective inhibitors. Computational methods have aided the discovery of HDAC inhibitors with the desired potency and/or selectivity. These methods include ligand-based approaches, such as scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure-activity relationships, and structure-based virtual screening (molecular docking). Moreover, recent developments in the field of molecular dynamics simulations, combined with Poisson-Boltzmann/molecular mechanics generalized Born surface area techniques, have improved the prediction of ligand binding affinity. In this review, we delve into the ways in which these methods have contributed to designing and identifying HDAC inhibitors.

COMPArison of Multi-Point Pacing and ConvenTional Cardiac Resynchronization Therapy Through Noninvasive Hemodynamics Measurement: Short- and Long-Term Results of the COMPACT-MPP Study.

Invasive hemodynamic studies have shown improved left ventricular (LV) performances when cardiac resynchronization therapy/defibrillator is delivered through multipoint pacing (MPP). Nowadays, strategies have become available that allow studying the same hemodynamic parameters at a noninvasive level. The aim of the present study was to evaluate the clinical implication of using a patient-tailored approach for cardiac resynchronization therapy programming based on noninvasively assessed LV hemodynamics to identify the best biventricular pacing modality between standard single-site pacing (STD) and MPP for each patient. Therefore, 51 patients with heart failure (age 69 ± 9 years, 35 men, 27% ischemic etiology) implanted with cardiac resynchronization therapy/defibrillator underwent noninvasive LV function assessment through photoplethysmography before hospital discharge for addressing dP/dt and stroke volume in both pacing modalities (STD and MPP). The modality that performed better in terms of hemodynamic improvement was permanently programmed. Global longitudinal strain (GLS) was also assessed, and repeated at 3 months. Compared with intrinsic rhythm (928 ± 486 mm Hg/s), dP/dtmax showed a trend to increase in both biventricular pacing modes (1,000 ± 577 mm Hg/s in STD, 1,036 ± 530 mm Hg/s in MPP, p = NS). MPP was associated with a wider hemodynamic improvement than was STD and was the modality of choice in 34 of 51 patients (67%). GLS at predischarge did not differ between groups (-10.3 ± 3.8% vs -10.2 ± 3.5%), but significant improvement of ejection fraction at 1 month (34.4 ± 5.3%, p <0.001) and of GLS at 3 months (-12.9 ± 2.9%, p <0.005) was observed across the entire cohort. At 3 months, 77% of patients were classified as responders. Interestingly, long-term (3 years) follow-up unveiled a reduction in all-cause mortality in the MPP group compared with the STD group. In conclusion, cardiac resynchronization therapy programming guided by acute noninvasive hemodynamics favored MPP modality and caused short-term LV positive remodeling and improved long-term outcomes. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT04299360.

Arrhythmic Mitral Valve Prolapse and Sports Activity: Pathophysiology, Risk Stratification, and Sports Eligibility Assessment.

Although mitral valve prolapse (MVP) is the most prevalent valvular abnormality in Western countries and generally carries a good prognosis, a small subset of patients is exposed to a significant risk of malignant ventricular arrhythmias (VAs) and sudden cardiac death (SCD), the so-called arrhythmic MVP (AMVP) syndrome. Recent work has emphasized phenotypical risk features of severe AMVP and clarified its pathophysiology. However, the appropriate assessment and risk stratification of patients with suspected AMVP remains a clinical conundrum, with the possibility of both overestimating and underestimating the risk of malignant VAs, with the inappropriate use of advanced imaging and invasive electrophysiology study on one hand, and the catastrophic occurrence of SCD on the other. Furthermore, the sports eligibility assessment of athletes with AMVP remains ill defined, especially in the grey zone of intermediate arrhythmic risk. The definition, epidemiology, pathophysiology, risk stratification, and treatment of AMVP are covered in the present review. Considering recent guidelines and expert consensus statements, we propose a comprehensive pathway to facilitate appropriate counseling concerning the practice of competitive/leisure-time sports, envisioning shared decision making and the multidisciplinary "sports heart team" evaluation of borderline cases. Our final aim is to encourage an active lifestyle without compromising patients' safety.

Idiopathic Premature Ventricular Contraction Catheter Ablation, Sedentary Population vs. Athlete's Populations: Outcomes and Resumption of Sports Activity.

There are no investigations about the outcomes of idiopathic PVC catheter ablation (CA) in athletes compared to the sedentary population. We conducted a prospective single-centre observational study. The primary and secondary procedural outcomes were the post-ablation reduction of premature ventricular contractions (PVCs) in an athletes vs. non-athletes group and in agonist vs. leisure-time athletes. The third was the evaluation of the resumption of physical activity and the improvement of symptoms in agonist and leisure-time athletes. From January 2020 to October 2022 we enrolled 79 patients with RVOT/LVOT/fascicular PVC presumed origin. The median percentage of decrease between the pre-procedure and post-procedure Holter monitoring in the non-athletes group was 96 (IQR 68-98) and 98 in the athletes group (IQR 92-99) (p = 0.08). Considering the athletes, the median percentage of decrease in the number of PVCs was 98 (IQR 93-99) and 98 (IQR 87-99), respectively, in leisure-time and agonistic athletes (p = 0.42). Sixteen (70%) leisure time and seventeen (90%) agonist athletes (p = 0.24) have resumed physical activity 3 months after PVC CA; among agonistic athletes, 59% have resumed competitive physical activity. Many leisure-time (88%) and agonist (70%) athletes experienced an improvement in symptoms after ablation. PVC CA was effective and safe in both groups, reducing symptoms and allowing a quick and safe return to sports activities in athletes.

Physical exercise in hypertensive heart disease: From the differential diagnosis to the complementary role of exercise.

Arterial hypertension (AH) is one of the most common pathologic conditions and uncontrolled AH is a leading risk factor for cardiovascular disease and mortality. AH chronically causes myocardial and arterial remodelling with hemodynamic changes affecting the heart and other organs, with potentially irreversible consequences leading to poor outcomes. Therefore, a proper and early treatment of AH is crucial after the diagnosis. Beyond medical treatment, physical exercise also plays a therapeutic role in reducing blood pressure, given its potential effects on sympathetic tone, renin-angiotensin-aldosterone system, and endothelial function. International scientific societies recommend physical exercise among lifestyle modifications to treat AH in the first stages of the disease. Moreover, some studies have also shown its usefulness in addition to drugs to reduce blood pressure further. Therefore, an accurate, personalized exercise prescription is recommended to optimize the prevention and treatment of hypertension. On the other hand, uncontrolled AH in athletes requires proper risk stratification and careful evaluation to practice competitive sports safely. Moreover, the differential diagnosis between hypertensive heart disease and athlete's heart is sometimes challenging and requires a careful and comprehensive interpretation in order not to misinterpret the clinical findings. The present review aims to discuss the relationship between hypertensive heart disease and physical exercise, from diagnostic tools to prevention and treatment strategies.

[SIC Position paper: Treat to prevent the first event - intensive LDL cholesterol lowering in patients at very high cardiovascular risk without a previous cardiovascular event. From ESC guidelines to clinical practice]. / Position paper SIC: Trattare per prevenire ­ la riduzione intensiva del colesterolo LDL nel paziente a rischio cardiovascolare molto alto senza pregresso evento. Dalle linee guida ESC alla pratica clinica.

Cardiovascular (CV) diseases account for over 4 million deaths every year in Europe and over 220 000 deaths in Italy, representing the leading cause of morbidity and mortality worldwide. The European Society of Cardiology (ESC) guidelines have visionary included in the at very high CV risk group patients without previous acute ischemic events, such as those with subclinical atherosclerosis, chronic coronary syndrome or peripheral arterial disease, familial hypercholesterolemia, diabetes mellitus with target organ damage or multiple associated risk factors, and those with high calculated CV risk score, recommending to consider them and to achieve the same LDL-cholesterol targets as for secondary prevention patients. The aim of this position paper is to provide an updated overview of ESC guidelines that focuses on these patient categories to raise awareness within the clinical community regarding CV risk reduction in this specific epidemiological context.

Evolocumab Treatment in Dyslipidemic Patients Undergoing Coronary Artery Bypass Grafting: One-Year Safety and Efficacy Results.

Background: The inhibition of PCSK9 lowered LDL cholesterol levels, reducing the risk of cardiovascular events. However, the effect on patients who have undergone surgical myocardial revascularization has not yet been evaluated. Methods: From January 2017 to December 2022, 180 dyslipidemic patients who underwent coronary artery bypass were included in the study. Until December 2019, 100 patients optimized therapy with statin ± ezetimibe (SG). Since January 2020, 80 matched patients added treatment with Evolocumab every 2 weeks (EG). All 180 patients were followed-up at 3 and 12 months, comparing outcomes. Results: The two groups are homogenous. At 3 months and 1 year, a significant decrease in the parameter mean levels of LDL cholesterol and total cholesterol is detected in the Evolocumab group compared to the standard group. No mortality was detected in either group. No complications or drug discontinuation were recorded. In the SG group, five patients (5%) suffered a myocardial infarction during the 1-year follow-up. In the EG group, two patients (2.5%) underwent PTCA due to myocardial infarction. There is no significant difference in overall survival according to the new treatment (p-value = 0.9), and the hazard ratio is equal to 0.94 (95% C.I.: [0.16-5.43]; p-value = 0.9397). Conclusions: The use of Evolocumab, which was started immediately after coronary artery bypass graft surgery, significantly reduced LDL cholesterol and total cholesterol levels compared to statin treatment alone and is completely safe. However, at one year of follow-up, this result did not have impact on the reduction in major clinical events.

MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo.

RATIONALE: MicroRNA (miR)-1 and -133 play a crucial role in skeletal and cardiac muscle biology and pathophysiology. However, their expression and regulation in vascular cell physiology and disease is currently unknown. OBJECTIVE: The aim of the present study was to evaluate the role, if any, of miR-1 and miR-133 in vascular smooth muscle cell (VSMC) phenotypic switch in vitro and in vivo. METHODS AND RESULTS: We demonstrate here that miR-133 is robustly expressed in vascular smooth muscle cells (VSMCs) in vitro and in vivo, whereas miR-1 vascular levels are negligible. miR-133 has a potent inhibitory role on VSMC phenotypic switch in vitro and in vivo, whereas miR-1 does not have any relevant effect per se. miR-133 expression is regulated by extracellular signal-regulated kinase 1/2 activation and is inversely correlated with VSMC growth. Indeed, miR-133 decreases when VSMCs are primed to proliferate in vitro and following vascular injury in vivo, whereas it increases when VSMCs are coaxed back to quiescence in vitro and in vivo. miR-133 loss- and gain-of-function experiments show that miR-133 plays a mechanistic role in VSMC growth. Accordingly, adeno-miR-133 reduces but anti-miR-133 exacerbates VSMC proliferation and migration in vitro and in vivo. miR-133 specifically suppresses the transcription factor Sp-1 expression in vitro and in vivo and through Sp-1 repression regulates smooth muscle gene expression. CONCLUSIONS: Our data show that miR-133 is a key regulator of vascular smooth muscle cell phenotypic switch in vitro and in vivo, suggesting its potential therapeutic application for vascular diseases.

Renal sympathetic denervation for treating resistant hypertension.

Systemic hypertension represents a significant global concern, because it contributes to vascular and renal morbidity, cardiovascular mortality, and economic burden, hence the impact of hypertension is a major issue in public health worldwide. Improving high blood pressure management is therefore fundamental to influencing clinical outcomes. Despite adherence to multiple available medical therapies, a significant proportion of patients has persistent blood pressure elevation, a condition termed "resistant hypertension". Renal sympathetic innervations contribute to lack of response of anti-hypertensive drugs through an imbalance of regulatory mechanisms. Renal afferent nerve fibers are responsible for sympathetic activation and contribute to blood pressure homeostasis while afferent signals from the kidneys are integrated at the central nervous system and enhance sympathetic nerve discharge. In this regard, a novel strategy that selectively removes these hypertensive contributors represents a new therapeutic opportunity. Recently, a catheter-based method to induce renal sympathetic denervation has been introduced into daily practice. Clinical evaluation of selective renal sympathetic denervation demonstrated a decrease of renal norepinephrine spillover and renin activity, an increase of renal plasma flow, and has confirmed clinically significant, sustained reductions in blood pressure in patients with resistant hypertension. This review summarizes the available data on the role of sympathetic activation in the pathophysiology of hypertension and the current concepts in transcatheter renal artery ablation with radiofrequency delivery for systemic hypertension. Suggestions regarding targets for future systemic hypertension management are also described.

Cardiovascular Prognosis in Patients with Peripheral Artery Disease and Approach to Therapy.

Peripheral artery disease (PAD), the pathophysiologic narrowing of the arterial blood vessels of the lower limbs due to atherosclerosis, is estimated to affect more than 200 million people worldwide and its prevalence ranges from 0.9 to 31.3% in people aged ≥50 years. It is an established marker of systemic obstructive atherosclerosis, which depicts patients at higher risk of myocardial infarction and stroke, due to the involvement of coronary and cerebral arteries in the atherosclerotic process. Therefore, identifying PAD, particularly in patients with coronary artery disease, is important to assess the cardiovascular risk score and implement specific therapies and prevention strategies. Since PAD emerged as an important clinical cardiovascular predictor, even more than other typical cardiovascular risk factors, an aggressive strategy to identify and treat PAD patients should be pursued by general practitioners, cardiologists, and vascular surgeons; similarly, preventive strategies should be implemented to improve prognosis and outcomes, particularly in patients suffering from both coronary artery disease and PAD. In this review, we describe the pathophysiology, including limb vasoconstriction after coronary angioplasty, the diagnosis of PAD, prognosis according to cardiovascular events, coronary artery disease, and heart failure. Furthermore, a large section of this review is on management, which spans from risk factors' modification to antithrombotic therapy, and revascularization is provided. Finally, considerations about newer therapeutic options for the "desert foot" are discussed, including gene therapy.

Revascularization and Left Ventricular Dysfunction for ICD Eligibility.

Common triggers for sudden cardiac death (SCD) are transient ischemia, hemodynamic fluctuations, neurocardiovascular influences, and environmental factors. SCD occurs rapidly when sinus rhythm degenerates into ventricular tachycardia (VT) and/or ventricular fibrillation (VF), followed by asystole. Such progressive worsening of the cardiac rhythm is in most cases observed in the setting of ischemic heart disease and often associated with advanced left ventricular (LV) impairment. Revascularization prevents negative outcomes including SCD and heart failure (HF) due to LV dysfunction (LVD). The implantable cardioverter-defibrillator (ICD) on top of medical therapy is superior to antiarrhythmic drugs for patients with LVD and VT/VF. The beneficial effects of ICD have been demonstrated in primary prevention of SCD as well. However, yet debated is the temporal management for patients with LVD who are eligible to ICD prior to revascularization, either through percutaneous or surgical approach. Restoration of coronary blood flow has a dramatic impact on adverse LV remodeling, while it requires aggressive long-term antiplatelet therapy, which might increase complication for eventual ICD procedure when percutaneous strategy is pursued; on the other hand, when LV and/or multiorgan dysfunction is present and coronary artery bypass grafting is chosen, the overall risk is augmented, mostly in HF patients. The aims of this review are to describe the pathophysiologic benefits of revascularization, the studies addressing percutaneous, surgical or no revascularization and ICD implantation, as well as emerging defibrillation strategies for patients deemed at transient risk of SCD and/or at higher risk for transvenous ICD implantation.