von Willebrand Factor and Venous Thromboembolism: Pathogenic Link and Therapeutic Implications.

Venous thromboembolism (VTE) is a frequent cause of disability and mortality worldwide. Von Willebrand factor (VWF) is a major determinant of hemostasis and clot formation, in both arteries and veins. Although VWF is mainly known for its role in arterial thrombosis, several studies suggest a pathogenic role for VWF and its regulator ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in venous thrombosis. Nongenetic and genetic factors, including gene mutations and polymorphisms, aging, hormone status, ABO blood groups, and systemic inflammation, have been involved in the modulation of both VTE predisposition and plasma levels of VWF. In several clinical settings, including inflammatory disease and cancer, VWF and ADAMTS-13 are currently investigated as possible determinants of vein thrombosis. These data indicate VWF as a potential therapeutic target in the management of VTE. Several studies report unselective antagonism of VWF for drugs used in daily clinical practice, including heparin and statins. Selective inhibition of VWF pathway has recently been tested in animal models of arterial and venous thrombosis as a novel therapeutic strategy to prevent platelet aggregation and thrombosis, promote vein lumen recanalization, and improve vein valve competency with excellent safety profile. In this review, we summarize the role of VWF in VTE, focusing on clinical and potential therapeutic implications.

The left atrial appendage: from embryology to prevention of thromboembolism.

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy.

Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions. Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis. All these features make VWF an attractive therapeutic target in thromboinflammation. Several lines of research have recently investigated "tailor-made" inhibitors of VWF. Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile. This review describes the role of VWF in vascular inflammation "from bench to bedside" and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis.

Right heart structural and functional remodeling in athletes.

Long-term intensive exercise training programs lead to numerous progressive cardiac adaptations, which are collectively termed "athlete's heart." Noninvasive diagnostic techniques, such as color Doppler echocardiography, have been widely used in the analysis of the athlete's heart. Initial experiences focused mainly on left heart adaptations to training. However, in recent years, substantial structural and functional adaptations of the right heart have been documented. The present review article focuses on recent data defining right heart adaptation to short- and long-term periods of exercise training. Right ventricular (RV) morphology and function may be more profoundly affected by intense exercise and, in some cases, functional recovery may be incomplete. Moreover, there is speculation that such changes may represent a substrate for proarrhythmic RV remodeling in some highly trained athletes, even in the absence of a known familial redisposition.

Platelet function and long-term antiplatelet therapy in women: is there a gender-specificity? A 'state-of-the-art' paper.

Although the female gender is generally less represented in cardiovascular studies, observational and randomized investigations suggest that-compared with men-women may obtain different benefits from antiplatelet therapy. Multiple factors, including hormonal mechanisms and differences in platelet biology, might contribute to such apparent gender peculiarities. The thrombotic and bleeding risks, as well as outcomes after a cardiovascular event, appear to differ between genders, partly in relation to differences in age, comorbidities and body size. Equally, the benefits of antiplatelet therapy may differ in women compared with men in different vascular beds, during primary or secondary prevention and according to the type of an antiplatelet agent used. This document is an attempt to bring together current evidence, clinical practices and gaps of knowledge on gender-specific platelet function and antiplatelet therapy. On the basis of the available data, we provide suggestions on current indications of antiplatelet therapy for cardiovascular prevention in women with different clinical features; no strong recommendation may be given because the available data derive from observational studies or post hoc/subgroup analyses of randomized studies without systematic adjustments for baseline risk profiles.

Inflammation and cardiovascular disease: from pathogenesis to therapeutic target.

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.

Immune-Checkpoint Inhibitor-Related Myocarditis: Where We Are and Where We Will Go.

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell-mediated immune response against cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic cancer (e.g., melanoma, non-small cell lung cancer, renal cell carcinoma). However, uncontrolled activation of anti-tumor T-cells could trigger an excessive immune response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence of ICIs-induced myocarditis is underestimated and the patients affected are poorly characterized. The diagnosis and management of this condition are mainly based on expert opinion and case reports. EKG and ultrasound are tests that can help identify patients at risk of myocarditis during treatment by red flags, such as QRS complex enlargement and narrowing of global longitudinal strain (GLS). Therapy of ICI-related myocarditis is based on immunosuppressors, monoclonal antibodies and fusion proteins. A future strategy could involve the use of microRNAs. This review considers the current state of the art of immune-related adverse cardiovascular events, focusing on histological and clinical features, diagnosis and management, including current treatments and future pharmacological targets.

Secondary Prevention and Extreme Cardiovascular Risk Evaluation (SEVERE-1), Focus on Prevalence and Associated Risk Factors: The Study Protocol.

INTRODUCTION: Despite significant improvement in secondary CardioVascular (CV) preventive strategies, some acute and chronic coronary syndrome (ACS and CCS) patients will suffer recurrent events (also called "extreme CV risk"). Recently new biochemical markers, such as uric acid (UA), lipoprotein A [Lp(a)] and several markers of inflammation, have been described to be associated with CV events recurrence. The SEcondary preVention and Extreme cardiovascular Risk Evaluation (SEVERE-1) study will accurately characterize extreme CV risk patients enrolled in cardiac rehabilitation (CR) programs. AIM:  Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. AIM: Our aims will be to describe the prevalence of extreme CV risk and its association with newly described biochemical CV risk factors. METHODS: We will prospectively enrol 730 ACS/CCS patients at the beginning of a CR program. Extreme CV risk will be retrospectively defined as the presence of a previous (within 2 years) CV events in the patients' clinical history. UA, Lp(a) and inflammatory markers (interleukin-6 and -18, tumor necrosis factor alpha, C-reactive protein, calprotectin and osteoprotegerin) will be assessed in ACS/CCS patients with extreme CV risk and compared with those without extreme CV risk but also with two control groups: 1180 hypertensives and 765 healthy subjects. The association between these biomarkers and extreme CV risk will be assessed with a multivariable model and two scoring systems will be created for an accurate identification of extreme CV risk patients. The first one will use only clinical variables while the second one will introduce the biochemical markers. Finally, by exome sequencing we will both evaluate polygenic risk score ability to predict recurrent events and perform mendellian randomization analysis on CV biomarkers. CONCLUSIONS: Our study proposal was granted by the European Union PNRR M6/C2 call. With this study we will give definitive data on extreme CV risk prevalence rising attention on this condition and leading cardiologist to do a better diagnosis and to carry out a more intensive treatment optimization that will finally leads to a reduction of future ACS recurrence. This will be even more important for cardiologists working in CR that is a very important place for CV risk definition and therapies refinement.

Out-of-hospital CPR: better outcome for our patients.

Out-of-hospital cardiac arrest is a leading cause of death in developed countries and early resuscitation attempts are crucial to improve survival rates and neurological outcome. Gräsner and colleagues performed an intriguing analysis on the combined approach of mild therapeutic hypothermia (MTH) and immediate percutaneous coronary intervention (PCI) for post-resuscitation care of 584 patients with out-of-hospital cardiac arrest from the German Resuscitation Registry. PCI was independently associated with good neurological outcome at hospital discharge after successful resuscitation, and MTH was associated as an independent factor with increased chance of 24-hour survival. Moreover, a binary logistic regression analysis did not show statistical significance for MTH, in addition to PCI, as an independent predictor for good neurological outcome. The present study supports the evidence that post-resuscitation care based on standardized protocols is beneficial after successful resuscitation. Further prospective and randomized studies are warranted to elucidate criteria for a better selection of candidates for those strategies and to evaluate the potential, in terms of neurological outcome at hospital discharge, of a prehospital cooling strategy in patients who cannot be referred to immediate PCI.

Left atrial volume index in highly trained athletes.

BACKGROUND: Increase of left atrial (LA) diameter in trained athletes has been regarded as another component of the "athlete's heart". AIMS: To evaluate the possible impact of competitive training on LA volume and to define reference values of LA volume index in athletes. METHODS AND RESULTS: Six hundred fifteen consecutive elite athletes (370 endurance- [ATE] vs 245 strength-trained athletes [ATS]; 385 men; 28.4 +/- 10.2 years, range 18-40 years) underwent a comprehensive transthoracic echocardiography exam. LA maximal volume was measured at the point of mitral valve opening using the biplane area-length method, and corrected for body surface area. LA mild dilatation was defined as a LA volume index between 29 and 33 mL/m(2), while a moderate dilatation was identified by a LA volume index > or =34 mL/m(2). Left ventricular (LV) mass index and ejection fraction did not significantly differ between the 2 groups. Conversely, ATS showed increased body surface area, sum of wall thickness (septum + LV posterior wall), LV circumferential end-systolic stress (ESSc) and relative wall thickness, whereas LA volume index, LV stroke volume and LV end-diastolic volume were greater in ATE. The range of LA volume index was 26 to 36 mL/m(2) (mean 28.2 +/- 9.2) in men and 22 to 33 mL/m(2) (mean 26.5 +/- 7.2) in women (P < .01). LA volume index was mildly enlarged in 150 athletes (24.3%) and moderately enlarged only in 20, all males (3.2%). Mild mitral regurgitation was observed in 64 athletes (10.3%). LA volume index was significantly greater in ATE (P < .01). By multivariate analysis, the overall population type (P < .01) and duration (P < .01) of training and LV end-diastolic volume (P < .001) were the only independent predictors of LA volume index. CONCLUSIONS: In a large population of highly trained athletes, a mild enlargement of LA volume index was relatively common and may be regarded as a physiologic adaptation to exercise conditioning.

Right ventricular myocardial involvement in either physiological or pathological left ventricular hypertrophy: an ultrasound speckle-tracking two-dimensional strain analysis.

AIMS: To analyse right ventricular (RV) myocardial deformation in patients with left ventricular (LV) hypertrophy secondary to either hypertrophic cardiomyopathy (HCM) or athlete's competitive endurance training. METHODS AND RESULTS: Standard Doppler echo, exercise stress echo, and 2D speckle-tracking strain echocardiography (2DSE) of RV longitudinal deformation in RV septal and lateral walls were performed in 50 top-level endurance athletes and in 35 patients with HCM, all men, having evidence of LV hypertrophy. Right ventricular global longitudinal strain (GLS) was calculated by averaging local strains along the entire right ventricle. The two groups were comparable for age and blood pressure, whereas athletes showed lower heart rate and increased body surface area than HCM. Interventricular septal thickness was higher in HCM, whereas both LV and RV end-diastolic diameters (LVEDD and RVEDD) and LV stroke volume were increased in athletes. Right ventricular tricuspid annulus systolic excursion was comparable between the two groups. Conversely, RV GLS and regional peaks of RV myocardial strain were significantly impaired in patients with HCM (all P < 0.001). Multiple linear regression models detected an independent association between RV GLS and LVEDD (beta-coefficient = -0.68, P < 0.0001) in athletes, as well as an independent correlation of the same RV GLS with septal thickness (beta = 0.63, P < 0.0001) in HCM. An RV GLS cut-off value of -0.16% differentiated athletes and HCM with an 86% sensitivity and a 92% specificity. Furthermore, in the overall population, RV GLS (beta = 0.51, P < 0.0001) was a powerful independent predictor of maximal workload during exercise stress echo. CONCLUSION: Right ventricular myocardial systolic deformation is positively influenced by preload increase in athletes and negatively associated with increased septal thickness in HCM. Therefore, 2DSE may represent a useful tool in the differential diagnosis between athlete's heart and HCM, underlining the different involvement of RV myocardial function in either physiological or pathological LV hypertrophy.

Prevention of atherothrombotic events in patients with diabetes mellitus: from antithrombotic therapies to new-generation glucose-lowering drugs.

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease.

Lomitapide in homozygous familial hypercholesterolemia: cardiology perspective from a single-center experience.

AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic dyslipidemia characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Frequently, traditional lipid-lowering therapy is ineffective in these patients, and lipoprotein apheresis is required. Lomitapide has been recently approved for HoFH. We reported our experience in HoFH patients treated with lomitapide, evaluating its efficacy and safety profile. METHODS: Probands suspected for familial hypercholesterolemia were extrapolated from the registry of patients admitted to our cardiology department. Dutch Lipid Clinic Network (DLCN) criteria were adopted to diagnose familial hypercholesterolemia clinically. Individuals receiving a definite or probable diagnosis of familial hypercholesterolemia underwent family cascade screening and genetic test. Patients with a genetic diagnosis of HoFH were treated with lomitapide and monitored with serial follow-up visits. RESULTS: Within 1 year of screening, from a population of 3250 patients admitted to our cardiology department, seven probands were selected with a DLCN score greater than 5. A total of two patients resulted genetically homozygotes for familial hypercholesterolemia and started lomitapide. A marked reduction in LDL-C occurred in both patients on lomitapide (78% reduction in patient 1 and 86% in patient 2 already on lipoprotein apheresis, compared with baseline LDL-C), allowing the apheresis treatment to be stopped in the second case. Lomitapide was well tolerated, and both patients experienced only mild gastrointestinal events. CONCLUSION: Lomitapide is an effective and well tolerated cholesterol-lowering drug approved for the treatment of HoFH patients. It would be useful to administer it early in these patients to reduce LDL-C and avoid the development of fatal cardiovascular complications.

Von Willebrand Factor as a Novel Player in Valvular Heart Disease: From Bench to Valve Replacement.

von Willebrand Factor (vWF) is a well-known mediator of hemostasis and vascular inflammation. Its dynamic modulation in the bloodstream, according to hemodynamic conditions, makes it an appealing biomarker in patients with valvular heart disease (VHD). Recent studies highlight the close connection between vWF and VHD, with possible implications in the pathogenesis of VHD, promoting valve aging and calcification or favoring the development of infective endocarditis. Moreover, vWF has been recently proposed as a new diagnostic and prognostic tool in patients with valve stenosis or regurgitation, showing a strict correlation with severity of valve disease, outcome, and bleeding (Heyde syndrome). A novel role for vWF is also emerging in patients undergoing percutaneous or surgical valve repair/replacement to select and stratify patients, evaluate periprocedural bleeding risk, and detect procedural complications. We also report our single-center experience, suggesting, for the first time, possible clinical implications for vWF in percutaneous mitral valve repair (MitraClip). This review summarizes recent advances in the role of vWF in VHD with an updated overview going from bench to operating room.

Von Willebrand Factor and Cardiovascular Disease: From a Biochemical Marker to an Attractive Therapeutic Target.

BACKGROUND: Despite recent advances, there is still an unmet need in antithrombotic therapy. New drugs have to overcome old targets, looking for new complementary strategies to counteract thrombus formation and propagation. Since its initial recognition in the 50's, von Willebrand Factor (VWF) has proved to be a contributor in clot formation. The contribution of VWF to platelet adhesion and aggregation is pivotal at high shear rates (i.e. microcirculation and critical artery stenosis), where globular-inactive-VWF elongates in a long chain-active conformation. Particularly, at sites of plaque erosion/disruption the activation of VWF may contribute critically to post-stenotic thrombus formation. In this context, VWF is a potential target of antithrombotic therapies. The plasma concentration of VWF increases in high risk population and predicts cardiovascular (CV) outcome. VWF demonstrates an emerging role in different clinical settings; for example, in valvular heart disease where it has been recently proposed as a new fluido-dynamic marker of disease severity and a predictor of successful correction. Drugs used in daily clinical practice (LMWHs, statins, N-acetylcysteine, glycoprotein IIb/IIIa inhibitors) may have an unselective antagonism on the VWF-pathway. Recently, several "tailor-made" inhibitors of VWF have been investigated. In animal models and clinical studies monoclonal antibodies, aptamers and nanobodies have been demonstrated to directly interfere with the VWF pathway. These studies proved the powerful antithrombotic property and the acceptable level of safety of this strategy. CONCLUSION: We provide an overview of the drugs that a have a role in VWF-antagonism, illustrating how they might become a potential option to overcome current limitations of antithrombotic therapy.

Management of pregnancy in cardiomyopathies and heart failure.

Pregnancy exposes women with inherited cardiomyopathies to increased risk for arrhythmias and heart failure. In asymptomatic patients with inherited cardiomyopathies, pregnancy is generally well tolerated. Preconception evaluation, risk assessment and proper counseling by a team of experienced physicians are mandatory in managing women with inherited cardiomyopathies planning pregnancy. In this paper, we reviewed the clinical course, risk assessment and management during pregnancy of women with cardiomyopathies.

Right Ventricular Changes in Highly Trained Athletes: Between Physiology and Pathophysiology.

Several studies have described the adaptive remodeling of the heart during exercise. In some more practiced endurance athletes, there is a disproportionate load on the right ventricle (RV), at least during exercise, and this might be the basis for a chronic pro-arrhythmic RV remodeling. Especially, in these kinds of athletes the recovery after detraining might be incomplete, in particular for RV changes. The observation of acute myocardial injury based on transient elevation of biomarkers and chronic myocardial scar, not completely reversible changes of the RV and an increased prevalence of some arrhythmias support the existence of an "exercise-induced cardiomyopathy." The aim of this paper is to review current knowledge about changes in the right heart in highly trained athletes and how these change influence cardiac function.

Adipose tissue and vascular inflammation in coronary artery disease.

Obesity has become an important public health issue in Western and developing countries, with well known metabolic and cardiovascular complications. In the last decades, evidence have been growing about the active role of adipose tissue as an endocrine organ in determining these pathological consequences. As a consequence of the expansion of fat depots, in obese subjects, adipose tissue cells develope a phenotypic modification, which turns into a change of the secretory output. Adipocytokines produced by both adipocytes and adipose stromal cells are involved in the modulation of glucose and lipid handling, vascular biology and, moreover, participate to the systemic inflammatory response, which characterizes obesity and metabolic syndrome. This might represent an important pathophysiological link with atherosclerotic complications and cardiovascular events. A great number of adipocytokines have been described recently, linking inflammatory mileu and vascular pathology. The understanding of these pathways is crucial not only from a pathophysiological point of view, but also to a better cardiovascular disease risk stratification and to the identification of possible therapeutic targets. The aim of this paper is to review the role of Adipocytokines as a possible link between obesity and vascular disease.