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.

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.

Optimal opportunistic screening of atrial fibrillation using pulse palpation in cardiology outpatient clinics: Who and how.

BACKGROUND: Atrial fibrillation (AF) remain a prevalent undiagnosed condition frequently encountered in primary care. OBJECTIVE: We aimed to find the parameters that optimize the diagnostic accuracy of pulse palpation to detect AF. We also aimed to create a simple algorithm for selecting which individuals would benefit from pulse palpation and, if positive, receive an ECG to detect AF. METHODS: Nurses from four Cardiology outpatient clinics palpated 7,844 pulses according to a randomized list of arterial territories and durations of measure and immediately followed by a 12-lead ECG, which we used as the reference standard. We calculated the sensitivity and specificity of the palpation parameters. We also assessed whether diagnostic accuracy depended on the nurse's experience or on a list of clinical factors of the patients. With this information, we estimated the positive predictive values and false omission rates according to very few clinical factors readily available in primary care (age, sex, and diagnosis of heart failure) and used them to create the algorithm. RESULTS: The parameters associated with the highest diagnostic accuracy were palpation of the radial artery and classifying as irregular those palpations in which the nurse was uncertain about pulse regularity or unable to palpate pulse (sensitivity = 79%; specificity = 86%). Specificity decreased with age. Neither the nurse's experience nor any investigated clinical factor influenced diagnostic accuracy. We provide the algorithm to select the ≥40 years old individuals that would benefit from a pulse palpation screening: a) do nothing in <60 years old individuals without heart failure; b) do ECG in ≥70 years old individuals with heart failure; c) do radial pulse palpation in the remaining individuals and do ECG if the pulse is irregular or you are uncertain about its regularity or unable to palpate it. CONCLUSIONS: Opportunistic screening for AF using optimal pulse palpation in candidate individuals according to a simple algorithm may have high effectiveness in detecting AF in primary care.

Long-Term Variation in Kidney Function and Its Impact After Acute Myocardial Infarction.

Kidney disease (KD) in patients with acute myocardial infarction (AMI) is associated with major cardiovascular events (MACE). We sought to compare the long-term variation in KD in patients with AMI versus controls and its value as a risk factor for MACE in patients with AMI. A cohort of 300 outpatients with AMI, recruited between 2014 and 2016 in Barcelona, Spain, were compared with a control cohort matched 1:1 based on age and several risk factors for developing KD. Annual estimated glomerular filtration rate (eGFR) using MDRD-4 formula and albuminuria were collected and patients were followed up for the occurrence of MACE (death, heart failure hospitalization, AMI, or stroke). After a median follow-up of 5.3 years, the decline in eGFR was more pronounced in patients with AMI (-1.15 ml/min/1.73 m2/ per year in patients with AMI vs -0.81 ml/min/1.73 m2 per year in controls, p = 0.018 between the ß coefficients of both regression slopes). In patients with AMI, those with the greatest eGFR decline during follow-up had more MACE (hazard ratio [HR] for first vs fourth quartiles = 3.33, p <0.001). In multivariate analysis, after excluding patients with baseline KD, a newly diagnosed eGFR <60 ml/min/1.73 m2 during follow-up was associated with MACE (HR = 3.21, p <0.001), as well as new onset albuminuria >30 mg/g (HR = 6.93, p <0.001) and the combination of both (HR 5.63, p <0.001). In conclusion, the decline in eGFR after AMI is more pronounced than in the general population. A longitudinal drop in eGFR and newly diagnosed albuminuria during follow-up are associated with MACE and can be useful tools to reclassify the risk profile after AMI.

Improving Adherence to Ticagrelor in Patients After Acute Coronary Syndrome: Results from the PROGRESS Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin and ticagrelor is recommended for at least 12 months in patients after an acute coronary syndrome (ACS). However, its underuse and premature discontinuation are common in clinical practice. We aimed to investigate the impact of a dedicated follow-up strategy with clinical visits and counselling on adherence levels to ticagrelor in patients after ACS. METHODS: PROGRESS (PROmotinG dual antiplatelet therapy adheREnce in the setting of acute coronary Syndromes) is a prospective, randomized trial enrolling 400 ACS patients treated with ticagrelor. Patients were randomized to be followed-up in a dedicated outpatient clinic (In-person follow-up group, [IN-FU], n=200), or with scheduled for phone interviews only (Telephone follow-up group [TEL-FU], n=200), to assess ticagrelor adherence and related complications. DAPT disruption was defined as an interruption of the administration of the drug due to complications or other reasons of non-adherence, and divided according to the duration into short (1-5 days), temporary (6-30 days) and permanent (≥30 days) disruption. The primary endpoint was the rate of DAPT disruption at 1-year follow-up. RESULTS: The rate of ticagrelor disruption at 1 year follow-up was higher in the TEL-FU group than in the IN-FU group (19.6 vs 5.5%; p<0.0001). The IN-FU group reported a significantly lower rate of short (3.0 vs 8.5%; p=0.012) and permanent (2.0 vs 9.6%; p=0.012) disruption than TEL-FU group. The rate of major bleeding did not differ significantly between the 2 groups (p=0.450). CONCLUSION: The PROGRESS trial showed a net reduction in DAPT disruption in patients followed-up with clinical (in-person) follow-up visits in a dedicated outpatient clinic compared with those scheduled for phone interviews only.

Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and atrial thrombosis: An appraisal of current evidence.

Major thromboembolic complications in patients with atrial fibrillation, secondary to thromboembolism from the left atrium or the left atrial appendage, are a major concern because of their burden of disabling stroke and mortality. To date, non-vitamin K antagonist oral anticoagulants (NOACs) are considered the first-line strategy in most patients with atrial fibrillation receiving chronic anticoagulation, as they have major advantages compared with vitamin K antagonists, including minimization of intracranial bleeding risk. Although several studies and post-hoc analyses have provided initial data on the use of NOACs in patients with documented atrial and/or left atrial appendage thrombosis, the benefit of NOACs in these patients has not been fully elucidated. In this review, we reappraise current evidence supporting the use of NOACs in patients with established atrial and/or left atrial appendage thrombosis, discussing potential mechanisms favouring the use of a NOAC-based strategy in this special setting.

[Atrial and left atrial appendage thrombosis in patients with atrial fibrillation: from pathophysiology to treatment]. / La trombosi atriale e auricolare sinistra nei pazienti con fibrillazione atriale: dalla fisiopatologia al trattamento.

Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia, and its prevalence is increasing, partly due to the progressive aging of the population. AF predisposes to thrombus formation in the atria and the atrial appendage through a complex interaction among local, systemic and hemodynamic factors, significantly increasing the risk for cerebral and systemic thromboembolic events. These complications have a major impact in terms of morbidity and mortality, and numerous therapeutic strategies have been proposed to reduce such risk. Systemic anticoagulation is the main strategy in the prevention of atrial and left atrial appendage thrombosis, and the advent of non-vitamin K antagonist oral anticoagulants (NOACs) has been a significant step forward, especially for safety, compared to warfarin. While prevention of atrial appendage thrombosis with NOACs has been widely explored, their role in the resolution of thrombi is less clear. The use of NOACs in this setting is largely unexplored, and some studies are underway to clarify their effectiveness. The objective of this paper is to review the literature on atrial and left atrial appendage thrombosis, describing pathophysiological mechanisms and current treatment strategies using NOACs.

Transradial access versus transfemoral access: a comparison of outcomes and efficacy in reducing hemorrhagic events.

Introduction: The radial artery is currently the most widely used access site for PCI procedures both acute and stable patient settings. Thanks to advantages in pharmacological therapy as well as in interventional devices, the rate of ischemic complications following PCI has significantly decreased. Nevertheless, this has been counterbalanced by an increased risk of periprocedural and late bleeding event, that can occur both at access and non-access sites. Choice of access site for PCI is of paramount importance to reduce the risk of access-related bleeding events. Areas covered: The aim of this review is to provide an overview of the actual available evidence comparing the transradial versus transfemoral approach to reduce hemorrhagic events. The most robust evidence comes from large randomized trials, partly also from observational registries, which compared the transradial and transfemoral approach. Expert opinion: Results show that radial access has proved to be decisive in reducing the incidence of hemorrhagic events. Furthermore, it showed a significant reduction in mortality and AKI compared to transfemoral access. However, increased experience in the use of the radial approach has led to less practice in the use of the femoral approach, which may be useful in cases of emergency, complications or inability to use the radial artery.

Functional assessment of coronary stenosis: an overview of available techniques. Is quantitative flow ratio a step to the future?

INTRODUCTION: The assessment of coronary lesions severity has always been a relevant topic in the management of the patient undergoing coronary angiography. Fractional flow reserve (FFR) has been introduced as an objective index to determine the significance of a coronary stenosis with a positive impact on clinical outcomes has been demonstrated for FFR-guided coronary interventions. However, several technical drawbacks have been pointed out in clinical practice limiting the diffusion of FFR worldwide. To exceed these limits, other indices and the quantitative flow ratio (QFR) have been recently developed and tested in clinical studies. Areas covered: This review aims to provide a brief overview of functional assessment of coronary stenosis and a particular attention to the QFR, to its validation and application studies for its potential applicability in clinical practice. QFR through a computational fluid dynamic analysis, proved to be useful in discriminating functionally significant stenosis, with an excellent correlation with FFR values, and considerable advantages in terms of acquisition time and costs. Expert opinion/commentary: QFR is an innovative angiographic-based technique that uses modern software for three-dimensional vessel reconstruction, and flow models calculation. The significant technical benefits reported in the management of patients with intermediate coronary stenosis, make it a modern, effective and usable tool.

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.