LDL-cholesterol target levels achievement in high-risk patients: An (un)expected gender bias.

BACKGROUND AND AIMS: Lowering low-density lipoprotein cholesterol (LDL-C) is the cornerstone of cardiovascular disease prevention. Collection of epidemiological data is crucial for monitoring healthcare appropriateness. This analysis aimed to evaluate the proportion of high-risk patients who achieved guidelines recommended LDL-C goal, and explore the predictors of therapeutic failure, with a focus on the role of gender. METHODS AND RESULTS: Health administrative and laboratory data from seven Local Health Districts in Tuscany were collected for residents aged ≥45 years with a history of major adverse cardiac or cerebrovascular event (MACCE) and/or type 2 diabetes mellitus (T2DM) from January 1, 2019, to January 1, 2021. The study aimed to assess the number of patients with optimal levels of LDL-C (<55 mg/dl for patients with MACCE and <70 mg/dl for patients with T2DM without MACCE). A cohort of 174 200 individuals (55% males) was analyzed and it was found that 11.6% of them achieved the target LDL-C levels. Female gender was identified as an independent predictor of LDL-C target underattainment in patients with MACCE with or without T2DM, after adjusting for age, cardiovascular risk factors, comorbidities, and district area (adjusted-IRR 0.58 ± 0.01; p < 0.001). This result was consistent in subjects without lipid-lowering therapies (adjusted-IRR 0.56 ± 0.01; p < 0.001). CONCLUSION: In an unselected cohort of high-risk individuals, females have a significantly lower probability of reaching LDL-C recommended targets. These results emphasize the need for action to implement education for clinicians and patients and to establish clinical care pathways for high-risk patients, with a special focus on women.

Digital droplet PCR versus quantitative PCR for lipoprotein (a) kringle IV type 2 repeat polymorphism genetic characterization.

BACKGROUND: Lipoprotein(a) [Lp(a)] level variability, related to atherothrombotic risk increase, is mainly attributed to LPA gene, encoding apolipoprotein(a), with kringle IV type 2 (KIV2) copy number variation (CNV) acting as the primary genetic determinant. Genetic characterization of Lp(a) is in continuous growth; nevertheless, the peculiar structural characteristics of this variant constitute a significant challenge to the development of effective detection methods. The aim of the study was to compare quantitative real-time PCR (qPCR) and digital droplet PCR (ddPCR) in the evaluation of KIV2 repeat polymorphism. METHODS: We analysed 100 subjects tested for cardiovascular risk in which Lp(a) plasma levels were assessed. RESULTS: Correlation analysis between CNV values obtained with the two methods was slightly significant (R = 0.413, p = 0.00002), because of the wider data dispersion in qPCR compared with ddPCR. Internal controls C1, C2 and C3 measurements throughout different experimental sessions revealed the superior stability of ddPCR, which was supported by a reduced intra/inter-assay coefficient of variation determined in this method compared to qPCR. A significant inverse correlation between Lp(a) levels and CNV values was confirmed for both techniques, but it was higher when evaluated by ddPCR than qPCR (R = -0.393, p = 0.000053 vs R = -0.220, p = 0.028, respectively). When dividing subjects into two groups according to 500 mg/L Lp(a) cut-off value, a significantly lower number of KIV2 repeats emerged among subjects with greater Lp(a) levels, with stronger evidence in ddPCR than in qPCR (p = 0.000013 and p = 0.001, respectively). CONCLUSIONS: Data obtained support a better performance of ddPCR in the evaluation of KIV2 repeat polymorphism.

Adenosine in Interventional Cardiology: Physiopathologic and Pharmacologic Effects in Coronary Artery Disease.

This review article focuses on the role of adenosine in coronary artery disease (CAD) diagnosis and treatment. Adenosine, an endogenous purine nucleoside, plays crucial roles in cardiovascular physiology and pathology. Its release and effects, mediated by specific receptors, influence vasomotor function, blood pressure regulation, heart rate, and platelet activity. Adenosine therapeutic effects include treatment of the no-reflow phenomenon and paroxysmal supraventricular tachycardia. The production of adenosine involves complex cellular pathways, with extracellular and intracellular synthesis mechanisms. Adenosine's rapid metabolism underscores its short half-life and physiological turnover. Furthermore, adenosine's involvement in side effects of antiplatelet therapy, particularly ticagrelor and cangrelor, highlights its clinical significance. Moreover, adenosine serves as a valuable tool in CAD diagnosis, aiding stress testing modalities and guiding intracoronary physiological assessments. Its use in assessing epicardial stenosis and microvascular dysfunction is pivotal for treatment decisions. Overall, understanding adenosine's mechanisms and clinical implications is essential for optimizing CAD management strategies, encompassing both therapeutic interventions and diagnostic approaches.

Pathophysiological and Molecular Basis of the Side Effects of Ticagrelor: Lessons from a Case Report.

Ticagrelor is currently considered a first-line choice in dual antiplatelet therapy (DAPT) following revascularization of acute coronary syndrome (ACS). However, its use is correlated with an increased incidence of two side effects, dyspnea and bradyarrhythmias, whose molecular mechanisms have not yet been defined with certainty and, consequently, neither of the therapeutic decisions they imply. We report the case of a patient with acute myocardial infarction treated with ticagrelor and aspirin as oral antithrombotic therapy after primary percutaneous coronary intervention (PCI), manifesting in a significant bradyarrhythmic episode that required a switch of antiplatelet therapy. Starting from this case report, this article aims to gather the currently available evidence regarding the molecular mechanisms underlying these side effects and propose possible decision-making algorithms regarding their management in clinical practice.

"Tailored" antiplatelet bridging therapy with cangrelor: moving toward personalized medicine.

In the setting of patients with indication to receive dual antiplatelet therapy undergoing surgery or invasive procedures, the risk of perioperative cardiac ischemic events, particularly stent thrombosis, is high, because surgery has a prothrombotic effect and antiplatelet therapy is withdrawn in order to avoid bleeding complications. Cangrelor, an intravenous P2Y12 receptor antagonist, has been tested in a randomized trial as a "bridge" to cardiac surgery from discontinuation of oral P2Y12 receptor antagonists. Thus, a consensus document extended its off-label use in this setting and before non-cardiac surgery. Currently, despite the implementation of a standardized bridging protocol with cangrelor, a residual risk of adverse outcome mainly due to bleeding events, still persist during the perioperative phase.Accordingly, a personalized management driven by platelet reactivity serial measurements and careful assessment of ischemic and bleeding risks has potential to optimize outcomes and costs as compared to a standardized bridging protocol, based on average pharmacodynamic data of oral P2Y12 inhibitors.While specific indications for bridging have been extensively addressed in the aforementioned consensus statement, the aim of the present document is the proposal of a "tailored" clinical decision-making algorithm inspired to the principle of personalized medicine dealing with complex clinical scenarios.

Mavacamten, a Novel Therapeutic Strategy for Obstructive Hypertrophic Cardiomyopathy.

PURPOSE OF REVIEW: Pharmacological treatment options for hypertrophic cardiomyopathy (HCM) are currently limited and comprise non-disease specific therapies such as ß-blockers, non-dihydropyridine calcium channel blockers, and disopyramide. These agents that offer a variable degree of symptomatic relief, often suboptimal, are often limited by side-effects and fail to address the key molecular abnormalities of the disease. RECENT FINDINGS: Mavacamten is a novel, first-in-class, allosteric inhibitor of cardiac myosin ATPase, which reduces actin-myosin cross-bridge formation, thereby reducing myocardial contractility and improving myocardial energetic consumption in experimental HCM models. Following a successful Phase 2 study, the recently published phase III, placebo-controlled, randomized EXPLORER-HCM trial demonstrated the efficacy and safety of mavacamten in reducing left ventricular outflow tract obstruction and ameliorating exercise capacity, New York Heart Association functional class and health status in patients with obstructive HCM. Mavacamten represents the first agent specifically developed for HCM successfully tested in a Phase III trial, to be registered soon for clinical use, representing a radical change of paradigm in the pharmacological treatment of HCM.

Pathophysiology and Treatment of Hypertrophic Cardiomyopathy: New Perspectives.

PURPOSE OF REVIEW: We provide a state of the art of therapeutic options in hypertrophic cardiomyopathy (HCM), focusing on recent advances in our understanding of the pathophysiology of sarcomeric disease. RECENT FINDINGS: A wealth of novel information regarding the molecular mechanisms associated with the clinical phenotype and natural history of HCM have been developed over the last two decades. Such advances have only recently led to a number of controlled randomized studies, often limited in size and fortune. Recently, however, the allosteric inhibitors of cardiac myosin adenosine triphosphatase, countering the main pathophysiological abnormality associated with HCM-causing mutations, i.e. hypercontractility, have opened new management perspectives. Mavacamten is the first drug specifically developed for HCM used in a successful phase 3 trial, with the promise to reach symptomatic obstructive patients in the near future. In addition, the fine characterization of cardiomyocyte electrophysiological remodelling has recently highlighted relevant therapeutic targets. Current therapies for HCM focus on late disease manifestations without addressing the intrinsic pathological mechanisms. However, novel evidence-based approaches have opened the way for agents targeting HCM molecular substrates. The impact of these targeted interventions will hopefully alter the natural history of the disease in the near future.

Impact of complete percutaneous revascularization in elderly patients with chronic total occlusion.

OBJECTIVE: The aim of the study was to assess the prognostic impact of successful chronic total occlusion (CTO) percutaneous coronary intervention (PCI) and completeness of revascularization in the elderly. BACKGROUND: Successful CTO-PCI is associated with clinical benefit. Notwithstanding elderly patients are currently underrepresented in CTO-PCI randomized controlled trials and registries. METHODS: From the Florence CTO-PCI registry 1,405 patients underwent CTO-PCI between 2004 and 2015; out of these, 460 consecutive patients were ≥75 years. End point of the study was long-term cardiac survival. The prognostic impact of successful CTO-PCI and complete revascularization on survival was assessed by Kaplan-Meier estimation and by Cox multivariable regression analysis. RESULTS: Patients were stratified according to success (72%) or failure of CTO-PCI. Completeness of revascularization was achieved in 57% of patients. Five-year cardiac survival was significantly higher in the successful CTO-PCI group (84 ± 3% vs. 72 ± 6%; p = .006) and it was further improved if complete coronary revascularization was achieved (90 ± 3% vs. 68 ± 5%; p < .001). At multivariable analysis, increasing age (hazard ratio [HR] 1.08; p = .001), diabetes (HR 1.55; p = .033), chronic kidney disease (HR 1.96, p = .002), left ventricular ejection fraction <0.40 (HR 2.10; p < .001), and completeness of revascularization (HR 0.58; p < .005) resulted independently associated with long-term cardiac survival. CONCLUSIONS: In the elderly successful CTO-PCI is associated with a long-term survival benefit. The results of this study suggest that, even in the elderly, a CTO-PCI attempt should be considered to achieve complete coronary revascularization.

Association of different oral anticoagulants use with renal function worsening in patients with atrial fibrillation: A multicentre cohort study.

AIMS: To investigate the decline of estimated glomerular filtration rate (eGFR) in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs). METHODS: Multicentre prospective cohort study including 1667 patients with nonvalvular AF. The eGFR was assessed by the CKD-EPI formula at baseline and during follow-up. The primary endpoint of the study was the median annual decline of eGFR according to VKA (n = 743) or NOAC (n = 924) use. As secondary endpoints, we analysed the transition to eGFR <50 mL/min/1.73 m2 and the eGFR class worsening. RESULTS: Median age was 73.7 ± 9.1 years and 43.3% were women. VKA-treated patients showed an eGFR decline of -2.11 (interquartile range [IQR] -5.68/-0.62), which was -0.27 (IQR -9.00/4.54, P < 0.001 vs VKAs), -1.21 (IQR -9.98/4.02, P = 0.004 vs VKAs) and -1.32 (IQR -8.70/3.99, P = 0.003 vs VKAs) in patients on dabigatran, rivaroxaban and apixaban, respectively. Transition to eGFR <50 mL/min/1.73 m2 was lower in dabigatran- and apixaban-treated patients: odds ratio (OR) 0.492, 95% confidence interval (CI) 0.298-0.813, P = 0.006 and OR 0.449, 95% CI 0.276-0.728, P = 0.001, respectively. A lower rate of eGFR class worsening was found in all groups of NOACs compared to VKAs. No difference between full and reduced dose of NOAC was found. Subgroup analysis showed that the association between NOAC and eGFR changes was markedly reduced in diabetic patients. CONCLUSION: Patients prescribed NOACs showed a lower decline of renal function compared to those prescribed VKAs. This effect was partially lost in patients with diabetes.

Impact of adherence to a Mediterranean Diet pattern on patients with first acute myocardial infarction.

BACKGROUND AND AIMS: The Mediterranean diet (MD) affects the risk of myocardial infarction and long-term prognosis after a coronary event. Limited data are available regarding the influence of MD on short-term prognosis. We assessed the impact of the MD adherence on in-hospital and short-term outcome in patients with first ST-elevation Myocardial Infarction (STEMI). METHODS AND RESULTS: As many as 533 European patients with STEMI and no previous history of coronary artery disease were included in this analysis. Previous dietary habits of each patient were collected with a food frequency questionnaire from which we calculated the FAMI Mediterranean Diet Score (FAMI MD Score), according to the MD adherence. A blood sample was drawn to each patient within 6 h of symptoms onset. Levels of high-sensitivity C-Reactive Protein (hsCRP), Interleukin-6 (IL-6) were measured. Clinical outcome at 180 days and myocardial reperfusion were assessed. Patients with higher FAMI MD Score had lower levels of hsCRP; there were no differences between IL-6 level among FAMI MD Score quintiles. There were no associations between adherence to MD and 180-day adverse events. Lower FAMI MD Score was associated with a higher risk of ineffective myocardial reperfusion after thrombolysis or percutaneous coronary intervention. Similar results were observed for daily consumption of ≥4 portions of fruit and vegetable. CONCLUSIONS: A positive effect of the Mediterranean diet, and fruit and vegetable intake was observed on hsCRP and the occurrence of effective myocardial reperfusion. These findings confirm the favorable impact of Mediterranean diet adherence not only in primary but also in secondary prevention.

Machine learning approach for prediction of outcomes in anticoagulated patients with atrial fibrillation.

BACKGROUND: The accuracy of available prediction tools for clinical outcomes in patients with atrial fibrillation (AF) remains modest. Machine Learning (ML) has been used to predict outcomes in the AF population, but not in a population entirely on anticoagulant therapy. METHODS AND AIMS: Different supervised ML models were applied to predict all-cause death, cardiovascular (CV) death, major bleeding and stroke in anticoagulated patients with AF, processing data from the multicenter START-2 Register. RESULTS: 11078 AF patients (male n = 6029, 54.3%) were enrolled with a median follow-up period of 1.5 years [IQR 1.0-2.6]. Patients on Vitamin K Antagonists (VKA) were 5135 (46.4%) and 5943 (53.6%) were on Direct Oral Anticoagulants (DOAC). Using Multi-Gate Mixture of Experts, a cross-validated AUC of 0.779 ± 0.016 and 0.745 ± 0.022 were obtained, respectively, for the prediction of all-cause death and CV-death in the overall population. The best ML model outperformed CHA2DSVA2SC and HAS-BLED for all-cause death prediction (p < 0.001 for both). When compared to HAS-BLED, Gradient Boosting improved major bleeding prediction in DOACs patients (0.711 vs. 0.586, p < 0.001). A very low number of events during follow-up (52) resulted in a suboptimal ischemic stroke prediction (best AUC of 0.606 ± 0.117 in overall population). Body mass index, age, renal function, platelet count and hemoglobin levels resulted the most important variables for ML prediction. CONCLUSIONS: In AF patients, ML models showed good discriminative ability to predict all-cause death, regardless of the type of anticoagulation strategy, and major bleeding on DOAC therapy, outperforming CHA2DS2VASC and the HAS-BLED scores for risk prediction in these populations.

The serum metabolomic profiles of atrial fibrillation patients treated with direct oral anticoagulants or vitamin K antagonists.

AIMS: Long-term oral anticoagulation is the primary therapy for preventing ischemic stroke in patients with atrial fibrillation (AF). Different types of oral anticoagulant drugs can have specific effects on the metabolism of patients. Here we characterize, for the first time, the serum metabolomic and lipoproteomic profiles of AF patients treated with anticoagulants: vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). MATERIALS AND METHODS: Serum samples of 167 AF patients (median age 78 years, 62 % males, 70 % on DOACs treatment) were analyzed via high resolution 1H nuclear magnetic resonance (NMR) spectroscopy. Data on 25 metabolites and 112 lipoprotein-related fractions were quantified and analyzed with multivariate and univariate statistical approaches. KEY FINDINGS: Our data provide evidence that patients treated with VKAs and DOACs present significant differences in their profiles: lower levels of alanine and lactate (odds ratio: 1.72 and 1.84), free cholesterol VLDL-4 subfraction (OR: 1.75), triglycerides LDL-1 subfraction (OR: 1.80) and 4 IDL cholesterol fractions (ORs âˆ¼ 1.80), as well as higher levels of HDL cholesterol (OR: 0.48), apolipoprotein A1 (OR: 0.42) and 7 HDL cholesterol fractions/subfractions (ORs: 0.40-0.51) are characteristic of serum profile of patients on DOACs' therapy. SIGNIFICANCE: Our results support the usefulness of NMR-based metabolomics for the description of the effects of oral anticoagulants on AF patient circulating metabolites and lipoproteins. The higher serum levels of HDL cholesterol observed in patients on DOACs could contribute to explaining their reduced cardiovascular risk, suggesting the need of further studies in this direction to fully understand possible clinical implications.

Ex Vivo Antiplatelet Effects of Oral Anticoagulants.

BACKGROUND: The impact of non-vitamin K antagonist oral anticoagulants (NOACs) on platelet function is still unclear. We conducted a comprehensive ex vivo study aimed at assessing the effect of the four currently marketed NOACs on platelet function. METHODS: We incubated blood samples from healthy donors with concentrations of NOACs (50, 150 and 250 ng/mL), in the range of those achieved in the plasma of patients during therapy. We evaluated generation of thrombin; light transmittance platelet aggregation (LTA) in response to adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), human γ-thrombin (THR) and tissue factor (TF); generation of thromboxane (TX)B2; and expression of protease-activated receptor (PAR)-1 and P-selectin on the platelet surface. RESULTS: All NOACs concentration-dependently reduced thrombin generation compared with control. THR-induced LTA was suppressed by the addition of dabigatran at any concentration, while TF-induced LTA was reduced by factor-Xa inhibitors. ADP- and TRAP-induced LTA was not modified by NOACs. TXB2 generation was reduced by all NOACs, particularly at the highest concentrations. We found a concentration-dependent increase in PAR-1 expression after incubation with dabigatran, mainly at the highest concentrations, but not with FXa inhibitors; P-selectin expression was not changed by any drugs. CONCLUSIONS: Treatment with the NOACs is associated with measurable ex vivo changes in platelet function, arguing for antiplatelet effects beyond the well-known anticoagulant activities of these drugs. There are differences, however, among the NOACs, especially between dabigatran and the FXa inhibitors.

Impact of pregnancy on the natural history of women with hypertrophic cardiomyopathy.

AIMS: Whether pregnancy is a modifier of the long-term course and outcome of women with hypertrophic cardiomyopathy (HCM) is unknown. We assessed the association of pregnancy with long-term outcomes in HCM women. METHODS AND RESULTS: Retrospective evaluation of women with HCM from 1970 to 2021. Only women with pregnancy-related information (pregnancy present or absent) and a follow-up period lasting ≥1 year were included. The peri-partum period was defined as -1 to 6 months after delivery. The primary endpoint was a composite for major adverse cardiovascular events [MACE: cardiovascular death, sudden cardiac death, appropriate defibrillator shock and heart failure (HF) progression]. Overall, 379 (58%) women were included. There were 432 pregnancies in 242 (63%) patients. In 29 (7.6%) cases, pregnancies (n = 39) occurred after HCM diagnosis. Among these, three carrying likely pathogenic sarcomeric variants suffered MACEs in the peri-partum period. At 10 ± 9 years of follow-up, age at diagnosis [hazard ratio (HR) 1.034, 95% confidence interval (CI) 1.018-1.050, P < 0.001] and New York Heart Association (NYHA) class (II vs. I: HR 1.944, 95% CI 0.896-4.218; III vs. I: HR 5.291, 95% CI 2.392-11.705, P < 0.001) were associated with MACE. Conversely, pregnancy was associated with reduced risk (HR 0.605; 95% CI 0.380-0.963, P = 0.034). Among women with pregnancy, multiple occurrences did not modify risk. CONCLUSIONS: Pregnancy is not a modifier of long-term outcome in women with HCM and mostly occurs before a cardiac diagnosis. Most patients tolerate pregnancy well and do not show a survival disadvantage compared to women without. Pregnancy should not be discouraged, except in the presence of severe HF symptoms or high-risk features.

Hypertrophic cardiomyopathy (HCM) is the most common genetic disorder of the myocardium and is characterized by important gender-related differences: women are typically 5 years older than men at diagnosis, over half are diagnosed >50 years of age and consistently show greater propensity than men for heart failure (HF)-related complications and adverse outcome. Whether pregnancy is a modifier of the long-term course and outcome of women with HCM is unknown. In this study, pregnancy was not a modifier of long-term outcome in women with HCM. In particular: At 10 ± 7 years, most patients tolerated pregnancy well and did not show a survival disadvantage compared to women without pregnancies. Only baseline heart failure symptoms and age were associated with adverse outcome.Pregnancy should not be discouraged, except in the presence of severe HF symptoms or high-risk features. Nevertheless, cardio-obstetric counselling and close supervision are key in all instances, particularly in the peri-partum period.

Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2-2.0), major bleedings (RR 1.8; 95% CI 1.3-1.7), and mortality (RR 2.8; 95% CI 1.9-4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

Monitoring antiplatelet therapy: where are we now?

Single antiplatelet therapy represents the cornerstone of thrombosis prevention in atherosclerotic cardiovascular disease. Dual antiplatelet therapy (DAPT), consisting of aspirin plus a P2Y 12 inhibitor, is the standard of care for patients with acute coronary syndrome or undergoing both coronary and peripheral percutaneous interventions. Recent data suggest the efficacy of DAPT also after minor stroke. In this setting, a large body of evidence has documented that genetic and acquired patients' characteristics may affect the magnitude of platelet inhibition induced by antiplatelet agents. The implementation of tools allowing the identification and prediction of platelet inhibition has recently been shown to improve outcomes, leading to an optimal balance between antithrombotic efficacy and bleeding risk. We are therefore clearly moving towards tailored antiplatelet therapy. The aim of this paper is to summarize the available evidence on the evaluation of platelet inhibition in patients with coronary, peripheral, or cerebrovascular atherosclerosis. We will here focus on antiplatelet therapy based on both aspirin and P2Y 12 inhibitors. In addition, we provide practical insights into the clinical settings in which it appears reasonable to implement antiplatelet therapy monitoring.

The Role of Extracellular Matrix and Inflammation in the Stratification of Bleeding and Thrombotic Risk of Atrial Fibrillation on Oral Anticoagulant Therapy: Insights from Strat-Af Study.

In anticoagulated atrial fibrillation (AF) patients, the validity of models recommended for the stratification of the risk ratio between benefits and hemorrhage risk is limited. We hypothesize that both circulating and neuroimaging-based markers might improve the prediction of bleeding and thrombotic risk in anticoagulated AF patients. The Strat-AF study is an observational, prospective, single-center study enrolling 170 patients with AF; recruited patients are evaluated by means of a comprehensive protocol, with clinical, cerebral magnetic resonance imaging and circulating biomarkers assessment. The main outcome is the evaluation of cerebral microangiopathy related to the levels of circulating biomarkers of inflammation and extracellular matrix (ECM) remodeling. At multivariate logistic regression analysis adjusted for age, sex, CHA2DS2-VASc, HAS-BLED and type of anticoagulant, matrix metalloproteinases (MMP)-2 levels were significantly and positively associated with the presence of cerebral microbleeds (CMBs). A significant association between MMP-2, tissue inhibitor of metalloproteinases (TIMP)-1,-2,-4 levels and white matter hyperintensity was also found. Concerning the small vessel disease (SVD) score, MMP-2 and TIMP-1,-2 levels were associated with the presence of two and three or more signs of SVD, whereas TIMP-4 levels were associated with the presence of three signs of SVD with respect to patients with no instrumental signs of SVD. As regarding the presence of enlarged perivascular spaces (EPVS), a significant association was found for high levels of interleukin (IL)-8 and TIMP 1-2-3. These results demonstrate that patients with AF have evidence of impaired ECM degradation, which is an independent risk factor for thrombotic complications of AF patients on oral anticoagulant therapy. The incorporation of these markers in the prognostic schemes might improve their clinical capability in predicting stroke risk and thrombotic complications.

Lifetime Clinical Course of Hypertrophic Cardiomyopathy: Outcome of the Historical Florence Cohort Over 5 Decades.

Background: The current understanding of the clinical course and long-term outcome of patients with hypertrophic cardiomyopathy (HCM) has been extrapolated from cohorts with relatively short follow-up, usually <10 years. Extended assessments more closely reflecting HCM lifetime burden are not available. Objectives: The purpose of this study was to report the lifetime clinical course of HCM. Methods: We analyzed the clinical course of HCM patients diagnosed at our center from 1970 to 1992 and followed annually to the present. Cumulative incidence functions were used to estimate the incidence of HCM-related mortality (including heart failure [HF]/stroke related, sudden cardiac death [SCD]) and non-HCM related. Results: A total of 202 patients (age 41 ± 17 years; 63% male) were followed 27 ± 6 [range: 3-50] years. Overall, 97 (48%) survived and 105 (52%) died during the particularly long follow-up; 69 deaths were related to HCM, including 53 HF related, 11 fatal embolic strokes, and 16 SCDs. Annual overall HCM-related mortality was 1.3%/y, increasing from 0.7% during the first decade to 1.8% in the second/third decade (P < 0.01), mainly driven by increase in HF-/stroke-related events (from 0.6% to 1.3%). The SCD mortality rate was similar in the 2 periods (0.1% vs 0.44%, P = 0.10). Of the 69 HCM deaths, 29 (42%) occurred before the widespread availability of effective contemporary treatment strategies and are considered potentially preventable. Conclusions: In this unique HCM cohort followed for up to 50 years, often before contemporary therapies became widely implemented for HCM, HF frequently progressed over time, while arrhythmic SCD events were less common and remained constant over time. Despite spanning different management eras over 5 decades, HCM-related mortality remained relatively low (1.3%/y).

Incidence of stroke in patients with hypertrophic cardiomyopathy in stable sinus rhythm during long-term monitoring.

INTRODUCTION: Patients with hypertrophic cardiomyopathy (HCM) are at increased risk of stroke, but the incidence and factors associated with cardioembolic events in HCM patients without atrial fibrillation (AF) remain unresolved. We determined the incidence of stroke in patients in sinus rhythm (SR) monitored with a cardiac implantable electronic device (CIED). METHODS: All consecutive patients diagnosed with HCM and referred to CIED implantation with >16 years at diagnosis and ≥ 1 year follow-up post CIED implantation were retrospectively reviewed. Severe LA dilatation was defined as ≥48 mm. Patients were stratified by rhythm as: Pre-existing AF (AF present prior to CIED); De novo AF (AF present after CIED implantation); SR: no episodes of AF. RESULTS: Of 1651 patients, 185 (11.2%) implanted with a CIED were included (57% men, age: 54 ± 17 years). Baseline, pre-existing AF was present in 73 (39%) patients. Ischemic stroke was reported in 19 (10.3%, 1.78%/year) patients and was similar across the three groups (2.3%/year vs 1.1%/year vs 0.6%/year in patients in SR vs pre-existing AF vs de novo AF, respectively, p = 0.235). In SR patients, a LAD≥48 mm posed the greatest risk of stroke (Hazard Ratio: 10.03,95% Confidence-Interval 2.79-16.01). At Cox multivariable analysis, after adjustment for oral anticoagulation, LA was independently associated with stroke while rhythm was not. CONCLUSIONS: in HCM patients with CIED long-term monitoring and no prior history of AF, stroke rates were similar in those with de novo AF or stable SR. Severe LA dilatation was a powerful risk factor, irrespective of AF.

MitraClip implantation in real-world: clinical relevance of different patterns of left ventricular remodeling.

OBJECTIVE: The role of left ventricular (LV) volumes and ejection fraction (EF) in the selection of patients for the MitraClip procedure remains matter of debate. The goal of this study is to assess the pattern of LV remodeling and its clinical implications after MitraClip procedures, and to evaluate the role of LV ejection fraction (EF) in patient selection. METHODS: Complete echocardiography was performed before, at discharge, 1,6, and 12-months in 45 patients treated with MitraClip for severe mitral regurgitation (MR) [age 78.2 ± 8.3 yrs, NYHA 3.74 ± 0.44, EF 36.5 ± 12.8%]. From baseline to 6-month, reverse and adverse LV-R were defined as a ≥15% decrease in LV end-systolic volume and a ≥10% increase in LV end-systolic volume, respectively. RESULTS: At 6-month, sustained reduction of MR ≤ 2 was observed in all patients, but two; reverse, adverse, and no LV-R occurred in 51% (N = 23), 18% (N = 8), and 31% (N = 14) of patients, respectively. Baseline LV end-diastolic volume was an independent predictor of reverse LV-R [P = 0.004], whereas EF was not. During follow-up (17.5 ± 9.3 months) period, 50% of adverse/no LV-R patients were free of the composite endpoint (mortality and hospitalization for heart failure) compared to 95.7% of reverse LV-R patients (P = 0.006). In Cox analysis, adverse LV-R and adverse/no LV-R were associated with composite endpoint with adjusted hazard ratios of 5.6 (95% CI 1.65-19.00) and 10.08 (95% CI 1.29-78.6), respectively. CONCLUSION: After MitraClip implantation, sustained adverse or no LV-R occurred in one-in-two patients and was associated with poor prognosis. Large LV volumes may help us to avoid the futility of the procedure.