Eva Jover

Growth differentiation factor-15, a novel biomarker related with disease severity in patients with hypertrophic cardiomyopathy

BACKGROUND The growth differentiation factor 15 (GDF-15) has been shown up-regulated in stress conditions and to have regulatory actions in myocyte hypertrophy. We hypothesized that GDF-15 could be related to disease severity and functional status in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS We performed a study which includes 102 consecutive outpatient HCM subjects, 73% males, aged 47.1±14.6 years. A complete history and clinical examination was performed, including 12-lead electrocardiogram, echocardiography, symptom-limited treadmill exercise, 24-hour ECG-Holter monitoring, and magnetic resonance with Gadolinium. Several biomarkers, associated with myocardial remodeling and damage, were compared to GDF-15 levels. The assays were performed with commercial ELISAs or standardized methods when available. There was a significant association between GDF-15 levels and comorbidities, being higher in hypertension (p=0.001), diabetes (p=0.030), atrial fibrillation (p=0.012), dyspnea (p=0.020) and NYHA≥II functional class (p=0.037). GDF-15 levels were positively correlated with clinical variables (age, worse exercise capacity and mild renal dysfunction) and biomarkers of interstitial remodeling, such as metalloproteinase-2 (r: 0.40; p=0.009), N-terminal pro-B-type natriuretic peptide (r: 0.28; p=0.049), high-sensitivity troponin T (r: 0.30; p=0.003) and von Willebrand factor (r: 0.33; p=0.001). Multivariate analysis was assessed to estimate the involvement of these different factors in the GDF-15 levels, confirming the independent implication of severe dyspnea and functional status. CONCLUSIONS The present results show that higher levels of GDF-15 are associated to conditions of severe disease in HCM. Hence, GDF-15 is suggested as a novel marker related to the severity and could represent a further useful tool in monitoring functional capacity of HCM patients.

Usefulness of N-Terminal Pro–B-Type Natriuretic Peptide Levels for Stroke Risk Prediction in Anticoagulated Patients With Atrial Fibrillation

Background and Purpose— Oral anticoagulation is highly effective in reducing stroke and mortality in atrial fibrillation (AF). Several risk stratification schemes have been developed using clinical characteristics. Elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) are important markers of increased mortality and morbidity in congestive heart failure and general community population. The aim of our study was to assess the predictive value of NT-proBNP levels in an unselected real-world cohort of anticoagulated patients with AF. Methods— We studied 1172 patients (49% male; median age, 76 years) with permanent AF who were well stabilized on oral anticoagulation (international normalized ratio, 2.0–3.0). Plasma NT-proBNP levels were quantified at baseline. We recorded thrombotic and vascular events, mortality, and major bleeding. The best cutoff points were assessed by receiver-operating characteristic curves. Results— Median levels (interquartile range) of NT-proBNP were 610 (318–1037) pg/mL. Median follow-up was 1007 (806–1279) days. On multivariate analysis, high NT-proBNP was significantly associated with the risk of stroke (hazards ratio, 2.71; P=0.001) and composite vascular events (acute coronary syndrome or acute heart failure; hazards ratio, 1.85; P=0.016), as well as a significant association with mortality (adjusted hazards ratio, 1.66; P=0.006). No association with bleeding was found (P=0.637). The integrated discrimination improvement (IDI) analysis demonstrated that NT-proBNP improved the Congestive heart failure, Hypertension, Age≥75 (doubled), Diabetes mellitus, Stroke (doubled)–Vascular disease and Sex category (female); CHA2DS2–VASc score for predicting embolic events (relative IDI, 2.8%; P=0.001) and all-cause death (relative IDI, 1.8%; P=0.001). Conclusions— In real-world cohort of anticoagulated patients with AF, NT-proBNP provided complementary prognostic information to an established clinical risk score (CHA2DS2–VASc) for the prediction of stroke/systemic embolism. NT-proBNP was also predictive of all-cause mortality, suggesting that this biomarker may potentially be used to refine clinical risk stratification in anticoagulated patients with AF.

Small‐size platelet microparticles trigger platelet and monocyte functionality and modulate thrombogenesis via P‐selectin

This study aimed to examine the mechanisms of cellular activation by small‐size platelet microparticles (sPMP) and to present the performance of high‐resolution flow cytometry for the analysis of subcellular entities from different origins. Plasma counts of sPMP were analysed in coronary artery disease patients (n = 40) and healthy controls (n = 40). The effect of sPMP and platelet debris (PD) in pathophysiologically relevant doses on platelet and monocyte activation parameters and thrombogenesis was investigated via flow cytometry and thromboelastometry. New generation flow cytometry identifies differences in size, levels and surface molecules of sPMP derived in the absence of stimulus, thrombin activation and platelet disruption. Addition of sPMP resulted in platelet degranulation and P‐selectin redistribution to the membrane (P = 0·019) in a dose and time‐dependent manner. Blood clotting time decreased after addition of sPMP (P = 0·005), but was not affected by PD. Blocking P‐selectin (CD62P) in sPMP markedly reverted the effect on thrombus kinetics (P = 0·035). Exposure to sPMP stimulated monocyte expression of intercellular adhesion molecule‐1 (P < 0·03) and decreased monocyte interleukin‐6 receptor density (P < 0·01). These results implicate sPMP as a direct source of downstream platelet and monocyte activation. In pathological coronary artery disease conditions, higher levels of sPMP favour a prothrombotic state, partly through P‐selectin expression.

Ankle brachial index as an independent predictor of mortality in anticoagulated atrial fibrillation

Eur J Clin Invest 2012; 42 (12): 1302–1308

Influencia de los polimorfismos de CYP2C19 en la reactividad plaquetaria y el pronóstico en una población no seleccionada de pacientes con síndrome coronario agudo sin elevación del ST

INTRODUCTION AND OBJECTIVES CYP2C19*2 and CYP2C19*17 alleles appear to contribute to heterogeneous clopidogrel metabolism. The aims of the present study were to assess the phenotype-genotype relationship of CYP2C19*2 and *17 allele carriage and to explore the clinical impact of those polymorphisms at 6-month follow-up of an acute event in an unselected population of non-ST elevation acute coronary syndrome. METHODS Recruitment for the first and second objectives was 40 stable acute coronary syndrome patients under dual antiplatelet therapy at 12 months after coronary stent placement and an unselected population of 493 consecutive patients with non-ST elevation acute coronary syndrome, respectively. Platelet reactivity was assessed by optical aggregometry induced by adenosine diphosphate and thrombin receptor activating peptide, and by vasodilator-stimulated phosphoprotein phosphorylation measurement using flow cytometry. Genotypes were determined with a TaqMan assay. RESULTS Only the vasodilator-stimulated phosphoprotein phosphorylation measurement detected significant differences in on-clopidogrel platelet reactivity between the wild-type subjects and the CYP2C19*2 (P=.020) and *17 allele carriers (P=.048). No significant difference was found between CYP2C19*2 ([HR (95%CI): 1 (0.94-1.55)], P=.984) or *17 ([HR (95%CI): 0.93 (0.61-1.43)], P=.753) allele carriage and the occurrence of adverse events at 6-month follow-up. CONCLUSIONS Even though CYP2C19 genotype is associated with variable on-clopidogrel platelet reactivity, it has no significant clinical influence. Prognosis of acute coronary syndromes may be influenced by a myriad of variables.

Impact of polymorphisms in the renin–angiotensin–aldosterone system on hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous autosomal dominant heart disease characterised by left ventricular hypertrophy in the absence of another cardiac or systemic disease that is capable of producing significant wall thickening. Microscopically it is characterised by cardiomyocyte hypertrophy, myofibrillar disarray and fibrosis. The phenotypic expression of HCM is multifactorial, with the majority of cases occurring secondary to mutations in genes encoding the sarcomere proteins. In conjunction with the genetic heterogeneity of HCM, phenotypic expression also exhibits a high level of variability even within families with the same aetiological mutation, and may be influenced by additional genetic factors. Polymorphisms of the renin–angiotensin–aldosterone system (RAAS) represent an attractive hypothesis as potential disease modifiers, as these genetic variants alter the ‘activation status’ of the RAAS, which leads to more left ventricular hypertrophy through different pathways. The main objective of this review is to provide an overview of the role of different polymorphisms identified in the RAAS, in patients with HCM.

The prognostic role of the adiponectin levels in atrial fibrillation

Patients with atrial fibrillation (AF) have a high morbidity and mortality from vascular events, even despite oral anticoagulation (OAC). Rather than being a risk factor, AF has been proposed as a risk marker, being a signal of advanced atherosclerosis. Circulating adiponectin levels, a cytokine with anti‐inflammatory and cardioprotector roles, are related to different atherosclerotic risk factors. The aim is to evaluate whether plasma adiponectin can be predictive of cardiovascular risk in anticoagulated patients with AF.

An Insight of Novel Pharmacological Therapies in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is microscopically characterized by cardiomyocyte hypertrophy, myofibrillar disarray, and fibrosis. During the evolvement of the hypertrophic disease, myocardium suffers a heterogeneous remodeling which includes enhancement of extracellular matrix. The most commonly used pharmacological agents are β- blockers and verapamil, a calcium antagonist, which are the mainstay of therapy. Their proposed mechanisms of effect include improved ventricular relaxation, and increased diastolic filling time but its impact on HCM pathophysiology remains unclear. The results of genetic and pharmacological studies in animal models suggest that cardiac hypertrophy and fibrosis in HCM are potentially reversible. However, current pharmacological treatments of HCM in patients, while are effective for symptomatic improvement, have not been established to prevent, ameliorate, or reverse cardiac hypertrophy in patients. An effective treatment of HCM has to target the molecular mechanisms that are involved in the pathogenesis of the phenotype and novel pharmacological therapies are moving in that direction. In this review, we analyse potential beneficial effects of specific experimental pharmacological agents on decreasing myocardial hypertrophy, regression of fibrosis or improving myocardial metabolic efficiency.

Platelet reactivity over time in coronary artery disease patients treated with a bioabsorbable everolimus-eluting scaffold

Abstract Everolimus-eluting bioabsorbable scaffolds (BVSs) have exhibited similar long-term clinical outcomes compared to its everolimus-eluting metallic counterparts. However, reports from earlier studies have shown a signal for an increased rate of stent thrombosis. The aim of the current investigation is to describe the platelet reactivity profiles over time in patients treated with everolimus-eluting BVS in comparison to everolimus-eluting metallic stents. This is a pilot study in which patients on aspirin and clopidogrel with at least 1 everolimus-eluting BVS were included (n = 24). Patients with at least 1 everolimus-eluting metallic stent implanted were included as control group (n = 25). Blood samples were taken at time of discharge and at 3- and 6-month follow-up. Platelet function tests included VerifyNow (VN-P2Y12), multiplate aggregometry (MEA), and light transmission aggregometry (LTA). There was no difference in platelet reactivity at discharge, 3- and 6-month visits (unadjusted p = 0.733 and p = 0.582; p = 0.432 and p = 0.899 after adjusting for discharge value platelet reactivity0, respectively) using VN-P2Y12. Similar findings were observed with LTA. However, patients with BVS showed significantly higher platelet reactivity than patients with metallic stents at 3 and 6 months in the crude analysis (p = 0.003) and after adjusting for discharge value (p = 0.013) measured with ADP-MEA. There were no differences in platelet reactivity mediated by the T × A2 pathway between both groups. Finally, there is no statistical difference in high on-clopidogrel platelet reactivity (HPR) rate between both groups. The results of this pilot study suggest that BVS might have different platelet reactivity profiles, and warrants further investigation in dedicated clinical studies.

Galectin-3 as a marker of interstitial atrial remodelling involved in atrial fibrillation

Remodelling in the atria could appear as a result of hypertension, diabetes or ischaemic heart disease. Galectin-3 (Gal-3) is a mediator of profibrotic pathways and a potential biomarker of cardiac remodelling. We prospectively recruited consecutive patients undergoing elective cardiac surgery. Preoperative Gal-3 levels were determined from serum samples, and the presence of fibrosis was assessed from atrial appendage tissue samples obtained during cardiac surgery. We included 100 patients with aortic valve or ischaemic heart diseases and 15 controls with permanent AF. Gal-3 levels were associated with sex, left atrial volume, previous cardiac disease, diabetes mellitus, hypertension, NYHA and NT-proBNP. We observed differences in serum Gal-3 concentrations between patients and controls with permanent AF (p = 0.020). We performed ROC curves related to fibrosis and established a cutoff point for Gal-3 >13.65 ng/ml. Multivariate analyses showed previous cardiac disease, NYHA scale and high Gal-3 to be independent predictors of fibrosis. After adjustment for confounding factors, atrial fibrosis remained the only independent factor for the development of AF (p = 0.022). High Gal-3 serum levels predict fibrosis of the atrial appendage. NYHA scale and previous cardiac disease were also associated with tissue fibrosis in patients undergoing surgery. Atrial fibrosis was the only independent predictor for post-operative AF occurrence in our model after correcting for confounding factors.