Marija Polovina

Gender-related differences in presentation, treatment and long-term outcome in patients with first-diagnosed atrial fibrillation and structurally normal heart: the Belgrade atrial fibrillation study.

BACKGROUND Several studies have investigated gender-related differences in atrial fibrillation (AF), but limited data are available in relation to gender-related differences in presentation, treatment and long-term outcomes of patients with first-diagnosed AF and structurally normal heart. OBJECTIVE To compare gender-related clinical characteristics, presentation, treatment and long-term outcomes in a cohort of patients with first-diagnosed non-valvular AF and a structurally normal heart, following a 10-year follow-up. METHODS Observational cohort study of patients with AF between 1992 and 2007. RESULTS Of 862 patients (mean age 52.2±12.1 years), 315 (36.5%) were female. Paroxysmal AF and hypertension were significantly more prevalent in females, while persistent AF was more common amongst males (all p<0.001). Female patients were more symptomatic (p=0.002). After a mean follow-up of 10.1±6.1 years, more male patients developed tachycardiomyopathy (6.0% vs. 1.9%, p=0.02). In multivariate analysis, male gender remained significantly associated with tachycardiomyopathy (HR 3.1, 95% CI: 1.3-7.4, p=0.012). The rate of transition to permanent AF, thromboembolism, hemorrhage, all-cause mortality, cardiovascular and sudden death did not significantly differ between male and female patients. CONCLUSIONS Gender differences are evident in AF. Male patients were less asymptomatic or more frequently developed persistent AF. Male patients were also at higher risk of tachycardiomyopathy, suggesting that these patients require more attention to rate control during follow-up.

Endothelial Dysfunction in Metabolic and Vascular Disorders

Abstract Vascular endothelium has important regulatory functions in the cardiovascular system and a pivotal role in the maintenance of vascular health and metabolic homeostasis. It has long been recognized that endothelial dysfunction participates in the pathogenesis of atherosclerosis from early, preclinical lesions to advanced, thrombotic complications. In addition, endothelial dysfunction has been recently implicated in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering that states of insulin resistance (eg, metabolic syndrome, impaired fasting glucose, impaired glucose tolerance, and T2DM) represent the most prevalent metabolic disorders and risk factors for atherosclerosis, it is of considerable scientific and clinical interest that both metabolic and vascular disorders have endothelial dysfunction as a common background. Importantly, endothelial dysfunction has been associated with adverse outcomes in patients with established cardiovascular disease, and a growing body of evidence indicates that endothelial dysfunction also imparts adverse prognosis in states of insulin resistance. In this review, we discuss the association of insulin resistance and T2DM with endothelial dysfunction and vascular disease, with a focus on the underlying mechanisms and prognostic implications of the endothelial dysfunction in metabolic and vascular disorders. We also address current therapeutic strategies for the improvement of endothelial dysfunction.

Predictors and prognostic implications of incident heart failure following the first diagnosis of atrial fibrillation in patients with structurally normal hearts: the Belgrade Atrial Fibrillation Study

Atrial fibrillation (AF) commonly co‐exists with heart failure (HF). The risk factors for and prognostic implications of incident HF development in patients with first‐diagnosed AF and structurally normal hearts are poorly defined. In a cohort of patients with first‐diagnosed AF and structurally normal hearts on baseline echocardiography, we investigated baseline risk factors for the development of incident HF and tested the hypothesis that incident HF was an independent predictor of adverse outcomes during a mean 10‐year follow‐up period.

Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30–40% of patients) and associated with a higher risk of HF hospitalization, all‐cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first‐line choice. Sulphonylureas and insulin have been the traditional second‐ and third‐line therapies although their safety in HF is equivocal. Neither glucagon‐like preptide‐1 (GLP‐1) receptor agonists, nor dipeptidyl peptidase‐4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium–glucose co‐transporter‐2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM.

The Association of CHA2DS2-VASc Score and Blood Biomarkers with Ischemic Stroke Outcomes: The Belgrade Stroke Study

Background Many blood biomarkers have a positive association with stroke outcome, but adding blood biomarkers to the National Institutes of Health Stroke Scale (NIHSS) did not significantly improve its discriminatory ability. We investigated the association of the CHA2DS2-VASc score with unfavourable functional outcome (defined as a 30-day modified Rankin Scale [mRS] ≥3) in patients presenting with acute ischemic stroke (AIS), and examined whether the addition of blood biomarkers (troponin I [TnI], fibrinogen, C-reactive protein [CRP]) affects the model discriminatory ability. Methods We conducted an observational single-centre study of consecutive patients with AIS. All patients were admitted to hospital within 24 hours from the neurological symptoms onset. Results Of 240 patients (mean age 70.0±8.9 years), unfavourable 30-day outcome occurred in 92 (38.3%). Patients with mRS≥3 were older and more likely to have atrial fibrillation or other comorbidities (all p<0.001). They had higher levels of CRP, fibrinogen, TnI and higher CHA2DS2-VASc and CHADS2 scores (all p<0.05). The adjusted CHA2DS2-VASc score had excellent predictive ability for poor stroke outcome (c-statistic 0.982;95%CI,0.964–1.000, p<0.001). Whilst CRP had the highest sensitivity (83.7%), cardiac TnI was the most specific (97.3%) for prediction of poor stroke outcome (cut-off: >0.09µg/L). Compared with each of these biomarkers, CHA2DS2-VASc score had significantly better predictive ability for poor stroke outcome (c-statistic for CRP, Fibrinogen and TnI was 0.853;95%CI,0.802–0.895, 0.848;95%CI,0.796–0.891, and 0.792;95%CI,0.736–0.842, all p<0.001, respectively, versus 0.932;95%CI,0.892–0.960, p<0.001 for the CHA2DS2-VASc, all p for the comparisons<0.01). There was no significant difference in the predictive ability of the CHA2DS2-VASc score vs. combinations of the CHA2DS2-VASc and TnI or TnI, fibrinogen and CRP (z statistic 0.369, p = 0.7119; integrated discrimination index 0.00801 and 0.00172, respectively, both p>0.05). Conclusions The CHA2DS2-VASc score alone reliably predicts 30-day unfavourable outcome of stroke. Adding blood biomarkers to the CHA2DS2-VASc score did not significantly increase the predictive ability of the model.

Relation of Biomarkers of Inflammation and Oxidative Stress with Hypertension Occurrence in Lone Atrial Fibrillation.

We compared plasma levels of biomarkers of inflammation (CRP) and oxidation (oxLDL), determined at study inclusion in lone atrial fibrillation (LAF) patients (48.6 ± 11.5 years; 74.0% men) and sinus rhythm controls (49.7 ± 9.3 years; 72.7% men, P > 0.05), and investigated the association of baseline CRP and oxLDL levels with the risk for vascular disease (VD) development (hypertension, cerebrovascular disease, coronary/peripheral artery disease, and pulmonary embolism) during prospective follow-up. Baseline CRP (1.2 [0.7–1.9] mg/L versus 1.1 [0.7–1.6] mg/L) and oxLDL levels (66.3 ± 21.2 U/L versus 57.1 ± 14.6 U/L) were higher in LAF patients (both P < 0.05). Following a median of 36 months, incident VD occurred in 14 (28.0%) LAF patients, all of whom developed arterial hypertension, and in 5 (11.4%) controls (hypertension, n = 4; coronary artery disease, n = 1), P < 0.05. LAF patients developed VD more frequently and at a younger age. Both CRP (HR, 2.54; 95% CI, 1.26–5.12; P = 0.009) and oxLDL (HR, 2.24; 95% CI, 1.14–4.40; P = 0.019) were multivariate predictors of incident hypertension in LAF patients, but not in the controls. Further research should clarify clinical relevance of investigated biomarkers for risk stratification and treatment of LAF patients.

Impaired endothelial function in lone atrial fibrillation

BACKGROUND/AIM Impaired endothelial function has been previously documented in patients with atrial fibrillation (AF) and underlying comorbidities or older patients with idiopathic AF. The aim of this study was to evaluate systemic endothelial function in younger AF patients (less than < 60 years old) with lone AF (that is, without associated cardiopulmonary comorbidities, including arterial hypertension), by comparing brachial artery flow-mediated dilation (FMD) in lone AF patients with FMD of healthy subjects in sinus rhythm. METHODS Two groups of participants were prospectively enrolled. The first group comprised of 38 AF patients (the mean age 45 +/- 11 years, 68% male) with persistent (> 7 days) lone AF. The second group comprised of 28 healthy controls in sinus rhythm (the mean age 43 +/- 13, 53% male), matched by age, gender and atherosclerotic risk factors. All the participants underwent physical examination, laboratory analysis [including determination of C-reactive protein (CRP)], standard echocardiography and exercise-stress testing. Brachial artery FMD and endothelium independent dilation (NMD) were assessed with a high-resolution ultrasound probe and arterial diameters taken from 5 consecutive cardiac cycles were averaged for each measurement to accommodate to beat-to-beat flow variations in AF. RESULTS There were no differences between the 2 groups regarding age, gender and most clinical, laboratory and echocardiographic characteristics (all p > 0.05), apart from the increased heart rate (p = 0.018), body mass index (p = 0.027), CRP levels (p = 0.007) and left atrial anteroposterior dimension (p < 0.001) in AF patients. FMD of AF patients [median value 5.0%, interquartile range (IQR) 2.87%-7.50%] was significantly lower (p < 0.001) than FMD of healthy controls (median value 8.85%, IQR 5.80%-12.50%), whereas there were no differences in median NMD values (p > 0.05). In the multivariate analysis, the independent FMD determinants in our study population were the presence of AF, smoking and total cholesterol levels (all p < 0.001). In patients with AF, the strongest independent FMD determinant was arrhythmia duration (p < 0.001), followed by smoking (p = 0.013) and total cholesterol levels (p = 0.045). CONCLUSIONS Our findings confirm that sustained AF is associated with systemic endothelial dysfunction even in relatively young patients with no cardiovascular disorders or risk factors. AF is an independent contributor to lower FMD and a prolonged arrhythmia duration may confer the risk for more profound endothelial damage.

Recent Advances in Antiarrhythmic Drug Treatment of Atrial Fibrillation

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia in clinical practice associated with significant morbidity and mortality. With the growing number of the affected individuals, the development of safe and effective treatment options for AF has become a worldwide priority. Currently available antiarrhythmic medications for the restoration and maintenance of sinus rhythm have limitations due to the modest efficacy and a potential for adverseeffects. Although substantial progress has been made in AF-ablation techniques, broad application of these nonpharmacological treatment modalities is limited and antiarrhythmic drug treatment is still the cornerstone and the first-line therapy for the majority of AF patients. Improvements in the understanding of the principal pathophysiological mechanisms of AF obtained in the last several years have provided promising treatment opportunities. New therapeutic options are based on the more selective targeting of ion channels and intercellular connection proteins predominantly expressed in the atria, the restoration of intracellular Ca(2+) homeostasis and the prevention of AF-associated electrical and structural remodeling. In this review, we provide a highlight of the most important pathophysiological mechanisms in AF with a relation to the potential therapeutic interventions, and discuss novel findings regarding the current and future pharmacological AF management and recent patents.

Patient preferences at ten years following initial diagnosis of atrial fibrillation: the Belgrade Atrial Fibrillation Study.

Background Many atrial fibrillation (AF) patients have a poor understanding of the management of this condition. We investigated patient attitudes towards AF and a potential invasive treatment following an average 10-year period of prospective rhythm control in a cohort of newly diagnosed AF patients. Methods This was a prospective registry-based study. At the regular annual visit in 2007, patients were asked at random to answer several AF-related questions. Results Of 390 patients, 277 (71.0%) reported symptom reduction over time, but only 45 (11.5%) reported that they had “got used” to AF; 201 patients (51.5%) stated they would always prefer sinus rhythm, and 280 (71.2%) would accept an invasive AF treatment. Independent predictors for choosing an invasive procedure were younger age, impaired career/working capacity, and male gender (all P < 0.05). Conclusion Our findings suggest that most AF patients prefer sinus rhythm and would readily accept an invasive procedure if it offered the possibility of a cure for their AF.

Adverse cardiovascular outcomes in atrial fibrillation: Validation of the new 2MACE risk score

BACKGROUND In addition to thromboembolism, atrial fibrillation (AF) may also predispose to major adverse cardiovascular events (MACE) attributable to coronary artery disease (CAD), including myocardial infarction (MI). The 2MACE score (2 points - Metabolic syndrome and Age≥75years, 1 point - MI/revascularization, Congestive heart failure/ejection-fraction <40%, and thrombo-Embolism) was recently proposed to help identify AF patients at risk of MACE. We assessed the predictive validity of the 2MACE score for MACE occurrence in AF patients free of CAD at baseline. METHODS Non-valvular AF patients (n=794) without CAD (mean-age, 62.5±12.1years, metabolic syndrome, 34.0%; heart failure/ejection-fraction <40%, 25.7%; thromboembolism, 9.7%) were prospectively followed for 5years, or until MACE (composite of non-fatal/fatal MI, revascularization and cardiovascular death). At inclusion, CAD was excluded by medical history, exercise-stress testing and/or coronary angiography. Also, the 2MACE score was determined. RESULTS At follow-up, 112 patients experienced MACE (2.8%/year). The 2MACE score demonstrated adequate discrimination (C-statistic, 0.699; 95% confidence interval [CI], 0.648-0.750; P<0.001) and calibration (Hosmer-Lemeshow P=0.79) for MACE. The score was significantly associated with MACE, with the adjusted Hazard Ratio (aHR) of 1.56 (95%CI, 1.35-1.73; P<0.001). As for individual outcomes, the score predicted MI (n=46; aHR, 1.49; 95%CI 1.23-1.80), revascularization (n=32; aHR, 1.41; 95%CI, 1.11-1.80) and cardiovascular death (n=34; aHR, 1.43; 95%CI, 1.14-1.81), all P<0.001. CONCLUSIONS The 2MACE score successfully predicts future MACE, including incident MI, coronary revascularization and cardiovascular death in AF patients free of CAD at baseline. It may have a role in risk-stratification and primary prevention of MACE in AF patients.