Aneta Aleksova

Natural history of dilated cardiomyopathy: from asymptomatic left ventricular dysfunction to heart failure--a subgroup analysis from the Trieste Cardiomyopathy Registry.

Background Few data are available in the literature regarding the characteristics and prognosis of asymptomatic patients with idiopathic dilated cardiomyopathy (DCM). Aim To determine the frequency with which patients affected by DCM are diagnosed in the asymptomatic state as well as to evaluate the natural history of such patients and the factors influencing their outcome. Moreover, we sought to compare the outcome of asymptomatic patients with that of patients with signs of overt heart failure at the time of first evaluation. Methods and results We analyzed the data of 747 patients with DCM enlisted in the Heart Muscle Disease Registry of Trieste from 1978 to 2007. We divided our population into four groups; group 1 comprised 118 asymptomatic [New York Heart Association (NYHA) I] patients without a history of congestive symptoms (16%), group 2 comprised 102 asymptomatic (NYHA I) patients (14%) with a positive anamnesis for heart failure stabilized in medical therapy, group 3 comprised 327 patients (44%) with signs of mild heart failure (NYHA II) and group 4 comprised 200 patients (26%) in NYHA III–IV. During the follow-up of 112 ± 63 months, 46 (21%) of 220 asymptomatic patients with DCM died or underwent heart transplantation. By Cox proportional model, left ventricular ejection fraction of 30% or less was a unique independent predictor either for death/heart transplantation (hazard ratio 3.15, 95% confidence interval 1.5–6.7, P = 0.003) or for sudden death/major ventricular arrhythmias (hazard ratio 3.9, 95% confidence interval 1.7–9.3, P = 0.002). Patients from group 1 had a trend for a better outcome with respect to those from group 2 (P = 0.06). In comparison with the asymptomatic patients, those with signs of overt heart failure at baseline had a worse prognosis. Conclusion The proportion of asymptomatic patients with DCM at the moment of first evaluation at our center is significant (30%). Among them, those without a previous history of heart failure had a less advanced disease and a trend for a better long-term outcome on optimal medical treatment. Therefore, early diagnosis may offer better long-term quality of life and even better survival. Further studies on larger populations are indicated.

Predicting atrial fibrillation recurrence with circulating inflammatory markers in patients in sinus rhythm at high risk for atrial fibrillation: data from the GISSI atrial fibrillation trial

Background Inflammation may play a significant role in the pathogenesis of atrial fibrillation (AF). Objectives To examine the roles of three systemic inflammatory markers in predicting recurrent AF. Methods The association between the plasma concentrations of high-sensitivity C reactive protein (hsCRP), interleukin-6 (IL-6) and pentraxin-3 (PTX3) with echocardiographic parameters and with the time to first recurrence of AF was tested in 382 patients with a history of AF but in sinus rhythm at randomisation, enrolled in the GISSI-AF biohumoral study. Results Baseline PTX3 was related to left atrial, but not to left ventricular chamber volume. During one year of follow-up, 204 patients (53.1%) had a recurrent AF. There were no significant differences in baseline median [Q1–Q3] plasma concentrations of IL-6, hsCRP and PTX3 among patients with (2.11 [1.47–3.74] pg/ml, 3.30 [1.40–6.80] mg/l and 4.66 [3.27–6.97] ng/ml, respectively) or without recurrent AF (2.09 [1.37–2.90] pg/ml, p=0.182; 3.00 [1.10–6.20] mg/l, p=0.333; 5.09 [3.22–7.98] ng/ml, p=0.637). At 6 and 12 months follow-up, AF patients had significantly higher concentrations of IL-6 and PTX3 than those in sinus rhythm, and those with most recent episodes of AF had higher hsCRP. Baseline levels of IL-6, hsCRP or PTX3 were not significantly associated with a higher risk of recurrence of AF. Conclusion In patients with a history of AF, but without significant left ventricular dysfunction or heart failure, inflammatory biomarkers may be raised but are, at best, weak predictors of the risk for first recurrence of AF.

Relation between the plasma levels of LDL-cholesterol and the expression of the early marker of inflammation long pentraxin PTX3 and the stress response gene p66(ShcA) in pacemaker-implanted patients

Our goal was to set up a pilot study to explore the possible relation between the expression of p66(ShcA) and PTX3, two emerging regulators of stress response and inflammation processes, respectively, and the circulating levels of LDL-cholesterol (LDL), a factor implicated in the development of inflammation and oxidative-stress associated diseases such as atherosclerosis. p66(ShcA) and PTX3 mRNA contents were determined locally, in subcutaneous adipose specimens of non-diabetic pacemakerimplanted patients, and systemically in the circulating white blood cells (WBC) obtained from the same patients. The mean of the circulating LDL levels (125 mg/dl) was chosen as a threshold to identify two groups here considered to have high (>125 mg/dl) and low (<125 mg/dl) LDL plasma levels. Our data show that PTX3 and p66(ShcA) mRNA levels are significantly more elevated in WBCs and in adipose tissue samples of patients with high levels of LDL compared to those with low levels. Additionally, a multiple regression analysis indicates that among LDL, TG, HDL, total cholesterol, CRP, creatinine and glucose levels, the only variable significantly affecting p66(ShcA) and PTX3 mRNA expressions either in adipose tissue or in WBCs is represented by the circulating amount of LDL. In conclusion, our results suggest a potential link between the level of LDL and the expression of two genes involved in inflammation/oxidative stress pathways, i.e., p66(ShcA) and PTX3, thus contributing to further understand the mechanism through which LDL may mediate the pathogenesis of inflammation and oxidative-stress associated diseases such as atherosclerosis.

n-3 polyunsaturated fatty acids and atrial fibrillation in patients with chronic heart failure: the GISSI-HF trial.

In the last few years, n‐3 polyunsaturated acids (PUFAs) have been extensively studied for the prevention of AF, mostly in patients without heart failure (HF) or LV dysfunction. This post‐hoc analysis of the GISSI‐HF trial assessed the effect of n‐3 PUFAs on AF in patients with chronic HF without AF at study entry over a median follow‐up of 3.9 years.

New-onset left bundle branch block independently predicts long-term mortality in patients with idiopathic dilated cardiomyopathy: data from the Trieste Heart Muscle Disease Registry.

AIMS Left bundle branch block (LBBB) is commonly associated with heart failure. We evaluated the prevalence, incidence, and impact of LBBB on long-term outcome in young patients with heart failure affected by idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS We included 608 patients with DCM from the Heart Muscle Disease Registry of Trieste in this retrospective analysis. At baseline electrocardiogram (ECG), 189 patients (31.1%) had LBBB. The patients with baseline LBBB had a significantly higher mortality rate than the patients without LBBB (38.6 vs. 27.9%, P = 0.002) at the univariate analysis. After a multiple covariate adjustment, the baseline LBBB was not associated with a significantly increased risk of death [hazard ratio (HR) 1.27, 95% confidence interval (CI): 0.88-1.81, P = 0.2]. Forty-seven (11.2%) patients without LBBB at baseline ECG developed LBBB during follow-up. Among these, the mortality rate was 49 vs. 25% in patients without new-onset LBBB (P = 0.001). New-onset LBBB was a strong and independent predictor of all-cause mortality (HR 3.18, 95% CI: 1.90-5.31, P < 0.001) at multivariate analysis. CONCLUSION After correcting for potential confounders, new-onset LBBB was found to be associated with an increased risk of all-cause mortality. The management of patients with new-onset LBBB may need to be more aggressive, possibly including early cardiac resynchronization therapy/implantable cardioverter-defibrillator therapy.

Obesity and high waist circumference are associated with low circulating pentraxin-3 in acute coronary syndrome

BackgroundLong pentraxin 3 (PTX3) is a component of the pentraxin superfamily and a potential marker of vascular damage and inflammation, associated with negative outcome in patients with acute coronary syndromes (ACS). Obesity is a risk factor for cardiovascular disease and PTX3 production is reported in abdominal adipose tissue. Low PTX3 is however reported in the obese population, and obesity per se may be associated with less negative ACS outcome.MethodsWe investigated the potential impact of obesity and high waist circumference (reflecting abdominal fat accumulation) on plasma PTX3 concentration in ACS patients (n = 72, 20 obese) compared to age-, sex- and BMI-matched non-ACS individuals.ResultsBoth obese and non-obese ACS patients had higher PTX3 than matched non-ACS counterparts, but PTX3 was lower in obese than non-obese individuals in both groups (all P < 0.05). PTX3 was also lower in ACS subjects with high than in those with normal waist circumference (WC). Plasma PTX3 was accordingly associated negatively with BMI and WC, independently of age and plasma creatinine. No associations were observed between PTX3 and plasma insulin, glucose or the short pentraxin and validated inflammation marker C-reactive protein, that was higher in ACS than in non-ACS individuals independently of BMI or WC.ConclusionsObesity is associated with low circulating PTX3 in ACS. This association is also observed in the presence of abdominal fat accumulation as reflected by elevated waist circumference. Low PTX3 is a novel potential modulator of tissue damage and outcome in obese ACS patients.

Critical role of lysosomes in the dysfunction of human Cardiac Stem Cells obtained from failing hearts

UNLABELLED The in vivo reparative potential of Cardiac Stem Cells (CSC), cultured from explanted failing hearts (E-), is impaired by cellular senescence. Moreover, E-CSC are characterized, with respect to CSC obtained from healthy donors (D-), by an arrest in the autophagic degradation. Although the lysosome plays a pivotal role in cellular homeostasis and defects of this organelle may be associated with aging and heart failure, the lysosomal function of CSC has never been investigated. The aim of this work was to focus on the Lysosomal Compartment (LC) of E-CSC, evaluating elements that could jeopardize lysosome functionality. METHODS AND RESULTS Bioinformatics analysis conducted on genes differentially expressed between D- and E-CSC identified lysosomal-related gene sets as significantly enriched. Moreover, 29 differentially expressed genes were part of CLEAR (Coordinated Lysosomal Expression and Regulation) gene network, by which Transcription Factor EB (TFEB) regulates cellular clearance. Consistently, live cell imaging and flow cytometry analyses showed that the lysosomes of E-CSC are less acidic than the D-CSC ones. Furthermore, confocal microscopy showed in E-CSC: an accumulation of intralysosomal lipofuscins, a reduction of cathepsin B activity, evidence of lysosome membrane permeabilization, and the reduction of the nuclear active TFEB. The use of Rapamycin (TORC1 inhibitor) was able on one hand to increase TFEB activation and, on the other hand, to reduce lipofuscin mass, potentiating the lysosomal functionality. CONCLUSIONS This study demonstrated for the first time that E-CSC are characterized by a blunted activation of TFEB and an altered proteostasis. TORC1 hyperactivation plays a central role in this phenomenon.

Impact of Atrial Fibrillation on Outcome of Patients with Idiopathic Dilated Cardiomyopathy: Data from the Heart Muscle Disease Registry of Trieste

Objective: There is a paucity and inconsistency of data regarding the natural history of patients affected by idiopathic dilated cardiomyopathy (IDCM) and atrial fibrillation (AF). We examined the prognostic implications of AF in a subset of patients with IDCM. Methods: We analyzed the data of 539 patients with IDCM enrolled in the Heart Muscle Disease Registry of Trieste. Results: At baseline, 52 (9.6%) of 539 patients had AF. There was no difference in survival of patients with either AF or sinus rhythm at enrollment (P=.28). During long-term follow-up (90±58 months), AF was detected on ECG/ECG-Holter monitoring in 28 (5.7%) of 487 patients in sinus rhythm at baseline. Predictors of new onset of AF at multivariate analysis were a more dilated left atrium (OR 1.35, 95% CI 1.06–1.72; P=.01) and a lower left ventricle ejection fraction (for 10% decrease, OR 2.41, 95% CI 1.24–4.69, P=.016). Patients developing AF had higher mortality/heart transplantation rate compared to patients who maintained sinus rhythm during follow-up (P<.001). At multivariate analysis, new onset AF (HR 3.67, 95% CI 2.07–6.5; P<.001) in the first three years after diagnosis, but not baseline AF, was found to be independently associated with a worse outcome. Conclusions: Atrial fibrillation is relatively frequent in patients with IDCM. The early development of AF during follow-up, but not its presence at baseline, is associated with poor survival.

Vitamin D Deficiency in Patients with Acute Myocardial Infarction: An Italian Single-Center Study

BACKGROUND Hypovitaminosis D is a vitamin deficiency that has been increasing in developed countries; it was also suggested as an emerging risk factor for developing of atherosclerosis and acute myocardial infarction. The primary source of vitamin D is its cutaneous synthesis under exposure to sunlight. It has been suggested that 30 min of sun exposure twice weekly leads to sufficient vitamin D synthesis. The residents of Trieste (Italy) are well-known for their high exposure to sunlight in all seasons. We aimed to investigate the vitamin D status in subjects with acute myocardial infarction living in this area. METHODS Vitamin D status was identified in 478 subjects diagnosed with acute myocardial infarction. RESULTS The median serum 25-hydroxyvitamin D concentration was 14.5 [7.8 - 22.7] ng/mL. Vitamin D deficiency and insufficiency were present in 324 (68 %) and 107 (22 %) subjects, respectively. Vitamin D deficiency was less frequent among subjects enrolled in the period from July to the end of September (p < 0.001). In a multivariate analysis vitamin D deficiency was predicted by older age (p = 0.02), female gender (p = 0.002), higher body mass index (p = 0.05), autumn/winter sampling (p < 0.001), increased parathyroid hormone (p = 0.03) and alkaline phosphatase (p = 0.003). CONCLUSIONS We observed very high prevalence of vitamin D deficiency among subjects with myocardial infarction in all seasons of enrollment. However, it was lower in the summer when sun exposure is higher. The exposure to sunlight may be a cost-saving therapeutic strategy for the management of vitamin D deficiency.

Circulating cardiac biomarkers and postoperative atrial fibrillation in the OPERA trial

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients.