Search

Background and Aims. Resynchronization therapy (CRT) improves mortality and induces reverse remodeling in heart failure (HF) patients with reduced ejection fraction and wide QRS. Nonetheless, some patients do not improve despite the optimal medical therapy and right indications for device implantation. Therefore, finding biomarkers suitable for identification of those patients is crucial. Vitamin D plays a classic hormonal role in the regulation of bone metabolism and also has physiological functions in wide range of nonskeletal tissues. Based on recent studies, low levels of vitamin D seem to directly contribute to pathogenesis and worsening of HF. We planned to assess the role of vitamin D levels on clinical outcomes of HF patients undergoing CRT. Methods and Results. We enrolled 136 HF patients undergoing CRT. Total plasma vitamin D levels were measured at baseline and 6 months later. Primary endpoint was 5-year all-cause mortality; secondary endpoint was lack of good clinical response, defined as less than 15% increase of left ventricular ejection fraction after six months. During follow-up, 58 patients reached the primary, and 45 patients reached the secondary endpoint. Vitamin D levels less than 24.13 ng/mL predicted 5-year mortality (p=0.045) and poor clinical response (p=0.03) after adjusting to all significant baseline predictors. Conclusion. Our study showed that vitamin D deficiency has a significant impact in heart failure patients; it is an independent predictor of lack of midterm clinical response and long-term mortality in patients undergoing CRT. Therefore, monitoring vitamin D status of heart failure patients could be of clinical significance.

INTRODUCTION AND OBJECTIVES Cardiac resynchronization therapy (CRT) is beneficial for selected heart failure (HF) patients, although nonresponse to therapy is still prevalent. We investigated a set of novel biomarkers associated with various pathophysiological pathways of HF. Our purpose was to assess their ability to predict clinical outcomes after CRT. METHODS We studied 136 chronic HF patients undergoing CRT. We measured the plasma levels of fractalkine, pentraxin-3, hepatocyte growth factor (HGF), carbohydrate antigen-125, and matrix metalloproteinase-9 before and 6 months after CRT. The primary endpoint of the study was 5-year all-cause mortality, and we considered the absence of 6-month reverse remodelling (defined as at least a 15% decrease in end-systolic volume) as a secondary endpoint. RESULTS Fifty-eight patients died during the 5-year follow-up period and 66 patients were categorized as nonresponders. In multivariable models, only an increased HGF was an independent predictor of both mortality (HR, 1.35; 95%CI, 1.11-1.64; P=.003; per 1 standard deviation increase) and the absence of reverse remodelling (OR, 1.83; 95%CI, 1.10-3.04; P=.01; per 1 standard deviation increase). Applying HGF to the basic multivariable model of both mortality (net reclassification improvement=0.69; 95%CI, 0.39-0.99; P

Introduction In patients with chronic heart failure (CHF) left ventricular dysfunction results in elevated left atrial (LA) pressure, triggering pathological atrial remodelling and atrial fibrillation (AF). Nevertheless, it has been reported that some patients with CHF remain in sinus rhythm (SR) despite of the pathological structural alterations (e.g. dilation and fibrosis) of the LA. Of particular interest, data is scarce regarding the molecular explanation for the observed variability in AF development among CHF patients. Recent studies have indicated that alterations in microRNA (miRNA) expression might contribute to the pathogenesis of AF. However, the majority of previous studies focusing on miRNA expression compared healthy LA with SR to pathologically remodelled, dilated LA with AF. Consequently, whether dysregulation of miRNA expression directly contribute to AF and not only to pathological LA remodelling has not been tested before. Purpose The present study aimed to investigate miRNA expression in comparably remodelled LA from end-stage CHF patients with permanent AF (CHF-AF) or SR (CHF-SR). Methods LA samples were collected from male, non-diabetic, ischemic end-stage CHF patients undergoing heart transplantation (n=24). Patients were carefully selected to avoid any differences in age (55±2 vs. 54±2 years, CHF-AF vs. CHF-SR, n.s.), ejection fraction ([EF]: 22.5±1.8 vs. 23.3±2.5%, CHF-AF vs. CHF-SR, n.s.) LA diameters (longitudinal LA diameter: 56±4 vs. 48±5mm.; CHF-AF vs. CHF-SR, n.s.; horizontal LA diameter: 61±2 vs. 54±3, CHF-AF vs. CHF-SR, n.s.) and NYHA stage. As a molecular marker of atrial load, the mRNA expression of atrial natriuretic peptide (ANP) was measured with qRT-PCR. The extent of left atrial fibrosis was assessed on picrosirius red stained histological sections. Global LA miRNA expression profiling (including the measurement of 800 human miRNA) was carried out using a commercially available kit. Results LA mRNA expression of ANP was comparable between the AF-CHF and the SR-CHF groups, suggesting that atrial load occurred to the same level in the two experimental groups. Furthermore, no differences could be observed in the extent of atrial collagen content between the AF-CHF and the SR-CHF groups (collagen area: 20.3±1.3% vs. 23.9±3.1%, n.s.), providing evidence that fibrotic remodelling had occurred to a similar magnitude. The high-throughput miRNA measurement revealed no differences in atrial miRNA expression between the two study groups. Conclusion The present study provides evidence for the first time that AF is not associated with different LA miRNA expression in end-stage CHF patients with comparable level of LA dilatation, ANP expression (atrial load) and interstitial fibrosis. Based on these findings, the potential of miRNA-based therapeutic interventions might be limited in AF patients with ischemic end-stage CHF. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Rationale The beta-O-linkage of N-acetylglucosamine (i.e., O-GlcNAc) to proteins is a pro-adaptive response to cellular insults. To this end, increased protein O-GlcNAcylation improves short-term survival of cardiomyocytes subjected to acute injury. This observation has been repeated by multiple groups and in multiple models; however, whether increased protein O-GlcNAcylation plays a beneficial role in more chronic settings remains an open question. Objective Here, we queried whether increasing levels of cardiac protein O-GlcNAcylation would be beneficial during infarct-induced heart failure. Methods and results To achieve increased protein O-GlcNAcylation, we targeted Oga, the gene responsible for removing O-GlcNAc from proteins. Here, we generated mice with cardiomyocyte-restricted, tamoxifen-inducible haploinsufficient Oga gene. In the absence of infarction, we observed a slight reduction in ejection fraction in Oga deficient mice. Overall, Oga reduction had no major impact on ventricular function. In additional cohorts, mice of both sexes and both genotypes were subjected to infarct-induced heart failure and followed for up to four weeks, during which time cardiac function was assessed via echocardiography. Contrary to our prediction, the Oga deficient mice exhibited exacerbated—not improved—cardiac function at one week following infarction. When the observation was extended to 4 wk post-MI, this acute exacerbation was lost. Conclusions The present findings, coupled with our previous work, suggest that altering the ability of cardiomyocytes to either add or remove O-GlcNAc modifications to proteins exacerbates early infarct-induced heart failure. We speculate that more nuanced approaches to regulating O-GlcNAcylation are needed to understand its role—and, in particular, the possibility of cycling, in the pathophysiology of the failing heart.

Aims There are previous studies on quality of life (QoL) in cardiac resynchronization therapy (CRT) patients; however, there are no data with the short EuroQol-five dimensions (EQ-5D) questionnaire predicting outcomes. We aimed to assess the predictive role of baseline QoL and QoL change at 6 months after CRT with EQ-5D on 5-year mortality and response. Methods and results In our prospective follow-up study, 130 heart failure (HF) patients undergoing CRT were enrolled. Clinical evaluation, echocardiography, and EQ-5D were performed at baseline and at 6 months of follow–up, continued to 5 years. Primary endpoint was all-cause mortality at 5 years. Secondary endpoints were (i) clinical response with at least one class improvement in New York Heart Association without HF hospitalization and (ii) reverse remodelling with 15% reduction in left ventricular end-systolic volume at 6 months. Fifty-four (41.5%) patients died during 5 years, 85 (65.3%) clinical responders were identified, and 63 patients (48.5%) had reverse remodelling. Baseline issues with mobility were associated with lower response [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.16–0.84; P = 0.018]. Lack of reverse remodelling correlated with self-care issues at baseline (OR 0.10, 95% CI 0.01–0.94; P = 0.04). Furthermore, self-care difficulties [hazard ratio (HR) 2.39, 95% CI 1.17–4.86; P = 0.01) or more anxiety (HR 1.51, 95% CI 1.00–2.26; P = 0.04) predicted worse long-term survival. At 6 months, mobility (HR 3.95, 95% CI 1.89–8.20; P

Background Cardiac resynchronization therapy (CRT) in chronic heart failure has been shown to improve mortality and morbidity. However, comprehensive data are not available as concerns how circulating biomarkers reflecting different organ functions, such as serum uric acid, blood urea nitrogen (BUN), albumin, cholesterol, or various liver enzymes, change over time as a consequence of CRT. The aim of this prospective study was to overview these possible changes. Methods A total of 20 routine laboratory parameters were measured in 122 control subjects and in 129 patients with chronic heart failure before CRT, 6 months, and 2 years later. Results The levels of serum uric acid [before: 432 (331–516) mmol/L, 6-month: 372 (304–452) mmol/L, 2-year: 340 (290–433) mmol/L; p

Background Cardiac Resynchronization Therapy (CRT) has well-known beneficial effects in patients with advanced heart failure, reduced ejection fraction and wide QRS complex. However, mortality rates still remain high in this patient population. Therefore, precise risk stratification would be essential, nonetheless, the currently available risk scores have several shortcomings which hamper their utilization in the everyday clinical practice. Purpose Accordingly, our objective was to design and validate a machine learning based risk stratification system to predict 2-year and 5-year mortality from pre-implant parameters of patients undergoing CRT implantation. Methods We trained two models separately to predict 2-year (model 1) and 5-year mortality (model 2). As training cohort of model 1 we used 1678 patients (67±10 years, 1251 [75%] males) undergoing CRT implantation. From this population, 1320 patients (66±10 years, 1005 [76%] males) also completed 5-year follow-up and they served as the training cohort for model 2. Forty-seven pre-implant parameters (demographics, cardiovascular risk factors and clinical characteristics) were used to train the models. Our models were designed in a way to tolerate missing values. Among non-linear classifiers, random forest demonstrated the best performance. We validated our models, along with the Seattle Heart Failure Model (SHFM), VALID-CRT risk score and EAARN score on an independent cohort of 136 patients (66±10 years, 110 [81%] males). Based on the predicted probability of survival, patients were split into quartiles and survival was plotted via Kaplan-Meier (KM) curves. Results There were 358 (21%) deaths in the 2-year, 697 (53%) deaths in the 5-year training cohort. In the validation cohort, there were 30 (22%) deaths at 2 years and 58 (43%) deaths at 5 years after CRT implantation. For the prediction of 2-year mortality, the Area Under the Receiver-Operating Characteristic Curve (AUC) for model 1 was 0.77 (95% CI: 0.67–0.87; p=0.002), for SHFM was 0.54 (95% CI: 0.39–0.69; p=0.006), for EAARN was 0.57 (95% CI: 0.46–0.68, p=0.002), and for VALID-CRT was 0.62 (95% CI: 0.52–0.71; p=0.002). To predict 5-year mortality, the AUC for model 2 was 0.85 (95% CI: 0.78–0.91; p=0.001), for SHFM was 0.62 (95% CI: 0.51–0.74; p=0.003), for EAARN was 0.61 (95% CI: 0.51–0.70, p=0.002), for VALID-CRT was 0.65 (95% CI: 0.56–0.74; p=0.002). The AUCs of the machine learning based models were significantly higher than the AUCs of the pre-existing scores (DeLong test, all p Conclusion Our results indicate that machine learning algorithms can outperform the already existing linear model based scores. By capturing the non-linear association of predictors, the utilization of these state-of-the-art approaches may facilitate optimal candidate selection and prognostication of patients undergoing CRT implantation.

Changes in the levels of serum creatinine and N-terminal of prohormone brain natriuretic peptide (NT-proBNP) are useful risk markers after cardiac resynchronization therapy (CRT). The diagnostic value of changes in serum uric acid levels has been established in chronic heart failure, but no data are available on the prognostic value of hyperuricemia in a CRT population.We measured markers of renal function [creatinine, blood urea nitrogen (BUN) and uric acid] and NT-proBNP levels of 129 heart failure patients undergoing CRT in a prospective, observational study. The 5-year all-cause mortality and the 6-month clinical response (≥ 15% increase in the left ventricular ejection fraction) were considered as study end points.In multivariable analyses, the uric acid was found to be a statistically significant predictor of the outcome. Uric acid levels exceeding 386 mmol/L before CRT increased the chances of mortality [n = 55, hazard ratio = 2.39 (1.30-4.39), p 0.01] and poor clinical response [n = 37, odds ratio = 2.89 (1.22-6.87), p = 0.01] independently of serum NT-proBNP and other factors.Elevated uric acid concentrations in patients with CRT are associated with an increased risk of mortality and poor clinical response independently of the NT-proBNP levels and other relevant clinical factors.

Aims The low lymphocyte counts and high neutrophil leucocyte fractions have been associated with poor prognosis in chronic heart failure. We hypothesized that the baseline ratio of the neutrophil leucocytes to the lymphocytes (NL ratio) would predict the outcome of chronic heart failure patients undergoing cardiac resynchronization therapy (CRT). Methods and results The qualitative blood counts and the serum levels of N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) of 122 chronic heart failure patients and 122 healthy controls were analysed prospectively in this observational study. The 2-year mortality was considered as primary endpoint and the 6-month reverse remodelling (≥15% decrease in the end-systolic volume) as secondary endpoint. Multivariable regression analyses were applied and net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. The NL ratio was elevated in chronic heart failure patients when compared with the healthy controls [2.93 (2.12–4.05) vs. 2.21 (1.64–2.81), P < 0.0001]. The baseline NL ratio exceeding 2.95 predicted the lack of the 6-month reverse remodelling [n = 63, odds ratio = 0.38 (0.17–0.85), P = 0.01; NRI = 0.49 (0.14–0.83), P = 0.005; IDI = 0.04 (0.00–0.07), P = 0.02] and the 2-year mortality [n = 29, hazard ratio = 2.44 (1.04–5.71), P = 0.03; NRI = 0.63 (0.24–1.01), P = 0.001; IDI = 0.04 (0.00–0.08), P = 0.02] independently of the NT-proBNP levels or other factors. Conclusion The NL ratio is elevated in chronic heart failure and predicts outcome after CRT. According to the reclassification analysis, 4% of the patients would have been better categorized in the prediction models by combining the NT-proBNP with the NL ratio. Thus, a single blood count measurement could facilitate the optimal patient selection for the CRT.

Objectives. Increases in red blood cell distribution width (RDW) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) predict the mortality of chronic heart failure patients undergoing cardiac resynchronization therapy (CRT). It was hypothesized that RDW is independent of and possibly even superior to NT-proBNP from the aspect of long-term mortality prediction.Design. The blood counts and serum NT-proBNP levels of 134 patients undergoing CRT were measured. Multivariable Cox regression models were applied and reclassification analyses were performed.Results. After separate adjustment to the basic model of left bundle branch block, beta blocker therapy, and serum creatinine, both the RDW > 13.35% and NT-proBNP > 1975 pg/mL predicted the 5-year mortality (n=57). In the final model including all variables, the RDW [HR = 2.49 (1.27–4.86);p=0.008] remained a significant predictor, whereas the NT-proBNP [HR = 1.18 (0.93–3.51);p=0.07] lost its predictive value. On addition of the RDW measurement, a 64% net reclassification improvement and a 3% integrated discrimination improvement were achieved over the NT-proBNP-adjusted basic model.Conclusions. Increased RDW levels accurately predict the long-term mortality of CRT patients independently of NT-proBNP. Reclassification analysis revealed that the RDW improves the risk stratification and could enhance the optimal patient selection for CRT.

Cardiac Resynchronization Therapy (CRT) is an effective treatment of chronic heart failure (HF) in patients with wide QRS and reduced ejection fraction. However, not every patient benefits equally from the treatment and still high mortality rates can be observed. Our aim was to identify patients