A. Kosztin

Effect of cardiac resynchronization therapy with implantable cardioverter defibrillator versus cardiac resynchronization therapy with pacemaker on mortality in heart failure patients : results of a high-volume, single-centre experience

There are limited and contradictory data on the effects of CRT with implantable cardioverter defibrillator (CRT‐D) on mortality as compared with CRT with pacemaker (CRT‐P).

Role of Right Ventricular Global Longitudinal Strain in Predicting Early and Long-Term Mortality in Cardiac Resynchronization Therapy Patients

Background Right ventricular (RV) dysfunction has been associated with poor prognosis in chronic heart failure (HF). However, less data is available about the role of RV dysfunction in patients with cardiac resynchronization therapy (CRT). We aimed to investigate if RV dysfunction would predict outcome in CRT. Design We enrolled prospectively ninety-three consecutive HF patients in this single center observational study. All patients underwent clinical evaluation and echocardiography before CRT and 6 months after implantation. We assessed RV geometry and function by using speckle tracking imaging and calculated strain parameters. We performed multivariable Cox regression models to test mortality at 6 months and at 24 months. Results RV dysfunction, characterized by decreased RVGLS (RV global longitudinal strain) [10.2 (7.0–12.8) vs. 19.5 (15.0–23.9) %, p<0.0001] and RVFWS (RV free wall strain) [15.6 (10.0–19.3) vs. 17.4 (10.5–22.2) %, p = 0.04], improved 6 months after CRT implantation. Increasing baseline RVGLS and RVFWS predicted survival independent of other parameters at 6 months [hazard ratio (HR) = 0.37 (0.15–0.90), p = 0.02 and HR = 0.42 (0.19–0.89), p = 0.02; per 1 standard deviation increase, respectively]. RVGLS proved to be a significant independent predictor of mortality at 24 months [HR = 0.53 (0.32–0.86), p = 0.01], and RVFWS showed a strong tendency [HR = 0.64 (0.40–1.00), p = 0.05]. The 24-month survival was significantly impaired in patients with RVGLS below 10.04% before CRT implantation [area under the curve = 0.72 (0.60–0.84), p = 0.002, log-rank p = 0.0008; HR = 5.23 (1.76–15.48), p = 0.003]. Conclusions Our findings indicate that baseline RV dysfunction is associated with poor short-term and long-term prognosis after CRT implantation.

Rationale and design of the BUDAPEST-CRT Upgrade Study: A prospective, randomized, multicentre clinical trial

Abstract Aims There is lack of conclusive evidence from randomized clinical trials on the efficacy and safety of upgrade to cardiac resynchronization therapy (CRT) in patients with implanted pacemakers (PM) or defibrillators (ICD) with reduced left ventricular ejection fraction (LVEF) and chronic heart failure (HF). The BUDAPEST-CRT Upgrade Study was designed to compare the efficacy and safety of CRT upgrade from conventional PM or ICD therapy in patients with intermittent or permanent right ventricular (RV) septal/apical pacing, reduced LVEF, and symptomatic HF. Methods and results The BUDAPEST-CRT study is a prospective, randomized, multicentre, investigator-sponsored clinical trial. A total of 360 subjects will be enrolled with LVEF ≤ 35%, NYHA functional classes II–IVa, paced QRS ≥ 150 ms, and a RV pacing ≥ 20%. Patients will be followed for 12 months. Randomization is performed in a 3:2 ratio (CRT-D vs. ICD). The primary composite endpoint is all-cause mortality, a first HF event, or less than 15% reduction in left ventricular (LV) end-systolic volume at 12 months. Secondary endpoints are all-cause mortality, all-cause mortality or HF event, and LV volume reduction at 12 months. Tertiary endpoints include changes in quality of life, NYHA functional class, 6 min walk test, natriuretic peptides, and safety outcomes. Conclusion The results of our prospective, randomized, multicentre clinical trial will provide important information on the role of cardiac resynchronization therapy with defibrillator (CRT-D) upgrade in patients with symptomatic HF, reduced LVEF, and wide-paced QRS with intermittent or permanent RV pacing. Clinical trials.gov identifier NCT02270840.

Signaling Via PI3K/FOXO1A Pathway Modulates Formation and Survival of Human Embryonic Stem Cell-Derived Endothelial Cells

Vascular derivatives of human embryonic stem cells (hESC) are being developed as sources of tissue-specific cells for organ regeneration. However, identity of developmental pathways that modulate the specification of endothelial cells is not known yet. We studied phosphatidylinositol 3-kinase (PI3K)-Forkhead box O transcription factor 1A (FOXO1A) pathways during differentiation of hESC toward endothelial lineage and on proliferation, maturation, and cell death of hESC-derived endothelial cells (hESC-EC). During differentiation of hESC, expression of FOXO1A transcription factor was linked to the expression of a cluster of angiogenesis- and vascular remodeling-related genes. PI3K inhibitor LY294002 activated FOXO1A and induced formation of CD31(+) hESC-EC. In contrast, differentiating hESC with silenced FOXO1A by small interfering RNA (siRNA) showed lower mRNA levels of CD31 and angiopoietin2. LY294002 decreased proliferative activity of purified hESC-EC, while FOXO1A siRNA increased their proliferation. LY294002 inhibits migration and tube formation of hESC-EC; in contrast, FOXO1A siRNA increased in vitro tube formation activity of hESC-EC. After in vivo conditioning of cells in athymic nude rats, cells retain their low FOXO1A expression levels. PI3K/FOXO1A pathway is important for function and survival of hESC-EC and in the regulation of endothelial cell fate. Understanding these properties of hESC-EC may help in future applications for treatment of injured organs.

Quantification of the relative contribution of the different right ventricular wall motion components to right ventricular ejection fraction: the ReVISION method

Three major mechanisms contribute to right ventricular (RV) pump function: (i) shortening of the longitudinal axis with traction of the tricuspid annulus towards the apex; (ii) inward movement of the RV free wall; (iii) bulging of the interventricular septum into the RV and stretching the free wall over the septum. The relative contribution of the aforementioned mechanisms to RV pump function may change in different pathological conditions.Our aim was to develop a custom method to separately assess the extent of longitudinal, radial and anteroposterior displacement of the RV walls and to quantify their relative contribution to global RV ejection fraction using 3D data sets obtained by echocardiography.Accordingly, we decomposed the movement of the exported RV beutel wall in a vertex based manner. The volumes of the beutels accounting for the RV wall motion in only one direction (either longitudinal, radial, or anteroposterior) were calculated at each time frame using the signed tetrahedron method. Then, the relative contribution of the RV wall motion along the three different directions to global RV ejection fraction was calculated either as the ratio of the given direction’s ejection fraction to global ejection fraction and as the frame-by-frame RV volume change (∆V/∆t) along the three motion directions.The ReVISION (Right VentrIcular Separate wall motIon quantificatiON) method may contribute to a better understanding of the pathophysiology of RV mechanical adaptations to different loading conditions and diseases.

Longer right to left ventricular activation delay at cardiac resynchronization therapy implantation is associated with improved clinical outcome in left bundle branch block patients.

Abstract Aims Data on longer right to left ventricular activation delay (RV-LV AD) predicting clinical outcome after cardiac resynchronization therapy (CRT) by left bundle branch block (LBBB) are limited. We aimed to evaluate the impact of RV-LV AD on N-terminal pro–B-type natriuretic peptide (NT-proBNP), ejection fraction (EF), and clinical outcome in patients implanted with CRT, stratified by LBBB at baseline. Methods and results Heart failure (HF) patients undergoing CRT implantation with EF ≤ 35% and QRS ≥ 120 ms were evaluated based on their RV-LV AD at implantation. Baseline and 6-month clinical parameters, EF, and NT-proBNP values were assessed. The primary endpoint was HF or death, the secondary endpoint was all-cause mortality. A total of 125 patients with CRT were studied, 62% had LBBB. During the median follow-up of 2.2 years, 44 (35%) patients had HF/death, 36 (29%) patients died. Patients with RV-LV AD ≥ 86 ms (lower quartile) had significantly lower risk of HF/death [hazard ratio (HR): 0.44; 95% confidence interval (95% CI): 0.23–0.82; P = 0.001] and all-cause mortality (HR: 0.48; 95% CI: 0.23–1.00; P = 0.05), compared with those with RV-LV AD < 86 ms. Patients with RV-LV AD ≥ 86 ms and LBBB showed the greatest improvement in EF (28–36%; P<0.001), NT-proBNP (2771–1216 ng/mL; P < 0.001), and they had better HF-free survival (HR: 0.23, 95% CI: 0.11–0.49, P < 0.001) and overall survival (HR: 0.35, 95% CI: 0.16–0.75; P = 0.007). There was no difference in outcome by RV-LV AD in non-LBBB patients. Conclusion Left bundle branch block patients with longer RV-LV activation delay at CRT implantation had greater improvement in NT-proBNP, EF, and significantly better clinical outcome.

Dominance of free wall radial motion in global right ventricular function of heart transplant recipients

Assessment of right ventricular (RV) function using conventional echocardiography might be inadequate as the radial motion of the RV free wall is often neglected. Our aim was to quantify the longitudinal and the radial components of RV function using three‐dimensional (3D) echocardiography in heart transplant (HTX) recipients. Fifty‐one HTX patients in stable cardiovascular condition without history of relevant rejection episode or chronic allograft vasculopathy and 30 healthy volunteers were enrolled. RV end‐diastolic (EDV) volume and total ejection fraction (TEF) were measured by 3D echocardiography. Furthermore, we quantified longitudinal (LEF) and radial ejection fraction (REF) by decomposing the motion of the RV using the ReVISION method. RV EDV did not differ between groups (HTX vs control; 96 ± 27 vs 97 ± 2 mL). In HTX patients, TEF was lower, however, tricuspid annular plane systolic excursion (TAPSE) decreased to a greater extent (TEF: 47 ± 7 vs 54 ± 4% [−13%], TAPSE: 11 ± 5 vs 21 ± 4 mm [−48%], P < .0001). In HTX patients, REF/TEF ratio was significantly higher compared to LEF/TEF (REF/TEF vs LEF/TEF: 0.58 ± 0.10 vs 0.27 ± 0.08, P < .0001), while in controls the REF/TEF and LEF/TEF ratio was similar (0.45 ± 0.07 vs 0.47 ± 0.07). Current results confirm the superiority of radial motion in determining RV function in HTX patients. Parameters incorporating the radial motion are recommended to assess RV function in HTX recipients.

Application of “AL-FINE CRT” risk score before cardiac resynchronisation therapy implantation

The study by Kisiel et al. [1] retrospectively investigated the prognostic value of various parameters in 552 chronic heart failure patients undergoing cardiac resynchronisation therapy (CRT). The goal of the study was to set up a risk score system able to predict long-term mortality following CRT implantation and easily applicable in clinical practice. The main strength of the created score system, termed “AL-FINE CRT score” (Age [> 75 years], non-LBBB morphology [according to Strauss criteria], Furosemide dose [> 80 mg], Ischaemic aetiology, NYHA class (> III) and left ventricular EF [< 20%]), lies in the fact that its components can be easily obtained during the routine preimplantation check-up (medical history, physical examination, electrocardiography, and echocardiography) to assess the long-term mortality risk. The presence of any of the above variables equates to one point, so a maximum of six points could be achieved. Depending on the AL-FINE CRT score, the patients can be divided into three risk categories: low risk (0–1 points, five-year survival of approx. 80%), medium risk (2 points, five-year survival of approx. 60%), and high risk (3–6 points, five-year survival of approx. 40%). A high-risk score, according to the authors, should alert both the physician and the patient to evaluate the long-term benefit of the procedure more realistically and should identify those patients, in whom the implantation procedure might require more attention and maybe more experienced implanters in order to maximise the benefit [1]. The identified high-risk patients might also need “special care” following the implantation: more frequent follow-ups, strict device optimisation, multidisciplinary patient care, aggressive up-titration of medication, participation in rehabilitation programs, etc. Nevertheless, because the results are derived from a retrospective analysis, further prospective studies should validate the usefulness of the AL-FINE CRT model. Altogether there is a clear need to create applicable risk scores for patients who have undergone CRT implantation, to predict their long-term outcome. However, the validation and further assessment of the utility of such a score system are always challenging. A risk score system should not only be useful in risk prediction, but ideally it should also allow the clinicians to guide therapy or make therapeutic decisions, for instance regarding the choice of the device (implantable defibrillator [CRT-D] vs. pacemaker [CRT-P]), or the selection of pacemaker patients requiring CRT upgrade. To date, no such risk score systems exist, and the current guidelines do not clearly define the decision algorithm for the above processes [2, 3]. On the other hand, one should be cautious about relying on risk score systems alone, as an automated procedure, because the therapeutic decisions, circumstances of the implantation, and further device programming also have an impact on the long-term clinical outcome of patients; therefore, risk score systems are an additional, but not the sole component of the decision making process. The authors presented the overall discriminative power of the AL-FINE CRT model (C-statistics of 0.701), which corresponds to the requirements of cardiovascular risk models laid down by the American Heart Association [4]. This discriminative power of the AL-FINE CRT model is very similar to that of other risk models already tested in CRT (e.g. VALID-CRT score reported C-statistics of 0.700 and CRT-SCORE reported C-statistics of 0.748). While the presented risk score is useful in predicting the long-term clinical outcome, it has some weaknesses, such as the lack of procedure-related parameters, e.g. the targeted coronary sinus side branch or the activation delays between the right and left ventricular leads, which might also influence the outcome of patients after CRT implantation [5]. The presented results support the utility of the AL-FINE CRT model [6, 7] and emphasise its importance and application.

Quality of life measured with EuroQol-five dimensions questionnaire predicts long-term mortality, response, and reverse remodelling in cardiac resynchronization therapy patients

Abstract 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 < 0.001), self-care (HR 7.69, 95% CI 2.23–25.9; P = 0.001), or ≥ 10% visual analogue scale (VAS) (HR 2.24, 95% CI 1.27–3.94; P = 0.005) improvement anticipated better survival at 5 years. Conclusion EuroQol-five dimension is a simple method assessing QoL in CRT population. Mobility issues at baseline are associated with lower clinical response, whereas self-care issues predict lack of reverse remodelling. Problems with mobility or anxiety before CRT and persistent issues with mobility, self-care, and VAS scale at 6 months predict adverse outcome.

QUALITY OF LIFE MEASURED WITH EUROQOL-5D QUESTIONNAIRE PREDICTS LONG TERM MORTALITY AND ECHOCARDIOGRAPHIC RESPONSE IN CRT PATIENTS

Background: There are previous studies about the prognostic significance of quality of life (QoL) in CRT-implanted patients measured with complex heart failure questionnaires. However, there is no data with the EuroQol-5 Dimensions (EQ-5D) questionnaire, which provides a simple descriptive profile