Niels Risum

Oral Branched-Chain Amino Acids Have a Beneficial Effect on Manifestations of Hepatic Encephalopathy in a Systematic Review with Meta-Analyses of Randomized Controlled Trials

Supplements with branched-chain amino acid (BCAA) have cerebral, metabolic, and nutritional effects that may benefit patients with hepatic encephalopathy (HE). We therefore conducted a systematic review on the effects of oral BCAAs compared with control supplements or placebo for patients with cirrhosis and recurrent overt or minimal HE. The quantitative analyses included data from 8 trials (n = 382 patients). Individual patient data were retrieved from 4 trials to recalculate outcomes (n = 255 patients). The mean dose of the oral BCAA supplements was 0.25 g/(kg body weight · d). Random effects meta-analysis showed that improvements in HE manifestations were registered for 87 of 172 patients in the BCAA group compared with 56 of 210 controls [risk ratio = 1.71 (95% CI: 1.17, 2.51) number needed to treat = 5 patients]. The effect of BCAAs differed (P = 0.04) for patients with overt [risk ratio = 3.26 (95% CI: 1.47, 7.22)] and minimal HE [risk ratio = 1.32 (95% CI: 0.97, 1.79)]. Subgroup, sensitivity, regression, and sequential analyses found no other sources of heterogeneity or bias. BCAA supplements had no effect on mortality or markers of nutritional status and did not induce adverse events. In conclusion, oral BCAA supplements improve manifestations of HE but have no effect on survival.

Left bundle-branch block: the relationship between electrocardiogram electrical activation and echocardiography mechanical contraction

BACKGROUND The relationship between myocardial electrical activation by electrocardiogram (ECG) and mechanical contraction by echocardiography in left bundle-branch block (LBBB) has never been clearly demonstrated. New strict criteria for LBBB based on a fundamental understanding of physiology have recently been independently published for both ECG and echocardiography. The relationship between the 2 modalities and the relation to cardiac resynchronization therapy (CRT) response was investigated. METHODS Sixty-six patients with LBBB by conventional criteria had a standard 12-lead ECG and 2-dimensional strain echocardiography performed before CRT implantation. Criteria for LBBB by echocardiography included early termination of contraction in one wall and prestretch and late contraction in opposing wall(s). New strict criteria by ECG included QRS duration ≥140 ms (men) or 130 ms (women), QS or rS in leads V1 and V2, and mid-QRS notching or slurring in ≥2 of leads V1, V2, V5, V6, I, and aVL. Response was defined as >15% decrease in left ventricular end-systolic volume after 6 months. RESULTS In 64 of 66 patients, ECG analysis was possible. Echo and ECG readings for LBBB presence were concordant in 54 (84%) of 64. Thirty-seven (82%) of 45 patients with LBBB by strict ECG criteria responded to CRT, whereas only 4 (21%) of the 19 patients without LBBB responded (sensitivity 90% and specificity 65%). Thirty-six (95%) of 38 patients with concordance for the presence of LBBB responded to CRT. In patients with concordance for the absence of LBBB, 15 (94%) of 16 did not respond. CONCLUSION For the first time, a close relation has been demonstrated between electrical activation by ECG and mechanical contraction by echocardiography. These findings may help identify CRT candidates.

Identification of Typical Left Bundle Branch Block Contraction by Strain Echocardiography Is Additive to Electrocardiography in Prediction of Long-Term Outcome After Cardiac Resynchronization Therapy

BACKGROUND Current guidelines suggest that patients with left bundle branch block (LBBB) be treated with cardiac resynchronization therapy (CRT); however, one-third do not have a significant activation delay, which can result in nonresponse. By identifying characteristic opposing wall contraction, 2-dimensional strain echocardiography (2DSE) may detect true LBBB activation. OBJECTIVES This study sought to investigate whether the absence of a typical LBBB mechanical activation pattern by 2DSE was associated with unfavorable long-term outcome and if this is additive to electrocardiographic (ECG) morphology and duration. METHODS From 2 centers, 208 CRT candidates (New York Heart Association classes II to IV, ejection fraction ≤35%, QRS duration ≥120 ms) with LBBB by ECG were prospectively included. Before CRT implantation, longitudinal strain in the apical 4-chamber view determined whether typical LBBB contraction was present. The pre-defined outcome was freedom from death, left ventricular assist device, or heart transplantation over 4 years. RESULTS Two-thirds of patients (63%) had a typical LBBB contraction pattern. During 4 years, 48 patients (23%) reached the primary endpoint. Absence of a typical LBBB contraction was independently associated with increased risk of adverse outcome after adjustment for ischemic heart disease and QRS width (hazard ratio [HR]: 3.1; 95% CI: 1.64 to 5.88; p < 0.005). Adding pattern assessment to a risk prediction model including QRS duration and ischemic heart disease significantly improved the net reclassification index to 0.14 (p = 0.04) and improved the C-statistics (0.63 [95% CI: 0.54 to 0.72] vs. 0.71 [95% CI: 0.63 to 0.80]; p = 0.02). Use of strict LBBB ECG criteria was not independently associated with outcome in the multivariate model (HR: 1.72; 95% CI: 0.89 to 3.33; p = 0.11. Assessment of LBBB contraction pattern was superior to time-to-peak indexes of dyssynchrony (p < 0.01 for all). CONCLUSIONS Contraction pattern assessment to identify true LBBB activation provided important prognostic information in CRT candidates.

Mechanical dyssynchrony evaluated by tissue Doppler cross-correlation analysis is associated with long-term survival in patients after cardiac resynchronization therapy

AIMS Pre-implant assessment of longitudinal mechanical dyssynchrony using cross-correlation analysis (XCA) was tested for association with long-term survival and compared with other tissue Doppler imaging (TDI)-derived indices. METHODS AND RESULTS In 131 patients referred for cardiac resynchronization therapy (CRT) from two international centres, mechanical dyssynchrony was assessed from TDI velocity curves using time-to-peak opposing wall delay (OWD) ≥80 ms, Yu index ≥32 ms, and the maximal activation delay (AD-max) >35 ms. AD-max was calculated by XCA of the TDI-derived myocardial acceleration curves. Outcome was a composite of all-cause mortality, cardiac transplantation, or implantation of a ventricular assist device (left ventricular assist device) and modelled using the Cox proportional hazards regression. Follow-up was truncated at 1460 days. Dyssynchrony by AD-max was independently associated with improved survival when adjusted for QRS > 150 ms and aetiology {hazard ratio (HR) 0.35 [95% confidence interval (CI) 0.16-0.77], P = 0.01}. Maximal activation delay performed significantly better than Yu index, OWD, and the presence of left bundle branch block (P < 0.05, all, for difference between parameters). In subgroup analysis, patients without dyssynchrony and QRS between 120 and 150 ms showed a particularly poor survival [HR 4.3 (95% CI 1.46-12.59), P < 0.01, compared with the group with dyssynchrony and QRS between 120 and 150 ms]. CONCLUSION Mechanical dyssynchrony assessed by AD-max was associated with long-term survival after CRT and was significantly better associated compared with other TDI-derived indices. Patients without dyssynchrony and QRS between 120 and 150 ms had a particularly poor prognosis. These results indicate a valuable role for XCA in selection of CRT candidates.

Right Ventricular Mechanics using a Novel Comprehensive Three-View Echocardiographic Strain Analysis in a Normal Population

BACKGROUND Although quantitative right ventricular (RV) strain analysis may be useful in congenital and acquired heart disease populations with RV failure, a comprehensive, standardized approach is lacking. An 18-segment RV strain analysis obtained from three standardized RV apical echocardiographic images was used to determine the feasibility, normal values, and reproducibility of the method in normal adults. METHODS Forty healthy, prospectively enrolled volunteers with no cardiac histories and normal QRS durations underwent echocardiography optimized for strain analysis including three RV apical views. Two-dimensional speckle-tracking longitudinal strain analysis was performed using EchoPAC software. Eleven retrospectively identified subjects with RV disease were included as a pilot population. All had been imaged using the same protocol including the three RV apical views. RESULTS All control subjects had normal anatomic morphology and function by echocardiography. Feasibility of the RV strain analysis was good (adequate tracking in 696 of 720 segments [97%]). RV global peak systolic strain was -23 ± 2%. Peak strain was highest in the RV free wall and lowest in the septum. Dyssynchrony indices demonstrated no dyssynchrony using left ventricular criteria. Reproducibility of most strain measures was acceptable. This methodology identified important disease not seen in the four-chamber apical view alone in the pilot population of 11 patients with RV disease. Strain patterns and values were different from those in the control population, indicating that differences do exist from normal. CONCLUSIONS Eighteen-segment RV strain analysis is feasible, with strain measures falling into discrete ranges in this normal population. Those with RV disease illustrate the potential utility of this approach. These data indicate that this model can be used for more detailed studies evaluating abnormal RV populations, in which its full potential can be assessed.

Management and outcomes in patients with moderate or severe functional mitral regurgitation and severe left ventricular dysfunction

AIMS The management and outcomes of patients with functional moderate/severe mitral regurgitation and severe left ventricular (LV) systolic dysfunction are not well defined. We sought to determine the characteristics, management strategies, and outcomes of patients with moderate or severe mitral regurgitation (MR) and LV systolic dysfunction. METHODS AND RESULTS For the period 1995-2010, the Duke Echocardiography Laboratory and Duke Databank for Cardiovascular Diseases databases were merged to identify patients with moderate or severe functional MR and severe LV dysfunction (defined as LV ejection fraction ≤ 30% or LV end-systolic diameter > 55 mm). We examined treatment effects in two ways. (i) A multivariable Cox proportional hazards model was used to assess the independent relationship of different treatment strategies and long-term event (death, LV assist device, or transplant)-free survival among those with and without coronary artery disease (CAD). (ii) To examine the association of mitral valve (MV) surgery with outcomes, we divided the entire cohort into two groups, those who underwent MV surgery and those who did not; we used inverse probability weighted (IPW) propensity adjustment to account for non-random treatment assignment. Among 1441 patients with moderate (70%) or severe (30%) MR, a significant history of hypertension (59%), diabetes (28%), symptomatic heart failure (83%), and CAD (52%) was observed. Past revascularization in 26% was noted. At 1 year, 1094 (75%) patients were treated medically. Percutaneous coronary intervention was performed in 114 patients, coronary artery bypass graft (CABG) surgery in 82, CABG and MV surgery in 96, and MV surgery alone in 55 patients. Among patients with CAD, compared with medical therapy alone, the treatment strategies of CABG surgery [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.42-0.76] and CABG with MV surgery (HR 0.58, 95% CI 0.44-0.78) were associated with long-term, event-free survival benefit. Percutaneous intervention treatment produced a borderline result (HR 0.78, 95% CI 0.61-1.00). However, the relationship with isolated MV surgery did not achieve statistical significance (HR 0.64, 95% CI 0.33-1.27, P = 0.202). Among those with CAD, following IPW adjustment, MV surgery was associated with a significant event-free survival benefit compared with patients without MV surgery (HR 0.71, 95% CI 0.52-0.95). In the entire cohort, following IPW adjustment, the use of MV surgery was associated with higher event-free survival (HR 0.69, 95% CI 0.53-0.88). CONCLUSION In patients with moderate or severe MR and severe LV dysfunction, mortality was substantial, and among those selected for surgery, MV surgery, though performed in a small number of patients, was independently associated with higher event-free survival.

Classic-Pattern Dyssynchrony and Electrical Activation Delays in Pediatric Dilated Cardiomyopathy

BACKGROUND Progressive heart failure leading to transplantation or death is common in pediatric dilated cardiomyopathy (DCM), and treatment options are limited. Select children with DCM have improved after cardiac resynchronization therapy (CRT), but predicting response is challenging. Nonetheless, considering the frequency of death or transplantation in this population, identifying any candidate would be valuable. Classic-pattern dyssynchrony (CPD) identifies mechanical dyssynchrony patterns consistent with underlying electrical activation delays and strongly predicts CRT response in adult DCM but has not been evaluated in pediatric DCM. The aim of this study was to test the hypothesis that CPD is present in a subgroup of patients with pediatric DCM and is associated with activation delays. METHODS Fifty-nine subjects with pediatric DCM (left ventricular end-diastolic diameter Z score > 2 and left ventricular ejection fraction < 40%) who underwent echocardiography with a functional protocol with apical images optimized for two-dimensional speckle-tracking strain analysis (EchoPAC) were retrospectively analyzed for CPD. Electrocardiograms were evaluated for activation delays (prolonged QRS duration and strict criteria for left bundle branch block [LBBB]). Forty control subjects with no cardiac disease and good imaging widows were also analyzed. RESULTS The mean age was 5.4 years (range, 1 day to 20 years); idiopathic DCM was most common (57%). Severe cardiomyopathy was present in 75% (end-diastolic diameter Z score > 4.6 and left ventricular ejection fraction < 32%). CPD was identified in seven subjects (12%), and prolonged QRS durations were present in 13 (22%), but only two subjects met strict criteria for LBBB. Six of seven subjects in the CPD group had prolonged QRS durations, and two of seven had LBBB. No control subjects had CPD. The CPD analysis was highly feasible and reproducible. CONCLUSIONS In this severely affected cohort, the small CPD subgroup is potentially important because their progressive disease may respond to CRT. CPD is associated with activation delays, although not necessarily strict LBBB. This has important potential implications for prospective evaluation of CRT in this disease.

Comparative long-term outcomes after cardiac resynchronization therapy in right ventricular paced patients versus native wide left bundle branch block patients

BACKGROUND The current guidelines do not clearly state when we should upgrade a patient with right ventricular pacing (RVP) to cardiac resynchronization therapy (CRT), although the deleterious effect of chronic RVP has been established with recent trials. OBJECTIVES The aims of this study were to compare the long-term survival after CRT in patients upgraded from RVP with that in patients with left bundle branch block (LBBB) with QRS duration ≥ 150 ms and to compare the mechanical properties associated with CRT response in these groups. METHODS Overall, 135 patients with implanted CRT from a single center (85 (63%) with native wide LBBB and 50 (37%) with RVP) were studied prospectively. Baseline left ventricular typical contraction pattern was determined using speckle tracking echocardiography in the apical 4-chamber view. The predefined end point was death, heart transplantation, or left ventricular assist device implantation over a period of 4 years. RESULTS Patients with RVP had a significantly favorable long-term outcomes with adjusted hazard ratio of 0.36 (95% confidence interval 0.14-0.96; P = .04). Both groups had ~70% of patients with typical contraction pattern. The absence of typical contraction pattern was associated with a higher risk of an end point with adjusted hazard ratio of 5.43 (95% confidence interval 2.31-12.72; P < .001). In patients with typical contraction pattern, activation of the apical septal segment occurred more frequently in the RVP group and of the base or mid septal segments in the LBBB group. CONCLUSION Patients with HF upgraded from RVP have more favorable long-term outcomes after CRT than do native LBBB patients with QRS duration ≥ 150 ms. Contraction pattern assessment can be used to identify potential responders in the RVP group.

Mechanical Dyssynchrony by Tissue Doppler Cross-Correlation is Associated with Risk for Complex Ventricular Arrhythmias after Cardiac Resynchronization Therapy.

BACKGROUND Tissue Doppler cross-correlation analysis has been shown to be associated with long-term survival after cardiac resynchronization defibrillator therapy (CRT-D). Its association with ventricular arrhythmia (VA) is unknown. METHODS From two centers 151 CRT-D patients (New York Heart Association functional classes II-IV, ejection fraction ≤ 35%, and QRS duration ≥ 120 msec) were prospectively included. Tissue Doppler cross-correlation analysis of myocardial acceleration curves from the basal segments in the apical views both at baseline and 6 months after CRT-D implantation was performed. Patients were divided into four subgroups on the basis of dyssynchrony at baseline and follow-up after CRT-D. Outcome events were predefined as appropriate antitachycardia pacing, shock, or death over 2 years. RESULTS Mechanical dyssynchrony was present in 97 patients (64%) at baseline. At follow-up, 42 of these 97 patients (43%) had persistent dyssynchrony. Furthermore, among 54 patients with no dyssynchrony at baseline, 15 (28%) had onset of new dyssynchrony after CRT-D. In comparison with the group with reduced dyssynchrony, patients with persistent dyssynchrony after CRT-D were associated with a substantially increased risk for VA (hazard ratio [HR], 4.4; 95% CI, 1.2-16.3; P = .03) and VA or death (HR, 4.0; 95% CI, 1.7-9.6; P = .002) after adjusting for other covariates. Similarly, patients with new dyssynchrony had increased risk for VA (HR, 10.6; 95% CI, 2.8-40.4; P = .001) and VA or death (HR, 5.0; 95% CI, 1.8-13.5; P = .002). CONCLUSIONS Persistent and new mechanical dyssynchrony after CRT-D was associated with subsequent complex VA. Dyssynchrony after CRT-D is a marker of poor prognosis.

Comparison of Dyssynchrony Parameters for VV-Optimization in CRT Patients

Optimization of the interventricular delay (VV‐optimization) in cardiac resynchronization therapy (CRT) patients can be performed by evaluation of mechanical dyssynchrony. However, there is no consensus on which method to use. In this study, three conceptually different methods were evaluated.