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Women might benefit more than men from cardiac resynchronization therapy (CRT) and do so at shorter QRS durations. This meta-analysis was performed to determine whether sex-based differences in CRT effects are better accounted for by height, body surface area (BSA), or left ventricular end-diastolic dimension (LVEDD). We analyzed patient-level data from CRT trials (MIRACLE, MIRACLE ICD, MIRACLE ICD II, REVERSE, RAFT, COMPANION, and MADIT-CRT) using bayesian hierarchical Weibull regression models. Relationships between QRS duration and CRT effects were examined overall and in sex-stratified cohorts; additional analyses indexed QRS duration by height, BSA, or LVEDD. End points were heart failure hospitalization (HFH) or death and all-cause mortality. Compared with men (n = 5628), women (n = 1439) were shorter (1.62 [interquartile range, 1.57–1.65] m vs 1.75 [1.70–1.80] m; P <.001), with smaller BSAs (1.76 [1.62–1.90] m2 vs 2.02 [1.89–2.16] m2; P <.001). In adjusted sex-stratified analyses, the reduction in HFH or death was greater for women (hazard ratio, 0.54; credible interval, 0.42–0.70) than for men (hazard ratio, 0.77; credible interval, 0.66–0.89; P interaction =.009); results were similar for all-cause mortality even after adjustment for height, BSA, and LVEDD. Sex-specific differences were observed only in nonischemic cardiomyopathy. The effect of CRT on HFH or death was observed at a shorter QRS duration for women (126 ms) than for men (145 ms). Indexing QRS duration by height, BSA, or LVEDD attenuated sex-specific QRS duration thresholds for the effects of CRT on HFH or death but not on mortality. Although body size partially explains sex-specific QRS duration thresholds for CRT benefit, it is not associated with the magnitude of CRT benefit. Indexing QRS duration for body size might improve selection of patients for CRT, particularly with a "borderline" QRS duration. [Display omitted] [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy (CRT) reduces heart failure hospitalizations (HFH) and mortality for guideline-indicated patients with heart failure (HF). Most patients with HF are aged ≥70 years but such patients are often under-represented in randomized trials. Patient-level data were combined from 8 randomized trials published 2002-2013 comparing CRT to no CRT (n = 6,369). The effect of CRT was estimated using an adjusted Bayesian survival model. Using age as a categorical (<70 vs ≥70 years) or continuous variable, the interaction between age and CRT on the composite end point of HFH or all-cause mortality or all-cause mortality alone was assessed. The median age was 67 years with 2436 (38%) being 70+; 1,554 (24%) were women; 2,586 (41%) had nonischemic cardiomyopathy and median QRS duration was 160 ms. Overall, CRT was associated with a delay in time to the composite end point (adjusted hazard ratio [aHR] 0.75, 95% credible interval [CI] 0.66-0.85, P =.002) and all-cause mortality alone (aHR of 0.80, 95% CI 0.69-0.96, P =.017). When age was treated as a categorical variable, there was no interaction between age and the effect of CRT for either end point (P >.1). When age was treated as a continuous variable, older patients appeared to obtain greater benefit with CRT for the composite end point (P for interaction =.027) with a similar but nonsignificant trend for mortality (P for interaction =.35). Reductions in HFH and mortality with CRT are as great or greater in appropriately indicated older patients. Age should not be a limiting factor for the provision of CRT. [ABSTRACT FROM AUTHOR]

Whether conduction system pacing (CSP) is an alternative option for cardiac resynchronization therapy (CRT) in patients with heart failure remains an area of active investigation. The purpose of this study was to assess the echocardiographic and clinical outcomes of CSP compared to biventricular pacing (BiVP). This multicenter retrospective study included patients who fulfilled CRT indications and received CSP. Patients with CSP were matched using propensity score matching and compared in a 1:1 ratio to patients who received BiVP. Echocardiographic and clinical outcomes were assessed. Response to CRT was defined as an absolute increase of ≥5% in left ventricular ejection fraction (LVEF) at 6 months post-CRT. A total of 238 patients were included. Mean age was 69.8 ± 12.5 years, and 66 (27.7%) were female. Sixty-nine patients (29%) had His-bundle pacing, 50 (21%) had left bundle branch area pacing, and 119 (50%) had BiVP. Mean follow-up duration in the CSP and BiVP groups was 269 ± 202 days and 304 ± 262 days, respectively (P =.293). The proportion of CRT responders was greater in the CSP group than in the BiVP group (74% vs 60%, respectively; P =.042). On Kaplan-Meier analysis, there was no statistically significant difference in the time to first heart failure hospitalization (log-rank P =.78) and overall survival (log-rank P =.68) between the CSP and BiVP groups. In patients with heart failure and reduced ejection fraction, CSP resulted in greater improvement in LVEF compared to BiVP. Large-scale randomized trials are needed to validate these outcomes and further investigate the different options available for CSP. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional endpoints, as well as mortality, may better assess CRT efficacy and inform patient management. However, the association between LV remodeling and functional outcomes after CRT is not well understood.Objective: To evaluate long-term CRT outcomes by extent of LV remodeling.Methods: REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction (NCT00271154) was a prospective, double-blind, randomized CRT trial. Patients were classified based on LV end-systolic volume (LVESV) change from baseline to 6-months post-CRT: Worsened (increase); Stabilized (0 to ≤15% reduction); Responder (>15 to < 30% reduction); and Super-responder (≥30% reduction). Subjects were evaluated annually for 5 years.Results: The analyses included 353 patients randomized to CRT-ON arm. All-cause mortality was higher in the worsened group compared with the 3 other response groups (29.8% vs 8.0%, p<0.0001), with no difference in survival among those groups (p=0.87). A significant interaction between LVESV group and time was observed for health status and quality of life (both p=0.02). The interaction was not significant for 6-minute hall walk (p=0.79); however, super-responders had increased walk distance compared to the 3 other response groups (p=0.03).Conclusion: Preventing further increase in LVESV with CRT was associated with reduced mortality, whereas functional measure improvement was associated with LV remodeling magnitude. These results support consideration of functional and mortality endpoints to assess CRT efficacy and provide further evidence the dichotomous 'responder and non-responder' classification should be modified. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary.Objective: We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations.Methods: Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios.Results: Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders.Conclusion: Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications.Methods and Results: In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (Pinteraction = .020).Conclusions: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF.Clinical Trial Registration: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) may be misdiagnosed. We assessed prevalence and consistency of Framingham criteria signs and symptoms in acute vs subsequent stable HFpEF.Methods: Three hundred ninety-nine patients with acute HFpEF according to Framingham criteria were re-assessed in stable condition. Four definitions of HFpEF at follow-up: (1) Framingham criteria alone, (2) Framingham criteria and natriuretic peptides (NPs), (3) Framingham criteria, NPs, and European Society of Cardiology HF guidelines echocardiographic criteria, (4) Framingham criteria, NPs, and the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON) trial echocardiographic criteria.Results: At follow-up, HFpEF was still present in 27%, 22%, 21%, and 22%, respectively. Most prevalent in acute HFpEF were dyspnea at exertion (90%), pulmonary rales (71%), persisting at follow-up in 70% and 13%, respectively. Characteristics at acute HF with greater or lesser odds of stable HFpEF; (1) jugular venous distention (odds ratio [OR] 1.80, 95% confidence interval [CI] 1.13-2.87; P = .013) and pleural effusion (OR 0.45, 95% CI 0.24-0.85; P = .014) and (4), older age (1.04, 95% CI 1.01-1.08; P = .014) and tachycardia (>100 bpm) 0.52, 95% CI 0.27-1.00; P = .048).Conclusions: In patients with acute HFpEF, one-quarter met the HF definition according to Framingham criteria at ambulatory follow-up. The proportion of patients with postdischarge HFpEF was largely unaffected by additional echocardiographic or NP criteria Older age and jugular venous distention at acute presentation predicted persistent HFpEF at follow-up, whereas pleural effusion and tachycardia may yield false HFpEF diagnoses. This finding has implications for HFpEF trial design. [ABSTRACT FROM AUTHOR]

Background: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan.Methods: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers.Results: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD.Conclusions: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) is common in patients with chronic heart failure (CHF), but the underlying causes are not fully understood. We investigated whether ID is associated with decreased iron absorption in patients with CHF.Methods and Results: We performed an oral iron-absorption test in 30 patients and 12 controls. The patients had CHF with reduced (n = 15) or preserved (n = 15) ejection fraction and ID, defined as s-ferritin < 100 µg/L, or s-ferritin 100-299 µg/L and transferrin saturation < 20%. The controls had no HF or ID and were of similar age and gender. Blood samples were taken before and 2 hours after ingestion of 100 mg ferroglycin sulphate. The primary endpoint was the delta plasma iron at 2 hours. The delta plasma iron was higher in the group with HF than in the control group (median increase 83.8 [61.5;128.5] µg/dL in HF vs 47.5 [30.7;61.5] µg/dL in controls, P = 0.001), indicating increased iron absorption. There was no significant difference between the groups with preserved or reduced ejection fraction (P = 0.46).Conclusion: We found increased iron absorption in patients with CHF and ID compared to controls without ID and HF, indicating that reduced iron absorption is not a primary cause of the high prevalence of ID in patients with CHF.Clinical Trial Registration: EudraCT 2017-000158-21. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Patients with heart failure eligible for cardiac resynchronization therapy (CRT) often have other medical conditions. To determine the association of comorbid disease with clinical outcomes of CRT. Original, patient-level data from eight clinical trials randomizing patients to CRT vs. no CRT were included (BLOCK HF, MIRACLE, MIRACLE ICD, and MIRACLE ICD II trials, REVERSE, RAFT, COMPANION, MADIT-CRT). A prior history of the following comorbidities was considered; atrial fibrillation (AF; n = 920), coronary artery disease (CAD; n =3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were stratified into the following 3 groups based on the number of comorbidities: 0, 1-2, or ≥ 3. The composite outcome of time to heart failure hospitalization (HFH) or all-cause mortality were evaluated within each morbidity group using a Bayesian Hierarchical Weibull survival regression model with a random intercept and a random treatment effect for each morbidity group at the trial level, adjusting for baseline characteristics (presence of an implantable cardioverter defibrillator, age, sex, New York Heart Association (NYHA) class, ejection fraction, QRS width, presence of left bundle branch block, use of antiarrhythmic drugs, use of beta-blockers, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). Of 6,324 patients enrolled, 970 (15%) had no comorbidities, 4,052 (64%) had 1-2 and 1,302 (21%) had ≥ 3 comorbidities. The pooled data are shown in the figure. The adjusted hazard ratios (HR) for CRT on time to HFH or all-cause mortality for the overall cohort was 0.74, (95% credible interval [CI] 0.65-0.84) (p<0.001), no comorbidities: HR 0.69, (95% CI 0.50-0.94) (p=0.021), 1-2 comorbidities: HR 0.77, (95% CI 0.66-0.90) (p=0.005) and ≥ 3 comorbidities HR 0.68, (95% CI 0.55-0.82) (p<0.001). Most patients eligible for CRT have a prior history of one or more co-morbid conditions, which do not generally detract from the effect of CRT on clinical outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Clinical trials have established the average benefit of cardiac resynchronization therapy (CRT), but estimating benefit for individual patients remains difficult because of the heterogeneity in treatment response. Accordingly, we created a multivariable model to predict changes in quality of life (QoL) with and without CRT. METHODS AND RESULTS: Patient-level data from 5 randomized trials comparing CRT with no CRT were used to create a prediction model of change in QoL at 3 months using a partial proportional odds model for no change, small, moderate, and large improvement, or deterioration of any magnitude. The C statistics for not worsening or obtaining at least a small, moderate, and large improvement were calculated. Among the 3614 patients, regardless of assigned treatment, 33.3% had a deterioration in QoL, 9.2% had no change, 9.2% had a small improvement, 13.5% had a moderate improvement, and the remaining 34.9% had a large improvement. Patients undergoing CRT were less likely to have a decrement in their QoL (28.2% versus 38.9%; P<0.001) and more likely to have a large QoL improvement (38.7% versus 30.6%; P<0.001). A partial proportional odds model identified baseline QoL, age, and an interaction of CRT with QRS duration as predictors of QoL benefits 3 months after randomization. C statistics of 0.65 for not worsening, 0.68 for at least a small improvement, 0.69 for at least a moderate improvement, and 0.73 for predicting a large improvement were observed. CONCLUSIONS: There is marked heterogeneity of treatment benefit of CRT that can be predicted based on baseline QoL, age, and QRS duration. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015. [ABSTRACT FROM AUTHOR]

Background: Anabolic drive is impaired in heart failure with reduced ejection fraction (HFrEF) but insufficiently studied in heart failure with preserved ejection fraction (HFpEF). Insulin-like growth factor 1 (IGF-1) mediates growth hormone effects and IGF binding protein 1 (IGFBP-1) regulates IGF-1 activity. We tested the hypothesis that HFpEF and HFrEF are similar with regard to IGF-1 and IGFBP-1.Methods and Results: In patients with HFpEF (n = 79), HFrEF (n = 85), and controls (n = 136), we analyzed serum IGF-1 and IGFBP-1 concentrations, correlations, and associations with outcome. Age-standardized scores of IGF-1 were higher in HFpEF, median arbitrary units (interquartile range); 1.21 (0.57-1.96) vs HFrEF, 0.09 (-1.40-1.62), and controls, 0.22 (-0.47-0.96), P overall <.001. IGFBP-1 was increased in HFpEF, 48 (28-79), and HFrEF, 65 (29-101), vs controls, 27(14-35) µg/L, P overall <.001. These patterns persisted after adjusting for metabolic and HF severity confounders. IGF-1 was associated with outcomes in HFrEF, hazard ratio per natural logarithmic increase in IGF-1 SD score 0.51 (95% confidence interval 0.32-0.82, P = .005), but not significantly in HFpEF. IGFBP-1 was not associated with outcomes in either HFpEF nor HFrEF.Conclusion: HFpEF and HFrEF phenotypes were similar with regard to increased IGFBP-1 concentrations but differed regarding IGF-1 levels and prognostic role. HFrEF and HFpEF may display different impairment in anabolic drive. [ABSTRACT FROM AUTHOR]

Background—Underlying mechanisms in heart failure (HF) with preserved ejection fraction remain unknown. We investigated cardiovascular plasma biomarkers in HF with preserved ejection fraction and their correlation to diastolic dysfunction, functional class, pathophysiological processes, and prognosis. Methods and Results—In 86 stable patients with HF and EF ≥45% in the Karolinska Rennes (KaRen) biomarker substudy, biomarkers were quantified by a multiplex immunoassay. Orthogonal projection to latent structures by partial least square analysis was performed on 87 biomarkers and 240 clinical variables, ranking biomarkers associated with New York Heart Association (NYHA) Functional class and the composite outcome (all-cause mortality and HF hospitalization). Biomarkers significantly correlated with outcome were analyzed by multivariable Cox regression and correlations with echocardiographic measurements performed. The orthogonal partial least square outcome-predicting biomarker pattern was run against the Ingenuity Pathway Analysis (IPA) database, containing annotated data from the public domain. The orthogonal partial least square analyses identified 32 biomarkers correlated with NYHA class and 28 predicting outcomes. Among outcome-predicting biomarkers, growth/differentiation factor-15 was the strongest and an additional 7 were also significant in Cox regression analyses when adjusted for age, sex, and N-terminal probrain natriuretic peptide: adrenomedullin (hazard ratio per log increase 2.53), agouti-related protein; (1.48), chitinase-3–like protein 1 (1.35), C–C motif chemokine 20 (1.35), fatty acid–binding protein (1.33), tumor necrosis factor receptor 1 (2.29), and TNF-related apoptosis-inducing ligand (0.34). Twenty-three of them correlated with diastolic dysfunction (E/e′) and 5 with left atrial volume index. The IPA suggested that increased inflammation, immune activation with decreased necrosis and apoptosis preceded poor outcome. Conclusions—In HF with preserved ejection fraction, novel biomarkers of inflammation predict HF severity and prognosis that may complement or even outperform traditional markers, such as N-terminal probrain natriuretic peptide. These findings lend support to a hypothesis implicating global systemic inflammation in HF with preserved ejection fraction. [ABSTRACT FROM AUTHOR]

Background Cardiac resynchronization therapy (CRT) reduces mortality, improves functional status, and induces reverse left ventricular remodeling in selected populations with heart failure (HF). The magnitude of reverse remodeling predicts survival with many HF medical therapies. However, there are few studies assessing the effect of remodeling on long-term survival with CRT. Objective The purpose of this study was to assess the effect of CRT-induced reverse remodeling on long-term survival in patients with mildly symptomatic heart failure. Methods The REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial was a multicenter, double-blind, randomized trial of CRT in patients with mild HF. Long-term follow-up of 5 years was preplanned. The present analysis was restricted to the 353 patients who were randomized to the CRT ON group with paired echocardiographic studies at baseline and 6 months postimplantation. The left ventricular end-systolic volume index (LVESVi) was measured in the core laboratory and was an independently powered end point of the REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction trial. Results A 68% reduction in mortality was observed in patients with ≥15% decrease in LVESVi compared to the rest of the patients ( P = .0004). Multivariable analysis showed that the change in LVESVi was a strong independent predictor ( P = .0002), with a 14% reduction in mortality for every 10% decrease in LVESVi. Other remodeling parameters such as left ventricular end-diastolic volume index and ejection fraction had a similar association with mortality. Conclusion The change in left ventricular end-systolic volume after 6 months of CRT is a strong independent predictor of long-term survival in mild HF. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Current guidelines recommend cardiac resynchronization therapy (CRT) in mild heart failure (HF) patients with QRS prolongation and ejection fraction (EF) 30%. To assess the effect of CRT in less severe systolic dysfunction, outcomes in the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study were evaluated in which patients with left ventricular (LV) ejection fraction (LVEF) >30% were included.The results of patients with baseline EF >30% (n=177) and those with EF 30% (n=431), as determined by a blinded core laboratory, were compared. In the LVEF >30% subgroup, there was a trend for improvement in the clinical composite response with CRT ON versus CRT OFF (P=0.06) and significant reductions in LV end systolic volume index (-6.7±21.1 versus 2.1±17.6 mL/m2; P=0.01) and LV mass (-20.6±50.5 versus 5.0±42.4 g; P=0.04) after 12 months. The time to death or first HF hospitalization was significantly prolonged with CRT (hazard ratio, 0.26; P=0.012). In the LVEF <30% subgroup, significant improvements in clinical composite response (P=0.02), reverse remodeling parameters, and time to death or first HF hospitalization (hazard ratio, 0.58; P=0.047) were observed. After adjusting for important covariates, the CRT ON assignment remained independently associated with improved time to death or first HF hospitalization (hazard ratio, 0.54; P=0.035), whereas there was no significant interaction with LVEF.Among subjects with mild HF, QRS prolongation, and LVEF >30%, CRT produced reverse remodeling and similar clinical benefit compared with subjects with more severe LV systolic dysfunction.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00271154. [ABSTRACT FROM AUTHOR]

Objectives: We sought a method for any reader to quantify the limit, imposed by variability, to sustainably observable R 2 between any baseline predictor and response marker. We then apply this to echocardiographic measurements of mechanical dyssynchrony and response. Background: Can mechanical dyssynchrony markers strongly predict ventricular remodeling by biventricular pacing (cardiac resynchronization therapy)? Methods: First, we established the mathematical depression of observable R 2 arising from: 1) spontaneous variability of response markers; and 2) test–retest variability of dyssynchrony measurements. Second, we contrasted published R 2 values between externally monitored randomized controlled trials and highly skilled single-center studies (HSSCSs). Results: Inherent variability of response markers causes a contraction factor in R 2 of 0.48 (change in left ventricular ejection fraction [ΔLVEF]), 0.50 (change in end-systolic volume [ΔESV]), and 0.40 (change in end-diastolic volume [ΔEDV]). Simultaneously, inherent variability of mechanical dyssynchrony markers causes a contraction factor of between 0.16 and 0.92 (average, 0.6). Therefore the combined contraction factor, that is, limit on sustainably observable R 2 between mechanical dyssynchrony markers and response, is ∼0.29 (ΔLVEF), ∼0.24 (ΔESV), and ∼0.30 (ΔEDV). Many R 2 values published in HSSCSs exceeded these mathematical limits; none in externally monitored trials did so. Overall, HSSCSs overestimate R 2 by 5- to 20-fold (p = 0.002). Absence of bias-resistance features in study design (formal enrollment and blinded measurements) was associated with more overstatement of R 2. Conclusions: Reports of R 2 > 0.2 in response prediction arose exclusively from studies without formally documented enrollment and blinding. The HSSCS approach overestimates R 2 values, frequently breaching the mathematical ceiling on sustainably observable R 2, which is far below 1.0, and can easily be calculated by readers using formulas presented here. Community awareness of this low ceiling may help resist future claims. Reliable individualized response prediction, using methods originally designed for group-mean effects, may never be possible because it has 2 currently unavailable and perhaps impossible prerequisites: 1) excellent blinded test–retest reproducibility of dyssynchrony; and 2) response markers reproducible over time within nonintervened individuals. Dispassionate evaluation, and improvement, of test–retest reproducibility is required before any further claims of strong prediction. Prediction studies should be designed to resist bias. [Copyright &y& Elsevier]