Association of left ventricular remodeling with cardiac resynchronization therapy outcomes.

BACKGROUND: Cardiac resynchronization therapy (CRT) response stratified by left ventricular (LV) remodeling revealed differing mortality profiles for distinct patient cohorts. Measuring functional end points, 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: The purpose of this study was to evaluate long-term CRT outcomes by extent of LV remodeling. METHODS: REsynchronization reVErses Remodeling in Systolic Left vEntricular dysfunction (ClinicalTrials.gov identifier NCT00271154) was a prospective, double-blind, randomized trial of CRT. Subjects were classified on the basis of LV end-systolic volume (LVESV) change from baseline to 6 months post-CRT: worsened (increase), stabilized (0%-≤15% reduction), responder (>15%-<30% reduction), and super-responder (≥30% reduction). Subjects were evaluated annually for 5 years. RESULTS: The analyses included 353 subjects randomized to CRT-ON arm. All-cause mortality was higher in the worsened group than in the other 3 response groups (29.8% vs 8.0%; P < .0001), with no difference in survival among those groups (P = .87). A significant interaction between the LVESV group and time was observed for health status and quality of life (P = .02 for both). The interaction was not significant for 6-minute hall walk (P = .79); however, super-responders had increased walk distance compared with the other 3 response groups (P = .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 the consideration of functional and mortality end points to assess CRT efficacy and provide further evidence that the dichotomous "responder and nonresponder" classification should be modified.

Redefining the Classifications of Response to Cardiac Resynchronization Therapy: Results From the REVERSE Study.

OBJECTIVES: This study sought to assess the impact of a more detailed classification of response on survival. BACKGROUND: Cardiac resynchronization therapy (CRT) improves functional status and outcomes in selected populations with heart failure (HF). However, approximately 30% of patients do not improve with CRT by various metrics, and they are traditionally classified as nonresponders. METHODS: REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) was a randomized trial of CRT among patients with mild HF. Patients were classified as Improved, Stabilized, or Worsened using prespecified criteria based on the clinical composite score (CCS) and change in left ventricular end-systolic volume index (LVESVi). All-cause mortality across CRT ON subgroups at 5 years was compared. RESULTS: Of the 406 subjects surviving 1 year, 5-year survival differed between CCS subgroups (p = 0.03), with increased mortality in the Worsened response group. Of the 353 subjects with adequate echocardiograms, survival differed significantly between response groups (p < 0.001), also due to increased mortality in the Worsened group. When combining CCS and LVESVi results, the lowest survival was observed among subjects who worsened for both measures, whereas the highest survival occurred in subjects who did not worsen by either endpoint. Multivariate analysis showed that LVESVi worsening with CRT at 6 months, baseline LVESVi, and gender were independent predictors of survival. CONCLUSIONS: For both CCS and reverse remodeling, patients who worsen with CRT have a high mortality, although remodeling was the more important endpoint. Patients who stabilize early with CRT have a much better prognosis than previously recognized, suggesting that the current convention of nonresponder classification should be modified. (REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction]; NCT00271154).

Left atrial rather than left ventricular impaired mechanics are associated with the pro-fibrotic ST2 marker and outcomes in heart failure with preserved ejection fraction.

AIMS: Left ventricular (LV) mechanics have been extensively investigated in heart failure with preserved ejection fraction (HFpEF) overshadowing for a long time the potential role of left atrium (LA) in that setting. Soluble suppression of tumorigenicity-2 receptor (ST2) is a novel biomarker of pro-fibrotic burden in HF. We hypothesized that due to the thinner LA wall, the fibrotic myocardial changes in HFpEF as indicated by elevated ST2 levels might more readily be reflected by impairments in the LA rather than the LV performance. METHODS AND RESULTS: In 86 patients with HFpEF, enrolled in the Karolinska Rennes (KaRen) biomarker prospective substudy, global LA strain (GL-LS) along with other echocardiographic as well as haemodynamic parameters and ST2 levels were measured. ST2 levels were inversely associated with LA-GS (r = -0.30, P = 0.009), but not with LA size, LV geometry, systolic or diastolic LV function (P > 0.05 for all). Furthermore, symptom severity correlated with ST2 and LA-GS, but not with LV structural or functional indices. Finally, during a median 18-month follow-up, LA-GS independently predicted the composite endpoint of HF hospitalization and all-cause mortality, even after adjustment for potential clinical and cardiac mechanical confounders, including LV global longitudinal strain and filling pressures (odds ratio: 4.15; confidence interval: 1.2-14, P = 0.023). CONCLUSIONS: Reduced LA-GS but not LV functional systolic and diastolic parameters were associated with the pro-fibrotic ST2 marker, HF symptoms and outcome in HFpEF.

The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individual-patient data meta-analysis.

AIMS: To explore possible associations that may explain the greater benefit from cardiac resynchronization therapy (CRT) reported amongst women. METHODS AND RESULTS: In an individual-patient data meta-analysis of five randomized controlled trials, all-cause mortality and the composite of all-cause mortality or first hospitalization for heart failure (HF) were compared among 794 women and 2702 men assigned to CRT or a control group. Multivariable analyses were performed to assess the impact of sex, QRS duration, HF aetiology, left ventricular end-diastolic diameter (LVEDD), and height on outcome. Women were shorter, had smaller LVEDD, more often left bundle branch block, and less often ischaemic heart disease, but QRS duration was similar between sexes. Women tended to obtain greater benefit from CRT but sex was not an independent predictor of either outcome. For all-cause mortality, QRS duration was the only independent predictor of CRT benefit. For the composite outcome, height and QRS duration, but not sex, were independent predictors of CRT benefit. Further analysis suggested increasing benefit with increasing QRS duration amongst shorter patients, of whom a great proportion were women. CONCLUSIONS: In this individual-patient data meta-analysis, CRT benefit was greater in shorter patients, which may explain reports of enhanced CRT benefit among women. Further analyses are required to determine whether recommendations on the QRS threshold for CRT should be adjusted for height. (ClinicalTrials.gov numbers: NCT00170300, NCT00271154, NCT00251251).

Pacemaker programming in patients with first-degree AV-block: Programming pattern and possible consequences.

BACKGROUND: The optimal way of pacing in patients with an indication for pacing and concomitant first-degree atrioventricular (AV)-block is not known, and consequently, firm guidelines on this topic are lacking. This study explored the current pacemaker programming pattern in patients with first-degree AV-block who have a dual chamber pacemaker without cardiac resynchronization. METHODS: The study was a retrospective chart review conducted at Duke University Hospital. Patients receiving a pacemaker due to sinus node dysfunction with coexistent first-degree AV-block were studied. Baseline demographics and characteristics, as well as pacemaker programming parameters and follow-up data, were collected through chart review. Preimplantation and postimplantation electrocardiograms were analyzed. RESULTS: A total of 74 patients were included (mean age, 75 ± 11 y; 53% men). The mean ± SD preimplant PR interval and QRS duration was 243 ± 46 and 110 ± 30 milliseconds, respectively. A history of atrial fibrillation was present in 49% of the patients, and 77% had a normal left ventricular ejection fraction. The majority of patients (65%) had their pacemakers programmed to atrial pacing (AAI/DDD +/-R), whereas 32% and 2.7% of the pacemakers were programmed to AV-sequential pacing (DDD) and ventricular pacing (VVI), respectively. There were no significant differences in baseline characteristics or electrocardiogram measures between patients programmed to the 3 pacing modes. Patients with pacemakers programmed to AAI had a lower ventricular pacing percentage at follow-up (8 vs 55, and 46% [DDD and VVI, respectively]; P < .001). CONCLUSIONS: There was no evident association between baseline characteristics and programmed pacing mode in patients with first-degree AV-block. The choice of pacing mode affects long-term pacing burden, which in turn has been shown to influence outcome.

Precision Medicine for Cardiac Resynchronization: Predicting Quality of Life Benefits for Individual Patients-An Analysis From 5 Clinical Trials.

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.

Pilot study using 3D-longitudinal strain computation in a multi-parametric approach for best selecting responders to cardiac resynchronization therapy.

BACKGROUND: Almost all attempts to improve patient selection for cardiac resynchronization therapy (CRT) using echo-derived indices have failed so far. We sought to assess: the performance of homemade software for the automatic quantification of integral 3D regional longitudinal strain curves exploring left ventricular (LV) mechanics and the potential value of this tool to predict CRT response. METHODS: Forty-eight heart failure patients in sinus rhythm, referred for CRT-implantation (mean age: 65 years; LV-ejection fraction: 26%; QRS-duration: 160 milliseconds) were prospectively explored. Thirty-four patients (71%) had positive responses, defined as an LV end-systolic volume decrease ≥15% at 6-months. 3D-longitudinal strain curves were exported for analysis using custom-made algorithms. The integrals of the longitudinal strain signals (I L,peak) were automatically measured and calculated for all 17 LV-segments. RESULTS: The standard deviation of longitudinal strain peak (SDI L,peak ) for all 17 LV-segments was greater in CRT responders than non-responders (1.18% s-1 [0.96; 1.35] versus 0.83% s-1 [0.55; 0.99], p = 0.007). The optimal cut-off value of SDI L,peak to predict response was 1.037%.s-1. In the 18-patients without septal flash, SDI L,peak was significantly higher in the CRT-responders. CONCLUSIONS: This new automatic software for analyzing 3D longitudinal strain curves is avoiding previous limitations of imaging techniques for assessing dyssynchrony and then its value will have to be tested in a large group of patients.

Predictors of short-term clinical response to cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with symptomatic heart failure and QRS prolongation but there is uncertainty about which patient characteristics predict short-term clinical response. METHODS AND RESULTS: In an individual patient meta-analysis of three double-blind, randomized trials, clinical composite score (CCS) at 6 months was compared in patients assigned to CRT programmed on or off. Treatment-covariate interactions were assessed to measure likelihood of improved CCS at 6 months. MIRACLE, MIRACLE ICD, and REVERSE trials contributed data for this analysis (n = 1591). Multivariable modelling identified QRS duration and left ventricular ejection fraction (LVEF) as predictors of CRT clinical response (P < 0.05). The odds ratio for a better CCS at 6 months increased by 3.7% for every 1% decrease in LVEF for patients assigned to CRT-on compared to CRT-off, and was greatest when QRS duration was between 160 and 180 ms. CONCLUSIONS: In symptomatic chronic heart failure patients (NYHA class II-IV), longer QRS duration and lower LVEF independently predict early clinical response to CRT.

Importance of combined left atrial size and estimated pulmonary pressure for clinical outcome in patients presenting with heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with various phenotypes and outcomes. The prognostic relevance of echocardiography and the E/e' ratio has previously been reported. We sought to study in addition, the value of estimated pulmonary pressure and left atrial size for diagnosing and determining a prognosis for HFpEF-patients in a prospective multi-centric cohort. METHODS AND RESULTS: Patients with an acute-HF event accompanied with NT-proBNP >300 pg/mL (BNP >100 pg/mL) and LVEF >45% were included (n = 237) and clinically reassessed using echo-Doppler after 4-8 weeks of HF treatment as part of the prospective KaRen HFpEF study. A core-centre performed the echocardiographic analyses. A combined primary endpoint of either HF hospitalizations and mortality over a span of 18-month, or simply mortality (secondary endpoint) were used. The mean LVEF was 62 ± 7%, E/e':12.9 ± 6.0, left atrial volume index (LAVI): 48.1 ± 15.9 ml/m2, TR: 2.9 ± 0.9 m/s. Patients with both LAVI > 40 ml/m2 and TR > 3.1 m/s had a significantly greater risk of death or heart failure related hospitalization than others (P = 0.014 after adjustment). CONCLUSION: The combination of enlarged LA and elevated estimated pulmonary pressure has a strong prognostic impact in patients suffering from HFpEF. Our results indicate that such patients constitute a risk group in HFpEF which requires dedicated medical attention. CLINICALTRIALS.GOV: NCT00774709.

Characteristics and prognosis of pneumococcal endocarditis: a case-control study.

Case series have suggested that pneumococcal endocarditis is a rare disease, mostly reported in patients with co-morbidities but no underlying valve disease, with a rapid progression to heart failure, and high mortality. We performed a case-control study of 28 patients with pneumococcal endocarditis (cases), and 56 patients with non-pneumococcal endocarditis (controls), not matched for sex and age, during the years 1991-2013, in one referral centre. Alcoholism (39.3% versus 10.7%; p <0.01), smoking (60.7% versus 21.4%; p <0.01), the absence of previously known valve disease (82.1% versus 60.7%; p 0.047), heart failure (64.3% versus 23.2%; p <0.01) and shock (53.6% versus 23.2%; p <0.01) were more common in pneumococcal than in non-pneumococcal endocarditis. Cardiac surgery was required in 64.3% of patients with pneumococcal endocarditis, much earlier than in patients with non-pneumococcal endocarditis (mean time from symptom onset, 14.1 ± 18.2 versus 69.0 ± 61.1 days). In-hospital mortality rates were similar (7.1% versus 12.5%). Streptococcus pneumoniae causes rapidly progressive endocarditis requiring life-saving early cardiac surgery in most cases.

Impact of exercise-induced mitral regurgitation on hypertrophic cardiomyopathy outcomes.

AIMS: Rest echocardiography plays a role in hypertrophic cardiomyopathy (HCM) diagnosis and risk stratification because left atrial enlargement, severe left ventricle (LV) hypertrophy, and rest LV outflow tract (LVOT) gradients ≥50 mmHg are sudden cardiac death risk factors that have been highlighted in recent guidelines. Conversely, the lack of evidence makes that exercise-echocardiography findings play a limited role. In clinical practice, LVOT gradient, but also mitral regurgitation (MR) or pulmonary pressure, seems relevant parameters to look for, during the exercise. Therefore, we sought to determine whether exercise-induced changes in myocardial and valvular functions could improve HCM risk stratification. METHODS AND RESULTS: Consecutive primitive HCM patients with a preserved LV ejection fraction underwent standardized exercise echocardiography (including the assessment of myocardial function, dynamic left intraventricular gradient, and valvular regurgitations) at baseline and were clinically followed for a median of 29.3 months. The primary endpoint was a composite criterion that included death from any cause, cardiorespiratory arrest, and hospitalization for a cardiovascular event. A total of 126 patients were included. Eighteen patients reached the primary endpoint. According to univariate Cox regression analysis, exercise LVOT gradient ≥50 mmHg [hazard ratio (HR) = 3.31, P = 0.01] and significant (≥2/4) exercise MR (HR = 3.64, P < 0.01) were associated with the primary endpoint. Patients with significant MR had significantly higher rest and exercise LVOT gradients (P = 0.001 and P = 0.001) and larger left atria volumes (P < 0.001). CONCLUSION: Significant exercise-induced MR appears to significantly impact the prognoses of HCM patients, and it is also associated with higher LVOT rest and exercise gradients.

Left atrial function, a new predictor of response to cardiac resynchronization therapy?

BACKGROUND: Cardiac resynchronization therapy (CRT) improves left ventricular (LV) function and induces LV remodeling, and it is an established therapy for advanced heart failure with prolonged QRS duration. One third of patients will not benefit from this invasive therapy. OBJECTIVE: The purpose of this study was to evaluate whether left atrial (LA) strain imaging (ε) parameters could help in predicting the response in terms of LV reverse remodeling after CRT. METHODS: A total of 79 patients who underwent CRT were evaluated with echography before implantation. LA function and LV function were assessed with M-mode, 2-dimensional echocardiography, Doppler, tissue Doppler velocity, and ε. LV reverse remodeling was defined as a >15% reduction in LV end-systolic volume. RESULTS: At 6 months, 54 patients (68%) were responders to CRT. In multivariable logistic regression, LA systolic peak of strain rate (SRA) (odds ratio [OR} 10.5, 95% confidence interval [CI] 1.76-62.1, P = .01), left bundle branch block (OR 6.8, 95% CI 1.06-43.9, P = .04), ischemic cardiomyopathy (OR 3.93, 95% CI 1.07-14.4, P = .04), and LV preejection index (OR 1.03, 95% CI 1.01-1.05, P = .01) were associated with CRT response. With an SRA cutoff of -0.75%, the negative predictive value for predicting CRT response was 0.62. CONCLUSION: This study demonstrated the possible relevance of assessing LA function before CRT. SRA appeared to be a good predictor of CRT response. Integrating this LA function analysis into the multivariable assessment of patient candidates for CRT should be considered.

Impact of Cardiac Resynchronization Therapy on Left Ventricular Mechanics: Understanding the Response through a New Quantitative Approach Based on Longitudinal Strain Integrals.

BACKGROUND: The mechanisms of improvement of left ventricular (LV) function with cardiac resynchronization therapy (CRT) are not yet elucidated. The aim of this study was to describe a new tool based on automatic quantification of the integrals of regional longitudinal strain signals and evaluate changes in LV strain distribution after CRT. METHODS: This was a retrospective observational study of 130 patients with heart failure before CRT device implantation and after 3 to 6 months of follow-up. Integrals of regional longitudinal strain signals (from the beginning of the cardiac cycle to strain peak [IL,peak] and to the instant of aortic valve closure [IL,avc]) were analyzed retrospectively with custom-made algorithms. Response to CRT was defined as a decrease in LV end-systolic volume of ≥15%. RESULTS: Responders (61%) and nonresponders (39%) showed similar baseline values of regional IL,peak and IL,avc. At follow-up, significant improvements of midlateral IL,peak and of midlateral IL,avc were noted only in responders. Midlateral IL,avc showed a relative increase of 151 ± 276% in responders, whereas a decrease of 33 ± 69% was observed in nonresponders. The difference between IL,avc and IL,peak (representing wasted energy of the LV myocardium) of the lateral wall showed a relative change of -59 ± 103% in responders between baseline and CRT, whereas in nonresponders, the relative change was 21 ± 113% (P = .009). CONCLUSIONS: Strain integrals revealed changes between baseline and CRT in the lateral wall, demonstrating the beneficial effects of CRT on LV mechanics with favorable myocardial reverse remodeling.

An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure.

AIMS: Cardiac resynchronization therapy (CRT) with or without a defibrillator reduces morbidity and mortality in selected patients with heart failure (HF) but response can be variable. We sought to identify pre-implantation variables that predict the response to CRT in a meta-analysis using individual patient-data. METHODS AND RESULTS: An individual patient meta-analysis of five randomized trials, funded by Medtronic, comparing CRT either with no active device or with a defibrillator was conducted, including the following baseline variables: age, sex, New York Heart Association class, aetiology, QRS morphology, QRS duration, left ventricular ejection fraction (LVEF), and systolic blood pressure. Outcomes were all-cause mortality and first hospitalization for HF or death. Of 3782 patients in sinus rhythm, median (inter-quartile range) age was 66 (58-73) years, QRS duration was 160 (146-176) ms, LVEF was 24 (20-28)%, and 78% had left bundle branch block. A multivariable model suggested that only QRS duration predicted the magnitude of the effect of CRT on outcomes. Further analysis produced estimated hazard ratios for the effect of CRT on all-cause mortality and on the composite of first hospitalization for HF or death that suggested increasing benefit with increasing QRS duration, the 95% confidence bounds excluding 1.0 at ∼140 ms for each endpoint, suggesting a high probability of substantial benefit from CRT when QRS duration exceeds this value. CONCLUSION: QRS duration is a powerful predictor of the effects of CRT on morbidity and mortality in patients with symptomatic HF and left ventricular systolic dysfunction who are in sinus rhythm. QRS morphology did not provide additional information about clinical response. CLINICALTRIALSGOV NUMBERS: NCT00170300, NCT00271154, NCT00251251.

Short communication: Feed utilization and its associations with fertility and productive life in 11 commercial Pennsylvania tie-stall herds.

The objectives of this study were to quantify the relationships of various definitions of feed utilization with both fertility and productive life. Intake and body measurement data were collected monthly on 970 cows in 11 tie-stall herds for 6 consecutive months. Measures of feed utilization for this study were dry matter intake (DMI), dry matter intake efficiency (DME, defined as 305-d fat-corrected milk/305-d DMI), DME with intake adjusted for maintenance requirements (DMEM), crude protein efficiency (defined as 305-d protein yield/305-d crude protein intake), and 2 definitions of residual feed intake (RFI). The first, RFI(reg), was calculated by regressing daily DMI on daily milk, fat, and protein yields, body weight (BW), daily body condition score (BCS) gain or loss, the interaction between BW and BCS gain or loss, and days in milk. The second, RFI(NRC), was estimated by subtracting 305-d DMI predicted according to their fat-corrected milk and BW from actual 305-d DMI. Data were analyzed with 8-trait animal models and included one measure of feed utilization and milk, fat, and protein yields, BW, BCS, days open (DO), and productive life (PL). The genetic correlation between DME and DO was 0.53 (± 0.19) and that between DME and PL was 0.66 (± 0.10). These results show that cows who had higher feed efficiency had greater DO (undesirable) and greater PL (desirable). Results were similar for the genetic correlation between DO and crude protein efficiency (0.42). Productive life had genetic correlations of -0.22 with BW and -0.48 with BCS, suggesting that larger, fatter cows in this study had shorter PL. Correlations between estimated breeding values for feed utilization and official sire genetic evaluations for fertility were in agreement with the results from the multiple-trait models. Selection programs intended to enhance feed efficiency should factor relationships with functional traits to avoid unfavorable effects on cow fertility.