Risk Factors for Short-Term Versus Long-Term Mortality in Patients Who Underwent Cardiac Resynchronization Therapy.

Cardiac resynchronization therapy (CRT) is an effective therapy in selected patients with advanced heart failure that reduces all-cause mortality at short-term follow-up. However, data regarding long-term mortality after CRT implantation are scarce, with no separate analysis available of the covariates associated with respectively short-term and long-term outcomes. Accordingly, the present study evaluated the risk factors associated with short-term (2-year follow-up) versus long-term (10-year follow-up) mortality after CRT implantation. Patients who underwent CRT implantation and had echocardiographic evaluation before implantation were included in the present study. The primary end point was all-cause mortality, and independent associates of short-term (2-year follow-up) and long-term (10-year follow-up) mortality were compared. In total, 894 patients (mean age 66 ± 10 years, 76% males) who underwent CRT implantation were included in the present study. The cumulative overall survival rates for the total population were 91%, 71%, and 45% at 2-, 5- and 10-year follow-up, respectively. Multivariable Cox regression analysis showed that short-term mortality was associated with both clinical and echocardiographic variables at the moment of CRT implantation; whereas long-term mortality was predominantly associated with baseline clinical parameters and was less strongly associated with baseline echocardiographic parameters. In conclusion, at long-term (10-year) follow-up, a significant proportion (45%) of patients with advanced heart failure who underwent CRT implantation were still alive. Importantly, the risk assessment for short-term (2-year follow-up) and long-term (10-year follow-up) mortality differ considerably, which may influence clinical decision making.

Prognostic implications of staging cardiac remodeling in patients undergoing cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) candidates often present with significant mitral and tricuspid regurgitation, pulmonary hypertension and right ventricular dysfunction when referred for device implantation. This study investigated the prognostic value of a novel cardiac staging system, based on the extent of cardiac remodeling prior to implantation. METHODS: Data were collected from an ongoing registry of CRT recipients. Patients were divided into 4 groups according to the extent of cardiac remodeling: group 1: left ventricular systolic dysfunction, group 2: left atrial dilatation and/or significant mitral regurgitation, group 3: pulmonary arterial hypertension and/or significant tricuspid regurgitation and group 4: right ventricular systolic impairment. Patients were followed up for the occurrence of all-cause mortality. RESULTS: A total of 844 patients (age 65 ± 10 years, 77% men) were included. Of the overall population, 145 (17%) patients were in group 1, 161 (19%) in group 2, 157 (19%) in group 3 and 381 (45%) in group 4. After a median follow-up of 95 (51-145) months, 517 (61%) patients died. Patients in groups 2, 3 and 4 had significantly higher mortality rates than those in group 1 (p = 0.025, p < 0.001 and p < 0.001, respectively). On multivariable analysis, groups 3 (HR 1.415; 95% CI 1.024-1.957; p = 0.032) and 4 (HR 1.599; 95% CI 1.204-2.123; p = 0.001) were independently associated with all-cause mortality. CONCLUSIONS: Most CRT candidates already present with extensive cardiac remodeling at the time of referral. Detection of the extent of cardiac remodeling before CRT implantation results in improved risk-stratification, and underscores the need for early referral.

Left ventricular remodelling and change in left ventricular global longitudinal strain after cardiac resynchronization therapy: prognostic implications.

AIMS: Cardiac resynchronization therapy (CRT) can reduce left ventricular end-systolic volume (LVESV), and a decrease of ≥15% is defined as a response. CRT can also improve LV global longitudinal strain (GLS). Changes in LVESV and LV GLS are individually associated with outcome post-CRT. We investigated LVESV and LV GLS changes and prognostic implications of improvement in LVESV and/or LV GLS, compared with no improvement in either parameter. METHODS AND RESULTS: Baseline and 6-month echocardiograms were analysed from CRT recipients with heart failure. LV reverse remodelling was defined as a ≥15% reduction in LVESV at 6 months post-CRT. A ≥5% absolute improvement in LV GLS was defined as a change in LV GLS. A total of 1185 patients were included (mean age 65 ± 10 years, 73% male), and those with an improvement in LVESV and LV GLS (n = 131, 11.1%) had significantly lower mortality compared with other groups. On multivariable analysis, an improvement in both LVESV and LV GLS [hazard ratio (HR): 0.47; 95% confidence interval (CI): 0.31-0.71; P < 0.001] or an improvement in either LVESV or LV GLS (HR: 0.57; 95% CI: 0.47-0.71; P < 0.001) were independently associated with better prognosis, compared with no improvement in either parameter. CONCLUSION: Either a reduction in LVESV and/or an improvement in LV GLS at 6 months post-CRT are independently associated with improved long-term prognosis, compared with no change in both LVESV and LV GLS. This supports the use of LV GLS as a meaningful parameter in defining CRT response.

Effect of Functional Mitral Regurgitation on Outcome in Patients Receiving Cardiac Resynchronization Therapy for Heart Failure.

Functional mitral regurgitation (FMR) is common in heart failure (HF), and negatively impacts prognosis. Cardiac resynchronization therapy (CRT) can improve FMR, but the long-term changes in and impact of FMR after CRT are still unclear. The present study investigated the prevalence, evolution and impact on mortality of FMR before and after CRT in patients with HF. A total of 1,313 patients (66 ± 11 years, 77% male, 59% ischemic heart disease) treated with CRT were evaluated. Patients were divided into 4 groups of FMR according to the evolution at 6 months after CRT: no or mild FMR at baseline which remained unchanged at 6 months (grade 0-1 FMR unchanged, n = 609 [51%]), no or mild FMR which worsened to moderate to severe (grade 0-1 FMR worsened, n = 66 [6%)]), moderate to severe FMR which improved to no or mild (grade 2-4 improved, n = 209 [18%]), and moderate to severe FMR which remained unchanged (grade 2-4 unchanged, n = 309 [26%]). Over a mean follow-up of 51 ± 38 months, 297 (25%) patients died. Those with baseline FMR grade 0-1 which remained unchanged at 6-month follow-up, as well as baseline FMR grade 2-4 which improved, had lower mortality rates than patients with 6-month FMR grade 2-4 regardless of baseline FMR grade (p <0.001). Baseline FMR grade 2-4 that remained unchanged at 6-month follow-up was associated with increased mortality, independent of the clinical and left ventricular volumetric responses to CRT (hazard ratio, 1.77; 95% confidence interval, 1.41-2.22, p <0.001). In conclusion, moderate to severe FMR at baseline which remains unchanged at 6 months after CRT implantation is strongly associated with long-term mortality in patients with HF.

Reduced left ventricular mechanical dispersion at 6 months follow-up after cardiac resynchronization therapy is associated with superior long-term outcome.

BACKGROUND: In heart failure (HF) patients, left ventricular mechanical dispersion (LVMD) reflects heterogeneous mechanical activation of the left ventricle. In HF patients, LVMD can be reduced after CRT. Whether lesser LVMD is associated with improved outcome is unknown. OBJECTIVE: The purpose of this study was to relate LVMD to long-term prognosis in a large cohort of HF patients after 6 months of cardiac resynchronization therapy (CRT). METHODS: Clinical, echocardiographic, and ventricular arrhythmia (VA) data were analyzed from an ongoing registry of HF recipients of CRT. Baseline (before CRT) and 6-month echocardiograms were evaluated. LVMD was calculated as the standard deviation of the time from onset of the QRS complex to the peak longitudinal strain in a 17-segment model. Patients were divided into 2 groups according to the median LVMD (84 ms) at 6 months post-CRT. RESULTS: Of 1185 patients (mean age 65 ± 10 years; 76% male), 343 (29%) died during a mean follow-up of 55 ± 36 months. Baseline LVMD was not associated with all-cause mortality and VA at follow-up. In contrast, patients with less LVMD (≤84 ms) at 6 months post-CRT had lower event rates (VA and mortality) compared to those with LVMD >84 ms. On multivariable analysis, greater LVMD at 6 months after CRT was independently associated with an increased risk of mortality (hazard ratio 1.002; P = .037) and VA (hazard ratio 1.003; P = .026). CONCLUSION: Larger LVMD at 6 months after CRT is independently associated with all-cause mortality and VA. LVMD may be valuable in identifying patients who remain at high mortality risk after CRT implantation.

Prognostic value of global longitudinal strain in heart failure patients treated with cardiac resynchronization therapy.

BACKGROUND: Myocardial fibrosis (macroscopic scar or diffuse reactive fibrosis) is one of the determinants of impaired left ventricular (LV) global longitudinal strain (GLS) in heart failure (HF) patients. OBJECTIVE: The purpose of this study was to evaluate the prognostic value of LV GLS in HF patients treated with cardiac resynchronization therapy (CRT). METHODS: The study included 829 HF patients (mean age 64.6 ± 10.4 years; 72% men) treated with CRT. Before CRT implantation, LV GLS was assessed using 2-dimensional speckle tracking echocardiography. The primary endpoint was the combination of all-cause mortality, heart transplantation, and LV assist device implantation. The secondary endpoint was the occurrence of ventricular arrhythmias or appropriate implantable defibrillator device therapies. RESULTS: During follow-up, 332 patients reached the primary endpoint, and 233 presented with the secondary endpoint. Patients were divided according to LV GLS quartiles. Patients with the most impaired LV GLS quartile had a 2-fold higher risk of reaching the combined endpoint compared with patients in the best LV GLS quartile (hazard ratio [HR] 2.088; 95% confidence interval [CI] 1.555-2.804; P <.001). LV GLS was significantly associated with the combined endpoint (HR 1.075; 95% CI 1.020-1.133; P = .007) after adjusting for clinical, electrocardiographic, and echocardiographic characteristics. Although patients in the most impaired LV GLS quartile showed higher event rates for the secondary endpoint compared with the other groups, LV GLS was not independently associated with the secondary endpoint (HR 1.047; 95% CI 0.989-1.107; P = .115). CONCLUSION: In this large cohort of CRT patients, baseline LV GLS was independently associated with the combined endpoint.

Usefulness of the CRT-SCORE for Shared Decision Making in Cardiac Resynchronization Therapy in Patients With a Left Ventricular Ejection Fraction of ≤35.

Individualized estimation of prognosis after cardiac resynchronization therapy (CRT) remains challenging. Our aim was to develop a multiparametric prognostic risk score (CRT-SCORE) that could be used for patient-specific clinical shared decision making about CRT implantation. The CRT-SCORE was derived from an ongoing CRT registry, including 1,053 consecutive patients (age 67 ± 10 years, 76% male). Using preimplantation variables, 100 multiple imputed datasets were generated for model calibration. Based on multivariate Cox regression models, cross-validated linear prognostic scores were calculated, as well as survival fractions at 1 and 5 years. Specifically, the CRT-SCORE was calculated using atrioventricular junction ablation, age, gender, etiology, New York Heart Association class, diabetes, hemoglobin level, renal function, left bundle branch block, QRS duration, atrial fibrillation, left ventricular systolic and diastolic functions, and mitral regurgitation, and showed a good discriminative ability (areas under the curve 0.773 at 1 year and 0.748 at 5 years). During the long-term follow-up (median 60 months, interquartile range 31 to 85), all-cause mortality was observed in 494 (47%) patients. Based on the distribution of the CRT-SCORE, lower- and higher-risk patient groups were identified. Estimated mean survival rates of 98% at 1 year and 92% at 5 years were observed in the lowest 5% risk group (L5 CRT-SCORE: -4.42 to -1.60), whereas the highest 5% risk group (H5 CRT-SCORE: 1.44 to 2.89) showed poor survival rates: 78% at 1 year and 22% at 5 years. In conclusion, the CRT-SCORE allows accurate prediction of 1- and 5-year survival rates after CRT using readily available and CRT-specific clinical, electrocardiographic, and echocardiographic parameters. The model may assist clinicians in counseling patients and in decision making.

Influence of Aging on Level and Layer-Specific Left Ventricular Longitudinal Strain in Subjects Without Structural Heart Disease.

Values for level- (apical, mid, and basal) and layer-based (endocardial, mid-myocardial, and epicardial) left ventricular (LV) longitudinal strain across age are scarce. The present study evaluates the effect of aging on level- and layer-specific LV longitudinal strain in subjects without structural heart disease. A total of 408 subjects (mean age 58 years [range 16 to 91]; 49% men) were evaluated retrospectively. Subjects were divided into equal groups based on age and gender. Subjects with evidence of structural heart disease or arrhythmias were excluded. Mean LV ejection fraction was 62 ± 6.2%. A gradual increase in magnitude of level LV longitudinal strain was observed from basal to mid and apical levels (-16.7 ± 2.1%, -18.8 ± 2.0%, -22.6 ± 3.8%; p <0.001, respectively). Across age groups, there was a borderline significant decrease in magnitude of basal longitudinal strain in older subjects, whereas the magnitude in the apical level significantly increased. On layer-based analysis, the magnitude of longitudinal strain increased from epicardium to endocardium across all age groups. On multivariable analysis, only diabetes mellitus was associated with more impaired longitudinal strain in the endocardium, and male gender was associated with more impaired longitudinal strain at the epicardium layer. In conclusion, with increasing age, the magnitude of LV longitudinal strain at the basal level declines while the apical LV longitudinal strain increases. In contrast, layer-specific LV longitudinal strain remains unchanged with aging. The presence of diabetes mellitus modulated the effect of age on the LV endocardial layer, and male gender was associated with more impaired longitudinal strain at the epicardial layer.

Relation of Myocardial Contrast-Enhanced T1 Mapping by Cardiac Magnetic Resonance to Left Ventricular Reverse Remodeling After Cardiac Resynchronization Therapy in Patients With Nonischemic Cardiomyopathy.

Myocardial scar is known to be associated with limited left ventricular (LV) reverse remodeling after cardiac resynchronization therapy (CRT). However, the impact of diffuse myocardial interstitial fibrosis, as assessed with myocardial T1 mapping cardiac magnetic resonance (CMR), has not been studied in patients with CRT. Therefore, we aimed at evaluating the association between diffuse myocardial interstitial fibrosis, in nonischemic cardiomyopathy patients, and LV reverse remodeling after CRT. A total of 40 patients (61 ± 11 years) with nonischemic cardiomyopathy who underwent CMR before CRT implantation were included. Myocardial T1 mapping was performed using an inversion-recovery Look-Locker sequence after gadolinium injection. Myocardial contrast-enhanced T1 time values were assessed from segments without delayed contrast enhancement and normalized for heart rate. At 6-month follow-up, LV reverse remodeling was assessed by the reduction in LV end-systolic volume. Before CRT implantation, mean myocardial contrast-enhanced T1 time was 351 ± 46 ms. At 6-month follow-up, LV end-systolic volume decreased by 24 ± 21%. Myocardial contrast-enhanced T1 time showed a significant correlation with LV reverse remodeling (r = 0.5, p = 0.001) together with hemoglobin level, renal function, LV dyssynchrony, and presence of delayed contrast enhancement. Multivariate regression analysis identified myocardial contrast-enhanced T1 time (ß -0.160, p = 0.022), LV dyssynchrony (ß -0.267, p = 0.002), and renal function (ß -0.334, p = 0.021) as independent associates of LV reverse remodeling. In conclusion, in nonischemic cardiomyopathy, diffuse interstitial myocardial fibrosis quantified with T1 mapping CMR is independently associated with LV reverse remodeling after CRT and might, therefore, be used to optimize patient selection.

QRS duration versus morphology and survival after cardiac resynchronization therapy.

AIMS: The prognostic implications of QRS duration and morphology in heart failure patients treated with cardiac resynchronization therapy (CRT) remains debated. The present evaluation investigated the association between QRS duration (<150 vs. ≥150 ms) and QRS morphology (left bundle brand block [LBBB] vs. non-LBBB) and long-term prognosis of a large cohort of unselected heart failure patients treated with CRT according to contemporary guidelines. METHODS AND RESULTS: Of 973 heart failure patients treated with CRT (mean age 66.1 ± 9.8 years, 76% male), 658 patients (68%) showed QRS duration ≥150 ms, and 772 patients (79%) had LBBB configuration. Compared with patients with QRS duration <150 ms, patients with QRS duration ≥150 ms had less frequently ischaemic cardiomyopathy and atrial fibrillation and showed larger left ventricular volumes and lower left ventricular ejection fraction. Compared with patients with non-LBBB configuration, patients with LBBB morphology were younger, less often males and less often had ischaemic cardiomyopathy and atrial fibrillation. On multivariable analysis, after correcting for relevant clinical and echocardiographic variables, LBBB morphology was significantly associated with better survival [hazard ratio (HR) 0.737; 95% confidence interval (CI) 0.584-0.931; P = 0.010], whereas there was no statistically significant association between QRS duration ≥150 ms and survival (HR 0.889; 95% CI 0.726-1.088; P = 0.252). CONCLUSIONS: In this large population of heart failure patients treated with CRT, QRS morphology was independently associated with long-term survival. The association between QRS duration and long-term survival was not statistically significant.

Impact of QRS complex duration and morphology on left ventricular reverse remodelling and left ventricular function improvement after cardiac resynchronization therapy.

AIMS: To evaluate the impact of the interaction of QRS duration and morphology on left ventricular (LV) reverse remodelling and LV functional improvement in heart failure (HF) patients treated with cardiac resynchronization therapy (CRT). METHODS AND RESULTS: From an ongoing registry of HF patients treated with CRT according to contemporary guidelines, demographic, clinical, electrocardiographic (ECG) and echocardiographic characteristics were analysed. Patients were divided according to QRS duration and morphology: <150 ms vs. ≥150 ms and left bundle branch block (LBBB) vs. non-LBBB, respectively. Echocardiographic measurements were performed at baseline and at 6 months' follow-up. The effect of the interaction between QRS duration and morphology on LV reverse remodelling and LV ejection fraction (LVEF) was analysed using linear, mixed models. Of 1467 patients (mean age 65 ± 10 years, 77% male), 884 (60%) had a QRS ≥150 ms and 814 (55%) showed LBBB. The group with QRS ≥150 ms demonstrated larger LV reverse remodelling (mean reduction in LV end-systolic volume 34.3 mL vs. 14.8 mL; P < 0.001) and improvement in LVEF (mean increase 6.8% vs. 5.2%; P < 0.001) compared with their counterparts. Similarly, patients with LBBB QRS morphology showed greater LV reverse remodelling (mean reduction in LV end-systolic volume 30.8 mL vs. 17.4 mL; P < 0.001) and improvement in LVEF (mean increase 6.9% vs. 3.7%; P < 0.001) than those with non-LBBB QRS morphology. CONCLUSIONS: Left ventricular reverse remodelling and LV functional improvement are greater among HF patients with LBBB morphology and increasing QRS duration who receive CRT.

Pump Speed Optimization in Stable Patients with a Left Ventricular Assist Device.

Optimal left ventricular assist device (LVAD) functioning and preservation of right ventricular (RV) function are major survival determinants in destination therapy (DT)-LVAD recipients. Currently, the indication for routine pump speed optimization in stable patients and its effect on RV function at follow-up remain underexplored. Hemodynamically stable patients (N = 17, age 61 [interquartile range {IQR} 51-66] years; 13 [77%] male) underwent a routine speed ramp test. Echocardiographic images were obtained at incremental speed settings to determine optimal pump speed. In 8 patients (47%), LVAD speed could be optimized. In these patients, RV fractional area change (26% [IQR 23-31] to 35% [IQR 27-45], p = 0.04) and RV longitudinal peak systolic strain (-13% [IQR -16 to -9] to -17% [IQR -18 to -11], p = 0.02) at 3 months follow-up improved without RV dilatation. Furthermore, N-terminal pro-brain natriuretic peptide level decreased (3,162 [IQR 1,336-4,487] ng/L to 2,294 [IQR 1,157-3,810] ng/L, p = 0.02). No significant follow-up changes were found in patients without indication for speed adjustment. In conclusion, routine evaluation of optimal LVAD speed reveals the potential of speed optimization in a substantial proportion of stable LVAD-DT patients and can improve RV function.

Mechanical dyssynchrony in patients with heart failure and reduced ejection fraction: how to measure?

PURPOSE OF REVIEW: This article summarizes the most recent imaging techniques to assess left ventricular mechanical dyssynchrony and discusses their value to predict response to cardiac resynchronization therapy (CRT) together with assessment of myocardial scar and cardiac venous anatomy. RECENT FINDINGS: Left ventricular mechanical dyssynchrony has been associated with prognosis of heart failure patients and has been shown to influence the efficacy of CRT. Although current guidelines do not recommend the assessment of left ventricular mechanical dyssynchrony to select heart failure patients for CRT, technological advances in echocardiography, cardiac magnetic resonance, nuclear imaging and computed tomography have provided powerful tools to characterize left ventricular mechanical dyssynchrony and predict response to CRT. Most important, these imaging techniques permit integration of additional information that is relevant for the efficacy of CRT, such as the extent and location of myocardial scar and the anatomy of the coronary sinus and tributaries where the left ventricular pacing lead may be positioned. SUMMARY: Left ventricular mechanical dyssynchrony is an important parameter to select heart failure patients who are candidates for CRT. The integration of this parameter together with extent and location of myocardial scar and cardiac venous anatomy is a key to optimize the efficacy of CRT.

Cardiac Resynchronization Therapy in CKD Stage 4 Patients.

BACKGROUND AND OBJECTIVES: Cardiac resynchronization therapy (CRT) is a well established heart failure treatment that has shown to improve renal function. However, landmark CRT trials excluded patients with severe renal dysfunction. Therefore, this study evaluated the effect of CRT on renal function and long-term prognosis in patients with stage 4 CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study evaluated 73 consecutive CRT patients (71±10 years) with stage 4 CKD who underwent echocardiographic and renal function evaluation at baseline and 6-month follow-up between 2000 and 2012. As a control group, 18 patients with stage 4 CKD who received an implantable cardioverter defibrillator (ICD) were selected. CRT recipients with ≥15% reduction in left ventricular end-systolic volume at 6-month follow-up were classified as CRT responders. During long-term follow-up (median, 33 months), appropriate defibrillator therapy, heart failure hospitalizations, and all-cause mortality (combined end point) were recorded. RESULTS: At 6-month follow-up, a significant reduction in left ventricular end-systolic volume was observed in CRT patients compared with patients with ICD (from 159±78 to 145±78 ml in CRT patients and from 126±54 to 119±49 ml in ICD patients; P=0.05), and CRT response was observed in 22 patients (30%). Compared with ICD patients, eGFR improved among CRT patients (from 25±4 to 30±9 ml/min per 1.73 m(2); interaction time and group, P=0.04) and was more pronounced among CRT responders (25±3 to 34±9 ml/min per 1.73 m(2); P<0.001). The combined end point was observed in 17 ICD and 62 CRT patients. CRT patients showed superior survival compared with ICD patients (log-rank P=0.03). More importantly, CRT response was independently associated with improved survival free from the combined end point (hazard ratio, 0.51; 95% confidence interval, 0.27 to 0.98; P=0.04) after adjustment for clinical and echocardiographic parameters. CONCLUSIONS: Response to CRT occurs in approximately 30% of patients with stage 4 CKD, which is less than in the average CRT population. CRT was associated with better clinical outcome, and particularly, CRT response was associated with improvement in eGFR and better long-term prognosis.