Cardiac Resynchronization Therapy Research Articles

CRT should be recommended for all heart failure patients with mechanical dyssynchrony and a ventricular conduction delay regardless of the QRS morphology

Abstract Introduction Two recent meta-analyses displayed the heterogeneous effect of cardiac resynchronization therapy (CRT) in patients with a non-left bundle branch block (non-LBBB) and found an increased burden of ventricular arrhythmias after CRT (1,2). Careful patient selection is therefore paramount. Evidence suggests the assessment of mechanical dyssynchrony may guide decision-making to CRT in this challenging population. Purpose To assess the effect of CRT in patients with and without mechanical dyssynchrony compared to medication only, and in particular in patients with a non-LBBB morphology. Methods We retrospectively screened for symptomatic heart failure patients who presented between 2012 and 2018 at our clinic with a QRS duration ≥130ms and a left ventricular ejection fraction (LVEF) ≤35%. We identified 361 patients who received CRT and 1107 patients who could have been considered for CRT. Patients were excluded if echocardiographic data was unavailable, they received CRT after 2018, were 80 years or older, or had other significant co-morbidities. We enrolled the remaining 220 CRT patients ("CRT") and 124 patients treated with medication only ("Control") for analysis. Patients were categorized for the presence of mechanical dyssynchrony on echocardiography, defined as the presence of either septal flash, apical rocking, or both. Multivariable-adjusted Cox regression analyses, including stratification by the presence of dyssynchrony, was performed to compare the effect of CRT to medication only. Hazard ratios (aHR) were obtained after adjustment for age, sex, atrial rhythm, QRS duration, QRS morphology, ischemic disease, kidney function, medication and presence of a defibrillator. Sensitivity analysis was performed in patients with a non-LBBB morphology. Results The CRT and Control group were comparable except for the QRS duration (163±22ms vs 152±16ms, p<0.001), the proportion of patients on optimal medical therapy (64% vs 47%, p=0.001), patients with a defibrillator (81% vs 19%, p<0.001), and patients with a LBBB morphology (75% vs 47%, p<0.001). During an average follow-up of 6.0(±3.2) years, 162 patients (47%) died. In the overall cohort, CRT did not significantly improve survival (aHR: 0.66, p=0.065). There was, however, a marked survival benefit for CRT over medication only in patients with mechanical dyssynchrony (aHR: 0.37, p=0.001). In patients without dyssynchrony there was a trend towards harm due to CRT (aHR: 2.05, p=0.062). These results were consistent in the sub-cohort of patients with a non-LBBB morphology. Conclusion CRT significantly improves the life expectancy of patients with mechanical dyssynchrony, including patients with a non-LBBB morphology. These results add to the evidence that all heart failure patients with LVEF≤35%, QRS≥130ms and mechanical dyssynchrony should be recommended (Class I) for CRT regardless of QRS morphology, while awaiting the results of ongoing randomized controlled trials.

QRS complex fragmentation status before and after cardiac resynchronization therapy predicts hospitalizations for heart failure

Abstract Introduction Cardiac resynchronization therapy (CRT) reduces mortality and hospitalization for heart failure (HF) in selected patients with HF with reduced ejection fraction (HFrEF). However, there is a significant percentage of non-responders who are readmitted for HF after implantation. Several biomarkers and electrocardiographic findings have been suggested as prognostic markers in this group of patients. Fragmentation of the QRS complex (QRSf) has been associated with worse prognosis in several cardiac diseases, but evidence in patients undergoing CRT remains to be limited. Purpose To evaluate if the changes in QRSf status before and after CRT implantation have a prognostic role in patients undergoing CRT in terms of hospitalization for HF. Methods Consecutive patients undergoing CRT were prospectively included from October 2009 to December 2022. Demographic clinical, electrocardiographic and echocardiographic variables were recorded. Prospective follow-up variables were collected from electronic clinical records and telephone interview. QRSf complex was defined by the presence of different RSR′ patterns including an additional R-waves (R′) and notches of the R-wave and S-wave in two contiguous leads corresponding to a main coronary artery territory in a 12-lead surface electrocardiogram performed before and after CRT. Results A total of 244 patients (mean age 72 ± 10 years, 80% male) were included. The etiology of the LV systolic dysfunction was ischemic in 50.0%. Mean LVEF before implantation was 25 ± 9% and mean paced QRS width was 141 ± 23 ms. CRT-D was implanted in 176 patients (72.2%). At baseline, 150 patients had a QRSf. After CRT implantation, 69 (28.4%) patients experimented a change in QRSf status: 29 patients (11.9%) without prior QRSf developed QRSf, whereas 40 patients (16.5%) resolved QRSf after CRT. Median follow-up time was 36.0 months (interquartile range 18.2-75.7). At follow-up, 90 patients died and 91 presented at least one hospitalization for HF. Multivariate Cox regression survival analysis showed that development of QRSf after CRT implantation (HR 8.87; 95% CI 1.85-42.50) and the presence of QRSf before implantation with or without paced QRSf after CRT (HR 8.21; 95% CI 1.75-38.50 and HR 16.70; 95% CI 3.88-71.80 respectively) were independently associated with hospitalizations for HF. Univariate and multivariate Cox regression analyses for HF hospitalization are presented in Table 1. Figure 1 presents Kaplan-Meier curves for QRSf status and hospitalizations for HF. Conclusions According to our results, QRSf status before and after CRT have a significant prognostic role in terms of hospitalization for HF after CRT, especially in those who develop QRSf after CRT and those with baseline QRSf regardless QRSf status after CRT. The worse prognosis was observed in those with QRSf before and after CRT. Therefore, these patients should be followed more strictly because they are at higher risk of decompensation.Table 1.Cox Regression Analyses

Effect of disabling biventricular pacing in patients with left ventricular assist device and cardiac resynchronization therapy

Abstract Introduction Taking into account the mechanism of the left ventricular assist device (LVAD) function, the cardiac resynchronization therapy (CRT) seems to be unnecessary and, according to the current reports, the left ventricular lead (LVL) should be disabled. However, observation of the patients suggests that deactivation of the left ventricle (LV) pacing leads to deterioration of the patients condition and progression of the heart failure (HF) symptoms. Purpose The study aimed to determine differences in survival of the patients with LVAD and maintained or disabled CRT, including patients subjected to heart transplantation, as well differences in left and right ventricle function, kidneys and liver condition, NTproBNP value, subjective exercise tolerance and frequency of HF exacerbation before and after CRT deactivation. Methods The study group involved 55 patients with LVAD and CRT devices, including 11 patients with disabled LV pacing. The statistical analysis concerned the comparison of groups with and without biventricular stimulation as well results within the group with disabled LVL before and after its deactivation. Analyzed data included laboratory results, echocardiographic parameters, number of HF exacerbation episodes and exercise tolerance by NYHA classification. Results Total CRT period did not differ in group with maintained and disabled CRT [24 (12-36)months vs. 30 IQR(12-48)months respectively; p=0,74]. The median period of CRT deactivation was 30 IQR(12-48) months after LVAD implantation. Time from LVAD implantation to heart transplantation differed significantly between patients with and without CRT [20 IQR(9-32)months vs. 49,5 IQR(46,5-62)months respectively; p=0,003]. LV disabling was connected with a significant increase of NTproBNP [3072 IQR(2287-6636) pg/ml vs. 2133 IQR(1618-3437) pg/ml before LVL deactivation; p=0,009), without an aggravation of the exercise intolerance by NYHA classification (p=0,11) or total number of HF exacerbation episodes (p=0,72). Lack of LV pacing was not related to change of concentration of creatinine (p=0,13), AST (p=0,89, ALT (p=0,5), bilirubin (p=0,06) and albumin (p=0,69) before and after LV deactivation. Comparison of echocardiographic parameters with and without CRT did not demonstrate significant differences in LV ejection fraction (p=0,37), LV end-diastolic diameter (p=0,33), TAPSE (p=0,72) and tricuspid regurgitation degree (p=0,39). Death-free survival from LVAD implantation has not differed in patients with and without CRT(p=0,08), similarly like death-free survival from heart transplantation (p=0,56), however with tendency to better outcome of patients with CRT till 12 months after the heart transplant. Conclusion CRT does not improve general health condition as well death-free survival in LVAD recipients, including patients subjected to heart transplantation, however with tendency to better outcome of patients with CRT till 12 months after the heart transplant.Death-free surival after LVADDeath-free survival after transplant

Impact of QRS complex fragmentation on all-cause mortality before and after cardiac resynchronization therapy

Abstract Introduction Cardiac resynchronization therapy (CRT) have demonstrated to reduce all-cause mortality in selected patients with HFrEF. However, there is still a high rate of non-responders, so risk stratification is crucial. Fragmentation of the QRS complex (QRSf) has been suggested as a valuable prognostic factor in different cardiac diseases, but the evidence in patients undergoing CRT is controversial and limited. Purpose To evaluate if changes in QRSf status before and after CRT implantation has a prognostic role in patients undergoing CRT in terms all-cause mortality. Methods Consecutive patients undergoing CRT were prospectively included from October 2009 to December 2022. Demographic clinical, electrocardiographic and echocardiographic variables were recorded. Prospective follow-up variables were collected from electronic clinical records and telephone interview. QRSf complex was defined by the presence of different RSR′ patterns including additional R-waves (R′) and notches of the R-wave and S-wave in two contiguous leads corresponding to a main coronary artery territory in a 12-lead electrocardiogram performed before and after CRT. Results A total of 244 patients (mean age 71.8 ± 9.8 years, 79.5% male) were included. The etiology of LV systolic disfunction was ischemic in 50.0%. Mean LVEF before implantation was 25 ± 9%. A CRT-D was implanted in 176 patients (72.2%). The mean width of the paced QRS was 141 ± 23 ms. At baseline, 150 patients had a QRSf. After CRT implantation, 69 (28.4%) patients experimented a change in QRSf status: 29 patients (11.9%) without prior QRSf developed QRSf, whereas 40 patients (16.5%) resolved QRSf after CRT. Median follow-up time was 36.0 months (interquartile range 18.2-75.7). During the follow-up period, 90 patients died. In the multivariate Cox regression survival analysis, the presence of QRSf before the implantation with or without paced QRSf after CRT were independently associated with all-cause mortality (HR 4.43; 95% CI 1.53-12.80 and HR 3.69; 95% CI 1.16-11.80 respectively). Those without QRSf prior implantation who developed QRSf after CRT did not present significantly higher risk of all-cause mortality. Univariate and multivariate Cox regression analyses for all-cause mortality are presented in Table 1. Figure 1 presents Kaplan-Meier curves for all-cause mortality according to QRSf status before and after CRT implantation. Conclusions According to our results, preimplantation QRSf is an independent predictor of all-cause mortality regardless the resolution or maintenance of QRSf after CRT in patients with HFrEF undergoing CRT. Therefore, patients with QRSf before CRT implantation regardless the paced QRSf status, should be followed more strictly because they are at higher mortality risk.Table 1.Cox Regression Analyses

Prediction of CRT response using a novel CRT responder score in an Asian patient population

Abstract Introduction Cardiac Resynchronization Therapy (CRT) guidelines, derived from trials among U.S. and European patients, assign weaker recommendations to those with midrange QRS duration (<150ms). Patient height and body size may modulate CRT efficacy. Moreover, these factors may affect CRT utilization and efficacy in Asia. Aim The purpose of this analysis was to determine the prediction scoring system model for CRT responders in a Japanese patient population. Methods We analyzed the database of the Multicenter Prospective Pilot Study to Test LV Intracardiac Conduction Time as a Predictor of CRT Response (BIO|SELECT) which was a single-arm study conducted at 28 hospitals in Japan. This study enrolled patients eligible for a de-novo CRT-defibrillator (CRT-D) based on current guideline indications, who had no recent or planned cardiac surgery and were planned to receive a Sentus ProMRI OTW quadripolar LV lead and a BIOTRONIK CRT-D with multipole pacing feature. Patients were followed for 7 months after implantation. Four accepted parameters to define CRT response [LVESV (cut-off -15%), LVEF (+5%), BNP (-25%), and NYHA class (one class improvement)] were combined into a composite benefit index (CBI) by forming the normalized sum, with CBI = 4.0 meaning response. The CBI was found to be more robust than the individual 4 parameters due to the reduced influence of noise and measurement errors in single parameters. Several factors were studied to create the scoring tool. The CRT responder score was the sum of these individual scores (range 0-100). To construct a predictive scoring system, logistic regression analysis was performed with a backward selection procedure. In addition, the Akaike information criterion (AIC) was applied to determine the best model among those tested. The score was then assigned employing the β coefficient of each variable divided by the reference value. The model's calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. Results A total of 196 patients were enrolled in this study (mean age 69 years, mean LVEF 30%, left bundle-branch block [LBBB] 58%). The Ooccurrence of CRT response during the 7-month follow-up was 54%. Future CRT responders were significantly predicted by low age (< 70 years)(18 points), female (19 points), prior heart failure hospitalization (16 points), body mass index (<20) (17 points), QRS/height (<0.858)(30 points). This score predicted CRT response well (area under curve 0.72; 95% CI 0.643-0.798). When the cut-off of 63 points or more was applied the sensitivity was 0.56, the specificity was 0.72, and the negative predictive value was 0.58. Conclusions The CRT responder score is a novel approach for the prediction of CRT response, but should be validated and further improved to increase its predictive value. This approach highlights the role of preventing the development of severe heart failure and could help to identify individuals who might benefit from CRT.

Left atrial function and long-term survival after cardiac resynchronization therapy

Abstract Background Left atrial (LA) reservoir strain after CRT has been linked to long-term outcome, but the role of LA function in response to cardiac resynchronization therapy (CRT) is incompletely understood. LA dyssynchrony during left bundle branch block has negative effects on LA function beyond LA reservoir strain. We hypothesized that correction of LA dyssynchrony after CRT has added value to LA reservoir strain as a marker of long-term outcome. Purpose To explore the role of LA function in long-term survival after CRT. Methods In a recent prospective multicenter study of 168 patients, LA segmental and global strains were measured by speckle-tracking echocardiography before and 7 ± 1 months after CRT. LA reservoir strain was measured as the difference between peak and minimum global strain during the atrial cycle and LA dyssynchrony as the time delay between onset systolic stretch of the interatrial septum and LA lateral wall. Since LA reservoir strain < 18% is associated with elevated LV filling pressure, we used 18% as cutoff and for LA dyssynchrony 43 ms (mean after CRT in the present study). All-cause mortality was used as clinical endpoint during follow-up. Results After 6 years ± 21 months (mean ± SD) follow-up, 35 (21%) patients died. LA reservoir strain was significantly lower (15 ± 9% vs 20 ± 10%, p = 0.003) and LA dyssynchrony numerically higher (61 ± 68 ms vs 39 ± 69 ms, p = 0.099) in patients who died compared to survivors. LA reservoir strain ≥ 18% after CRT was associated with favorable long-term survival (HR: 0.51, 95% CI: 0.26 - 0.98) (upper panel in the Figure). LA dyssynchrony was not independently associated with mortality. However, when used in concert with LA reservoir strain ≥ 18% after CRT, it identified patients with perticularly excellent long-term survival (HR: 0.17, 95% CI: 0.05 - 0.58 vs patients with reservoir strain ≥ 18% and persistent LA dyssynchrony) (lower panel in the Figure). Patients with preserved LA reservoir strain but persistent LA dyssynchrony had similar outcome as patients with reduced LA reservoir strain (HR: 0.98, 95% CI: 0.45 - 2.12). Conclusion LA reservoir strain ≥ 18% and absence of LA dyssynchrony is associated with excellent long-term survival after CRT.LA strain after CRT and survival

Beating the clock: the impact of heart failure duration on CRT efficacy

Abstract Background Cardiac Resynchronization Therapy (CRT) stands as an established intervention for selected patients with heart failure (HF) presenting with a wide QRS complex. The optimal timing for CRT implantation remains uncertain. Current evidence suggests superior outcomes post-CRT in patients who have not been previously hospitalised for HF and those receiving the implant during their initial hospitalisation for HF.1 Purpose The primary objective of this study is to investigate the long-term clinical outcomes following CRT implantation relative to the duration of HF previous to the implant. It was analysed in a cohort of consecutive patients from a HF Unit who met the criteria for CRT as recommended by the ESC guidelines (QRS duration ≥150ms, left bundle branch block morphology, and left ventricular ejection fraction (LVEF) ≤35% despite optimal medical therapy). Methods We evaluated all patients who received CRT from January 2011 through September 2022. Follow-up ended in September 2023. Patients with CRT indicated for ventricular pacing due to high-degree atrioventricular block were excluded. Patients were categorized into two groups based on the duration of HF progression prior to CRT implantation: more than 3 years and 3 years or less. The primary outcome was all-cause mortality (ACM). Secondary outcomes included a composite of ACM and HF hospitalisation and the proportion of patients who demonstrated a significant improvement in LVEF (defined as an increase of ≥10% from baseline and a subsequent measurement of LVEF ≥40%). Results The cohort consisted of 127 patients, mean age 65.8±10.7 years, 23.6% were women, mean LVEF was 28.4±8.6% and 36.2% had ischaemic aetiology (Table 1). 62 patients either died or were hospitalized for HF. Mean follow-up was 4.9±2.7 years. After adjusting for age, sex and baseline LVEF, patients with HF for more than three years before CRT implantation had a worse prognosis: HRs of 2.31 for ACM (p=0.016) and 2.13 for the combined endpoint of ACM+HFH (p=0.010) (Figure 1). The proportion of patients with improved LVEF after CRT was significantly higher in the group with shorter HF duration (68.25%) compared to the group with longer HF duration (25%), p <0.001. Conclusions Our findings reveal that patients with a shorter history of HF (less than three years) prior to CRT implantation exhibit significantly better clinical outcomes. These results highlight the role of early intervention with CRT in patients with HF, suggesting that shorter HF duration prior to CRT may lead to more favourable long-term outcomes.

Extracellular volume analysis on cardiac computed tomography is useful to predict prognosis after cardiac resynchronization therapy

Abstract Background Left-ventricular (LV) extracellular volume (ECV) (LVECV) is often evaluated on magnetic resonance imaging (MRI), and the value is well correlated with biopsy-identified myocardial fibrosis. Recently, mechanical development has been achieved, and ECV analysis on cardiac computed tomography (CCT) has been eligible using the latest software, and the ECV on CCT is well correlated with the ECV on MRI. Cardiac resynchronization therapy (CRT) has been usually performed in cases with severe heart failure, but almost 30 percent of them are non-responders. Therefore, the indicators to predict non-responders to cardiac resynchronization therapy (CRT) have been sought in advance. Purpose The purpose of this study is to reveal the utility of LVECV on CCT for the prediction of patient prognosis in the candidates of cardiac resynchronization therapy (CRT) who have low LV function. Methods We analyzed 53 patients (30 males, 65 ± 14 years old) with heart failure who underwent CCT, including late phase scan, using 320-row detector CT (Aquilion One or Aquilion One ViSion Edition, Cannon Medical Systems) or 256-row detector CT (Revolution CT Apex, GE Healthcare), before the implantation of a CRT device from December 2008 to January 2024. The primary outcomes were defined as cardiac death, hospitalization due to HF, and fatal arrhythmia after CRT implantation. CRT responders were defined as the patients whose LV endo-systolic volume was decreased by 15% or more on transthoracic echocardiography. Results Twenty-two patients (42%) had primary outcomes (10 cardiac death, 7 fatal arrhythmia, 5 hospitalization due to HF). LVECV was lower in CRT responder (n = 23) than the others (n = 25) (35 ± 6.3% vs 41 ± 6.8%, P = 0.006). LVECV was higher in the patients with primary outcomes (n = 22) than the others (n = 31) (35 ± 5.0% vs 41 ± 7.8%, P = 0.019). Based on the receiver-operating characteristics curve analysis, the best cut-off of LVECV for predicting primary outcomes was 44.03% (B). In the survival analysis using the Cox proportional hazard model, LVECV on CCT was a significant predictor of primary outcomes (HR, 1.07; 95% CI, 1.13-1.01; P = 0.012). On Kaplan-Meier analysis, the higher LVECV group (≥ 44.03%) had a significantly greater number of primary outcomes than the others (P = 0.010) (C). Conclusion LVECV on CCT may be useful for predicting responders of CRT and prognosis after CRT implantation.ROC curve and Kaplan-Meier analysis

The role of fibrosis and inflammation for response and outcome prediction in candidates to cardiac resynchronization therapy: is response the right answer?

Abstract Background Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Purpose Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods 86 consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. An echocardiographic reduction of LV end-systolic volume ≥15% was used to define a patient as responder to CRT. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results 44% of patients experienced the primary outcome. the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 38.5 ng/ml, AUC: 0.63, p=0.03, (OR 7.13 [1.12;45.41], p=0.03), together with TAPSE>17.5 mm (OR 10.86 [3.15;37.44], p<0.001) significantly correlated with the structural response to CRT in several prediction models. Baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p<0.001, HR 8.33 (1.88–33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p<0.001, HR 333 (250–1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood (Table). At Kaplan-Meyer curve patients with both high baseline sST2 and Gal-3 had the lowest survival probability (Figure). Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08–1.22), p < 0.001; HR: 0.84 (0.74–0.91), p = 0.04; HR: 1.26 (1.10–1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

A larger reduction of spatial mean QRS-T angle during cardiac resynchronisation therapy is associated with a lower risk of mortality and heart failure hospitalisation

Abstract Background Predicting clinical outcome in heart failure patients undergoing cardiac resynchronization therapy (CRT) remains challenging, necessitating improved risk stratification for CRT recipients. Previous studies have shown an association between large spatial peak and mean QRS-T angles and cardiovascular disease. Little is known, however, about their relation to clinical outcome following CRT. Purpose To investigate the association between spatial peak and mean QRS-T angles and long-term clinical outcome following CRT initiation. Methods All patients with native LBBB receiving CRT at a large-volume tertiary care center between 2015 and 2020 were retrospectively evaluated. Spatial peak and mean QRS-T angles were derived from digital pre- and post-CRT 12-lead ECGs that were processed using Glasgow algorithm and Kors’ regression transformation. The QRS-T angles and their change after CRT were analyzed in relation to the primary composite endpoint of heart failure hospitalisation or all-cause mortality using Cox regression analysis adjusted for clinical covariates (age, gender, CRT-P or CRT-D, secondary ICD indication, ischemic etiology, NYHA class, LVEF, diabetes, atrial fibrillation, baseline QRS duration, NT-proBNP, and eGFR). Results The study group comprised 250 patients (a median age [Q1–Q3] of 72.2 years [64.5–76.3]; 22% female; 58% New York Heart Association (NYHA) class III-IV; LVEF 27% [22–30]) who were followed over a median follow-up time of 4.5 years [3.2–5.8] after CRT implantation. The median post-CRT spatial peak and mean QRS-angles were 142° [116–160] and 152° [127–166], and the median angle was decreased by 16° [-0.6–41] and 14° [-0.4–38], respectively. Both a larger post-CRT mean QRS-T angle (HR 1.20, 95%CI 1.08-1.33, p=<.001) and peak QRS-T angle (HR 1.08, 95%CI 1.01-1.17, p=0.046) were associated with the primary endpoint. A larger reduction of mean QRS-T angle, but not peak QRS-T angle, was associated with a risk reduction (HR 0.87, 95%CI 0.79-0.95, p<0.003). In Kaplan-Meier analysis, patients with a post-CRT mean QRS-T angle above median had a higher risk of reaching the endpoint (log-rank p=0.002, Figure 1). Conclusion Our results show that a larger magnitude of the post-CRT spatial peak and mean QRS-T angles, and a larger reduction of the latter, are associated with long-term heart failure hospitalisation and death. These findings suggest that spatial QRS-T angle may have a potential role in refined risk stratification of CRT patients.Figure 1.K-M curve spatial mean QRS-T

Assessment of mechanical dyssynchrony can improve the new ESC-2021 guidelines for cardiac resynchronization therapy

Abstract Background In 2021, new guidelines for cardiac resynchronization therapy (CRT) were published by the European society of cardiology (ESC-2021), where the different classes of recommendations were based on a new ECG-based definition of left bundle branch block (LBBB). However, its association with reverse LV remodeling and additive prognostic value remain unknown. Aim To investigate (1) the association between the ESC-2021 CRT guidelines and reverse LV remodeling at follow up, and (2) the additive prognostic value of baseline assessment of mechanical dyssynchrony to the ESC-2021 guidelines. Methods We investigated 244 heart failure patients in sinus rhythm treated with CRT in two European centers. 70% of the population were males. Mean age was 69 ± 10 years, QRS duration: 154 ± 24 msec. Mechanical dyssynchrony at baseline was defined as the presence of apical rocking or septal flash (ApRock/SF) in 2D transthoracic echocardiography. LV volumes were measured at baseline and at 12 ± 6 months after CRT, where the amount of CRT induced reverse LV remodeling was calculated as the percent change of LVESV at follow-up compared to baseline. Results Applying the ESC-2021 LBBB definition, only 18% (n=45) of patients had LBBB. Applying the guidelines, only 14% (n=35) had class I recommendation (LBBB + QRS ≥ 150 msec), 44% (n=107) had class IIa (LBBB + QRS 130-149 msec or non-LBBB + QRS ≥ 150 msec), 29% (n=70) had class IIb (Non-LBBB + QRS 130-149 msec), and 13% (n = 33) were not recommended according to the ESC-2021 because of having baseline QRS duration between 120 and 129 msec. On the other hand, ApRock/SF was evident in 57% (n=140) of the patients. There was non-significant difference in the relative decrease in LVESV at follow up between patients with LBBB and non-LBBB applying the new LBBB definition (44% [IQR: 32-63], vs. 39%, IQR [20-57], P = 0.08, panel A). Similarly, there was no significant difference in the relative decrease in LVESV at CRT follow up among the four guideline recommendation classes, panel B. We combined presence of mechanical asynchrony at baseline with each of the guideline recommendation classes. The combination of ApRock/SF with classes IIa and IIb improved the prediction of reverse LV remodeling significantly (P<0.001 and <0.01 respectively), while adding mechanical asynchrony did not significantly improve prediction in the class I and the not-recommended subgroups. However, results of these last 2 may have been impacted by a small number of patients, panel C. Conclusion The new ESC-2021 definition of LBBB is associated with few patients with LBBB and consequently small number of patients with class I recommendation according to the new guidelines. There was weak association between the new ESC-2021 guideline classes of recommendation and reverse LV remodeling after CRT. However, baseline assessment of ApRock and SF can significantly improve the guidelines in predicting CRT outcome.

Myocardial single photon emission computed tomography imaging to identify non-responders to cardiac resynchronization therapy in patients with non-left bundle branch block

Abstract Background Non-response to cardiac resynchronization therapy (CRT) is an important issue in the treatment of heart failure with reduced ejection fraction (HFrEF) and non-left bundle branch block (LBBB). Although the QRS duration and morphology are crucial parameters for selecting CRT candidates, electrocardiogram (ECG) markers may inadequately represent the mechanical activation patterns within the heart. Owing to limitations associated with the ECG criteria, there is increasing interest in advanced multimodality imaging to improve patient selection. Recently, myocardial single-photon emission computed tomography imaging (G-MPI) is used for assessing left ventricular (LV) dyssynchrony. This technique is mostly automatic and has high intra- and inter-observer reproducibility and repeatability. Objectives This study aimed to examine whether preoperative G-MPI evaluation could predict non-responsiveness to CRT in patients with HFrEF with non-LBBB. Methods Between January 2021 and December 2022, 128 patients underwent CRT, of whom 73 with pre-operative evaluation using G-MPI were selected. Forty-three patients with non-LBBB (21 and 22 CRT responders and non-responders, respectively) were assessed. These patients were divided into CRT responder and non-responder groups. We evaluated the cut-off and clinical impact of pre-operative G-MPI parameters in predicting non-responsiveness to CRT. In addition, 30 patients with LBBB were analyzed. Results Among patients with non-LBBB, CRT responders and non-responders showed no significant differences in baseline characteristics, except for the LV dimension. A receiver operating characteristic curve analysis identified 108° and 27.7° as the optimal cut-offs for the bandwidth and phase standard deviation (SD), respectively, to predict non-responsiveness to CRT (area under the curve [AUC]=0.762; 95% confidence interval [CI]: 0.601–0.923 and AUC=0.742; 95% CI: 0.576–0.909, respectively). A multivariate analysis revealed that a cut-off bandwidth of ≥108° and phase SD of ≥27.7° are independent predictors of non-responsiveness to CRT in patients with non-LBBB (hazard ratios 5.65; 95% CI: 1.53–20.9; P=0.009). In contrast, there were no relationships between G-MPI parameters and non-responsiveness to CRT in patients with LBBB. Conclusions Pre-operative G-MPI findings were associated with non-responsiveness to CRT in patients with non-LBBB. The identification of potentially nonresponsive patients could influence patient management and alter outcomes.

Interplay between strain pattern-based classification of dyssynchrony and myocardial scar in CRT patients

Abstract Introduction Echocardiography-derived septal strain patterns are valuable for predicting volumetric reverse remodelling and survival in patients undergoing cardiac resynchronization therapy (CRT). Nevertheless, presence of myocardial scarring in the left ventricle (LV) is known to attenuate CRT treatment response. Purpose This study aims to investigate the interplay between septal strain patterns and myocardial scarring in CRT candidates, and how they link to outcome after CRT. Methods In this prospective multicentre study, CRT candidates from five European institutions underwent pre-implantation assessments using speckle-tracking strain analysis on echocardiography and cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE). Dyssynchrony was graded through analysis of septal strain curves, categorizing patients into five distinct patterns, denoted as strain Stage-0 through strain Stage-4 (Fig. A). LGE of the LV wall was quantitatively assessed using CMR (as a percentage). The study endpoints were volumetric reverse remodelling (volume responder = more than 15% decrease LV end-systolic volume) after one year, and all-time all-cause mortality. Results A total of 267 patients, with a mean age of 66±11 years (69% males, 90% left bundle branch block [LBBB]) presented with an average LV ejection fraction (EF) of 30±7%. With each stepwise increase in strain stage, global LV scarring decreased (p<0.01; Fig. B) and the proportion of volume responders increased (all p<0.0001; Fig. C). ROC curves demonstrated that the predictive power of strain stages for CRT volumetric response was not significantly improved when scarring percentage was added (AUC 0.78 [95% CI: 0.69-0.83] vs. 0.81 [95% CI: 0.71-0.90]; p>0.05; Fig. D). In a multivariate cox regression model – including clinical characteristics that were significantly related to survival in univariate analysis – a patients’ strain stage was the only significant predictor of survival, also outperforming scar burden as determinant of outcome (HR 0.68; p=0.041; Fig. E). Conclusions Septal strain patterns show a strong association with the extent of reverse remodelling and outcome in CRT-treated patients. An inverse relationship is observed between pre-implant strain stages and the extent of myocardial scarring. However, scar burden did not provide incremental predictive value over the strain stages. Strain-pattern-based dyssynchrony assessment is a meaningful predictive marker which integrates information on myocardial dysfunction due to dyssynchrony as well as scar burden.

Long-term efficacy of cardiac resynchronization therapy with triple-site ventricular stimulation in heart failure patients

Abstract Background Cardiac resynchronization therapy (CRT) reduces cardiac electrical dyssyncrhony and improves clinical outcomes in selected symptomatic patients with left ventricular (LV) systolic dysfunction. However, patients after conventional CRT (Bi-V) have residual cardiac electrical dyssynchrony. CRT with multi-site pacing has gained attention to improve short-term outcome refractory to BiV. However, long-term follow up outcome is still uncertain. We evaluated the efficacy of CRT with triple-site ventricular stimulation (Tri-V), involving 2 LV lead in 2 anatomically separated veins and a single RV lead in RV apex for long-term follow up period. Methods Ninety-two consecutive patients with New York Heart Association class II-IV heart failure, LV ejection fraction <0.35, and QRS interval >120ms, who underwent CRT implantation between 2010 and 2016, were enrolled. Acute hemodynamic responses to temporary dual-site and triple-site ventricular pacing were evaluated, and patients were assigned to either the Bi-V or Tri-V group based on the results. The primary endpoint was the HF clinical composite score, which scores patients as improved, unchanged, or worsened. The secondary endpoint included cumulative survival from any cause of death and HF hospitalization. Results Tri-V was successfully implanted in 32 patients. Five patients were excluded during follow-up because of uncaptured pacing in one of the LV leads. One year post-implantation, the clinical composite score significantly improved in 84% of Tri-V patients compared to 57% in the Bi-V group (p=0.026). After a median follow-up of 12.0 years, there was no significant difference about all-cause mortality between Tri-V and Bi-V (p=0.147). However, Tri-V group showed significant lower HF hospitalization (p=0.005) than Bi-V group. The number of battery exchange was not significantly different between Tri-V than Bi-V group (1.4±0.7 vs. 1.2±0.8, p=0.361). Conclusion CRT with Tri-V, characterized by stable lead parameters, appears to offer greater long-term benefits than Bi-V in terms of clinical status without excessive battery exchanges.figure

Cardiac resynchronization therapy in adult congenital heart disease: single center cohort study

Abstract Introduction Cardiac resynchronization therapy (CRT) is a recommended therapeutic measure for patients with heart failure. Heart failure is a major morbidity amongst patients with adult congenital heart disease (ACHD). However, the data on the efficacy and safety of CRT amongst ACHD is limited. Methods Data was analyzed from a retrospective cohort of patients with a known diagnosis of ACHD and implantation of CRT between 2015-2022. The primary outcome was echocardiographic response to CRT. This was defined as either:1) an increase in systemic ventricular ejection fraction (EF) of ≥5% in patients with EF <50% (therapeutic) or 2) maintenance of EF in patients with EF≥50% (preventative). Secondary outcomes included change in QRS duration, heart failure admissions, death and CIED (cardiovascular implantable electronic devices) infection during follow up. The outcomes were also assessed by subgroup of systemic left or right ventricle systemic ventricle. Results Our cohort included 46 patients, 96% male and average age was 54±14 years. 26 patients had a systemic left ventricle (56.6%) and 20 patients had a systemic right ventricle (44.4%). The indication for CRT implantation was 1) Reduced EF with wide QRS (n=10, 22%), 2) Reduced EF and RV (right ventricular) pacing (n=22, 49%), and 3) Normal EF with RV pacing (n=14, 33%). 25 patients (55%) had an implanted defibrillator at baseline. Primary outcome amongst patients with preserved EF at baseline was achieved in 22/32 patients (68.7%) and was achieved in 12/14 patients (85.7%) amongst patients with reduced EF at baseline. During follow up, QRS duration was shortened in 68.7%, 13 patients had heart failure admissions (30%), 4 patients underwent heart transplants/mechanical support device implantation (8.6%), death occurred in 11 patients (24%) and 3 had CIED infection (7%). There was no significant difference in complication or efficacy rates between the left systemic and right systemic group. Conclusion CRT is effective in patients with ACHD both as a therapeutic and as a preventative measure for heart failure. There was no difference in clinical response to CRT between patients with SRV compared to SLV. The percentage of patients with a safety outcome was relatively high in this subpopulation due to advanced ACHD.

Comparative study of the effects of preferential left ventricular and biventricular pacing on echocardiographic and cardiorespiratory indices and clinical status of heart failure patients: preliminary

Abstract Introduction Nonresponse to cardiac resynchronization therapy (CRT) has been related with right ventricular dysfunction. Preferential left ventricular pacing (pLV-P) can achieve left ventricle resynchronization allowing for intrinsic activation of the right side, and benefit cardiac output while reducing atrial fibrillation occurrence. Moreover, the AdaptivCRT® algorithm also automatically adjusts interventricular (V-V) delay every minute. Methods We evaluated the effects of a pLVP algorithm on 100 systolic heart failure patients ( all Caucasians, 49% male; 67 +/- 8 years old; 51% ischemic cardiomyopathy; 44% diabetics; NYHA II-III) following randomization to standard biventricular pacing and pLVP, on echocardiographic and cardiopulmonary exercise test indices of functional status. Device programming was based on echocardiography-evaluated maximization of stroke volume and subsequent interventricular and atrioventricular delay adjustments delegated to the device. The follow-up consisted of 6 and 12-months visits; after the 1rst month of optimizing maximum CRT response. Results Significant comparative effects of pLV-P over optimized CRT were noted regarding right ventricle systolic velocity in TDI at 12-months from baseline (mean (SE); 4.5(0.8), p=0.035); decrease in end-diastolic volume of left ventricle (mean (SE); 11.33(7), p=0.035); decrease in right ventricle strain mean ((SE); 9.2(2.1), p=0.03). According to other echocardiographic indices, again taking into account baseline levels, patients in pLV-P group exhibited lower E/e value at 6-months (mean (SE); 8.390(4,3), p=0.04), and at 12 -months (mean (SE); 7.45(3.9), p=0.035); improved values in left atrium contractility strain at 12-months (mean (SE); 8.390(0.8), p=0.04); a borderline improvement in left ventricular ejection fraction (mean (SE); 8.7(433), p=0.05) at 12-months; and borderline improvement in left ventricular longitudinal strain at 6-months (mean (SE); 4.9(2.6), p=0.035), compared to optimized CRT. In CPET, taking into account baseline levels, patients in the pLVP group showed higher METs at 12-months (mean (SE); 1,16(0.8), p=0.03) compared to opt CRT group; higher predicted Ventilation rate (%) even from 6-months (mean (SE); 8.167(5,7), p=0.03) and higher predicted peak VO2 (%) at 6 months (mean (SE); 34,13(14), p=0.03) and borderline significance at 12 months (mean (SE); 4.88(3), p=0.08), compared to opt CRT. Conclusions In the preliminary findings of READAPT study, it seems that pLVP optimized by a standardized echocardiographic protocol in patients with preserved AV conduction and LBBB, can achieve improvement in parameters of right ventricular and left atrium structure and function, as well as in survival-predictive parameters of CPET compared to optimized CRT during the 12-months of follow-up.

Implementing dynamic atrioventricular delay optimization for cardiac resynchronization therapy: an economic analysis in the EU5 countries

Abstract Background Heart failure (HF) poses an escalating public health challenge, contributing significantly to patient morbidity, mortality and healthcare expenditures [1,2]. Cardiac resynchronization therapy (CRT) is a well-established intervention that improves functional capacity and enhances quality of life while mitigating symptoms, hospitalizations, and mortality in HF patients [3]. Nevertheless, the reaction to CRT varies among individuals; some experience positive responses and others show resistance to the therapy, with unfavourable outcomes and increased healthcare costs [4]. The introduction of the dynamic atrioventricular (AV) optimization algorithm aims to enhance CRT response by enabling dynamic optimization of the AV delay [4]. Purpose Despite the strong clinical evidence supporting the effectiveness of dynamic AV optimization algorithm, a comprehensive assessment of its economic implications is still lacking. This study aims to evaluate the economic impact of activating dynamic AV optimization algorithm in patients undergoing CRT treatment across the Big 5 European countries (EU5; France, Germany, Spain, Italy, and the UK). Methods The study examines two scenarios over a 3-year timeframe: a) current scenario, where dynamic AV optimization algorithm activation is limited to a small segment of the population, and b) future scenario, where dynamic AV optimization algorithm activation is progressively expanded per year from 15% to 50%. Treatment efficacy data, measured in terms of HF hospitalization and mortality rates, were sourced from Varma et al. studies [1,4]. Hospitalization and mortality costs were extracted from national DRG tariffs and relevant literature [5–14]. It is important to note that there is no additional cost for algorithm activation if the device is already equipped with it. Results In this hypothetical analysis of 1,000 patients, around 30% undergo CRT implantation compatible with dynamic AV optimization algorithm activation. The treatment cost of patients with the algorithm ON is reduced by -15% compared to patients with the algorithm OFF, considering a weighted average across the EU5 countries (France: -11%, Germany: -16%, Italy: -14%, Spain -17%, UK: -16%), as shown in Table 1. The steady increase in algorithm activation led to an annual expenditure reduction equal to €21,109, calculated on the weighted average across the EU5 countries (France: €15,549, Germany: €33,753, Italy: €13,844, Spain: €20,385, UK: £13,423). When compared to the current scenario, the future scenario saved €36,468 on average across the EU5 countries. Further country-specific cost savings are shown in Table 2. Conclusion The conducted economic analysis gives confidence in dynamic AV optimization algorithm, positioning it as a valuable and economically sustainable asset for enhancing CRT treatment outcomes in patients with HF.

The implementation of speckle tracking echocardiography for cardiac resynchronization therapy optimization. A rotational myocardial mechanics interpretation

Abstract Background Cardiac resynchronization therapy (CRT) has an additive therapeutic influence on left ventricular (LV) function in heart failure (HF) patients, but the underlying mechanisms through which it works are not completely explained. Our aim was to further elucidate the role of this intervention via rotational mechanics using 2D speckle tracking echocardiography (2D-STE). Methods We investigated 46 patients (65 ± 9 years) who received CRT. All enrolled patients were assessed on admission by 2D-STE and 6 min walk test (6m WT) and followed in the outpatient device clinic by 2D-STE (at one week and 6 months post-implantation) and 6m WT (at 6 months post-implantation). On their first appointment all biventricular systems were optimized by atrioventricular delay optimization and by changing the temporal activation of ventricular electrodes aiming to reach the highest effective LV stroke volume (eff SV) across all activation options. A new 2D-STE based index (twist integral – TI) targeting to assess the rotational mechanics of the whole cardiac cycle was also measured to further explain the CRT response. For the calculation of LV TI of the full cardiac cycle, serial isochronal apical and basal rotation measurements (in degrees) were exported to a worksheet Excel file and the final algebraic summation was calculated by the formula: Twist Integral = (systolic twist integral – diastolic twist integral) Σ twisti= twist1+twist2+...+twistn (table 1). Results Twenty-two (48%) patients with dilated cardiomyopathy as the predominant aetiology of HF were responders at 6-month follow-up. The commonest selected mode that was related with the greatest LV performance response was the simultaneous activation of the 2 ventricular leads (39%). The strongest predictor of CRT response was the improvement of eff SV between admission and first appointment at clinic, followed by the improvement of TI, the non-existence of CAD, and the improvement of peak systolic twist (table 2). Conclusions Additional CRT optimization via changing the temporal activation of ventricular electrodes is beneficial for LV performance in HF patients. Rotational mechanics essentially explain the beneficial CRT contribution to these patients.

Optimizing patient selection for cardiac resynchronization therapy in a multicenter study of Japanese patients: assessment of the MADIT-ICD benefit group

Abstract Background The MADIT-ICD benefit group, derived from ventricular tachycardia (VT)/ventricular fibrillation (VF) scores and non-arrhythmic mortality scores (Table 1), facilitates the appropriate selection of candidates for implantable cardioverter-defibrillator (ICD) therapy. While the 2021 European Society of Cardiology Guidelines have discussed the advantages and considerations of adding a defibrillator in patients undergoing cardiac resynchronization therapy (CRT), the optimal selection of CRT with or without a defibrillator remains unclear, particularly in Asian populations. This is especially relevant for primary prevention using ICD, which is characterized by fewer cases of ischemic etiology compared to Western countries. Purpose This study aimed to evaluate the utility of the MADIT-ICD benefit group in Japanese CRT patients and identify key indicators for determining the necessity of CRT with or without a defibrillator. Methods We conducted a retrospective, multicenter evaluation of 505 consecutive Japanese CRT patients enrolled between 2012 and 2020. Among these patients, 76% were male, with a mean age of 65 years and a mean body mass index of 22.5 kg/m2. Ischemic etiology was present in 25% of patients, with 20% undergoing secondary prevention. The study assessed the cumulative incidences of VT/VF and non-arrhythmic mortality based on the MADIT-ICD benefit group (lowest, intermediate, and highest). Predictors for each outcome were explored, and the MADIT-ICD benefit group was validated in the Japanese cohort. Results Of the 400 included patients, 60 (15%) were categorized into the lowest MADIT-ICD benefit group, 279 (70%) into the intermediate group, and 61 (15%) into the highest group. Over a median follow-up period of 34 months, VT/VF occurred in 4 (13%), 68 (24%), and 14 (23%) patients in the lowest, intermediate, and highest benefit groups, respectively (Gray’s test, P = 0.027, Figure 1A). Non-arrhythmic death occurred in 15 (25%), 91 (33%), and 9 (15%) patients in the lowest, intermediate, and highest benefit groups, respectively (Log-rank test, P = 0.025, Figure 1B). Multivariable analysis identified MADIT-ICD VT/VF score (hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.12-1.35; P < 0.001) and left bundle branch block (LBBB) (HR 0.48; 95% CI 0.27-0.86; P = 0.014) as significant predictors for VT/VF, while MADIT-ICD non-arrhythmic mortality score (HR 1.16; 95% CI 1.07-1.27; P < 0.001), serum creatinine (Cr) (HR 1.28; 95% CI 1.13-1.45; P < 0.001), and mineral corticoid receptor antagonist (MRA) use (HR 1.84; 95% CI 1.21-2.79; P = 0.004) were significant predictors for non-arrhythmic death (Table 2). Conclusion The MADIT-ICD benefit group, in conjunction with left bundle branch block and renal function, may serve as valuable predictors for determining the necessity of cardioverter-defibrillator therapy in Japanese CRT patients.Table 1 and Figure 1

Impact of left ventricular lead position on echocardiographic response after upgrading from right to biventricular pacing - Insights from the BUDAPEST CRT Upgrade Trial

Abstract Introduction Left ventricular (LV) lead position is strongly associated with the long-term outcome of patients undergoing de novo cardiac resynchronization therapy (CRT) implantation. However, data is scarce about patients who undergo upgrade CRT from right ventricular (RV) pacing. Aims To investigate the impact of the LV lead location on the primary outcome of heart failure (HF) hospitalization, all-cause mortality, or echocardiographic reverse remodelling in the BUDAPEST CRT Upgrade trial cohort. Methods Heart failure patients with reduced ejection fraction (HFrEF), with previously implanted pacemaker (PM) or implantable cardioverter defibrillator (ICD) and intermittent or permanent RV pacing, who were randomly assigned to the CRT-D arm (n=215) and those who were cross-overs from the ICD arm (n=27) were investigated. Short-axis position (anterior / posterior / lateral) of the LV lead was assessed. Primary endpoint encompassed HF hospitalization, all-cause mortality, and the end-systolic volume (ESV) decrease less than 15% from baseline to 12 months follow-up. Echocardiographic response was evaluated by percent change of ESV and LVEF. Results LV lead location was available for 223 patients (age 72.8 ± 8 years, 14% female, 38% diabetic, 49% with prior myocardial infarction, 30% with prior ICD) with a median follow-up time of 12.4 months. There was no difference in the occurrence of the primary endpoint by the lead positions (anterior vs. lateral OR 0.33; 95%CI 0.09-1.22, p=0.10, anterior vs. posterior OR 0.58; 95%CI 0.14-2.50, p=0.47). However, LVEF change was more pronounced in those with lateral LV lead location compared with anterior position (adjusted LVEF difference 7.43%, 95%CI 1.25 – 13.62; p=0.02), while those with posterior leads did not differ from the anterior ones (adjusted LVEF difference 3.00%, 95%CI -3.92 – 9.93; p=0.39). Decrease in ESV was also more remarkable with a lateral position as compared to the other locations (lateral vs. anterior adjusted ESV difference -0.17 mL, 95%CI -0.32 – (-0.01); p=0.03, posterior vs. anterior adjusted ESV difference -0.09 mL, 95%CI -0.26– 0.08; p=0.31). Conclusion Upgrade CRT results in better outcomes as compared to ICD alone; however, lateral LV lead position is associated with the most beneficial mid-term echocardiographic response as compared to other short-axis locations. This finding may translate into better clinical outcomes in the long term.