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.

Sites of left and right ventricular lead implantation and response to cardiac resynchronization therapy observations from the REVERSE trial.

OBJECTIVES: The objective of this study is to ascertain the effects of the left (LV) and right (RV) ventricular lead tip position in response to cardiac resynchronization therapy (CRT). BACKGROUND: The REVERSE randomized trial examined the effects of CRT in patients with asymptomatic or mildly symptomatic heart failure (HF). METHODS: We analysed data collected from the active group (CRT-ON) of REVERSE in whom the precise locations of the LV and RV ventricular lead tips were determined from postoperative chest roentgenograms as part of a prespecified sub-study. LV position was classified as lateral or non-lateral, and apical or non-apical. RV position was classified as apical or non-apical. Echocardiographic LV end-systolic volume index (LVESVi), QRS duration, and clinical outcomes at 12-24 months of follow-up were evaluated with respect to the lead tip position. The primary trial endpoint was the proportion of patients with a worsened HF clinical composite response, scored as improved, unchanged, or worsened. RESULTS: Totally 346 patients included in this analysis were followed for a median of 12.6 months (interquartile range: 11.9-23.9 months). The proportion of worsened HF clinical composite response did not correlate with lead position, whereas a significantly greater decrease in the powered secondary endpoint of LVESVi was observed with the non-apical vs. the apical LV lead positions. CRT-paced QRS duration was significantly shorter than at baseline in patients with lateral vs. non-lateral LV position, as well non-apical vs. apical LV position. The incidence of composite endpoint of death and first hospitalization for HF was lower in the LV lateral than in the non-lateral (HR 0.44; 95% CI 0.19-0.99; P= 0.04), and in the LV non-apical than in the apical group (HR 0.27; 95% CI 0.11-0.63; P= 0.001). No significant differences were observed between RV apical and non-apical positions of the lead tip. CONCLUSIONS: A more favourable outcome of CRT with regard to LV reverse remodelling and the composite of time to death or first HF hospitalization was observed when the LV lead tip was implanted in the lateral wall, away from the apex, while the position of the RV lead tip was indifferent. The long-term change in QRS duration was significantly associated with the position of the LV lead tip. ClinicalTrials.gov Identifier: NCT00271154.

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 function assessed by trans-thoracic echocardiography in patients treated by ablation for a lone paroxysmal atrial fibrillation.

AIMS: Atrial fibrillation (AF) may induce three kinds of atrial remodelling: morphological, contractile, and electrical. Maintain of sinus rhythm is usually associated with left atrial (LA) volume decrease, but little is known about the evolution of its mechanical properties. We sought to explore LA mechanical and morphological remodelling in patients with lone paroxysmal-AF treated by catheter ablation (CA). METHODS AND RESULTS: We prospectively included 31 patients (56.4 ± 10 years). We also followed 15 age- and gender-matched controls to get normal values. Each patient had a complete echocardiography at baseline and at 3-month and 1-year follow-up. LA-anatomical reverse remodelling was documented: indexed LA volume decreased from 39 mL/m(2) at baseline to 31 mL/m(2) at 1 year (P < 0.001). However, it remained larger than controls (31 vs. 23 mL/m(2), P = 0.001). LA compliance improved (LA lateral systolic peaks of strain = 50 vs. 31%, P < 0.05) without reaching controls values as estimated by 50 vs. 81%, P < 0.05). LA contractility increased as highlighted by A'-peak velocity (10 cm/s at 1Y-F/up vs. 7.5 at baseline, P = 0.01) and LA late diastolic peaks of strain rate (septal: -3 vs. -1 s(-1), lateral: -3 vs. -1.4 s(-1), P < 0.05). We show a functional remodelling at 1 year, with most contractile parameters being comparable to controls, whereas LA compliance remains significantly altered. CONCLUSION: AF-CA could reverse LA anatomical and functional remodelling. Despite improvement, LA compliance remains altered after 1 year, probably reflecting irreversible fibrosis.

Cardiac resynchronization therapy in combination with implantable cardioverter-defibrillator.

Device therapy for heart failure has a spectacular development during the last 10 years. Patients with chronic heart failure might benefit from electrical therapy with a view to: (i) resynchronize the failing and dyssynchronized heart and improve its mechanical performance or (ii) prevent the risk of sudden death by automatic defibrillation. These two therapies can be applied together with a combined device, the biventricular implantable cardioverter-defibrillator (CRT-D). Today, the proportion of CRT-D devices among all CRT devices implanted around the world is more than 75% and more than 85% in the USA. This review article will try to answer some important questions for clinical practice: is the growing use of CRT-D devices supported by clinical evidence? Is the risk-benefit profile of CRT-D favourable in particular in mildly symptomatic patients?

Responders to cardiac resynchronization therapy with narrow or intermediate QRS complexes identified by simple echocardiographic indices of dyssynchrony: the DESIRE study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is recommended for patients with NYHA class III-IV refractory heart failure (HF), ejection fraction <35% and a QRS >120 ms. We attempted to identify responders to CRT from echocardiographic (echo) indices of mechanical dyssynchrony in patients with QRS<150 ms. METHODS AND RESULTS: The study enrolled 51 men and 9 women (mean age: 64.5 years) in NYHA class III (n=54) or IV (n=6) presenting with a mean ejection fraction: 25.7%, LV end-diastolic diameter: 69.1 mm, and QRS=121+/-19 ms. All patients were implanted with a CRT system and followed for 1 year. Implantation was preceded and followed by clinical, functional and Doppler (D)-echo evaluation. The primary combined endpoint included 1) death from any cause, 2) HF-related hospitalisations, and 3) NYHA class at 6 months. Before implant, 27 patients had > or =1 echo criterion of mechanical dyssynchrony (DES+ group) and 33 had no evidence of dyssynchrony (DES- group). At 12 months, 8 patients (4 per group) had died, 7 from HF. As regards the primary endpoint at 6 months, 33 patients (55%) had improved, 10 (16%) were unchanged, and 17 (29%) had deteriorated. Clinical improvement was observed in 19 of 27 DES+ (70%), versus 14 of 33 DES- (42%) patients (P<0.04). Baseline QRS duration did not predict response to CRT. CONCLUSIONS: In this population of HF patients with QRS<150 ms, the presence of mechanical dyssynchrony at baseline D-echo examination, but not the QRS width, predicted 6-month 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.

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.

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.

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.

Cardiac resynchronisation therapy in heart failure: current status.

Cardiac resynchronization in heart failure already has a history of 12 years. However, the major advances have been the result of large multi center trials dating from 2001. In all these trials patients with a LVEF < or = 35% were included, and a QRS above 120 msec. Follow up was from 3-36 months. The majority of these trials showed a positive effect in reduction of composite and points of death or hospitalization for major cardiovascular events. Many of these trials also showed a diminution of left ventricular and systolic diameter or volume. Even in NYHA class II patients an improvement was seen. Some unanswered questions still remain as regards the agreement on electrical or electromechanical dyssynchrony criteria. There is a number of patients with "wide" QRS who do not improve and conversely a number of patients with a narrow QRS who witness improvement. The benefit in patients with atrial fibrillation also remains unanswered. Finally the value of this modality in patients with mild heart failure or asymptomatic left ventricular systolic dysfunction, NYHA class I-II remains to be determined in large on going trials. Another question is whether biventricular or left ventricular patient is preferable. Finally whether biventricular patient should be complemented by a defibrillator insertion is being currently studied. Cardiac resynchronization therapy along or in combination with an ICD improves symptoms, reduces major morbidity and mortality in patients with a left ventricular EF<35%, ventricular dilatation and a QRS > or = 120 msec in NYHA class III-IV. Further indications are currently being examined.

A randomized comparison of permanent septal versus apical right ventricular pacing: short-term results.

OBJECTIVES: This study compared chronic right ventricular (RV) pacing at the septum versus apex. BACKGROUND: Chronic RV apical pacing may be detrimental to ventricular function. This randomized, pilot study examined whether, compared with apical, permanent septal pacing preserves cardiac function. METHODS: Ablation of the atrioventricular junction for permanent AF, followed by implantation of a DDDR pacemaker connected to two ventricular leads was performed in 28 patients. One lead screwed into the septum and another placed at the apex were connected to the atrial and ventricular port, respectively. Septum or apex was paced by programming AAIR or VVIR modes, respectively. Patients were randomly assigned, 4 months later, to pacing at one site for 3 months, and crossed over to the other for 3 months. New York Heart Association class, QRS width and axis, left ventricular ejection fraction (LVEF), exercise duration, and peak oxygen uptake were measured. Results in patients with LVEF > 45% and < or = 45% were compared. RESULTS: Septal pacing was associated with shorter QRS (145 +/- 4 msec vs 170 +/- 4 msec, P < 0.01) and normal axis (40 degrees +/- 10 degrees vs -71 +/- 4 degrees , P < 0.01). At 3 months, among patients with baseline LVEF < or = 45%, LVEF was 42 +/- 5% after septal pacing versus 37 +/- 4% after apical pacing (P < 0.001). CONCLUSION: In contrast to RV apical pacing, chronic RV septal pacing preserved LVEF in patients with baseline LVEF < or = 45%.