Stepwise application of ECG and electrogram-based criteria to ensure electrical resynchronization with left bundle branch pacing.

AIMS: To define a stepwise application of left bundle branch pacing (LBBP) criteria that will simplify implantation and guarantee electrical resynchronization. Left bundle branch pacing has emerged as an alternative to biventricular pacing. However, a systematic stepwise criterion to ensure electrical resynchronization is lacking. METHODS AND RESULTS: A cohort of 24 patients from the LEVEL-AT trial (NCT04054895) who received LBBP and had electrocardiographic imaging (ECGI) at 45 days post-implant were included. The usefulness of ECG- and electrogram-based criteria to predict accurate electrical resynchronization with LBBP were analyzed. A two-step approach was developed. The gold standard used to confirm resynchronization was the change in ventricular activation pattern and shortening in left ventricular activation time, assessed by ECGI. Twenty-two (91.6%) patients showed electrical resynchronization on ECGI. All patients fulfilled pre-screwing requisites: lead in septal position in left-oblique projection and W paced morphology in V1. In the first step, presence of either right bundle branch conduction delay pattern (qR or rSR in V1) or left bundle branch capture Plus (QRS ≤120 ms) resulted in 95% sensitivity and 100% specificity to predict LBBP resynchronization, with an accuracy of 95.8%. In the second step, the presence of selective capture (100% specificity, only 41% sensitivity) or a spike-R <80 ms in non-selective capture (100% specificity, sensitivity 46%) ensured 100% accuracy to predict resynchronization with LBBP. CONCLUSION: Stepwise application of ECG and electrogram criteria may provide an accurate assessment of electrical resynchronization with LBBP (Graphical abstract).

Plasma tissue inhibitor of matrix metalloproteinase-1 a predictor of long-term mortality in patients treated with cardiac resynchronization therapy.

AIMS: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in cardiac remodelling. Available information regarding their prognostic utility in heart failure (HF) and cardiac resynchronization therapy (CRT) is controversial. The aim of this study was to analyse MMP-2 and TIMP-1 levels as predictors of long-term mortality in HF patients treated with CRT. METHODS AND RESULTS: We prospectively included 42 consecutive patients with successfully implanted CRT. Matrix metalloproteinase-2 and TIMP-1 assays were performed prior to implant. Patients were evaluated at baseline and at the outpatient clinic at 6-month intervals. Clinical response, left ventricular (LV) remodelling, and mortality were analysed. During a mean follow-up of 60 ± 34 months, long-term mortality from any cause was 36% (15 patients). The cause of death was end stage of HF in 12 patients, sudden death in 2 patients, and 1 unknown. After adjustment using a Cox regression model, the independent predictors of long-term mortality were baseline TIMP-1, hazard ratio (HR) 1.18 (95% confidence interval (95% CI) [1.05-1.33], P = 0.007), baseline glomerular filtration rate (GFR), HR 0.97 (95% CI [0.94-1.00], P = 0.05), and permanent atrial fibrillation (AF), HR 3.14 (95% CI [1.02-9.67], P = 0.04). Area under receiver operating characteristic curve for TIMP-1 was 0.79 (95% CI [0.63-0.94]). Tissue inhibitor of matrix metalloproteinase-1 ≥ 248 ng/mL predicts mortality with 80% sensitivity and 71% specificity. CONCLUSION: Tissue inhibitor of matrix metalloproteinase-1 is a powerful predictor of long-term mortality in HF patients treated with CRT.

Longitudinal comparison of dyssynchrony correction and 'strain' improvement by conduction system pacing: LEVEL-AT trial secondary findings.

AIMS: Longitudinal dyssynchrony correction and 'strain' improvement by comparable cardiac resynchronization therapy (CRT) techniques is unreported. Our purpose was to compare echocardiographic dyssynchrony correction and 'strain' improvement by conduction system pacing (CSP) vs. biventricular pacing (BiVP) as a marker of contractility improvement during 1-year follow-up. METHODS AND RESULTS: A treatment-received analysis was performed in patients included in the LEVEL-AT trial (NCT04054895), randomized to CSP or BiVP, and evaluated at baseline (ON and OFF programming) and at 6 and 12 months (n = 69, 32% women). Analysis included intraventricular (septal flash), interventricular (difference between left and right ventricular outflow times), and atrioventricular (diastolic filling time) dyssynchrony and 'strain' parameters [septal rebound, global longitudinal 'strain' (GLS), LBBB pattern, and mechanical dispersion). Baseline left ventricular ejection fraction (LVEF) was 27.5 ± 7%, and LV end-systolic volume (LVESV) was 138 ± 77 mL, without differences between groups. Longitudinal analysis showed LVEF and LVESV improvement (P < 0.001), without between-group differences. At 12-month follow-up, adjusted mean LVEF was 46% with CSP (95% CI 42.2 and 49.3%) vs. 43% with BiVP (95% CI 39.6 and 45.8%), (P = 0.31), and LVESV was 80 mL (95% CI 55.3 and 104.5 mL) vs. 100 mL (95% CI 78.7 and 121.6 mL), respectively (P = 0.66). Longitudinal analysis showed a significant improvement of all dyssynchrony parameters and GLS over time (P < 0.001), without differences between groups. Baseline GLS significantly correlated with LVEF and LVESV at 12-month follow-up. CONCLUSION: CSP and BiVP provided similar dyssynchrony and 'strain' correction over time. Baseline global longitudinal 'strain' predicted ventricular remodelling at 12-month follow-up.

Predictors of failed left bundle branch pacing implant in heart failure with reduced ejection fraction: Importance of left ventricular diameter and QRS morphology.

BACKGROUND: Left bundle branch pacing (LBBP) is considered an alternative to cardiac resynchronization therapy (CRT). However, LBBP is not suitable for all patients with heart failure. OBJECTIVE: The aim of our study was to identify predictors of unsuccessful LBBP implantation in CRT candidates. METHODS: A cohort of consecutive patients with indications for CRT were included. Clinical, echocardiographic, and electrocardiographic variables were prospectively recorded. RESULTS: A total of 187 patients were included in the analysis. LBBP implantation was successful in 152 of 187 patients (81.2%) and failed in 35 of 187 patients (18.7%). The causes of unsuccessful implantation were unsatisfactory paced QRS morphology (28 of 35 [80%]), inability to screw the helix (4 of 35 [11.4%]), lead instability (2 of 35 [5.7%]), and high pacing thresholds (1 of 35 [2.8%]). The left ventricular end-diastolic diameter (LVEDD), non-LBBB (left bundle branch block) QRS morphology, and QRS width were predictors of failed implantation according to the univariate analysis. According to the multivariate regression analysis, LVEDD (odds ratio 1.31 per 5-mm increase; 95% confidence interval 1.05-1.63 per 5-mm increase; P = .02) and non-LBBB (odds ratio 3.07; 95% confidence interval 1.08-8.72; P = .03) were found to be independent predictors of unsuccessful LBBP implantation. An LVEDD of 60 mm has 60% sensitivity and 71% specificity for predicting LBBP implant failure. CONCLUSION: When LBBP was used as CRT, LVEDD and non-LBBB QRS morphology predicted unsuccessful implantation. Non-LBBB triples the likelihood of failed implantation independent of LVEDD. Caution should be taken when considering these parameters to plan the best pacing strategy for patients.

Noncompaction cardiomyopathy is associated with mechanical dyssynchrony: a potential underlying mechanism for favorable response to cardiac resynchronization therapy.

BACKGROUND: The aim of this study was to assess the presence of evidence of ventricular mechanical dyssynchrony in patients with isolated left ventricular noncompaction cardiomyopathy (IVNC) and the potential usefulness of cardiac resynchronization therapy (CRT) in those patients. METHODS AND RESULTS: We studied 25 patients consecutively diagnosed with IVNC and a control group of 50 patients with dilated cardiomyopathy of different etiologies. Mechanical dyssynchrony was assessed by echocardiography by the presence of a septal flash, the time from peak septal to posterior wall displacement, and the time from septal to lateral wall peak systolic velocity. Among the patients with IVNC, 9 received CRT and were followed at 12 months. Overall, dyssynchrony parameters were significantly more frequent in IVNC, regardless of QRS duration. All 9 IVNC patients treated with CRT showed a septal flash, and a favorable response was observed in 8/9 patients (89%) regardless of QRS width. CONCLUSIONS: The presence of mechanical dyssynchrony, amenable to correction with CRT, is common in patients with IVNC, independently from QRS width. This might be related to altered electrical endocardial activation associated with abnormal myocardium and could be the justification for the high response rate to CRT observed in these patients.

Conduction System Pacing vs Biventricular Pacing in Heart Failure and Wide QRS Patients: LEVEL-AT Trial.

BACKGROUND: Conduction system pacing (CSP) has emerged as an alternative to biventricular pacing (BiVP). Randomized studies comparing both therapies are scarce and do not include left bundle branch pacing. OBJECTIVES: This study aims to compare ventricular resynchronization achieved by CSP vs BiVP in patients with cardiac resynchronization therapy indication. METHODS: LEVEL-AT (Left Ventricular Activation Time Shortening with Conduction System Pacing vs Biventricular Resynchronization Therapy) was a randomized, parallel, controlled, noninferiority trial. Seventy patients with cardiac resynchronization therapy indication were randomized 1:1 to BiVP or CSP, and followed up for 6 months. Crossover was allowed when primary allocation procedure failed. Primary endpoint was the change in left ventricular activation time, measured using electrocardiographic imaging. Secondary endpoints were left ventricular reverse remodeling and the combined endpoint of heart failure hospitalization or death at 6-month follow-up. RESULTS: Thirty-five patients were allocated to each group. Eight (23%) patients crossed over from CSP to BiVP; 2 patients (6%) crossed over from BiVP to CSP. Electrocardiographic imaging could not be performed in 2 patients in each group. A similar decrease in left ventricular activation time was achieved by CSP and BiVP (-28 ± 26 ms vs -21 ± 20 ms, respectively; mean difference -6.8 ms; 95% CI: -18.3 ms to 4.6 ms; P < 0.001 for noninferiority). Both groups showed a similar change in left ventricular end-systolic volume (-37 ± 59 mL CSP vs -30 ± 41 mL BiVP; mean difference: -8 mL; 95% CI: -33 mL to 17 mL; P = 0.04 for noninferiority) and similar rates of mortality or heart failure hospitalizations (2.9% vs 11.4%, respectively) (P = 0.002 for noninferiority). CONCLUSIONS: Similar degrees of cardiac resynchronization, ventricular reverse remodeling, and clinical outcomes were attained by CSP as compared to BiVP. CSP could be a feasible alternative to BiVP. (LEVEL-AT [Left Ventricular Activation Time Shortening With Conduction System Pacing vs Biventricular Resynchronization Therapy]; NCT04054895).

Pulmonary hypertension is related to peripheral endothelial dysfunction in heart failure with preserved ejection fraction.

BACKGROUND: Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.; METHODS AND RESULTS: Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (-0.81 to 4.92) versus 5.02% (3.90 to 10.12), P=0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27-52) mm Hg, wedge capillary pressure 18 (16-22) mm Hg, pulmonary vascular resistance 362 (235-603) dyn s cm(-5). There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH (r=-0.679; P=0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure (r=0.553; P=0.014), transpulmonary gradient (r=0.560; P=0.013), and pulmonary vascular resistance (r=0.626; P=0.004). CONCLUSIONS: In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.

Complete atrioventricular block does not reduce long-term mortality in patients with permanent atrial fibrillation treated with cardiac resynchronization therapy.

AIMS: A maximum percentage of ventricular pacing is mandatory to obtain a good response to CRT. Atrioventricular junction (AVJ) ablation has been recommended to attain this objective in patients with AF. THE AIMS OF OUR STUDY WERE: (i) to determine whether the presence of complete AVJ block (induced or spontaneous) improves survival in patients with permanent AF treated with CRT and (ii) to analyse the predictors of mortality in AF patients treated with CRT. METHODS AND RESULTS: From a series of 608 patients treated with CRT in our centre from 2000 to 2011, a cohort of 155 patients with permanent AF was analysed. Patients in AF were divided into two groups, AF + AVJ block [76 (49%)] and AF non-AVJ block [79 (51%)]. Mean follow-up was 30 months (interquartile range 13-51 months). During the follow-up, 62 patients died. Overall and cardiovascular mortality were similar between both groups: hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.51-1.39, P = 0.51 and HR 0.94, 95% CI 0.52-1.68, P = 0.82. Multivariate analysis identified three independent predictors of mortality: basal NYHA functional class IV (HR 2.25, 95% CI 1.12-4.22, P = 0.03), glomerular filtration rate (HR 0.98, 95% CI 0.96-0.99, P = 0.03), and LVEF (HR 0.94, 95% CI 0.89-0.99, P = 0.02). CONCLUSIONS: AVJ block did not improve survival for patients in AF treated with CRT. Basal NYHA functional class IV, poor renal function, and LVEF were the independent predictors of mortality.

Analysis of temporal delay in myocardial deformation throughout the cardiac cycle: utility for selecting candidates for cardiac resynchronization therapy.

BACKGROUND: Analysis of myocardial strain using two-dimensional (2D) echocardiography to assess left ventricular (LV) mechanical dyssynchrony by measuring time differences in peak systolic strains from opposing LV walls has been proposed. However, peak systolic strain may be difficult to identify. OBJECTIVE: The purpose of this study was to evaluate (1) LV dyssynchrony by assessing the overlap among strain traces of the LV walls throughout the cardiac cycle and (2) its usefulness in identifying responders to cardiac resynchronization therapy (CRT). METHODS: Fifty patients with heart failure and LV systolic dysfunction undergoing CRT were studied with 2D echocardiography at baseline and 6-month follow-up. Myocardial radial strain and circumferential strain were analyzed using commercially available software. The resulting strain traces were postprocessed with a mathematical script. RESULTS: Quantification of LV dyssynchrony was expressed as an index of temporal overlap from the analyzed traces. Responders to CRT were defined by ≥15% reduction of LV end-systolic volume at 6-month follow-up. Responders to CRT had higher LV dyssynchrony in both radial strain and circumferential strain analysis. A cutoff time overlap ≥7% for radial strain (area under the curve 0.79) and ≥8.5% for circumferential strain (area under the curve 0.66) identified responders to CRT. CONCLUSION: Quantifying the temporal superposition of LV wall deformations with a computed algorithm allows measurement of LV intraventricular dyssynchrony throughout the cardiac cycle. The derived index is useful in stratifying the probability of response to CRT.

Plasma tissue inhibitor of matrix metalloproteinase-1 (TIMP-1): an independent predictor of poor response to cardiac resynchronization therapy.

AIMS: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular structural remodelling. The aim of our study was to analyse MMP-2 and TIMP-1 levels as predictors of poor response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: A cohort of 42 CRT patients from our centre was prospectively evaluated at baseline and after 12-month follow-up. MMP-2 and TIMP-1 assays were performed prior to CRT implant. Cardiac resynchronization therapy responders were defined as patients who survived, were not transplanted, and increased their basal 6 min walking distance test (6MWDT) by >or=10% or improved their NYHA functional class. Overall, 25 patients (60%) were classed as responders. At 12-month follow-up, six patients (14.2%) had died and one (2.4%) patient had been transplanted. Compared with responders, non-responders had higher levels of TIMP-1 (277 +/- 59 vs. 216 +/- 46 ng/mL, P = 0.001), MMP-2 (325 +/- 115 vs. 258 +/- 56 ng/mL, P = 0.02), and creatinine (1.76 +/- 0.8 vs. 1.25 +/- 0.3 mg/dL, P = 0.01). In a multivariate analysis, TIMP-1 was the only independent predictor of non-response to CRT [OR 0.97, 95% (CI 0.96-0.99) P = 0.005]. TIMP-1>or=248 ng/mL predicted non-response with 71% sensitivity and 72% specificity. CONCLUSION: TIMP-1 is an independent predictor of non-response in patients treated with CRT.