Cardiac Magnetic Resonance Identifies Responders to Cardiac Resynchronization Therapy with an Assessment of Septal Scar and Left Ventricular Dyssynchrony.

Background: The response to cardiac resynchronization therapy (CRT) depends on septal viability and correction of abnormal septal motion. This study investigates if cardiac magnetic resonance (CMR) as a single modality can identify CRT responders with combined imaging of pathological septal motion (septal flash) and septal scar. Methods: In a prospective, multicenter, observational study of 136 CRT recipients, septal scar was assessed using late gadolinium enhancement (LGE) (n = 127) and septal flash visually from cine CMR sequences. The primary endpoint was CRT response, defined as ≥15% reduction in LV end-systolic volume with echocardiography after 6 months. The secondary endpoint was heart transplantation or death of any cause assessed after 39 ± 13 months. Results: Septal scar and septal flash were independent predictors of CRT response in multivariable analysis (both p < 0.001), while QRS duration and morphology were not. The combined approach of septal scar and septal flash predicted CRT response with an area under the curve of 0.86 (95% confidence interval (CI): 0.78-0.94) and was a strong predictor of long-term survival without heart transplantation (hazard ratio 0.27, 95% CI: 0.10-0.79). The accuracy of the approach was similar in the subgroup with intermediate (130-150 ms) QRS duration. The combined approach was superior to septal scar and septal flash alone (p < 0.01). Conclusions: The combined assessment of septal scar and septal flash using CMR as a single-image modality identifies CRT responders with high accuracy and predicts long-term survival.

Scar imaging in the dyssynchronous left ventricle: Accuracy of myocardial metabolism by positron emission tomography and function by echocardiographic strain.

PURPOSE: Response to cardiac resynchronization therapy (CRT) is reduced in patients with high left ventricular (LV) scar burden, in particular when scar is located in the LV lateral wall or septum. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can identity scar, but is not feasible in all patients. This study investigates if myocardial metabolism by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contractile function by echocardiographic strain are alternatives to LGE-CMR. METHODS: In a prospective multicenter study, 132 CRT candidates (91% with left bundle branch block) were studied by speckle tracking strain echocardiography, and 53 of these by FDG-PET. Regional myocardial FDG metabolism and peak systolic strain were compared to LGE-CMR as reference method. RESULTS: Reduced FDG metabolism (<70% relative) precisely identified transmural scars (≥50% of myocardial volume) in the LV lateral wall, with area under the curve (AUC) 0.96 (95% confidence interval (CI) 0.90-1.00). Reduced contractile function by strain identified transmural scars in the LV lateral wall with only moderate accuracy (AUC = 0.77, CI 0.71-0.84). However, absolute peak systolic strain >10% could rule out transmural scar with high sensitivity (80%) and high negative predictive value (96%). Neither FDG-PET nor strain identified septal scars (for both, AUC < 0.80). CONCLUSIONS: In CRT candidates, FDG-PET is an excellent alternative to LGE-CMR to identify scar in the LV lateral wall. Furthermore, preserved strain in the LV lateral wall has good accuracy to rule out transmural scar. None of the modalities can identify septal scar. CLINICAL TRIAL REGISTRATION: The present study is part of the clinical study "Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy (CRID-CRT)", which was registered at clinicaltrials.gov (identifier NCT02525185).

Determinants of LV dP/dtmax and QRS duration with different fusion strategies in cardiac resynchronisation therapy.

BACKGROUND: We designed this study to assess the acute effects of different fusion strategies and left ventricular (LV) pre-excitation/post-excitation on LV dP/dtmax and QRS duration (QRSd). METHODS: We measured LV dP/dtmax and QRSd in 19 patients having cardiac resynchronisation therapy (CRT). Two groups of biventricular pacing were compared: pacing the left ventricle (LV) with FUSION with intrinsic right ventricle (RV) activation (FUSION), and pacing the LV and RV with NO FUSION with intrinsic RV activation. In the NO FUSION group, the RV was paced before the expected QRS onset. A quadripolar LV lead enabled distal, proximal and multipoint pacing (MPP). The LV was stimulated relative in time to either RV pace or QRS-onset in four pre-excitation/post-excitation classes (PCs). We analysed the interactions of two groups (FUSION/NO FUSION) with three different electrode configurations, each paced with four different degrees of LV pre-excitation (PC1-4) in a statistical model. RESULTS: LV dP/dtmax was higher with NO FUSION than with FUSION (769±46 mm Hg/s vs 746±46 mm Hg/s, p<0.01), while there was no difference in QRSd (NO FUSION 156±2 ms and FUSION 155±2 ms). LV dP/dtmax and QRSd increased with LV pre-excitation compared with pacing timed to QRS/RV pace-onset regardless of electrode configuration. Overall, pacing LV close to QRS-onset (FUSION) with MPP shortened QRSd the most, while LV dP/dtmax increased the most with LV pre-excitation. CONCLUSION: We show how a beneficial change in QRSd dissociates from the haemodynamic change in LV dP/dtmax with different biventricular pacing strategies. In this study, LV pre-excitation was the main determinant of LV dP/dtmax, while QRSd shortens with optimal resynchronisation.

Septal contraction predicts acute haemodynamic improvement and paced QRS width reduction in cardiac resynchronization therapy.

AIMS: Three distinct septal contraction patterns typical for left bundle branch block may be assessed using echocardiography in heart failure patients scheduled for cardiac resynchronization therapy (CRT). The aim of this study was to explore the association between these septal contraction patterns and the acute haemodynamic and electrical response to biventricular pacing (BIVP) in patients undergoing CRT implantation. METHODS AND RESULTS: Thirty-eight CRT candidates underwent speckle tracking echocardiography prior to device implantation. The patients were divided into two groups based on whether their septal contraction pattern was indicative of dyssynchrony (premature septal contraction followed by various amount of stretch) or not (normally timed septal contraction with minimal stretch). CRT implantation was performed under invasive left ventricular (LV) pressure monitoring and we defined acute CRT response as ≥10% increase in LV dP/dtmax. End-diastolic pressure (EDP) and QRS width served as a diastolic and electrical parameter, respectively. LV dP/dtmax improved under BIVP (737 ± 177 mmHg/s vs. 838 ± 199 mmHg/s, P < 0.001) and 26 patients (68%) were defined as acute CRT responders. Patients with premature septal contraction (n = 27) experienced acute improvement in systolic (ΔdP/dtmax: 18.3 ± 8.9%, P < 0.001), diastolic (ΔEDP: -30.6 ± 29.9%, P < 0.001) and electrical (ΔQRS width: -23.3 ± 13.2%, P < 0.001) parameters. No improvement under BIVP was observed in patients (n = 11) with normally timed septal contraction (ΔdP/dtmax: 4.0 ± 7.8%, P = 0.12; ΔEDP: -8.8 ± 38.4%, P = 0.47 and ΔQRS width: -0.9 ± 11.4%, P = 0.79). CONCLUSION: Septal contraction patterns are an excellent predictor of acute CRT response. Only patients with premature septal contraction experienced acute systolic, diastolic, and electrical improvement under BIVP.

Mechanical Effects on Right Ventricular Function From Left Bundle Branch Block and Cardiac Resynchronization Therapy.

OBJECTIVES: The purpose of this study was to investigate how LBBB and CRT modify RV free wall function by direct ventricular interaction. BACKGROUND: Right ventricular (RV) function influences prognosis in patients with left bundle branch block (LBBB) and cardiac resynchronization therapy (CRT). There is, however, limited insight into how LBBB and CRT affect RV function. METHODS: In 24 patients with LBBB with nonischemic cardiomyopathy, RV and left ventricular (LV) strain by speckle-tracking echocardiography was measured before and after CRT. Underlying mechanisms were studied in 16 anesthetized dogs with ultrasonic dimension crystals and micromanometers. RESULTS: Patients with LBBB demonstrated distinct early systolic shortening in the RV free wall, which coincided with the typical abnormal early systolic septal shortening. In animals, this RV free wall contraction pattern resulted in reduced myocardial work as a large portion of the shortening occurred against low pressure during early systole, coinciding with abnormal leftward septal motion. RV systolic function was maintained by vigorous contraction in the late-activated LV lateral wall, which pushed the septum toward the RV. CRT reduced abnormal septal motion and increased RV free wall work because there was less inefficient shortening against low pressure. CONCLUSIONS: LBBB reduces workload on the RV free wall because of abnormal septal motion and delayed activation of the LV lateral wall. Restoring septal and LV function by CRT increases workload in RV free wall and may explain why patients with RV failure respond poorly to CRT. (Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy [CRID-CRT]; NCT02525185).

Regional myocardial work by cardiac magnetic resonance and non-invasive left ventricular pressure: a feasibility study in left bundle branch block.

AIMS: Regional myocardial work may be assessed by pressure-strain analysis using a non-invasive estimate of left ventricular pressure (LVP). Strain by speckle tracking echocardiography (STE) is not always accessible due to poor image quality. This study investigated the estimation of regional myocardial work from strain by feature tracking (FT) cardiac magnetic resonance (CMR) and non-invasive LVP. METHODS AND RESULTS: Thirty-seven heart failure patients with reduced ejection fraction, left bundle branch block (LBBB), and no myocardial scar were compared to nine controls without LBBB. Circumferential strain was measured by FT-CMR in a mid-ventricular short-axis cine view, and longitudinal strain by STE. Segmental work was calculated by pressure-strain analysis. Twenty-five patients underwent 18F-fluorodeoxyglucose (FDG) positron emission tomography. Segmental values were reported as percentages of the segment with maximum myocardial FDG uptake. In LBBB patients, net CMR-derived work was 51 ± 537 (mean ± standard deviation) in septum vs. 1978 ± 1084 mmHg·% in the left ventricular (LV) lateral wall (P < 0.001). In controls, however, there was homogeneous work distribution with similar values in septum and the LV lateral wall (non-significant). Reproducibility was good. Segmental CMR-derived work correlated with segmental STE-derived work and with segmental FDG uptake (average r = 0.71 and 0.80, respectively). CONCLUSION: FT-CMR in combination with non-invasive LVP demonstrated markedly reduced work in septum compared to the LV lateral wall in patients with LBBB. Work distribution correlated with STE-derived work and energy demand as reflected in FDG uptake. These results suggest that FT-CMR in combination with non-invasive LVP is a relevant clinical tool to measure regional myocardial work.

Mechanism of Abnormal Septal Motion in Left Bundle Branch Block: Role of Left Ventricular Wall Interactions and Myocardial Scar.

OBJECTIVES: This study sought to investigate how regional left ventricular (LV) function modifies septal motion in left bundle branch block (LBBB). BACKGROUND: In LBBB, the interventricular septum often has marked pre-ejection shortening, followed by immediate relengthening (rebound stretch). This motion, often referred to as septal flash, is associated with positive response to cardiac resynchronization therapy (CRT). METHODS: In 10 anesthetized dogs, we induced LBBB by radiofrequency ablation and occluded the circumflex (CX) (n = 10) and left anterior descending (LAD) (n = 6) coronary arteries, respectively. Myocardial dimensions were measured by sonomicrometry and myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB, including 20 with post-infarct scar and 20 with nonischemic cardiomyopathy, myocardial strain was measured by speckle-tracking echocardiography and myocardial work by pressure-strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late gadolinium enhancement. RESULTS: During LBBB, each animal showed typical septal flash with pre-ejection shortening and rebound stretch, followed by reduced septal systolic shortening (p < 0.01). CX occlusion caused LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch (p < 0.0001). Furthermore, CX occlusion restored septal systolic shortening to a similar level as before induction of LBBB and substantially improved septal work (p < 0.001). LAD occlusion, however, accentuated septal flash by increasing rebound stretch (p < 0.05). Consistent with the experimental findings, septal flash was absent in patients with LV lateral wall scar due to lack of rebound stretch (p < 0.001), and septal systolic shortening and septal work far exceeded values in nonischemic cardiomyopathy (p < 0.0001). Septal flash was present in most patients with anteroseptal scar. CONCLUSIONS: LV lateral wall dysfunction and scar abolished septal flash and markedly improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should be taken into account when septal motion is used to evaluate dyssynchrony.

Afterload Hypersensitivity in Patients With Left Bundle Branch Block.

OBJECTIVES: This study sought to investigate the hypothesis that patients with left bundle branch block (LBBB) are hypersensitive to elevated afterload. BACKGROUND: Epidemiological data suggest that LBBB can provoke heart failure in patients with hypertension. METHODS: In 11 asymptomatic patients with isolated LBBB and 11 age-matched control subjects, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were measured by echocardiography. Systolic arterial pressure was increased by combining pneumatic extremity constrictors and handgrip exercise. To obtain more insight into mechanisms of afterload response, 8 anesthetized dogs with left ventricular (LV) micromanometer and dimension crystals were studied during acutely induced LBBB and aortic constriction. Regional myocardial work was assessed by LV pressure-dimension analysis. RESULTS: Consistent with normal afterload dependency, elevation of systolic arterial pressure by 38 ± 12 mm Hg moderately reduced LVEF from 60 ± 4% to 54 ± 6% (p < 0.01) in control subjects. In LBBB patients, however, a similar blood pressure increase caused substantially larger reduction in LVEF (p < 0.01), from 56 ± 6% to 42 ± 7% (p < 0.01). There were similar findings for GLS. In the dog model, aortic constriction abolished septal shortening (p < 0.02), and septal work decreased to negative values (p < 0.01). Therefore, during elevated systolic pressure, the septum made no contribution to global LV work, as indicated by net negative work, and instead absorbed energy from work done by the LV lateral wall. CONCLUSIONS: Moderate elevation of arterial pressure caused marked reductions in LVEF and GLS in patients with LBBB. This reflects a cardiodepressive effect of elevated afterload in the dyssynchronous ventricle and was attributed to loss of septal function.

Left ventricular end-systolic volume is a more sensitive marker of acute response to cardiac resynchronization therapy than contractility indices: insights from an experimental study.

AIMS: There are conflicting data and no consensus on how to measure acute response to cardiac resynchronization therapy (CRT). This study investigates, which contractility indices are best markers of acute CRT response. METHODS AND RESULTS: In eight anaesthetized dogs with left bundle branch block, we measured left ventricular (LV) pressure by micromanometer and end-diastolic volume (EDV) and end-systolic volume (ESV) by sonomicrometry. Systolic function was measured as LV ejection fraction (EF), peak rate of LV pressure rise (LV dP/dtmax) and as a gold standard of contractility, LV end-systolic elastance (Ees), and volume axis intercept (V0) calculated from end-systolic pressure-volume relations (ESPVR). Responses to CRT were compared with inotropic stimulation by dobutamine. Both CRT and dobutamine caused reduction in ESV (P < 0.01) and increase in LV dP/dtmax (P < 0.05). Both interventions shifted the ESPVR upwards indicating increased contractility, but CRT which reduced V0 (P < 0.01), caused no change in Ees. Dobutamine markedly increased Ees, which is the typical response to inotropic stimulation. Preload (EDV) was decreased (P < 0.01) by CRT, and there was no change in EF. When adjusting for the reduction in preload, CRT increased EF (P = 0.02) and caused a more marked increase in LV dP/dtmax (P < 0.01). CONCLUSION: Increased contractility by CRT could not be identified by Ees, which is a widely used reference method for contractility. Furthermore, reduction in preload by CRT attenuated improvement in contractility indices such as EF and LV dP/dtmax. These results suggest that changes in LV volume may be more sensitive markers of acute CRT response than conventional contractility indices.

Contractility surrogates derived from three-dimensional lead motion analysis and prediction of acute haemodynamic response to CRT.

Background: Patient-specific left ventricular (LV) lead optimisation strategies with immediate feedback on cardiac resynchronisation therapy (CRT) effectiveness are needed. The purpose of this study was to compare contractility surrogates derived from biventricular lead motion analysis to the peak positive time derivative of LV pressure (dP/dtmax) in patients undergoing CRT implantation. Methods: Twenty-seven patients underwent CRT implantation with continuous haemodynamic monitoring. The right ventricular (RV) lead was placed in apex and a quadripolar LV lead was placed laterally. Biplane fluoroscopy cine films facilitated construction of three-dimensional RV-LV interlead distance waveforms at baseline and under biventricular pacing (BIVP) from which the following contractility surrogates were derived; fractional shortening (FS), time to peak systolic contraction and peak shortening of the interlead distance (negative slope). Acute haemodynamic CRT response was defined as LV ∆dP/dtmax ≥ 10 %. Results: We observed a mean increase in dP/dtmax under BIVP (899±205 mm Hg/s vs 777±180 mm Hg/s, p<0.001). Based on ΔdP/dtmax, 18 patients were classified as acute CRT responders and nine as non-responders (23.3%±10.6% vs 1.9±5.3%, p<0.001). The baseline RV-LV interlead distance was associated with echocardiographic LV dimensions (end diastole: R=0.61, p=0.001 and end systole: R=0.54, p=0.004). However, none of the contractility surrogates could discriminate between the acute CRT responders and non-responders (ΔFS: -2.5±2.6% vs - 2.0±3.1%, p=0.50; Δtime to peak systolic contraction: -9.7±18.1% vs -10.8±15.1%, p=0.43 and Δpeak negative slope: -8.7±45.9% vs 12.5±54.8 %, p=0.09). Conclusion: The baseline RV-LV interlead distance was associated with echocardiographic LV dimensions. In CRT recipients, contractility surrogates derived from the RV-LV interlead distance waveform could not discriminate between acute haemodynamic responders and non-responders.

Cardiac resynchronization therapy when no lateral pacing option exists: vectorcardiographic guided non-lateral left ventricular lead placement predicts acute hemodynamic response.

Aims: A difficult cardiac resynchronization therapy (CRT) implantation scenario emerges when no lateral pacing option exists. The aim of this study was to explore the effect of biventricular pacing (BIVP) on vectorcardiographic parameters in patients with a non-lateral left ventricular (LV) lead position. We hypothesized that perimeter and area reduction for both the QRS complex and T-wave would predict acute CRT response. Methods and results: Twenty-six patients (14 ischaemic) with a mean age of 63 ± 10 years and standard CRT indication underwent device implantation with continuous LV pressure registration. The LV lead was placed in either an anterior or apical position. Biventricular pacing was performed at a rate 10% above intrinsic rhythm with acute CRT response defined as LV ΔdP/dtmax >10%. Using this criterion 12 patients were identified as acute CRT responders (responders: 16.7 ± 4.8% vs. non-responders: 1.9 ± 5.3%, P < 0.001). Vectorcardiographic assessment of the QRS complex and T-wave were performed at baseline and under BIVP. Based on the observed changes in three-dimensional area and perimeter, ΔQRS-area (responders: -46.7 ± 39.6% vs. non-responders: 1.1 ± 50.9%, P = 0.006) was considered as the preferred parameter. Receiver operating characteristic curve analysis identified -40% as the optimal cut-off value (sensitivity 67% and specificity 93%) for prediction of acute CRT response (AUC = 0.81, P < 0.01). A significant correlation was observed between LV ΔdP/dtmax and ΔQRS-area (R2 = 0.37, P = 0.001). Conclusion: ΔQRS-area is correlated to LV ΔdP/dtmax and predicts acute CRT response in patients with a non-lateral LV lead position. Assessment of ΔQRS-area might be a useful tool for patient specific LV lead placement when no lateral pacing option exists.

Left ventricular markers of mortality and ventricular arrhythmias in heart failure patients with cardiac resynchronization therapy.

AIMS: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure. However, prediction of the outcome remains difficult. We aimed to investigate for echocardiographic predictors of ventricular arrhythmias and fatal outcome and to explore how myocardial function is changed by biventricular pacing in heart failure. METHODS AND RESULTS: We prospectively included 170 heart failure patients (66 ± 10 years, New York Heart Association class 2.8 ± 0.5, 48% ischaemic cardiomyopathy) and recorded ventricular arrhythmias and fatal end point defined as death, heart transplantation, or left ventricular assist device implantation during 2 years. Two-dimensional echocardiography was performed before and 6 months after CRT implantation. CRT response was defined as ≥15% reduction in end-systolic volume at 6 months. Speckle-tracking technique was performed to assess longitudinal and circumferential left ventricular function, defined as global longitudinal (GLS) and circumferential strain (GCS), and to assess mechanical dyssynchrony, defined as mechanical dispersion. GLS before CRT was a predictor of fatal end point independently of CRT response [hazard ratio, HR 1.14 (1.02-1.27), P = 0.02]. Patients with GLS better than -8.3% showed event-free survival benefit (log rank, P < 0.001). Mechanical dispersion at 6 months was an independent predictor of ventricular arrhythmias [HR 1.20 (1.06-1.35), P = 0.005]. CRT responders (59%) had improvement of both GLS and GCS. CONCLUSION: In heart failure patients with CRT, worse longitudinal function before CRT was an important predictor of fatal outcome during 2 years, independently of CRT response. Mechanical dispersion at 6 months was a strong predictor of ventricular arrhythmias. CRT response by reverse remodelling was dependent on improvement of both longitudinal and circumferential function.

A novel ECG-index for prediction of ventricular arrhythmias in patients after myocardial infarction.

BACKGROUND: Risk prediction of ventricular arrhythmias after myocardial infarction (MI) is still insufficient. Prolonged QTc is a known risk marker of mortality and ventricular arrhythmias. QTc has not achieved clinical importance in predicting arrhythmic events in patients after MI. Recent studies have displayed that the terminal part of the QT-interval, Tpeak to Tend (TpTe), may be a more promising predictor of adverse outcome. Herein, we assessed whether TpTe may serve as a predictor of ventricular arrhythmias in patients with previous MI fulfilling current implantable cardioverter-defibrillator (ICD) indications. METHODS: Seventy-six patients with previous MI eligible for ICD therapy were prospectively enrolled. ECG measurements at baseline were recorded using a 12-lead ECG with 50 mm/s paper speed. TpTe was measured from peak of the T wave to end of T wave. Events during follow up were defined as ventricular arrhythmias requiring appropriate ICD therapy, including antitachycardia pacing and shock. RESULTS: During 23 ± 19 months, arrhythmic events occurred in 36 (47%) patients. TpTe was longer in ICD patients with recorded ventricular arrhythmias compared with those without (116 ± 26 ms vs. 102 ± 20 ms; P = 0.01), whereas ejection fraction (EF) at baseline did not differ (35 ± 9% vs. 35 ± 11%; P = 0.87). TpTe was an independent predictor of ventricular arrhythmias when adjusted for age, EF and QRS duration (HR 1.16; 95% CI 1.03-1.31; P = 0.02). CONCLUSIONS: TpTe predicted malignant arrhythmias in patients after MI independently of EF. TpTe may contribute in the risk stratification of patients to identify post-MI patients disposed to malignant arrhythmias and their need of ICD therapy.

Dynamic relationship of left-ventricular dyssynchrony and contractile reserve in patients undergoing cardiac resynchronization therapy.

AIMS: Contradicting reports have been published regarding the relation between a dobutamine-induced increase in either cardiac dyssynchrony or left-ventricular ejection fraction (LVEF) and the response to cardiac resynchronization therapy (CRT). Using apical rocking (ApRock) as surrogate dyssynchrony parameter, we investigated the dobutamine stress echocardiography (DSE)-induced changes in left-ventricular (LV) dyssynchrony and LVEF and their potential pathophysiological interdependence. METHODS AND RESULTS: Fifty-eight guideline-selected CRT candidates were prospectively enrolled for low-dose DSE. Dyssynchrony was quantified by the amplitude of ApRock. An LVEF increase during stress of >5% was regarded significant. Scar burden was assessed by magnetic resonance imaging. Mean follow-up after CRT implantation was 41 ± 13 months for the occurrence of cardiac death. ApRock during DSE predicted CRT response (AUC 0.88, 95% CI 0.77-0.99, P < 0.001) and correlated inversely with changes in EF (r = -0.6, P < 0.001). Left-ventricular ejection fraction changes during DSE were not associated with CRT response (P = 0.082). Linear regression analysis revealed an inverse association of LVEF changes during DSE with both, total scar burden (B = -2.67, 95CI -3.77 to -1.56, P < 0.001) and the DSE-induced change in ApRock amplitude (B = -1.23, 95% CI -1.53 to -0.94, P < 0.001). Kaplan-Meier analysis revealed that DSE-induced increase in ApRock, but not LVEF, was associated with improved long-term survival. CONCLUSION: During low-dose DSE in CRT candidates with baseline dyssynchrony, myocardial contractile reserve predominantly results in more dyssynchrony, but less in an increase in LVEF. Dyssynchrony at baseline and its dobutamine-induced changes are predictive of both response and long-term survival following CRT.

Peak oxygen uptake during cardiopulmonary exercise testing determines response to cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established treatment modality for advanced heart failure (HF) but 20-30% of patients treated with CRT do not experience clinical improvement. Hence, in this study we aimed to investigate whether baseline cardiopulmonary exercise testing (CPX) can help improve the prediction of a positive functional CRT response. METHODS: This prospective observational study included 76 HF patients undergoing elective CRT implantation and clinical CPX and echocardiographic assessment were performed at baseline, 6, and 12 months. RESULTS: Peak VO2 increased from 11.0±2.5 ml/min/kg to 12.0±4.1 ml/min/kg and 12.2±3.5 ml/min/kg at 6 and 12 months after CRT, respectively. The number of patients classified as "CRT-responders" (Δ peak VO2≥1 ml/kg/min) was 33 (46%) and 36 (52%) at 6 and 12 months after CRT, respectively. Patients with baseline peak VO2<40% of predicted (lowest tertile) demonstrated a 68% and 69% response rate at 6 and 12 months, respectively, as compared to a 35% and 42% response rate among patients with baseline peak VO2≥40% of predicted (p=0.01 and p=0.02, respectively). In multivariate analysis patients with baseline peak VO2<40% of predicted had an adjusted odds ratio of 4.4 (95% CI 1.6-12.5; p<0.01) and 3.1 (95% CI 1.1-8.8; p=0.03) for positive CRT response at 6 and 12 months, respectively. CONCLUSIONS: Treatment with CRT improves exercise capacity but this increase is most substantial among patients with a lower baseline peak VO2 (% of predicted). Baseline CPX can, therefore, be utilized to identify patients more likely to exhibit a functional improvement after CRT.

Prognostic value of cardiac troponin T in patients with moderate to severe heart failure scheduled for cardiac resynchronization therapy.

BACKGROUND: Predicting response to cardiac resynchronization therapy (CRT) is challenging. Highly sensitive cardiac troponin T (hsTnT) might predict response to CRT and identify patients at a high risk of experiencing severe cardiovascular events. We investigated whether baseline levels of hsTnT were associated with response to CRT and with severe cardiovascular events after long-term follow-up. METHODS: Eighty-one consecutive patients were included according to the current guidelines for CRT. Biochemical, functional, and clinical parameters were assessed at baseline and at 3, 6, and 12 months of follow-up; and mortality/cardiac transplantation after 46 ± 6 months of follow-up was investigated. Cardiac magnetic resonance imaging and echocardiography were used to assess left ventricular function including viability and remodeling. RESULTS: Seventy-five patients completed 12 months of follow-up; and after a follow-up of 46 ± 6 months, a total of 15 patients died, 13 of these from cardiovascular causes, and 7 underwent heart transplantation. Baseline hsTnT <15 ng/L predicted response to CRT and was associated with a more favorable outcome with regard to severe cardiovascular events. Multivariate analysis found that presence of transmural scar tissue/fibrosis on magnetic resonance imaging and use of statins were independently associated with higher concentrations of hsTnT at baseline. There was a strong correlation between hsTnT and N-terminal pro-B-type natriuretic peptide levels. CONCLUSIONS: Highly sensitive TnT levels were elevated in the majority of heart failure patients who were scheduled for CRT. The HsTnT levels predicted response to CRT as well as long-time survival.

Right ventricular mechanical dispersion is related to malignant arrhythmias: a study of patients with arrhythmogenic right ventricular cardiomyopathy and subclinical right ventricular dysfunction.

AIMS: We evaluated if right ventricular (RV) mechanical dispersion by strain was related to ventricular arrhythmias (VT/VF) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and if mechanical dispersion was increased in so far asymptomatic mutation carriers. METHODS AND RESULTS: We included 69 patients, 42 had symptomatic ARVC and 27 were mutation positive asymptomatic family members. Forty healthy individuals served as controls. Myocardial strain was assessed in 6 RV and 16 left ventricular (LV) segments. Contraction duration (CD) in 6 RV and 16 LV segments were measured as the time from onset R on electrocardiogram to maximum myocardial shortening in each segment. The standard deviation of CD was defined as mechanical dispersion. Mechanical dispersion was more pronounced in ARVC patients with arrhythmias compared with asymptomatic mutation carriers and healthy individuals in RV [52(41,63) vs. 35(23,47) vs. 13(9,19)ms, P < 0.001]. Mechanical dispersion was more pronounced in asymptomatic mutation carriers compared with healthy individuals (P < 0.001). Right ventricular mechanical dispersion predicted VT/VF in a multivariate logistic regression analysis [odds ratio (OR), 1.66 (95% confidence interval (CI) 1.06-2.58), P < 0.03]. Right ventricular and LV function by strain were reduced in symptomatic ARVC patients and correlated significantly (R = 0.81, P < 0.001). Right ventricular and LV strain were reduced in asymptomatic mutation carriers compared with healthy individuals (P < 0.001). CONCLUSION: Right ventricular mechanical dispersion was pronounced in patients with ARVC with VT/VF. Right ventricular mechanical dispersion was present in asymptomatic mutation carriers and may be helpful in risk stratification. Right ventricular and LV function correlated in ARVC patients implying that ARVC is a biventricular disease.

Mechanisms of abnormal systolic motion of the interventricular septum during left bundle-branch block.

BACKGROUND: In a majority of patients with left bundle-branch block (LBBB), there is abnormal leftward motion of the interventricular septum during the preejection phase. This motion was considered to be passive, caused by early rise in right ventricular (RV) pressure, and has therefore been excluded from most indices of left ventricular (LV) dyssynchrony. If considered active, however, the leftward motion reflects onset of septal activation and should be included. We therefore investigated if the motion was a passive response to pressure changes or caused by active contraction. METHODS AND RESULTS: LBBB was induced in 8 anesthetized dogs with micromanometers. Cardiac dimensions were measured by sonomicrometry and echocardiography. Induction of LBBB resulted in preejection leftward motion of the septum, simultaneously with shortening of septal segments (P<0.01). In each experiment, preejection septal shortening occurred against rising LV pressure, consistent with active contraction. Furthermore, the LV pressure-segment length relationships were shifted upward (P<0.01) relative to the passive elastic curve, indicating stiffening of septal myocardium, confirming an active mechanism. Initially, RV pressure increased faster than LV pressure, suggesting that the leftward septal motion may have a passive pressure component. However, the passive component appeared to play a minor role. The magnitude of preejection septal shortening was modified by load alterations. CONCLUSIONS: Leftward preejection motion of the septum during LBBB is mainly a result of active septal contraction, whereas alterations in diastolic ventricular pressures modulate the amplitude of this motion. The findings imply that the preejection phase should be included when assessing LV dyssynchrony.

Evaluation of left ventricular dyssynchrony by onset of active myocardial force generation: a novel method that differentiates between electrical and mechanical etiologies.

BACKGROUND: Better clinical tools for measuring left ventricular electrical dyssynchrony are needed. The present study investigates if onset of active myocardial force generation (AFG) may serve as a measure of electrical dyssynchrony. METHODS AND RESULTS: In anesthetized dogs, we evaluated left ventricular mechanical dyssynchrony by 2 different approaches. First, we measured timing of peak myocardial shortening velocity and strain. Second, we measured the first sign of tension development by onset AFG as defined by the myocardial pressure-segment length loop upward shift from its passive-elastic state. Electrical dyssynchrony was measured by intramyocardial electromyograms (IM-EMG). Dyssynchrony was quantified as peak intersegment time difference and as standard deviation of timing for 6 to 8 myocardial segments. During baseline, reduced preload and myocardial ischemia shortening velocity and strain indicated segmental mechanical heterogeneity, whereas onset AFG and onset R in IM-EMG indicated synchronous activation of all segments. After induction of left bundle-branch block, all methods indicated dyssynchrony. Peak intersegment time difference for shortening velocity and strain showed weak correlations (r=0.17 and 0.16) and weak agreements (mean differences, -48+/-27 ms and -28+/-27 ms, respectively) with IM-EMG. Onset AFG by pressure-segment length loops, however, correlated well with IM-EMG (r=0.93), and agreement was good (mean difference, -0.6+/-6.8 ms). Results were similar for standard deviation of timing. Onset AFG from pressure-strain analysis by echocardiography showed accuracy similar to sonomicrometry. CONCLUSIONS: Onset AFG was an accurate marker of myocardial electrical activation and was superior to shortening velocity and strain. Identification of electrical dyssynchrony by onset AFG may be feasible clinically using left ventricular pressure-strain analysis.