Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the Markers and Response to CRT (MARC) study.

Aims: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in systolic heart failure patients with ventricular conduction delay. Variability of individual response to CRT warrants improved patient selection. The Markers and Response to CRT (MARC) study was designed to investigate markers related to response to CRT. Methods and results: We prospectively studied the ability of 11 clinical, 11 electrocardiographic, 4 echocardiographic, and 16 blood biomarkers to predict CRT response in 240 patients. Response was measured by the reduction of indexed left ventricular end-systolic volume (LVESVi) at 6 months follow-up. Biomarkers were related to LVESVi change using log-linear regression on continuous scale. Covariates that were significant univariately were included in a multivariable model. The final model was utilized to compose a response score. Age was 67 ± 10 years, 63% were male, 46% had ischaemic aetiology, LV ejection fraction was 26 ± 8%, LVESVi was 75 ± 31 mL/m2, and QRS was 178 ± 23 ms. At 6 months LVESVi was reduced to 58 ± 31 mL/m2 (relative reduction of 22 ± 24%), 130 patients (61%) showed ≥ 15% LVESVi reduction. In univariate analysis 17 parameters were significantly associated with LVESVi change. In the final model age, QRSAREA (using vectorcardiography) and two echocardiographic markers (interventricular mechanical delay and apical rocking) remained significantly associated with the amount of reverse ventricular remodelling. This CAVIAR (CRT-Age-Vectorcardiographic QRSAREA -Interventricular Mechanical delay-Apical Rocking) response score also predicted clinical outcome assessed by heart failure hospitalizations and all-cause mortality. Conclusions: The CAVIAR response score predicts the amount of reverse remodelling after CRT and may be used to improve patient selection. Clinical Trials: NCT01519908.

Effects of simultaneous and optimized sequential cardiac resynchronization therapy on myocardial oxidative metabolism and efficiency.

INTRODUCTION: Cardiac resynchronization therapy (CRT) can improve left ventricular (LV) hemodynamics and function. Recent data suggest the energy cost of such improvement is favorable. The effects of sequential CRT on myocardial oxidative metabolism (MVO(2)) and efficiency have not been previously assessed. METHODS AND RESULTS: Eight patients with NYHA class III heart failure were studied 196 +/- 180 days after CRT implant. Dynamic [(11)C]acetate positron emission tomography (PET) and echocardiography were performed after 1 hour of: 1) AAI pacing, 2) simultaneous CRT, and 3) sequential CRT. MVO(2) was calculated using the monoexponential clearance rate of [(11)C]acetate (k(mono)). Myocardial efficiency was expressed in terms of the work metabolic index (WMI). P values represent overall significance from repeated measures analysis. Global LV and right ventricular (RV) MVO(2) were not significantly different between pacing modes, but the septal/lateral MVO(2) ratio differed significantly with the change in pacing mode (AAI pacing = 0.696 +/- 0.094 min(-1), simultaneous CRT = 0.975 +/- 0.143 min(-1), and sequential CRT = 0.938 +/- 0.189 min(-1); overall P = 0.001). Stroke volume index (SVI) (AAI pacing = 26.7 +/- 10.4 mL/m(2), simultaneous CRT = 30.6 +/- 11.2 mL/m(2), sequential CRT = 33.5 +/- 12.2 mL/m(2); overall P < 0.001) and WMI (AAI pacing = 3.29 +/- 1.34 mmHg*mL/m(2)*10(6), simultaneous CRT = 4.29 +/- 1.72 mmHg*mL/m(2)*10(6), sequential CRT = 4.79 +/- 1.92 mmHg*mL/m(2)*10(6); overall P = 0.002) also differed between pacing modes. Compared with simultaneous CRT, additional changes in septal/lateral MVO(2), SVI, and WMI with sequential CRT were not statistically significant on post hoc analysis. CONCLUSION: In this small selected population, CRT increases LV SVI without increasing MVO(2), resulting in improved myocardial efficiency. Additional improvements in LV work, oxidative metabolism, and efficiency from simultaneous to sequential CRT were not significant.

Cardiac resynchronization therapy improves renal function in human heart failure with reduced glomerular filtration rate.

BACKGROUND: Renal dysfunction is an important independent prognostic factor in heart failure (HF). Cardiac resynchronization therapy (CRT) improves functional status and left ventricular (LV) function in HF patients with ventricular dyssynchrony, but the impact of CRT on renal function is less defined. We hypothesized that CRT would improve glomerular filtration rate as estimated by the abbreviated Modification of Diet in Renal Disease equation (eGFR). METHODS AND RESULTS: The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study evaluated CRT in HF patients with NYHA Class III-IV, ejection fraction or=130 ms. Patients were evaluated before and 6 months after randomization to control (n = 225) or CRT (n = 228). Patients were categorized according to their baseline eGFR: >or=90 (category A), 60

Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism.

BACKGROUND: Recent studies have demonstrated increased left ventricular contractility with cardiac resynchronization therapy (CRT) using atriobiventricular stimulation. This study evaluated the effect of CRT on myocardial oxidative metabolism and efficiency. METHODS AND RESULTS: Eight patients with New York Heart Association functional class III-IV congestive heart failure were studied during atrial pacing (control) and atriobiventricular stimulation at the same rate. The monoexponential clearance rate of [11C]acetate (k(mono)) was measured with positron emission tomography to assess myocardial oxidative metabolism in the left and right ventricles (LV and RV, respectively). Myocardial efficiency was measured using the work metabolic index (WMI). Stroke volume index improved by 10% (P=0.011) with CRT, although both global LV and RV k(mono) were unchanged compared with control. Septal k(mono) increased by 15% (P=0.04), and the septal/lateral wall k(mono) ratio increased by 22% (P=0.01). WMI increased by 13% (P=0.024) with CRT. CONCLUSIONS: CRT improves LV function without increasing global LV oxidative metabolism, resulting in improved myocardial efficiency. Oxidative metabolism of the interventricular septum increases relative to the lateral wall, which suggests successful resynchronization.

Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure.

BACKGROUND: Biventricular pacing has been proposed to improve symptoms and exercise capacity in patients with advanced heart failure and wide electrocardiographic wave complexes. This study investigated the effect of biventricular pacing on reverse remodeling and the underlying mechanisms. METHODS AND RESULTS: Twenty-five patients with NYHA class III to IV heart failure and electrocardiographic wave complex duration >140 ms receiving biventricular pacing therapy were assessed serially up to 3 months after pacing and when pacing was withheld for 4 weeks. Tissue Doppler echocardiography was performed using a 6-basal, 6-mid segmental model to assess the time to peak sustained systolic contraction (T(S)). There was significant improvement of ejection fraction, dP/dt, and myocardial performance index; decrease in mitral regurgitation, left ventricular (LV) end-diastolic (205+/-68 versus 168+/-67 mL, P<0.01) and end-systolic volume (162+/-54 versus 122+/-42 mL, P<0.01); and improved 6-minute hall-walk distance and quality of life score after pacing for 3 months. The mechanisms of benefits were as follows: (1) improved LV synchrony, as evident by homogeneous delay of T(S) to a timing close to the latest (usually the lateral) segment abolishing the intersegmental difference in T(S) and decreasing the standard deviation of T(S) within the left ventricle (37.7+/-10.9 versus 29.3+/-8.3 ms, P<0.05); (2) improved interventricular synchrony; and (3) shortened isovolumic contraction time (122+/-57 versus 82+/-36 ms, P<0.05) but increased diastolic filling time. These benefits are pacing dependent, because withholding the pacing resulted in varying speeds in the loss of cardiac improvements. CONCLUSIONS: Biventricular pacing reverses LV remodeling and improves cardiac function. Improvement of LV mechanical synchrony seems to be the predominant mechanism.

Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) has recently emerged as an effective treatment for patients with moderate to severe systolic heart failure and ventricular dyssynchrony. The purpose of the present study was to determine whether improvements in left ventricular (LV) size and function were associated with CRT. METHODS AND RESULTS: Doppler echocardiograms were obtained at baseline and at 3 and 6 months after therapy in 323 patients enrolled in the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) trial. Of these, 172 patients were randomized to CRT on and 151 patients to CRT off. Measurements were made of LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, severity of mitral regurgitation (MR), peak transmitral velocities during early (E-wave) and late (A-wave) diastolic filling, and the myocardial performance index. At 6 months, CRT was associated with reduced end-diastolic and end-systolic volumes (both P<0.001), reduced LV mass (P<0.01), increased ejection fraction (P<0.001), reduced MR (P<0.001), and improved myocardial performance index (P<0.001) compared with control. beta-Blocker treatment status did not influence the effect of CRT. Improvements with CRT were greater in patients with a nonischemic versus ischemic cause of heart failure. CONCLUSIONS: CRT in patients with moderate-to-severe heart failure who were treated with optimal medical therapy is associated with reverse LV remodeling, improved systolic and diastolic function, and decreased MR. LV remodeling likely contributes to the symptomatic benefits of CRT and may herald improved longer-term survival.

Functional and echocardiographic improvement following multisite biventricular pacing for congestive heart failure.

BACKGROUND: Heart failure remains a major cause of morbidity and mortality despite advances in pharmacological treatment. Recently, multisite biventricular pacing has been used in the treatment of patients with heart failure. OBJECTIVES AND METHODS: The short and medium term effects of this treatment modality were assessed, and the association between baseline clinical characteristics and the positive response to treatment was investigated. Consecutive patients who received this treatment modality were included. They underwent comprehensive clinical and echocardiographic assessment including a 6 min walk at baseline, one month and three months. RESULTS: Between January 1998 and June 1999, 95 patients received multisite biventricular pacing therapy in the three participating hospitals. In 63 patients with complete three-month follow-ups, there were improvements from baseline to three-month follow-up in New York Heart Association heart failure (3.3 +/- 0.5 to 2.2 +/- 0.6, P<0.001) and 6 min walk (305 +/- 120 to 403 +/- 113 m, P<0.001). Significant salutary changes in echocardiographic measurements were also observed in left ventricular (LV) diastolic dimension, ejection fractions (EFs), interventricular contraction delay and severity of mitral regurgitation (MR). The 63 patients were categorized into responders (n=42) and nonresponders (n=21) based on the clinical response. Clinical characteristics were similar between the two groups. The responders had a more pronounced decrease in QRS width. An increase in LVEF and a reduction in LV diastolic dimension, interventricular mechanical delay and severity of MR were observed in the responders but not in the nonresponders. Furthermore, there was a positive association between the reduction in QRS width and the increase in LVEF. CONCLUSIONS: Cardiac resynchronization by means of multisite pacing appears to be a promising therapy in the treatment of heart failure. The salutary clinical response is associated with echocardiographic improvement.

Physical activity measured with implanted devices predicts patient outcome in chronic heart failure.

BACKGROUND: Physical activity (PA) predicts cardiovascular mortality in the population at large. Less is known about its prognostic value in patients with chronic heart failure (HF). METHODS AND RESULTS: Data from 836 patients with implantable cardioverter defibrillator without or with cardiac resynchronization therapy enrolled in the Sensitivity of the InSync Sentry OptiVol feature for the prediction of Heart Failure (SENSE-HF)(1) study and the Diagnostic Outcome Trial in Heart Failure (DOT-HF) were pooled. The devices continuously measured and stored total daily active time (single-axis accelerometer). Early PA (average daily activity over the earliest 30-day study period) was studied as a predictor of time to death or HF-related hospital admission (primary end point). Data from 781 patients were analyzed (65±10 years; 85% men; left ventricular ejection fraction, 26±7%). Older age, shorter height, ischemic cause, peripheral artery disease, atrial fibrillation, diabetes mellitus, rales, peripheral edema, higher New York Heart Association class, lower diastolic blood pressure, and no angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were associated with reduced early PA. The primary end point occurred in 135 patients (15±7 months of follow-up). In multivariable analysis including baseline variables, early PA predicted death or HF hospitalization, with a 4% reduction in risk for each 10 minutes per day additional activity (hazard ratio [HR], 0.96; confidence interval [CI], 0.94-0.98; P=0.0002 compared with a model with the same baseline variables but without PA). PA also predicted death (HR, 0.93; CI, 0.90-0.96; P<0.0001) and HF hospitalization (HR, 0.97; CI, 0.95-0.99; P=0.011). CONCLUSIONS: Early PA, averaged over a 30-day window early after defibrillator implantation or cardiac resynchronization therapy in patients with chronic HF, predicted death or HF hospitalization, as well as mortality and HF hospitalization separately, accounting for baseline HF severity. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00400985, NCT00480077.

Clinical utility of intrathoracic impedance monitoring to alert patients with an implanted device of deteriorating chronic heart failure.

AIMS: To evaluate the utility of intrathoracic impedance monitoring for detecting heart failure (HF) deterioration in patients with an implanted cardiac resynchronization/defibrillation device. METHODS AND RESULTS: Patients enrolled in the European InSync Sentry Observational Study were audibly alerted by a device algorithm if a decrease in intrathoracic impedance suggested fluid accumulation. Clinical HF status and device data were assessed at enrolment, during regular follow-up, and if patients presented with an alert or HF deterioration. Data from 373 subjects were analysed. Fifty-three alert events and a total of 53 clinical events (HF deterioration defined by worsening of HF signs and symptoms) were reported during a median of 4.2 months. Adjusted for multiple events per patient, the alert detected clinical HF deterioration with 60% sensitivity (95% CI 46-73) and with a positive predictive value of 60% (95% CI 46-73). Higher NYHA class at baseline was predictive for adequate alert events during follow-up (P < 0.05). In 11 of 20 HF deteriorations without preceding alert, an upstroke of the fluid index occurred without reaching the programmed alert threshold. CONCLUSION: A device-based algorithm that alerts patients in case of decreasing intrathoracic impedance facilitates the detection of HF deterioration. Future randomized, controlled trials are needed to test whether the tailored use of intrathoracic impedance monitoring can improve the ambulatory management of patients with chronic HF and an implanted device.