Berthold Stegemann

Effect of Posterolateral Left Ventricular Scar on Mortality and Morbidity following Cardiac Resynchronization Therapy

Objectives: To determine the effect of a posterolateral (PL) left ventricular scar on mortality and morbidity following cardiac resynchronization therapy (CRT).

Left Ventricular Midwall Fibrosis as a Predictor of Mortality and Morbidity After Cardiac Resynchronization Therapy in Patients With Nonischemic Cardiomyopathy

OBJECTIVES The aim of this study was to determine whether left ventricular (LV) midwall fibrosis, detected by midwall hyperenhancement (MWHE) on late gadolinium enhancement cardiovascular magnetic resonance (CMR) imaging, predicts mortality and morbidity in patients with dilated cardiomyopathy (DCM) undergoing cardiac resynchronization therapy (CRT). BACKGROUND Midwall fibrosis predicts mortality and morbidity in patients with DCM. METHODS Patients with DCM with (+) or without (-) MWHE (n = 20 and n = 77, respectively) as well as 161 patients with ischemic cardiomyopathy (ICM) undergoing CRT (n = 258) were followed up for a maximum of 8.7 years. RESULTS Among patients with DCM, +MWHE predicted cardiovascular mortality (hazard ratio [HR]: 18.6; 95% confidence intervals [CI]: 3.51 to 98.5; p = 0.0008), total mortality or hospitalization for major adverse cardiovascular events (HR: 7.57; 95% CI: 2.71 to 21.2; p < 0.0001), and cardiovascular mortality or heart failure hospitalizations (HR: 9.56; 95% CI: 2.72 to 33.6; p = 0.0004), independent of New York Heart Association class, QRS duration, atrial fibrillation, LV volumes, LV ejection fraction, and a CMR-derived measure of dyssynchrony. Among patients with DCM and ICM, the risk of cardiovascular mortality for DCM +MWHE (adjusted HR: 18.5; 95% CI: 3.93 to 87.3; p = 0.0002) was similar to that for ICM (adjusted HR: 21.0; 95% CI: 5.06 to 87.2; p < 0.0001). Both DCM +MWHE and ICM were predictors of pump failure death as well as sudden cardiac death. LV reverse remodeling was observed in DCM -MWHE and in ICM but not in DCM +MWHE. CONCLUSIONS Midwall fibrosis is an independent predictor of mortality and morbidity in patients with DCM undergoing CRT. The outcome of DCM with midwall fibrosis is similar to that of ICM. This relationship is mediated by both pump failure and sudden cardiac death.

Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values.

AIMS Myocardial deformation is a key to clinical decision-making. Feature-tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena. METHODS AND RESULTS One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 ± 4.8%, peak systolic circumferential strain (Ecc) was -26.1 ± 3.8%, and peak systolic radial strain (Err) was 39.8 ± 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 ± 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 ± 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%). CONCLUSION Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability.

Short-Term Hemodynamic Effects of Cardiac Resynchronization Therapy in Patients With Heart Failure, a Narrow QRS Duration, and No Dyssynchrony

Background— Cardiac resynchronization therapy produces both short-term hemodynamic and long-term symptomatic/mortality benefits in symptomatic heart failure patients with a QRS duration >120 ms. This is conventionally believed to be due principally to relief of dyssynchrony, although we recently showed that relief of external constraint to left ventricular filling may also play a role. In this study, we evaluated the short-term hemodynamic effects in symptomatic patients with a QRS duration <120 ms and no evidence of dyssynchrony on conventional criteria and assessed the effects on contractility and external constraint. Methods and Results— Thirty heart failure patients (New York Heart Association class III/IV) with a left ventricular ejection fraction ≤35% who were in sinus rhythm underwent pressure-volume studies at the time of pacemaker implantation. External constraint, left ventricular stroke work, dP/dtmax, and the slope of the preload recruitable stroke work relation were measured from the end-diastolic pressure-volume relation before and during delivery of biventricular and left ventricular pacing. The following changes were observed during delivery of cardiac resynchronization therapy: Cardiac output increased by 25±5% (P<0.05), absolute left ventricular stroke work increased by 26±5% (P<0.05), the slope of the preload recruitable stroke work relation increased by 51±15% (P<0.05), and dP/dtmax increased by 9±2% (P<0.05). External constraint was present in 15 patients and was completely abolished by both biventricular and left ventricular pacing (P<0.05). Conclusion— Cardiac resynchronization therapy results in an improvement in short-term hemodynamic variables in patients with a QRS <120 ms related to both contractile improvement and relief of external constraint. These findings provide a potential physiological basis for cardiac resynchronization therapy in this patient population.

Atrial fibrillation burden during the post-implant period after crt using device-based diagnostics.

Aims: Cardiac resynchronization therapy (CRT) is increasingly used in congestive heart failure (CHF) patients (with cardiac dyssynchrony). In addition to delivering therapy, CRT devices offer a variety of diagnostic tools for continuous long‐term monitoring of clinically relevant information (i.e., occurrence and duration of arrhythmia episodes).

The Limit of Plausibility for Predictors of Response: Application to Biventricular Pacing

OBJECTIVES We sought a method for any reader to quantify the limit, imposed by variability, to sustainably observable R(2) between any baseline predictor and response marker. We then apply this to echocardiographic measurements of mechanical dyssynchrony and response. BACKGROUND Can mechanical dyssynchrony markers strongly predict ventricular remodeling by biventricular pacing (cardiac resynchronization therapy)? METHODS First, we established the mathematical depression of observable R(2) arising from: 1) spontaneous variability of response markers; and 2) test-retest variability of dyssynchrony measurements. Second, we contrasted published R(2) values between externally monitored randomized controlled trials and highly skilled single-center studies (HSSCSs). RESULTS Inherent variability of response markers causes a contraction factor in R(2) of 0.48 (change in left ventricular ejection fraction [ΔLVEF]), 0.50 (change in end-systolic volume [ΔESV]), and 0.40 (change in end-diastolic volume [ΔEDV]). Simultaneously, inherent variability of mechanical dyssynchrony markers causes a contraction factor of between 0.16 and 0.92 (average, 0.6). Therefore the combined contraction factor, that is, limit on sustainably observable R(2) between mechanical dyssynchrony markers and response, is ~0.29 (ΔLVEF), ~0.24 (ΔESV), and ~0.30 (ΔEDV). Many R(2) values published in HSSCSs exceeded these mathematical limits; none in externally monitored trials did so. Overall, HSSCSs overestimate R(2) by 5- to 20-fold (p = 0.002). Absence of bias-resistance features in study design (formal enrollment and blinded measurements) was associated with more overstatement of R(2). CONCLUSIONS Reports of R(2) > 0.2 in response prediction arose exclusively from studies without formally documented enrollment and blinding. The HSSCS approach overestimates R(2) values, frequently breaching the mathematical ceiling on sustainably observable R(2), which is far below 1.0, and can easily be calculated by readers using formulas presented here. Community awareness of this low ceiling may help resist future claims. Reliable individualized response prediction, using methods originally designed for group-mean effects, may never be possible because it has 2 currently unavailable and perhaps impossible prerequisites: 1) excellent blinded test-retest reproducibility of dyssynchrony; and 2) response markers reproducible over time within nonintervened individuals. Dispassionate evaluation, and improvement, of test-retest reproducibility is required before any further claims of strong prediction. Prediction studies should be designed to resist bias.

Cardiac resynchronisation therapy in patients with heart failure and a normal QRS duration: the RESPOND study

Objectives To evaluate the clinical response to cardiac resynchronisation therapy (CRT) in patients with heart failure and a normal QRS duration (<120 ms). Setting Single centre. Patients 60 patients with heart failure and a normal QRS duration receiving optimal pharmacological treatment (OPT). Interventions Patients were randomly assigned to CRT (n=29) or to a control group (OPT, n=31). Cardiovascular magnetic resonance was used in order to avoid scar at the site of left ventricular (LV) lead deployment. Main outcome measures The primary end point was a change in 6 min walking distance (6-MWD). Other measures included a change in quality of life scores (Minnesota Living with Heart Failure questionnaire) and New York Heart Association class. Results In 93% of implantations, the LV lead was deployed over non-scarred myocardium. At 6 months, the 6-MWD increased with CRT compared with OPT (p<0.0001), with more patients reaching a ≥25% increase (51.7% vs 12.9%, p=0.0019). Compared with OPT, CRT led to an improvement in quality-of-life scores (p=0.0265) and a reduction in NYHA class (p<0.0001). The composite clinical score (survival for 6 months free of heart failure hospitalisations plus improvement by one or more NYHA class or by ≥25% in 6-MWD) was better in CRT than in OPT (83% vs 23%, respectively; p<0.0001). Although no differences in total or cardiovascular mortality emerged between OPT and CRT, patients receiving OPT had a higher risk of death from pump failure than patients assigned to CRT (HR=8.41, p=0.0447) after a median follow-up of 677.5 days. Conclusions CRT leads to an improvement in symptoms, exercise capacity and quality of life in patients with heart failure and a normal QRS duration. (ClinicalTrials.gov number, NCT00480051.)

Growth differentiation factor-15 predicts mortality and morbidity after cardiac resynchronization therapy

Aims The aim of this study was to determine whether growth differentiation factor-15 (GDF-15) predicts mortality and morbidity after cardiac resynchronization therapy (CRT). Growth differentiation factor-15, a transforming growth factor-β-related cytokine which is up-regulated in cardiomyocytes via multiple stress pathways, predicts mortality in patients with heart failure treated pharmacologically. Methods and results Growth differentiation factor-15 was measured before and 360 days (median) after implantation in 158 patients with heart failure [age 68 ± 11 years (mean ± SD), left ventricular ejection fraction (LVEF) 23.1 ± 9.8%, New York Class Association (NYHA) class III (n = 117) or IV (n = 41), and QRS 153.9 ± 28.2 ms] undergoing CRT and followed up for a maximum of 5.4 years for events. In a stepwise Cox proportional hazards model with bootstrapping, adopting log GDF-15, log NT pro-BNP, LVEF, and NYHA class as independent variables, only log GDF-15 [hazard ratio (HR), 3.76; P = 0.0049] and log NT pro-BNP (HR, 2.12; P = 0.0171) remained in the final model. In the latter, the bias-corrected slope was 0.85, the optimism (O) was −0.06, and the c-statistic was 0.74, indicating excellent internal validity. In univariate analyses, log GDF-15 [HR, 5.31; 95% confidence interval (CI), 2.31–11.9; likelihood ratio (LR) χ2 = 14.6; P < 0.0001], NT pro-BNP (HR, 2.79; 95% CI, 1.55–5.26; LR χ2 = 10.4; P = 0.0004), and the combination of both biomarkers (HR, 7.03; 95% CI, 2.91–17.5; LR χ2 = 19.1; P < 0.0001) emerged as significant predictors. The biomarker combination was associated with the highest LR χ2 for all endpoints. Conclusion Pre-implant GDF-15 is a strong predictor of mortality and morbidity after CRT, independent of NT pro-BNP. The predictive value of these analytes is enhanced by combined measurement.

Development and validation of a clinical index to predict survival after cardiac resynchronisation therapy

Objective: To develop and validate a prognostic risk index of cardiovascular mortality after cardiac resynchronisation therapy (CRT). Design: Prospective cohort study. Setting: District general hospital. Patients: 148 patients with heart failure (mean age 66.7 (SD 10.4) years), New York Heart Association class III or IV, LVEF <35%) who underwent CRT. Interventions: CRT device implantation. Main outcome measures: Value of a composite index in predicting cardiovascular mortality, validated internally by bootstrapping. The predictive value of the index was compared to factors that are known to predict mortality in patients with heart failure. Results: All patients underwent assessment of 16 prognostic risk factors, including cardiovascular magnetic resonance (CMR) measures of myocardial scarring (gadolinium-hyperenhancement) and dyssynchrony, before implantation. Clinical events were assessed after a median follow-up of 913 (interquartile range 967) days. At follow-up, 37/148 (25%) of patients died from cardiovascular causes. In Cox proportional hazards analyses, (DSC) Dyssynchrony, posterolateral Scar location (both p<0.0001) and Creatinine (p = 0.0046) emerged as independent predictors of cardiovascular mortality. The DSC index, derived from these variables combined, emerged as a powerful predictor of cardiovascular mortality. Compared to patients with a DSC <3, cardiovascular mortality in patients in the intermediate DSC index (3–5; HR: 11.1 (95% confidence interval (CI) 3.00 to 41.1), p = 0.0003) and high DSC index (⩾5; HR: 30.5 (95% CI 9.15 to 101.8), p<0.0001) were higher. Bootstrap validation confirmed excellent calibration and internal validity of the prediction model. Conclusion: The DSC index, derived from a standard CMR scan and plasma creatinine before implantation, is a powerful predictor of cardiovascular mortality after CRT.

Radial dyssynchrony assessed by cardiovascular magnetic resonance in relation to left ventricular function, myocardial scarring and QRS duration in patients with heart failure

BackgroundIntuitively, cardiac dyssynchrony is the inevitable result of myocardial injury. We hypothezised that radial dyssynchrony reflects left ventricular remodeling, myocardial scarring, QRS duration and impaired LV function and that, accordingly, it is detectable in all patients with heart failure.Methods225 patients with heart failure, grouped according to QRS duration of <120 ms (A, n = 75), between 120-149 ms (B, n = 75) or ≥150 ms (C, n = 75), and 50 healthy controls underwent assessment of radial dyssynchrony using the cardiovascular magnetic resonance tissue synchronization index (CMR-TSI = SD of time to peak inward endocardial motion in up to 60 myocardial segments).ResultsCompared to 50 healthy controls (21.8 ± 6.3 ms [mean ± SD]), CMR-TSI was higher in A (74.8 ± 34.6 ms), B (92.4 ± 39.5 ms) and C (104.6 ± 45.6 ms) (all p < 0.0001). Adopting a cut-off CMR-TSI of 34.4 ms (21.8 plus 2xSD for controls) for the definition of dyssynchrony, it was present in 91% in A, 95% in B and 99% in C. Amongst patients in NYHA class III or IV, with a LVEF<35% and a QRS>120 ms, 99% had dyssynchrony. Amongst those with a QRS<120 ms, 91% had dyssynchrony. Across the study sample, CMR-TSI was related positively to left ventricular volumes (p < 0.0001) and inversely to LVEF (CMR-TSI = 178.3 e (-0.033 LVEF) ms, p < 0.0001).ConclusionRadial dyssynchrony is almost universal in patients with heart failure. This vies against the notion that a lack of response to CRT is related to a lack of dyssynchrony.