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.

Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance.

BACKGROUND: Myocardial scarring at the LV pacing site leads to incomplete resynchronization and a suboptimal symptomatic response to CRT. We sought to determine whether the use of late gadolinium cardiovascular magnetic resonance (LGE-CMR) to guide left ventricular (LV) lead deployment influences the long-term outcome of cardiac resynchronization therapy (CRT). METHODS: 559 patients with heart failure (age 70.4 ± 10.7 yrs [mean ± SD]) due to ischemic or non-ischemic cardiomyopathy underwent CRT. Implantations were either guided (+CMR) or not guided (-CMR) by LGE-CMR prior to implantation. Fluoroscopy and LGE-CMR were used to localize the LV lead tip and and myocardial scarring retrospectively. Clinical events were assessed in three groups: +CMR and pacing scar (+CMR+S); CMR and not pacing scar (+CMR-S), and; LV pacing not guided by CMR (-CMR). RESULTS: Over a maximum follow-up of 9.1 yrs, +CMR+S had the highest risk of cardiovascular death (HR: 6.34), cardiovascular death or hospitalizations for heart failure (HR: 5.57) and death from any cause or hospitalizations for major adverse cardiovascular events (HR: 4.74) (all P < 0.0001), compared with +CMR-S. An intermediate risk of meeting these endpoints was observed for -CMR, with HRs of 1.51 (P = 0.0726), 1.61 (P = 0.0169) and 1.87 (p = 0.0005), respectively. The +CMR+S group had the highest risk of death from pump failure (HR: 5.40, p < 0.0001) and sudden cardiac death (HR: 4.40, p = 0.0218), in relation to the +CMR-S group. CONCLUSIONS: Compared with a conventional implantation approach, the use of LGE-CMR to guide LV lead deployment away from scarred myocardium results in a better clinical outcome after CRT. Pacing scarred myocardium was associated with the worst outcome, in terms of both pump failure and sudden cardiac death.

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.).

Female gender is associated with a better outcome after cardiac resynchronization therapy.

BACKGROUND: Some studies have suggested that women respond differently to cardiac resynchronization therapy (CRT). We sought to determine whether female gender influences long-term clinical outcome, symptomatic response as well as echocardiographic response after CRT. METHODS AND RESULTS: A total of 550 patients (age 70.4 ± 10.7 yrs [mean ± standard deviation]) were followed up for a maximum of 9.1 years (median: 36.2 months) after CRT-pacing (CRT-P) or CRT-defibrillation (CRT-D) device implantation. Outcome measure included mortality as well as unplanned hospitalizations for heart failure or major adverse cardiovascular events (MACE). Female gender predicted survival from cardiovascular death (hazard ratio [HR]: 0.52, P = 0.0051), death from any cause (HR: 0.52, P = 0.0022), the composite endpoints of cardiovascular death /heart failure hospitalizations (HR: 0.56, P = 0.0036) and death from any cause/hospitalizations for MACE (HR: 0.67, P = 0.0214). Female gender predicted death from pump failure (HR: 0.55, P = 0.0330) but not sudden cardiac death. Amongst the 322 patients with follow-up echocardiography, left ventricular (LV) reverse remodelling (≥ 15% reduction in LV end-systolic volume) was more pronounced in women (62% vs 44%, P = 0.0051). In multivariable Cox proportional hazards analyses, the association between female gender and cardiovascular survival was independent of age, LV ejection fraction, atrial rhythm, QRS duration, CRT device type, New York Heart Association (NYHA) class, and LV reverse remodelling (adjusted HR: 0.48, P = 0.0086). At one year, the symptomatic response rate (improvement by ≥ 1 NYHA classes or ≥ 25% increase in walking distance) was 78% for both women and men. CONCLUSIONS: Female gender is independently associated with a lower mortality and morbidity after CRT.

Left ventricular reverse remodelling, long-term clinical outcome, and mode of death after cardiac resynchronization therapy.

AIMS: To determine whether reverse left ventricular (LV) remodelling relates to long-term outcome, major adverse cardiovascular events (MACE), mode of death, and symptomatic response after cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Three hundred and twenty-two patients with heart failure (HF) [age 69.2 ± 10.7 years (mean ± standard deviation)] underwent a clinical assessment and echocardiography before and at a maximum of 9.1 years (median: 36.2 months) after CRT device implantation. Left ventricular reverse remodelling (≥15% reduction in LV end-systolic volume) predicted survival from cardiovascular death (HR: 0.57, P = 0.0066), death from any cause (HR: 0.59, P = 0.0064), death from any cause/hospitalizations for MACE (HR: 0.67, P = 0.0158), and death from pump failure (HR: 0.45, P = 0.0024), independent of beta-blocker use, HF aetiology, gender, baseline NYHA class, and atrial rhythm. Left ventricular reverse remodelling did not predict sudden cardiac death. At 1 year, the symptomatic response rate (improvement by ≥1 NYHA classes or ≥25% increase in walking distance) was 86% in survivors and 76% in non-survivors (P = NS). Left ventricular reverse remodelling did not predict symptomatic response and the symptomatic response did not predict clinical outcome. CONCLUSION: Left ventricular reverse remodelling is an independent predictor of clinical outcome for up to 5 years after CRT device implantation. Pump failure, rather than sudden cardiac death, is primarily responsible for this association. Left ventricular reverse remodelling, however, does not predict a symptomatic response. There is discordance between the symptomatic response to and the survival benefit of CRT.

Effects of cardiac resynchronization therapy in patients unselected for mechanical dyssynchrony.

BACKGROUND: Observational echocardiographic studies have suggested that pre-implant dyssynchrony is required for a response to cardiac resynchronization therapy. Some clinical guidelines on CRT have adopted dyssynchrony as a requirement prior to CRT. AIMS: To assess the effects of CRT in patients with heart failure who are unselected for mechanical dyssynchrony. METHODS: 248 consecutive patients with heart failure (sinus rhythm, NYHA class III [n=171, 89%]) or IV (n=77, 31%; LVEFor=120 ms) underwent a clinical assessment, including NYHA class, 6-min walking distance and quality of life (Minnesota Living with Heart Failure questionnaire) before and after CRT. Clinical event variables included mortality and hospitalizations for major cardiovascular events and for heart failure. RESULTS: At follow-up, NYHA class was reduced from 3.25+/-0.56 to 2.06+/-0.84 (mean+/-SD, p<0.0001). There were also improvements in 6-min walking distance (232.2+/-113.8 to 302.9+/-119.5 m) and quality of life scores (56.1+/-20.4 to 32.5+/-23.4) (both p<0.0001). Responder rate, defined as improvement by >or=1 NYHA classes or>or=25% in 6-min walking distance, was 81% (202/248 patients). Over a follow-up period of up to 7.4 years (median 720 days), the annualized total and cardiovascular mortality rates were 11.7% and 9.89%, respectively. CONCLUSIONS: In patients undergoing CRT, the improvements in functional capacity and quality of life as well as the event rates expected from landmark trials are achievable by selecting patients on the basis of NYHA class, LVEF and QRS duration alone. The added value of echocardiographic measures of dyssynchrony remains questionable.

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

BACKGROUND: Intuitively, cardiac dyssynchrony is the inevitable result of myocardial injury. We hypothesized 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. METHODS: 225 patients with heart failure, grouped according to QRS duration of <120 ms (A, n = 75), between 120-149 ms (B, n = 75) or >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). RESULTS: Compared 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). CONCLUSION: Radial 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.

Long-term effects of upgrading from right ventricular pacing to cardiac resynchronization therapy in patients with heart failure.

AIMS: To determine the effects of upgrading from right ventricular (RV) pacing to cardiac resynchronization therapy (CRT) in patients with heart failure. METHODS AND RESULTS: Patients with heart failure [age 67.3 +/- 9.6 years (mean +/- SD), NYHA class III or IV, left ventricular ejection fraction (LVEF) or= 120 ms] underwent de novo CRT (n = 336) or upgrading from RV pacing [n = 58; VVIR in 24, DDDR in 34] to CRT. The endpoint of death from any cause or major cardiovascular events, cardiovascular death or hospitalization for heart failure, and cardiovascular death or death from any cause was determined after a maximum follow-up of 7.7 years. No differences emerged between the de novo CRT and the upgrade-to-CRT groups with respect to any of the clinical endpoints. The de novo CRT and upgrade-to-CRT groups derived similar improvements in NYHA class [-1.2 vs. -1.3 (mean), both P < 0.0001), 6 min walking distance [75.9 (P < 0.0001) vs. 46.4 (P = 0.0205) m], and quality of life scores [-25.2 vs. -18.7 (both P < 0.0001)] 1 year after implantation. Response rates using a combined clinical score (>or=1 NYHA classes or >or=25% increase in 6 min walking distance plus survival with freedom from heart failure hospitalizations for 1 year) were 73.2% and 75.4%, respectively (P = NS). There were reductions in left ventricular end-systolic volume [median of 20.3 mL (P = 0.0012) and 22.7 mL (P = 0.0066), respectively] and improvements in LVEF [median of 2.9% and 9.3%, respectively (both P < 0.0001)]. CONCLUSION: In patients with heart failure who are RV-paced, upgrading to CRT is associated with a similar long-term risk of mortality and morbidity to patients undergoing de novo CRT. Symptomatic improvements and degree of reverse remodelling are also comparable.

Cardiac resynchronization therapy in patients with mildly impaired left ventricular function.

AIMS: We sought to determine the unknown effects of cardiac resynchronization therapy (CRT) in patients with a left ventricular ejection fraction (LVEF) >35%. Because of its technical limitations, echocardiography (Echo) may underestimate LVEF, compared with cardiovascular magnetic resonance (CMR). METHODS: Of 157 patients undergoing CRT (New York Heart Association [NYHA] functional class III or IV, QRS > or = 120 ms), all of whom had a preimplant Echo-LVEF < or =35%, 130 had a CMR-LVEF < or =35% (Group A, 19.7 +/- 7.0%[mean +/- standard deviation]) and 27 had a CMR-LVEF >35% (Group B, 43.6 +/- 7.7%). All patients underwent a CMR scan at baseline and a clinical evaluation, including a 6-minute walk test and a quality of life questionnaire, at baseline and after CRT. RESULTS: Both groups derived similar improvements in NYHA functional class (A =-1.3, B =-1.2, [mean]), quality of life scores (A =-21.6, B =-33.0; all P < 0.0001 for changes from baseline), and 6-minute walking distance (A = 64.5, B = 70.1 m; P < 0.001 and P < 0.0001, respectively). Symptomatic response rates (increase by > or =1 NYHA classes or 25% 6-minute walking distance) were 79% in group A and 92% in group B. Over a maximum follow-up period of 5.9 years for events, patients in group A were at a higher risk of death from any cause, hospitalization for major cardiovascular events (P = 0.0232), or cardiovascular death (P = 0.0411). There were borderline differences in the risk of death from any cause (P = 0.0664) and cardiovascular death or hospitalization for heart failure (P = 0.0526). CONCLUSIONS: This observational study suggests that the benefits of CRT extend to patients with a LVEF > 35%.

Long-term effects of cardiac resynchronization therapy in octogenarians: a comparative study with a younger population.

AIMS: Heart failure is a disease of octogenarians. The evidence base for cardiac resynchronization therapy (CRT) has emerged from trials of patients in their 60s. We compared the effectiveness of CRT in octogenerians with younger patients. METHODS AND RESULTS: Patients aged >or=80 years [n = 53, age 83.7 +/- 2.6 years (mean +/- SD)] and <80 years (n = 277, age 66.9 +/- 9.5 years) with ischaemic or non-ischaemic cardiomyopathy (NYHA class III or IV heart failure, left ventricular ejection fraction <35%, QRS >or= 120 ms) underwent CRT. A clinical assessment, including a 6-min walk test, and a quality of life assessment (Minnesota Living with Heart Failure questionnaire) were undertaken at baseline and after CRT. In octogenarians, CRT was associated with similar changes in NYHA class [-1.28 vs. -1.22, P < 0.0001 (P-values refer to changes from baseline)], 6-min walking distance (77.2 vs. 78.6 m, P < 0.0001), and quality of life scores (-20.4 vs. -31.4, P = 0.0084) to <80 year olds. A symptomatic response to CRT (improvement by >or=1 NYHA classes or >or=25% 6-min walking distance) was observed in 80% of <80 year olds and in 81% of octogenarians (P = NS). Using a combined clinical score (CCS; survival for 1 year with no heart failure hospitalizations, and; improvement by >or=1 NYHA classes or >or=25% 6-min walking distance), a response was observed in 201 out of 277 (73%) patients <80 years and in 36 out of 53 (68%) octogenarians (P = NS). After a maximum follow-up of 7.6 years (median 634 days), no group differences emerged with respect to the composite endpoints of cardiovascular death or hospitalization for major cardiovascular events, the composite endpoint of cardiovascular death or heart failure hospitalization, cardiovascular mortality, or total mortality. CONCLUSION: Octogenarians derive similar benefits from CRT to younger patients.

Late gadolinium enhancement-cardiovascular magnetic resonance as a predictor of response to cardiac resynchronization therapy in patients with ischaemic cardiomyopathy.

AIM: To determine whether myocardial scarring, quantified using late gadolinium enhancement-cardiovascular magnetic resonance (LGE-CMR), predicts response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: A total of 45 patients with ischaemic cardiomyopathy [age 67.1 +/- 10.4 years (mean +/- SD)] underwent assessment of 6 min walking distance (6MWD) and quality of life (QoL) before and after CRT. Scar size (percentage of left ventricular mass), location, and transmurality were assessed prior to CRT using LGE-CMR. Responders (survived for 1 year with no heart failure hospitalizations, and improvement by >or=1 NYHA classes or >or=25% 6MWD) had a higher left ventricular ejection fraction (P = 0.048), smaller scars (<33%) (P = 0.009), and fewer scars with >or=51% transmurality (P = 0.002). Scar size correlated negatively with change in 6MWD (r = -0.54, P < 0.001) and positively with changes in QoL scores (r = 0.35, P = 0.028). Responder rates in patients with <33% scar were higher than in those with >or=33% scar (82 vs. 35%, P < 0.01). Responder rates in patients with scar transmurality <51% were higher than in those with >or=51% (89 vs. 46%, P < 0.01). Among the patients with posterolateral scars, a transmurality value of >or=51% was associated with a particularly poor response rate (23%), compared with scars with <51% transmurality (88%, P < 0.001). In multivariate analyses, both scar size (P = 0.022) and transmurality (P = 0.004) emerged as predictors of response. In patients with posterolateral scars, pacing outside the scar was associated with a better responder rate than pacing over the scar (86 vs. 33%, P = 0.004). CONCLUSIONS: In patients with ischaemic cardiomyopathy, a scar size >or=33%, a transmurality >or=51%, and pacing over a posterolateral scar are associated with a suboptimal response to CRT.

Intraventricular dyssynchrony predicts mortality and morbidity after cardiac resynchronization therapy: a study using cardiovascular magnetic resonance tissue synchronization imaging.

OBJECTIVES: We aimed to assess a novel measure of left ventricular (LV) dyssynchrony, a cardiovascular magnetic resonance-tissue synchronization index (CMR-TSI), in patients with heart failure (HF). A further aim was to determine whether CMR-TSI predicts mortality and major cardiovascular events (MCE) after cardiac resynchronization therapy (CRT). BACKGROUND: Cardiac dyssynchrony is a predictor of mortality in patients with HF. The unparalleled spatial resolution of CMR may render CMR-TSI a predictor of clinical benefit after CRT. METHODS: In substudy A, CMR-TSI was assessed in 66 patients with HF (age 60.8 +/- 10.8 years, LV ejection fraction 23.9 +/- 12.1% [mean +/- SD]) and 20 age-matched control subjects. In substudy B, CMR-TSI was assessed in relation to clinical events in 77 patients with HF and with a QRS > or =120 ms undergoing CRT. RESULTS: In analysis A, CMR-TSI was higher in patients with HF and a QRS <120 ms (79.5 +/- 31.2 ms, p = 0.0003) and in those with a QRS > or =120 ms (105.9 +/- 55.8 ms, p < 0.0001) than in control subjects (21.2 +/- 8.1 ms). In analysis B, a CMR-TSI > or =110 ms emerged as an independent predictor of the composite end points of death or unplanned hospitalization for MCE (hazard ratio [HR] 2.45; 95% confidence interval [CI] 1.51 to 4.34, p = 0.0002) or death from any cause or unplanned hospitalization for HF (HR 2.15; 95% CI 1.23 to 4.14, p = 0.0060) as well as death from any cause (HR: 2.6; 95% CI 1.29 to 6.73, p = 0.0061) and cardiovascular death (HR 3.82; 95% CI 1.63 to 16.5, p = 0.0007) over a mean follow-up of 764 days. CONCLUSIONS: Myocardial dyssynchrony assessed by CMR-TSI is a powerful independent predictor of mortality and morbidity after CRT.

Pacing-induced increase in QT dispersion predicts sudden cardiac death following cardiac resynchronization therapy.

OBJECTIVES: This study was designed to determine whether cardiac resynchronization therapy (CRT) by means of biventricular pacing (BiVP) alters the QT interval (QT(c)) and QT dispersion (QTD), and whether such changes relate to the risk of developing major arrhythmic events (MAE). BACKGROUND: Prolonged QT(c) is associated with MAE. Left ventricular pacing and BiVP alter QT(c). METHODS: A total of 75 patients with drug-resistant heart failure (New York Heart Association functional class III/IV) and QRS duration > or =120 ms underwent CRT. The QT(c) and QTD were measured before and 48 days after BiVP. RESULTS: Over 807 days (range 93 to 1,543 days), 11 patients had a MAE. Compared to baseline, at 48 days after CRT, QTD increased in 47% of patients and QT(c) decreased in 53%. The QT(c) at follow-up was higher in MAE patients compared with no-MAE patients (35.9 +/- 14.2 ms vs. 0.52 +/- 6.0 ms; p = 0.0323). Similar differential responses for QTD were observed (46.4 +/- 13.5 ms in MAE vs. -5.1 +/- 4.1 ms in no MAE, p < 0.0001). The MAE occurred in 29% of patients exhibiting an increase in QTD and in 3% of those exhibiting a decrease (p = 0.0017). In multiple regression analyses, change in QTD from baseline (DeltaQTD) strongly predicted MAE, independent of DeltaQT(c), QRS duration, and left ventricular ejection fraction and end-diastolic volume (p < 0.001). Differences in survival curves were observed when patients were dichotomized according to whether QTD increased or decreased in relation to baseline values (p < 0.0001). CONCLUSIONS: The MAE in patients with BiVP are related to pacing-induced increases in QTD. Measures of ventricular repolarization at the time of pacemaker implantation may guide selection of patients for combined CRT and defibrillator therapy.