Prognostic value of the 12-lead surface electrocardiogram in sarcomeric hypertrophic cardiomyopathy: data from the REMY French register.

AIMS: To identify independent electrocardiogram (ECG) predictors of long-term clinical outcome based on standardized analysis of the surface ECG in a large multicentre cohort of patients with sarcomeric hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Retrospective observational study from the REMY French HCM clinical research observatory. Primary endpoint was a composite of all-cause mortality, major non-fatal arrhythmic events, hospitalization for heart failure (HF), and stroke. Secondary endpoints were components of the primary endpoint. Uni- and multivariable Cox proportional hazard regression analysis was performed to identify independent predictors. Among 994 patients with HCM, only 1.8% had a strictly normal baseline ECG. The most prevalent abnormalities were inverted T waves (63.7%), P-wave abnormalities (30.4%), and abnormal Q waves (25.5%). During a mean follow-up of 4.0 ± 2.0 years, a total of 272 major cardiovascular events occurred in 217 patients (21.8%): death or heart transplant in 98 (9.8%), major arrhythmic events in 40 (4.0%), HF hospitalization in 115 (11.6%), and stroke in 23 (2.3%). At multivariable analysis using ECG covariates, prolonged QTc interval, low QRS voltage, and PVCs of right bundle branch block pattern predicted worse outcome, but none remained independently associated with the primary endpoint after adjustment on main demographic and clinical variables. For secondary endpoints, abnormal Q waves independently predicted all-cause death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.23-4.47; P = 0.009] and prolonged QTc the risk of HF hospitalization (HR 1.006, 95% CI 1.001-1.011; P = 0.024). CONCLUSION: The 12-lead surface ECG has no independent value to predict the primary outcome measure in patients with HCM. The 12-lead surface ECG has been widely used as a screening tool in HCM but its prognostic value remains poorly known. The value of baseline surface ECG to predict long-term clinical outcomes was studied in a cohort of 994 patients with sarcomeric HCM. The surface ECG has no significant additional value to predict outcome in this patient population.

Pacing for hypertrophic obstructive cardiomyopathy: an update and future directions.

In hypertrophic cardiomyopathy (HCM) patients with symptoms caused by left ventricular outflow tract obstruction (LVOTO), treatment options include negative inotropic drugs, myectomy, septal alcohol ablation and AV sequential pacing with or without an implantable cardioverter defibrillator (ICD). Pacing is rarely used in spite of its relative simplicity and promising results. In this review the current evidence of AV sequential pacing from observational, randomised studies and long and very long-term follow-up studies is given and put in the context of present guidelines recommendations. These studies indicate that AV sequential pacing improves symptoms and quality of life through decreases in LVOTO, systolic anterior movement and mitral regurgitation. Effects on morbidity and mortality are lacking. We describe the mechanisms of action, the prerequisites for successful pacing and provide practical advice on how to optimise therapy. Moreover, the role of the ICD for primary and secondary prevention is discussed with reference to the ESC HCM guidelines. In summary, AV sequential pacing for HOCM is underused in clinical practise despite evidence from two randomised controlled studies. This concept is currently the focus of two randomised studies: a planned randomised controlled study that will compare AV sequential pacing to TASH and an ongoing study that compares CRT to AAI pacing in HOCM patients. In this review we highlight the current evidence and the new interest for this therapy.

Avoiding non-responders to cardiac resynchronization therapy: a practical guide.

Over two decades after the introduction of cardiac resynchronization therapy (CRT) into clinical practice, ∼30% of candidates continue to fail to respond to this highly effective treatment of drug-refractory heart failure (HF). Since the causes of this non-response (NR) are multifactorial, it will require multidisciplinary efforts to overcome. Progress has, thus far, been slowed by several factors, ranging from a lack of consensus regarding the definition of NR and technological limitations to the delivery of therapy. We critically review the various endpoints that have been used in landmark clinical trials of CRT, and the variability in response rates that has been observed as a result of these different investigational designs, different sample populations enrolled and different means of therapy delivered, including new means of multisite and left ventricular endocardial simulation. Precise recommendations are offered regarding the optimal device programming, use of telemonitoring and optimization of management of HF. Potentially reversible causes of NR to CRT are reviewed, with emphasis on loss of biventricular stimulation due to competing arrhythmias. The prevention of NR to CRT is essential to improve the overall performance of this treatment and lower its risk-benefit ratio. These objectives require collaborative efforts by the HF team, the electrophysiologists and the cardiac imaging experts.

Reduced appropriate implantable cardioverter-defibrillator therapy after cardiac resynchronization therapy-induced left ventricular function recovery: a meta-analysis and systematic review.

AIMS: For patients undergoing cardiac resynchronization therapy (CRT) with implantable cardioverter-defibrillator (ICD; CRT-D), the effect of an improvement in left ventricular ejection fraction (LVEF) on appropriate ICD therapy may have significant implications regarding management at the time of ICD generator replacement. METHODS AND RESULTS: We conducted a meta-analysis to determine the effect of LVEF recovery following CRT on the incidence of appropriate ICD therapy. A search of multiple electronic databases identified 709 reports, of which 6 retrospective cohort studies were included (n = 1740). In patients with post-CRT LVEF ≥35% (study n = 4), the pooled estimated rate of ICD therapy (5.5/100 person-years) was significantly lower than patients with post-CRT LVEF <35% [incidence rate difference (IRD): -6.5/100 person-years, 95% confidence interval (95% CI): -8.8 to -4.2, P < 0.001]. Similarly, patients with post-CRT LVEF ≥45% (study n = 4) demonstrated lower estimated rates of ICD therapy (2.3/100 person-years) compared with patients without such recovery (IRD: -5.8/100 person-years, 95% CI: -7.6 to -4.0, P < 0.001). Restricting analysis to studies discounting ICD therapies during LVEF recovery (study n = 3), patients with LVEF recovery (≥35 or ≥45%) had significantly lower rates of ICD therapy compared with patients without such recovery (P for both <0.001). Patients with primary prevention indication for ICD, regardless of LVEF recovery definition, had very low rates of ICD therapy (0.4 to 0.8/100-person years). CONCLUSION: Recovery of LVEF post-CRT is associated with significantly reduced appropriate ICD therapy. Patients with improvement of LVEF ≥45% and those with primary prevention indication for ICD appear to be at lowest risk.

Long-term impact of cardiac resynchronization therapy in mild heart failure: 5-year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study.

BACKGROUND: The benefit of cardiac resynchronization therapy (CRT) among patients with mild heart failure (HF), reduced left ventricular (LV) function and wide QRS is well established. We studied the long-term stability of CRT. METHODS: REVERSE was a randomized, double-blind study on CRT in NYHA Class I and II HF patients with QRS ≥120 ms and left ventricular ejection fraction (LVEF) ≤40%. After the randomized phase, all were programmed to CRT ON and prospectively followed through 5 years for functional capacity, echocardiography, HF hospitalizations, mortality, and adverse events. We report the results of the 419 patients initially assigned to CRT ON. FINDINGS: The mean follow-up time was 54.8 ± 13.0 months. After 2 years, the functional and LV remodelling improvements were maximal. The 6-min hall walk increased by 18.8 ± 102.3 m and the Minnesota and Kansas City scores improved by 8.2 ± 17.8 and 8.2 ± 17.2 units, respectively. The mean decrease in left ventricular end-systolic volume index and left ventricular end-diastolic volume index was 23.5 ± 34.1 mL/m(2) (P < 0.0001) and 25.4 ± 37.0 mL/m2 (P < 0.0001) and the mean increase in LVEF 6.0 ± 10.8% (P < 0.0001) with sustained improvement thereafter. The annualized and 5-year mortality was 2.9 and 13.5% and the annualized and 5-year rate of death or first HF hospitalization 6.4, and 28.1%. The 5-year LV lead-related complication rate was 12.5%. CONCLUSION: In patients with mild HF, CRT produced reverse LV remodelling accompanied by very low mortality and need for heart failure hospitalization. These effects were sustained over 5 years. Cardiac resynchronization therapy in addition to optimal medical therapy produces long-standing clinical benefits in mild heart failure. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00271154.

Cost-effectiveness analysis of cardiac resynchronization therapy in patients with NYHA I and NYHA II heart failure in Spain.

OBJECTIVES: The aim of the study was to combine clinical results from the European Cohort of the REVERSE study and costs associated with the addition of cardiac resynchronization therapy (CRT) to optimal medical therapy (OMT) in patients with mild symptomatic (NYHA I-II) or asymptomatic left ventricular dysfunction and markers of cardiac dyssynchrony in Spain. METHODS: A Markov model was developed with CRT + OMT (CRT-ON) versus OMT only (CRT-OFF) based on a retrospective cost-effectiveness analysis. Raw data was derived from literature and expert opinion, reflecting clinical and economic consequences of patient's management in Spain. Time horizon was 10 years. Both costs (euro 2010) and effects were discounted at 3 percent per annum. RESULTS: CRT-ON showed higher total costs than CRT-OFF; however, CRT reduced the length of hospitalization in ICU by 94 percent (0.006 versus 0.091 days) and general ward in by 34 percent (0.705 versus 1.076 days). Surviving CRT-ON patients (88.2 percent versus 77.5 percent) remained in better functional class longer, and they achieved an improvement of 0.9 life years (LYGs) and 0.77 years quality-adjusted life years (QALYs). CRT-ON proved to be cost-effective after 6 years, except for the 7th year due to battery depletion. At 10 years, the results were €18,431 per LYG and €21,500 per QALY gained. Probabilistic sensitivity analysis showed CRT-ON was cost-effective in 75.4 percent of the cases at 10 years. CONCLUSIONS: The use of CRT added to OMT represents an efficient use of resources in patients suffering from heart failure in NYHA functional classes I and II.

Cardiac resynchronization induces major structural and functional reverse remodeling in patients with New York Heart Association class I/II heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves LV structure, function, and clinical outcomes in New York Heart Association class III/IV heart failure with prolonged QRS. It is not known whether patients with New York Heart Association class I/II systolic heart failure exhibit left ventricular (LV) reverse remodeling with CRT or whether reverse remodeling is modified by the cause of heart failure. METHODS AND RESULTS: Six hundred ten patients with New York Heart Association class I/II heart failure, QRS duration > or =120 ms, LV end-diastolic dimension > or =55 mm, and LV ejection fraction < or =40% were randomized to active therapy (CRT on; n=419) or control (CRT off; n=191) for 12 months. Doppler echocardiograms were recorded at baseline, before hospital discharge, and at 6 and 12 months. When CRT was turned on initially, immediate changes occurred in LV volumes and ejection fraction; however, these changes did not correlate with the long-term changes (12 months) in LV end-systolic (r=0.11, P=0.31) or end-diastolic (r=0.10, P=0.38) volume indexes or LV ejection fraction (r=0.07, P=0.72). LV end-diastolic and end-systolic volume indexes decreased in patients with CRT turned on (both P<0.001 compared with CRT off), whereas LV ejection fraction in CRT-on patients increased (P<0.0001 compared with CRT off) from baseline through 12 months. LV mass, mitral regurgitation, and LV diastolic function did not change in either group by 12 months; however, there was a 3-fold greater reduction in LV end-diastolic and end-systolic volume indexes and a 3-fold greater increase in LV ejection fraction in patients with nonischemic causes of heart failure. CONCLUSIONS: CRT in patients with New York Heart Association I/II resulted in major structural and functional reverse remodeling at 1 year, with the greatest changes occurring in patients with a nonischemic cause of heart failure. CRT may interrupt the natural disease progression in these patients. Clinical Trial Registration- Clinicaltrials.gov Identifier: NCT00271154.

Circulating neuregulin1-ß in heart failure with preserved and reduced left ventricular ejection fraction.

AIMS: Neuregulin1-ß (NRG1-ß) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-ß is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). METHODS AND RESULTS: Circulating NRG1-ß was quantified in 86 stable patients with HFpEF (EF ≥45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-ß and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th-75th percentile) NRG1-ß was 6.5 (2.1-11.3) ng/mL; in HFrEF, 3.6 (2.1-7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9-3.6) ng/mL; after HTx 2.1 (1.4-3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1-34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-ß was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04-2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-ß with outcomes was modified by ischaemia (log-rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1-ß was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-ß trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085). CONCLUSIONS: Neuregulin1-ß was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-ß with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-ß from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Surface electrocardiogram to predict outcome in candidates for cardiac resynchronization therapy: a sub-analysis of the CARE-HF trial.

AIMS: In CARE-HF, cardiac resynchronization therapy (CRT) lowered morbidity and mortality in patients with moderate to severe heart failure. We examined whether baseline and follow-up electrocardiographic characteristics might predict long-term outcome. METHODS AND RESULTS: CARE-HF randomly assigned 409 patients to medical therapy (MT) plus CRT, and 404 patients to MT alone. Electrocardiographic measurements were made at baseline during sinus rhythm, and at 3 months during paced or spontaneous rhythm depending on treatment assignment. Favourable outcome was defined as freedom from death, urgent transplantation, or cardiovascular hospitalization. Among patients assigned to CRT, 39% had unfavourable outcomes including 55 deaths. By single variable analysis, (i) prolonged PR interval, left QRS axis (but not QRS duration), and left bundle branch block (BBB) at baseline, and (ii) heart rate, PR, and QRS duration at 3 months predicted unfavourable outcome. By multiple variable analysis, treatment assignment (P = 0.0001), PR (P = 0.0004), and right BBB (P < 0.00013) at baseline predicted outcome, whereas baseline JTc and QRS duration at 3 months predicted all-cause mortality and heart failure hospitalization (P = 0.0071). CONCLUSION: In CARE-HF, QRS duration at baseline did not predict outcome, but QRS at 3 months was a predictor by single variable analysis. Patients with prolonged PR interval and the 5% of patients with right BBB had a particularly high event rate.