Jeffrey Wing-Hong Fung

Left Ventricular Reverse Remodeling but Not Clinical Improvement Predicts Long-Term Survival After Cardiac Resynchronization Therapy

Background—In patients with severe heart failure and dilated cardiomyopathy, cardiac resynchronization therapy (CRT) improves left ventricular (LV) systolic function associated with LV reverse remodeling and favorable 1-year survival. However, it is unknown whether LV reverse remodeling translates into a better long-term prognosis and what extent of reverse remodeling is clinically relevant, which were investigated in this study. Methods and Results—Patients (n=141) with advanced heart failure (mean±SD age, 64±11 years; 73% men) who received CRT were followed up for a mean (±SD) of 695±491 days. The extent of reduction in LV end-systolic volume (LVESV) at 3 to 6 months relative to baseline was examined for its predictive value on long-term clinical outcome. The cutoff value for LV reverse remodeling in predicting mortality was derived from the receiver operating characteristic curve. Then the relation between potential predictors of mortality and heart failure hospitalizations were compared by Kaplan-Meier survival analysis, followed by Cox regression analysis. There were 22 (15.6%) deaths, mostly due to heart failure or sudden cardiac death. The receiver operating characteristic curve found that a reduction in LVESV of ≥9.5% had a sensitivity of 70% and specificity of 70% in predicting all-cause mortality and of 87% and 69%, respectively, for cardiovascular mortality. With this cutoff value, there were 87 (61.7%) responders to reverse remodeling. In Kaplan-Meier survival analysis, responders had significantly lower all-cause morality (6.9% versus 30.6%, log-rank &khgr;2=13.26, P=0.0003), cardiovascular mortality (2.3% versus 24.1%, log-rank &khgr;2=17.1, P<0.0001), and heart failure events (11.5% versus 33.3%, log-rank &khgr;2=8.71, P=0.0032) than nonresponders. In the Cox regression analysis model, the change in LVESV was the single most important predictor of all-cause (&bgr;=1.048, 95% confidence interval=1.019 to 1.078, P=0.001) and cardiovascular (&bgr;=1.072, 95% confidence interval=1.033 to 1.112, P<0.001) mortality. Clinical parameters were unable to predict any outcome event. Conclusions—A reduction in LVESV of 10% signifies clinically relevant reverse remodeling, which is a strong predictor of lower long-term mortality and heart failure events. This study suggests that assessing volumetric changes after an intervention in patients with heart failure provides information predictive of natural history outcomes.

Biventricular pacing in patients with bradycardia and normal ejection fraction.

BACKGROUND Observational studies suggest that conventional right ventricular apical pacing may have a deleterious effect on left ventricular function. In this study, we examined whether biventricular pacing is superior to right ventricular apical pacing in preventing deterioration of left ventricular systolic function and cardiac remodeling in patients with bradycardia and a normal ejection fraction. METHODS In this prospective, double-blind, multicenter study, we randomly assigned 177 patients in whom a biventricular pacemaker had been successfully implanted to receive biventricular pacing (89 patients) or right ventricular apical pacing (88 patients). The primary end points were the left ventricular ejection fraction and left ventricular end-systolic volume at 12 months. RESULTS At 12 months, the mean left ventricular ejection fraction was significantly lower in the right-ventricular-pacing group than in the biventricular-pacing group (54.8+/-9.1% vs. 62.2+/-7.0%, P<0.001), with an absolute difference of 7.4 percentage points, whereas the left ventricular end-systolic volume was significantly higher in the right-ventricular-pacing group than in the biventricular-pacing group (35.7+/-16.3 ml vs. 27.6+/-10.4 ml, P<0.001), with a relative difference between the groups in the change from baseline of 25% (P<0.001). The deleterious effect of right ventricular apical pacing occurred in prespecified subgroups, including patients with and patients without preexisting left ventricular diastolic dysfunction. Eight patients in the right-ventricular-pacing group (9%) and one in the biventricular-pacing group (1%) had ejection fractions of less than 45% (P=0.02). There was one death in the right-ventricular-pacing group, and six patients in the right-ventricular-pacing group and five in the biventricular-pacing group were hospitalized for heart failure (P=0.74). CONCLUSIONS In patients with normal systolic function, conventional right ventricular apical pacing resulted in adverse left ventricular remodeling and in a reduction in the left ventricular ejection fraction; these effects were prevented by biventricular pacing. (Centre for Clinical Trials number, CUHK_CCT00037.)

The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction

Background: Although heart failure with a preserved or normal ejection fraction (HFNEF or diastolic heart failure) is common, treatment outcomes on quality of life and cardiac function are lacking. The effect of renin–angiotensin blockade by irbesartan or ramipril in combination with diuretics on quality of life (QoL), regional and global systolic and diastolic function was assessed in HFNEF patients. Methods: 150 patients with HFNEF (LVEF >45%) were randomised to (1) diuretics alone, (2) diuretics plus irbesartan, or (3) diuretics plus ramipril. QoL, 6-minute walk test (6MWT) and Doppler echocardiography were performed at baseline, 12, 24 and 52 weeks. Results: The QoL score improved similarly in all three groups by 52 weeks (−46%, 51%, and 50% respectively, all p<0.01), although 6MWT increased only slightly (average +3–6%). Recurrent hospitalisation rates were equal in all groups (10–12% in 1 year). At 1 year, LV dimensions or LVEF had not changed in any group, though both systolic and diastolic blood pressures were lowered in all three groups from 4 weeks onwards. At baseline both mean peak systolic (Sm) and early diastolic (Em) mitral annulus velocities were reduced, and increased slightly in the diuretic plus irbesartan (Sm 4.5 (SEM 0.17) to 4.9 (SEM 0.16) cm/sec; Em 3.8 (SEM 0.25) to 4.2 (SEM 0.25) cm/sec) and ramipril (Sm 4.5 (SEM 0.24) to 4.9 (SEM 0.20) cm/sec; Em 3.3 (SEM 0.25) to 4.04 (SEM 0.32) cm/sec) groups (both p<0.05). NT-pro-BNP levels were raised at baseline (595 (SD 905) pg/ml; range 5–4748) and fell in the irbesartan (−124 (SD 302) pg/ml, p = 0.01) and ramipril (−173 (SD 415) pg/ml, p = 0.03) groups only. Conclusions: In this typically elderly group of HF patients with normal LVEF, diuretic therapy significantly improved symptoms and neither irbesartan nor ramipril had a significant additional effect. However, diuretics in combination with irbesartan or ramipril marginally improved LV systolic and diastolic longitudinal LV function, and lowered NT-proBNP over 1 year.

Understanding Nonresponders of Cardiac Resynchronization Therapy—Current and Future Perspectives

Introduction: Cardiac resynchronization therapy (CRT) is now an established nonpharmacologic therapy for advanced heart failure with electromechanical delay. Despite compelling evidence of the benefits of CRT, one troubling issue is the lack of a favorable response in about one‐third of patients.

Tissue Doppler velocity is superior to displacement and strain mapping in predicting left ventricular reverse remodelling response after cardiac resynchronisation therapy

Objective: To compare the values of three different forms of tissue Doppler imaging (TDI) processing in predicting left ventricular (LV) reverse remodelling—namely, tissue velocity, displacement and strain mapping. Design: Standard echocardiography with TDI was performed before and 3 months after cardiac resynchronisation therapy (CRT). Setting: University teaching hospital. Patients: 55 patients with heart failure who received CRT and were followed up for at least 3 months were recruited. Interventions: During off-line analysis, the time to peak systolic velocity in the ejection phase, time to peak positive displacement and time to peak negative strain were measured in the six basal, six mid-segmental model. Parameters of systolic asynchrony derived by velocity, displacement and strain mapping were correlated with percentage reduction in LV end systolic volume (LVESV) and absolute gain in ejection fraction (EF). Results: Among the three TDI processing technologies, all parameters of tissue velocity correlated with LV reverse remodelling (r  = −0.49 to r  =  −0.76, all p < 0.001), but the predictive value was strongest in models with 12 LV segments. For displacement mapping, only the two parameters that included 12 LV segments correlated modestly with reduction in LVESV (r  =  −0.36, p < 0.05) and gain in EF. However, none of the strain mapping parameters predicted a favourable echocardiographic response. The receiver operating characteristic (ROC) curve areas were higher for parameters of tissue velocity based on 12 LV segments (ROC areas 0.88 and 0.94) than the corresponding areas derived from displacement mapping (ROC areas 0.72 and 0.71). Conclusion: Tissue velocity parameters of systolic asynchrony are superior to those of displacement and strain mapping in predicting LV reverse remodelling response after CRT.

Effect of beta blockade (carvedilol or metoprolol) on activation of the renin-angiotensin-aldosterone system and natriuretic peptides in chronic heart failure

Beta blockers are known to suppress renin release in hypertension and in patients taking angiotensin-converting enzyme (ACE) inhibitors. This study sought to explore the effect of additional beta blockade on neurohumoral modulation in patients with severe heart failure (HF) who received ACE inhibitors. Forty-nine patients with chronic HF who received ACE inhibitors were given metoprolol 50 mg or carvedilol 25 mg twice daily after a 4-week dose titration period in addition to standard therapy in a prospective trial. Samples of plasma renin activity (PRA), aldosterone, aminoterminal B-type natriuretic peptide (N-BNP), and atrial natriuretic peptide (ANP) were taken at baseline and at 4, 12, and 52 weeks after starting therapy. Treatment with either beta blocker significantly lowered PRA at 4 weeks compared with baseline (-2.0 +/- 0.6 nmol/L/hour, p = 0.006), but at 12 weeks, PRA had reduced to -1.1 +/- 0.6 nmol/L/hour (p = 0.08), but at 52 weeks, it was not significantly different from baseline (+1.05 +/- 0.6 nmol/L/hour, p = 0.13). Aldosterone levels did not change significantly from baseline at 4 or 12 weeks, although there was a nonsignificant trend for lower levels at 52 weeks (baseline 232 +/- 154 pmol/L, 52 weeks 192 +/- 100 pmol/L, p = 0.09). There was significant reduction in N-BNP and ANP together with an improvement in symptom and left ventricular systolic function at 1-year follow-up. These results indicate that the suppressive effect of beta blockers on PRA in patients with HF taking ACE inhibitors is temporary, and that there is no significant effect on serum aldosterone levels.

Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial.

AIMS The Pacing to Avoid Cardiac Enlargement (PACE) trial is a prospective, double-blinded, randomized, multicentre study that reported the superiority of biventricular (BiV) pacing to right ventricular apical (RVA) pacing in the prevention of left ventricular (LV) adverse remodelling and deterioration of systolic function at 1 year. In the current analysis, we report the results at extended 2-year follow-up for changes in LV function and remodelling. METHODS AND RESULTS Patients (n = 177) with bradycardia and preserved LV ejection fraction (EF ≥45%) were randomized to receive RVA or BiV pacing. The co-primary endpoints were LVEF and LV end-systolic volume (LVESV). Eighty-one (92%) of 88 in the RVA pacing group and 82 (92%) of 89 patients in the BiV pacing group completed 2-year follow-up with a valid echocardiography. In the RVA pacing group, LVEF further decreased from the first to the second year, but it remained unchanged in the BiV pacing group, leading to a significant difference of 9.9 percentage points between groups at 2-year follow-up (P < 0.001). Similarly, LVESV continues to enlarge from the first to the second year in the RVA pacing group, leading to a difference of 13.0 mL (P < 0.001) between groups. Predefined subgroup analysis showed consistent results with the whole study population for both co-primary endpoints, which included patients with pre-existing LV diastolic dysfunction. Eighteen patients in the BiV pacing group (20.2%) and 55 in the RVA pacing group (62.5%) had a significant reduction of LVEF (of ≥5%, P < 0.001). CONCLUSION Left ventricular adverse remodelling and deterioration of systolic function continues at the second year after RVA pacing. This deterioration is prevented by BiV pacing.

Comparison of Efficacy of Reverse Remodeling and Clinical Improvement for Relatively Narrow and Wide QRS Complexes After Cardiac Resynchronization Therapy for Heart Failure

Introduction: Cardiac resynchronization therapy (CRT) has been shown to reverse left ventricular (LV) remodeling and improve symptoms in heart failure patients with wide QRS complexes; however, its role in patients with mildly prolonged QRS complexes is unclear. This study investigated if CRT benefited patients with mildly prolonged QRS complexes >120 to 150 ms and explored if the severity of systolic asynchrony determined such a response.

Comparison of intensive and low-dose atorvastatin therapy in the reduction of carotid intimal–medial thickness in patients with coronary heart disease

Background: Intensive statin therapy has been shown to improve prognosis in patients with coronary heart disease (CHD). It is unknown whether such benefit is mediated through the reduction of atherosclerotic plaque burden. Aim: To examine the efficacy of high-dose atorvastatin in the reduction of carotid intimal–medial thickness (IMT) and inflammatory markers in patients with CHD. Design: Randomised trial. Setting: Single centre. Patients: 112 patients with angiographic evidence of CHD. Interventions: A high dose (80 mg daily) or low dose (10 mg daily) of atorvastatin was given for 26 weeks. Main outcome measures: Carotid IMT, C-reactive protein (CRP) and proinflammatory cytokine levels were assessed before and after therapy. Results: The carotid IMT was reduced significantly in the high-dose group (left: mean (SD), 1.24 (0.48) vs 1.15 (0.35) mm, p = 0.02; right: 1.12 (0.41) vs 1.01 (0.26) mm, p = 0.01), but was unchanged in the low-dose group (left: 1.25 (0.55) vs 1.20 (0.51) mm, p = NS; right: 1.18 (0.54) vs 1.15 (0.41) mm, p = NS). The CRP levels were reduced only in the high-dose group (from 3.92 (6.59) to 1.35 (1.83) mg/l, p = 0.01), but not in the low-dose group (from 2.25 (1.84) to 3.36 (6.15) mg/l, p = NS). A modest correlation was observed between the changes in carotid IMT and CRP (r = 0.21, p = 0.03). Conclusions: In patients with CHD, intensive atorvastatin therapy results in regression of carotid atherosclerotic disease, which is associated with reduction in CRP levels. On the other hand, a low-dose regimen only prevents progression of the disease.

Effect of Left Ventricular Endocardial Activation Pattern on Echocardiographic and Clinical Response to Cardiac Resynchronization Therapy

Objective: To explore the left ventricular (LV) electrical activation pattern in heart failure (HF) and its implication to cardiac resynchronization therapy (CRT). Design and setting: Observational study at the University Teaching Hospital. Patients: 23 optimally treated patients with HF with New York Heart Association class III, QRS duration >120 ms and LV ejection fraction <35%. Interventions: The LV endocardial activation pattern and total activation time (Tat) was determined by non-contact mapping and the LV mechanical dys-synchrony was determined by standard deviation (Ts-SD) and maximal difference (Ts-diff) of time to peak systolic contraction (Ts) among 12 LV segments using tissue Doppler imaging before receiving CRT. Main outcome measures: Correlation between electrical and mechanical dys-synchrony; volumetric responder to CRT at 3 months; HF hospitalisation or death by Kaplan–Meier analysis. Results: Homogenous (type I, n = 8) and presence of conduction block (type II, n = 15) patterns were identified. Significant correlation between Tat and Ts-SD/Ts-diff was noted only in type II (r = 0.73/0.56, p = 0.002/0.03). Ts-SD and Ts-diff in type II were significantly longer than type I. 12 patients in type II and 2 in type I were CRT responders (p = 0.01). After 487 (447) days, patients with type II pattern had significantly lower risk of HF hospitalisation or death than those with type I (log rank χ2 = 5.25; p = 0.02). Conclusion: Patients with type II LV endocardial activation pattern had a more favourable echocardiographic and clinical response to CRT than those with type I pattern.