Exercise for the Prevention of Anthracycline-Induced Functional Disability and Cardiac Dysfunction: The BREXIT Study.

BACKGROUND: Breast cancer survivors treated with anthracycline-based chemotherapy (AC) have increased risk of functional limitation and cardiac dysfunction. We conducted a 12-month randomized controlled trial in 104 patients with early-stage breast cancer scheduled for AC to determine whether 12 months of exercise training (ExT) could attenuate functional disability (primary end point), improve cardiorespiratory fitness (VO2peak), and prevent cardiac dysfunction. METHODS: Women 40 to 75 years of age with stage I to III breast cancer scheduled for AC were randomized to 3 to 4 days per week aerobic and resistance ExT for 12 months (n=52) or usual care (UC; n=52). Functional measures were performed at baseline, at 4 weeks after AC (4 months), and at 12 months, comprising: (1) cardiopulmonary exercise testing to quantify VO2peak and functional disability (VO2peak ≤18.0 mL·kg-1·min-1); (2) cardiac reserve (response from rest to peak exercise), quantified with exercise cardiac magnetic resonance measures to determine changes in left and right ventricular ejection fraction, cardiac output, and stroke volume; (3) standard-of-care echocardiography-derived resting left ventricular ejection fraction and global longitudinal strain; and (4) biochemistry (troponin and BNP [B-type natriuretic peptide]). RESULTS: Among 104 participants randomized, greater study attrition was observed among UC participants (P=0.031), with 93 women assessed at 4 months (ExT, n=49; UC, n=44) and 87 women assessed at 12 months (ExT, n=49; UC, n=38). ExT attenuated functional disability at 4 months (odds ratio, 0.32 [95% CI, 0.11-0.94]; P=0.03) but not at 12 months (odds ratio, 0.27 [95% CI, 0.06-1.12]; P=0.07). In a per-protocol analysis, functional disability was prevented entirely at 12 months among participants adherent to ExT (ExT, 0% versus UC, 20%; P=0.005). Compared with UC at 12 months, ExT was associated with a net 3.5-mL·kg-1·min-1 improvement in VO2peak that coincided with greater cardiac output, stroke volume, and left and right ventricular ejection fraction reserve (P<0.001 for all). There was no effect of ExT on resting measures of left ventricular function. Postchemotherapy troponin increased less in ExT than in UC (8-fold versus 16-fold increase; P=0.002). There were no changes in BNP in either group. CONCLUSIONS: In women with early-stage breast cancer undergoing AC, 12 months of ExT did not attenuate functional disability, but provided large, clinically meaningful benefits on VO2peak and cardiac reserve. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12617001408370.

Impact of sex, socio-economic status, and remoteness on therapy and survival in heart failure.

AIMS: This study aims to determine if traditional markers of disadvantage [female sex, low socio-economic status (SES), and remoteness] are associated with lower prescription of evidence-based therapy and higher mortality among patients with moderate-severe heart failure with reduced ejection fraction. METHODS AND RESULTS: We recruited 452 consecutive class II-III heart failure with reduced ejection fraction patients. Baseline clinical data were recorded prospectively. The primary outcome was the association of female sex on overall survival. Secondary outcomes included association between evidence-based therapy delivery and sex and association of SES and remoteness on heart failure therapy and survival. The Australian Bureau of Statistics generated all indices. Median follow-up was 37.9 months. One hundred and nine patients (24.3%) were women. There was no difference in overall survival based on sex (hazard ratio = 1.19, 95% confidence interval: 0.74-1.92, 0.48). There was no difference in prescription of beta-blockers [χ2 (1) = 0.91, 0.66], angiotensin-converting enzyme inhibitors [χ2 (1) = 0.001, 0.97], nor aldosterone antagonists [χ2 (1) = 2.71, 0.10]. There was no difference in rates of primary prevention implantable cardioverter-defibrillator implantation in men compared with women [χ2 (1) = 0.35, 0.56]. Neither higher SES nor inner city residence conferred an overall survival benefit. CONCLUSIONS: In this Australian cohort of heart failure patients, delivery of care and likelihood of death are comparable between the sexes, SES groups, and rural vs. city residents.

Regression of Diffuse Ventricular Fibrosis Following Restoration of Sinus Rhythm With Catheter Ablation in Patients With Atrial Fibrillation and Systolic Dysfunction: A Substudy of the CAMERA MRI Trial.

OBJECTIVES: This study sought to determine if diffuse ventricular fibrosis improves in patients with atrial fibrillation (AF)-mediated cardiomyopathy following the restoration of sinus rhythm. BACKGROUND: AF coexists in 30% of heart failure (HF) patients and may be an underrecognized reversible cause of left ventricular systolic dysfunction. Myocardial fibrosis is the hallmark of adverse cardiac remodeling in HF, yet its reversibility is unclear. METHODS: Patients with persistent AF and an idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%) were randomized to catheter ablation (CA) or ongoing medical rate control as a pre-specified substudy of the CAMERA-MRI (Catheter Ablation versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction-an MRI-Guided Multi-centre Randomised Controlled Trial) trial. All patients had cardiac magnetic resonance imaging scans (including myocardial T1 time), serum B-type natriuretic peptide, 6-min walk tests, and Short Form-36 questionnaires performed at baseline and 6 months. Sixteen patients with no history of AF or left ventricular systolic dysfunction were enrolled as normal controls for T1 time. RESULTS: Thirty-six patients (18 in each treatment arm) were included in this substudy. Demographics, comorbidities, and myocardial T1 times were well matched at baseline. At 6 months, patients in the CA group had a significant reduction in myocardial T1 time from baseline compared with the medical rate control group (-124 ms; 95% confidence interval [CI]: -23 to -225 ms; p = 0.0176), although it remained higher than that of normal controls at 6 months (p = 0.0017). Improvements in myocardial T1 time with CA were associated with significant improvements in absolute LVEF (+12.5%; 95% CI: 5.9% to 19.0%; p = 0.0004), left ventricular end-systolic volume (p = 0.0019), and serum B-type natriuretic peptide (-216 ng/l; 95% CI: -23 to -225 ng/l; p = 0.0125). CONCLUSIONS: The improvement in LVEF and reverse ventricular remodeling following successful CA of AF-mediated cardiomyopathy is accompanied by a regression of diffuse fibrosis. This suggests timely treatment of arrhythmia-mediated cardiomyopathy may minimize irreversible ventricular remodeling.

Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction: The CAMERA-MRI Study.

BACKGROUND: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy. OBJECTIVES: The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF. METHODS: This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months. RESULTS: A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 ± 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 ± 13% in the CA group compared with 4.4 ± 13% in the MRC group (p < 0.0001) and normalized (LVEF ≥50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093). CONCLUSIONS: AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI]; ACTRN12613000880741).