Changes in clinical and imaging variables during withdrawal of heart failure therapy in recovered dilated cardiomyopathy.

AIMS: This study aimed to profile the changes in non-invasive clinical, biochemical, and imaging markers during withdrawal of therapy in patients with recovered dilated cardiomyopathy, providing insights into the pathophysiology of relapse. METHODS AND RESULTS: Clinical, biochemical, and imaging data from patients during phased withdrawal of therapy in the randomized or single-arm cross-over phases of TRED-HF were profiled. Clinical variables were measured at each study visit and imaging variables were measured at baseline, 16 weeks, and 6 months. Amongst the 49 patients [35% women, mean age 53.6 years (standard deviation 11.6)] who withdrew therapy, 20 relapsed. Increases in mean heart rate [7.6 beats per minute (95% confidence interval, CI, 4.5, 10.7)], systolic blood pressure [6.6 mmHg (95% CI 2.7, 10.5)], and diastolic blood pressure [5.8 mmHg (95% CI 3.1, 8.5)] were observed within 4-8 weeks of starting to withdraw therapy. A rise in mean left ventricular (LV) mass [5.1 g/m2 (95% CI 2.8, 7.3)] and LV end-diastolic volume [3.9 mL/m2 (95% CI 1.1, 6.7)] and a reduction in mean LV ejection fraction [-4.2 (95% CI -6.6, -1.8)] were seen by 16 weeks, the earliest imaging follow-up. Plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) fell immediately after withdrawing beta-blockers and only tended to increase 6 months after beginning therapy withdrawal [mean change in log NT-proBNP at 6 months: 0.2 (95% CI -0.1, 0.4)]. CONCLUSIONS: Changes in plasma NT-proBNP are a late feature of relapse, often months after a reduction in LV function. A rise in heart rate and blood pressure is observed soon after withdrawing therapy in recovered dilated cardiomyopathy, typically accompanied or closely followed by early changes in LV structure and function

Myocardial remodelling after withdrawing therapy for heart failure in patients with recovered dilated cardiomyopathy – insights from TRED-HF

Aims: To characterize adverse ventricular remodelling after withdrawing therapy in recovered dilated cardiomyopathy (DCM). Methods and results: TRED-HF was a randomized controlled trial with a follow-on single-arm cross-over phase that examined the safety and feasibility of therapy withdrawal in patients with recovered DCM over 6 months. The primary endpoint was relapse of heart failure defined by (i) a reduction in left ventricular (LV) ejection fraction >10% and to 10% increase in LV end-diastolic volume and to above the normal range, (iii) a twofold rise in N-terminal pro-B-type natriuretic peptide and to >400 ng/L, or (iv) evidence of heart failure. LV mass, LV and right ventricular (RV) global longitudinal strain (GLS) and extracellular volume were measured using cardiovascular magnetic resonance at baseline and follow-up (6 months or relapse) for 48 patients. LV cell and extracellular matrix masses were derived. The effect of withdrawing therapy, stratified by relapse and genotype, was investigated in the randomized and follow-on phases. In the randomized comparison, withdrawing therapy led to an increase in mean LV mass [5.4 g/m 2; 95% confidence interval (CI) 1.3–9.5] and cell mass (4.2 g/m 2; 95% CI 0.5–8.0) and a reduction in LV (3.5; 95% CI 1.6–5.5) and RV (2.4; 95% CI 0.1–4.7) GLS. In a non-randomized comparison of all patients (n = 47) who had therapy withdrawn in either phase, there was an increase in LV mass (6.2 g/m 2; 95% CI 3.6–8.9; P = 0.0001), cell mass (4.0 g/m 2; 95% CI 1.8–6.2; P = 0.0007) and matrix mass (1.7 g/m 2; 95% CI 0.7–2.6; P = 0.001) and a reduction in LV GLS (2.7; 95% CI 1.5–4.0; P = 0.0001). Amongst those who had therapy withdrawn and did not relapse, similar changes were observed (n = 28; LV mass: 5.1 g/m 2, 95% CI 1.5–8.8, P = 0.007; cell mass: 3.7 g/m 2, 95% CI 0.3–7.0, P = 0.03; matrix mass: 1.7 g/m 2, 95% CI 0.4–3.0, P = 0.02; LV GLS: 1.7, 95% CI 0.1–3.2, P = 0.04). Patients with TTN variants (n = 10) who had therapy withdrawn had a greater increase in LV matrix mass (mean effect of TTN: 2.6 g/m 2; 95% CI 0.4–4.8; P = 0.02). Conclusion: In TRED-HF, withdrawing therapy caused rapid remodelling, with early tissue and functional changes, even amongst patients who did not relapse

Heart Rate as a Marker of Relapse During Withdrawal of Therapy in Recovered Dilated Cardiomyopathy.

OBJECTIVES: The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy trial). BACKGROUND: Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management. METHODS: The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase. RESULTS: The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0-16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (P = 0.002). After data were adjusted for age, log N-terminal pro-B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate (per 10 beats/min; hazard ratio [HR]: 1.65; 95% CI: 1.10-2.57; P = 0.01) and change in heart rate from baseline (per 10 beats/min; HR: 1.70; 95% CI: 1.12-2.57; p = 0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose. CONCLUSIONS: For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED]; NCT02859311)

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust

Novel Phenotyping of the Myocardium by Diffusion Tensor Cardiovascular Magnetic Resonance

Novel Phenotyping of the Myocardium by Diffusion Tensor Cardiovascular Magnetic Resonance Dr Zohya Khalique Introduction The heart has a complex microarchitecture facilitating its function. The helical cardiomyocyte arrangement (left-handed in the epicardium through to right-handed in the endocardium) drives torsion. Sheetlets are aggregated cardiomyocytes that realign from wall-parallel in diastole, to wall-perpendicular in systole. This sheetlet mobility is integral to wall thickening. Diffusion tensor cardiovascular magnetic resonance (DT-CMR) is a novel, non-invasive technique informing about myocardial microstructure, including cardiomyocytes and sheetlets. Few in-vivo human studies exist. This research aims to investigate microstructural changes in disease and assess the utility of DT-CMR as a novel phenotyping tool. Methods Biphasic DT-CMR was performed in controls and in patients with dilated cardiomyopathy (DCM), including recovered dilated cardiomyopathy (R-DCM) and congenital disease, as exemplified by situs inversus totalis (SIT). Two main DT-CMR sequences, stimulated echo acquisition mode (STEAM) and second-order motion-compensated spin echo (M2-SE) were compared in a hypertrophic cardiomyopathy cohort. Volumetric analysis, strain assessment and late gadolinium imaging was performed. Results In DCM sheetlet mobility was reduced, with a more diastolic orientation at both cardiac phases. In R-DCM, despite normalisation of left ventricular size and ejection fraction, microstructural abnormalities persisted, with impaired sheetlet mobility. In SIT, there was gross cardiomyocyte derangement, with an overall pattern of inversion of the helical arrangement basally, transitioning to a more normal pattern apically. This microstructural derangement led to reduced torsion and strain. Finally, STEAM and M2-SE results differ due to intrinsic differences in the two sequence types. Overall STEAM was more reliable than M2-SE in biphasic DT-CMR. Conclusion DT-CMR identified novel cardiomyocyte and sheetlet abnormalities in-vivo. DT-CMR offers unique insight into microstructural changes in disease, and this work supports its potential as a powerful clinical tool assessing course and prognosis in cardiac conditions

An in-vivo comparison of stimulated-echo and motion compensated spin-echo sequences for 3 T diffusion tensor cardiovascular magnetic resonance at multiple cardiac phases

Abstract Background Stimulated-echo (STEAM) and, more recently, motion-compensated spin-echo (M2-SE) techniques have been used for in-vivo diffusion tensor cardiovascular magnetic resonance (DT-CMR) assessment of cardiac microstructure. The two techniques differ in the length scales of diffusion interrogated, their signal-to-noise ratio efficiency and sensitivity to both motion and strain. Previous comparisons of the techniques have used high performance gradients at 1.5 T in a single cardiac phase. However, recent work using STEAM has demonstrated novel findings of microscopic dysfunction in cardiomyopathy patients, when DT-CMR was performed at multiple cardiac phases. We compare STEAM and M2-SE using a clinical 3 T scanner in three potentially clinically interesting cardiac phases. Methods Breath hold mid-ventricular short-axis DT-CMR was performed in 15 subjects using M2-SE and STEAM at end-systole, systolic sweet-spot and diastasis. Success was defined by ≥50% of the myocardium demonstrating normal helix angles. From successful acquisitions DT-CMR results relating to tensor orientation, size and shape were compared between sequences and cardiac phases using non-parametric statistics. Strain information was obtained using cine spiral displacement encoding with stimulated echoes for comparison with DT-CMR results. Results Acquisitions were successful in 98% of STEAM and 76% of M2-SE cases and visual helix angle (HA) map scores were higher for STEAM at the sweet-spot and diastasis. There were significant differences between sequences (p < 0.05) in mean diffusivity (MD), fractional anisotropy (FA), tensor mode, transmural HA gradient and absolute second eigenvector angle (E2A). Differences in E2A between systole and diastole correlated with peak radial strain for both sequences (p ≤ 0.01). Conclusion M2-SE and STEAM can be performed equally well at peak systole at 3 T using standard gradients, but at the sweet-spot and diastole STEAM is more reliable and image quality scores are higher. Differences in DT-CMR results are potentially due to differences in motion sensitivity and the longer diffusion time of STEAM, although the latter appears to be the dominant factor. The benefits of both sequences should be considered when planning future studies and sequence and cardiac phase specific normal ranges should be used for comparison