Comparative prognostic importance of measures of left atrial structure and function in non-ischaemic dilated cardiomyopathy

AimsThis study aimed to compare the association between measures of left atrial (LA) structure and function, derived from cardiovascular magnetic resonance (CMR), with cardiovascular death or non-fatal heart failure events in patients with non-ischaemic dilated cardiomyopathy (DCM). Methods and resultsCMR studies of 580 prospectively recruited patients with DCM in sinus rhythm [median age 54 (interquartile range 44-64) years, 61% men, median left ventricular ejection fraction 42% (30-51%)] were analysed for measures of LA structure [LA maximum volume index (LAVImax) and LA minimum volume index (LAVImin)] and function (LA emptying fraction, LA reservoir strain, LA conduit strain (LACS), and LA booster strain]. Over a median follow-up of 7.4 years, 103 patients (18%) met the primary endpoint. Apart from LACS, each measure of LA structure and function was associated with the primary endpoint after adjusting for other important prognostic variables. The addition of each LA metric to a baseline model containing the same important prognostic covariates improved model discrimination, with LAVImin providing the greatest improvement [C-statistic improvement: 0.702-0.738; χ2 test comparing likelihood ratio P &lt; 0.0001; categorical net reclassification index: 0.210 (95% CI 0.023-0.392)]. Patients in the highest tercile of LAVImin had similar event rates to those with persistent atrial fibrillation. Measures of LA strain did not enhance model discrimination above LA volumetric measures. ConclusionMeasures of LA structure and function offer important prognostic information in patients with DCM and enhance the prediction of adverse outcomes. LA strain was not incremental to volumetric analysis for risk prediction.</p

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)

Long‐term follow‐up of the TRED ‐ HF trial: Implications for therapy in patients with dilated cardiomyopathy and heart failure remission

Aims: In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after therapy withdrawal. This follow-up investigates the longer-term effects of therapy withdrawal. Methods and results: TRED-HF was a randomized trial investigating heart failure therapy withdrawal in patients with recovered DCM over 6 months. Those randomized to continue therapy subsequently withdrew treatment between 6 and 12 months. Participants were recommended to restart therapy post-trial and were followed until May 2023. Clinical outcomes are reported in a non-randomized fashion from enrolment and from the end of the trial. The primary outcome was relapse defined as ≥10% reduction in left ventricular ejection fraction to &lt;50%, doubling in N-terminal pro-B-type natriuretic peptide to &gt;400 ng/L, or clinical features of heart failure. From enrolment to the last follow-up (median 6 years, interquartile range 6–7), 33 of 51 patients (65%) relapsed. The 5-year relapse rate from enrolment was 61% (95% confidence interval [CI] 45–73) and from the end of the trial was 39% (95% CI 19–54). Of 20 patients who relapsed during the trial, nine had a recurrent relapse during follow-up. Thirteen relapsed for the first time after the trial; seven had restarted low intensity therapy, four had not restarted therapy and two did not have therapy withdrawn. The mean intensity of therapy was lower after the trial compared to enrolment (mean difference −6 [−8 to −4]; p &lt; 0.001). One third of relapses during follow-up had identifiable triggers (arrhythmia [n = 4], pregnancy [n = 1], hypertension [n = 1], infection [n = 1]). Corrected atrial fibrillation was associated with reduced risk of relapse (hazard ratio 0.33, 95% CI 0.12–0.96; p = 0.042). Conclusions: The risk of relapse in the 5 years following the TRED-HF trial remained high. Restarting lower doses of heart failure medications at the end of the trial, external triggers and disease progression are likely to have contributed to relapse

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

Fibrosis Entropy Is Associated With Life-Threatening Arrhythmia in Nonischemic Cardiomyopathy

Background: Greater precision is required for arrhythmic risk stratification of patients with nonischemic cardiomyopathy (NICM). We sought to evaluate whether fibrosis entropy, a measure of scar texture heterogeneity derived from late gadolinium enhancement cardiovascular magnetic resonance, has incremental utility to fibrosis presence for arrhythmic risk prediction in NICM.  Methods: In this prospective observational cohort study, fibrosis entropy was calculated for patients with NICM and fibrosis (late gadolinium enhancement positive, LGE+), including regions of core fibrosis, gray zone fibrosis and combined core and gray zone fibrosis. Patients with NICM and no fibrosis (LGE-) were included as a comparator group. Adjudicated follow-up for life-threatening arrhythmia included sudden cardiac death, aborted sudden cardiac death, or sustained ventricular tachycardia.  Results: Of 291 patients with LGE+ NICM, 38 (13.1%) experienced life-threatening arrhythmia over a median follow-up of 6.3 years. Core fibrosis entropy (per-SD hazard ratio [HR], 1.77 [95% CI, 1.25-2.52]; =0.001), gray zone fibrosis entropy (HR, 1.97 [95% CI, 1.20-2.54]; =0.004), and combined fibrosis entropy (HR, 1.98 [95% CI, 1.30-3.02]; =0.004) were each associated with life-threatening arrhythmia after adjustment for variables used to determine implantable cardioverter-defibrillator candidacy in clinical practice (left ventricular ejection fraction ≤35% and New York Heart Association class >1) and remained associated after accounting for core and gray zone fibrosis mass. Left ventricular ejection fraction ≤35% was not associated with life-threatening arrhythmia (HR, 1.45 [95% CI, 0.77-2.74]; =0.250). Integration of fibrosis presence with fibrosis entropy classified patients into low-, intermediate-, and high-arrhythmic-risk groups.  Conclusions: Deeper phenotypic characterization of scar using fibrosis entropy offers incremental utility to left ventricular ejection fraction and fibrosis presence for arrhythmic risk stratification in NICM

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