Your Heart Function Has Normalized-What Next After TRED-HF?

PURPOSE OF REVIEW: With the widespread implementation of contemporary disease-modifying heart failure therapy, the rates of normalization of ejection fraction are continuously increasing. The TRED-HF trial confirmed that heart failure remission rather than complete recovery is typical in patients with dilated cardiomyopathy who respond to therapy. The present review outlines key points related to the management and knowledge gaps of this growing patient group, focusing on patients with non-ischaemic dilated cardiomyopathy. RECENT FINDINGS: There is substantial heterogeneity among patients with normalized ejection fraction. The specific etiology is likely to affect the outcome, although a multiple-hit phenotype is frequent and may not be identified without comprehensive characterization. A monogenic or polygenic genetic susceptibility is common. Ongoing pathophysiological processes may be unraveled with advanced cardiac imaging, biomarkers, multi-omics, and machine learning technologies. There are limited studies that have investigated the withdrawal of specific heart failure therapies in these patients. Diuretics may be safely withdrawn if there is no evidence of congestion, while continued therapy with at least some disease-modifying therapy is likely to be required to reduce myocardial workload and sustain remission for the vast majority. Understanding the underlying disease mechanisms of patients with normalized ejection fraction is crucial in identifying markers of myocardial relapse and guiding individualized therapy in the future. Ongoing clinical trials should inform personalized approaches to therapy.

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 <50%, doubling in N-terminal pro-B-type natriuretic peptide to >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 < 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.

Precision prediction of heart failure events in patients with dilated cardiomyopathy and mildly reduced ejection fraction using multi-parametric cardiovascular magnetic resonance.

AIMS: To assess whether left ventricular (LV) global longitudinal strain (GLS), derived from cardiovascular magnetic resonance (CMR), is associated with (i) progressive heart failure (HF), and (ii) sudden cardiac death (SCD) in patients with dilated cardiomyopathy with mildly reduced ejection fraction (DCMmrEF). METHODS AND RESULTS: We conducted a prospective observational cohort study of patients with DCM and LV ejection fraction (LVEF) ≥40% assessed by CMR, including feature-tracking to assess LV GLS and late gadolinium enhancement (LGE). Long-term adjudicated follow-up included (i) HF hospitalization, LV assist device implantation or HF death, and (ii) SCD or aborted SCD (aSCD). Of 355 patients with DCMmrEF (median age 54 years [interquartile range 43-64], 216 men [60.8%], median LVEF 49% [46-54]) followed up for a median 7.8 years (5.2-9.4), 32 patients (9%) experienced HF events and 19 (5%) died suddenly or experienced aSCD. LV GLS was associated with HF events in a multivariable model when considered as either a continuous (per % hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.00-1.21, p = 0.045) or dichotomized variable (LV GLS > -15.4%: HR 2.70, 95% CI 1.30-5.94, p = 0.008). LGE presence was not associated with HF events (HR 1.49, 95% CI 0.73-3.01, p = 0.270). Conversely, LV GLS was not associated with SCD/aSCD (per % HR 1.07, 95% CI 0.95-1.22, p = 0.257), whereas LGE presence was (HR 3.58, 95% CI 1.39-9.23, p = 0.008). LVEF was neither associated with HF events nor SCD/aSCD. CONCLUSION: Multi-parametric CMR has utility for precision prognostic stratification of patients with DCMmrEF. LV GLS stratifies risk of progressive HF, while LGE stratifies SCD risk.

Automated analysis and detection of abnormalities in transaxial anatomical cardiovascular magnetic resonance images: a proof of concept study with potential to optimize image acquisition.

The large number of available MRI sequences means patients cannot realistically undergo them all, so the range of sequences to be acquired during a scan are protocolled based on clinical details. Adapting this to unexpected findings identified early on in the scan requires experience and vigilance. We investigated whether deep learning of the images acquired in the first few minutes of a scan could provide an automated early alert of abnormal features. Anatomy sequences from 375 CMR scans were used as a training set. From these, we annotated 1500 individual slices and used these to train a convolutional neural network to perform automatic segmentation of the cardiac chambers, great vessels and any pleural effusions. 200 scans were used as a testing set. The system then assembled a 3D model of the thorax from which it made clinical measurements to identify important abnormalities. The system was successful in segmenting the anatomy slices (Dice 0.910) and identified multiple features which may guide further image acquisition. Diagnostic accuracy was 90.5% and 85.5% for left and right ventricular dilatation, 85% for left ventricular hypertrophy and 94.4% for ascending aorta dilatation. The area under ROC curve for diagnosing pleural effusions was 0.91. We present proof-of-concept that a neural network can segment and derive accurate clinical measurements from a 3D model of the thorax made from transaxial anatomy images acquired in the first few minutes of a scan. This early information could lead to dynamic adaptive scanning protocols, and by focusing scanner time appropriately and prioritizing cases for supervision and early reporting, improve patient experience and efficiency.