Background: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)–based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. Methods: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. Results: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P =0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P =0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P =0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. Conclusions: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. Registration: HREC/13/SVH/66 and HREC/17/SVH/80. Australian New Zealand Clinical Trials Registry: ACTRN12618000672257.

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Truncating TTN variants (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but disease manifestations in human TTNtv carriers vary widely. We hypothesised that individual context of background genetic and environmental factors is an important determinant of TTNtv phenotype. To investigate this hypothesis, we used a zebrafish model of a human A-band TTNtv to evaluate the effects of chronic alcohol exposure. 7-month-old male fish (n=50/genotype/treatment) were randomly assigned to immersion in plain water with/without 0.5(v/v)% ethanol (EtOH) for 6 weeks. Heart were evaluated using high-frequency echocardiography, ECG, micro-computed tomography, histology, and RNA-sequencing (RNAseq). There were significant genotype x environment (G x E) effects on ventricular systolic function with EtOH-treated TTN tv/+ fish showing reduced ejection fraction (p=0.001, two-way ANOVA) and global longitudinal strain (p=0.005), relative to EtOH-treated WT fish and vehicle-treated TTN tv/+ fish. There were modest EtOH effects on isovolumic relaxation time (p=0.033) and peak E wave velocity (p=0.006), with G x E interactions (p=0.046) for peak A wave velocity and PR interval (p=0.016). No myocardial hypertrophy, fibrosis or apoptosis was evident. RNAseq revealed a distinct molecular signature in EtOH-treated TTN tv/+ cardiomyocytes, with .400 differentially expressed genes that affected pathways involving transcription, ribosome assembly, mRNA splicing and protein translation. Our data indicate that titin deficiency provides a sensitised template for cardio-depressant effects of EtOH. A failure of TTN tv/+ hearts to upregulate protein biosynthesis in response to mechanical stress may contribute to disease progression. We propose that alcohol is an important modifiable risk factor for patients with TTNtv-related DCM.

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