Myocarditis Following COVID-19 Vaccination: A Systematic Review (October 2020-October 2021).

INTRODUCTION: Reports of SARS-CoV-2 coronavirus (COVID-19) vaccine-related myocarditis, particularly after mRNA vaccines, have raised concerns amongst the general public. This review examined the literature regarding myocarditis post COVID-19 vaccination, drawing from vaccine safety surveillance databases and case reports. METHODS: Combinations of search terms were used in PubMed and COVID-19-specific repositories - LitCovid and the Cochrane COVID-19 Study Register - between 1 October 2020 and 31 October 2021. Manual searches of GoogleScholar and screening of article bibliographies were also performed. RESULTS: Information was obtained from five vaccine safety surveillance databases. Fifty-two (52) case reports totalling 200 cases of possible COVID-19 vaccine-related myocarditis were summarised. Vaccine surveillance databases differed in reporting formats and vaccination rates; however, gross estimates suggested low overall incidence rates of 2-5 per million mRNA vaccines. The incidence appeared to be higher in younger male populations, with onset of symptoms within a few days, usually after the second dose. Some with prior COVID-19 infections had onset after the first dose. Cases with prior unrelated myocarditis were also noted. Almost all presented with chest pain (98.0%). Troponin elevation was universally described and cardiac magnetic resonance imaging was commonly reported based on the updated Lake Louise criteria. Clinical course was mild in the majority, with response to anti-inflammatory treatment. CONCLUSION: COVID-19 vaccine-related myocarditis is an important but rare adverse event. More research is needed into its pathogenesis and reasons for its predominance in young males, while gaps in data exist in those aged <16 years, as well as those with prior COVID-19 infections and prior myocarditis.

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. METHODS: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. RESULTS: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. CONCLUSIONS: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.

Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is a complication reported in patients post left ventricular assist device (LVAD) implantation that is associated with high mortality rates. Thalidomide is an anti-angiogenic compound that may offer a potential option for management of refractory LVAD-related GIB. METHODS: A single-center, retrospective review was conducted from January 2009 to October 2016 at a tertiary cardiology center. It included LVAD patients initiated on thalidomide for refractory GIB. RESULTS: All patients (n = 11) were started on thalidomide 50 mg nocte and there was resolution of GIB in all patients except one (90.9%) during initial thalidomide treatment.The median duration of thalidomide therapy was 98 days (interquartile range: 34-215). The dose of thalidomide was reduced for 2 patients due to adverse effects. Thalidomide therapy was discontinued in 6 patients due to cessation of GIB (n = 4) and adverse effects (n = 2). Reported adverse effects included LVAD thrombosis (n = 2), somnolence (n = 1), neuropathy (n = 1), constipation (n = 1), and transaminitis (n = 1).Recurrent GIB occurred in 4 patients (45.4%) post-discontinuation of thalidomide therapy, which led to the re-initiation of therapy. CONCLUSIONS: Thalidomide appears to be a safe and effective option for management of refractory LVAD-related GIB. Monitoring for recurrent GIB should be performed closely following cessation of thalidomide therapy.

Titin-truncating variants affect heart function in disease cohorts and the general population.

Titin-truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ∼1% of the general population, where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv, we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout titin were significantly associated with DCM. Ribosomal profiling in rat showed the translational footprint of premature stop codons in Ttn, TTNtv-position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-learning-based analysis of high-resolution cardiac imaging showed TTNtv to be associated with eccentric cardiac remodeling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.