Minimal inflammatory foci of unknown etiology may be a tentative sign of early stage inherited cardiomyopathy

Hata, Yukiko; Hirono, Keiichi; Yamaguchi, Yoshiaki; Ichida, Fukiko; Oku, Yuko; Nishida, Naoki

doi:10.1038/s41379-019-0274-0

Cited by 18 publications

(14 citation statements)

References 49 publications

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“…An interesting observation in the reported family is a first diagnosis of pericarditis as the underlying etiology during the initial manifestation, as reported by others (Reichl, Kreykes, Martin, & Shenoy, 2018). A study based on post-mortem cases showed the importance of genetic testing in patients with minimal inflammatory foci (<1% of the whole examined ventricle) with unknown specific etiology in the setting of the inconclusive cause of death (Hata et al, 2019). In a cohort of 1,072 serial autopsy subjects, 10 patients with minimal unexplained inflammatory foci, eight of which died of a sudden unexpected death, were genotyped.…”

Section: Systematic Review Of Dsp Missense Variantssupporting

confidence: 64%

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

Grondin

Wazirian

Jordà

et al. 2020

American J of Med Genetics Pt A

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Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life‐threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.

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Section: Systematic Review Of Dsp Missense Variantssupporting

confidence: 64%

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

Grondin

Wazirian

Jordà

et al. 2020

American J of Med Genetics Pt A

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“…Moreover, etiology of myocarditis is various, including not only infective (mostly viral) but also non-infective causes (toxic, immune, genetic predisposition, etc.) [ 11 , 21 – 25 ]. When molecular pathology investigation was applied systematically in the setting of inflammatory cardio-respiratory diseases, such as interstitial pneumonia, bronchiolitis, and lymphocytic myocarditis, it provided additional data in terms of disease etiopathogenesis, by revealing viral genomes in three-quarter of SUID cases vs none of the histologically “negative” cases (SIDS), thus supporting a causative association.…”

Section: Discussionmentioning

confidence: 99%

A standardized postmortem protocol to assess the real burden of sudden infant death syndrome

et al. 2020

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Sudden unexpected infant death (SUID) is a major cause of death in infants < 1 year of age. Sudden infant death syndrome (SIDS) is a SUID still unexplained after post-mortem examination. In 2014, a protocol of post-mortem investigation was introduced to assess both the prevalence and the etiopathogenesis of SUID. Our aim was to compare SUID data before and after the application of a standardized autopsy protocol of investigation. In the time interval 2004-2018, SUID cases occurring in the Veneto Region, NorthEast Italy, were referred to our Core Lab. Since 2014, a complete autopsy was performed, including gross and histological study with toxicologic and molecular analysis carried out at the referral center. A total of 36 SUIDs (22 M, mean age 95.5 ± 80 days), 17 before (group A) and 19 after (group B) 2014, were collected. In group A, only 1 (6%) resulted as explained SUID, due to lymphocytic myocarditis and 16 (94%) were SIDS. In group B, 8 were SIDS (42%) and 11 (58%) explained SUID cases (p < 0.01), consisting of interstitial pneumonia and bronchiolitis in 9 and lymphocytic myocarditis in 2 cases. Molecular analysis was positive for viruses in 8 of them (73%). In conclusion, since the application of a standardized protocol of post-mortem investigation, inflammatory, mostly infective, cardio-pulmonary diseases have been identified as the most common cause of SUID, with SIDS falling from 94 to 42% of SUID. Efforts must be made to implement a uniform autopsy protocol to provide reliable epidemiological data on SIDS.

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“…Monogenetic familial forms of acute myocarditis or chronic inflammatory cardiomyopathies are rare. Nevertheless, arrhythmogenic cardiomyopathies, in particular those caused by heterozygous pathogenic variants in DSP , have been associated with increased cardiac inflammation and a clinical presentation of acute myocarditis with elevated plasma troponin levels in addition to typical cardiac MRI or PET-CT scan abnormalities 216 – 220 . A homozygous but not heterozygous carrier state of rare variants in genes associated with inherited arrhythmogenic cardiomyopathies is significantly more frequent in children with acute myocarditis than in healthy individuals 221 .…”

Section: Diagnosis and Prognosismentioning

confidence: 99%

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

et al. 2020

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Inflammatory cardiomyopathy is defined as myocarditis in association with cardiac dysfunction and ventricular remodelling 1,2. Despite extensive research and improved diagnosis and understanding of the pathogenesis of inflammatory cardiomyopathy, this disorder is still associated with a poor prognosis when complicated by left ventricular (LV) dysfunction, heart failure (HF) or arrhythmia 3. Furthermore, fulminant myocarditis, a rare, sudden and severe cardiac inflammation, is one of the main causes of cardiogenic shock in young adults 4,5. Prompt diagnosis and specific treatment strategies are needed to reduce mortality and the need for heart transplantation in these patients 4,5. Many questions remain unanswered regarding the pathogenesis of inflammatory cardiomyopathy and the role of the viral infection, the immune system, the host genetic background and the environment in disease progression and prognosis. These gaps in knowledge highlight the need for advanced experimental systems that can better model the human immune system and the need to improve the characterization and classification of the patients, for example, with the use of phenomapping and phenomics, which involve detailed evaluation of immune status, viral presence and/or other biomarkers. In this Review, we discuss the available evidence and identify the gaps in our understanding of the pathogenesis, diagnosis, treatment and prognosis of myocarditis and inflammatory cardiomyopathy, appraise the available animal and cell models of these conditions and propose future directions for the field. We discuss the role

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Minimal inflammatory foci of unknown etiology may be a tentative sign of early stage inherited cardiomyopathy

Cited by 18 publications

References 49 publications

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review

A standardized postmortem protocol to assess the real burden of sudden infant death syndrome

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

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