Novel Imaging and Genetic Risk Markers in Takotsubo Syndrome

Takotsubo syndrome (TTS) is an increasingly recognized condition burdened by significant acute and long-term adverse events. The availability of novel techniques expanded the knowledge on TTS and allowed a more accurate risk-stratification, potentially guiding clinical management. The present review aims to summarize the recent advances in TTS prognostic evaluation with a specific focus on novel imaging and genetic markers. Parametric deformation analysis by speckle-tracking echocardiography, as well as tissue characterization by cardiac magnetic resonance imaging T1 and T2 mapping techniques, currently appear the most clinically valuable applications. Notwithstanding, computed tomography and nuclear imaging studies provided limited but promising data. A genetic predisposition to TTS has been hypothesized, though available evidence is still not sufficient. Although a genetic predisposition appears likely, further studies are needed to fully characterize the genetic background of TTS, in order to identify genetic markers that could assist in predicting disease recurrences and help in familial screening.

Dorfman-Chanarin Syndrome: A Rare Cause of Metabolic Associated Fatty Liver Disease Related to Homozygosity of the Nonsense Mutation c.934C>T (p.R312*)

Metabolic associated fatty liver disease became the most common form of chronic liver disease, in the vast majority of the cases related to increased insulin resistance or metabolic dysregulation. Yet, other causes may be implied. We report the late diagnosis of Dorfman-Chanarin syndrome in a non-alcoholic steatohepatitis previously labeled cirrhotic middle-aged man, with consanguineous parents, complicated with hepatocellular carcinoma. Congenital ichthyosis, neurosensory hearing loss and elevated muscular enzymes hit on the track of Dorfman-Chanarin syndrome. The genetic analysis uncovered a first-time described homozygotic nonsense mutation in the <i>ABHD5</i> gene, responsible for coding the ABHD5 protein. The patient was successfully submitted to liver transplantation. Inborn errors of metabolism are a rare cause of metabolic associated fatty liver disease, but they need to be kept in consideration in all patients who present with atypical clinical features. This shall raise the awareness of physicians to rare forms of presentation since it may imply not only a different prognosis, but also other actions, like particular therapies as liver transplantation due to related complications of cirrhosis, or familial screening.

Unmet needs in the treatment of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a complex heterogeneous cardiovascular disorder characterized by hypertrophied and disorganized myocytes with varying degrees of interstitial fibrosis. The current management strategies include genetic and familial screening, symptom control and prevention of sudden cardiac death in those at high risk. Until recently, septal reduction therapy and heart transplantation were the only disease modifying treatments available to manage HCM, but emerging pharmacotherapies show promising results in controlled clinical trials. In this article, we will review the unmet needs in the treatment of HCM incorporating novel therapies.

Case Report: Novel Likely Pathogenic ACTN2 Variant Causing Heterogeneous Phenotype in a Korean Family With Left Ventricular Non-compaction

Left ventricular non-compaction (LVNC) is a very rare primary cardiomyopathy with a genetic etiology, resulting from the failure of myocardial development during embryogenesis, and it carries a high risk of left ventricular dysfunction, thromboembolic phenomenon, and malignant arrhythmias. Here, we report the first case of familial LVNC in Korea, caused by a novel ACTN2 missense variant. We performed duo exome sequencing (ES) to examine the genome of the proband and his father. A 15-year-old boy was admitted for the evaluation of exertional dyspnea for 2 weeks. He was diagnosed with LVNC with a dilated cardiomyopathy phenotype [left ventricular end-diastolic dimension 60 mm, interventricular septal dimension 8.2 mm by transthoracic echocardiography (TTE)]. For the screening of familial cardiomyopathy, TTE and cardiac magnetic resonance imaging (cMRI) were performed, which revealed hypertrophic and isolated LVNC in the proband's father and sister, respectively. In particular, the cMRI revealed dense hypertrabeculation with focal aneurysmal changes in the apical septal wall in the proband's father. ES of the father–son duo identified a novel heterozygous c.668T&gt;C variant of the ACTN2 gene (NM_001103.3:c.668T&gt;C, p.Leu223Pro; no rsID) as the candidate cause of autosomal dominant LVNC. Sanger sequencing confirmed this novel variant in the proband, his father, and sister, but not in the proband's grandmother. Even within families harboring the same variant, a variable risk of adverse outcomes is common. Therefore, familial screening for patients with LVNC associated with ACTN2 variant should be performed for early detection of the LVNC phenotype associated with poor outcomes, such as dilated LVNC.

IPF cluster analysis highlights diagnostic delay and cardiovascular comorbidities association with outcome

IntroductionIdiopathic pulmonary fibrosis (IPF) prognosis is heterogeneous despite antifibrotic treatment. Cluster analysis has proven to be a useful tool in identifying interstitial lung disease phenotypes, which has yet to be performed in IPF. The aim of this study is to identify phenotypes of IPF with different prognoses and requirements.MethodsObservational retrospective study including 136 IPF patients receiving antifibrotic treatment between 2012–2018. Six patients were excluded due to follow-up in other centers. Cluster analysis of 30 variables was performed using approximate singular value-based tensor decomposition method and comparative statistical analysis.ResultsThe cluster analysis identified 3 different groups of patients according to disease behavior and clinical features, including mortality, lung transplant and progression-free survival time after 3-year follow-up. Cluster 1 (n=60) was significantly associated (p=0.02) with higher mortality. Diagnostic delay was the most relevant characteristic of this cluster, as 48% of patients had ≥2 years from first respiratory symptoms to antifibrotic treatment initiation. Cluster 2 (n=22) had the longest progression-free survival time and was correlated to subclinical patients evaluated in the context of incidental findings or familial screening. Cluster 3 (n=48) showed the highest percentage of disease progression without cluster 1 mortality, with metabolic syndrome and cardiovascular comorbidities as the main characteristics.ConclusionThis cluster analysis of IPF patients suggests that diagnostic and treatment delay are the most significant factors associated with mortality, while IPF progression was more related to metabolic syndrome and cardiovascular comorbidities.

Genomics and Epigenomics in Parathyroid Neoplasia: from Bench to Surgical Pathology Practice

The majority of parathyroid disease encountered in routine practice is due to single parathyroid adenoma, of which the majority arise as sporadic tumors. This is usually a straightforward diagnosis in endocrine pathology when in the appropriate clinical setting, although subsets of cases will exhibit atypical histological features that may warrant additional immunohistochemical and genetic analyses to estimate the malignant potential. Parathyroid carcinomas on the other hand, are bona fide malignant tumors characterized by their unequivocal invasion demonstrated through routine histology or metastasis. The ultimate endpoint for any molecular marker discovered through laboratory investigations is to be introduced in clinical routine practice and guide the surgical pathologist in terms of diagnostics and prognostication. For parathyroid tumors, the two main diagnostic challenges include the distinction between parathyroid adenoma and parathyroid carcinoma, as well as the pinpointing of hereditable disease for familial screening purposes. While numerous markers on genetic, epigenetic, and protein levels have been proposed as discriminative in these aspects, this review aims to condense the scientific coverage of these enigmatic topics and to propose a focused surgical pathology approach to the subject.

2423Familial cardiomyopathy in patients affected by acute myocarditis is strongly associated to DSP gene mutations

Background The link between acute myocarditis (AM) and familial cardiomyopathy remains unclear. Purpose To assess the clinical significance of AM in families with cardiomyopathy. Methods and results We describe the pedigree of 6 families with at least one familial case of AM and a familial history of cardiomyopathy or sudden death (SD). AM was defined as an infarct-like clinical presentation with normal coronary arteries and myocardial inflammation (MI) documented by cardiac magnetic resonance (CMR), or as an autopsy proven AM. Detailed familial pedigrees are shown in the picture. In family 1 to 5, genetic testing was triggered by the association of a documented case of AM with an index case of cardiomyopathy or early SD. In this setting, all genetic testing revealed a mutation in the desmoplakin (DSP) gene. In family 1, patient II.1 (15 y.o) was diagnosed with AM, 6 months after his sister died suddenly at the age of 12. In family 2, patient II.4 (17 y.o) was diagnosed with AM. His mother had a DCM, with a CMR revealing the presence of MI. In family 3, patient IV.3 (22 y.o) died suddenly from an AM, attested by post-mortem autopsy. Her aunt had a DCM. In family 4, patient II.4 (41 y.o) had an AM, progressing toward a DCM. Her mother had died suddenly at the age of 39, and her niece had a DCM. In family 5, patient V.16 (9 y.o) presented 4 recurrent episodes of AM. Her cousin's mother had a DCM. In family 6, patient IV.3 had 3 episodes of AM, his father had previously been diagnosed with an arrythmogenic right ventricular cardiomyopathy (ARVC) with a desmoglein 2 (DSG2) mutation. Table shows detailed genotype-phenotype relationship in all mutation carriers screened in the 6 families. Phenotypes observed in mutation carriers Mutation DCM ARVC AM Isolated LGE (no cardiomyopathy, no AM) Family 1 (n=3) DSP 0 0 1 1 Family 2 (n=3) DSP 1 0 1 0 Family 3 (n=11) DSP 5 0 1 0 Family 4 (n=3) DSP 2 0 1 0 Family 5 (n=7) DSP 2 0 1 3 Family 6 (n=5) DSG2 0 1 1 1 Family Pedigrees Conclusion AM is strongly associated to desmosomal mutations when a familial history of cardiomyopathy is present, particularly in DSP gene. In these families, DCM phenotype and SD are frequent, and a notable proportion of isolated LGE suggestive of myocardial fibrosis is present in asymptomatic relatives. These results highlight the need for a comprehensive familial screening in case of AM.