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Abstract Background Alkaptonuria is a rare congenital metabolic disorder characterized by homogentisic acid accumulation in body cartilage and connective tissues due to a deficient homogentisic acid dioxygenase enzyme. This disorder manifests in various clinical symptoms, including spondyloarthropathy, ocular and dermal pigmentation, genitourinary tract obstruction by ochronosis stones, and cardiovascular system involvement. Cardiac ochronosis is a rare manifestation of alkaptonuria that may present as aortic stenosis, sometimes accompanied by other cardiovascular complications. Case presentation We report an unexpected case of ochronosis diagnosed during cardiac surgery. Due to the fragile, thin, and atheromatous nature of the ascending aorta in patients with ochronosis, we opted for a sutureless aortic valve replacement procedure. This approach appears to be more suitable for patients with ochronosis. Conclusions Although cardiac ochronosis is rare, surgeons should remain vigilant and consider the possibility of this condition when examining patients with aortic valve stenosis, paying close attention to the clinical manifestations of alkaptonuria.

Abstract Aims Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease where polyglucosan accumulation leads to cardiomyopathy and skeletal muscle myopathy. Variants of RBCK1 is related with PGBM1. We present a newly discovered pathogenic RBCK1 variant resulting in dilated cardiomyopathy (DCM) and a comprehensive literature review. Methods and results Whole‐exome sequencing (WES) was utilized to detect genetic variations in a 7‐year‐old girl considered the proband. Sanger sequencing was performed to validate the variant in the patient and all the available family members, whether affected or unaffected. The variant's pathogenicity was assessed by conducting a cosegregation analysis within the family with in silico predictive software. WES showed that the proband's RBCK1 gene contained a missense likely pathogenic homozygous nucleotide variant, c.598_599insT: p.His200LeufsTer14 (NM_001323956.1), in exon 8. The computational analysis supported the variant's pathogenicity. The variant was identified in a heterozygous form among all the healthy members of the family. Variants with changes in N‐terminal part of the protein were more likely to manifest immunodeficiency and auto‐inflammation than those with C‐terminal protein modifications according to prior variations of RBCK1 reported in the literature. Conclusions Our study offers novel findings indicating an RBCK1 variant in individuals of Iranian ancestry presenting with DCM leading to heart transplantation and myopathy without immunodeficiency or auto‐inflammation.

Introduction: Cytomegalovirus (CMV) infection is mainly associated with acute or chronic graft rejection in various solid organs. This study was conducted with the aim of evaluating the plasma viral load of CMV infection in postheart transplant patients and its correlation with the grading of cellular graft rejection in endomyocardial biopsies. Materials and Methods: In a cross-sectional study, 90 samples from 65 asymptomatic heart transplant recipients scheduled for routine endomyocardial biopsy were obtained. All the recipients had a history of positive serology for CMV infection before transplantation. Evaluation of their DNA was tracked using the polymerase chain reaction technique and the use of specific virus DNA primers, and based on this, the peak virus load (the number of virus copies per milliliter) was determined. A peak viral load >10,000 copies/mL was considered positive. Graft rejection grading was determined based on the ISHLT grading system. Results: The mean (standard deviation) age of the patients (37 men) was 67 (37.3) years. The graft rejection grading was as follows: 22.2% grade 0, 38.9% Quilty effect (QE), 35.6% grade 1, and 3.3% grade 2. The mean plasma viral load level of CMV infection was 2197.4 (1256.2) μg/μL, 1970.4 (1150.3) μg/μL, and 4567.2 (1669.1) μg/μL in grades 0, QE, and 1 and/or 2, respectively (P < 0.001). The virus load was significantly higher in those with higher grades of cellular rejection. Conclusion: The relationship between the plasma level of CMV viral load and the grading of cellular graft rejection in heart transplant patients could emphasize the role of CMV virus in the pathophysiology of graft rejection. A closer surveillance for CMV infection using the viral load is also recommended in particular in those who have higher grades of graft rejection.

Abstract Background Limb girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders with a very variable clinical presentation and overlapping traits. The clinical symptoms of LGMD typically appear in adolescence or early adulthood. Genetic variation in the dysferlin gene (DYSF) has been associated with LGMD. Methods We characterized a recessive LGMD in a young adult from consanguineous Irani families using whole-exome sequencing (WES) technology. Sanger sequencing was performed to verify the identified variant. Computational modeling and protein-protein docking were used to investigate the impact of the variant on the structure and function of the DYSF protein. Results By WES, we identified a novel homozygous missense variant in DYSF (NM_003494.4: c.5876T > C: p. Leu1959Pro) previously been associated with LGMD phenotypes. Conclusions The identification and validation of new pathogenic DYSF variant in the present study further highlight the importance of this gene in LGMD.

Abstract The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype–phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.

Abstract Background Mediastinal gray zone lymphoma is a newly recognized rare B cell neoplasm, which is challenging in diagnosis and treatment. Case presentation In the current study, we aimed to report a 25-year-old pregnant woman at 25 weeks of gestation who presented with chronic cough and progressive shortness of breath, hypotension, tachycardia, and tachypnea. A large circumferential pericardial effusion with compressive effect on the right atrium and right ventricle and a large extracardiac mass with external pressure to mediastinal structures were seen on trans thoracic echocardiography. The emergency pericardiocentesis was performed with the diagnosis of cardiac tamponade. Also, CMR revealed a huge heterogeneous anterior mediastinal mass, and the pathology and the immunohistochemistry of the mass biopsy revealed gray zone lymphoma with positive CD3, CD20, CD30, CD45, PAX5, and negative CD15 expression. Three courses of chemotherapy with the CHOP regimen were performed with an acceptable response every three weeks before delivery. A caesarian section was performed at 37 weeks without any problem for the patient and fetus, and chemotherapy will be started three weeks after delivery. Conclusion Cardiac tamponade as an emergency condition occurred in this pregnant patient by malignant pericardial effusion and mediastinal mass pressure. Accurate diagnosis and on time interventions caused a significant improvement and a successful delivery.

Resumo Os últimos meses de 2019 foram marcados pelo surgimento de uma nova pandemia, denominada “COVID-19”. Desde então, essa infecção e suas complicações têm sido a prioridade de profissionais de saúde, com muitos sintomas atribuídos às suas apresentações precoces e tardias. Até o momento, outras doenças, mesmo em situações fatais, têm sido negligenciadas ou diagnosticadas incorretamente devido à atribuição dos sintomas do paciente à presença da infecção por COVID-19. Apresentamos aqui um caso de angiossarcoma cardíaco, em um menino que, cerca de 2 meses antes, havia sido infectado com COVID-19. Dado o histórico de infecção, a abordagem inicial foi o manejo da miopericardite pós-COVID-19. No entanto, o quadro do paciente piorou, exigindo reavaliação por multimodalidades com maior precisão. Por fim, o paciente foi diagnosticado com um tumor cardíaco. Este artigo procura enfatizar a importância da atenção a outras doenças e condições fatais na era COVID-19, com ênfase em evitar diagnósticos incorretos de outras doenças.

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a heritable cardiac disease with two main features: electric instability and myocardial fibro-fatty replacement. There is no defined treatment except for preventing arrhythmias and sudden death. Detecting causative mutations helps identify the disease pathogenesis and family members at risk. We used whole-exome sequencing to determine a genetic explanation for an ACM-positive patient from a consanguineous family. Methods After clinical analysis, cardiac magnetic resonance, and pathology, WES was performed on a two-year-old ACM proband. Variant confirmation and segregation of available pedigree members were performed by PCR and Sanger sequencing. The PPP1R13L gene was also analyzed for possible causative variants and their hitherto reported conditions. Results We found a novel homozygous stop-gain pathogenic variant, c.580C > T: p.Gln194Ter, in the PPP1R13L gene, which was confirmed and segregated by PCR and Sanger sequencing. This variant was not reported in any databases. Conclusions WES is valuable for the identification of novel candidate genes. To our knowledge, this research is the first report of the PPP1R13L c.580C > T variant. The PPP1R13L variant was associated with ACM as confirmed by cardiac magnetic resonance and pathology. Our findings indicate that PPP1R13L should be included in ACM genetic testing to improve the identification of at-risk family members and the diagnostic yield.

Abstract While severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection primarily causes inflammation in the respiratory system, there is growing evidence of extrapulmonary tissue damage mediated by the host innate immune system in children and adults. A cytokine storm can manifest as a viral‐induced haemophagocytic lymphohistiocytosis (HLH). Here, we present a previously healthy 8‐year‐old boy with newly diagnosed cardiac injury and COVID‐19‐related HLH syndrome with haemophagocytosis in bone marrow biopsy. After remission of inflammation, the patient underwent a heart transplant due to persistent cardiac failure. The histology of the explanted heart showed only a focal subtle subendocardial inflammation. Three days after transplant, he developed progressive acute respiratory distress syndrome (ARDS) with the rise of inflammatory markers. He unfortunately died after 20 days because of disseminated intravascular coagulation (DIC). For the first time, we described a child with COVID‐19‐related HLH and severe cardiac failure, which had a poor prognosis despite a heart transplant.

Abstract Phaeochromocytomas/paragangliomas (PPGL) are rare tumours that can cause cardiovascular complications following the secretion of catecholamines. We present a young female presented with heart failure with reduced ejection fraction as a result of norepinephrine secreting para‐aortic paraganglioma and improvement of heart failure sign and symptoms and left ventricular ejection fraction following tumour resection.

Background. Health and economies are both affected by the coronavirus disease-19 (COVID-19) global pandemic. Angiotensin-converting enzyme 2 (ACE2) is a polymorphic enzyme that is a part of the renin-angiotensin system, and it plays a crucial role in viral entry. Previous investigations and studies revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ACE2 have a considerable association. Recently, ACE2 variants have been described in human populations in association with cardiovascular and pulmonary conditions. In this study, genetic susceptibility to COVID-19 in different populations was investigated. Methods and Results. We evaluated the identified variants based on the predictive performance of 5 deleteriousness-scoring methods and the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. The results indicated 299 variants within the ACE2 gene. The variants were analyzed by different in-silico analysis tools to assess their functional effects. Ultimately, 5 more deleterious variants were found in the ACE2 gene. Conclusions. Collecting more information about the variations in binding affinity between SARS-CoV-2 and host-cell receptors due to ACE2 variants leads to progress in treatment strategies for COVID-19. The evidence accumulated in this study showed that ACE2 variants in different populations may be associated with the genetic susceptibility, symptoms, and outcome of SARS-CoV-2 infection.

Abstract Carcinoid heart disease is a rare condition that occurs in less than half of patients with carcinoid syndrome. The disease mainly affects right‐sided heart valves; however, in 5%–10%, it can also involve left‐sided valves. This case illustrates the most complicated form of the disease involving four heart valves.