Browsing by Subject "Hypertrophic cardiomyopathy"

Now showing 1 - 4 of 4
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    Familial Hypertrophic Cardiomyopathy With Fasciculoventricular Accessory Pathway
    (Elsevier, 2022) Kalra, Vikas; Akrawinthawong, Krittapoom; Kalra, Maitri; Jain, Rahul; Medicine, School of Medicine
    Hypertrophic cardiomyopathy (HCM) is a common but an underdiagnosed condition. Fasciculoventricular bypass tract (FVBT) is rare. Concomitant presence of both conditions is well described in Danon disease. We report a case of familial HCM with FVBT linked to a heterozygous pathogenic variant, c.655G>C (p.Val219Leu), in the cardiac myosin binding protein C3 (MYBPC3) gene.
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    Harmonizing the Collection of Clinical Data on Genetic Testing Requisition Forms to Enhance Variant Interpretation in Hypertrophic Cardiomyopathy (HCM): A Study from the ClinGen Cardiomyopathy Variant Curation Expert Panel
    (Elsevier, 2021-05) Morales, Ana; Ing, Alexander; Antolik, Christian; Austin-Tse, Christina; Baudhuin, Linnea M.; Bronicki, Lucas; Cirino, Allison; Hawley, Megan H.; Fietz, Michael; Garcia, John; Ho, Carolyn; Ingles, Jodie; Jarinova, Olga; Johnston, Tami; Kelly, Melissa A.; Kurtz, C. Lisa; Lebo, Matt; Macaya, Daniela; Mahanta, Lisa; Maleszewski, Joseph; Manrai, Arjun K.; Murray, Mitzi; Richard, Gabriele; Semsarian, Chris; Thomson, Kate L.; Winder, Tom; Ware, James S.; Hershberger, Ray E.; Funke, Birgit H.; Vatta, Matteo; Medical and Molecular Genetics, School of Medicine
    Diagnostic laboratories gather phenotypic data through requisition forms, but there is no consensus as to which data are essential for variant interpretation. The ClinGen Cardiomyopathy Variant Curation Expert Panel defined a phenotypic data set for hypertrophic cardiomyopathy (HCM) variant interpretation, with the goal of standardizing requisition forms. Phenotypic data elements listed on requisition forms from nine leading cardiomyopathy testing laboratories were compiled to assess divergence in data collection. A pilot of 50 HCM cases was implemented to determine the feasibility of harmonizing data collection. Laboratory directors were surveyed to gauge potential for adoption of a minimal data set. Wide divergence was observed in the phenotypic data fields in requisition forms. The 50-case pilot showed that although demographics and assertion of a clinical diagnosis of HCM had 86% to 98% completion, specific phenotypic features, such as degree of left ventricular hypertrophy, ejection fraction, and suspected syndromic disease, were completed only 24% to 44% of the time. Nine data elements were deemed essential for variant classification by the expert panel. Participating laboratories unanimously expressed a willingness to adopt these data elements in their requisition forms. This study demonstrates the value of comparing and sharing best practices through an expert group, such as the ClinGen Program, to enhance variant interpretation, providing a foundation for leveraging cumulative case-level data in public databases and ultimately improving patient care.
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    In the Weeds: Identifying the Underlying Etiology in a Patient with Suspected Hypertrophic Obstructive Cardiomyopathy
    (2024-03-22) Wojciechowska, Klaudia; Denning, Ellen; Bice, Caroline; Nadeem, Manahil; Robles, Maria
    BACKGROUND Many cases of Hypertrophic Obstructive Cardiomyopathy (HOCM) go undetected or are underdiagnosed. Patients are typically young athletes who experience decreased cardiac output, syncope with exercise, or sudden death. The disease is diagnosed with echo but cannot be certain unless a gene mutation is identified. This creates challenges for those who do not fit the classic profile nor have an identified gene mutation. METHODS A 57 y.o. black female presented with a heart murmur. A referral was made to cardiology where imaging results pointed to HOCM, but due to a history of hypertension (HTN) and missing medical records, an underlying etiology of hypertrophy secondary to HTN could not be ruled out. Genetic testing for HOCM was negative despite the patient’s extensive family history of cardiac disease. Due to these conflicting findings, a cardiac MRI was performed. While HTN could not be ruled out as a contributing factor, HOCM was placed as the leading differential. RESULTS The fragmentation of the patient’s medical records meant that the duration of the murmur and HTN is unknown. In addition, each cardiology provider had different interpretations of the radiologic imaging. The led to difficulties obtaining a diagnosis of HOCM vs HCM due to HTN. Given that the patient did not fit the classic demographic presentation of HOCM, it is possible that the diagnosis was not initially considered. By the time a full work-up had been conducted, her HTN had been poorly controlled for years and therefore delineating the root cause of HOCM was difficult. Lastly, the patient tested negative for the 24 gene mutations linked to HOCM, despite an extensive family history of cardiac disease. This highlights that there are likely more unknown mutations and there is a need for improved diagnostic criteria independent of genetic tests. CONCLUSION This case demonstrates the importance of keeping an expanded differential diagnosis, maintaining coherent and comprehensive medical records, and pursuing prompt diagnoses.
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    Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy
    (American Heart Association, 2022) Riaz, Muhammad; Park, Jinkyu; Sewanan, Lorenzo R.; Ren, Yongming; Schwan, Jonas; Das, Subhash K.; Pomianowski, Pawel T.; Huang, Yan; Ellis, Matthew W.; Luo, Jiesi; Liu, Juli; Song, Loujin; Chen, I-Ping; Qiu, Caihong; Yazawa, Masayuki; Tellides, George; Hwa, John; Young, Lawrence H.; Yang, Lei; Marboe, Charles C.; Jacoby, Daniel L.; Campbell, Stuart G.; Qyang, Yibing; Pediatrics, School of Medicine
    Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.