Project description:A 70-year-old woman was admitted to our hospital complaining of shortness of breath. She was diagnosed with acute decompensated heart failure due to left ventricular dysfunction. Her symptoms began to improve with standard therapy for heart failure with diuretics, noninvasive pressure ventilation, and inotropes, but paroxysmal atrial fibrillation and premature ventricular contractions (PVCs) occurred. After treatment with amiodarone, the number of PVCs decreased, and the left ventricular wall motion gradually improved. However, on day 28, ventricular fibrillation and cardiopulmonary arrest occurred suddenly, and she could not be resuscitated. She was diagnosed with giant cell myocarditis via an autopsy. The autopsy revealed diffuse inflammatory cells that comprised giant cells and eosinophils as well as cellular degeneration and necrosis. <Learning objective: We herein report a case of sudden cardiac death due to giant cell myocarditis diagnosed at an autopsy.>.
Project description:BackgroundPathogenic variants in the lamin A/C gene (LMNA) can lead to a wide range of phenotypes from dilated and arrhythmogenic cardiomyopathies and conduction abnormalities to partial lipodystrophies. This case highlights a coincidental pathogenic LMNA variant identified in a patient with sudden cardiac arrest (SCA). We demonstrate the need for careful interpretation of pathogenic variants identified in cardiomyopathy genes by highlighting a case in which a coincidental pathogenic LMNA variant was found in a patient with premature ventricular complex (PVC)-induced ventricular fibrillation (VF).Case summaryWe present the case of a 16-year-old male with SCA secondary to VF. Genetic testing identified a maternally inherited pathogenic variant in LMNA annotated c.1961dup; p.T655Nfs*49. The patient received an implantable cardiac defibrillator and was discharged on nadolol. The patient's two brothers were also variant-positive. However, the patient and both brothers had normal chamber dimensions on echocardiogram and no late gadolinium enhancement on cardiac magnetic resonance imaging. The family members with the variant were recommended to have prophylactic implantable cardiac defibrillators and thus sought a second opinion. The patient received an appropriate shock and device interrogation identified PVCs. Electrophysiology study identified PVC-induced VF which was ablated with no recurrent ventricular arrhythmias/implantable cardioverter defibrillator therapies over 8 months of follow-up. Although the variant in LMNA could lead to cardiac arrest, the clinical phenotype was consistent with a non-genetic aetiology. The family members were told to have periodic cardiac evaluation.DiscussionThis case demonstrates the identification of a coincidental pathogenic variant in a cardiomyopathy gene in a patient with cardiac arrest. Although this variant could lead to cardiomyopathy, it appears the cardiac arrest was not due to the pathogenic variant. This highlights the need to consider the clinical phenotype when interpreting genetic test results for cardiomyopathies even in the presence of a positive genetic test result.
Project description:Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%-30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19-year-old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery-Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra-rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188-6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.
Project description:ObjectivesThis study aimed to develop a novel clinical prediction algorithm for avertable sudden cardiac death.BackgroundSudden cardiac death manifests as ventricular fibrillation (VF)/ ventricular tachycardia (VT) potentially treatable with defibrillation, or nonshockable rhythms (pulseless electrical activity/asystole) with low likelihood of survival. There are no available clinical risk scores for targeted prediction of VF/VT.MethodsSubjects with out-of-hospital sudden cardiac arrest presenting with documented VF or pulseless VT (33% of total cases) were ascertained prospectively from the Portland, Oregon, metro area with population ≈1 million residents (n = 1,374, 2002-2019). Comparisons of lifetime clinical records were conducted with a control group (n = 1,600) with ≈70% coronary disease prevalence. Prediction models were constructed from a training dataset using backwards stepwise logistic regression and applied to an internal validation dataset. Receiver operating characteristic curves (C statistic) were used to evaluate model discrimination. External validation was performed in a separate, geographically distinct population (Ventura County, California, population ≈850,000, 2015-2020).ResultsA clinical algorithm (VFRisk) constructed with 13 clinical, electrocardiogram, and echocardiographic variables had very good discrimination in the training dataset (C statistic = 0.808; [95% CI: 0.774-0.842]) and was successfully validated in internal (C statistic = 0.776 [95% CI: 0.725-0.827]) and external (C statistic = 0.782 [95% CI: 0.718-0.846]) datasets. The algorithm substantially outperformed the left ventricular ejection fraction (LVEF) ≤35% (C statistic = 0.638) and performed well across the LVEF spectrum.ConclusionsAn algorithm for prediction of sudden cardiac arrest manifesting with VF/VT was successfully constructed using widely available clinical and noninvasive markers. These findings have potential to enhance primary prevention, especially in patients with mid-range or preserved LVEF.
Project description:Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms. We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.
Project description:Right ventricular outflow tract (RVOT) aneurysm is a rare cause of RVOT ventricular tachycardia (RVOT-VT). We present a very unusual case of RVOT-VT due to an RVOT aneurysm diagnosed by cardiovascular magnetic resonance imaging.
Project description:Pheochromocytomas are catecholamine-producing tumors and a rare cause of sudden cardiac death. We describe the case of a previously healthy 28-year-old man who presented after a ventricular fibrillation out-of-hospital cardiac arrest (OHCA). His clinical investigation, including a coronary evaluation, was unremarkable. A protocolized head-to-pelvis computed tomography (CT) scan was ordered and revealed a large right adrenal mass with subsequent laboratory studies showing markedly elevated urine and plasma catecholamines. This raised suspicion for a pheochromocytoma as the underlying etiology behind his OHCA. He received appropriate medical management, underwent adrenalectomy with subsequent normalization of his metanephrines, and fortunately did not have recurrent arrythmias. This case highlights the first documented case of a ventricular fibrillation arrest as the initial presentation of pheochromocytoma crisis in a previously healthy individual, and how the use of early protocolized sudden death CT scan allowed for the prompt diagnosis and management of a rare cause of OHCA.Learning objectiveWe review the typical cardiac manifestations of pheochromocytoma and describe the first case of a pheochromocytoma crisis presenting as sudden cardiac death (SCD) in a previously asymptomatic individual. In young patients with unexplained SCD, it is important to consider pheochromocytoma in the differential diagnosis. We also review why an early head-to-pelvis sudden death computed tomography scan protocol may be helpful in the evaluation of patients resuscitated from SCD without an obvious etiology.
Project description:Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release (SOICR) in human embryonic kidney 293 (HEK293) cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype (WT) channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.