RBM20 mutation and ventricular arrhythmias in a young patient with dilated cardiomyopathy: a case report.
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ABSTRACT:
SUBMITTER: Liatakis I
PROVIDER: S-EPMC8303033 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPremature ventricular complexes (PVCs) are ectopic heartbeats caused by early myocardial depolarizations, previously thought to be benign. Recent studies found high PVC burden above 24% can induce or contribute to cardiomyopathy and heart failure. We present a case of PVC-induced dilated cardiomyopathy (DCM).Case summaryA 68-year-old woman was admitted with pneumonia after an overseas trip with a preceding viral respiratory tract infection. An initial chest X-ray was suggestive of cardiomegaly. A transthoracic echocardiogram (TTE) revealed DCM with global systolic dysfunction (left ventricular ejection fraction <30%) without valvular lesions. Biochemistry and coronary angiography were normal. Clinical deterioration occurred despite medical therapy. A 24-h Holter monitoring detected 27% PVCs, which was thought to have caused DCM. As an alternative to cardiac resynchronization therapy and an implantable cardiac defibrillator for primary prevention, ablation of the PVC focus led to complete suppression of ectopy. Post-procedure TTEs and Holter monitoring showed normalized systolic function and low PVC burden.DiscussionBecause high PVC burden can lead to cardiomyopathy and heart failure, suppression of PVC should be considered to restore ventricular function for patients with structural heart disease and frequent symptomatic PVCs. This case highlights that PVCs may be a modifiable risk factor for heart failure that can be successfully treated with pharmacological therapies or catheter ablation.
| S-EPMC6458864 | biostudies-literature
Project description:IntroductionIt is not clear whether patients with sinus rhythm and reduced left ventricular function should be treated with anticoagulation therapy during or after treatment for heart failure.Case presentationA 67-year-old Japanese man was hospitalized at our institution with heart failure due to dilated cardiomyopathy. On day after discharge, he developed cerebral infarction and showed persistence of multiple left ventricular thrombi. His paralysis completely improved at 2 days after edaravone and heparin administration; however, his left visual field defect persisted.ConclusionPatients in sinus rhythm with reduced left ventricular function might benefit from anticoagulation therapy during treatment for heart failure.
| S-EPMC4215575 | biostudies-literature
Project description:RBM20 (RNA-binding motif protein 20) is a splicing factor targeting multiple cardiac genes, and its mutations cause cardiomyopathies. Originally, RBM20 mutations were discovered to cause the development of dilated cardiomyopathy by erroneous splicing of the gene TTN (titin). Titin is a giant protein found in a structure of the sarcomere that functions as a molecular spring and provides a passive stiffness to the cardiomyocyte. Later, RBM20 mutations were also described in association with arrhythmogenic right ventricular cardiomyopathy and left ventricular noncompaction cardiomyopathy. Here, we present a clinical case of a rare arrhythmogenic phenotype and no structural cardiac abnormalities associated with a RBM20 genetic variant of uncertain significance.
| S-EPMC7828370 | biostudies-literature
Project description:BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmogenic disorder characterized by adrenergically induced ventricular tachycardia manifesting as stress-induced syncope and sudden cardiac death. While CPVT is not associated with dilated cardiomyopathy (DCM) in most cases, the combination of both disease entities poses a major diagnostic and therapeutic challenge.Case summaryWe present the case of a young woman with CPVT. The clinical course since childhood was characterized by repetitive episodes of exercise-induced ventricular arrhythmias and a brady-tachy syndrome due to rapid paroxysmal atrial fibrillation and sinus bradycardia. Medical treatment included propranolol and flecainide until echocardiography showed a dilated left ventricle with severely depressed ejection fraction when the patient was 32 years old. Cardiac magnetic resonance imaging revealed non-specific late gadolinium enhancement. Myocardial inflammation, however, was excluded by subsequent endomyocardial biopsy. Genetic analysis confirmed a mutation in the cardiac ryanodine receptor but no pathogenetic variant associated with DCM. Guideline-directed medical therapy for HFrEF was limited due to symptomatic hypotension. Over the next months, the patient developed progressive heart failure symptoms that were finally managed by heart transplantation.DiscussionManagement in patients with CPVT and DCM is challenging, as Class I antiarrhythmic drugs are not recommended in structural heart disease and prophylactic internal cardioverter-defibrillator implantation without adjuvant antiarrhythmic therapy can be detrimental. Regular echocardiographic screening for DCM is recommendable in patients with CPVT. A multidisciplinary team of heart failure specialists, electrophysiologists, geneticists, and imaging specialists is needed to collaborate in the delivery of clinical care.
| S-EPMC7793240 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) and malignant ventricular arrhythmias are important causes of congestive heart failure, heart transplantation, and sudden cardiac death in young patients. Cypher/ZASP is a cytoskeletal protein localized in the sarcomeric Z-line that has a pivotal role in maintaining adult cardiac structure and function. The putative mutation p.(D117N) in Cypher/ZASP has been suggested to cause systolic dysfunction, dilated left ventricle with hypertrabeculated myocardium, and intraventricular conduction disturbance, based on two reported sporadic cases. In two unrelated Bedouin families, one with pediatric DCM and the other with DCM and ventricular arrhythmias at young adulthood searching for the causative mutation by exome sequencing we identified the p.(D117N) variant in Cypher/ZASP. However, p.(D117N) did not segregate as the causative mutation in these families, i.e. it was not present in some patients and was found in several individuals who had no clinical manifestations. Furthermore, the carrier frequency in the Bedouin population of origin is estimated to be 5.2%, which is much higher than the incidence of idiopathic DCM in this population. Thus, our data support the notion that the p.(D117N) variant in Cypher/ZASP is not a causative mutation in the families tested by us. The results also indicates that at least in some cases, the p.(D117N) in Cypher/ZASP is not a causative mutation and the role of D117N in Cypher/ZASP in cardiac pathologies should be further clarified and re-evaluated.
| S-EPMC4930098 | biostudies-literature
Project description:Familial dilated cardiomyopathy prognosis and disease progression vary greatly depending upon the type of genetic mutation. Family history and genetic testing are paramount in developing the best treatment plan for a patient. However, with rare or novel mutations, the significance may be unknown. Regarding this, the following case report highlights the importance of vigilance and suspicion when treating a patient with a variant of unknown significance. Additionally, it shows the importance of thoroughly investigating the family history of cardiovascular disease. A 25-year-old Caucasian male was found to have a right bundle branch block and dilated cardiomyopathy upon presentation to the emergency department. Later testing showed that the dilated cardiomyopathy was due to an incredibly rare lamin A/C (LMNA) gene mutation, R349L. Despite treatment with a maximum-tolerable medication regimen and an automatic implantable cardioverter-defibrillator, the patient continued to decline and required a heart transplant. This case provides more information on the severity of this specific LMNA mutation that has only been documented once before. Of note, the time from the initial emergency department visit to the heart transplant was approximately 2 years. Given the patient's young age and rapid disease progression, in addition to a strong family history of sudden cardiac death, the significance of this mutation should not be understated. The additional knowledge gained from this case report can be used to aid in timely interventions and prognosis evaluation.
| S-EPMC11375576 | biostudies-literature
Project description:Mutations in RNA binding motif protein 20 (RBM20) are a common cause of dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine rich (RS-rich) domain, resulting in mis-localization of RBM20 to ribonucleoprotein granules within the cytoplasm, abnormal splicing of cardiac genes, and cardiomyocyte dysfunction. We used adenine base editing (ABE) and prime editing to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell-derived cardiomyocytes. We also created humanized Rbm20R636Q mutant mice, which succumbed to severe cardiac dysfunction, heart failure and premature death. Systemic delivery of ABE components by adeno-associated virus in these mice restored cardiac function and extended life span. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.
2022-08-14 | GSE211005 | GEO
Project description:Mutations in RNA binding motif protein 20 (RBM20) are a common cause of dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine rich (RS-rich) domain, resulting in mis-localization of RBM20 to ribonucleoprotein granules within the cytoplasm, abnormal splicing of cardiac genes, and cardiomyocyte dysfunction. We used adenine base editing (ABE) and prime editing to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell-derived cardiomyocytes. We also created humanized Rbm20R636Q mutant mice, which succumbed to severe cardiac dysfunction, heart failure and premature death. Systemic delivery of ABE components by adeno-associated virus in these mice restored cardiac function and extended life span. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.
2022-08-11 | GSE210783 | GEO
Project description:AimsPatients with non-ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter-defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM.Methods and resultsWe searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow-up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74-1.00)], hypertension [HR 1.95; 95% CI (1.26-3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32-13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19-1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02-7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non-sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin-C (FLNC)] were associated with arrhythmic outcome in non-pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high.ConclusionsIn patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non-)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter-defibrillator implantation.
| S-EPMC7373946 | biostudies-literature
Project description:X-linked dilated cardiomyopathy (XLDCM) is a rare but rapidly progressive cardiomyopathy caused by dystrophin gene mutation. Mutations are more often associated with Duchenne and Becker Muscular Dystrophy, which are characterized by skeletal muscle weakness or limb girdle dystrophy. However, patients with isolated XLDCM have normal skeletal muscle but complete dystrophin loss in cardiac muscle resulting in isolated myocardial involvement without overt signs of skeletal myopathy. A previously well 16-year-old boy developed sudden onset dense left-sided weakness and facial droop. Computed tomography (CT) angiography and CT brain showed an occluded right internal carotid artery extending to the right middle cerebral artery. He underwent successful endovascular clot retrieval but developed frank pulmonary oedema and cardiogenic shock requiring inotropic support and intubation. Transthoracic echocardiography demonstrated severe left ventricular (LV) cardiomyopathy and an apical thrombus. Subsequent cardiac magnetic resonance (CMR) imaging confirmed the LV parameters and diffuse late gadolinium enhancement. Despite absence of skeletal manifestations, subsequent genetic testing revealed an X-linked dystrophin gene mutation [c.31+G>T (IVS1G>T)]. He was commenced on empirical heart failure therapy and underwent successful cardiac transplantation. X-linked dilated cardiomyopathy is a rare, rapidly progressing cardiomyopathy. Patients show normal skeletal muscle dystrophin but absent expression in cardiac muscle, resulting fibrosis, and atrophy. About 20% of affected young males have significantly reduced survival and thus the diagnosis must be considered in cases of idiopathic cardiomyopathy with CMR and genetic testing key to the diagnosis. Whilst evidence exists for empirical heart failure medications, cardiac transplantation remains the definitive treatment.
| S-EPMC6601194 | biostudies-literature