scholarly journals A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kensuke Ihara ◽  
Tetsuo Sasano ◽  
Yuichi Hiraoka ◽  
Marina Togo-Ohno ◽  
Yurie Soejima ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Dilated Cardiomyopathy ◽  
Missense Mutation ◽  
Cardiac Dysfunction ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Clinical State ◽  
Missense Mutations ◽  
Nuclear Localization Signals

Abstract Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH

2002 ◽  
Vol 282 (2) ◽  
pp. H726-H733 ◽  
Author(s):  
Nina B. Radford ◽  
Bang Wan ◽  
Angela Richman ◽  
Lidia S. Szczepaniak ◽  
Jia-Ling Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Cardiac Dysfunction ◽  
Mechanical Performance ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Stroke Work ◽  
Wild Type ◽  
Oxidase Subunit ◽  
End Diastolic Volume

Cytochrome -c oxidase subunit VIaH (COXVIaH) has been implicated in the modulation of COX activity. A gene-targeting strategy was undertaken to generate mice that lacked COXVIaH to determine its role in regulation of oxidative energy production and mechanical performance in cardiac muscle. Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX. However, total myocardial ATP was not significantly different in wild-type and mutant mice. Myocardial performance was examined using the isolated working heart preparation. As left atrial filling pressure increased, hearts from mutant mice were unable to generate equivalent stroke work compared with hearts from wild-type mice. Direct measurement of left ventricular end-diastolic volume using magnetic resonance imaging revealed that cardiac dysfunction was a consequence of impaired ventricular filling or diastolic dysfunction. These findings suggest that a genetic deficiency of COXVIaH has a measurable impact on myocardial diastolic performance despite the presence of normal cellular ATP levels.

scholarly journals Incidence of Ventricular Arrhythmias and 1‐Year Predictors of Mortality in Patients Treated With Implantable Cardioverter‐Defibrillator Undergoing Generator Replacement

2021 ◽  
Vol 10 (4) ◽  
Author(s):  
Andrea Demarchi ◽  
Stefano Cornara ◽  
Antonio Sanzo ◽  
Simone Savastano ◽  
Barbara Petracci ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Disease ◽  
Implantable Cardioverter Defibrillator ◽  
Ventricular Arrhythmias ◽  
Multivariable Analysis ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Cardioverter Defibrillator ◽  
Generator Replacement

Background When implantable cardioverter defibrillator (ICD) battery is depleted most patients undergo generator replacement (GR) even in the absence of persistent ICD indication. The aim of this study was to assess the incidence of ventricular arrhythmias and the overall prognosis of patients with and without persistent ICD indication undergoing GR. Predictors of 1‐year mortality were also analyzed. Methods and Results Patients with structural heart disease implanted with primary prevention ICD undergoing GR were included. Patients were stratified based on the presence/absence of persistent ICD indication (left ventricular ejection fraction ≤35% at the time of GR and/or history of appropriate ICD therapies during the first generator's life). The study included 371 patients (82% male, 40% with ischemic heart disease). One third of patients (n=121) no longer met ICD indication at the time of GR. During a median follow‐up of 34 months after GR patients without persistent ICD indication showed a significantly lower incidence of appropriate ICD shocks (1.9% versus 16.2%, P <0.001) and ICD therapies. 1‐year mortality was also significantly lower in patients without persistent ICD indication (1% versus 8.3%, P =0.009). At multivariable analysis permanent atrial fibrillation, chronic advanced renal impairment, age >80, and persistent ICD indication were found to be significant predictors of 1‐year mortality. Conclusions Patients without persistent ICD indication at the time of GR show a low incidence of appropriate ICD therapies after GR. Persistent ICD indication, atrial fibrillation, advanced chronic renal disease, and age >80 are significant predictors of 1‐year mortality. Our findings enlighten the need of performing a comprehensive clinical reevaluation of ICD patients at the time of GR.

P337Natural history, reversibility and arrhythmias associated with truncating titin variants in dilated cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
C R Vissing ◽  
T B Rasmussen ◽  
M S Olesen ◽  
L N Pedersen ◽  
A Dybro ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Medical Therapy ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Reverse Remodeling ◽  
Absolute Increase ◽  
The Mean

Abstract Background Truncating genetic variants in titin (TTNtv) are identified in 15–25% of patients with primary dilated cardiomyopathy (DCM). Previous genotype/phenotype studies have reported conflicting results regarding disease severity and pathologic features associated with TTNtv. Purpose To investigate the natural history, reversibility and burden of arrhythmias associated with TTNtv in a Danish cohort with long-term follow-up. Methods Patients with DCM, recruited from two Danish tertiary centers, were included based on the presence of a TTNtv in a cardiac expressed titin exon. Data on patients' medical history including symptoms, demography, family history, comorbidities, treatment, ECG features, and echocardiograms were registered. Outcome data including all-cause mortality, need of heart transplantation (HTX) or left ventricular assist device (LVAD), and presence of ventricular and supraventricular arrhythmias were registered. Left ventricular reverse remodeling (LVRR) was defined as an absolute increase in left ventricular ejection fraction (LVEF) ≥10% points or normalization. Results A total of 104 patients (71 men, 69%; 72 probands) with definite TTNtv-DCM were included. The mean age at DCM diagnosis was (mean±SD) 45±13 years (43±13 for men; 49±14 for women, p<0.04) and median follow-up was 8.1 years. The mean LVEF was 28±13% at time of diagnosis (26±12% for men; 30±13% for women, p=0.173). During follow-up, 31 patients (30%; 24 men) died or needed HTX/LVAD. Medical therapy was associated with LVRR in 79% of patients 3.6 years after diagnosis. LVRR was maintained long-term in 64% of patients. Women had a better response to medical therapy compared to men (mean LVEF increase 19%; vs 15% in men, p<0.04). Atrial fibrillation/flutter was observed in 40% of patients and ventricular arrhythmias in 23% of patients. Men had an earlier occurrence of both supraventricular and ventricular arrhythmias (p=0.005) with half of the men having experienced an arrhythmia at the age of 54 years. Freedom from arrhythmias with age Conclusion TTNtv leads to a DCM phenotype associated with a marked gender-difference in age at DCM diagnosis and high burden of both supraventricular and ventricular arrhythmias. Importantly, the DCM-TTNtv phenotype was associated with a high degree of reversibility of systolic function following medical therapy.

scholarly journals Expanding Spectrum of Human RYR2 -Related Disease

Circulation ◽  
2007 ◽  
Vol 116 (14) ◽  
pp. 1569-1576 ◽  
Author(s):  
Zahurul A. Bhuiyan ◽  
Maarten P. van den Berg ◽  
J. Peter van Tintelen ◽  
Margreet T.E. Bink-Boelkens ◽  
Ans C.P. Wiesfeld ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Polymerase Chain Reaction ◽  
Ventricular Arrhythmias ◽  
Sinoatrial Node ◽  
Atrioventricular Node ◽  
Left Ventricular ◽  
Polymorphic Ventricular Tachycardia ◽  
Chain Reaction ◽  
Genomic Deletion ◽  
Polymerase Chain

Background— Catecholaminergic polymorphic ventricular tachycardia is a disease characterized by ventricular arrhythmias elicited exclusively under adrenergic stress. Additional features include baseline bradycardia and, in some patients, right ventricular fatty displacement. The clinical spectrum is expanded by the 2 families described here. Methods and Results— Sixteen members from 2 separate families have been clinically evaluated and followed over the last 15 years. In addition to exercise-related ventricular arrhythmias, they showed abnormalities in sinoatrial node function, as well as atrioventricular nodal function, atrial fibrillation, and atrial standstill. Left ventricular dysfunction and dilatation was present in several affected individuals. Linkage analysis mapped the disease phenotype to a 4-cM region on chromosome 1q42-q43. Conventional polymerase chain reaction–based screening did not reveal a mutation in either the Ryanodine receptor 2 gene ( RYR2 ) or ACTN2 , the most plausible candidate genes in the region of interest. Multiplex ligation-dependent probe amplification and long-range polymerase chain reaction identified a genomic deletion that involved RYR2 exon-3, segregated in all the affected family members (n=16) in these 2 unlinked families. Further investigation revealed that the genomic deletion occurred in both families as a result of Alu repeat–mediated polymerase slippage. Conclusions— This is the first report on a large genomic deletion in RYR2 , which leads to extended clinical phenotypes (eg, sinoatrial node and atrioventricular node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy). These features have not previously been linked to RYR2 .

Dilated cardiomyopathy caused by truncating titin variants: long-term outcomes, arrhythmias, response to treatment and sex differences

2020 ◽  
pp. jmedgenet-2020-107178
Author(s):  
Christoffer Rasmus Vissing ◽  
Torsten Bloch Rasmussen ◽  
Anne Mette Dybro ◽  
Morten Salling Olesen ◽  
Lisbeth Nørum Pedersen ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Dilated Cardiomyopathy ◽  
Ventricular Arrhythmias ◽  
Left Ventricular ◽  
Response To Treatment ◽  
Composite Outcome ◽  
Long Term Outcomes ◽  
Female Sex ◽  
Negative Predictor

BackgroundTruncating variants in titin (TTNtv) are the most common cause of dilated cardiomyopathy (DCM). We evaluated the genotype-phenotype correlation in TTNtv-DCM, with a special focus on long-term outcomes, arrhythmias, response to treatment and sex-related presentation.MethodsData on patient characteristics and outcomes were collected retrospectively from electronic health records of patients genotyped at two Danish heart transplantation centres.ResultsWe included 115 patients (66% men). At diagnosis of DCM, mean age was 46±13 years and left ventricular ejection fraction (LVEF) was 28%±13%. During a median follow-up of 7.9 years, 26% reached a composite outcome of left ventricular assist device implantation, heart transplantation or death. In 20% an arrhythmia preceded the DCM diagnosis. In total, 43% had atrial fibrillation (AF) and 23% had ventricular arrhythmias. Long-term left ventricular reverse remodelling (LVRR; LVEF increase ≥10% points or normalisation) was achieved in 58% and occurred more frequently in women (72% vs 51%, p=0.042).In multivariable proportional hazards analyses, occurrence of LVRR was a strong independent negative predictor of the composite outcome (HR: 0.05 (95% CI 0.02 to 0.14); p<0.001). Female sex independently predicted lower rates of ventricular arrhythmias (HR: 0.33 (95% CI 0.11 to 0.99); p=0.05), while the location of the TTNtv was not associated with cardiovascular outcomes.ConclusionDCM caused by TTNtv presented in midlife and was associated with a high burden of AF and ventricular arrhythmias, which often preceded DCM diagnosis. Furthermore, LVRR occurred in a high proportion of patients and was a strong negative predictor of the composite outcome. Female sex was positively associated with occurrence of LVRR and longer event-free survival.

scholarly journals SAT-470 When The Heart Can’t Clap To The Thyroid’s Beat

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aditi Thakkar ◽  
Maria Camila Trejo-Parades ◽  
Anantha Sriharsha Madgula ◽  
Margaret Stevenson
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Reduced Ejection Fraction ◽  
Tachycardia Induced Cardiomyopathy

Abstract Hyperthyroidism is associated with multiple cardiac pathologies including dilated cardiomyopathy, isolated right ventricular heart failure, and atrial fibrillation (AF). Long standing untreated hyperthyroidism in conjunction with AF can cause severe dilated cardiomyopathy with reduced ejection fraction that is completely reversible with treatment. We present the case of a previously healthy male who presented with florid congestive heart failure (CHF) as an initial presentation for hyperthyroidism. A 37-year-old male presented to the emergency department with progressively worsening dyspnea on exertion and lower extremity edema for one month. His heart rate was noted to be 172 bpm and an EKG was done that showed AF. He was clinically noted to be in heart failure and was admitted for further management. He was started on metoprolol with good heart rate control and was started on furosemide for diuresis. A transthoracic echocardiogram was done and showed severe global hypokinesis with left ventricular ejection fraction reduced to 20% along with bi-atrial enlargement and dilated left ventricular cavity. Ischemic cardiomyopathy was ruled out with left heart catheterization. A TSH level was checked as a part of workup for non-ischemic cardiomyopathy and atrial fibrillation and was markedly reduced to &lt;0.01mIU/L with free T4 of 1.49ng/dL and free T3 of 6.7ng/dL. A diagnosis of hyperthyroid cardiomyopathy with concomitant tachycardia induced cardiomyopathy was made. Autoimmune workup was negative for anti-thyroid-peroxidase and anti-thyroid-stimulating antibodies. Ultrasound of his thyroid gland revealed multiple thyroid nodules concerning for toxic multinodular goiter. He was started on methimazole and discharged after volume optimization with diuresis to closely follow up with endocrinology and cardiology for further management. CHF can be the primary presentation in about 6% of patients with hyperthyroidism. T3 is the main thyroid hormone that binds to cardiomyocytes. It increases the expression of beta-adrenergic receptors on cardiomyocytes and subsequently increases heart rate and contractility. T3 can also cause atrial arrhythmias such as AF by decreasing the parasympathetic tone. Concomitant AF and hyperthyroidism can cause reduced ejection fraction due to tachycardia induced cardiomyopathy and dilated cardiomyopathy. Treatment mainly is with beta-blockers that slow down the heart as well decrease serum T3 levels by blocking 5-monodeiodinase which converts T4 to T3. Our patient was started on beta-blocker and methimazole with good reduction in heart rate and improvement of symptoms. Recovery of cardiac function will be assessed with longitudinal follow up. As hyperthyroidism is one of the few causes of CHF that is completely reversible, clinicians must maintain low degree of suspicion in patients with new onset heart failure especially when associated with AF.

scholarly journals Prognostic Significance of Left Ventricular Noncompaction

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Nay Aung ◽  
Sara Doimo ◽  
Fabrizio Ricci ◽  
Mihir M. Sanghvi ◽  
Cesar Pedrosa ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiovascular Mortality ◽  
Ventricular Arrhythmias ◽  
Incidence Rates ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Ventricular Noncompaction

Background: Although left ventricular noncompaction (LVNC) has been associated with an increased risk of adverse cardiovascular events, the accurate incidence of cardiovascular morbidity and mortality is unknown. We, therefore, aimed to assess the incidence rate of LVNC-related cardiovascular events. Methods: We systematically searched observational studies reporting the adverse outcomes related to LVNC. The primary end point was cardiovascular mortality. Results: We identified 28 eligible studies enrolling 2501 LVNC patients (mean age, 46 years; male/female ratio, 1.7). After a median follow-up of 2.9 years, the pooled event rate for cardiovascular mortality was 1.92 (95% CI, 1.54–2.30) per 100 person-years. LVNC patients had a similar risk of cardiovascular mortality compared with a dilated cardiomyopathy control group (odds ratio, 1.10 [95% CI, 0.18–6.67]). The incidence rates of all-cause mortality, stroke and systemic emboli, heart failure admission, cardiac transplantation, ventricular arrhythmias, and cardiac device implantation were 2.16, 1.54, 3.53, 1.24, 2.17, and 2.66, respectively, per 100 person-years. Meta-regression and subgroup analyses revealed that left ventricular ejection fraction, not the extent of left ventricular trabeculation, had an important influence on the variability of incidence rates. The risks of thromboembolism and ventricular arrhythmias in LVNC patients were similar to dilated cardiomyopathy patients. However, LVNC patients had a higher incidence of heart failure hospitalization than dilated cardiomyopathy patients. Conclusions: Patients with LVNC carry a similar cardiovascular risk when compared with dilated cardiomyopathy patients. Left ventricular ejection fraction—a conventional indicator of heart failure severity, not the extent of trabeculation—appears to be an important determinant of adverse outcomes in LVNC patients. Registration: https://www.crd.york.ac.uk/PROSPERO/ Unique identifier: CRD42018096313.

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