Abstract 1238: Myofilament Calcium Sensitization Creates Arrhythmia Susceptibility in Familial Hypertrophic Cardiomyopathy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Franz Baudenbacher ◽  
Veniamin Y Sidorov ◽  
Tilmann Schober ◽  
Nagesh Chopra ◽  
Raghav Venkataraman ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Hypertrophic Cardiomyopathy ◽  
Action Potential ◽  
Ventricular Arrhythmias ◽  
Calcium Sensitivity ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Arrhythmogenic Substrate ◽  
Sarcomeric Mutations ◽  
Underlying Mechanisms ◽  
Myofilament Calcium Sensitivity

Although sudden cardiac death is a common feature in hypertrophic cardiomyopathy (HCM), the underlying mechanisms are unclear. We recently reported that some but not all mice expressing troponin mutations associated with HCM display increased myofilament calcium sensitivity. Here, we used these mice as well as acute challenge with the Ca 2+ sensitizing agent EMD57033 (EMD) in isolated mouse and rabbit hearts to test the hypothesis that myofilament sensitization leads directly to arrhythmia susceptibility. HCM mice with Ca 2+ sensitizing troponin mutations displayed significantly higher rate of ventricular ectopy (TnT-I79N 10±3, TnT-F110I 11±5, ssTnI 15±4 PVC/h) than mice expressing non-sensitizing troponins (TnT-R278C 1±1, TnT-WT 1±1, non-Tg 2±1 PVC/h, n=5–14 per group, p<0.01). Myofilament sensitization by troponin mutations or EMD shortened the effective refractory period and the ventricular action potential of isolated perfused mouse and rabbit hearts, and caused early afterdepolarizations and triggered beats after fast pacing trains. The action potential shortening was attributable to increased cytosolic Ca 2+ buffering by the Ca 2+ sensitized myofilaments, which resulted in decreased systolic and increased end-diastolic Ca 2+ during fast pacing. Optical mapping demonstrated that Ca 2+ sensitization slowed the ventricular conduction velocity and increased the size of the vulnerable window for ventricular tachycardia both in mouse and rabbit hearts, resulting in a significantly higher incidence of sustained ventricular tachycardia in Ca 2+ sensitized compared with control hearts (5/6 vs 0/6, p<0.05). Conclusion: Myofilament Ca 2+ sensitization alters Ca 2+ buffering to render hearts susceptible to ventricular arrhythmias by creating both an arrhythmogenic substrate and trigger. These results identify a novel mechanism linking sarcomeric mutations to susceptibility to ventricular arrhythmias and raise the prospect of a molecular approach to stratifying arrhythmia risk in HCM.

Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

2007 ◽  
Vol 293 (2) ◽  
pp. H949-H958 ◽  
Author(s):  
Ganapathy Jagatheesan ◽  
Sudarsan Rajan ◽  
Natalia Petrashevskaya ◽  
Arnold Schwartz ◽  
Greg Boivin ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Thin Filament ◽  
Calcium Sensitivity ◽  
Contractile Proteins ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Physiological Effects ◽  
Calcium Response ◽  
Normal Morphology ◽  
Filament Protein ◽  
Myofilament Calcium Sensitivity

Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein α-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy, with death ensuing by 6 mo. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric α-/β-TM protein that decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the FHC mutation. These double-transgenic mice “rescue” the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.

Abstract 15921: Correlation Between Repolarization Changes in Signal Averaged Electrocardiography and Myocardial Fibrosis in Adults With Hypertrophic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ramses Ramirez Damera ◽  
Hernan L Vera-Sarmiento ◽  
David Hurtado-de-Mendoza ◽  
Ketty Dolores-Cerna ◽  
Muhammad I Khan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Fibrosis ◽  
Ventricular Arrhythmias ◽  
Interstitial Fibrosis ◽  
Objective Assessment ◽  
Left Ventricular ◽  
Noninvasive Technique ◽  
Arrhythmogenic Substrate ◽  
Study Results ◽  
Replacement Fibrosis

Introduction: Hypertrophic Cardiomyopathy (HCM) is known as one of the most common causes of sudden cardiac death. Its propensity to lethal arrhythmias is a result of myocardial remodeling leading to aberrant conduction and increased reentrant electrical activity. Previous studies suggest an association between the amount of myocardial fibrosis found on Cardiac Magnetic Resonance (CMR) and the risk of these ventricular arrhythmias. Signal Average Electrocardiography ( SAECG) is a noninvasive technique used to detect subtle conduction abnormalities that can be missed on standard Electrocardiography ( ECG ). Hypothesis: Non-uniform conduction through fibrotic tissue seen in CMR leads to unsynchronized myocardial depolarization which correlates with further repolarization abnormalities that can be detected by SAECG. Method: In this retrospective study, results of SAECG were used to classify 73 HCM patients into Normal or Abnormal groups based on the presence of two or more of three predetermined criteria (fQRS, RMS40, LAS40). Replacement fibrosis was assessed by measuring late gadolinium enhancement (LGE) . Interstitial fibrosis was assessed by measuring T1 relaxation times, using the Look-Locker sequence. Results: A statistically significant association between the presence of myocardial fibrosis on CMR and abnormal SAECG was found with a difference of proportions of 41.3% between the subgroups. Left ventricular mass index was found to be significantly higher in the abnormal subgroup (Normal: 61.2 ± 19.6; Abnormal: 82.4 ± 37.1; p = <0.003, CI 95% [2.93; 39.47]). The presence of T wave inversions on standard ECG was only seen in those who had an abnormal SAECG exam. Conclusion: Abnormal SAECG in patients with HCM is associated with the presence of LGE on CMR. This study showed a subset of patients with absence of LGE despite having abnormal SAECG, which implies that there are other complex mechanisms besides replacement fibrosis, that predisposes this population to ventricular arrhythmias. This can also be highlighted by the fact that there was no difference between the two groups in the T1 mapping time. We believe that SAECG could be an objective assessment of the arrhythmogenic substrate present in patients with HCM.

Human-based computational and experimental investigation of disease mechanisms in mutation-specific hypertrophic cardiomyopathy

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
F Margara ◽  
Y Psaras ◽  
B Rodriguez ◽  
CN Toepfer ◽  
A Bueno-Orovio
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
In Silico ◽  
Calcium Transient ◽  
Calcium Sensitivity ◽  
Human Cardiomyocytes ◽  
Calcium Affinity ◽  
Myofilament Calcium Sensitivity ◽  
Vitro Data ◽  
In Vitro Data

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 764738. British Heart Foundation Intermediate Basic Science Fellowship (FS/17/22/32644). Background The pathogenic TNNI3R21C/+ variant causes malignant hypertrophic cardiomyopathy (HCM) with high incidence of sudden cardiac death, even in individuals absent of hypertrophy. There is evidence to support a known biophysical defect in the protein, yet the cellular mechanisms that precipitate adverse clinical outcomes remain unclear. Purpose We aim to computationally model and map the TNNI3R21C/+ cellular phenotype observed in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) to human disease, thereby explaining the key mechanisms driving HCM in TNNI3R21C/+ variant carriers.  Methods Wild-type (WT) and TNNI3R21C/+ iPSC-CMs were characterised by calcium transient analysis and direct sarcomere tracking to assess cellular contraction and relaxation. In-vitro data was used to inform the in-silico modelling of human cardiomyocytes. We constructed an in-silico population of WT adult cardiomyocytes and used it to transform the in-vitro data into corresponding adult phenotypes by means of a novel iPSC-to-adult data mapping. We tested the hypothesis that the abnormal TNNI3R21C/+ phenotype observed in iPSC-CMs would be explained by alterations in calcium affinity of troponin and increased myofilament calcium sensitivity.  Results Analysis of in-vitro iPSC-CM data showed that TNNI3R21C/+ cells exhibit increased contractility with slowed relaxation when compared to WT. They also exhibited a faster rise in the calcium transient with a slowed calcium decay in comparison to WT. The in-silico adult TNNI3R21C/+ phenotype from the iPSC-to-adult mapping replicated the abnormalities observed in iPSC-CMs. The WT in-silico population accurately covered the ranges of electromechanical biomarkers providing a representative cohort of physiological variability. The TNNI3R21C/+ calcium phenotype could be recovered by our in-silico mutant models. Simulation results suggest that calcium abnormalities in TNNI3R21C/+ are a direct consequence of abnormal calcium buffering by thin filaments, mediated by increases in calcium affinity of troponin and myofilament calcium sensitivity. The TNNI3R21C/+ phenotype could not be recovered if these two factors were considered in isolation. Corresponding contractility analyses of in-silico models showed that the calcium level changes caused by the TNNI3R21C/+ phenotype are associated with hypercontractility and diastolic dysfunction, well-known hallmarks of HCM, which were also observed in the iPSC-CM model of disease. Conclusions This study showcases human-based computational and experimental methodologies that unearth direct mechanistic explanations of phenotypes driven by the TNNI3R21C/+ HCM variant. We show that the TNNI3R21C/+ HCM-causing mutation exhibits multifactorial remodelling of troponin calcium affinity and myofilament calcium sensitivity. Unearthing mechanistic pathways in mutation-specific HCM will be key to develop effective pharmacological interventions for a wide variety of understudied variants.

scholarly journals Role of Electrophysiological Study and Catheter Ablation for Recurrent Ventricular Tachycardia Complicating Myocarditis

2012 ◽  
Vol 55 (2) ◽  
pp. 96-99
Author(s):  
Emanuele Cecchi ◽  
Serena Fatucchi ◽  
Elena Crudeli ◽  
Cristina Giglioli
Keyword(s):  
Ventricular Tachycardia ◽  
Cardiac Magnetic Resonance ◽  
Catheter Ablation ◽  
Ventricular Arrhythmias ◽  
Acute Myocarditis ◽  
Electrophysiological Study ◽  
Interventricular Septum ◽  
Arrhythmogenic Substrate ◽  
Rule Out

Here we report the case of a 31-year-old man admitted to our hospital with echocardiografic and Cardiac Magnetic Resonance signs of myocarditis complicated by ventricular tachycardia, initially resolved with direct current shock. After the recurrence of ventricular tachycardia the patient was submitted to electrophysiological study revealing a re-entrant circuit at the level of the medium segment of interventricular septum, successfully treated with transcatheter ablation. This case highlights how the presence of recurrent ventricular arrhythmias at the onset of acute myocarditis, suspected or proven, could be associated with a pre-existing arrhythmogenic substrate, therefore these patients should be submitted to electrophysiological study in order to rule out the presence of arrhythmogenic focuses that can be treated with transcatheter ablation.

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