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Fat infiltration in the infarcted heart as a paradigm for ventricular arrhythmias.

ABSTRACT: Infiltrating adipose tissue (inFAT) has been recently found to co-localize with scar in infarcted hearts and may contribute to ventricular arrhythmias (VAs), a life-threatening heart rhythm disorder. However, the contribution of inFAT to VA has not been well-established. We investigated the role of inFAT versus scar in VA through a combined prospective clinical and mechanistic computational study. Using personalized computational heart models and comparing the results from simulations of VA dynamics with measured electrophysiological abnormalities during the clinical procedure, we demonstrate that inFAT, rather than scar, is a primary driver of arrhythmogenic propensity and is frequently present in critical regions of the VA circuit. We determined that, within the VA circuitry, inFAT, as opposed to scar, is primarily responsible for conduction slowing in critical sites, mechanistically promoting VA. Our findings implicate inFAT as a dominant player in infarct-related VA, challenging existing paradigms and opening the door for unexplored anti-arrhythmic strategies.

SUBMITTER: Sung E

PROVIDER: S-EPMC9802586 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Fat infiltration in the infarcted heart as a paradigm for ventricular arrhythmias.

Sung Eric E Prakosa Adityo A Zhou Shijie S Berger Ronald D RD Chrispin Jonathan J Nazarian Saman S Trayanova Natalia A NA

Nature cardiovascular research 20221006 10

Infiltrating adipose tissue (inFAT) has been recently found to co-localize with scar in infarcted hearts and may contribute to ventricular arrhythmias (VAs), a life-threatening heart rhythm disorder. However, the contribution of inFAT to VA has not been well-established. We investigated the role of inFAT versus scar in VA through a combined prospective clinical and mechanistic computational study. Using personalized computational heart models and comparing the results from simulations of VA dyna ...[more]

PMID: 36589896

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Project description:AimsRecent studies have demonstrated electrotonic coupling between scar tissue and the surrounding myocardium in cryoinjured hearts. However, the electrical dynamics occurring at the myocyte-nonmyocyte interface in the fibrotic heart remain undefined. Here, we sought to develop an assay to interrogate the nonmyocyte cell type contributing to heterocellular coupling and to characterize, on a cellular scale, its voltage response in the infarct border zone of living hearts.Methods and resultsWe used two-photon laser scanning microscopy in conjunction with a voltage-sensitive dye to record transmembrane voltage changes simultaneously from cardiomyocytes and adjoined nonmyocytes in Langendorff-perfused mouse hearts with healing myocardial infarction. Transgenic mice with cardiomyocyte-restricted expression of a green fluorescent reporter protein underwent permanent coronary artery ligation and their hearts were subjected to voltage imaging 7-10 days later. Reporter-negative cells, i.e. nonmyocytes, in the infarct border zone exhibited depolarizing transients at a 1:1 coupling ratio with action potentials recorded simultaneously from adjacent, reporter-positive ventricular myocytes. The electrotonic responses in the nonmyocytes exhibited slower rates of de- and repolarization compared to the action potential waveform of juxtaposed myocytes. Voltage imaging in infarcted hearts expressing a fluorescent reporter specifically in myofibroblasts revealed that the latter were electrically coupled to border zone myocytes. Their voltage transient properties were indistinguishable from those of nonmyocytes in hearts with cardiomyocyte-restricted reporter expression. The density of connexin43 expression at myofibroblast-cardiomyocyte junctions was ∼5% of that in the intercalated disc regions of paired ventricular myocytes in the remote, uninjured myocardium, whereas the ratio of connexin45 to connexin43 expression levels at heterocellular contacts was ∼1%.ConclusionMyofibroblasts contribute to the population of electrically coupled nonmyocytes in the infarct border zone. The slower kinetics of myofibroblast voltage responses may reflect low electrical conductivity across heterocellular junctions, in accordance with the paucity of connexin expression at myofibroblast-cardiomyocyte contacts.

Project description:BackgroundGray zone, a measure of tissue heterogeneity on late gadolinium enhanced-cardiac magnetic resonance (LGE-CMR) imaging, has been shown to predict ventricular arrhythmias (VAs) in ischemic cardiomyopathy (ICM) patients. However, no studies have described whether left ventricular (LV) tissue heterogeneity and intramyocardial fat mass on contrast-enhanced computed tomography (CE-CT), which provides greater spatial resolution, is useful for assessing the risk of VAs in ICM patients with LV systolic dysfunction and no previous VAs.ObjectiveThe purpose of this proof-of-concept study was to determine the feasibility of measuring global LV tissue heterogeneity and intramyocardial fat mass by CE-CT for predicting the risk of VAs in ICM patients with LV systolic dysfunction and no previous history of VAs.MethodsPatients with left ventricular ejection fraction ≤35% and no previous VAs were enrolled in a prospective, observational registry and underwent LGE-CMR. From this cohort, patients with ICM who additionally received CE-CT were included in the present analysis. Gray zone on LGE-CMR was defined as myocardium with signal intensity (SI) > peak SI of healthy myocardium but <50% maximal SI. Tissue heterogeneity on CE-CT was defined as the standard deviation of the Hounsfield unit image gradients (HU/mm) within the myocardium. Intramyocardial fat on CE-CT was identified as regions of image pixels between -180 and -5 HU. The primary outcome was VAs, defined as appropriate implantable cardioverter-defibrillator shock or sudden arrhythmic death.ResultsThe study consisted of 47 ICM patients, 13 (27.7%) of whom experienced VA events during mean follow-up of 5.6 ± 3.4 years. Increasing tissue heterogeneity (per HU/mm) was significantly associated with VAs after multivariable adjustment, including for gray zone (odds ratio [OR] 1.22; P = .019). Consistently, patients with tissue heterogeneity values greater than or equal to the median (≥22.2 HU/mm) had >13-fold significantly increased risk of VA events, relative to patients with values lower than the median, after multivariable adjustment that included gray zone (OR 13.13; P = .028). The addition of tissue heterogeneity to gray zone improved prediction of VAs (area under receiver operating characteristic curve increased from 0.815 to 0.876). No association was found between intramyocardial fat mass on CE-CT and VAs (OR 1.00; P = .989).ConclusionIn ICM patients, CE-CT-derived LV tissue heterogeneity was independently associated with VAs and may represent a novel marker useful for risk stratification.

Project description:BackgroundOsimertinib is a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor that has become the first-line treatment for non-small cell lung cancer harboring EGFR mutations, with the potential risk of QT prolongation and heart failure. However, few cases have reported malignant ventricular arrhythmias. Here, we report a case of recurrent ventricular fibrillation (VF) and Torsade de Pointes (TdP) secondary to QT prolongation and heart failure induced by osimertinib.Case summaryA 70-year-old woman presented with chest tightness and dyspnea for 1 week and ventricular fibrillation upon admission, with a medical history of lung adenocarcinoma harboring an EGFR exon 21 p.L858R mutation. She was under osimertinib for 3 months. Electrocardiography after defibrillation suggested QTc prolongation (655 ms) and T wave alternans. Ultrasound cardiography displayed left ventricular ejection fraction (LVEF) of 29% and severe mitral regurgitation. Laboratory tests indicated elevated N-terminal pro-B-type natriuretic peptide and hypokalemia. Genetic testing suggested no pathogenic mutations. We considered acquired long QT syndrome and heart failure with reduced ejection fraction induced by osimertinib as the chief causes of ventricular arrhythmia and hypokalemia as an important trigger. Despite intubation, sedation, and the administration intravenous magnesium and potassium and lidocaine, the patient presented with recurrent TdP, which was managed by a low dose of isoproterenol (ISO, 0.17 ug/min). An implantable cardioverter defibrillator was declined. The patient is surviving without any relapse, with QTc of 490 ms and LVEF of 42% after a 6-month follow up.ConclusionRegular monitoring is required during osimertinib administration, considering the risk of life-threatening cardiac events, such as malignant arrhythmias and heart failure. ISO, with an individual dose and target heart rate, may be beneficial for terminating TdP during poor response to other therapies.

Dataset Information

Fat infiltration in the infarcted heart as a paradigm for ventricular arrhythmias.

Publications

Fat infiltration in the infarcted heart as a paradigm for ventricular arrhythmias.

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