Electrical and structural remodeling of the heart can contribute to the development of cardiac arrhythmias. Ex vivo optical mapping has been used to visualize cardiac electrophysiological properties, activation and phase maps to further elucidate the mechanisms of atrial fibrillation and ventricular fibrillation initiation and persistence. Here we show an epicardial three-dimensional panoramic optical mapping tool integrated with micro-computed tomography automatically segmented with a deep learning model relying on a convolutional neural network to provide structural and electrical activation information in a single three-dimensional volume of a mouse heart. This technique allows for the acquisition and analysis of electrical activity of the entire epicardial surface with submillimeter spatial resolution and a temporal resolution of 1 ms. We establish the use of this method in transgenic mouse hearts with spontaneous atrial fibrillation and ventricular fibrillation, and mouse surgical models of myocardial infarction and left ventricular hypertrophy.

Atrial fibrillation (AF) is a prevalent arrhythmia with known detriments such as heart failure, stroke, and cognitive decline even in patients without prior stroke. The mechanisms by which AF leads to cognitive dysfunction are yet unknown, and there is a lack of animal models to study this disease process. We previously developed a murine model of spontaneous and prolonged episodes of AF, a double transgenic mouse model with cardiac-specific expression of a gain-of-function mutant voltage-gated sodium channel (DTG-AF mice). Herein, we show, for the first time to our knowledge, a murine model of AF without any cerebral infarcts exhibiting cognitive dysfunction, including impaired visual learning and cognitive flexibility on touch screen testing. Mesenteric resistance arterial function of DTG-AF mice showed significant loss of myogenic tone, increased wall thickness and distensibility, and mitochondrial dysfunction. Brain pial arteries also showed increased wall thickness and mitochondrial enlargement. Furthermore, DTG-AF mice have decreased brain perfusion on laser speckle contrast imaging compared with controls. Cumulatively, these findings demonstrate that AF leads to vascular structural and functional alterations necessary for dynamic cerebral autoregulation, resulting in increased cerebral stress and cognitive dysfunction. Expression of mitochondrial catalase (mCAT) to reduce mitochondrial reactive oxygen species (ROS) was sufficient to prevent vascular dysfunction due to AF, restore perfusion, and improve cognitive flexibility.

Atrial fibrillation (AF) is the most common clinical arrhythmia, however there is limited understanding of its pathophysiology including the cellular and ultrastructural changes rendered by the irregular rhythm, which limits pharmacological therapy development. Prior work has demonstrated the importance of reactive oxygen species (ROS) and mitochondrial dysfunction in the development of AF. Mitochondrial structure, interactions with other organelles such as sarcoplasmic reticulum (SR) and T-tubules (TT), and degradation of dysfunctional mitochondria via mitophagy are important processes to understand ultrastructural changes due to AF. However, most analysis of mitochondrial structure and interactome in AF has been limited to two-dimensional (2D) modalities such as transmission electron microscopy (EM), which does not fully visualize the morphological evolution of the mitochondria during mitophagy. Herein, we utilize focused ion beam-scanning electron microscopy (FIB-SEM) and perform reconstruction of three-dimensional (3D) EM from murine left atrial samples and measure the interactions of mitochondria with SR and TT. We developed a novel 3D quantitative analysis of FIB-SEM in a murine model of AF to quantify mitophagy stage, mitophagosome size in cardiomyocytes, and mitochondrial structural remodeling when compared with control mice. We show that in our murine model of spontaneous and continuous AF due to persistent late sodium current, left atrial cardiomyocytes have heterogenous mitochondria, with a significant number which are enlarged with increased elongation and structural complexity. Mitophagosomes in AF cardiomyocytes are located at Z-lines where they neighbor large, elongated mitochondria. Mitochondria in AF cardiomyocytes show increased organelle interaction, with 5X greater contact area with SR and are 4X as likely to interact with TT when compared to control. We show that mitophagy in AF cardiomyocytes involves 2.5X larger mitophagosomes that carry increased organelle contents. In conclusion, when oxidative stress overcomes compensatory mechanisms, mitophagy in AF faces a challenge of degrading bulky complex mitochondria, which may result in increased SR and TT contacts, perhaps allowing for mitochondrial Ca2+ maintenance and antioxidant production.

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Importance:Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc). Objective:To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19. Design, Setting, and Participants:This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline. Exposures:COVID-19, hydroxychloroquine, azithromycin. Main Outcomes and Measures:Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater. Results:A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19. Conclusions and Relevance:In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Reentrant cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF) are common cardiac arrhythmias that account for substantial morbidity and mortality throughout the world. However, the mechanisms and optimal ablation treatment strategies for such arrhythmias are still unclear. Using 2D optical mapping of a mouse model with AF and VF, we have identified regional heterogeneity of the action potential duration (APD) in the atria and ventricles of the heart as key drivers for the initiation and persistence of reentry. The purpose of this paper is to discuss theoretical patterns of dispersion, demonstrate patterns of dispersion seen in our mouse model and discuss the computational analysis of APD dispersion patterns. These analyses and discussions may lead to better understanding of dispersion patterns in patients with these arrhythmias, as well as help comprehend whether and how reducing dispersion can lead to arrhythmia risk stratification and treatment strategies for arrhythmias.

Optical mapping of murine hearts is currently limited to the epicardium. Action potential duration (APD) heterogeneity is a key driver for initiation and persistence of reentry. When combined with micro CT, optical mapping can provide data on anatomical alterations and structural remodeling contributing to arrhythmogenesis.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown. We crossbred mice expressing human F1759A-NaV1.5 channels with mice expressing human mitochondrial catalase (mCAT). Increased expression of mCAT attenuated mitochondrial and cellular reactive oxygen species (ROS) and the structural remodeling that was induced by persistent F1759A-Na+ current. Despite the heterogeneously prolonged atrial action potential, which was unaffected by the reduction in ROS, the incidences of spontaneous AF, pacing-induced after-depolarizations, and AF were substantially reduced. Expression of mCAT markedly reduced persistent Na+ current–induced ryanodine receptor oxidation and dysfunction. In summary, increased persistent Na+ current in atrial cardiomyocytes, which is observed in patients with AF, induced atrial enlargement, fibrosis, mitochondrial dysmorphology, early after-depolarizations, and AF, all of which can be attenuated by resolving mitochondrial oxidative stress.

Obesity and diabetes increase the risk of arrhythmia and sudden cardiac death. However, the molecular mechanisms of arrhythmia caused by metabolic abnormalities are not well understood. We hypothesized that mitochondrial dysfunction caused by high fat diet (HFD) promotes ventricular arrhythmia. Based on our previous work showing that saturated fat causes calcium handling abnormalities in cardiomyocytes, we hypothesized that mitochondrial calcium uptake contributes to HFD-induced mitochondrial dysfunction and arrhythmic events. For experiments, we used mice with conditional cardiac-specific deletion of the mitochondrial calcium uniporter ( Mcu ), which is required for mitochondrial calcium uptake, and littermate controls. Mice were used for in vivo heart rhythm monitoring, perfused heart experiments, and isolated cardiomyocyte experiments. MCU KO mice are protected from HFD-induced long QT, inducible ventricular tachycardia, and abnormal ventricular repolarization. Abnormal repolarization may be due, at least in part, to a reduction in protein levels of voltage gated potassium channels. Furthermore, isolated cardiomyocytes from MCU KO mice exposed to saturated fat are protected from increased reactive oxygen species (ROS), mitochondrial dysfunction, and abnormal calcium handling. Activation of calmodulin-dependent protein kinase (CaMKII) corresponds with the increase in arrhythmias in vivo. Additional experiments showed that CaMKII inhibition protects cardiomyocytes from the mitochondrial dysfunction caused by saturated fat. Hearts from transgenic CaMKII inhibitor mice were protected from inducible ventricular tachycardia after HFD. These studies identify mitochondrial dysfunction caused by calcium overload as a key mechanism of arrhythmia during HFD. This work indicates that MCU and CaMKII could be therapeutic targets for arrhythmia caused by metabolic abnormalities.

Avula, Uma Mahesh R.; Harris, Liliia; Shafi, Tariq; Dossabhoy, Neville R. Author Information

The Ca2+-binding protein calmodulin has emerged as a pivotal player in tuning Na+ channel function, although its impact in vivo remains to be resolved. Here, we identify the role of calmodulin and the NaV1.5 interactome in regulating late Na+ current in cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA). The mutations rendered the channels incapable of binding calmodulin to the C-terminus. The IQ/AA transgenic mice exhibited normal ventricular repolarization without arrhythmias and an absence of increased late Na+ current. In comparison, transgenic mice expressing a lidocaine-resistant (F1759A) human NaV1.5 demonstrated increased late Na+ current and prolonged repolarization in cardiomyocytes, with spontaneous arrhythmias. To determine regulatory factors that prevent late Na+ current for the IQ/AA mutant channel, we considered fibroblast growth factor homologous factors (FHFs), which are within the NaV1.5 proteomic subdomain shown by proximity labeling in transgenic mice expressing NaV1.5 conjugated to ascorbate peroxidase. We found that FGF13 diminished late current of the IQ/AA but not F1759A mutant cardiomyocytes, suggesting that endogenous FHFs may serve to prevent late Na+ current in mouse cardiomyocytes. Leveraging endogenous mechanisms may furnish an alternative avenue for developing novel pharmacology that selectively blunts late Na+ current.

This study examined whether African American race was associated with an elevated risk of chronic kidney disease (CKD) post-cardiac transplantation. CKD often occurs after cardiac transplantation and may require renal replacement therapy (RRT) or renal transplant. African American patients have a higher risk for kidney disease as well as worse post-cardiac transplant morbidity and mortality. It is unclear, however, if there is a propensity for African Americans to develop CKD after cardiac transplant. The Institutional Review Board of Columbia University Medical Center approved the retrospective study of 151 adults (57 African American and 94 non-African American) who underwent single-organ heart transplant from 2013 to 2016. The primary outcome was a decrease in estimated glomerular filtration rate (eGFR), development of CKD, and end-stage renal disease (ESRD) requiring RRT after 2 years. African American patients had a significant decline in eGFR post-cardiac transplant compared to non-African American patients (− 34 ± 6 vs. − 20 ± 4 mL/min/1.73 m2, p < 0.0006). African American patients were more likely to develop CKD stage 2 or worse (eGFR < 90 mL/min/1.73 m2) than non-African American patients (81% vs. 59%, p < 0.0005). This is the first study to report that African American patients are at a significantly higher risk for eGFR decline and CKD at 2 years post-cardiac transplant. Future investigation into risk reduction is necessary for this patient population.

BACKGROUND:Leadless pacemakers (LPMs) have been shown to have lower postoperative complications than traditional permanent pacemakers but there have been no studies on the outcomes of LPMs in patients with transcatheter heart valve replacements (THVRs). This study determined outcomes of LPMs compared to transvenous single-chamber pacemakers (SCPs) post-THVR. METHODS:This is a retrospective single-center study including 10 patients who received LPMs post-THVR between February 2017 and August 2018 and a comparison group of 23 patients who received SCP post-THVR between July 2008 and August 2018. LPM or SCP was implanted at the discretion of electrophysiologists for atrial fibrillation with slow ventricular response or sinus node dysfunction with need for single-chamber pacing only. RESULTS:LPMs were associated with decreased tricuspid regurgitation (P = 0.04) and decreased blood loss during implantation (7.5 ± 2.5 cc for LPMs vs 16.8 ± 3.2 cc for SCPs, P = 0.03). Five LPM patients had devices positioned in the right ventricular septum as seen on transthoracic echocardiogram. Frequency of ventricular pacing was similar between LPM and SCP groups. In the LPM group, one case was complicated by a pseudoaneurysm and one death was due to noncardiac causes. There was one pneumothorax and one pocket infection in the SCP group. CONCLUSIONS:In this small retrospective study, LPMs were feasible post-THVR and found to perform as well as SCPs, had less intraprocedural blood loss, and were associated with less tricuspid regurgitation. Further, larger studies are required to follow longer-term outcomes and complications.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the NaV1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of novel treatment strategies. The mice have regional heterogeneity of action potential duration of the atria similar to observations in patients with AF. In these mice, we found that the initiation and persistence of the rotational reentrant AF arrhythmias, known as spiral waves or rotors, were dependent upon action potential duration heterogeneity. The centers of the rotors were localized to regions of greatest heterogeneity of the action potential duration. Pharmacologically attenuating the action potential duration heterogeneity reduced both spontaneous and pacing-induced AF. Computer-based simulations also demonstrated that the action potential duration heterogeneity is sufficient to generate rotors that manifest as AF. Taken together, these findings suggest that action potential duration heterogeneity in mice and humans is one mechanism by which AF is initiated and that reducing action potential duration heterogeneity can lessen the burden of AF.

Prophylactic DeVega tricuspid annuloplasty (DVA) of the donor heart has been reported to improve tricuspid regurgitation (TR), renal dysfunction, and mortality in cardiac transplant recipients. This is the first study to investigate the electrical, as well as, hemodynamic effects of DVA during orthotopic heart transplantation (OHT). Electrocardiographic, echocardiographic, and hemodynamic data of 76 patients with DVA and 104 patients without DVA who underwent OHT between 2013 and 2017 at Columbia University Medical Center (New York, NY) were studied. Patients with DVA were older (56.5 ± 1.2 vs . 52.4 ± 1.0 years of age; p = 0.017) and predominantly men (78% vs . 68%; p = 0.02). There were no significant differences in right ventricular function and TR. Patients with DVA had increased incidence of right bundle branch block compared with without DVA (37% ± 5.9% vs. 9% ± 2.9%; p < 0.001). Three patients with DVA developed complete heart block (CHB), whereas no patients without DVA developed CHB ( p = 0.04). Four patients with DVA received a pacemaker (PPM), whereas only one patient in the without DVA group received a PPM. Complete heart block was significantly increased in patients who received prophylactic DVA. Possible risk of conduction abnormalities should be considered with performance of DVA annuloplasty in cardiac transplant recipients.