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13. Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction‐induced cardiomyopathy.

Author

Balderas‐Villalobos, Jaime, Medina‐Contreras, J. M. Lourdes, Lynch, Christopher, Kabadi, Rajiv, Hayles, Janée, Ramirez, Rafael J., Tan, Alex Y., Kaszala, Karoly, Samsó, Montserrat, Huizar, Jose F., and Eltit, Jose M.

Subjects
ARRHYTHMIA, ATRIAL natriuretic peptides, CARDIAC hypertrophy, PHOSPHOPROTEIN phosphatases, CARDIOMYOPATHIES, MYOSIN
Abstract

Frequent premature ventricular contractions (PVCs) promoted eccentric cardiac hypertrophy and reduced ejection fraction (EF) in a large animal model of PVC‐induced cardiomyopathy (PVC‐CM), but the molecular mechanisms and markers of this hypertrophic remodeling remain unexplored. Healthy mongrel canines were implanted with pacemakers to deliver bigeminal PVCs (50% burden with 200–220 ms coupling interval). After 12 weeks, left ventricular (LV) free wall samples were studied from PVC‐CM and Sham groups. In addition to reduced LV ejection fraction (LVEF), the PVC‐CM group showed larger cardiac myocytes without evident ultrastructural alterations compared to the Sham group. Biochemical markers of pathological hypertrophy, such as store‐operated Ca2+ entry, calcineurin/NFAT pathway, β‐myosin heavy chain, and skeletal type α‐actin were unaltered in the PVC‐CM group. In contrast, pro‐hypertrophic and antiapoptotic pathways including ERK1/2 and AKT/mTOR were activated and/or overexpressed in the PVC‐CM group, which appeared counterbalanced by an overexpression of protein phosphatase 1 and a borderline elevation of the anti‐hypertrophic factor atrial natriuretic peptide. Moreover, the potent angiogenic and pro‐hypertrophic factor VEGF‐A and its receptor VEGFR2 were significantly elevated in the PVC‐CM group. In conclusion, a molecular program is in place to keep this structural remodeling associated with frequent PVCs as an adaptive pathological hypertrophy. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy

Author

Balderas-Villalobos, Jaime, primary, Medina-Contreras, J. M. L., additional, Lynch, Christopher, additional, Kabadi, Rajiv, additional, Ramirez, Rafael J., additional, Tan, Alex Y., additional, Kaszala, Karoly, additional, Samsó, Montserrat, additional, Huizar, Jose F., additional, and Eltit, Jose M., additional

Published
2022
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16. Alterations of sarcoplasmic reticulum-mediated Ca2+ uptake in a model of premature ventricular contraction (PVC)-induced cardiomyopathy.

Author

Balderas-Villalobos, Jaime, Medina-Contreras, J. M. L., Lynch, Christopher, Kabadi, Rajiv, Ramirez, Rafael J., Tan, Alex Y., Kaszala, Karoly, Samsó, Montserrat, Huizar, Jose F., and Eltit, Jose M.

Abstract

Premature ventricular contractions (PVCs) are the most frequent ventricular arrhythmias in the overall population. PVCs are known to acutely enhance contractility by the post-extrasystolic potentiation phenomenon, but over time persistent PVCs promote PVC-induced cardiomyopathy (PVC-CM), characterized by a reduction of the left ventricular (LV) ejection fraction. Ca2+ cycling in myocytes commands muscle contraction and in this process, SERCA2 leads the Ca2+ reuptake into the sarcoplasmic reticulum (SR) shaping cytosolic Ca2+ signal decay and muscle relaxation. Altered Ca2+ reuptake can contribute to the contractile dysfunction observed in PVC-CM. To better understand Ca2+ handling using our PVC-CM model (canines with 50% PVC burden for 12 weeks), SR-Ca2+ reuptake was investigated by measuring Ca2+ dynamics and analyzing protein expression. Kinetic analysis of Ca2+ reuptake in electrically paced myocytes showed a ~ 21 ms delay in PVC-CM compared to Sham in intact isolated myocytes, along with a ~ 13% reduction in SERCA2 activity assessed in permeabilized myocytes. Although these trends were not statistically significant between groups using hierarchical statistics, relaxation of myocytes following contraction was significantly slower in PVC-CM vs Sham myocytes. Western blot analyses indicate a 22% reduction in SERCA2 expression, a 23% increase in phospholamban (PLN) expression, and a 50% reduction in PLN phosphorylation in PVC-CM samples vs Sham. Computational analysis simulating a 20% decrease in SR-Ca2+ reuptake resulted in a ~ 22 ms delay in Ca2+ signal decay, consistent with the experimental result described above. In conclusion, SERCA2 and PLB alterations described above have a modest contribution to functional adaptations observed in PVC-CM. [ABSTRACT FROM AUTHOR]

Published
2023
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22. Safety and feasibility of left bundle branch area pacing following valvular interventions: Multicenter study

Author

Gul, Enes Elvin, primary, Kabadi, Rajiv A., additional, Padala, Santosh K., additional, Sanchez Somonte, Paula, additional, Kron, Jordana, additional, Shepard, Richard K., additional, Koneru, Jayanthi N., additional, Kalahasty, Gautham, additional, Terricabras, Maria, additional, Tsang, Bernice, additional, Khaykin, Yaariv, additional, Wulffhart, Zaev, additional, Pantano, Alfredo, additional, Ellenbogen, Kenneth A., additional, and Verma, Atul, additional

Published
2021
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26. The Pulmonary Venous Ridge Length to Stratify Stroke Risk in Atrial Fibrillation

Author

Singh, Varun, Li, Joy, Keroles, Mark, Frisch, Daniel, Pavri, Behzad B., Sundaram, MD, Baskaran, Jacobson, Jason, Kabadi, Rajiv, Singh, Varun, Li, Joy, Keroles, Mark, Frisch, Daniel, Pavri, Behzad B., Sundaram, MD, Baskaran, Jacobson, Jason, and Kabadi, Rajiv

Abstract

Purpose of Study: To evaluate the left superior pulmonary venous ridge length (RL) and the left atrial appendage fractal dimension (LAA FD) as predictors of cardioembolic ischemic stroke (CVA) and transient ischemic attack (TIA) in patients with atrial fibrillation (AF). Materials, Methods and Procedures: A multicenter, retrospective multicenter study was conducted on patients with AF who underwent cardiac CT prior to catheter ablation between 01/01/2010 and 12/31/2015. Patients were grouped by the presence or absence of prior CVA/TIA. Patients with mitral stenosis, prior mechanical aortic valve replacement, ascending aortic arch atheroma, highrisk patent foramen ovale, history of atrial septal repair or device, preexisting LAA thrombus or intra-cardiac tumor, or prior open-heart surgery were excluded. Further exclusion was performed for patients with sub-optimal or unavailable cardiac CT imaging by investigators blinded to clinical data. Blinded investigators obtained RL by measuring the distance between the left superior pulmonary venous ostium and the internal ostium of the left atrial appendage. LAA FD was calculated using semi-automated volume rendering and processing software (ImageJ, Bethesda, MD) [1] and LAA FD are presented as means (95% confidence interval) and were compared between groups using unpaired t-tests. Logistic regression analysis was used to construct receiver operating curves and to assess the abilities of RL and LAA FD to predict prior CVA/TIA. Results: 225 patients met inclusion criteria. Mean RL were 4.32 (3.80-4.93) and 5.20 (4.93-5.48) for patients with (n=24; mean age: 59.4; 70.8% male) and without (n=165; mean age: 59.3; 75.4% male) prior CVA/TIA, respectively(p=0.033). Mean LAA FD were 2.29 (95% CI: 2.24-2.34) and 2.33 (2.32-2.34) for patients with (n=22; mean age: 60.3; 68.2% male) and without (n=171; mean age: 59.3; 74.9% male) prior CVA/TIA, respectively (p=0.052). In a regression model including LAA FD, RL, and established predicti

Published
2020

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