Aging Impairs Reverse Remodeling and Recovery of Ventricular Function after Isoproterenol-Induced Cardiomyopathy

Information about heart failure with reduced ejection fraction (HFrEF) in women and the potential effects of aging in the female heart is scarce. We investigated the vulnerability to develop HFrEF in female elderly mice compared to young animals, as well as potential differences in reverse remodeling. First, HF was induced by isoproterenol infusion (30 mg/kg/day, 28 days) in young (10-week-old) and elderly (22-month-old) female mice. In a second set of animals, mice underwent isoproterenol infusion followed by no treatment during 28 additional days. Cardiac remodeling was assessed by echocardiography, histology and gene expression of collagen-I and collagen-III. Following isoproterenol infusion, elderly mice developed similar HFrEF features compared to young animals, except for greater cell hypertrophy and tissue fibrosis. After beta-adrenergic withdrawal, young female mice experienced complete reversal of the HFrEF phenotype. Conversely, reversed remodeling was impaired in elderly animals, with no significant recovery of LV ejection fraction, cardiomyocyte hypertrophy and collagen deposition. In conclusion, chronic isoproterenol infusion is a valid HF model for elderly and young female mice and induces a similar HF phenotype in both. Elderly animals, unlike young, show impaired reverse remodeling, with persistent tissue fibrosis and cardiac dysfunction even after beta-adrenergic withdrawal.

Split Accessory Pathway Potentials in a Patient with Antidromic AVRT

A 27-year-old female presenting palpitation without ECG documentation underwent electrophysiology study. EP study revealed atrioventricular accessory pathway with poor and unidirectional pathway conduction, and a fasciculoventricular pathway. During isoproterenol infusion, delta wave promptly became prominent, after which an antidromic AV reentrant tachycardia was induced. When the pathway was mapped, widely split double pathway potentials were observed at 12 o’clock site of tricuspid annulus during mild preexcitation, demonstrating an example of intra-pathway conduction delay, which can be reversed by isoproterenol. Ablation at the site caused accelerated pathway rhythm and eliminated the pathway, rendering the tachycardia non-inducible.

Successful treatment of bepridil-induced intraoperative torsades de pointes by isoproterenol infusion

Background Several types of antiarrhythmic drugs are known to induce QT prolongation and torsades de pointes. Case presentation An 84-year-old man was scheduled for open gastrectomy for residual cancer. He had been prescribed bepridil for atrial fibrillation that converted to sinus rhythm with prolonged QT interval in the operating room. After the surgery was initiated under general and epidural anesthesia, the patient’s heart rate decreased to 50/min and multifocal premature ventricular contractions appeared, followed by several episodes of torsades de pointes, each lasting for 5 to 15 s. Infusion of isoproterenol was started (0.01 μg/kg/min), and the heart rate was maintained at around 80/min. Premature ventricular contractions disappeared, and torsades de pointes did not recur during the surgery. The operation was completed uneventfully. The serum bepridil concentration was found to be extremely high postoperatively. Conclusions Bepridil-induced intraoperative episodes of torsades de pointes were successfully treated by increasing the heart rate with isoproterenol.

Abstract P499: Histone H4K20 Trimethylation Is Differentially Regulated In Heart Disease

It has been well established that many cardiac pathologies result from dynamic changes in gene expression and conversely that modulating key epigenetic factors in murine models is capable of preventing or abrogating ischemic injury and pathological remodeling. One epigenetic mechanism is the post-translational modification of histones, which are reversibly methylated on lysine (K) residues and can accept up to three methyl groups (Me1, Me2 and Me3). In the heart, significant changes in global levels of histone H3K4Me3 and H3K9Me3 have been previously reported to be upregulated and downregulated, respectively, during hypertrophy and failure in mice. However, the majority of post-translational modifications on histones have never been examined to quantify global abundance in the heart during disease. In particular, histone H4K20Me3 is important in heterochromatin formation and gene repression in non-cardiac cells but has never been evaluated in the heart. Therefore, we utilized cardiac tissue from three animal models of cardiac stress and employed western blotting and mass spectrometry to quantify the global abundance of total histone H4 and H4K20 methylation. We specifically evaluated tissue from mice subjected to LAD ligation, transverse aortic banding and isoproterenol infusion (via mini-osmotic pump). In addition, we also utilized primary neonatal cardiomyocytes treated with the hypertrophic agonist phenylephrine to quantify H4K20 methylation. Our data show that global levels of histone H4K20Me3 are differentially regulated in some models of cardiac dysfunction, but not all (i.e. isoproterenol infusion). In addition, we measured the abundance of histone methyltransferases and demethylases (via western blotting and qPCR) which are responsible for adding or removing this methyl mark in mouse cardiac tissue, and compared this to published data from human heart failure patients. These analyses allowed us to identify two enzymes, the methyltransferase Smyd5 and demethylase KDM7B, which are also differentially expressed in cardiac tissue during disease. Together these results are the first analysis of histone H4K20 methylation in the heart and suggest a novel role for this methylation site in the pathophysiology of cardiovascular disease.

Deletion of Kvβ2 (AKR6) Attenuates Isoproterenol Induced Cardiac Injury with Links to Solute Carrier Transporter SLC41a3 and Circadian Clock Genes

Kvβ subunits belong to the aldo-keto reductase superfamily, which plays a significant role in ion channel regulation and modulates the physiological responses. However, the role of Kvβ2 in cardiac pathophysiology was not studied, and therefore, in the present study, we hypothesized that Kvβ2 plays a significant role in cardiovascular pathophysiology by modulating the cardiac excitability and gene responses. We utilized an isoproterenol-infused mouse model to investigate the role of Kvβ2 and the cardiac function, biochemical changes, and molecular responses. The deletion of Kvβ2 attenuated the QTc (corrected QT interval) prolongation at the electrocardiographic (ECG) level after a 14-day isoproterenol infusion, whereas the QTc was significantly prolonged in the littermate wildtype group. Monophasic action potentials verified the ECG changes, suggesting that cardiac changes and responses due to isoproterenol infusion are mediated similarly at both the in vivo and ex vivo levels. Moreover, the echocardiographic function showed no further decrease in the ejection fraction in the isoproterenol-stimulated Kvβ2 knockout (KO) group, whereas the wildtype mice showed significantly decreased function. These experiments revealed that Kvβ2 plays a significant role in cardiovascular pathophysiology. Furthermore, the present study revealed SLC41a3, a major solute carrier transporter affected with a significantly decreased expression in KO vs. wildtype hearts. The electrical function showed that the decreased expression of SLC41a3 in Kvβ2 KO hearts led to decreased Mg2+ responses, whereas, in the wildtype hearts, Mg2+ caused action potential duration (APD) shortening. Based on the in vivo, ex vivo, and molecular evaluations, we identified that the deletion of Kvβ2 altered the cardiac pathophysiology mediated by SLC41a3 and altered the NAD (nicotinamide adenine dinucleotide)-dependent gene responses.

Abstract 15059: Prevalence of Recovery of Conduction in the Left Atrial Appendage Following Electrical Isolation of the Appendage in Patients With Atrial Fibrillation

Background: Electrical isolation of the left atrial appendage (LAAEI) is considered in patients presenting with recurrence following effective PV isolation. Objective: We evaluated the prevalence of LAA reconnection following LAAEI in patients undergoing repeat procedure for AF recurrence. Methods: Consecutive AF patients undergoing repeat ablation for arrhythmia recurrence following LAAEI were included in this analysis. Transesophageal echocardiogram (TEE) was performed in all at baseline to evaluate LAA function. Isoproterenol infusion up to 30 μg/min for 10 to 15 min was administered to detect LAA triggers. Re-isolation of the LAA was performed if triggers were detected. Off-drug success rate was assessed in all. Results: A total of 594 post-LAAEI patients with recurrent AF were included in the analysis. At the redo, PVs were found to be electrically silent in all. LAA reconnection was detected in 214 (36%) patients. Baseline TEE revealed normal LAA contractility and flow-velocity in all. Re-isolation of the LAA was performed in these 214 patients. In patients with no LAA reconnection (n=380), non-PV triggers from other sites were targeted for ablation. There was no difference in the clinical characteristics of patients with vs. without LAA reconnection (Table). At 2 years after the repeat procedure, 201 (94%) patients with and 351 (92.3%) without LAA reconnection were arrhythmia-free off-drugs (p=0.47). Conclusion: In this series, LAA reconnection rate was 36% after single LAAEI procedure and re-isolation of the appendage led to high success rate. Additionally, normal LAA functions detected by TEE correctly predicted recovery of conduction in the LAA.