Research ArticleCardiology Open Access | 10.1172/jci.insight.157956

Al-Hassan J. Dajani,1 Michael B. Liu,1 Michael A. Olaopa,1 Lucian Cao,1 Carla Valenzuela-Ripoll,2 Timothy J. Davis,1 Megan D. Poston,3,4 Elizabeth H. Smith,3,4 Jaime Contreras,1 Marissa Pennino,1 Christopher M. Waldmann,5,6 Donald B. Hoover,3,4 Jason T. Lee,7,8 Patrick Y. Jay,9 Ali Javaheri,2,10 Roger Slavik,5 Zhilin Qu,1 and Olujimi A. Ajijola1

1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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1UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program of Excellence, and Department of Medicine, UCLA, Los Angeles, California, USA.

2Washington University School of Medicine, St. Louis, Missouri, USA.

3Department of Biomedical Sciences, Quillen College of Medicine, and

4Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, Tennessee, USA.

5Ahmanson Translational Theranostics Division, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

6Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

7Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

8Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, California, USA.

9Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.

10John J. Cochran Veterans Hospital, St. Louis, Missouri, USA.

Address correspondence to: Olujimi A. Ajijola, UCLA Cardiac Arrhythmia Center, UCLA Neurocardiology Research Program, David Geffen School of Medicine at UCLA, 100 Medical Plaza, Suite 660, Westwood Blvd, Los Angeles, California 90095-1679, USA. Phone: 310.206.6433; Email: oajijola@mednet.ucla.edu.

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Published October 10, 2023 - More info

Published in Volume 8, Issue 22 on November 22, 2023
JCI Insight. 2023;8(22):e157956. https://doi.org/10.1172/jci.insight.157956.
© 2023 Dajani et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published October 10, 2023 - Version history
Received: December 28, 2021; Accepted: September 29, 2023 View PDF Abstract

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Introduction

Ventricular arrhythmias (VAs) remain a leading cause of death in nonischemic dilated cardiomyopathy (DCM) (1). The autonomic nervous system (ANS), through its parasympathetic and sympathetic divisions, extensively innervates the heart and is an important modulator of cardiac electrophysiology (2, 3). Dysfunction within the ANS, specifically increased cardiac sympathetic tone and withdrawal of parasympathetic signaling, has been linked to arrhythmogenesis (4). The role of sympathetic signaling in promoting cardiac dysfunction and arrhythmias is underscored by the strong clinical data supporting the use of β-adrenergic receptor blockers (5–7) and other forms of neurohormonal blockade in chronic DCM. Further, nonpharmacologic antiadrenergic therapies such as bilateral cardiac sympathetic denervation, stellate ganglion blockade using anesthetic agents, and other neural interventions in the setting of cardiac dysfunction suppress VAs. These interventions physically or functionally interrupt signaling from sympathetic neurons and the fibers directly innervating the heart, distinct from circulating catecholamines from the adrenal glands.

Paradoxically, while congestive heart failure (CHF), whether ischemic or DCM, is characterized by chronic sympathetic excess, it is associated with reduced cardiac sympathetic innervation in humans (8) and in canine (9) and rodent (10) experimental models of CHF. This finding has been mechanistically related to reduced expression of the neurotrophin nerve growth factor (Ngf) and increased production of the neurorepellant semaphorin 3A (Sema3a) by cardiomyocytes in the failing heart (11–13). The detrimental consequence of reduced sympathetic innervation was clinically demonstrated in the ADMIRE-HF study (14), using delayed functional imaging of cardiac sympathetic nerves with a radiolabeled tracer, iodine-123 meta-iodobenzylguanidine ([123I]-mIBG). In this study, reduced sympathetic innervation, identified by lower heart/mediastinal uptake of [123I]-mIBG, was associated with higher risk of severe VAs, heart failure hospitalization, and mortality.

However, the mechanisms by which loss of sympathetic innervation in chronic CHF enhances arrhythmogenesis remain poorly understood. We hypothesized that 1) the loss of sympathetic nerves in the failing heart is heterogeneous and 2) this heterogeneity permits the emergence of dynamic substrates that permit reentry and the triggers that initiate them during sympathetic activation. The goal of the present study was to test this hypothesis in an established mouse model of nonischemic DCM (DCM Tg9) (15–17). This model exhibits similar traits to human heart failure (15) without the potential confounding factors associated with surgical models (e.g., coronary artery ligation) and thus is an ideal model to study innervation in an unperturbed fashion.

We demonstrate that progression of DCM increases susceptibility to ventricular arrhythmogenesis. Importantly, we correlate this susceptibility to an increased transmural gradient of sympathetic innervation. Finally, we show how the heterogeneity in sympathetic innervation gradients promotes arrhythmogenesis using in silico models of normal and failing human myocardium and heart. This study provides what we believe are novel insights into how neural remodeling in nonischemic heart failure promotes ventricular arrhythmogenesis.

Results

DCM Tg9 model recapitulates human heart failure and demonstrates decreased functional sympathetic innervation. First, we confirmed that the DCM mouse model exhibits features of human heart failure, particularly differential changes in functional sympathetic innervation as assessed by delayed PET imaging. DCM mice exhibited cardiomegaly compared with controls (Figure 1A), progressive interstitial fibrosis (Figure 1, B and D), and on echocardiography, progressive decline in left ventricular ejection fraction (LVEF) and increased left ventricular EDD (Figure 1, C and D).

Figure 1

Transgenic DCM mouse model recapitulates human heart failure. (A) Control (top row) and DCM (bottom row) mouse hearts imaged using a light microscope. (B) Digitally scanned images of transmural myocardial sections from control and DCM mice in early (left) and late (right) stages stained with Masson’s trichrome to indicate fibrosis. Image scale bars are 100 μm. (C) Images of left ventricular end systolic diameter (ESD, left) and end diastolic diameter (EDD, right) taken using echocardiography for control and DCM mice. Image scale bars are 2 mm. (D) Fibrosis levels in WT vs. DCM in myocardium of left ventricle in early (left, n = 5 for control, n = 7 for DCM, **P = 0.0045, Shapiro-Wilk test, Welch’s t test) and late stages (right, n = 6 for control, n = 5 DCM, ***P < 0.0001, Shapiro-Wilk test, Welch’s t test). LVEF (%) in control and DCM mice in early (left, n = 8 for control, n = 8 for DCM, ***P < 0.0001, Shapiro-Wilk test, Welch’s t test) and late stages (right, n = 8 for control, n = 8 for DCM, ***P < 0.0001, Shapiro-Wilk test, Welch’s t test). EDD in WT vs. DCM mice in early (left, n = 8 for control, n = 8 for DCM, ***P < 0.0001, Shapiro-Wilk test, Welch’s t test) and late stages (right, n = 8 for control, n = 8 for DCM, ***P < 0.0001, Shapiro-Wilk test, Welch’s t test). “Early” refers to mice less than or equal to 8 weeks of age, while “late” refers to mice older than 8 weeks.

Next, [11C]meta-Hydroxyephedrine ([11C]-mHED) PET-CT was performed to quantify functional sympathetic cardiac innervation on delayed imaging in DCM and control mice. To validate the synthesis of [11C]-mHED and its specificity for sympathetic nerve endings, delayed PET-CT imaging was performed following depletion of cardiac sympathetic nerves using 6-hydroxydopamine (6-OHDA). As shown in Supplemental Figure 1, A–D (supplemental material available online with this article; https://doi.org/10.1172/jci.insight.157956DS1), mice treated with 6-OHDA demonstrated little to no sympathetic innervation on immunohistochemistry. Consistent with this, PET-CT imaging using [11C]-mHED demonstrated severely reduced uptake in the heart but not hind leg or mediastinum, where sympathetic innervation is lower. When performed in late-stage DCM versus age-matched control littermates, noncardiac tissues, including liver and hind leg muscle, were not significantly different in radioactivity level. However, the base, apex, anterior wall, and posterior wall of the heart showed significantly less radioactivity in DCM mice compared with control mice (Figure 2), indicating that sympathetic innervation is reduced structurally and functionally in DCM mice.

Figure 2

DCM model shows decreased cardiac sympathetic innervation. (A) Representative [11C]meta-Hydroxyephedrine PET-CT images taken at the 60-minute time point of WT (top) and DCM (bottom) mouse models scaled to units of percentage injected dose per gram of tissue (% ID/g) (head, heart, and tail labeled for orientation). (B) [11C]meta-Hydroxyephedrine time-activity curves (0–60 minutes) showing uptake in adrenergic nerve terminals of various tissues in control and DCM mice. (C) Quantification at 60 minutes to show uptake of [11C]meta-Hydroxyephedrine in adrenergic nerve terminals of various tissues in control and DCM mice: cardiac base (n = 4 for control, n = 4 for DCM, *P = 0.0286, Mann-Whitney test), cardiac apex (n = 4 for control, n = 4 for DCM, *P = 0.0286, Mann-Whitney test), cardiac ant. wall (n = 4 for control, n = 4 for DCM, *P = 0.0286, Mann-Whitney test), cardiac post. wall (n = 4 for control, n = 4 for DCM, *P = 0.0286, Mann-Whitney test), hind leg (n = 4 for control, n = 4 for DCM, P = 0.3429, Mann-Whitney test), and superior mediastinum (n = 4 for control, n = 4 for DCM, P = 0.1143, Mann-Whitney test).

DCM is characterized by spatially heterogeneous cardiac sympathetic innervation. To test the hypothesis that loss of sympathetic innervation in DCM mice is spatially heterogeneous, we quantified sympathetic nerves (immunoreactivity to tyrosine hydroxylase and neuropeptide Y) across the entire left ventricle in short axis (anterior, septal, posterior, and lateral walls) and long axis (base, mid, and apex) (Figure 3A). As expected, DCM hearts exhibited LV chamber enlargement and wall thinning. However, compared with control hearts, DCM hearts exhibited greater denervation in the endocardium compared with the epicardium, resulting in transmural innervation gradients (Figure 3, B–D). As depicted in Figure 3E, increased transmural gradients were present at the base, mid, and apical levels of the LV. Interestingly, gradients were nonuniform across the anterior, septal, posterior, and lateral walls, such that sites with stark differences in transmural gradient were adjacent to each other (Figure 3F