Author + information
- Received March 14, 2019
- Revision received May 29, 2019
- Accepted June 24, 2019
- Published online September 2, 2019.
- Roddy Hiram, PhDa,
- Patrice Naud, PhDa,
- Feng Xiong, PhDb,
- Doa’a Al-u’datt, DDSa,
- Vincent Algalarrondo, MDa,
- Martin G. Sirois, PhDa,
- Jean-François Tanguay, MDa,
- Jean-Claude Tardif, MDa and
- Stanley Nattel, MDa,b,c,d,∗ (, )@StanleyNattel
- aMontreal Heart Institute (MHI), Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
- bDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
- cIHU Liryc and Fondation Bordeaux Université, Bordeaux, France
- dInstitute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
- ↵∗Address for correspondence:
Dr. Stanley Nattel, Montreal Heart Institute Research Center, 5000 Belanger Street, Montreal, Quebec H1T 1C8, Canada.
Background Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.
Objectives This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.
Methods PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.
Results Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p < 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.
Conclusions Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.
Funding was provided by the Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada. Dr. Algalarrondo has received consulting fees from Pfizer; and has received scholarship funds from Medtronic, Abbott, Boston Scientific, Biotronik, and Microport. Dr. Tardif has received research grants from Amarin, AstraZeneca, DalCor, Esperion, Ionis, Pfizer, Sanofi, Servier, and RegenX bio; has received honoraria from DalCor, Pfizer, Sanofi, and Servier; and holds equity in DalCor. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received March 14, 2019.
- Revision received May 29, 2019.
- Accepted June 24, 2019.
- 2019 American College of Cardiology Foundation
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