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      Atrial Arrhythmia in Ageing Spontaneously Hypertensive Rats: Unraveling the Substrate in Hypertension and Ageing

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          Abstract

          Background

          Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR).

          Methods

          SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis.

          Results

          Compared to WKY controls, the SHR demonstrated: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages.

          Conclusions

          Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria.

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          Most cited references42

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          Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study.

          E Benjamin, D. Levy, S Vaziri … (1994)
          To determine the independent risk factors for atrial fibrillation. Cohort study. The Framingham Heart Study. A total of 2090 men and 2641 women members of the original cohort, free of a history of atrial fibrillation, between the ages of 55 and 94 years. Sex-specific multiple logistic regression models to identify independent risk factors for atrial fibrillation, including age, smoking, diabetes, electrocardiographic left ventricular hypertrophy, hypertension, myocardial infarction, congestive heart failure, and valve disease. During up to 38 years of follow-up, 264 men and 298 women developed atrial fibrillation. After adjusting for age and other risk factors for atrial fibrillation, men had a 1.5 times greater risk of developing atrial fibrillation than women. In the full multivariable model, the odds ratio (OR) of atrial fibrillation for each decade of advancing age was 2.1 for men and 2.2 for women (P < .0001). In addition, after multivariable adjustment, diabetes (OR, 1.4 for men and 1.6 for women), hypertension (OR, 1.5 for men and 1.4 for women), congestive heart failure (OR, 4.5 for men and 5.9 for women), and valve disease (OR, 1.8 for men and 3.4 for women) were significantly associated with risk for atrial fibrillation in both sexes. Myocardial infarction (OR, 1.4) was significantly associated with the development of atrial fibrillation in men. Women were significantly more likely than men to have valvular heart disease as a risk factor for atrial fibrillation. The multivariable models were largely unchanged after eliminating subjects with valvular heart disease. In addition to intrinsic cardiac causes such as valve disease and congestive heart failure, risk factors for cardiovascular disease also predispose to atrial fibrillation. Modification of risk factors for cardiovascular disease may have the added benefit of diminishing the incidence of atrial fibrillation.
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            Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.

            M. C. E. F. Wijffels, C Kirchhof, R Dorland … (1995)
            In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia. Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF. Whereas during control episodes of AF were short lasting (6 +/- 3 seconds), artificial maintenance of AF resulted in a progressive increase in the duration of AF to become sustained (> 24 hours) after 7.1 +/- 4.8 days (10 of 11 goats). During the first 24 hours of AF the median fibrillation interval shortened from 145 +/- 18 to 108 +/- 8 ms and the inducibility of AF by a single premature stimulus increased from 24% to 76%. The atrial effective refractory period (AERP) shortened from 146 +/- 19 to 95 +/- 20 ms (-35%) (S1S1, 400 ms). At high pacing rates the shortening was less (-12%), pointing to a reversion of the normal adaptation of the AERP to heart rate. In 5 goats, after 2 to 4 weeks of AF, sinus rhythm was restored and all electrophysiological changes were found to be reversible within 1 week. Artificial maintenance of AF leads to a marked shortening of AERP, a reversion of its physiological rate adaptation, and an increase in rate, inducibility and stability of AF. All these changes were completely reversible within 1 week of sinus rhythm.
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              Electrical remodeling of the atria in congestive heart failure: electrophysiological and electroanatomic mapping in humans.

              Jonathan Kalman, B Morton, Anthony C. Davidson … (2003)
              Atrial fibrillation (AF) frequently complicates congestive heart failure (CHF). However, the electrophysiological substrate for AF in humans with CHF remains unknown. We evaluated the electrophysiological and electroanatomic characteristics of the atria in patients with CHF. Twenty-one patients (aged 53.7+/-13.6 years) with symptomatic CHF (left ventricular ejection fraction 25.5+/-6.0%) and 21 age-matched controls were studied. The following were evaluated: effective refractory periods (ERPs) from the high and low lateral right atrium (LRA), high septal right atrium, and distal coronary sinus (CS); conduction time along the CS and LRA; corrected sinus node recovery times; P-wave duration; and conduction at the crista terminalis. In a subset, electroanatomic mapping was performed to determine atrial activation, regional conduction velocity, double potentials, fractionated electrograms, regional voltage, and areas of electrical silence. Patients with CHF demonstrated an increase in atrial ERP with no change in the heterogeneity of refractoriness, an increase of atrial conduction time along the LRA and the CS, prolongation of the P-wave duration and corrected sinus node recovery times, and greater number and duration of double potentials along the crista terminalis. Electroanatomic mapping demonstrated regional conduction slowing with a greater number of electrograms with fractionation or double potentials, associated with areas of low voltage and electrical silence (scar). Patients with CHF demonstrated an increased propensity for AF with single extrastimuli, and induced AF was more often sustained. Atrial remodeling due to CHF is characterized by structural changes, abnormalities of conduction, sinus node dysfunction, and increased refractoriness. These abnormalities may be responsible in part for the increased propensity for AF in CHF.
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                Author and article information

                Contributors
                Marcello Rota: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 27 August 2013
                Volume: 8
                Issue: 8
                Electronic Location Identifier: e72416
                Affiliations
                [1 ]Centre for Heart Rhythm Disorders (CHRD), University of Adelaide and Royal Adelaide Hospital, Adelaide, Australia
                [2 ]Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Melbourne, Australia
                [3 ]University of Southern Queensland, Toowoomba, Australia
                Brigham & Women’s Hospital - Harvard Medical School, United States of America
                Author notes

                Competing Interests: Dr. Sanders reports having served on the advisory board of St. Jude Medical, Bard Electrophysiology, Biosense-Webster, Medtronic, Sanofi- Aventis, and Merck. Dr. Sanders reports having received lecture fees from St. Jude Medical, Bard Electrophysiology, Biosense-Webster, Medtronic and Merck. Dr. Sanders reports having received research funding from St. Jude Medical, Bard Electrophysiology, Biosense-Webster and Medtronic. However, this does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: DHL PK DAS PS. Performed the experiments: DHL NJS ST HSL HD YZ NHC MN CXW DAS KD. Analyzed the data: DHL AGB NJS MN YZ DJK CXW KD PK. Contributed reagents/materials/analysis tools: DHL DJK PS CXW LB HD DAS. Wrote the paper: DHL PS DAS DJK LB HSL.

                Article
                Publisher ID: PONE-D-13-14633
                DOI: 10.1371/journal.pone.0072416
                PMC ID: 3754972
                PubMed ID: 24013508
                SO-VID: 0b3892f7-c286-4bd1-b5eb-ccf57c4f34af
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 10 April 2013
                Date accepted : 10 July 2013
                Page count
                Pages: 9
                Funding
                This work was supported by the Heart Foundation of Australia [Grant-in-Aid G08A3653, H.D., P.K., A.G.B. & P.S.]; National Health and Medical Research Council of Australia [Postdoctoral Fellowship to D.H.L., Senior Research Fellowship to D.J.K., Postgraduate Medical Scholarship to H.S.L, H.D.]; The University of Adelaide [Peter Hetzel Electrophysiology Scholarship to S.T.]; and Cardiac Society of Australia and New Zealand [Postgraduate Medical Scholarship to H.D.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Rat
                Subject: Mathematics
                Subject: Statistics
                Subject: Biostatistics
                Subject: Medicine
                Subject: Anatomy and Physiology
                Subject: Physiological Processes
                Subject: Aging
                Subject: Cardiovascular
                Subject: Arrhythmias
                Subject: Electrophysiology
                Subject: Hypertension
                Subject: Clinical Immunology
                Subject: Immunity
                Subject: Inflammation
                Subject: Clinical Research Design
                Subject: Animal Models of Disease

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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