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      Congestive Heart Failure Leads to Prolongation of the PR Interval and Atrioventricular Junction Enlargement and Ion Channel Remodelling in the Rabbit

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          Abstract

          Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RT-PCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Ca v1.3 in the transitional tissue. Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Na vβ1 was increased with heart failure; Na v1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied by downregulation of HCN1, Ca v1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ.

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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.
          Article 0 comments Cited 117 times – based on 0 reviews     Review now
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            Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block.

            Susan Cheng, R Vasan, Christopher Newton-Cheh … (2009)
            Prolongation of the electrocardiographic PR interval, known as first-degree atrioventricular block when the PR interval exceeds 200 milliseconds, is frequently encountered in clinical practice. To determine the clinical significance of PR prolongation in ambulatory individuals. Prospective, community-based cohort including 7575 individuals from the Framingham Heart Study (mean age, 47 years; 54% women) who underwent routine 12-lead electrocardiography. The study cohort underwent prospective follow-up through 2007 from baseline examinations in 1968-1974. Multivariable-adjusted Cox proportional hazards models were used to examine the associations of PR interval with the incidence of arrhythmic events and death. Incident atrial fibrillation (AF), pacemaker implantation, and all-cause mortality. During follow-up, 481 participants developed AF, 124 required pacemaker implantation, and 1739 died. At the baseline examination, 124 individuals had PR intervals longer than 200 milliseconds. For those with PR intervals longer than 200 milliseconds compared with those with PR intervals of 200 milliseconds or shorter, incidence rates per 10 000 person-years were 140 (95% confidence interval [CI], 95-208) vs 36 (95% CI, 32-39) for AF, 59 (95% CI, 40-87) vs 6 (95% CI, 5-7) for pacemaker implantation, and 334 (95% CI, 260-428) vs 129 (95% CI, 123-135) for all-cause mortality. Corresponding absolute risk increases were 1.04% (AF), 0.53% (pacemaker implantation), and 2.05% (all-cause mortality) per year. In multivariable analyses, each 20-millisecond increment in PR was associated with an adjusted hazard ratio (HR) of 1.11 (95% CI, 1.02-1.22; P = .02) for AF, 1.22 (95% CI, 1.14-1.30; P < .001) for pacemaker implantation, and 1.08 (95% CI, 1.02-1.13; P = .005) for all-cause mortality. Individuals with first-degree atrioventricular block had a 2-fold adjusted risk of AF (HR, 2.06; 95% CI, 1.36-3.12; P < .001), 3-fold adjusted risk of pacemaker implantation (HR, 2.89; 95% CI, 1.83-4.57; P < .001), and 1.4-fold adjusted risk of all-cause mortality (HR, 1.44, 95% CI, 1.09-1.91; P = .01). Prolongation of the PR interval is associated with increased risks of AF, pacemaker implantation, and all-cause mortality.
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              Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity.

              M E Mangoni, B Couette, E Bourinet … (2003)
              The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate under physiological conditions. Pacemaker activity in SAN cells is due to the presence of the diastolic depolarization, a slow depolarization phase that drives the membrane voltage from the end of an action potential to the threshold of a new action potential. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in pacemaker activity and we still do not know which channels play a prominent role in the generation of the diastolic depolarization. It is thus important to provide genetic evidence linking the activity of genes coding for ionic channels to specific alterations of pacemaker activity of SAN cells. Here, we show that target inactivation of the gene coding for alpha(1D) (Ca(v)1.3) Ca(2+) channels in the mouse not only significantly slows pacemaker activity but also promotes spontaneous arrhythmia in SAN pacemaker cells. These alterations of pacemaker activity are linked to abolition of the major component of the L-type current (I(Ca,L)) activating at negative voltages. Pharmacological analysis of I(Ca,L) demonstrates that Ca(v)1.3 gene inactivation specifically abolishes I(Ca,L) in the voltage range corresponding to the diastolic depolarization. Taken together, our data demonstrate that Ca(v)1.3 channels play a major role in the generation of cardiac pacemaker activity by contributing to diastolic depolarization in SAN pacemaker cells.
              Article 0 comments Cited 115 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Alexander V Panfilov: 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, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 28 October 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 10
                Electronic Location Identifier: e0141452
                Affiliations
                [1 ]Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
                [2 ]School of Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
                [3 ]The Manchester Henry Moseley X-ray Imaging Facility, University of Manchester, Manchester, United Kingdom
                [4 ]School of Medical Sciences, Health Campus, University Sains Malaysia, Kubang Kerian, Malaysia
                Gent University, BELGIUM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TN XJC RSS PJW JCJ GH MRB. Performed the experiments: TN XJC RSS JY TL AJA CBJ RS AFC JCJ GH MRB. Analyzed the data: TN XJC RSS TL AJA CBJ RS AFC GH MRB. Contributed reagents/materials/analysis tools: RSS JY TL AJA HD. Wrote the paper: TN RSS TL PJW JCJ GH MRB.

                [¤]

                Current address: Department of Academic Cardiology, University of Hull, Hull, United Kingdom

                Article
                Publisher ID: PONE-D-15-13967
                DOI: 10.1371/journal.pone.0141452
                PMC ID: 4624927
                PubMed ID: 26509807
                SO-VID: e1ba06c4-70ca-4dd6-9e72-fa68bb6fc510
                Copyright statement: Copyright @ 2015
                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 : 9 April 2015
                Date accepted : 8 October 2015
                Page count
                Figures: 8, Tables: 1, Pages: 18
                Funding
                This work was funded by a programme grant from the British Heart Foundation RG/06/005. The Manchester X-ray Imaging Facility was funded in part by the EPSRC (grants EP/F007906/1, EP/F001452/1 and EP/I02249X/1). The Bioimaging Facility microscopes used in this study were purchased with grants from the Biotechnology and Biological Sciences Research Council, Wellcome Trust and the University of Manchester Strategic Fund. TN was funded by the Manchester Biomedical Research Centre. RSS was funded by the Alder Hey Children's NHS Foundation Trust. GH held the David A. Price Evans Chair of Medicine at the University of Liverpool during the course of this work.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
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