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. 2020 Jun;17(6):1025-1033.
doi: 10.1016/j.hrthm.2020.02.007. Epub 2020 Feb 15.

Mechanisms of atrial fibrillation in aged rats with heart failure with preserved ejection fraction

Thassio Ricardo Ribeiro Mesquita  1 , Rui Zhang  2 , Geoffrey de Couto  1 , Jackelyn Valle  1 , Lizbeth Sanchez  1 , Russell G Rogers  1 , Kevin Holm  1 , Weixin Liu  1 , Eduardo Marbán  1 , Eugenio Cingolani  3
Affiliations

Mechanisms of atrial fibrillation in aged rats with heart failure with preserved ejection fraction

Thassio Ricardo Ribeiro Mesquita et al. Heart Rhythm. 2020 Jun.

Abstract

Background: Although ∼20% of the elderly population develops atrial fibrillation (AF), little is known about the mechanisms. Heart failure with preserved ejection fraction (HFpEF), which is associated with AF, is more common in aged women than in men.

Objective: The purpose of this study was to identify potential mechanisms of AF in an age-related HFpEF model.

Methods: In aged female Fischer F344 rats (21- to 24-month-old), which are prone to HFpEF, we induced AF by atrial pacing. Young Fischer F344 female rats (3- to 4-month-old) and age-matched Sprague Dawley female rats (27-month-old) served as controls. Phenotyping included echocardiography to assess left ventricular structure/function; in vivo electrophysiology and ex vivo high-resolution optical mapping to assess AF vulnerability; systemic and atrial inflammatory profiling; atrial histology; and expression of inflammasome signaling proteins.

Results: Aged rats developed left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, and pulmonary congestion, without ejection fraction impairment, thus meeting the criteria for HFpEF. Increased serum inflammatory markers, hypertension, and obesity further characterize aged females. Sinoatrial and atrioventricular node dysfunction was associated with the high inducibility of AF in aged rats. Ex vivo electrical activation mapping revealed abnormal β-adrenergic responsiveness and slowed conduction velocity. Atrial inflammasome signaling was enhanced in aged rats, which may contribute to fibrotic remodeling and high AF susceptibility.

Conclusion: Together, our data demonstrate that aging-related atrial remodeling and HFpEF are associated with atrial enlargement, fibrosis, conduction abnormalities, and nodal dysfunction, favoring a substrate conducive to AF.

Keywords: Aging; Atrial fibrillation; Fibrosis; HFpEF; Inflammation.

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Conflict of interest statement

Conflicts of Interest: none.

Figures

Figure 1.
Figure 1.. Aging-related diastolic dysfunction is associated with increased proinflammatory stress.
A, Representative echocardiography images (top) of ejection fraction analysis (bottom); B, Representative images (top) of pulse-wave Doppler showing E (early filling) and A (atrial filling) wave changes (bottom); C, Representative images (top) of tissue Doppler describing E’ and A’ wave changes (bottom); D, LW/TL: lungs weight/tibia length ratio; E, Non-invasive blood pressure (SAP: systolic, DAP: diastolic, and MAP: mean arterial pressure, n= 5 animals each group) measurements. F, Electrocardiograms intervals analyses (n= 8 animals each group); G, Representative flow cytometry histograms of CD11b+ cells and granulocytes; H, Quantification of flow cytometry data. I, Expression of proinflammatory and profibrotic cytokines in serum (n= 4 animals each group). Data are expressed as mean ± SEM. Unpaired Student’s t-test. *P<0.05, **P<0.01, ***P<0.001 vs. young females.
Figure 2.
Figure 2.. Atrial enlargement and SAN/AV dysfunction underlie high atrial fibrillation incidence in aged rats.
A, Representative B-mode echocardiography recordings (left) and quantification of left atrial (LA) area (right); B, Relationship between E/E’ ratio and LA area, data fit by linear regression; 95% confidence limits. C, Representative ECG recordings (left), dashed lines highlight prolonged P wave duration in aged animals and quantification of P wave duration (right); D, Representative ECG recordings (left) and quantification of corrected sinoatrial node recovery time (cSNRT, right); E-F, 2:1 AV conduction cycle length (E) and Wenckebach cycle length (F) assess AV node function; G, Quantification of atrial effective refractory period (AERP); H, Representative simultaneous recordings of intracardiac potentials (red line) and surface ECG (lead II, black line) protocol used to induce atrial fibrillation (AF, left) and incidence of pacing-induced AF (right); I, Duration of AF in young and aged animals. Data are expressed as mean ± SEM. Unpaired Student’s t-test. χ2-test without Yates correction (H). *P<0.05, **P<0.01, ***P<0.001 vs. young females.
Figure 3.
Figure 3.. Chronotropic reserve is impaired in aged rats.
A, In vivo dobutamine stress was used to determine the chronotropic reserve in young and aged animals; Representative ECG recordings (B) and quantification of β-adrenergic-induced heart rate (HR) increase (C, circle: baseline and square: dobutamine-induced HR response); D, β-adrenergic responsiveness in both groups; E, HR recovery time after maximal effect of dobutamine. Data are expressed as individual values (before-after, C) and mean ± SEM. Paired (C) and unpaired Student’s t-test (D). Double-exponential fit of HR decay phase was used. ***P<0.01 vs. baseline and *P<0.05 vs. young females.
Figure 4.
Figure 4.. Slowed conduction velocity underlies β-adrenergic-induced abnormal rhythm in aged rats.
A, Representative image of electrodes placement surrounding the ex vivo SAN/atrial tissue loaded with a voltage-sensitive dye (left) and simultaneous recordings of electrograms (EGM) and optical action potential in the left atrial (LA) appendage of young and aged females rats under baseline and isoproterenol (Iso) conditions (right); Spontaneous sinus rhythm and concentration-response curve for isoproterenol was applied to evaluate ex vivo beating rate (B) and action potential duration at 90% (APD90) (C). D, Representative images of isochronal voltage maps and conduction velocity (CV, E) in the LA; F, Occurrence of abnormal rhythm throughout the dose-response curve to Iso (left) and representative EGM traces (right). Data are expressed as mean ± SEM. Sigmoidal dose-response curve fits were generated to calculate the half maximal effective (EC50) and inhibitory (IC50) concentration. χ2-test without Yates correction (F). n= 5 animals each group. *P<0.05 vs. young females.
Figure 5.
Figure 5.. Increased atrial fibrosis and inflammation are critical substrates for atrial fibrillation-promoting reentry circuit in aged rats.
A, Representative Masson’s trichrome-stained sections of left atrial (LA) tissue (left) and quantification (right); B, Representative atrial action potential duration (APD) maps of young and aged females (left) and standard deviation (SD) of APD 90% (APD90 dispersion) measured at three random regions in LA appendage (right); C, Relationship between atrial fibrosis and area, data fit by linear regression; 95% confidence limits. D, Representative images of isochronal voltage maps (left) and incidence of atrial fibrillation (AF) obtained ex vivo (right). E, Cytokines levels in LA samples (nd= not detected, n= 4 animals each group); F, CD68 immunostaining of LA (left; scale bar: 20 m) and pooled data from CD68+ cells within the LA tissue (right). Data are expressed as mean ± SEM. Unpaired Student’s t-test. χ2-test without Yates correction (E). *P<0.05 and ***P<0.001 vs. young females.
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