Atrial Remodeling in Right Ventricular Pacing-induced Cardiomyopathy

Michael Georg Paulus (Regensburg)1, M. Mayer (Regensburg)1, L.-M. Köhler (Regensburg)1, S. Iberl (Regensburg)1, G. Pietrzyk (Regensburg)1, A. Nickel (Würzburg)2, S. Wagner (Regensburg)1, L. S. Maier (Regensburg)1, A. Dietl (Regensburg)1

1Universitätsklinikum Regensburg Klinik und Poliklinik für Innere Med. II, Kardiologie Regensburg, Deutschland; 2Universitätsklinikum Würzburg Deutsches Zentrum für Herzinsuffizienz Würzburg, Deutschland


Pacing-induced cardiomyopathy is an increasingly recognized condition characterized by progressive left ventricular (LV) dysfunction caused by high burden of right ventricular (RV) pacing. As the clinically observed increased prevalence of atrial fibrillation during RV pacing suggests concomitant atrial myopathy, we aimed to evaluate atrial remodeling in an animal model of pacing-induced cardiomyopathy.
Permanent pacemaker implantation was performed on eighteen rabbits. Ten animals served as sham-operated controls (SHAM), eight rabbits underwent RV pacing with up to 380 bpm over thirty days, leading to pacing-induced cardiomyopathy (PICM). Cardiac dimension and function were evaluated by echocardiography. Left atrial (LA) and right atrial (RA) tissue were harvested and subjected to further analysis. Wheat germ agglutinin staining was used to determine cardiomyocyte size by automated image processing. Apoptosis rate was assessed by TUNEL staining. Tissue and mitochondrial redox state were assessed by fluorometric assays as the ratio of reduced nicotinamide adenine dinucleotide (NADH) to NAD+ or reduced to oxidized glutathione (GSH/GSSG), respectively. Mitochondria were visualized by confocal microscopy, staining tissue with antibodies against HSP60 and N-Cadherin. To evaluated intracellular mitochondrial distribution, images were automatically processed with analysis of histogram, grey-level co-occurrence matrix derived and dislocation parameters.
PICM animals developed clinical signs of heart failure as well as LV systolic dysfunction (SHAM vs. PICM LV fractional shortening 38.2±4.9 vs. 21.2±4.4 %, p<0.0001) and dilatation (LV end diastolic diameter 14.1±1.1 vs. 17.6±1.4 mm, p<0.001). Echocardiography revealed significant LA enlargement (LA diameter 1.0±0.1 vs. 1.3±0.1 mm, p<0.001), which was mirrored by cardiomyocyte hypertrophy in histology (LA cell cross-sectional area 4216±1161 vs. 5996±1394 a.u., p<0.05). Concomitantly, cardiomyocyte size was also increased by trend in RA specimen (5089±2622 vs. 8214±1081 a.u., p=0.056). We did not observe signs of oxidative stress, with tissue redox state being shifted significantly to a reduced state in LA (ratio GSH/GSSG 25.2±17.2 vs. 88.8±24.6, p<0.05) and by trend in RA (12.4±11 vs. 47.0±21, p=0.092) instead. Consistently, TUNEL-staining did not demonstrate increased apoptosis in both atria (apoptotic cells/field of view LA 1.13±0.57 vs. 1.38±1.58, p=0.802; RA 1.37±0.94 vs. 1.24±1.20, p=0.884). Intracellular distribution of the mitochondrial network remained unchanged in both atria (LA angular second momentum 0.040±0.027 vs. 0.043±0.030, p=0.84; RA 0.015±0.009 vs. 0.019±0.015, p=0.54). Also, mitochondrial redox state was not altered in both LA and RA (ratio NADH/NAD+ LA 4.04±1.57 vs. 3.70±0.44, p=0.47; RA 2.80±2.27 vs. 3.86±1.07; p=0.28), implying preserved mitochondrial function and architecture. 
In addition to LV dysfunction, pacing-induced cardiomyopathy is associated with distinct atrial remodeling in an animal model, comprising cardiomyocyte hypertrophy, reduced tissue redox state, and preserved mitochondrial function.
Diese Seite teilen