Tachycardiomyopathy is characterised by unique clinical features and specific remodeling processes. As previous proteomic profiling studies pointed towards interatrial and -ventricular differences of molecular alterations in tachycardiomyopathy, we aimed to investigate chamber-specific functional and structural remodeling in an established animal model.

Permanent pacemaker implantation was performed on 39 rabbits. Eighteen animals served as sham-operated controls (SHAM), 21 rabbits underwent right ventricular (RV) incremental tachypacing with up to 380 bpm over 30 days, inducing tachycardiomyopathy (TCM). Cardiac dimension and function were evaluated by echocardiography. Left ventricular (LV), RV, 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, Masson’s trichrome staining to quantify connective tissue.  Distribution of mitochondria was evaluated by confocal microscopy, staining tissue with antibodies against HSP60 and N-Cadherin. Tissue redox state was assessed as the ratio of glutathione (GSH) to glutathione disulfide (GSSG) by a colorimetric assay.

TCM animals developed clinical signs of heart failure, including ascites and pericardial effusion. Echocardiography showed significant remodeling of the left heart chambers with LV and LA dilatation (SHAM vs. TCM LV end diastolic diameter 8.1±0.2 vs. 13.3±0.6 mm, p<0.0001; LA diameter 10.1±0.3 vs. 14.1±0.6 mm, p<0.0001), which was accompanied by LV dysfunction and reduced cardiac output (LV fractional shortening 37.8±1.0 vs. 21.9±1.2 %, p<0.0001; stroke volume 1.23±0.12 vs. 0.65±0.08 mL; p<0.05). Autopsy revealed cardiac hypertrophy (heart weight 7.59±0.26 vs. 9.89±0.97 g, p<0.05), which was driven by increased cardiomyocyte size in LV and both atria as observed in histology (cell cross-sectional area LV 393.2±14.5 vs. 538.9±23.8 µm2, LA 174.5±15.3 vs. 362.3±20.3 µm2, RA 222.8±20.6 vs. 350.3±9.7 µm2; p<0.01 each). Remodeling was more subtle in RV, with RV diameter remaining unchanged and cardiomyocyte size increasing only by trend (RV end diastolic diameter 4.4±0.4 vs. 6.61±1.0, p=0.26; cell cross-sectional area 322.0±38.4 vs. 416.8±13.4 µm2, p=0.080). In contrast to other cardiomyopathies, we did not observe increased fibrosis in both LV and RV, with even a trend towards decreased connective tissue in RV (Trichrome positive area LV 7.0±0.7 vs. 9.7±1.9 %, p=0.19; RV 13.7±2.2 vs. 9.0±1.0 %, p=0.08). Tissue redox state remained unchanged in LV and was shifted to a reduced state in the atria (ratio GSH/GSSH LV 68.9±8.0 vs. 73.5±12.5, p=0.75; LA 22.5±4.8 vs. 156.5±56.9, p<0.05; RA 11.1±2.8 vs. 43.5±19.5, p=0.077). Confocal microscopy of LV demonstrated pathognomonic enrichment of mitochondria at the intercalated disks, which was not detectable in RV specimen.

Tachycardiomyopathy implies primarily functional and structural LV remodeling, while RV involvement is less pronounced. Lack of fibrosis and of oxidative stress are unique to tachycardiomyopathy, consistently absent in all four heart chambers.