Abstract Body (Do not enter title and authors here): Introduction
Tricuspid regurgitation (TR) contributes to severe cardiovascular complications by causing atrial and ventricular dilation, retrograde blood flow, and abnormal cardiac remodeling, leading to electrical disturbances and disease progression. The lack of reliable preclinical models limits our understanding of TR pathophysiology and hinders early biomarkers for timely intervention of disease.
Hypothesis
Our study aims to establish a new reproducible, minimally-invasive, and valve-harmless porcine model to mimic TR, enabling the investigation of disease progression and the identification of novel molecular signatures underlying this condition.
Methods
TR was induced by catheter-based placement of an inferior vena cava filter to prevent tricuspid leaflet coaptation between right chambers. Hemodynamic, echocardiographic and electrophysiological assessments, jet flow, heart rate, and chamber dimensions, were weekly assessed over 30- and 60-days post implantation.
Results
Following device implantation, TR led to significant increases in heart rate, right chamber dilation, and arrhythmogenic events. Early manifestations included sinus tachycardia and multifocal atrial tachycardia, progressing to brief episodes of paroxysmal atrial fibrillation. Histological analysis also revealed cellular hypertrophy and fibrosis in both the right atrium (RA) and sinoatrial node (SAN), accompanied by upregulation of the TGF-β/Smad2/3, and -4 signaling axis, along with increased MMP2, and MMP9, suggesting its involvement in disease progression.
To investigate in further detail, progressive downregulation and spatial redistribution of the pacemaker HCN4 channel were observed over time (Figure 1), accompanied by increased phosphorylation of Gap junction Connexins -43, and -45, along with elevated CaMKII and PKA levels, while SERCA2A and PLN levels remained unchanged. These findings addresses for the first time, how TR signaling disrupts cardiac conduction velocity and pacemaker function through dual pathways: (1) impairing SAN electrophysiology via HCN4 dysregulation, and (2) creating electrical uncoupling through connexin remodeling mediated by CaMKII/PKA-dependent phosphorylation.
Conclusions
We successfully established a percutaneous porcine model of TR that recapitulates human disease pathophysiology. This experimental breakthrough bridges the gap between mechanistic and phenotyping manifestations, accelerating therapeutic discovery for TR-related cardiac complications.