The role of the cardiac lymphatic system in diastolic dysfunction

The cardiac lymphatic system is a crucial yet underexplored component of cardiovascular physiology. Evidence in rodent and canine models suggest that cardiac lymphatic dysfunction promotes myocardial oedema, inflammation, and fibrosis, potentially contributing to diastolic dysfunction. However, whether cardiac lymphatic obstruction (CLO) alone can induce diastolic dysfunction has not been examined in a large animal model. Hence, we tested the hypothesis that CLO would exacerbate cardiovascular hemodynamics and impair exercise tolerance. CLO was performed in anaesthetized female sheep (n=8) by injecting Evans blue dye into the left ventricular wall to identify and ligate the left main cardiac lymphatic collector vessel. Hemodynamic and echocardiographic assessment before and three hours post-obstruction revealed elevated left-ventricular end-diastolic pressure (LVEDP) (peak Δ: +3.6±1.1 mmHg; n=8 vs time controls: peak Δ: -0.5±0.8 mmHg; n=4; interaction p=0.0175, two-way ANOVA) indicating reduced ventricular compliance. Echocardiographic E/A ratio remained unchanged (1.10 ± 0.12 vs 1.25 ± 0.09; n=6; p=0.4103, paired t-test). Other hemodynamic variables – including mean arterial pressure, heart rate, cardiac output and coronary blood flow – were unaffected. We then examined hemodynamic variables during exercise in a separate group of conscious animals following three weeks post- obstruction (or sham control) surgery. At three weeks post-CLO, LVEDP was significantly higher in the obstructed animals (14.1±2 mmHg; n=7 vs 7±1 mmHg; n=6; p=0.0168, unpaired t-test). This was not accompanied by a difference in the response to exercise. There was also a significant reduction in E/A ratio over time in the CLO group compared to controls (∆-0.53±0.19; n=4 vs ∆0.38±0.24; n=3; interaction p=0.031, two-way ANOVA). Interestingly, variability in E/A ratio was correlated with LVEDP (R2 =0.48, p=0.026), and those that had lower E/A ratios tended to have larger changes in pulmonary capillary wedge pressure during exercise. This suggests that the degree of impaired lymphatic clearance may underlie the development of diastolic dysfunction. Preliminary histological data indicated that lymphatic obstructed animals showed higher levels of left ventricular myocardial collagen, or fibrosis, stained with Masson’s Trichrome (1.46±0.14%; n=7 vs 0.44±0.06%; n=2). Both fibrosis and LVEDP was significantly correlated with reduced cardiac lymphatic density which was stained with PMAb-256 and imaged under confocal microscopy (fibrosis vs lymphatic density: R2 = 0.58, p=0.047: lymphatic density vs LVEDP: R2 = 0.80, p=0.016). These findings demonstrate that CLO alone elevates LVEDP and alters diastolic function in a large animal model, both acutely and chronically, independent of systemic hemodynamics. The level of dysfunction may depend on the degree of cardiac lymphatic rarefaction and subsequent increase in myocardial collagen deposition. This work extends current understanding of cardiac lymphatic physiology and highlights its substantial impact on heart function. Funding support was provided by the Heart Foundation of New Zealand and the Grace Craston Charitable Trust. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.