(557.17) Stretch-induced Myocardial Injury and Inflammation After Transient Vasopressin-Mediated Left Ventricular Pressure Overload in Swine

Poster Board Number: E140

Tyler Rolland (University at Buffalo), Ronzon Shihab (University at Buffalo), Dorcas Nsumbu (University at Buffalo), Arezou Tajlil (University at Buffalo), John Canty, Jr. (University at Buffalo, University at Buffalo), Brian Weil (University at Buffalo)

Objective:  Using the α1-adrenergic agonist phenylephrine (PE), we have previously demonstrated that an acute episode of transient pressure overload (TPO) elicits stretch-induced myocardial injury and reversible left ventricular (LV) systolic dysfunction. Although this was accompanied by leukocyte mobilization, a rise in inflammatory cytokine levels, and increased pro-inflammatory gene expression in the heart, the extent to which this resulted from direct activation of α1-adrenergic receptors on immune cells vs. an inflammatory response to mechanical stretch-induced myocardial injury is unclear.  Accordingly, the present study was designed to determine if an inflammatory response to myocardial injury is evident when TPO is produced by vasopressin (VP), a vasoconstrictor without direct α1-adrenergic agonist properties.

Methods: Hemodynamic and echocardiographic parameters were assessed in propofol-anesthetized swine before, during, and after a 30-minute infusion of VP (VP-TPO; 0.04 U/kg/min, n=7) to increase LV end-diastolic pressure (EDP) to ~30mmHg. Serial jugular venous blood sampling was performed to quantify circulating cardiac troponin I (cTnI), leukocytes, and inflammatory cytokines (TNF-α and IL-6) at baseline and 3-hours after cessation of VP-TPO. Leukocyte and cytokine levels were compared with those observed after PE-mediated TPO in a separate group of animals (PE-TPO; n=6).

Results: VP elicited a significant rise in mean arterial pressure (91±5 to 165±11 mmHg) and LV EDP (10±1 to 29±2 mmHg; both plt;0.05 vs. baseline).  This was accompanied by a significant rise in LV end-diastolic volume (73±5 to 110±7 mL) and end-systolic volume (20±3 to 53±6 mL), as well as a reduction in LV ejection fraction (EF; 72±3 to 52±3 %; all plt;0.05 vs. baseline).  One hour after cessation of VP-TPO, LV EF remained depressed vs. baseline (60±3 %; plt;0.05) and circulating cTnI levels began to rise, reaching a concentration that was ~10-fold higher than baseline concentrations at the 3-hour post-TPO timepoint (18±5 to 118±21 ng/L; plt;0.05). These changes were accompanied by a significant rise in circulating neutrophils, monocytes, TNF-α, and IL-6 that was similar to that observed after PE-TPO (Figure).

Conclusions: VP-TPO elicits myocardial injury, leukocyte mobilization, and an acute rise in circulating pro-inflammatory cytokines, thereby recapitulating several features of PE-TPO in the absence of direct α1-adrenergic stimulation. These findings suggest that stretch-induced myocardial injury provokes an inflammatory response that may play an important role in promoting the development of cardiac fibrosis and diastolic dysfunction after exposure to repetitive episodes of TPO.

Supported by The National Heart Lung and Blood Institute (1R56HL14135901A1), the National Center for Advancing Translational Sciences (UL1TR001412), and the Department of Veterans Affairs (1IO1BX002659)



FIGURE: Comparisons of circulating leukocytes and pro-inflammatory cytokines before and after PE-TPO vs. VP-TPO. All values are represented as mean ± SEM. *p < 0.05 vs. Baseline.