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

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 p<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 p<0.05 vs. baseline). One hour after cessation of VP-TPO, LV EF remained depressed vs. baseline (60±3 %; p<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; p<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.