D. Banerjee1, N. Sodha1, A. Ehsan1, J. Feng1, F. Sellke1 1Brown University School Of Medicine, Department Of Surgery, Providence, RI, USA
Introduction: Cardiac thromboxane A2 induces vasoconstriction of coronary microvascular resistance arterioles and has been implicated in no-reflow phenomenon and hemodynamic deterioration following coronary revascularization. Aging independently alters microvascular reactivity and has been associated with worse postoperative outcomes, but the precise underlying mechanisms are unknown and human studies are lacking.
Methods: Human atrial tissue was examined from patients before and after cardioplegic arrest and cardiopulmonary bypass (CP/CPB). Patients were divided into younger (age <65) and older (age ≥65) cohorts (N = 42). Ex vivo response of coronary microvessels (<200μm in diameter) dissected from myocardial samples to U46619, a stable thromboxane A2 analogue, was assessed using video microscopy. Molecular signaling was assessed using RNA deep-sequencing and immunoblotting.
Results: Viable coronary microvessels isolated from older patients exhibited increased contraction to U46619 when compared to responses in younger counterparts pre-CP/CPB (p = 0.038). This difference did not persist post-CP/CPB (p = 0.5). RNA deep-sequencing of myocardial samples showed significant differences in gene expression of enzymes involved in thromboxane signaling upstream of the thromboxane A2 receptor. Older patients had decreased expression of gene PLA2G2A that encodes phospholipase A2 (p = 0.02) and relatively increased expression of gene PLCG1 that encodes phospholipase C gamma 1 subunit (p = 0.08) pre-CP/CPB. Post-CP/CPB, expression of gene PTGS1 was decreased (p = 0.02), while changes in gene expression of PTGS2 (p = 0.1) and PLCG1 (p = 0.1) approached significance. Older patients had decreased myocardial expression of thromboxane A2 receptor pre-CP/CPB (p = 0.04), while there was a trend toward decreased receptor expression post-CP/CPB (p = 0.1). There were no differences in total myocardial levels of downstream signaling molecules involved in vasoconstriction pathways between the cohorts either pre- or post-CP/CPB, including protein kinase C-α (PKC-α), phosphorylated PKC-α (p-PKC-α), p-PKC:PKC ratio, phospholipase C β3 (PLC β3), phosphorylated PLC β3 (p-PLC β3), p-PLC:PLC ratio, Erk1/2, phosphorylated Erk1/2 (p-Erk1/2), and p-Erk/Erk ratio.
Conclusion: Older patients (≥65) have pronounced coronary microvascular contractile response to U46619, with compensatory decrease in myocardial thromboxane A2 receptor at baseline. Altered gene expression related to thromboxane-specific vasoconstrictive signaling may partially explain this observed phenotype. Older patients undergoing CP/CPB are predisposed to myocardial malperfusion resulting from increased thromboxane-induced vasospasm.