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Age-Specific Increase in Vasopressin-Induced Coronary Microvascular Contractile Response in Patients Undergoing Cardiac Surgery
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Debolina Banerjee, *Sharif Sabe, William Cioffi, Thomas Miner, *Neel Sodha, *Afshin Ehsan, *Janelle Li, *M Ruhul Abid, *Jun Feng, Frank Sellke
Department of Surgery, Brown University, Providence, RI
Objectives: Older patients undergoing cardioplegia and cardiopulmonary bypass (CP/CPB) have worse clinical outcomes. Aging may reduce myocardial perfusion through altered coronary microvascular function, but human translational studies are lacking. We aimed to study the effects of advanced age on myogenic tone and vasomotor responses of coronary microvasculature in patients undergoing CP/CPB.
Methods: Human atrial tissue was examined from patients undergoing CP/CPB (
N = 101). Viable coronary microvessels (<200um) were harvested from atrial samples;
ex vivo microvascular myogenic tone and vasomotor responses to vasopressin, adenosine diphosphate (ADP), and sodium nitroprusside (SNP) were assessed using video microscopy. RNA deep-sequencing, immunoblotting, and immunohistochemistry were used to quantify gene expression, protein expression, and receptor localization, respectively. Multivariate regression was used to assess the effects of age and vasopressin-induced coronary microvascular vasoconstriction on cardiac index.
Results: Coronary microvascular contractile response to vasopressin was increased in older (age 65+) patients compared to younger (age <65) counterparts pre- (p = 0.048) and post-CP/CPB (p = 0.03). Endothelium-dependent vasodilatory response to ADP, endothelium-independent vasodilatory response to SNP, and myogenic tone of coronary arterioles did not vary with age (p >0.2). Vasopressin-induced contractile response was increased following CP/CPB (p = 0.006 in <65, p = 0.001 in 65+). Myogenic tone was similarly increased post-CP/CPB in both cohorts (p <0.0001). Vasodilatory response to ADP was decreased post-CP/CPB in younger (p = 0.02) and older (p <0.0001) patients, while response to SNP was unchanged (p = 0.2 in <65, p = 0.1 in 65+). Transcriptomics showed increased expression of genes encoding phospholipase C (PLC) isoforms in older patients (
PLCZ1 p = 0.007,
PLCL2 p = 0.04). Total myocardial expression of putative vasopressin receptors, V1aR and V1bR, did not vary with age, nor did myocardial expression of pro-vasoconstrictive intermediate signaling molecules, protein kinase C (PKC), PLC, and their phosphorylated forms. Phosphorylated-PLC:PLC (p-PLC:PLC) ratio increased following CP/CPB (p = 0.01). Immunohistochemistry showed differential perimicrovascular V1aR expression. Age and % constriction to vasopressin (10
-5 M) correlated significantly pre-CP/CPB (R = 0.58, p = 0.003) and post-CP/CPB (R = 0.59, p = 0.002). Both variables predicted cardiac index pre-CP/CPB (% constriction, p = 0.045; age 65+, p = 0.03) and post-CP/CPB (% constriction, p = 0.07; age 65+, p = 0.02).
Conclusions: Older patients have more pronounced coronary microvascular contractile response to vasopressin, with predictive value for cardiac index. CP/CPB results in further increased coronary microvascular contractile response accompanied by decreased vasodilatory capacity from baseline, predisposing these patients to myocardial malperfusion and worse outcomes.
Age-related effects on coronary microvascular reactivity and molecular signaling pathways following CP/CPB, and clinical correlation with cardiac index
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