Cardioplegic arrest and cardiopulmonary bypass (CP/CPB) are known to engender microvascular dysfunction in patients undergoing cardiac surgery. These effects are significantly varied by patient comorbidities including diabetes and hypertension. Both diabetes and hypertension are associated with worse outcomes after cardiac surgery, partly related to increased microvascular complications. In this review, we examine several key facets of microvascular dysfunction after CP/CPB: microvascular endothelial and vasomotor dysfunction, altered gene and protein expression, endothelial adherens junction dysfunction, and programmed cell death as they relate to diabetes and hypertension. This review examines both classical techniques, including microvessel reactivity assays, and modern multiomic approaches to characterizing these microvascular changes.

Ischemic heart disease (IHD) is the leading cause of global mortality and is often complicated by metabolic syndrome (MetS), making its management challenging. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors, such as canagliflozin (CAN), have demonstrated cardioprotective effects, but the precise molecular mechanisms underlying these benefits in the setting of IHD and MetS remain unclear. This study aimed to investigate the myocardial phenotypic changes induced by CAN treatment using a highly sensitive proteomic approach in a large animal model of IHD and MetS. In a swine model of MetS and chronic myocardial ischemia, CAN treatment led to significant metabolic shifts, including the downregulation of glycolysis and gluconeogenesis and the upregulation of oxidative phosphorylation and electron transport chain activity. Proteomic analysis revealed increased expression of vesicular and mitochondrial transport proteins in chronically ischemic myocardium and elevated thioredoxin levels in non-ischemic myocardium, indicating improved mitochondrial function, reduced oxidative stress, and enhanced cytoskeletal remodeling. CAN treatment induces extensive myocardial adaptations that contribute to its cardioprotective effects, particularly by optimizing myocardial metabolism, mitigating oxidative stress, and promoting ventricular remodeling. These findings provide valuable insights into the therapeutic potential of CAN in IHD and MetS and highlight the utility of proteomics in advancing heart failure treatment strategies.

Vasoplegia is a well-established risk after cardiopulmonary bypass. Angiotensin II is a polypeptide integral to blood pressure and intravascular volume regulation, yet limited evidence explores angiotensin II in post–cardiopulmonary bypass vasoplegia. This study aims to investigate microvascular functional and mechanistic changes to angiotensin II response after cardiopulmonary bypass. Skeletal muscle samples were collected from the left internal mammary bed before and after cardiopulmonary bypass in patients undergoing cardiac surgery. Skeletal muscle arterioles were dissected and mounted on microvessel arrays, and internal diameter changes in response to angiotensin II were noted by videomicroscopy. Paired skeletal muscle tissue was sent for deep RNA sequencing per third-party company protocol, and angiotensin II type 1 and type2 receptor expression was quantified by immunoblotting. Microvascular constriction to angiotensin II in microvessels isolated from skeletal muscle (n = 7) was significantly attenuated in post–cardiopulmonary bypass vessels (P < .05 at 10⁻⁸ [M], 5 × 10⁻⁸ [M], 5 × 10⁻⁷ [M], and 10⁻⁶ [M], P < .01 at 10⁻⁷ [M]). Twelve paired pre–cardiopulmonary bypass and post–cardiopulmonary bypass samples used for deep transcriptomics demonstrated decreased RNA transcripts of G_q/11, a G-protein involved in angiotensin II type 1 receptor–mediated vasoconstriction, in post–cardiopulmonary bypass tissue. There were no significant differences in angiotensin II receptor expression by immunoblotting. These novel findings demonstrate a significant decrease in functional microvascular response to angiotensin II after cardiopulmonary bypass, which may explain postoperative vasoplegia and blood pressure dysregulation. Although there were no changes in angiotensin II receptor expression, changes in G-protein–related signaling may explain this diminished response.

This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM). Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling. Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide-mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways. SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.

This study evaluated the effects of metformin (MET) on non-ischemic myocardium in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS). While prior work has shown MET improves perfusion and function in ischemic tissue, this study assessed whether its cardioprotective effects extend to non-ischemic regions. Yorkshire swine (n = 12) were fed a high-fat diet to induce MS, and then underwent ameroid constrictor placement around the left circumflex artery to simulate CAD. Animals received either oral MET (1000 mg/day) or placebo for 7 weeks. Regional myocardial perfusion was assessed via microsphere injections at rest and during pacing. Non-ischemic myocardial tissue was identified using gold microsphere distribution and analyzed using immunoblotting, immunofluorescence, and hemodynamic assessment. Statistical significance was evaluated using Student's t-test or the Mann Whitney U test. Despite no significant changes in perfusion, MET-treated animals demonstrated significantly reduced apoptotic markers (caspase 9, cleaved caspase 9, AIF, BAD; p < 0.05) and increased pBAD/BAD ratios. Pro-survival signaling was enhanced with elevated pAKT/AKT, pmTOR/mTOR, and pAMPK/AMPK ratios (p < 0.05). TUNEL staining confirmed decreased apoptosis histologically. Functionally, MET improved cardiac output, stroke volume, and dV/dt Max in the myocardium (p < 0.05), correlating with reductions in apoptotic signaling. MET was associated with significantly reduced apoptosis and promoted pro-survival signaling in non-ischemic myocardium without altering perfusion. These findings suggest that MET's cardioprotective effects are not limited to ischemic tissue, highlighting its potential role as a systemic therapy for CAD and MS, including as an adjunct in cardiac surgery.

Vasoplegia and endothelial dysfunction are well-known complications of cardioplegia and cardiopulmonary bypass (CP/CPB). Our lab has previously shown that endothelial adherens junction impairment is driven by vascular endothelial (VE)-cadherin phosphorylation. In this study we investigate the interplay of hypertension and CP/CPB. Right atrial tissue was harvested pre- and post-CP/CPB from patients undergoing surgery. Patients were stratified into nonhypertensive, controlled hypertension, and uncontrolled hypertension groups based on history and in-office blood pressure measurements. Atrial tissue was sent for transcriptomics. Expression, phosphorylation, and localization of VE-cadherin was assessed by immunoblotting and immunohistochemistry. Atrial microvascular reactivity to adenosine diphosphate was assessed by videomicroscopy. Several genes related to reactive oxygen species handling, nitric oxide signaling, and adherens junctions were suppressed in patients with uncontrolled hypertension versus nonhypertensive patients pre-CP/CPB. By immunoblotting, patients with uncontrolled hypertension had significantly higher levels of phosphorylated VE-cadherin (p-VE cadherin) and higher ratios of p-VE cadherin/VE-cadherin compared with nonhypertensive (P < .05). Perivascular p-VE cadherin density by immunofluorescence was higher in patients with uncontrolled hypertension compared with nonhypertensive patients and patients with controlled hypertension (P < .05). There were significant decreases in vasodilatory response to adenosine diphosphate after CP/CPB (P < .05) in patients with uncontrolled hypertension compared with nonhypertensive patients. Patients with uncontrolled hypertension had significantly higher increases in weight on postoperative day 1 compared with nonhypertensive patients (P < .05). Our study supports a 2-hit model in which hypertension primes the endothelium for dysfunction, and CP/CPB amplifies this injury through impaired reactive oxygen species handling, nitric oxide dysregulation, and adherens junction destabilization. These findings highlight the importance of preoperative hypertension management to improve postoperative outcomes.