Cardioplegic arrest and cardiopulmonary bypass (CP/CPB) are essential components of modern cardiac surgery, facilitating intricate procedures by temporarily stopping the heart and diverting blood flow through a machine. However, these interventions can cause significant microvascular dysfunction, exacerbated by pre-existing conditions such as diabetes and hypertension. This review provides a comprehensive overview of the mechanisms underlying microvascular impairment following CP/CPB and explores potential therapeutic interventions to mitigate adverse outcomes.
Microvascular Dysfunction in Diabetes and Hypertension
Microvascular dysfunction in the context of CP/CPB arises from multiple factors, including oxidative stress, endothelial inflammation, impaired vasomotor regulation, and disruptions in gene expression. Patients with diabetes and hypertension experience worse post-surgical outcomes due to increased endothelial permeability, vascular stiffness, and impaired responses to vasodilators. The review categorizes these dysfunctions into endothelial/vasomotor impairment, gene/protein expression changes, adherens junction disruption, and programmed cell death.
Endothelial and Vasomotor Dysfunction
CP/CPB significantly alters microvascular endothelial function, with diabetes and hypertension compounding these effects. Diabetes leads to glycosylation of endothelial proteins, thickening of capillary basement membranes, and excessive extracellular matrix proliferation. Additionally, increased reactive oxygen species (ROS) further damage endothelial cells, reducing their ability to regulate vascular tone. In diabetic patients, vasoconstrictive responses to endothelin-1 (ET-1), thromboxane-A-2 (TXA2), and phenylephrine are diminished, contributing to vascular instability.
Similarly, hypertension negatively impacts microvascular function by decreasing nitric oxide (NO) production, increasing oxidative stress, and promoting vascular stiffness. CP/CPB-induced ischemia and reoxygenation further impair vasomotor responses by triggering neutrophil-mediated ROS production. Studies demonstrate that hypertensive patients undergoing CP/CPB exhibit exaggerated vasoconstriction in response to serotonin (5-HT) and TXA2, while showing diminished responses to vasodilators like bradykinin and adenosine diphosphate (ADP).
Gene and Protein Expression Alterations
Diabetes profoundly affects gene expression in myocardial tissues following CP/CPB. In one study, 851 genes were upregulated in diabetic patients compared to 480 in non-diabetics. Key inflammatory markers, such as interleukin-6 (IL-6), FOS, and CYR61, were elevated in both groups, but diabetic patients showed additional upregulation of pro-inflammatory genes like MYC, IL-8, and IL-1. The review also highlights epigenetic changes, including alterations in DNA methylation patterns affecting the Hippo–YAP/TAZ pathway, which plays a crucial role in cell survival and stress response.
Hypertension also induces significant gene expression changes, particularly affecting the angiotensin II (Ang II) and endothelin-1 (ET-1) pathways. Ang II increases ET-A receptor expression, heightening vasoconstriction. Additionally, hypertension disrupts matrix metalloproteinase (MMP) activity, leading to extracellular matrix degradation and increased vascular remodeling. These molecular changes collectively impair vascular homeostasis and contribute to the high incidence of complications following cardiac surgery in hypertensive patients.
Adherens Junction Disruption and Increased Vascular Permeability
Adherens junctions, primarily mediated by VE-cadherin, are essential for maintaining endothelial integrity. CP/CPB induces phosphorylation and degradation of VE-cadherin, weakening endothelial junctions and increasing vascular permeability. Diabetic patients exhibit further reductions in VE-cadherin and associated proteins like β-catenin, leading to exacerbated endothelial dysfunction. Hypertension similarly disrupts adherens junction integrity by increasing shear stress, inflammatory cytokines, and ROS production.
Programmed Cell Death and Cardioplegia
Apoptosis and autophagy play crucial roles in post-surgical recovery. CP/CPB induces apoptosis in endothelial and myocardial cells through both intrinsic and caspase-dependent pathways. Diabetic patients exhibit heightened apoptosis due to reduced activation of the cardioprotective STAT3 pathway and lower levels of urocortin, a protective peptide. CP/CPB also alters autophagic responses, with increased expression of ATG4A, ATG4C, and ATG4D genes, as well as markers of chaperone-mediated autophagy. These findings suggest that tailored interventions are needed to modulate programmed cell death in patients with diabetes and hypertension undergoing cardiac surgery.
Pharmacological Interventions and Future Directions
Several pharmacological agents may help mitigate CP/CPB-induced microvascular dysfunction.
- Antidiabetic Medications: GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors show promise in reducing oxidative stress and improving endothelial function. These agents enhance NO bioavailability and decrease ROS production, though clinical studies in CP/CPB patients are still needed.
- Antihypertensive Medications: Beta-blockers, ACE inhibitors, and calcium channel blockers help regulate microvascular tone, reduce inflammation, and improve coronary blood flow. These agents may counteract the deleterious effects of hypertension on microvascular reactivity.
The review also highlights the need for personalized surgical strategies tailored to patients’ metabolic profiles, as well as the potential of multiomic approaches to better understand molecular changes associated with CP/CPB. Given the increasing prevalence of diabetes and hypertension, future research should focus on optimizing preoperative interventions and developing targeted therapies to preserve microvascular integrity.
Conclusion
Diabetes and hypertension significantly worsen microvascular dysfunction following CP/CPB, leading to increased surgical complications. Understanding the molecular mechanisms underlying these changes can guide the development of personalized treatments and pharmacological interventions. As cardiac surgery advances, a focus on protecting microvascular integrity will be crucial in improving patient outcomes.
Study Ranking = 4/5 (High-Quality Study) Strengths: Extensive review of molecular mechanisms, inclusion of gene/protein expression data, discussion of pharmacological interventions. Limitations: Lacks large-scale clinical trial data on pharmacological interventions in CP/CPB patients.
