P190. Like Abdomen, Unlike Thorax: SGLT-2 Inhibitors Do Not Modulate Ascending Aortic Signaling
Presented During: POD Abstracts (Available for viewing in the exhibit hall for the duration of the meeting)
Brown University
Providence, RI
United States - Contact Me
Christopher Stone is a surgical resident at Brown Universirty and postdoctoral research fellow in the Department of Cardiothoracic Surgery. Working in the lab of Dr. Frank Sellke, his research involves investigation of the mechanisms underlying for the cardiovascular benefits of SGLT-2 inhibitors and GLP-1 agonists. Through this work, along with other projects within the field of regnerative cardiovascular medicine, he hopes to expand the breadth of options available for patients with advanced ischemic disease.
Thursday, April 25, 2024: 5:38 PM - 7:00 PM
Sheraton Times Square
Room: Central Park
Description
Objective: Sodium-glucose cotransporter-2 inhibitors (SGLTIs, such as canagliflozin) are anti-diabetic medications that primarily have acquired significance in the field of cardiothoracic surgery as a result of their capacity to reduce the incidence of adverse cardiovascular events regardless of diabetic status. SGLT-2 receptors are expressed in the aorta, and SGLTIs have been extensively studied in the context of abdominal aortic aneurysmal disease, where they have been found to interrupt pathogenesis by reducing aortic inflammation and oxidative stress, improving endothelial cell survival and flow-mediated dilation, and improving hemodynamics. The potential of SGLTIs to affect ascending aortic pathology, however, has not been investigated. Given that our group studies the use of SGLTIs in a clinically relevant, large animal model of myocardial ischemia with metabolic syndrome, and given the relevance of metabolic syndrome to the pathogenesis of aortic aneurysms, we set out to determine whether administration of canagliflozin would also modulate parameters associated with ascending aortic aneurysmal/dissection pathogenesis.
Methods: Twenty-one Yorkshire swine aged 5-6 weeks arrived at our facility and were fed a high-fat diet for 12 weeks, as this has been validated to induce metabolic syndrome in experimental animals. At week 6, an ameroid constrictor device is placed around the left circumflex coronary artery to induce chronic myocardial ischemia. Beginning on the second postoperative week and extending for five weeks thereafter, animals were administered either 300 mg oral canagliflozin (high-fat canagliflozin group, or HCAN, n=10) or a drug-free vehicle (high-fat control group, or HFC, n=10). After 5 weeks of treatment, all animals underwent a terminal harvest procedure entailing the acquisition of hemodynamic parameters and collection of myocardial and ascending aortic tissue. Tissue sections were snap-frozen in liquid nitrogen. Tissue lysates were made using proteolytic digestion, and immunoblotting for proteins demonstrated to be associated with ascending aortic aneurysmal pathogenesis was performed. T-tests or nonparametric analogs were used to compare the relative expression of proteins between groups after normalization to a loading control; t-tests were also used to compare hemodynamics.
Results: Precise intra-arterial quantification using femoral arterial and direct myocardial puncture and catheterization yielded no significant difference in mean arterial pressure (p>0.8), a significant increase in heart rate (p=0.01), and no change in left ventricular dP/dt (p>0.4) in the HCAN treatment group compared with the HFC control group. Immunoblotting for proteins related to oxidative stress (eNOS, NOX-1, catalase, SOD-1, and GPX-1), inflammation (IL-1ß, IL-17, and IL-6), and TGF-ß signaling (TGF-ß, SMAD 2/3) did not demonstrate consistently significant differences between groups (p>0.05 for all but IL-6).
Conclusions: Despite the pleiotropic salubrious effects demonstrated following SGLTI administration on the myocardium and the abdominal aorta, our results indicate that these benefits do not extend to the ascending aorta. This provides further evidence of the biological heterogeneity between thoracic and abdominal aortic signaling and suggests that the administration of SGLTI therapy is unlikely to affect thoracic aortic disease processes.
Authors
Christopher Stone (1), Dwight Harris (2), Meghamsh Kanuparthy (3), Mark Broadwin (4), Jad Hamze (5), M. Ruhul Abid (6), Frank Sellke (7)
Institutions
(1) Brown University, N/A, (2) Beth Israel Deaconess Medical Center, United States, (3) Division of Cardiac Surgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, (4) Lehigh Valley Health Network/University of South Florida, Allentown, PA, (5) Brown University, Providence, RI, (6) Cardiovascular Research Center, Rhode Island Hospital, Providence, RI; Division of Cardiothoracic S, Providence, RI, (7) Rhode Island Hospital, Providence, RI
Methods: Twenty-one Yorkshire swine aged 5-6 weeks arrived at our facility and were fed a high-fat diet for 12 weeks, as this has been validated to induce metabolic syndrome in experimental animals. At week 6, an ameroid constrictor device is placed around the left circumflex coronary artery to induce chronic myocardial ischemia. Beginning on the second postoperative week and extending for five weeks thereafter, animals were administered either 300 mg oral canagliflozin (high-fat canagliflozin group, or HCAN, n=10) or a drug-free vehicle (high-fat control group, or HFC, n=10). After 5 weeks of treatment, all animals underwent a terminal harvest procedure entailing the acquisition of hemodynamic parameters and collection of myocardial and ascending aortic tissue. Tissue sections were snap-frozen in liquid nitrogen. Tissue lysates were made using proteolytic digestion, and immunoblotting for proteins demonstrated to be associated with ascending aortic aneurysmal pathogenesis was performed. T-tests or nonparametric analogs were used to compare the relative expression of proteins between groups after normalization to a loading control; t-tests were also used to compare hemodynamics.
Results: Precise intra-arterial quantification using femoral arterial and direct myocardial puncture and catheterization yielded no significant difference in mean arterial pressure (p>0.8), a significant increase in heart rate (p=0.01), and no change in left ventricular dP/dt (p>0.4) in the HCAN treatment group compared with the HFC control group. Immunoblotting for proteins related to oxidative stress (eNOS, NOX-1, catalase, SOD-1, and GPX-1), inflammation (IL-1ß, IL-17, and IL-6), and TGF-ß signaling (TGF-ß, SMAD 2/3) did not demonstrate consistently significant differences between groups (p>0.05 for all but IL-6).
Conclusions: Despite the pleiotropic salubrious effects demonstrated following SGLTI administration on the myocardium and the abdominal aorta, our results indicate that these benefits do not extend to the ascending aorta. This provides further evidence of the biological heterogeneity between thoracic and abdominal aortic signaling and suggests that the administration of SGLTI therapy is unlikely to affect thoracic aortic disease processes.
Authors
Christopher Stone (1), Dwight Harris (2), Meghamsh Kanuparthy (3), Mark Broadwin (4), Jad Hamze (5), M. Ruhul Abid (6), Frank Sellke (7)
Institutions
(1) Brown University, N/A, (2) Beth Israel Deaconess Medical Center, United States, (3) Division of Cardiac Surgery, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI, (4) Lehigh Valley Health Network/University of South Florida, Allentown, PA, (5) Brown University, Providence, RI, (6) Cardiovascular Research Center, Rhode Island Hospital, Providence, RI; Division of Cardiothoracic S, Providence, RI, (7) Rhode Island Hospital, Providence, RI
Presentation Duration
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