Browsing by Author "Anderson, Todd"
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- ItemOpen AccessAdministration of the Ca2+-Activated K+ Channel Activator SKA-31 Improves Endothelial Function in Atherosclerosis-Prone Mice(2023-06) Vera, Oscar Daniel; Braun, Andrew; Thompson, Jennifer; Anderson, ToddAtherosclerosis is a major risk factor for cardiovascular disease and is induced by hyperlipidemia and endothelial dysfunction, leading to fatty plaque formation and impaired vascular function. Recent studies have reported that pharmacological activation of endothelial Ca2+-activated K+ channels (KCa2.3 and KCa3.1) can oppose endothelial dysfunction by enhancing endothelium-dependent vasodilation in animal models of aging and type 2 diabetes. In my project, I hypothesized that improving endothelial function via pharmacological enhancement of endothelial KCa2.3 and KCa3.1 channels with SKA-31 would mitigate the development and/or severity of atherosclerosis. Experimentally, I utilized apoliproprotein E knockout (Apoe-/-) mice subjected to a high fat diet (HFD) as a model of human aortic atherosclerosis. Male Apoe-/- mice were administered one of three daily oral treatments for 12 weeks: the KCa channel activator SKA-31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle alone. Cardiac function was assessed by echocardiography, atherosclerotic lesions in the aorta were visualized by Oil Red O (ORO) staining and immunohistochemistry, abdominal aortic contractility and relaxation were measured by wire myography, and select tissues were evaluated by histology. At ~20 weeks of age, left ventricular ejection fraction and fractional shortening were not different in Apoe-/- mice following treatment with either SKA-31 or senicapoc vs. vehicle. ORO staining of the thoracic aorta and aortic arch revealed that neither SKA-31 nor senicapoc treatments decreased plaque formation vs. vehicle. Aortae from sex/age matched wild-type (WT) mice showed no visible plaque formation. Phenylephrine (PE)-evoked contraction of abdominal aortic rings was similar in WT and vehicle/drug treated Apoe-/- mice. Conversely, endothelium-dependent, acetylcholine-induced maximal relaxation was significantly enhanced in PE-constricted aortic rings from SKA-31-treated mice (~81%) vs. vehicle (~53%, P<0.0001), whereas senicapoc administration had no beneficial effect. Maximal relaxation induced by the endothelium-independent vasodilator sodium nitroprusside was similar in WT and vehicle/drug treated Apoe-/- mice. Finally, neither SKA-31 nor senicapoc treatments produced adverse effects on histological features of the brain, liver, and kidneys from Apoe-/- mice. In summary, my results indicate that enhancement of KCa channel activity in vivo via SKA-31 administration improved aortic endothelial function without decreasing plaque formation.
- ItemOpen AccessCardiovascular Magnetic Resonance Imaging in Cardiometabolic Disease(2016-01-26) Schmidt, Anna; Anderson, Todd; Friedrich, Matthias; White, James; Pacaud, Danièle; Lau, DavidThe unrelenting incidence of obesity and type 2 diabetes has become a global public health concern. Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in these cohorts. Cardiovascular Magnetic Resonance (CMR) imaging is a robust imaging modality with techniques to provide sensitive detection of early cardiovascular changes in obesity and diabetes. In a prospective study of obese adolescents (n=11, 10 to 20 years old) and a healthy weight control group (n=14), we found obesity was associated with increases in Left ventricular (LV) mass, LV wall thickness and mass:volume ratio. In this “early stage” of remodeling, these structural changes were not associated with elevations in Native T1, a surrogate marker of tissue fibrosis. Strain analysis, by novel CMR tissue tracking analysis, revealed a hyper-contractile state, likely representing a combined contribution of elevated systolic blood pressure with compensatory myocyte hypertrophy. Obese subjects were additionally enrolled in a comprehensive 6-month lifestyle intervention; subjects did not experience weight loss or any change in cardiac parameters after 6 months. Further along the natural history of CVD as related to metabolic disease, the second study looked to examine possible sub-clinical changes in the hearts of otherwise healthy diabetic patients. This study examined twenty-eight healthy type 2 diabetic patients without any observable vascular complications. The complementary use of CMR-based T1 mapping and 3-dimensional strain analysis demonstrated expansion of the extracellular matrix and a reduction in global longitudinal strain. In the endpoint of the cardiometabolic disease spectrum, we analyzed individuals with known or suspected Coronary Artery Disease. This study explored the relationship between intra-thoracic fat volume (ITFV) and 4D myocardial strain-based markers of adverse remodeling. In non-infarcted myocardium, ITFV is associated with reductions in myocardial strain. These findings suggest ITFV to be a potentially important marker of adverse ventricular remodeling. The findings of these three studies suggest a capacity of contemporary CMR to identify early changes in cardiometabolic disease and also lend insight into the progression of diabetic heart disease. CMR provides a non-invasive, accurate and reproducible imaging modality with the potential to be useful in screening and CVD risk-stratification.
- ItemOpen AccessIntegration of longitudinal and circumferential strain predicts volumetric change across the cardiac cycle and differentiates patients along the heart failure continuum(2023-10-02) Samuel, T. J.; Oneglia, Andrew P.; Cipher, Daisha J.; Ezekowitz, Justin A.; Dyck, Jason R. B.; Anderson, Todd; Howlett, Jonathan G.; Paterson, D. I.; Thompson, Richard B.; Nelson, Michael D.Abstract Background Left ventricular (LV) circumferential and longitudinal strain provide important insight into LV mechanics and function, each contributing to volumetric changes throughout the cardiac cycle. We sought to explore this strain-volume relationship in more detail, by mathematically integrating circumferential and longitudinal strain and strain rate to predict LV volume and volumetric rates of change. Methods Cardiac magnetic resonance (CMR) imaging from 229 participants from the Alberta HEART Study (46 healthy controls, 77 individuals at risk for developing heart failure [HF], 70 patients with diagnosed HF with preserved ejection fraction [HFpEF], and 36 patients with diagnosed HF with reduced ejection fraction [HFrEF]) were evaluated. LV volume was assessed by the method of disks and strain/strain rate were assessed by CMR feature tracking. Results Integrating endocardial circumferential and longitudinal strain provided a close approximation of LV ejection fraction (EFStrain), when compared to gold-standard volumetric assessment (EFVolume: r = 0.94, P < 0.0001). Likewise, integrating circumferential and longitudinal strain rate provided a close approximation of peak ejection and peak filling rates (PERStrain and PFRStrain, respectively) compared to their gold-standard volume-time equivalents (PERVolume, r = 0.73, P < 0.0001 and PFRVolume, r = 0.78, P < 0.0001, respectively). Moreover, each integrated strain measure differentiated patients across the HF continuum (all P < 0.01), with the HFrEF group having worse EFStrain, PERStrain, and PFRStrain compared to all other groups, and HFpEF having less favorable EFStrain and PFRStrain compared to both at-risk and control groups. Conclusions The data herein establish the theoretical framework for integrating discrete strain components into volumetric measurements across the cardiac cycle, and highlight the potential benefit of this approach for differentiating patients along the heart failure continuum.
- ItemOpen AccessLayer-specific strain in patients with heart failure using cardiovascular magnetic resonance: not all layers are the same(2020-12-03) Xu, Lingyu; Pagano, Joseph J; Haykowksy, Mark J; Ezekowitz, Justin A; Oudit, Gavin Y; Mikami, Yoko; Howarth, Andrew; White, James A; Dyck, Jason R B; Anderson, Todd; Paterson, D. I; Thompson, Richard BAbstract Background Global longitudinal strain (GLS), most commonly measured at the endocardium, has been shown to be superior to left ventricular (LV) ejection fraction (LVEF) for the identification of systolic dysfunction and prediction of outcomes in heart failure (HF). We hypothesized that strains measured at different myocardial layers (endocardium = ENDO, epicardium = EPI, average = AVE) will have distinct diagnostic and predictive performance for patients with HF. Methods Layer-specific GLS, layer-specific global circumferential strain (GCS) and global radial strain (GRS) were evaluated by cardiovascular magnetic resonance imaging (CMR) feature tracking in the Alberta HEART study. A total of 453 subjects consisted of healthy controls (controls, n = 77), at-risk for HF (at-risk, n = 143), HF with preserved ejection fraction (HFpEF, n = 87), HF with mid-range ejection fraction (HFmrEF, n = 88) and HF with reduced ejection fraction (HFrEF, n = 58). For outcomes analysis, CMR-derived imaging parameters were adjusted with a base model that included age and N-terminal prohormone of b-type natriuretic peptide (NT-proBNP) to test their independent association with 5-year all-cause mortality. Results GLS_EPI distinguished all groups with preserved LVEF (controls − 16.5 ± 2.4% vs. at-risk − 15.5 ± 2.7% vs. HFpEF − 14.1 ± 3.0%, p < 0.001) while GLS_ENDO and all GCS (all layers) were similar among these groups. GRS was reduced in HFpEF (41.1 ± 13.8% versus 48.9 ± 10.7% in controls, p < 0.001) and the difference between GLS_EPI and GLS_ENDO were significantly larger in HFpEF as compared to controls. Within the preserved LVEF groups, reduced GRS and GLS_EPI were significantly associated with increased LV mass (LVM) and LVM/LV end-diastolic volume EDV (concentricity). In multivariable analysis, only GLS_AVE and GRS predicted 5-year all-cause mortality (all ps < 0.05), with the strongest association with 5-year all-cause mortality by Akaike Information Criterion analysis and significant incremental value for outcomes prediction beyond LVEF or GLS_ENDO by the likelihood ratio test. Conclusion Global strains measured on endocardium, epicardium or averaged across the wall thickness are not equivalent for the identification of systolic dysfunction or outcomes prediction in HF. The endocardium-specific strains were shown to have poorest all-around performance. GLS_AVE and GRS were the only CMR parameters to be significantly associated with 5-year all-cause mortality in multivariable analysis. GLS_EPI and GRS, as well as the difference in endocardial and epicardial strains, were sensitive to systolic dysfunction among HF patients with normal LVEF (> 55%), in whom lower strains were associated with increased concentricity.
- ItemOpen AccessRisks of Dysglycemia Over the First 4 Years After a Hypertensive Disorder of Pregnancy(2019-07-25) Wen, Chuan; Metcalfe, Amy; Anderson, Todd; Sigal, Ronald J; Johnson, Jo-Ann; Carson, Michael; Nerenberg, Kara AWomen with the hypertensive disorders of pregnancy (HDP) (preeclampsia [PE] and gestational hypertension [GHTN]) have increased risks of future diabetes. Postpartum glycemic testing offers early identification and treatment of dysglycemia, but evidence-based recommendations for this high-risk population are lacking. The objective of this study was to describe the risks of developing dysglycemia in women with normotensive and hypertensive pregnancies over the first 4 years postpartum.