Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms

Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes

Surgeon Speaks-Paul J. DiMuzio, MD, FACS

“Patients with extensive acute deep vein thrombosis (DVT) of the legs provide an excellent example of why effective medical-surgical collaboration is so important. “These patients typically benefit from emergency catheter-directed thrombolysis, an endovascular procedure performed by vascular surgeons. Subsequent medical management is directed toward preventing re-thrombosis and preventing the long-term complications of DVT. At the Jefferson Vascular Center, vascular medicine specialists initiate and transition that care, as well as provide long-term management of blood thinners and other medical measures. “Across vascular diseases and conditions, Jefferson’s vascular medicine specialists provide many outpatient services. In addition to the excellent care they afford, this collaboration allows the surgeons to focus on complex surgical and endovascular procedures.” Paul J. DiMuzio, MD, FACS William M. Measey Professor of Surgery Director, Division of Vascular and Endovascular Surger

Drug treatment of hypertension: focus on vascular health

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health

Clinical Studies Target Fewer Complications, Better Outcomes for Vascular Surgery

Two studies at the Jefferson Vascular Center (JVC) are assessing innovative methods to reduce risk of complications — and increase positive outcomes — for vascular surgery patients. Here, Paul DiMuzio, MD, FACS, William M. Measey Professor of Surgery and Co-Director, Jefferson Vascular Center, reviews what both studies mean for patient care. ‘Game-changer’ for groin wounds As Dr. DiMuzio explains, groin incisions in vascular surgery are a source of significant morbidity and healthcare costs. When groin wounds become infected, patients may have to be readmitted and undergo additional surgery. Some patients are at greater risk because of diabetes and obesity, others because of the surgical technique required for their treatment. In exploring ways to decrease groin wound infections in high-risk patients, the JVC identified a possible solution in PrevenaTM — a sponge covered in adhesive that attaches to a small suction device. The suction device removes fluids from the region, helping reduce the risk of infection. Already FDA-approved, Prevena is used by cardiac surgeons for sternal incisions and by orthopedic surgeons in total joint replacements. “No one had conducted a prospective randomized trial to determine if Prevena is a viable option for highrisk groin wounds,” he says. “We were the first.” The results of Jefferson’s two-year study — which will be presented later this Spring at the 2017 Annual Meeting of the Society for Vascular Surgery in San Diego — showed a significant reduction in infections and re-admissions. Hospital costs declined by an average of $6,000 per patient. “We are now using this device for every patient with high-risk groin incisions, and we expect it to become a standard of care everywhere once the findings are published,” he adds. “It’s a game changer.” In February, Megan Lundgren, MD, a third-year General Surgery resident and Sidney Kimmel Medical College alumna, presented the study at the Philadelphia Academy of Surgery’s Annual Surgical Research Competition. Dr. Lundgren, who helped enroll and care for trial participants, won the inaugural Chris Tzarnas Surgical Research Award for the work. Follow-up trial of new treatment for carotid artery disease Following the promising multi-center ROADSTER trial, the ROADSTER 2 trial is observing and evaluating real-world results of a newly approved procedure for treating carotid artery disease. The most widely used treatment for carotid artery disease has been the carotid endarterectomy (CEA) procedure, in which plaque is surgically removed from the blocked artery. For patients who may be at high medical or anatomic risk for carotid endarterectomy, carotid stenting may be a better option. Though both procedures are generally safe, heart attack risk is higher with CEA, while stroke risk is higher with stenting. Trans-carotid Artery Revascularization (TCAR) is designed to lower both risks, and the initial ROADSTER trial demonstrated its success. “The TCAR procedure is a hybrid of the other two treatments,” Dr. DiMuzio says. “It places a carotid stent through a minimally invasive incision in the carotid artery at the level of the neck. Blood flow in the artery is temporarily reversed to protect the brain from plaque fragments that may come loose during the procedure. A stent is then inserted into the blood vessel to support the artery walls and prevent blockage or collapse.” Dr. DiMuzio adds that stent deployment via access directly through the common carotid artery avoids the need to traverse the aortic arch with catheters, which can lead to embolic stroke. Though approved by the FDA, the TCAR procedure will not be marketed until the ROADSTER 2 trial is completed. To date, Jefferson is the first and only study location in the Philadelphia area. Dr. DiMuzio and his team have already performed the TCAR procedure and are actively enrolling more patients. “Nationally, the study is more than halfway to completion — and the TCAR procedure is on its way to becoming an exciting new standard of care for carotid artery disease,” he says. For more information, contact the Jefferson Vascular Center at 215-955-8304 or visit Jefferson.edu/JV

Evaluation of the zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles

Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D) are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF) rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD) and cardiovascular disease (CVD) biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin) or related to disease development (collagen). Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level

Examining the role of insulin in the regulation of cardiovascular health

A substantial body of evidence has reported that insulin has direct actions on the cardiovascular system independent of its systemic effects on plasma glucose or lipids. In particular, insulin regulates endothelial synthesis of the vasoactive mediators nitric oxide and endothelin-1, yet the importance of this in the maintenance of cardiovascular health remains poorly understood. Recent studies using animals with targeted downregulation of insulin signaling in vascular tissues are improving our understanding of the role of insulin in vascular health. This article focuses on the direct actions of insulin in cardiovascular tissues, with particular emphasis on the molecular mechanisms of insulin action on endothelial function. The potential contribution of impaired vascular insulin action to the cardiovascular complications of diabetes will also be discussed

Reconstituted high-density lipoproteins promote wound repair and blood flow recovery in response to ischemia in aged mice

Background: The average population age is increasing and the incidence of age-related vascular complications is rising in parallel. Impaired wound healing and disordered ischemia-mediated angiogenesis are key contributors to age-impaired vascular complications that can lead to amputation. High-density lipoproteins (HDL) have vasculo-protective properties and augment ischemia-driven angiogenesis in young animals. We aimed to determine the effect of reconstituted HDL (rHDL) on aged mice in a murine wound healing model and the hindlimb ischemia (HLI) model. Methods: Murine wound healing model—24-month-old aged mice received topical application of rHDL (50 μg/wound/ day) or PBS (vehicle control) for 10 days following wounding. Murine HLI model—Femoral artery ligation was performed on 24-month-old mice. Mice received rHDL (40 mg/kg) or PBS, intravenously, on alternate days, 1 week pre-surgery and up to 21 days post ligation. For both models, blood flow perfusion was determined using laser Doppler perfusion imaging. Mice were sacrificed at 10 (wound healing) or 21 (HLI) days post-surgery and tissues were collected for histological and gene analyses. Results: Daily topical application of rHDL increased the rate of wound closure by Day 7 post-wounding (25 %, p < 0.05). Wound blood perfusion, a marker of angiogenesis, was elevated in rHDL treated wounds (Days 4–10 by 22–25 %, p < 0. 05). In addition, rHDL increased wound capillary density by 52.6 %. In the HLI model, rHDL infusions augmented blood flow recovery in ischemic limbs (Day 18 by 50 % and Day 21 by 88 %, p < 0.05) and prevented tissue necrosis and toe loss. Assessment of capillary density in ischemic hindlimb sections found a 90 % increase in rHDL infused animals. In vitro studies in fibroblasts isolated from aged mice found that incubation with rHDL was able to significantly increase the key pro-angiogenic mediator vascular endothelial growth factor (VEGF) protein (25 %, p < 0.05). Conclusion: rHDL can promote wound healing and wound angiogenesis, and blood flow recovery in response to ischemia in aged mice. Mechanistically, this is likely to be via an increase in VEGF. This highlights a potential role for HDL in the therapeutic modulation of age-impaired vascular complications