Proponents for electronic cigarettes (E-cigs) claim that they are a safe alternative to tobacco-based cigarettes; however, little is known about the long-term effects of exposure to E-cig vapor on vascular function. The purpose of this study was to determine the cardiovascular consequences of chronic E-cig exposure. Female mice (C57BL/6 background strain) were randomly assigned to chronic daily exposure to E-cig vapor, standard (3R4F reference) cigarette smoke, or filtered air ( n = 15/group). Respective whole body exposures consisted of four 1-h-exposure time blocks, separated by 30-min intervals of fresh air breaks, resulting in intermittent daily exposure for a total of 4 h/day, 5 days/wk for 8 mo. Noninvasive ultrasonography was used to assess cardiac function and aortic arterial stiffness (AS), measured as pulse wave velocity, at three times points (before, during, and after chronic exposure). Upon completion of the 8-mo exposure, ex vivo wire tension myography and force transduction were used to measure changes in thoracic aortic tension in response to vasoactive-inducing compounds. AS increased 2.5- and 2.8-fold in E-cig- and 3R4F-exposed mice, respectively, compared with air-exposed control mice ( P < 0.05). The maximal aortic relaxation to methacholine was 24% and 33% lower in E-cig- and 3R4F-exposed mice, respectively, than in controls ( P < 0.05). No differences were noted in sodium nitroprusside dilation between the groups. 3R4F exposure altered cardiac function by reducing fractional shortening and ejection fraction after 8 mo ( P < 0.05). A similar, although not statistically significant, tendency was also observed with E-cig exposure ( P < 0.10). Histological and respiratory function data support emphysema-associated changes in 3R4F-exposed, but not E-cig-exposed, mice. Chronic exposure to E-cig vapor accelerates AS, significantly impairs aortic endothelial function, and may lead to impaired cardiac function. The clinical implication from this study is that chronic use of E-cigs, even at relatively low exposure levels, induces cardiovascular dysfunction. NEW & NOTEWORTHY Electronic cigarettes (E-cigs) are marketed as safe, but there has been insufficient long-term exposure to humans to justify these claims. This is the first study to report the long-term in vivo vascular consequences of 8 mo of exposure to E-cig vapor in mice (equivalent to ~25 yr of exposure in humans). We report that E-cig exposure increases arterial stiffness and impairs normal vascular reactivity responses, similar to other risk factors, including cigarette smoking, which contribute to the development of cardiovascular disease.

The metabolic syndrome (MetS) is associated with a threefold increase risk of cardiovascular disease (CVD) mortality partly due to increased arterial stiffening. We compared the effects of aerobic exercise training on arterial stiffening/mechanics in MetS subjects without overt CVD or type 2 diabetes. MetS and healthy control (Con) subjects underwent 8 wk of exercise training (ExT; 11 MetS and 11 Con) or remained inactive (11 MetS and 10 Con). The following measures were performed pre- and postintervention: radial pulse wave analysis (applanation tonometry) was used to measure augmentation pressure and index, central pressures, and an estimate of myocardial efficiency; arterial stiffness was assessed from carotid-femoral pulse-wave velocity (cfPWV, applanation tonometry); carotid thickness was assessed from B-mode ultrasound; and peak aerobic capacity (gas exchange) was performed in the seated position. Plasma matrix metalloproteinases (MMP) and CVD risk (Framingham risk score) were also assessed. cfPWV was reduced (P < 0.05) in MetS-ExT subjects (7.9 ± 0.6 to 7.2 ± 0.4 m/s) and Con-ExT (6.6 ± 1.8 to 5.6 ± 1.6 m/s). Exercise training reduced (P < 0.05) central systolic pressure (116 ± 5 to 110 ± 4 mmHg), augmentation pressure (9 ± 1 to 7 ± 1 mmHg), augmentation index (19 ± 3 to 15 ± 4%), and improved myocardial efficiency (155 ± 8 to 168 ± 9), but only in the MetS group. Aerobic capacity increased (P < 0.05) in MetS-ExT (16.6 ± 1.0 to 19.9 ± 1.0) and Con-ExT subjects (23.8 ± 1.6 to 26.3 ± 1.6). MMP-1 and -7 were correlated with cfPWV, and both MMP-1 and -7 were reduced post-ExT in MetS subjects. These findings suggest that some of the pathophysiological changes associated with MetS can be improved after aerobic exercise training, thereby lowering their cardiovascular risk.

Croston TL, Thapa D, Holden AA, Tveter KJ, Lewis SE, Shepherd DL, Nichols CE, Long DM, Olfert IM, Jagannathan R, Hollander JM. Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol 307: H54 -H65, 2014. First published April 28, 2014 doi:10.1152/ajpheart.00845.2013.-The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulationbased mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I-and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P Յ 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P Յ 0.05 for both), with a concomitant decline in their levels (P Յ 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels. mitochondria; diabetes mellitus; diabetic cardiomyopathy DIABETES MELLITUS IS A CONDITION that is becoming epidemic in proportion, with an estimated 330 million to be affected worldwide by the year 2030 (12). Of the individuals diagnosed, type 2 diabetes mellitus accounts for ϳ90 -95% of cases (12), which has been attributed to poor diet and sedentary lifestyles (21). Type 2 diabetes mellitus is characterized by insulin resistance resulting from an imbalance in glucose homeostasis (21). The body does not properly use the insulin produced in response to increased blood glucose levels, and over time the pancreas eventually loses its ability to produce insulin (12).Cardiomyopathies are a leading cause of morbidity and mortality in individuals with diabetes mellitus (18). Mitochondrial dysfunction contributes to the development of cardiovascular complications resulting from type 2 diabetes mellitus (7, 9, 15). The cardiomyocyte possesses spatially distinct subpopulati...

Epidemiological studies provide strong evidence that obesity and the associated adipose tissue inflammation are risk factors for breast cancer; however, the molecular mechanisms are poorly understood. We evaluated the effect of a high-fat/high-calorie diet on mammary carcinogenesis in the immunocompetent MMTV-PyMT murine model. Four-week old female mice (20/group) were randomized to receive either a high-fat (HF; 60% kcal as fat) or a low-fat (LF; 16% kcal) diet for eight weeks. Body weights were determined, and tumor volumes measured by ultrasound, each week. At necropsy, the tumors and abdominal visceral fat were weighed and plasma collected. The primary mammary tumors, adjacent mammary fat, and lungs were preserved for histological and immunohistochemical examination and quantification of infiltrating macrophages, crown-like structure (CLS) formation, and microvessel density. The body weight gains, visceral fat weights, the primary mammary tumor growth rates and terminal weights, were all significantly greater in the HF-fed mice. Adipose tissue inflammation in the HF group was indicated by hepatic steatosis, pronounced macrophage infiltration and CLS formation, and elevations in plasma monocyte chemoattractant protein-1 (MCP-1), leptin and proinflammatory cytokine concentrations. HF intake was also associated with higher tumor-associated microvascular density and the proangiogenic factor MCP-1. This study provides preclinical evidence in a spontaneous model of breast cancer that mammary adipose tissue inflammation induced by diet, enhances the recruitment of macrophages and increases tumor vascular density suggesting a role for obesity in creating a microenvironment favorable for angiogenesis in the progression of breast cancer.