Introduction: Whether and to what extent postmenopausal estrogen therapy has beneficial effects on progression of coronary artery atherosclerosis is controversial. In previous studies with monkey models we have shown that the stage of plaque progression modulates estrogen benefits and have led to the “timing hypothesis”. In this study, we used a histomorphometric approach to understand better the effects of estrogen therapy on critical components of atherosclerosis pathogenesis. Our hypothesis was that estrogen therapy would inhibit the initial development of atherosclerotic plaques, result in smaller but not less complicated plaques and among subjects that developed plaques, it would promote positive arterial remodeling. Methods: Forty-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and randomly assigned to receive no treatment (CTL) or a women’s equivalent dose of conjugated equine estrogen (CEE) (0.45 mg/day). The experimental period lasted for 20 months (equivalent to 5 years in humans). At the end of the experiment, prevalence of atherosclerotic plaques was determined. From those monkeys with affected arteries, plaque extent, severity and prevalence of stenosis were determined. Results: Prevalence: The CEE treated group had significantly fewer monkeys with coronary artery atherosclerosis compared to the CTL group (CTL: 57 % vs. CEE: 33 % p=0.005). Extent: Among affected monkeys, the mean plaque size was significantly smaller in the CEE treated group compared to the CTL group (CTL: 0.30 ± 0.048 mm2 vs. CEE: 0.153 ± 0.028 mm2 p=0.015). Remodeling: The proportion of stenotic plaques was lower in the CEE group compared to the CTL group (CTL: 11.14 % vs. CEE: 1.34 % p= 0.008). Severity: CEE treatment did not have a beneficial effect on coronary artery severity (% of complicated [AHA grade≥ III] plaques- CTL: 52.34 % vs. 49.61 %, p=0.397). Conclusions: These histomorphometric findings support previous evidence that beginning of estrogen therapy in the perimenopausal transition prevents plaque initiation. Among affected cases, estrogen treated monkeys had smaller plaques but were equally complicated. Notably, estrogen also promoted positive arterial remodeling among affected arteries.
Exposure to elevated levels of airborne pollutants causes cardiac mast cell activation. Sulfur dioxide, a derived from fossil fuel combustion, has been shown to induce mast cell degranulation in an immortalized cell line. However, it is not known whether sulfur dioxide induced oxidative stress can directly trigger the activation of cardiac mast cells. This study sought to determine if ionization of sodium sulfite (Na2SO3) can induce degranulation of cardiac mast cells, and whether mast cell activation can be prevented by inhibition of oxidative stress. Cardiac mast cells were isolated from the pericardial sac and incubated with increasing concentrations of Na2SO3. Antioxidant compounds targeting different mechanisms of free radical generation, including ebselen, dyphenyleneiodinium (DPI) and tocopherol, were incubated with Na2SO3 in order to determine their efficacy in preventing mast cell degranulation. Sodium sulfite induced a concentration-dependent histamine release from cardiac mast cells which was prevented by ebselen and attenuated by DPI. In contrast, the histamine release was exacerbated by tocopherol. These findings indicate that sulfur dioxide is capable of causing cardiac mast cell degranulation and the variable effectiveness of the antioxidants evaluated is indicative of a multifactorial mechanism mediating sulfur dioxide induced cardiac mast cell degranulation. EPA grant RD-83195301 (GLB)
Substance P, which is found in sensory nerves, has recently been shown to mediate adverse myocardial remodeling following initiation of myocarditis in mice. We sought to determine whether substance P and its receptor, the neurokinin-1 (NK-1) receptor also play a role in adverse remodeling stemming from systemic hypertension. Accordingly, 12 week old spontaneously hypertensive rats (SHR) were treated for 3 weeks with the NK-1 receptor antagonist L 732 138 (5mg/kg/d). Antagonism of the NK-1 receptor normalized cardiac fibrosis in the left ventricle (LV) while hypertrophy remained unchanged. The effect on remodeling was independent of blood pressure since the SHR remained hypertensive. Inflammation is an important component of the fibrotic response in the hypertensive left ventricle. We isolated inflammatory cells, including T cells, mast cells and macrophages, from the LV of rats and incubated them with substance P. Substance P stimulated production of angiotensin II and TNF-α by this mixed population of inflammatory cells. Thus, substance P activation of inflammatory cells results in the local production of angiotensin II and TNF-α which are known to lead to adverse remodeling in the hypertensive heart. This work was supported by award number K99HL093215 from the National Heart, Lung, And Blood Institute.
Introduction: Breast cancer (BC) treatment toxicity contributes to elevated rates of cardiovascular morbidities, such as reduced exercise capacity, a risk factor for long-term cardiovascular disease (CVD) and mortality. Past studies have shown that Black women experience greater cardiotoxicity after BC treatment than white women. No studies have investigated racial differences in exercise capacity. The lack of longitudinal data leaves uncertainty as to whether greater declines in exercise capacity are experienced by Black BC survivors. Methods: This cohort was comprised of 236 women with stage I-III BC (80% white; 20% Black) and 130 cancer-free controls in the UPBEAT (NCT02791581) and DETECT (NCT01719562) studies. Submaximal exercise capacity was obtained via 6-Minute Walk Distance (6MWD, meters [m]) at baseline (pre-treatment) and 3 months. Linear regression was used to examine associations of race with baseline 6MWD and changes in 6MWD. Results: Mean age [SD] of BC survivors was 55.7 [10.9] years. Mean [SD] total meters walked pre-treatment was lower in Black women with BC (423 m [81.0]) than white women with BC (475 m [87.7]; p=0.01), and lower than Black women without BC (471 m [76.9]; p=0.07). Black BC survivors experienced a greater mean decline from baseline to 3-months in 6MWD (30 m [68.5]) than white BC survivors (21.7 m [86.6]; Table 1; p=0.02) or Black women without BC (9.2 m [67.3]; p=0.001), translating to a mean difference of 60 m between Black and white BC survivors during BC treatment. Conclusions: This is the first study to suggest racial differences in submaximal exercise capacity during BC treatment. Black BC survivors experienced a greater reduction in exercise capacity than white BC survivors after cancer treatment as early as 3-months post-diagnosis. This clinically-meaningful difference in exercise capacity warrants further investigation, particularly to determine interventions to reverse the loss of exercise capacity.
Induction of inflammatory cytokines has been implicated in the progression of myocardial remodeling and heart failure (HF). Increased levels of circulating TNF-α and interleukin-6 (IL-6) in patients with HF, suggest that these cytokines may be involved in the pathogenesis of heart disease. In previous studies we have shown that TNF-α is an important contributor to the adverse myocardial remodeling. TNF-α is known to mediate collagen degradation as well as in-series sarcomeric addition contributing to ventricular dilatation. However, the effects of IL-6 on cardiac remodeling in vivo have not been investigated. Accordingly, in this study we explore the hypothesis that up-regulation of IL-6 mediates adverse myocardial remodeling. To this end, a group of adult male Sprague Dawley rats was infused with IL-6 (2.5 μg/kg/hr, IP) for 7 days via osmotic minipump and compared to aged-matched shams. LV pressure, size, and function were measured using a blood-perfused isolated heart preparation. At the end of the experiment, hearts were weighed and analyzed for collagen volume fraction (CVF) and isolated cardiomyocyte size. The EDP-EDV (End Diastolic Pressure and Volume) relationship provided that IL-6 infusion produced LV stiffness and a clear tendency for a shift of the EDP-EDV curve to the left due to ventricular hypertrophy and diastolic dysfunction. LV weight differences demonstrate concentric hypertrophy (749 mg versus 660 mg in control hearts; p< 0.05) and a marked increase in interstitial collagen in the IL-6 infused hearts relative to that in control hearts (CVF of 6.2% vs. 1.7%, respectively; p< 0.001). The cardiomyocyte hypertrophy at the cellular level also reflected a concentric phenotype, with cells being significantly longer and thicker (18% and 32%, respectively; p< 0.01). These novel observations demonstrate a direct effect of IL-6 on cardiac remodeling in vivo, which in contrast to TNF-α, induces a dramatic myocardial fibrosis together with concentric cardiac hypertrophy. This suggests that IL-6 may contribute to the development of diastolic dysfunction, and as such could drive the transition to heart failure.
