Reducing Cardiovascular Disparities Through Community-Engaged Implementation Research: A National Heart, Lung, and Blood Institute Workshop Report.

Cardiovascular disparities remain pervasive in the United States. Unequal disease burden is evident among population groups based on sex, race, ethnicity, socioeconomic status, educational attainment, nativity, or geography. Despite the significant declines in cardiovascular disease mortality rates in all demographic groups during the last 50 years, large disparities remain by sex, race, ethnicity, and geography. Recent data from modeling studies, linked micromap plots, and small-area analyses also demonstrate prominent variation in cardiovascular disease mortality rates across states and counties, with an especially high disease burden in the southeastern United States and Appalachia. Despite these continued disparities, few large-scale intervention studies have been conducted in these high-burden populations to examine the feasibility of reducing or eliminating cardiovascular disparities. To address this challenge, on June 22 and 23, 2017, the National Heart, Lung, and Blood Institute convened experts from a broad range of biomedical, behavioral, environmental, implementation, and social science backgrounds to summarize the current state of knowledge of cardiovascular disease disparities and propose intervention strategies aligned with the National Heart, Lung, and Blood Institute mission. This report presents the themes, challenges, opportunities, available resources, and recommended actions discussed at the workshop.

PCB 126 toxicity is modulated by cross-talk between caveolae and Nrf2 signaling.

Environmental toxicants such as polychlorinated biphenyls (PCBs) have been implicated in the promotion of multiple inflammatory disorders including cardiovascular disease, but information regarding mechanisms of toxicity and cross-talk between relevant cell signaling pathways is lacking. To examine the hypothesis that cross-talk between membrane domains called caveolae and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways alters PCB-induced inflammation, caveolin-1 was silenced in vascular endothelial cells, resulting in a decreased PCB-induced inflammatory response. Cav-1 silencing (siRNA treatment) also increased levels of Nrf2-ARE transcriptional binding, resulting in higher mRNA levels of the antioxidant genes glutathione s-transferase and NADPH dehydrogenase quinone-1 in both vehicle and PCB-treated systems. Along with this upregulated antioxidant response, Cav-1 siRNA treated cells exhibited decreased mRNA levels of the Nrf2 inhibitory protein Keap1 in both vehicle and PCB-treated samples. Silencing Cav-1 also decreased protein levels of Nrf2 inhibitory proteins Keap1 and Fyn kinase, especially in PCB-treated cells. Further, endothelial cells from wildtype and Cav-1-/- mice were isolated and treated with PCB to better elucidate the role of functional caveolae in PCB-induced endothelial inflammation. Cav-1-/- endothelial cells were protected from PCB-induced cellular dysfunction as evidenced by decreased vascular cell adhesion molecule (VCAM-1) protein induction. Compared to wildtype cells, Cav-1-/- endothelial cells also allowed for a more effective antioxidant response, as observed by higher levels of the antioxidant genes. These data demonstrate novel cross-talk mechanisms between Cav-1 and Nrf2 and implicate the reduction of Cav-1 as a protective mechanism for PCB-induced cellular dysfunction and inflammation.

Noncommunicable Diseases in Low- and Middle-Income Countries: A Strategic Approach to Develop a Global Implementation Research Workforce.

Globally, most of the burden from noncommunicable disease is now evident in low- and middle-income countries (LMICs). At the same time, many effective noncommunicable disease interventions are now available and recommended for implementation and scale-up across LMIC health systems-yet are not being widely implemented. Understanding optimal and sustainable implementation strategies for these interventions within the LMIC context will need locally led and conducted implementation research- a research capacity which currently is lacking. The National Institutes of Health institutes, centers, and offices work with the Fogarty International Center to support biomedical research and research training across the globe. The National Heart, Lung, and Blood Institutes' Center for Translation Research and Implementation Science has a strategic focus on implementation research in global health. The Center for Translation Research and Implementation Science is considering strategies for developing research capacity and skill sets to conduct this priority research along with National Institutes of Health institutes and centers and other key global institutions that highly value implementation research. Short-term and medium-term strategies will be needed along with building on current efforts and investments and considering new efforts to address gaps. Developing and sustaining this research workforce will present many challenges and require much effort, but the returns could be transformative in advancing the prevention, treatment, and control of noncommunicable diseases within LMICs.

Polychlorinated biphenyls and links to cardiovascular disease.

The pathology of cardiovascular disease is multi-faceted, with links to many modifiable and non-modifiable risk factors. Epidemiological evidence now implicates exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs), with an increased risk of developing diabetes, hypertension, and obesity; all of which are clinically relevant to the onset and progression of cardiovascular disease. PCBs exert their cardiovascular toxicity either directly or indirectly via multiple mechanisms, which are highly dependent on the type and concentration of PCBs present. However, many PCBs may modulate cellular signaling pathways leading to common detrimental outcomes including induction of chronic oxidative stress, inflammation, and endocrine disruption. With the abundance of potential toxic pollutants increasing globally, it is critical to identify sensible means of decreasing associated disease risks. Emerging evidence now implicates a protective role of lifestyle modifications such as increased exercise and/or nutritional modulation via anti-inflammatory foods, which may help to decrease the vascular toxicity of PCBs. This review will outline the current state of knowledge linking coplanar and non-coplanar PCBs to cardiovascular disease and describe the possible molecular mechanism of this association.

Modulation of persistent organic pollutant toxicity through nutritional intervention: emerging opportunities in biomedicine and environmental remediation.

Environmental pollution is increasing worldwide, and there is evidence that exposure to halogenated persistent organic pollutants (POPs) such as polychlorinated biphenyls can contribute to the pathology of inflammatory diseases such as atherosclerosis, diabetes, and cancer. Pollutant removal from contaminated sites and subsequent pollutant degradation are critical for reducing the long-term health risks associated with exposure. However, complete remediation of a toxicant from the environment is very difficult and cost-prohibitive. Furthermore, remediation technologies often result in the generation of secondary toxicants. Considering these circumstances, environmentally-friendly and sustainable remediation technologies and biomedical solutions to reduce vulnerability to environmental chemical insults need to be explored to reduce the overall health risks associated with exposure to environmental pollutants. We propose that positive lifestyle changes such as healthful nutrition and consumption of diets rich in fruits and vegetables or bioactive nutrients with antioxidant and/or anti-inflammatory properties will reduce the body's vulnerability to environmental stressors and thus reduce toxicant-mediated disease pathologies. Interestingly, emerging evidence now implicates the incorporation of bioactive nutrients, such as plant-derived polyphenols, in technologies focused on the capture, sensing and remediation of halogenated POPs. We propose that human nutritional intervention in concert with the use of natural polyphenol sensing and remediation platforms may provide a sensible means to develop primary and long-term prevention strategies of diseases associated with many environmental toxic insults including halogenated POPs.

Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes.

Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the up-regulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low-fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 µmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited fivefold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both messenger RNA and protein analyses, and it was determined that many genes transcriptionally controlled by aryl hydrocarbon receptor and nuclear factor (erythroid-derived 2)-like 2 proteins were up-regulated in PCB-exposed mice fed the green tea-supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126, which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants.