Blood Levels of Angiotensinogen and Hypertension in the Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND: Angiotensinogen is the proximal precursor of the angiotensin peptide hormones of the renin-angiotensin-aldosterone system (RAAS). Clinical trials are ongoing targeting angiotensinogen for the treatment of hypertension and heart failure. The epidemiology of angiotensinogen is not well defined, particularly its relationship to ethnicity, sex, and blood pressure (BP)/hypertension. OBJECTIVES: The authors sought to determine the relationship of circulating angiotensinogen levels to ethnicity, sex, BP, incident hypertension, and prevalent hypertension in a modern sex-balanced ethnically diverse cohort. METHODS: Plasma angiotensinogen levels were measured in 5,786 participants from the MESA (Multi-Ethnic Study of Atherosclerosis). Linear, logistic, and Cox proportional hazards models were utilized to examine the associations of angiotensinogen with BP, prevalent hypertension, and incident hypertension, respectively. RESULTS: Angiotensinogen levels were significantly higher in females than males and differed across self-reported ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. Higher levels were associated with higher BP and odds of prevalent hypertension, after adjusting for other risk factors. Equivalent relative differences in angiotensinogen were associated with greater differences in BP in males vs females. In males not taking RAAS-blocking medications, a standard deviation increment in log-angiotensinogen was associated with 2.61 mm Hg higher systolic BP (95% CI: 1.49-3.80), while in females the same increment in angiotensinogen was associated with 0.97 mm Hg higher systolic BP (95% CI: 0.30-1.65). CONCLUSIONS: Significant differences in angiotensinogen levels are present between sexes and ethnicities. A positive association is present between levels and prevalent hypertension and BP, which differs between sexes

Mesenchymal niche-derived neuregulin-1 drives intestinal stem cell proliferation and regeneration of damaged epithelium

Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates proliferation in crypts and induces budding in organoids, in part through elevated and sustained activation of mitogen-activated protein kinase (MAPK) and AKT. Consistently, NRG1 treatment induces a proliferative gene signature and promotes organoid formation from progenitor cells and enhances regeneration following injury. These data suggest mesenchymal-derived NRG1 is a potent mediator of tissue regeneration and may inform the development of therapies for enhancing intestinal repair after injury.Jardé, Abud, and colleagues show that neuregulin 1 (NRG1) is upregulated within distinct mesenchymal niche cells to support intestinal tissue regeneration following damage. NRG1 robustly drives the proliferative response in intestinal stem cells, promotes stem cell identity, and can further enhance the regenerative response when added exogenously

Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases