Cardiovascular health trajectories and subsequent cardiovascular disease and mortality: The multi-ethnic study of atherosclerosis (MESA).

Objective: Longitudinal trajectories of cardiovascular health (CVH) may reflect vascular risk burden due to prolonged cumulative exposure to non-ideal CVH levels. Identifying individuals who have a higher risk CVH trajectory may facilitate treatment, screening, and prevention. We aimed to characterize 10-year trajectories of CVH and examine the associations between CVH trajectories and subsequent cardiovascular disease (CVD) and mortality. Methods: We analyzed 3674 MESA participants who completed four exams and remained CVD-free from 2000 to 2011. A 12-point CVH score was calculated based on physical activity, smoking status, body mass index, cholesterol, blood pressure, and glucose. Ideal CVH was defined as a score ≥ 9. Group-based trajectory modeling was used to identify trajectories of ideal CVH. Cox models were used to examine the association of CVH trajectories with incident CVD and death from 2011 to 2018, adjusting for age, sex, race/ethnicity, income, education, and marital status. Results: Three trajectories were identified based on the probability of achieving ideal CVH: high (n = 1251), medium (n = 760), and persistently low (n = 1663). Almost half (45.3%) of the participants had a persistently low trajectory. During a median of 7.7 years follow-up, 392 incident CVD events and 459 deaths occurred. Compared with the high CVH group, participants in the persistently low CVH trajectory group had elevated risks for CVD (adjusted hazard ratios 1.49, 95% confidence interval 1.15-1.93) and mortality (1.34, 1.06-1.70), and participants in the medium group had moderate risks for CVD (1.17, 0.86-1.59) and mortality (1.15, 0.87-1.53) (p-value for trend 0.002 for CVD, 0.014 for mortality). Conclusion: Persistently nonideal CVH is a common trajectory. Targeted prevention programs might benefit individuals with persistently nonideal CVH given their elevated risk of subsequent CVD and mortality.

Secular Trends in Risk Profiles Among Adults With Cardiovascular Disease in the United States.

BACKGROUND: Documenting trends in risk factors among individuals with cardiovascular disease (CVD) may inform policy and secondary prevention initiatives. OBJECTIVES: This study aimed to examine 20-year trends in risk profiles among U.S. adults with CVD and any racial/ethnic disparities. METHODS: In this serial cross-sectional analysis of 6,335 adults with self-reported CVD participating in the National Health and Nutrition Examination Survey from 1999 through 2018, we calculated age- and sex-adjusted proportions with ideal risk factor attainment. RESULTS: The proportions with ideal hemoglobin A1c (<7% if diabetes or <5.7% if not) and body mass index (<25 kg/m2) worsened from 58.7% (95% CI: 55.2%-62.1%) to 52.4% (95% CI: 48.2%-56.6%) and 23.9% (95% CI: 21.5%-26.4%) to 18.2% (95% CI: 15.6%-21.2%) from 1999-2002 to 2015-2018, respectively. After initial improvement, the proportion with blood pressure <130/80 mm Hg declined from 52.1% (95% CI: 48.9%-55.4%) in 2007-2010 to 48.6% (95% CI: 44.2%-52.7%) in 2015-2018. The proportion with non-high-density lipoprotein cholesterol levels <100 mg/dL increased from 7.3% (95% CI: 5.6%-9.5%) in 1999-2002 to 30.3% (95% CI: 25.7%-35.5%) in 2015-2018. The proportions with ideal smoking, physical activity, and diet profiles were unchanged over time, and in 2015-2018 were 77.8% (95% CI: 73.6%-81.4%), 22.4% (95% CI: 19.3%-25.9%), and 1.3% (95% CI: 0.7%-2.6%). Worsening trends were observed in Hispanic adults for cholesterol, and in Black adults for smoking (both P < 0.05 for nonlinear and linear trends). Persistently lower ideal risk factor attainment was observed for blood pressure in Black adults and for hemoglobin A1c levels in Asian adults compared with White adults (all P < 0.05 for differences). CONCLUSIONS: Trends in cardiovascular risk factor profiles in U.S. adults with CVD were suboptimal from 1999 through 2018, with persistent racial/ethnic disparities.

Critical role of synovial tissue-resident macrophage niche in joint homeostasis and suppression of chronic inflammation.

Little is known about the mechanisms regulating the transition of circulating monocytes into pro- or anti-inflammatory macrophages in chronic inflammation. Here, we took advantage of our novel mouse model of rheumatoid arthritis, in which Flip is deleted under the control of a CD11c promoter (HUPO mice). During synovial tissue homeostasis, both monocyte-derived F4/80int and self-renewing F4/80hi tissue-resident, macrophage populations were identified. However, in HUPO mice, decreased synovial tissue-resident macrophages preceded chronic arthritis, opened a niche permitting the influx of activated monocytes, with impaired ability to differentiate into F4/80hi tissue-resident macrophages. In contrast, Flip-replete monocytes entered the vacated niche and differentiated into tissue-resident macrophages, which suppressed arthritis. Genes important in macrophage tissue residency were reduced in HUPO F4/80hi macrophages and in leukocyte-rich rheumatoid arthritis synovial tissue monocytes. Our observations demonstrate that the macrophage tissue-resident niche is necessary for suppression of chronic inflammation and may contribute to the pathogenesis of rheumatoid arthritis.

Quantitative benzimidazole resistance and fitness effects of parasitic nematode beta-tubulin alleles.

Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense against these infections. Unfortunately, resistance to these drugs is rampant and continues to spread. To improve treatment strategies, we must understand the genetics and molecular mechanisms that underlie resistance. Studies of the fungus Aspergillus nidulans and the free-living nematode Caenorhabditis elegans discovered that a beta-tubulin gene is mutated in benzimidazole (BZ) resistant strains. In parasitic nematode populations, three beta-tubulin alleles, F167Y, E198A, and F200Y, have long been correlated with resistance. Additionally, improvements in sequencing technologies have identified new alleles - E198V, E198L, E198K, E198I, and E198Stop - also correlated with BZ resistance. However, none of these alleles have been proven to cause resistance. To empirically demonstrate this point, we independently introduced the F167Y, E198A, and F200Y alleles as well as two of the newly identified alleles, E198V and E198L, into the BZ susceptible C. elegans N2 genetic background using the CRISPR-Cas9 system. These genome-edited strains were exposed to both albendazole and fenbendazole to quantitatively measure animal responses to BZs. We used a range of concentrations for each BZ compound to define response curves and found that all five of the alleles conferred resistance to BZ compounds equal to a loss of the entire beta-tubulin gene. These results prove that the parasite beta-tubulin alleles cause resistance. The E198V allele is found at low frequencies along with the E198L allele in natural parasite populations, suggesting that it could affect fitness. We performed competitive fitness assays and demonstrated that the E198V allele reduces animal health, supporting the hypothesis that this allele might be less fit in field populations. Overall, we present a powerful platform to quantitatively assess anthelmintic resistance and effects of specific resistance alleles on organismal fitness in the presence or absence of the drug.