Midlife Determinants of Healthy Cardiovascular aging: the atherosclerosis Risk in Communities (Aric) Study

BACKGROUND AND AIMS: Risk factor cutoffs are derived from associations with clinical cardiovascular disease (CVD), but how these risk factors associate with preserved cardiovascular health into old age is not well studied. We investigated midlife determinants of healthy versus nonhealthy cardiovascular aging in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: ARIC participants were categorized by cardiovascular status in older age (mean age 75.8 ± 5.3 years, range 66-90): healthy, subclinical disease (assessed by biomarkers and left ventricular function), clinical CVD (coronary heart disease, stroke, or heart failure), or prior death. We examined associations of midlife (mean age 52.1 ± 5.1 years) systolic and diastolic blood pressure (SBP, DBP), low-density lipoprotein cholesterol (LDL-C), triglycerides, hemoglobin A1c (HbA1c), and body mass index (BMI) with cardiovascular status in older age using multinomial logistic regression analyses. RESULTS: Compared with healthy status, odds for subclinical disease (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.09-1.55) and clinical CVD (OR 1.87, 95% CI 1.53-2.29) at older age increased starting with midlife SBP 120-129 mmHg, whereas odds for death increased starting with SBP 110-119 mmHg (OR 1.29, 95% CI 1.10-1.52); findings were similar for DBP. Odds for subclinical disease increased for HbA1c ≥ 6.5% and BMI starting at 30-/m CONCLUSIONS: More-stringent levels of modifiable risk factors in midlife beyond current clinical practice and guidelines were associated with preserved cardiovascular health in older age

Environmental Report 1998

This summary provides an overview of LLNL's environmental activities in 1998, including radiological and nonradiological surveillance, effluent, and compliance monitoring, remediation, assessment of radiological releases and doses, and determination of the impact of LLNL operations on the environment and public health

High-Sensitivity Troponin T and Cardiovascular Events in Systolic Blood Pressure CategoriesNovelty and Significance: Atherosclerosis Risk in Communities Study

Based on observational studies there is a linear increase in cardiovascular risk with higher systolic blood pressure, yet clinical trials have not shown benefit across all systolic blood pressure categories. We assessed if troponin-T measured using high-sensitivity assay was associated with cardiovascular disease within systolic blood pressure categories in 11191 Atherosclerosis Risk in Communities study participants. Rested sitting systolic blood pressure by 10-mmHg increments and troponin categories were identified. Incident heart failure hospitalization, coronary heart disease and stroke were ascertained over a median of 12 years after excluding individuals with corresponding disease. Approximately 53% of each type of cardiovascular event occurred in individuals with systolic blood pressure<140 mmHg and troponin-T≥3ng/L. Higher troponin-T was associated with increasing cardiovascular events across most systolic blood pressure categories. The association was strongest for heart failure and least strong for stroke. There was no similar association of systolic blood pressure with cardiovascular events across troponin-T categories. Individuals with troponin-T≥3ng/L and systolic blood pressure<140mmHg had higher cardiovascular risk compared to those with troponin-T<3ng/L and systolic blood pressure 140-159 mmHg

Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases

MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival