Clinical relevance of the relationship between Trabecular Bone Score and metabolic syndrome

The Trabecular Bone Score (TBS) is an indirect measurement of bone quality, and studies have shown that TBS is an independent predictor of fracture risk. This cross-sectional investigation aimed to explore the relationship between metabolic syndrome (MetS) and TBS using data from the 2005–2006 US National Health and Nutrition Examination Survey. The association between individual MetS components and TBS was examined. There was a significant linear decrease in TBS with an increase in the number of MetS components. The β coefficients of TBS among participants with 3 and ≥4 MetS components were −0.015 and −0.041 (p=0.006 and p<0.001, respectively). Among participants with MetS, high systolic blood pressure, abdominal obesity, and high serum levels of triglycerides and glucose were significantly associated with lower TBS in fully adjusted models (p<0.05). Furthermore, there was a significant linear decrease in TBS with an increase in the number of MetS components in both sexes. TBS significantly decreased with an increasing number of MetS components in a US population. The components of MetS, including systolic blood pressure, waist circumference, and serum levels of triglyceride and glucose, exhibited a negative association with TBS.

Associations Between Blood Pressure and Accelerated DNA Methylation Aging

Background Individuals of the same chronological age may exhibit diverse susceptibilities to death. However, few studies have investigated the associations between blood pressure and the accelerated aging. Methods and Results A cross‐sectional study was conducted in 288 adults aged ≥50 years. We assessed the DNA methylation‐based measures of biological age using CpG sites on the Illumina HumanMethylationEPIC BeadChip. Epigenetic age acceleration metrics were derived by regressing residuals (ΔAge) and ratios (aging rate) of DNA methylation age on chronological age. Dose‐response relationships between blood pressure and epigenetic age acceleration were quantified using multiple linear regression and restricted cubic regression models. We found that each 10–mm Hg increase in systolic blood pressure was associated with 0.608 (95% CI, 0.231–0.984) years increase in ΔAge and 0.007 (95% CI, 0.002–0.012) increase in aging rate; meanwhile, for pulse pressure, the increase was 1.12 (95% CI, 0.625–1.61) years for ΔAge and 0.013 (95% CI, 0.007–0.020) for aging rate. Subgroup analysis showed that the significant associations of systolic blood pressure and pulse pressure with epigenetic age acceleration appeared to be limited to women, although interactions between blood pressure and sex were not significant ( P values for interaction >0.05). The combination of women and hypertension was associated with a much higher increase in ΔAge (β [95% CI], 4.05 [1.07–7.02]) and aging rate (β [95% CI], 0.047 [0.008–0.087]), compared with male participants without hypertension. Conclusions Our findings suggested that high systolic blood pressure and pulse pressure were associated with the epigenetic age acceleration, providing important clues for relationships between blood pressure and epigenetic aging.

Burden of chronic kidney disease and its risk-attributable burden in 137 low-and middle-income countries, 1990–2019: results from the global burden of disease study 2019

Background Chronic kidney disease (CKD) is a global public health concern, but its disease burden and risk-attributable burden in CKD has been poorly studied in low - and middle-income countries (LMICs). This study aimed to estimate CKD burden and risk-attributable burden in LMICs from 1990 to 2019. Methods Data were collected from the Global Burden of Disease (GBD) Study 2019, which measure CKD burden using the years lived with disability (YLDs), years of life lost (YLLs), disability-adjusted life-years (DALYs) and calculate percentage contributions of risk factors to age-standardized CKD DALY using population attributable fraction (PAF) from 1990 to 2019. Trends of disease burden between 1990 and 2019 were evaluated using average annual percent change (AAPC). The 95% uncertainty interval (UI) were calculated and reported for YLDs, YLLs, DALYs and PAF. Results In 2019, LICs had the highest age-standardized DALY rate at 692.25 per 100,000 people (95%UI: 605.14 to 785.67), followed by Lower MICs (684.72% (95%UI: 623.56 to 746.12)), Upper MICs (447.55% (95%UI: 405.38 to 493.01)). The age-standardized YLL rate was much higher than the YLD rate in various income regions. From 1990 to 2019, the age-standardized DALY rate showed a 13.70% reduction in LICs (AAPC = -0.5, 95%UI: − 0.6 to − 0.5, P < 0.001), 3.72% increment in Lower MICs (AAPC = 0.2, 95%UI: 0.0 to 0.3, P < 0.05). Age-standardized YLD rate was higher in females than in males, whereas age-standardized rates of YLL and DALY of CKD were all higher in males than in females in globally and LMICs. Additionally, the YLD, YLL and DALY rates of CKD increased with age, which were higher in aged≥70 years in various income regions. In 2019, high systolic blood pressure, high fasting plasma glucose, and high body-mass index remained the major causes attributable age-standardized CKD DALY. From 1990 to 2019, there were upward trends in the PAF of age-standardized DALY contributions of high fasting plasma glucose, high systolic blood pressure, and high body-mass index in Global, LICs, Lower MICs and Upper MICs. The greatest increase in the PAF was high body-mass index, especially in Lower MICs (AAPC = 2.7, 95%UI: 2.7 to 2.8, P < 0.001). The PAF of age-standardized DALY for high systolic blood pressure increased the most in Upper MICs (AAPC = 0.6, 95%UI: 0.6 to 0.7, P < 0.001). Conclusions CKD burden remains high in various income regions, especially in LICs and Lower MICs. More effective and targeted preventive policies and interventions aimed at mitigating preventable CKD burden and addressing risk factors are urgently needed, particularly in geographies with high or increasing burden.

Mongolia health situation: based on the Global Burden of Disease Study 2019

Background Over the past few decades, economic, political, and social changes have directly and indirectly affected the health of the Mongolian population. To date, no comprehensive analysis has been conducted on the burden of diseases in this country. Thus, we aimed to describe the leading causes of death and disabling conditions and their trends between 1990 and 2019 in the Mongolian population. Methods We used the data from the Global Burden of Disease (GBD) 2019 study. In the current study, we examined life expectancy at birth, healthy life expectancy, the 20 leading causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted-life-years (DALYs), and the contribution of major risk factors to DALYs in Mongolia. Findings The life expectancy at birth in Mongolia has gradually increased since 1995 and reached 63.8 years for men and 72.7 for women in 2019. The highest increase in the age-standardised death rate between 1990 and 2019 occurred in alcohol use disorders (628.6%; 95% UI 10.0–1109.6) among men, and in liver cancer (129.1%; UI 65.3–222.4) among women. Ischaemic heart disease and stroke showed the highest rates of death, YLLs, and DALYs among both men and women. In 2019, the highest age-standardised rates of DALYs were attributable to high systolic blood pressure and dietary risks. Interpretation Although Mongolia saw substantial improvements across many communicable diseases, maternal and neonatal disorders, and under-5 mortality between 1990 and 2019, non-communicable diseases remained leading causes of mortality. The mortality from the most preventable causes such as injury, alcohol use, and dietary risks remain substantially high, suggesting that individual and social efforts are needed to tackle these diseases. Our analyses will support the development of policy priorities and action plans in multiple sectors to improve the overall health of the Mongolian population. Funding Bill & Melinda Gates Foundation.

A Retrospective Cohort Study of the Association between Serum Osteopontin Levels and Aortic Stiffness in Hypertensive Patients

By suppressing mineralization and preventing ectopic calcium deposits, osteopontin (OPN) has an inhibitory effect on vascular calcification. Also, there is an association between OPN and aortic stiffness (AS). We aimed to investigate the association between serum OPN levels and AS measured by carotid–femoral pulse wave velocity (cfPWV) in hypertensive patients. Baseline characteristics and fasting blood sampling of 120 participants with hypertension and 120 participants without hypertension were acquired. Serum OPN concentrations were determined by enzyme-linked immunosorbent assay. In total, 43 (35.9%) participants were assigned to the AS group with cfPWV of >10 m/s in hypertensive patients. There were more patients with diabetes mellitus, old age, high systolic blood pressure, high serum intact parathyroid hormone (iPTH), elevated C-reactive protein, and high OPN levels in the AS group compared with the control group in hypertensive participants. A multivariate logistic regression analysis discloses that age, SBP, serum OPN, and iPTH levels were independently associated with AS in hypertensive patients. Moreover, according to a multivariate forward stepwise linear regression analysis, OPN level is positively associated with cfPWV. In conclusion, serum OPN level is assumed to be a potential biomarker to predict AS and is positively associated with cfPWV in patients with hypertension.

Colorado Burden of Disease, Injuries and Risk Factors, 1990–2019: A Sub-Analysis of the Global Burden of Disease Study

(1) Background: Health disparities across the United States (U.S.) are increasing. Large variations in risk factors and health outcomes have been described among states from the U.S. (2) AIM. This study aims to describe health trends in morbidity, mortality, and risk factors from 1990 to 2019 in the State of Colorado. (3) Methods: We describe the measures of health loss for 286 causes of death, 369 diseases and injuries, and 87 risk factors for the state of Colorado from the Global Burden of Disease project estimates between 1990 to 2019. (4) Results: We found that 21,171 and 40,724 deaths were estimated in 1990 and 2019, respectively, in Colorado. The leading cause of death, in both sexes, in 1990 and 2019 was ischemic heart disease (IHD). The top leading disability-adjusted life years (DALY) diagnoses were IHD, followed by low back pain, chronic obstructive pulmonary disease, and opioid use disorder. In 2019, the top risk factors by DALYs in Colorado were smoking, drug use, high body mass index (BMI), alcohol use, high fasting plasma glucose, and high systolic blood pressure. (5) Conclusion: Non-communicable diseases and their related risk factors are the top leading causes of DALYs in Colorado. Findings support the need for policies to prevent non-communicable diseases, with special attention to musculoskeletal disorders and interventions to reduce tobacco, alcohol, and drug use.

Angiotensin-(3–4) (Val-Tyr) Normalizes the Elevated Arterial Blood Pressure and Abnormal Na+/Energy Handling Associated With Chronic Undernutrition by Counteracting the Effects Mediated by Type 1 Angiotensin II Receptors

Purpose To investigate the mechanisms by which chronic administration of a multideficient diet after weaning alters bodily Na+ handling, and culminates in high systolic blood pressure (SBP) at a juvenile age.Methods From 28 to 93 days of age, weaned male Wistar rats were given a diet with low content and poor-quality protein, low lipid, without vitamin supplementation, which mimics the diets consumed in impoverished regions worldwide. We measured food, energy and Na+ ingestion, together with urinary Na+ excretion, Na+ density (Na+ intake/energy intake), plasma Na+ concentration, SBP), and renal proximal tubule Na+-transporting ATPases. Results Undernourished rats aged 93 days had only one-third of the control body mass, lower plasma albumin, higher SBP, higher energy intake, and higher positive Na+ balance accompanied by decreased plasma Na+ concentration. SBP was normalized with Losartan and with Ang-(3–4), and the combination of the 2 substances induced an accentuated negative Na+ balance as a result of strong inhibition of Na+ ingestion. Na+ density in undernourished rats was higher than in control, irrespective of the treatment, and they had downregulated (Na++K+)ATPase and upregulated Na+-ATPase in proximal tubule cells, which returned to control levels after Losartan or Ang-(3–4).Conclusions Na+ density, not only Na+ ingestion, plays a central role in the pathophysiology of elevated SBP in chronically undernourished rats. The observations that Losartan and Ang-(3–4) normalized SBP together with Na+ distribution and handling give support to the proposal that Ang IIÞAT1R and Ang IIÞAT2R axes have opposite roles within the renin-angiotensin-aldosterone system of undernourished juvenile rats.

Heavy Disease Burden of High Systolic Blood Pressure During 1990-2019: Highlighting Regional, Sex, and Age Specific Strategies in Blood Pressure Control

Objective: High systolic blood pressure (HSBP) remains the leading risk factor for mortality worldwide; however, limited data have revealed all-cause and cause-specific burdens attributed to HSBP at global and regional levels. This study aimed to estimate the global burden and priority diseases attributable to HSBP by region, sex, and age.Methods: Based on data and evaluation methods from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, we estimated trends of age-standardized mortality rate (ASMR), the age-standardized rate of disability-adjusted life years (ASDRs), and the age-standardized rate of years lived with disability (ASYRs) attributable to HSBP during 1990-2019. Further, we analyzed cause-specific burdens attributable to HSBP by sex, age, year, and region.Results: Globally, a significant downtrend was found in the ASMR attributed to HSBP while ASYRs did not change substantially during 1990-2019. The majority of HSBP burden has shifted from high-middle sociodemographic index (SDI) regions to lower SDI regions. All-cause and most cause-specific burdens related to HSBP were improved in high SDI regions but the downtrends have stagnated in recent years. Although many cause-specific deaths associated with HSBP declined, chronic kidney disease (CKD) and endocarditis associated deaths were aggravated globally and ischemic heart disease (IHD), atrial fibrillation and flutter, aortic aneurysm (AA), and peripheral artery disease (PAD) associated deaths were on the rise in low/low-middle/middle SDI regions. Additionally, males had higher disease burdens than females. Middle-aged people with CVDs composed the major subgroup affected by HSBP while older people had the highest ASMRs associated with HSBP.Conclusions: This study revealed the global burden and priority diseases attributable to HSBP with wide variation by region, sex, and age, calling for effective and targeted strategies to reduce the prevalence and mortality of HSBP, especially in low/low-middle/middle SDI regions.

Reaching 80 Years of Age: Clinical, Behavioral, and Psychosocial Related Risk Factors in a Large Cohort of Israeli Working Men

The objective of this study was to estimate the probability of long-term overall survival based on total number of risk factors (RF). We also sought to examine the role of midlife clinical, behavioral, and psychosocial predictors of longevity in a large cohort of Israeli men. This study was based on the Israeli Ischemic Heart Disease (IIHD) cohort that included over 10,000 men who were followed up for mortality over more than four decades. During the 43 years of follow-up, 4634 (46.1%) men survived to 80 years of age or older. We considered cigarette smoking, diabetes mellitus, high systolic blood pressure, hypercholesterolemia, low socioeconomic status, and serious family problems as RF at ages 40–65. Cox proportional hazards regression models, with age as the time scale, were constructed to estimate the hazard ratios (HRs) for failure to survive 80 years of age. Compared with men free of all the above RF, those with one identified RF (HR = 1.58, 95% CI: 1.42–1.75) and counterparts with two identified RF (HR = 2.18, 95% CI: 1.96–2.43) were at a significantly greater risk of death before 80. Additional RF further increased the risk of early mortality (HR = 3.62, 95% CI: 1.50–8.73 for men with 5 RF). The results suggest a role of physiological, behavioral, and psychological risk factors at midlife in predicting longevity.

Novel CUL3 Variant Causing Familial Hyperkalemic Hypertension Impairs Regulation and Function of Ubiquitin Ligase Activity

Familial hyperkalemic hypertension is caused by pathogenic variants in genes of the CUL3 (cullin-3)-KLHL3 (kelch-like-family-member-3)-WNK (with no-lysine [K] kinase) pathway, manifesting clinically as hyperkalemia, metabolic acidosis, and high systolic blood pressure. The ubiquitin E3 ligase CUL3-KLHL3 targets WNK kinases for degradation to limit activation of the thiazide-sensitive NCC (Na-Cl cotransporter). All known variants in CUL3 lead to exon 9 skipping (CUL3Δ9) and typically result in severe familial hyperkalemic hypertension and growth disturbances in patients. Whether other variants in CUL3 cause familial hyperkalemic hypertension is unknown. Here, we identify a novel de novo heterozygous CUL3 variant (CUL3Δ474–477) in a pediatric familial hyperkalemic hypertension patient with multiple congenital anomalies and reveal molecular mechanisms by which CUL3Δ474–477 leads to dysregulation of the CUL3-KLHL3-WNK signaling axis. Using patient-derived urinary extracellular vesicles and dermal fibroblasts, in vitro assays, and cultured kidney cells, we demonstrate that CUL3Δ474–477 causes reduced total CUL3 levels due to increased autoubiquitination. The CUL3Δ474–477 that escapes autodegradation shows enhanced modification with NEDD8 (neural precursor cell expressed developmentally down-regulated protein 8) and increased formation of CUL3-KLHL3 complexes that are impaired in ubiquitinating WNK4. Proteomic analysis of CUL3 complexes revealed that, in addition to increased KLHL3 binding, the CUL3Δ474–477 variant also exhibits increased interactions with other BTB (Bric-a-brac, Tramtrack, and Broad complex) substrate adaptors, providing a rationale for the patient’s diverse phenotypes. We conclude that the pathophysiological effects of CUL3Δ474–477 are caused by reduced CUL3 levels and formation of catalytically impaired CUL3 ligase complexes.