All Publications

  • Antihypertensive Medication and Fracture Risk in Older Veterans Health Administration Nursing Home Residents. JAMA internal medicine Dave, C. V., Li, Y., Steinman, M. A., Lee, S. J., Liu, X., Jing, B., Graham, L. A., Marcum, Z. A., Fung, K. Z., Odden, M. C. 2024


    Limited evidence exists on the association between initiation of antihypertensive medication and risk of fractures in older long-term nursing home residents.To assess the association between antihypertensive medication initiation and risk of fracture.This was a retrospective cohort study using target trial emulation for data derived from 29 648 older long-term care nursing home residents in the Veterans Health Administration (VA) from January 1, 2006, to October 31, 2019. Data were analyzed from December 1, 2021, to November 11, 2023.Episodes of antihypertensive medication initiation were identified, and eligible initiation episodes were matched with comparable controls who did not initiate therapy.The primary outcome was nontraumatic fracture of the humerus, hip, pelvis, radius, or ulna within 30 days of antihypertensive medication initiation. Results were computed among subgroups of residents with dementia, across systolic and diastolic blood pressure thresholds of 140 and 80 mm Hg, respectively, and with use of prior antihypertensive therapies. Analyses were adjusted for more than 50 baseline covariates using 1:4 propensity score matching.Data from 29 648 individuals were included in this study (mean [SD] age, 78.0 [8.4] years; 28 952 [97.7%] male). In the propensity score-matched cohort of 64 710 residents (mean [SD] age, 77.9 [8.5] years), the incidence rate of fractures per 100 person-years in residents initiating antihypertensive medication was 5.4 compared with 2.2 in the control arm. This finding corresponded to an adjusted hazard ratio (HR) of 2.42 (95% CI, 1.43-4.08) and an adjusted excess risk per 100 person-years of 3.12 (95% CI, 0.95-6.78). Antihypertensive medication initiation was also associated with higher risk of severe falls requiring hospitalizations or emergency department visits (HR, 1.80 [95% CI, 1.53-2.13]) and syncope (HR, 1.69 [95% CI, 1.30-2.19]). The magnitude of fracture risk was numerically higher among subgroups of residents with dementia (HR, 3.28 [95% CI, 1.76-6.10]), systolic blood pressure of 140 mm Hg or higher (HR, 3.12 [95% CI, 1.71-5.69]), diastolic blood pressure of 80 mm Hg or higher (HR, 4.41 [95% CI, 1.67-11.68]), and no recent antihypertensive medication use (HR, 4.77 [95% CI, 1.49-15.32]).Findings indicated that initiation of antihypertensive medication was associated with elevated risks of fractures and falls. These risks were numerically higher among residents with dementia, higher baseline blood pressures values, and no recent antihypertensive medication use. Caution and additional monitoring are advised when initiating antihypertensive medication in this vulnerable population.

    View details for DOI 10.1001/jamainternmed.2024.0507

    View details for PubMedID 38648065

    View details for PubMedCentralID PMC11036308

  • Plasma proteomic signature of human longevity. Aging cell Liu, X., Axelsson, G. T., Newman, A. B., Psaty, B. M., Boudreau, R. M., Wu, C., Arnold, A. M., Aspelund, T., Austin, T. R., Gardin, J. M., Siggeirsdottir, K., Tracy, R. P., Gerszten, R. E., Launer, L. J., Jennings, L. L., Gudnason, V., Sanders, J. L., Odden, M. C. 2024: e14136


    The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3067 participants from the Cardiovascular Health Study (discovery cohort) and 4690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (replication cohort). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the replication cohort and 105 were replicated (corrected p value <0.05). The most significant proteins were GDF-15 and N-terminal pro-BNP in both cohorts. A parsimonious protein-based prediction model was built using 33 proteins selected by LASSO with 10-fold cross-validation and validated using 27 available proteins in the validation cohort. This protein model outperformed a basic model using traditional factors (demographics, height, weight, and smoking) by improving the AUC from 0.658 to 0.748 in the discovery cohort and from 0.755 to 0.802 in the validation cohort. We also found that the associations of 169 out of 211 proteins were partially mediated by physical and/or cognitive function. These findings could contribute to the identification of biomarkers and pathways of aging and potential therapeutic targets to delay aging and age-related diseases.

    View details for DOI 10.1111/acel.14136

    View details for PubMedID 38440820

  • Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study. Alzheimer's & dementia : the journal of the Alzheimer's Association Cronjé, H. T., Liu, X., Odden, M. C., Moseholm, K. F., Seshadri, S., Satizabal, C. L., Lopez, O. L., Bis, J. C., Djoussé, L., Fohner, A. E., Psaty, B. M., Tracy, R. P., Longstreth, W. T., Jensen, M. K., Mukamal, K. J. 2023


    Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated.We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline.In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline.Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.

    View details for DOI 10.1002/alz.13367

    View details for PubMedID 37392405

  • Systolic blood pressure, antihypertensive treatment, and cardiovascular and mortality risk in VA nursing home residents. Journal of the American Geriatrics Society Liu, X., Steinman, M. A., Lee, S. J., Peralta, C. A., Graham, L. A., Li, Y., Jing, B., Fung, K. Z., Odden, M. C. 2023


    Optimal systolic BP (SBP) control in nursing home residents is uncertain, largely because this population has been excluded from clinical trials. We examined the association of SBP levels with the risk of cardiovascular (CV) events and mortality in Veterans Affairs (VA) nursing home residents on different numbers of antihypertensive medications.Our study included 36,634 residents aged ≥65 years with a VA nursing home stay of ≥90 days from October 2006-June 2019. SBP was averaged over the first week after admission and divided into categories. Cause-specific hazard ratios (HRs) of SBP categories with CV events (primary outcome) and all-cause mortality (secondary outcome) were examined using Cox regression and multistate modeling stratified by the number of antihypertensive medications used at admission (0, 1 or 2, and ≥3 medications).More than 76% of residents were on antihypertensive therapy and 20% received ≥3 medications. In residents on antihypertensive therapy, a low SBP < 110 mmHg (compared with SBP 130 ~ 149 mmHg) was associated with a greater CV risk (adjusted HR [95% confidence interval]: 1.47 [1.28-1.68] in 1 or 2 medications group, and 1.41 [1.19-1.67] in ≥3 medications group). In residents on no antihypertensives, both low SBP < 110 mmHg and high SBP ≥ 150 mmHg were associated with higher mortality; while in residents receiving any antihypertensives, a low SBP was associated with higher mortality and the highest point estimates were for SBP < 110 mmHg (1.36 [1.28-1.45] in 1 or 2 medications group, and 1.47 [1.31-1.64] in ≥3 medications group).The associations of SBP with CV and mortality risk varied by the intensity of antihypertensive treatment among VA nursing home residents. A low SBP among those receiving antihypertensives was associated with increased CV and mortality risk, and untreated high SBP was associated with higher mortality. More research is needed on the benefits and harms of SBP lowering in long-term care populations.

    View details for DOI 10.1111/jgs.18301

    View details for PubMedID 36826917

  • Plasma proteomic signature of decline in gait speed and grip strength. Aging cell Liu, X., Pan, S., Xanthakis, V., Vasan, R. S., Psaty, B. M., Austin, T. R., Newman, A. B., Sanders, J. L., Wu, C., Tracy, R. P., Gerszten, R. E., Odden, M. C. 2022: e13736


    The biological mechanisms underlying decline in physical function with age remain unclear. We examined the plasma proteomic profile associated with longitudinal changes in physical function measured by gait speed and grip strength in community-dwelling adults. We applied an aptamer-based platform to assay 1154 plasma proteins on 2854 participants (60% women, aged 76 years) in the Cardiovascular Health Study (CHS) in 1992-1993 and 1130 participants (55% women, aged 54 years) in the Framingham Offspring Study (FOS) in 1991-1995. Gait speed and grip strength were measured annually for 7 years in CHS and at cycles 7 (1998-2001) and 8 (2005-2008) in FOS. The associations of individual protein levels (log-transformed and standardized) with longitudinal changes in gait speed and grip strength in two populations were examined separately by linear mixed-effects models. Meta-analyses were implemented using random-effects models and corrected for multiple testing. We found that plasma levels of 14 and 18 proteins were associated with changes in gait speed and grip strength, respectively (corrected p < 0.05). The proteins most strongly associated with gait speed decline were GDF-15 (Meta-analytic p = 1.58 × 10-15 ), pleiotrophin (1.23 × 10-9 ), and TIMP-1 (5.97 × 10-8 ). For grip strength decline, the strongest associations were for carbonic anhydrase III (1.09 × 10-7 ), CDON (2.38 × 10-7 ), and SMOC1 (7.47 × 10-7 ). Several statistically significant proteins are involved in the inflammatory responses or antagonism of activin by follistatin pathway. These novel proteomic biomarkers and pathways should be further explored as future mechanisms and targets for age-related functional decline.

    View details for DOI 10.1111/acel.13736

    View details for PubMedID 36333824

  • PLASMA PROTEOMIC SIGNATURE OF DECLINE IN GAIT SPEED AND GRIP STRENGTH Liu, X., Pan, S., Xanthakis, V., Ramachandran, V., Newman, A., Sanders, J., Austin, T., Odden, M. OXFORD UNIV PRESS. 2022: 215
  • Association of Peripheral Lymphocyte Subsets with Cognitive Decline and Dementia: The Cardiovascular Health Study. Journal of Alzheimer's disease : JAD Fohner, A. E., Sitlani, C. M., Buzkova, P., Doyle, M. F., Liu, X., Bis, J. C., Fitzpatrick, A., Heckbert, S. R., Huber, S. A., Kuller, L., Longstreth, W. T., Feinstein, M. J., Freiberg, M., Olson, N. C., Seshadri, S., Lopez, O., Odden, M. C., Tracy, R. P., Psaty, B. M., Delaney, J. A., Floyd, J. S. 2022

    View details for DOI 10.3233/JAD-220091

    View details for PubMedID 35527553

  • Cardiovascular Disease Risk Across a Spectrum of Adverse Plasma Lipid Combinations by Gender and Glycemic Status AMERICAN JOURNAL OF CARDIOLOGY Liu, X., Yang, Y., Kang, F., Li, J., Zhou, M., Ma, X., Yu, T., Zhang, T., Xue, F. 2019; 124 (5): 702-708


    High triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) and high non-HDL-C levels are risk factors for cardiovascular disease (CVD). It is unclear whether the combinations of their adverse changes are related with CVD risk in different gender and diabetes status, particularly in Chinese population. This study aims to evaluate the CVD risk associated with different adverse lipid combinations. A total of 38,989 participants from Chinese Multicenter Longitudinal Health Management Cohorts (mean age 42 years; 62% male) without baseline CVD were followed up for incident CVD from 2007 to 2015. Participants with various combinations of baseline TG, non-HDL-C, and HDL-C levels within- or out of range according to Adult Treatment Panel III were grouped into 8 distinct lipid categories. Cox models estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of different lipid categories for CVD. After multivariable adjustment, a low level of HDL-C combined with either a high level of non-HDL-C alone or TG alone were associated with increased CVD risk with adjusted HRs (95% CIs) of 1.77 (1.36 to 2.30) and 2.08 (1.30 to 3.34) in male participants. Diabetic participants with high non-HDL-C and low HDL-C levels (adjusted HR 2.93, 95% CI 1.15 to 7.46), and non-diabetic participants with high TG and low HDL-C levels (adjusted HR 1.73, 95% CI 1.33 to 2.26) had greater risk of incident CVD. These relations remained significant when limited analysis to participants with normal LDL-C levels of <3.4 mmol/L, indicating the various combinations of out-of-range lipid profiles other than LDL-C are associated with different CVD risk and the associations depend on gender and glycemic status.

    View details for DOI 10.1016/j.amjcard.2019.05.058

    View details for Web of Science ID 000487572700008

    View details for PubMedID 31311663

  • The associations of lipids and lipid ratios with stroke: A prospective cohort study JOURNAL OF CLINICAL HYPERTENSION Liu, X., Yan, L., Xue, F. 2019; 21 (1): 127-135


    Lipids and lipid ratios have been proven to be associated with cardiovascular disease; however, their relationships with stroke and stroke subtypes had not been fully understood. This study aims to assess the associations of lipids and lipid ratios with type-specific stroke and compare their predictive capacities for stroke occurrence. In this prospective cohort study, a total of 42 005 Chinese participants aged 20 to 80 who were free of stroke at baseline were included and selected into subgroups of stroke subtypes (ischemic, hemorrhagic, and total). Total stroke outcome included a combination of ischemic and hemorrhagic stroke. Over an average follow-up of 3.6 years, 781 participants developed stroke (623 ischemic and 158 hemorrhagic). In men, the highest TC/HDL-C quartile was significantly associated with increased ischemic stroke risk (multivariable-adjusted hazard ratio [HR], 1.52, 95% confidence interval [CI], 1.14-2.03) and total stroke risk (HR, 1.45, 95% CI, 1.12-1.87), and TC/HDL-C had the highest area under the receiver operating characteristic curve (AUC) for predicting ischemic (AUC, 0.868) and total stroke (AUC, 0.874). In women, the highest TG quartile was significantly associated with increased risk of ischemic (HR, 1.99, 95% CI, 1.11-3.59) and total stroke (HR, 1.85, 95% CI, 1.07-3.20), with AUCs of 0.850 and 0.861, respectively. No lipid variables were significantly associated with hemorrhagic stroke in both sex. In conclusion, TC/HDL-C ratio may better predict stroke risk in men, whereas TG was more valuable in predicting stroke risk in women. TC/HDL-C and TG may help to discriminate high stroke risk individuals and serve as potential targets for stroke prevention.

    View details for DOI 10.1111/jch.13441

    View details for Web of Science ID 000455593000020

    View details for PubMedID 30461182

    View details for PubMedCentralID PMC8030570

  • Salt reduction in China: a state-of-the-art review RISK MANAGEMENT AND HEALTHCARE POLICY Shao, S., Hua, Y., Yang, Y., Liu, X., Fan, J., Zhang, A., Xiang, J., Li, M., Yan, L. L. 2017; 10: 17-28


    This study aimed to reveal the latest evidence on salt reduction initiatives in China in order to identify the contextual cost-effective interventions, as well as the barriers encountered during China's long march to reach its population salt reduction goal.Population-based salt reduction has been considered as one of the most cost-effective strategies in the world for the prevention and control of noncommunicable diseases. China, along with its sustained economic growth, faces increasing burdens from chronic diseases such as cardiovascular and kidney diseases. With policy support and cross-sector collaboration, various salt reduction initiatives have been adopted in China in order to reduce such dietary risk, especially since the beginning of this millennium.This study conducted structured literature reviews in both English and Chinese databases and synthesized the latest evidence on the association of salt intake and health, as well as salt intake among Chinese and population-based salt reduction strategies in China and around the world.Dietary salt restriction has been found to contribute to the reduction of blood pressure among both the normotensives and hypertensives bringing associated reduced disease burdens and great public health benefits. With gender, ethnic, and regional variations, salt intake levels in the population in China are well above the recommended threshold and physiological need. Admittedly, excessive salt intake precipitates the high prevalence of hypertension and cardiovascular disease among the Chinese. Considering that the majority of the dietary salt is added during cooking in China, salt substitutes, salt restriction tools, and health education are the most common salt reduction initiatives with varying levels of effectiveness and acceptability among the Chinese population.Overwhelming evidence is in support of a well-coordinated nationwide salt restriction initiative as a key public health strategy for the prevention and control of hypertension and its related diseases. Orchestrated efforts from the government, industries, academia, health professionals, and the general public are required to achieve China's long-term goal for salt reduction.

    View details for DOI 10.2147/RMHP.S75918

    View details for Web of Science ID 000395323000001

    View details for PubMedID 28260957

    View details for PubMedCentralID PMC5328139