@article {8376, title = {Soluble CD14 and Risk of Heart Failure and Its Subtypes in Older Adults.}, journal = {J Card Fail}, volume = {26}, year = {2020}, month = {2020 May}, pages = {410-419}, abstract = {

BACKGROUND: CD14 is a membrane glycoprotein primarily expressed by myeloid cells that plays a key role in inflammation. Soluble CD14 (sCD14) levels carry a poor prognosis in chronic heart failure (HF), but whether elevations in sCD14 precede HF is unknown. We tested the hypothesis that sCD14 is associated with HF incidence and its subtypes independent of major inflammatory biomarkers among older adults.

METHODS AND RESULTS: We included participants in the Cardiovascular Health Study without preexisting HF and available baseline sCD14. We evaluated the associations of sCD14, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, and white blood cell count (WBC) with incident HF and subtypes using Cox regression. Among 5217 participants, 1878 had incident HF over 13.6 years (609 classifiable as HF with preserved ejection fraction [HFpEF] and 419 as HF with reduced ejection fraction [HFrEF]). After adjusting for clinical and laboratory covariates, sCD14 was significantly associated with incident HF (hazard ratio [HR]: 1.56 per doubling, 95\% confidence interval [CI]: 1.29-1.89), an association that was numerically stronger than for hsCRP (HR per doubling: 1.10, 95\% CI: 1.06-1.15), IL-6 (HR: 1.18, 95\% CI: 1.10-1.25), and WBC (HR: 1.24, 95\% CI: 1.09-1.42), and that remained significant after adjustment for the other markers of inflammation. This association for sCD14 was observed with HFpEF (HR: 1.50, 95\% CI: 1.07-2.10) but not HFrEF (HR: 0.99, 95\% CI: 0.67-1.49).

CONCLUSIONS: Plasma sCD14 was associated with incident HF independently and numerically more strongly than other major inflammatory markers. This association was only observed with HFpEF in the subset with classifiable HF subtypes. Pending replication, these findings have potentially important therapeutic implications.

}, issn = {1532-8414}, doi = {10.1016/j.cardfail.2020.03.003}, author = {Al-Kindi, Sadeer G and B{\r u}zkov{\'a}, Petra and Shitole, Sanyog G and Reiner, Alex P and Garg, Parveen K and Gottdiener, John S and Psaty, Bruce M and Kizer, Jorge R} } @article {9155, title = {The Association of Measures of Cardiovascular Autonomic Function, Heart Rate, and Orthostatic Hypotension With Incident Glucose Disorders: The Cardiovascular Health Study.}, journal = {Diabetes Care}, volume = {45}, year = {2022}, month = {2022 10 01}, pages = {2376-2382}, abstract = {

OBJECTIVE: The autonomic nervous system (ANS) innervates pancreatic endocrine cells, muscle, and liver, all of which participate in glucose metabolism. We tested whether measures of cardiovascular ANS function are independently associated with incident diabetes and annual change in fasting glucose (FG) levels as well as with insulin secretion and insulin sensitivity in older adults without diabetes.

RESEARCH DESIGN AND METHODS: Heart rate (HR) and measures of HR variability (HRV) were derived from 24-h electrocardiographic monitoring. Blood pressure, seated and standing, was measured. Cox proportional hazards models and linear mixed models were used to analyze the associations between HRV, HR, and orthostatic hypotension (SBP >20 mmHg decline) and incident diabetes or longitudinal FG change.

RESULTS: The mean annual unadjusted FG change was 1 mg/dL. Higher detrended fluctuation analyses (DFA) values, averaged over 4-11 (DFA1) or 12-20 beats (DFA2)-reflecting greater versus less organization of beat-to-beat intervals-were associated with less FG increase over time (per 1-SD increment: DFA1: -0.49 mg/dL/year [-0.96, -0.03]; DFA2: -0.55 mg/dL/year [-1.02, -0.09]). In mutually adjusted analyses, higher SD of the N-N interval (SDNN) was associated with less FG increase over time (per 1-SD increment: SDNN: -0.62 mg/dL/year [-1.22, -0.03]). Higher values of DFA1, DFA2, and SDNN were each associated with greater insulin secretion and insulin sensitivity but not with incident diabetes. We observed no association of HR or orthostatic hypotension with diabetes or FG change.

CONCLUSIONS: Specific measures of cardiac autonomic function are prospectively related to FG level changes and insulin secretion and action.

}, keywords = {Aged, Autonomic Nervous System, Blood Glucose, Diabetes Mellitus, Glucose, Heart Rate, Humans, Hypotension, Orthostatic, Insulin Resistance}, issn = {1935-5548}, doi = {10.2337/dc22-0553}, author = {Barzilay, Joshua I and Tressel, William and Biggs, Mary L and Stein, Phyllis K and Kizer, Jorge R and Shitole, Sanyog G and Bene-Alhasan, Yakubu and Mukamal, Kenneth J} } @article {9295, title = {Fasting and Postload Nonesterified Fatty Acids and Glucose Dysregulation in Older Adults.}, journal = {Am J Epidemiol}, volume = {191}, year = {2022}, month = {2022 Jun 27}, pages = {1235-1247}, abstract = {

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio~= 1.18, 95\% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio~= 1.12, 95\% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

}, keywords = {Aged, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Fatty Acids, Nonesterified, Female, Glucose, Humans, Insulin, Insulin Resistance, Male, Prospective Studies}, issn = {1476-6256}, doi = {10.1093/aje/kwac044}, author = {Shitole, Sanyog G and Biggs, Mary L and Ix, Joachim H and Fretts, Amanda M and Tracy, Russell P and Siscovick, David S and Djouss{\'e}, Luc and Mukamal, Kenneth J and Kizer, Jorge R} } @article {9905, title = {Non-Esterified Fatty Acid Profiles and Cause-Specific Mortality: The Cardiovascular Health Study.}, journal = {J Clin Endocrinol Metab}, year = {2025}, month = {2025 Mar 24}, abstract = {

CONTEXT: Total fasting non-esterified fatty acid (NEFA) levels have been associated with mortality. The corresponding associations with NEFA levels following an oral glucose tolerance test (OGTT) and with individual fasting NEFA species are unclear.

OBJECTIVE: We evaluated the associations of post-load NEFA, fasting subclasses and individual NEFA with mortality.

DESIGN AND SETTING: The Cardiovascular Health Study is a population-based cohort study of community-dwelling adults over 64 years from four US communities that began in 1989-1990. Participants had total NEFA measured enzymatically before and two hours after an OGTT from archived serum samples collected in 1996-1997. Fasting individual NEFA were also measured using gas chromatography. Cox proportional hazard models were used to evaluate adjusted hazard ratios (aHR) for mortality associated with fasting and post-load total NEFA, and fasting individual and fatty acid subclasses (saturated, monounsaturated, n-3 and n-6 polyunsaturated, and trans).

RESULTS: The final population included 1996 participants with a mean age of 78 years. 60.5\% were female. Over a median 11-year follow-up period, 1678 participants died. Total fasting NEFA was associated with higher risk of all-cause mortality (aHR per standard deviation: 1.17, 95\% CI [1.10-1.23]). Total post-load NEFA was not associated with mortality. Among subclasses, only monounsaturated fatty acid (MUFA) was associated with total mortality (aHR 1.24, 95\% CI [1.09-1.41]). For individual NEFAs, nervonic acid (aHR 1.06, 95\% CI [1.01-1.12]), petroselaidic acid (aHR 1.21, 95\% CI [1.03-1.42]) and eicosapentaenoic acid (aHR 0.90, 95\% CI [0.82-0.99]) were associated with all-cause mortality.

CONCLUSION: Individual fasting NEFAs represent attractive candidates for medical and public health interventions aimed at improving survivorship in older adults and should be investigated further.

}, issn = {1945-7197}, doi = {10.1210/clinem/dgaf182}, author = {Bene-Alhasan, Yakubu and Shitole, Sanyog G and B{\r u}zkov{\'a}, Petra and Hirsch, Calvin H and Ix, Joachim H and Kizer, Jorge R and Siscovick, David S and Matthan, Nirupa R and Lichtenstein, Alice H and Djouss{\'e}, Luc and Mukamal, Kenneth J} }