Physiological Role of Serum Growth Differentiation Factor-15 (GDF-15) Level and Iron Metabolism in Community-Dwelling Older Adults.

Background Anemia is common in older adults and, together with heart failure and chronic kidney disease, forms a vicious cycle, whereas diseases such as chronic inflammation and cancer are associated with the anemia of chronic disease (ACD). Researchers have linked growth differentiation factor-15 (GDF-15) to a variety of conditions such as cardiovascular disease, inflammation, cancer, and kidney disease, and have reported hepcidin as a biomarker for iron regulation in ACD. Therefore, anemia, GDF-15, and hepcidin have significance in aging physiology. Hypothesis GDF-15 and hepcidin play important physiological roles in community-dwelling older adults. This study sought to explore the relationship between these biomarkers and anemia, inflammation, or other health outcomes. Methods This was a prospective study of 73 community-dwelling older adults (six men and 67 women, mean age of 76.3 years). Their serum iron level, percentage transferrin saturation (TSAT), high-sensitivity C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) were measured. Enzyme-linked immunosorbent assays were used to assess their serum GDF-15, ferritin, and hepcidin levels. The participants' grip strength and walking speed were measured. The skeletal muscle mass index (SMI) of each participant was determined by bioelectrical impedance analysis. Results The GDF-15 level was significantly inversely correlated with serum iron, ferritin, and hepcidin levels; percentage TSAT; the eGFR; and gait speed. Serum hepcidin was positively correlated with levels of ferritin, albumin, and hemoglobin. Handgrip strength, SMI, and hs-CRP were not correlated with either GDF-15 or hepcidin levels. After adjusting for age, sex, and body mass index (BMI), multivariate analysis identified the log GDF-15 and serum iron level (log GDF-15: ß=-0.248, iron: ß=0.296) as significant factors determining hemoglobin levels, whose findings have significance due to novel results. Multivariate analysis identified eGFR and levels of hemoglobin and hepcidin as significant factors associated with log GDF-15 (eGFR: ß=-0.406, hemoglobin: ß=-0.269, hepcidin: ß=-0.235). Similarly, ferritin and albumin levels were identified as significant factors associated with hepcidin levels (ferritin: ß=0.590, Alb: ß=0.277). Conclusions Anemia in community-dwelling older adults was determined not only by increasing serum iron levels but also by decreasing GDF-15 levels. Also, the increasing GDF-15 level was determined by a decreasing hepcidin level as well as the presence of anemia and renal dysfunction, and the decreasing hepcidin level was determined by decreasing stored iron and decreasing albumin levels. Serum GDF-15 and hepcidin could potentially inform diagnostic or treatment strategies for anemia or age-related health conditions.

Flow-Mediated Vasodilation and Reactive Hyperemia Index in Heart Failure with Reduced or Preserved Ejection Fraction.

Vascular endothelial dysfunction is part of the underlying pathophysiology of heart failure. However, there are no reports in which vascular endothelial function of both conduit arteries and microvasculature was assessed in patients with heart failure. This study was aimed to assess vascular endothelial function separately in heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF). We performed simultaneous measurement of both flow-mediated vasodilation for endothelial function of conduit arteries and reactive hyperemia-peripheral arterial tonometry for that of microvasculature in 88 consecutive patients with chronic heart failure. In 55 patients with ischemic heart disease as an underlying cause of heart failure, flow-mediated vasodilation value was comparable between the two groups of HFrEF (left ventricular ejection fraction < 50%, n = 31) and HFpEF (left ventricular ejection fraction ≥ 50%, n = 24). Reactive hyperemia index measured by reactive hyperemia peripheral arterial tonometry, however, was lower in HFrEF patients compared to HFpEF patients (P = 0.014). In contrast, among 33 patients with non-ischemic heart disease, the degree of flow-mediated vasodilation was lower in HFpEF patients (n = 18) compared with HFrEF patients (n = 15) (P = 0.009), while reactive hyperemia index was comparable between the two groups. The clinical and pathophysiological significance of endothelial function in heart failure differs between conduit artery and microvasculature, and these differences may contribute to the underlying pathophysiology of HFpEF and HFrEF, as well as in ischemic heart disease and non-ischemic heart disease.

Relationship between brachial flow-mediated dilation and carotid intima-media thickness in patients with coronary artery disease.

BACKGROUND: Although flow-mediated vasodilation (FMD) of brachial artery and carotid intima-media thickness (IMT) are important surrogate markers in the process of atherosclerosis, information about relationship between both markers is insufficient. In the present study, we assessed extensively the relationship in patients with coronary artery disease (CAD). METHODS: The values of brachial FMD and carotid ultrasonography findings in 159 patients (67±8 years, 130 males) with angiographically verified CAD were retrospectively analyzed. RESULTS: In all patients, mean carotid IMT tended to be correlated with FMD, although the correlation was not statistically significant (R=-0.149, P=0.061). Maximum IMT was not correlated with the FMD (R=0.053, P=0.508). In addition, carotid artery diameter was significantly correlated with the FMD (R=0.290, P=0.0002). Prevalence of high IMT value (≥1.0 mm) was higher in the abnormal FMD group (4%>; N.=67), compared with the normal FMD group (≥7%; N.=24; P<0.05). Carotid artery diameter was larger in abnormal FMD group, compared with both groups of normal FMD (P<0.01) and borderline FMD (4-7%; N.=68) (P<0.01). In all patients, receiver operating characteristics analysis demonstrated that cut-off value of FMD to predict the prevalence of ischemic stroke was 3.7% (AUC=0.735, P<0.001). The cut-off value of maximum IMT was 1.9 mm, but was not significant (AUC=0.522, P=0.829). CONCLUSIONS: Brachial FMD and carotid IMT would be different in clinical significance as a surrogate marker for pathophysiology of atherosclerotic disease.

The comparison of endothelial function between conduit artery and microvasculature in patients with coronary artery disease.

BACKGROUND: Flow-mediated dilation (FMD) and reactive hyperemia-peripheral arterial tonometry (RH-PAT) are both established modalities to assess vascular endothelial function. However, clinical significance of FMD and RH-PAT may be different because these methods measure vascular function in different vessels (conduit arteries and resistance vessels). METHODS: To elucidate differences in the clinical significance of FMD and RH-PAT, a simultaneous determination of FMD was performed and reactive hyperemia index (RHI) measured by RH-PAT in 131 consecutive patients who underwent coronary angiography for suspicion of coronary artery disease (CAD). RESULTS: There was no significant correlation between FMD and RHI in patients overall. When patients were divided into four groups: FMD ≥ 6%/RHI ≥ 1.67 group, FMD ≥ 6%/RHI < 1.67 group, FMD < 6%/RHI ≥ 1.67 group and FMD < 6%/RHI < 1.67 group, the highest incidence of multivessel CAD was seen in the FMD < 6%/RHI < 1.67 group (52%). Multiple logistic regression analysis showed that a prevalence of both FMD < 6% and RHI < 1.67 was an independent predictor of multivessel CAD (odds ratio: 4.160, 95% confidence interval: 1.505-11.500, p = 0.006). RHI was negatively correlated with the baseline vessel diameter (R = -0.268, p = 0.0065) and maximum vessel diameter (R = -0.266, p = 0.0069) in patients with FMD < 6%, whereas these correlations were absent in patients with FMD ≥ 6%. CONCLUSIONS: Present results suggest that noninvasive assessment of vascular endothelial functions provide pathophysiological information on both conduit arteries and resistance vessels in patients with CAD.