Alanna A. Morris

Vitamin D Status Is Associated With Arterial Stiffness and Vascular Dysfunction in Healthy Humans

OBJECTIVES The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults. BACKGROUND Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function. METHODS We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness. RESULTS Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (β = 0.1, p = 0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09, p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02). CONCLUSIONS Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.

Oxidative stress is associated with impaired arterial elasticity

AIMS Arterial stiffening may lead to hypertension, greater left ventricular after-load and adverse clinical outcomes. The underlying mechanisms influencing arterial elasticity may involve oxidative injury to the vessel wall. We sought to examine the relationship between novel markers of oxidative stress and arterial elastic properties in healthy humans. METHODS AND RESULTS We studied 169 subjects (mean age 42.6 ± 14 years, 51.6% male) free of traditional cardiovascular risk factors. Indices of arterial stiffness and wave reflections measured included carotid-femoral Pulse Wave Velocity (PWV), Augmentation Index (Aix) and Pulse Pressure Amplification (PPA). Non-free radical oxidative stress was assessed as plasma oxidized and reduced amino-thiol levels (cysteine/cystine, glutathione/GSSG) and their ratios (redox potentials), and free radical oxidative stress as derivatives of reactive oxygen metabolites (dROMs). Inflammation was assessed as hsCRP and interleukin-6 levels. The non-free radical marker of oxidative stress, cystine was significantly correlated with all arterial indices; PWV (r=0.38, p<0.001), Aix (r=0.35, p<0.001) and PPA (r=-0.30, p<0.001). Its redox potential, was also associated with PWV (r=0.22, p=0.01), while the free radical marker of oxidative stress dROMS was associated with Aix (r=0.25, p<0.01). After multivariate adjustment for age, gender, arterial pressure, height, weight, heart rate and CRP, of these oxidative stress markers, only cystine remained independently associated with PWV (p=0.03), Aix (p=0.01) and PPA (p=0.05). CONCLUSIONS In healthy subjects without confounding risk factors or significant systemic inflammation, a high cystine level, reflecting extracellular oxidant burden, is associated with increased arterial stiffness and wave reflections. This has implications for understanding the role of oxidant burden in pre-clinical vascular dysfunction.

Racial differences in arterial stiffness and microcirculatory function between Black and White Americans.

Background Compared with whites, black Americans suffer from a disproportionate burden of cardiovascular disease (CVD). We hypothesized that racial differences in the prevalence of CVD could be attributed, in part, to impaired vascular function in blacks after adjustment for differences in risk factor burden. Methods and Results We assessed vascular function in 385 black and 470 white subjects (mean age, 48±11 years; 45% male). Using digital pulse amplitude tonometry (EndoPAT) we estimated the reactive hyperemia index (RHI), a measure of microvascular endothelial function, and peripheral augmentation index (PAT‐AIx). Central augmentation index (C‐AIx) and pulse‐wave velocity (PWV) were measured as indices of wave reflections and arterial stiffness, respectively, using applanation tonometry (Sphygmocor). Compared with whites, blacks had lower RHI (2.1±0.6 versus 2.3±0.6, P<0.001), greater arterial wave reflections assessed as both PAT‐AIx (20.4±21.5 versus 17.0±22.4, P=0.01) and CAIx (20.8±12.3 versus 17.5±13.3, P=0.001), and greater arterial stiffness, measured as PWV (7.4±1.6 versus 7.1±1.6 m/s, P=0.001). After adjustment for traditional CVD risk factors, black race remained a significant predictor of lower RHI and higher PAT‐AIx and CAIx (all P<0.001) in all subjects and of higher PWV in men (P=0.01). Furthermore, these associations persisted in a subgroup analysis of “healthy” individuals free of CVD risk factors. Conclusion Black race is associated with impaired microvascular vasodilatory function, and greater large arterial wave reflections and stiffness. Because impairment in these vascular indices may be associated with worse long‐term outcomes, they may represent underlying mechanisms for the increased CVD risk in blacks.

Association between Depression and Inflammation - Differences by Race and Sex: The META-Health Study

Objective: To test whether the association between depression and inflammation differs by race and sex. Depressive symptoms have been associated with higher levels of C-reactive protein (CRP). However, few studies have examined this association in samples including a significant number of African Americans, or examined whether the association differs by race and sex. Methods: Depressive symptoms and CRP were assessed in 512 African American and white participants, age 30 to 65 years, as part of the community-based Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study. Depression was determined by responses to the Beck Depression Inventory II (BDI-II). Multivariable linear regression models were used to adjust for demographic and metabolic risk factors. Results: African American men had higher total BDI-II scores than white men (p =.03), whereas there was no difference in women. There was a significant race-sex-depression interaction in predicting CRP levels (p =.02). White women with mild to severe depressive symptoms had higher levels of CRP compared with those with minimal to no depressive symptoms (p <.05). There were no differences in levels of CRP by severity of depressive symptoms in white men or African Americans of either sex. Higher BDI-II scores were related to higher CRP levels in white women after adjusting for age and level of education (&bgr; = 0.227, p =.006). However, the association was eliminated after further adjustment for metabolic risk factors (&bgr; = 0.077, p =.35). Conclusions: Although depressive symptoms are associated with inflammation, the association varies by race and sex.CVD = cardiovascular disease; BDI-II = Beck Depression Inventory II; CRP = C-reactive protein; BMI = body mass index; HDL-C = high-density lipoprotein cholesterol

The Association between Depression and Leptin is Mediated by Adiposity

Objective Animal models suggest that impaired leptin production, or leptin resistance despite increased leptin levels, may contribute to depression. The link between leptin and depression could be mediated by obesity, which is more common in depression and increases leptin production. Methods We administered the Beck Depression Inventory–II (BDI-II) to 537 participants (mean [standard deviation (SD)] age = 51 [9] years; female, 61%) enrolled in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study. Leptin levels were examined as continuous log-transformed values. Results Participants with moderate to severe depression had higher levels of leptin (median [interquartile range] 37.7 [17.6–64.9] ng/mL) than those with mild depression (22.9 [7.0–57.9] ng/mL) or minimal to no depression (19.8 ng/mL [7.8–39.1], p = .003). Participants with moderate to severe depression had higher body mass index (BMI) than those with mild or minimal depression (mean [SD] = 33 [8] versus 31 [9] versus 29 [7] kg/m2, p = .001). After multivariate adjustment for age, sex, race, smoking status, hypertension, diabetes, blood pressure, lipids, and C-reactive protein, the BDI-II score remained a significant predictor of leptin levels (&bgr; = 0.093, p = .01). Further adjustment for BMI eliminated the association between the BDI-II score and leptin (&bgr; = 0.03, p = .3). Adjusting for waist circumference in place of BMI revealed similar findings. Conclusions The association between depression and leptin seems to be mediated by increased adiposity in depressed individuals. Abbreviations BDI-II = Beck Depression Inventory–II BMI = body mass index HDL-C = high-density lipoprotein cholesterol

Differences in weight perception among blacks and whites.

BACKGROUND The prevalence of obesity is higher in blacks than whites, especially in black women, and is known to be associated with major cardiovascular disease risk factors, which are also more prevalent in blacks than whites. Weight perception may contribute to these differences if blacks are more likely to underestimate their weight. We explored race and gender differences in underestimation of weight using body mass index (BMI) and waist circumference (WC), after adjusting for other cardiovascular risk factors. METHODS AND RESULTS We studied 219 white and 240 black women and men as part of the META-Health Study. Perceived weight was assessed over the phone and categorized into three categories: underweight or normal weight, overweight, or obesity. Height, weight, and WC were measured at a subsequent visit, and BMI was calculated. Logistic regression was used to compare the likelihood of underestimating actual weight category by race, before and after adjusting for sociodemographic, lifestyle factors, and medical history. In multivariate analysis, the odds of underestimating BMI category was greater than threefold in blacks compared with whites (OR 3.1, 95% CI 1.9-4.8) and was larger for black women than for black men (p<0.01 for interaction). When abdominal adiposity was taken into account by utilizing WC as a measure of weight, the observed difference in weight underestimation remained. CONCLUSION Our data reveal a significant misperception of weight among blacks, particularly black women, who have the highest burden of obesity. A multifaceted approach with efficient identification of social, cultural, and environmental factors that give rise to obesity tolerance in blacks will provide potential targets for intervention, which may ameliorate weight misperception and the prevalence of excess weight in the black population.

Differences in Systemic Oxidative Stress Based on Race and the Metabolic Syndrome: The Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study

BACKGROUND Classification schema such as metabolic syndrome may underestimate cardiovascular disease (CVD) risk in African Americans, despite a higher burden of CVD in African Americans. Oxidative stress results from an imbalance of prooxidants and antioxidants and leads to endothelial dysfunction that promotes vascular inflammation and atherosclerosis. Aminothiol markers of oxidative stress are associated with CVD risk factors and metabolic syndrome; however, little is known about racial differences in levels of oxidative stress. We sought to investigate whether oxidative stress would be higher in African Americans compared to whites independently of traditional risk factor burden. METHODS We assessed oxidative stress in a biracial, community-based cohort. In 620 subjects (59% female, 52% African American) in the Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) study, we measured plasma levels of glutathione, an intracellular antioxidant, and its redox potential as a ratio of reduced and oxidized glutathione (E(h) glutathione). RESULTS African Americans had lower glutathione levels (P<0.001) compared to whites. There was a trend toward more oxidized E(h) glutathione (P = 0.07) in African Americans; however, this did not reach statistical significance. After adjustment for demographics and CVD risk factors, African-American race remained a significant correlate of lower glutathione levels (P<0.001) and a more oxidized E(h) glutathione (P = 0.04). After further adjustment for high-sensitivity C-reactive protein (hsCRP), glutathione remained significantly lower in African Americans (P = 0.001). African Americans with or without metabolic syndrome had lower glutathione levels compared to whites with or without metabolic syndrome, respectively (both P ≤ 0.001), and African Americans without metabolic syndrome had a more oxidized E(h) glutathione compared to whites without metabolic syndrome (P = 0.003). CONCLUSIONS African Americans have higher levels of oxidative stress than whites, even after adjustment for differences in CVD risk factors and inflammation. Racial differences in oxidative stress may play a key role in understanding observed racial disparities in CVD.

Validation of clinical scores for right ventricular failure prediction after implantation of continuous-flow left ventricular assist devices.

BACKGROUND Several clinical prediction schemes for right ventricular failure (RVF) risk after left ventricular assist device (LVAD) implantation have been developed in both the pulsatile- and continuous-flow LVAD eras. The performance of these models has not been evaluated systematically in a continuous-flow LVAD cohort. METHODS We evaluated 6 clinical RVF prediction models (Michigan, Penn, Utah, Kormos et al, CRITT, Pittsburgh Decision Tree) in 116 patients (age 51 ± 13 years; 41.4% white and 56.0% black; 66.4% men; 56.0% bridge to transplant, 37.1% destination therapy, 17.4% bridge to decision) who received a continuous-flow LVAD (HeartMate II: 79 patients, HeartWare: 37 patients) between 2008 and 2013. RESULTS Overall, 37 patients (31.9%) developed RVF, defined: as pulmonary vasodilator use for ≥48 hours or inotrope use for ≥14 days post-operatively; re-institution of inotropes; multi-organ failure due to RVF; or need for mechanical RV support. Median (Quartile 1 to Quartile 3) time to initial discontinuation of inotropes was 6 (range 4 to 8) days. Among scores, the Michigan score reached significance for RVF prediction but discrimination was modest (C = 0.62 [95% CI 0.52 to 0.72], p = 0.021; positive predictive value [PPV] 60.0%; negative predictive value [NPV] 75.8%), followed by CRITT (C = 0.60 [95% CI 0.50 to 0.71], p = 0.059; PPV 40.5%; NPV 72.2%). Other models did not significantly discriminate RVF. The newer, INTERMACS 3.0 definition for RVF, which includes inotropic support beyond 7 days, was reached by 57 patients (49.1%). The Kormos model performed best with this definition (C = 0.62 [95% CI 0.54 to 0.71], p = 0.005; PPV 64.3%; NPV 59.5%), followed by Penn (C = 0.61), Michigan (C = 0.60) and CRITT (C = 0.60), but overall score performance was modest. CONCLUSION Current schemes for post-LVAD RVF risk prediction perform only modestly when applied to external populations.

Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.

IMPORTANCE Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown. OBJECTIVE To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTS In a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012. INTERVENTIONS Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURES The primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTS Of the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, -6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, -0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, -0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups. CONCLUSIONS AND RELEVANCE Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01041417.

Gender differences in the risk of stroke during support with continuous-flow left ventricular assist device

BACKGROUND There is increasing recognition that the risk of stroke after left ventricular assist device (LVAD) implantation varies based on gender, with a higher risk in female patients. We reviewed our own data to determine gender differences in the risk of stroke. METHODS Frequency of stroke, including intracranial hemorrhage and ischemic stroke, was retrospectively evaluated in 110 heart failure patients (mean age 49.6 ± 13.6 years, 32% women) discharged from the hospital after implantation of a HeartMate II (N = 74) or HeartWare (N = 36) LVAD. Competing outcomes analysis was used to determine which clinical risk factors were associated with the risk of stroke and death, with the primary end-point being time to first stroke event. RESULTS During a median follow-up of 1.3 years, 26 patients had a stroke (23.6%, 0.14 case per person-year). The median time to first stroke was 0.7 (interquartile range 0.3 to 1.4) years. After adjusting for covariates, risk of stroke was higher for women than for men (hazard ratio 3.1, 95% confidence interval 1.4 to 6.9; p = 0.007). There was no difference in overall survival between men and women. CONCLUSION The risk of stroke after LVAD varies based on gender, with a higher risk in female patients. More research is needed to fully understand these differences, and whether device management strategies should be tailored based on gender.