Todd S. Perlstein

Red Blood Cell Distribution Width and Mortality Risk in a Community-Based Prospective Cohort

BACKGROUND Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (eg, anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with established cardiovascular disease (CVD). It is unknown whether RDW is associated with mortality in the general population or whether this association is specific to CVD. METHODS We examined the association of RDW with all-cause mortality and with CVD, cancer, and chronic lower respiratory tract disease mortality in 15 852 adult participants in the Third National Health and Nutrition Examination Survey (1988-1994), a nationally representative sample of the US population. Mortality status was obtained by matching to the National Death Index, with follow-up through December 31, 2000. RESULTS Estimated mortality rates increased 5-fold from the lowest to the highest quintile of RDW after accounting for age and 2-fold after multivariable adjustment (P(trend) < .001 for each). A 1-SD increment in RDW (0.98%) was associated with a 23% greater risk of all-cause mortality (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.18-1.28) after multivariable adjustment. The RDW was also associated with risk of death due to CVD (HR, 1.22; 95% CI, 1.14-1.31), cancer (1.28; 1.21-1.36), and chronic lower respiratory tract disease (1.32; 1.17-1.49). CONCLUSIONS Higher RDW is associated with increased mortality risk in this large, community-based sample, an association not specific to CVD. Study of anisocytosis may, therefore, yield novel pathophysiologic insights, and measurement of RDW may contribute to risk assessment.

Uric Acid and the Development of Hypertension: The Normative Aging Study

Experimental evidence supports a causative role for uric acid in the pathogenesis of hypertension. Prospective studies have variably adjusted for relevant confounders and have been of relatively limited duration. We prospectively examined the relationship between uric acid level and the development of hypertension in the Normative Aging Study, a longitudinal cohort of healthy adult men. Of the 2280 initial men in the Normative Aging Study, 2062 had available information for inclusion in the analysis. Cox proportional hazards model was used to examine the relationship between baseline serum uric acid level and the development of hypertension adjusting for age, body mass index, abdominal circumference, smoking, alcohol, plasma triglycerides, total cholesterol, and plasma glucose. A total of 892 men developed hypertension over a mean of 21.5 years of follow-up. Serum uric acid level independently predicted the development of hypertension in age-adjusted (relative risk [RR]: 1.10; 95% CI: 1.06 to 1.15: P<0.001) and multivariable (RR: 1.05; 95% CI: 1.01 to 1.10; P=0.02) models. Among 1277 men at risk for the development of hypertension at the time of their first serum creatinine measurement, 508 (39.8%) developed hypertension over a mean of 10.3±5.5 years of follow-up. Additionally adjusting for calculated glomerular filtration rate in this subset, serum uric acid remained associated with the development of hypertension (RR: 1.06; 95% CI: 1.01 to 1.12; P=0.03). The baseline serum uric acid level is a durable marker of risk for the development of hypertension. The association is independent of elements of the metabolic syndrome, alcohol intake, and renal function.

Secondary Prevention and Mortality in Peripheral Artery Disease National Health and Nutrition Examination Study, 1999 to 2004

Background— Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease. Methods and Results— We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index ⩽0.90. Of 7458 eligible participants ≥40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to ≈7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P=0.02). Conclusions— Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality.Background— Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease. Methods and Results— We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index ≤0.90. Of 7458 eligible participants ≥40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to ≈7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P <0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P =0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P =0.02). Conclusions— Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality. # Clinical Perspective {#article-title-27}

Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism

Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter1,2 but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with sub-micron resolution3,4. Here we apply MIMS to diverse organisms, including Drosophila, mice, and humans. We test the “immortal strand hypothesis,” which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labeling mice with 15N-thymidine from gestation through post-natal week 8, we find no 15N label retention by dividing small intestinal crypt cells after 4wk chase. In adult mice administered 15N-thymidine pulse-chase, we find that proliferating crypt cells dilute label consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human hematopoietic system. These studies show that MIMS provides high-resolution quantitation of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the ‘immortal strand hypothesis’, which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with 15N-thymidine from gestation until post-natal week 8, we find no 15N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered 15N-thymidine pulse-chase, we find that proliferating crypt cells dilute the 15N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.

Serum Total Bilirubin Level and Prevalent Lower-Extremity Peripheral Arterial Disease National Health and Nutrition Examination Survey (NHANES) 1999 to 2004

Background—Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD). Methods and Results—We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [95% CI 0.85 to 0.96]) compared with women (OR 0.97 [95% CI 0.91 to 1.04]; Pinteraction=0.05), and was stronger among active smokers (OR 0.81 [95% CI 0.73 to 0.90]) compared with nonsmokers (OR 0.97 [95% CI 0.93 to 1.02]; Pinteraction<0.01). Conclusions—Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.

Cadmium exposure in association with history of stroke and heart failure.

BACKGROUND It is unclear whether environmental cadmium exposure is associated with cardiovascular disease, although recent data suggest associations with myocardial infarction and peripheral arterial disease. OBJECTIVE The objective of this study was to evaluate the association of measured cadmium exposure with stroke and heart failure (HF) in the general population. METHODS We analyzed data from 12,049 participants, aged 30 years and older, in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) for whom information was available on body mass index, smoking status, alcohol consumption, and socio-demographic characteristics. RESULTS At their interviews, 492 persons reported a history of stroke, and 471 a history of HF. After adjusting for demographic and cardiovascular risk factors, a 50% increase in blood cadmium corresponded to a 35% increased odds of prevalent stroke [OR: 1.35; 95% confidence interval (CI): 1.12-1.65] and a 50% increase in urinary cadmium corresponded to a 9% increase in prevalent stroke [OR: 1.09; 95% CI: 1.00-1.19]. This association was higher among women [OR: 1.38; 95% CI: 1.11-1.72] than men [OR: 1.30; 95% CI: 0.93-1.79] (p-value for interaction=0.05). A 50% increase in blood cadmium corresponded to a 48% increased odds of prevalent HF [OR: 1.48; 95% CI: 1.17-1.87] and a 50% increase in urinary cadmium corresponded to a 12% increase in prevalent HF [OR: 1.12; 95% CI: 1.03-1.20], with no difference in sex-specific associations. CONCLUSIONS Environmental exposure to cadmium was associated with significantly increased stroke and heart failure prevalence. Cadmium exposure may increase these important manifestations of cardiovascular disease.

Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis

AIMS The effect of resistant hypertension on outcomes in patients with atherothrombotic disease is currently unknown. Accordingly, we sought to determine the prevalence and outcomes of resistant hypertension in stable hypertensive outpatients with subclinical or established atherothombotic disease enrolled in the international Reduction of Atherothrombosis for Continued Health (REACH) registry. METHODS AND RESULTS Resistant hypertension was defined as a blood pressure ≥140/90 mmHg at baseline (≥130/80 mmHg if diabetes/renal insufficiency) with the use of ≥3 antihypertensive medications, including a diuretic. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 4 years. A total of 53 530 hypertensive patients were included. The prevalence of resistant hypertension was 12.7%; 6.2% on 3 antihypertensive agents, 4.6% on 4 agents, and 1.9% on ≥5 agents (mean: 4.7 ± 0.8). In addition to a diuretic, these patients were being treated mostly with ACE-inhibitors/angiotensin receptor blockers (90.1%), beta-blockers (67.0%), and calcium channel blockers (50.8%). Patients with resistant hypertension had a higher risk of the primary endpoint on multivariable analysis [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.02-1.20; P = 0.017], including an increased non-fatal stroke risk (HR: 1.26; 95% CI: 1.10-1.45; P = 0.0008). Hospitalizations due to congestive heart failure were higher (P < 0.0001). Patients on ≥5 agents had a higher adjusted risk for the primary endpoint when compared with those on ≤3 agents (P = 0.03). CONCLUSION The presence of resistant hypertension identifies a subgroup of patients with hypertension and atherothrombosis who are at heightened risk for adverse long-term outcomes.

Serum Total Bilirubin Level, Prevalent Stroke, and Stroke Outcomes: NHANES 1999–2004

BACKGROUND Bilirubin inhibits experimental atherosclerosis, is inversely associated with carotid plaque burden, and confers neuroprotection in experimental stroke. Clinical data addressing the association of bilirubin with stroke are not available. We hypothesized that higher bilirubin levels would be associated with reduced stroke prevalence and improved stroke outcomes. METHODS We used the National Health and Nutrition Examination Survey 1999 to 2004, a nationally representative cross-sectional examination of the United States civilian population, to examine the association of bilirubin with stroke. Of 13,214 adult participants with data on stroke history, serum total bilirubin level, and stroke risk factors, 453 reported a history of stroke. Of these, 138 participants reported an adverse stroke outcome, defined as a long-term health problem or disability due to stroke. We performed multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for demographic characteristics and stroke risk factors. RESULTS After multivariable adjustment, a 1.71 micromol/L (0.1 mg/dL) increment in bilirubin level was associated with a 9% reduced odds of stroke (OR 0.91; 95% CI, 0.86-0.96) among all participants and with a 10% reduced odds of an adverse stroke outcome (OR 0.90; 95% CI, 0.80-1.00) among participants with a history of stroke. CONCLUSIONS These results suggest that a higher serum total bilirubin level is associated with reduced stroke prevalence and improved stroke outcomes. Our findings support the hypothesis that bilirubin may protect from stroke events and from neurologic damage in stroke.

Smoking, Metalloproteinases, and Vascular Disease

Smoking causes up to 11% of total global cardiovascular deaths. Smoking has numerous effects that may promote atherosclerosis through vascular inflammation and oxidative stress, but the pathogenesis of smoking-related cardiovascular disease remains incompletely understood. The matrix metalloproteinases, a family of endopeptidases that can degrade extracellular matrix components in both physiological and pathophysiological states, play an important role in smoking-associated chronic obstructive pulmonary disease, the second leading cause of smoking attributable mortality. Emerging evidence indicates that the matrix metalloproteinases may also contribute to smoking-related vascular disease. Here we discuss the potential relationship between smoking, matrix metalloproteinases, and acceleration of vascular disease.

Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation

Anemia and vitamin D deficiency are conditions that both result in significant morbidity and increase with age. The potential relationship between them remains poorly understood, particularly in the elderly. We used the Third National Health and Nutrition Examination Survey to examine the association of vitamin D deficiency with anemia subtypes in persons aged ≥ 60 years. Vitamin D deficiency was defined as serum levels < 20 ng/mL, and anemia was defined according to World Health Organization criteria. Vitamin D deficiency was associated with anemia prevalence independent of age, sex, or race/ethnicity (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P = .02) and varied significantly by anemia subtype (P overall = .003). The prevalence of vitamin D deficiency was 33.3% in the nonanemic population, 56% in anemia of inflammation (AI; P = .008), and 33.0% in unexplained anemia (P = .55). Non-Hispanic blacks had a 7-fold increased risk of AI compared with whites, and this was partially attenuated after adjusting for vitamin D deficiency. These data show that vitamin D deficiency is associated with specific subtypes of anemia in the elderly, especially in those with AI. Vitamin D may suppress inflammatory pathways, and studies to determine whether vitamin D supplementation ameliorates AI are warranted.