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1.  Heart Rate Variability is a Predictor of Mortality in CKD - A Report from the CRIC Study 
American journal of nephrology  2013;38(6):517-528.
Low heart rate variability (HRV) is a risk factor for adverse outcomes in the general population. We aimed to determine the factors associated with HRV and evaluate the association between low HRV and clinical outcomes in patients with chronic kidney disease (CKD).
A 10 second electrocardiogram was obtained at baseline in the Chronic Renal Insufficiency Cohort (CRIC) Study. HRV was measured by the standard deviation of all R-R intervals (SDNN) and the root mean square of successive differences between R-R intervals (RMSSD).
In 3245 CRIC participants with available baseline SDNN and RMSSD, lower HRV was associated with older age, lack of exercise, heart failure, elevated phosphorus and hemoglobin A1c, and low estimated glomerular filtration rate. After a median follow-up of 4.2 years, in fully adjusted models, lower HRV was not associated with renal (SDNN: HR=0.96 (95% CI 0.88–1.05); RMSSD: HR=0.97 (95% CI 0.88–1.07)) or cardiovascular outcomes (SDNN: HR=1.02 (95% CI 0.92–1.13); RMSSD: HR=1.00 (95% CI 0.90–1.10)). There was a non-linear relationship between RMSSD and all-cause mortality with increased risk with both low and high RMSSD (P=0.04).
In a large cohort of participants with CKD, multiple risk factors for renal and cardiovascular disease were associated with lower HRV. Lower HRV was not associated with increased risk for renal or cardiovascular outcomes, but both low and high RMSSD were associated with increased risk for all-cause mortality. In conclusion, HRV as measured by RMSSD may be a novel and independent risk factor for mortality in CKD patients.
PMCID: PMC3920657  PMID: 24356377
electrocardiography; autonomic nervous system; chronic renal insufficiency; cardiovascular diseases; mortality
2.  CPAP versus Oxygen in Obstructive Sleep Apnea 
The New England journal of medicine  2014;370(24):2276-2285.
Obstructive sleep apnea is associated with hypertension, inflammation, and increased cardiovascular risk. Continuous positive airway pressure (CPAP) reduces blood pressure, but adherence is often suboptimal, and the benefit beyond management of conventional risk factors is uncertain. Since intermittent hypoxemia may underlie cardiovascular sequelae of sleep apnea, we evaluated the effects of nocturnal supplemental oxygen and CPAP on markers of cardiovascular risk.
We conducted a randomized, controlled trial in which patients with cardiovascular disease or multiple cardiovascular risk factors were recruited from cardiology practices. Patients were screened for obstructive sleep apnea with the use of the Berlin questionnaire, and home sleep testing was used to establish the diagnosis. Participants with an apnea–hypopnea index of 15 to 50 events per hour were randomly assigned to receive education on sleep hygiene and healthy lifestyle alone (the control group) or, in addition to education, either CPAP or nocturnal supplemental oxygen. Cardiovascular risk was assessed at baseline and after 12 weeks of the study treatment. The primary outcome was 24-hour mean arterial pressure.
Of 318 patients who underwent randomization, 281 (88%) could be evaluated for ambulatory blood pressure at both baseline and follow-up. On average, the 24-hour mean arterial pressure at 12 weeks was lower in the group receiving CPAP than in the control group (−2.4 mm Hg; 95% confidence interval [CI], −4.7 to −0.1; P = 0.04) or the group receiving supplemental oxygen (−2.8 mm Hg; 95% CI, −5.1 to −0.5; P = 0.02). There was no significant difference in the 24-hour mean arterial pressure between the control group and the group receiving oxygen. A sensitivity analysis performed with the use of multiple imputation approaches to assess the effect of missing data did not change the results of the primary analysis.
In patients with cardiovascular disease or multiple cardiovascular risk factors, the treatment of obstructive sleep apnea with CPAP, but not nocturnal supplemental oxygen, resulted in a significant reduction in blood pressure. (Funded by the National Heart, Lung, and Blood Institute and others; HeartBEAT number, NCT01086800.)
PMCID: PMC4172401  PMID: 24918372
3.  Cycling Memory CD4+ T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation 
Journal of Virology  2014;88(10):5369-5380.
The mechanisms of increased memory CD4+ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and Vβ family distribution in cycling memory CD4+ T cells among 52 healthy and 59 HIV-positive (HIV+) donors. Cycling memory CD4+ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4+ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV+ donors, memory CD4+ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8+ T cell cycling and was inversely related to peripheral blood CD4+ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4+ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV+ donors, cycling memory CD4+ T cells had a broad distribution of Vβ families comparable to that of noncycling cells. Increased memory CD4+ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines.
IMPORTANCE This work provides evidence that the increased memory CD4+ T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection.
PMCID: PMC4019138  PMID: 24522925
4.  Association Between Obstructive Sleep Apnea Severity and Endothelial Dysfunction 
Journal of sleep research  2013;22(4):443-451.
The objective of the study is to examine whether increasing OSA severity is associated with worsening endothelial function.
The design is a cross-sectional examination of the baseline assessment of a multicenter randomized controlled clinical trial examining the effects of oxygen, CPAP therapy, or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an Apnea Hypopnea Index (AHI) of 15 to 50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included.
OSA severity indices (oxygen desaturation index [ODI], AHI, and percent sleep time below 90% oxygen saturation [TST<90]) and a measure of endothelium mediated vasodilatation (Framingham Reactive Hyperemia Index, F-RHI derived from peripheral arterial tonometry, PAT) were assessed.
The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 (SD) and mean F-RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (p=0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% (95% CI: (0%, 5%); p=0.05) while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: (0%, 27%); p=0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with TST<90 and F-RHI.
There was evidence of a graded decline in endothelial function in association withn higher levels of intermittent hypoxemia.
PMCID: PMC4011016  PMID: 23331757
Sleep apnea; Cardiovascular disease; Endothelial dysfunction
5.  Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk 
Journal of hypertension  2014;32(2):267-275.
We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk.
Baseline data from 298 cardiology patients recruited for a multicenter randomized controlled trial were examined. Dipping was defined as a sleep-related BP or heart rate (HR) reduction of at least 10%. Logistic regression models were fit, adjusting for age, sex, race, BMI, CVD risk factors, CVD, and study site.
There was a statistically significant 4% increase in the odds of nondipping SBP per 1-unit increase in both Apnea Hypopnea Index (AHI) and Oxygen Desaturation Index (ODI). There was no significant relationship between AHI and nondipping mean arterial pressure (MAP); however, a 3% increase in the odds of nondipping MAP per 1-unit increase in ODI was observed (odds ratio, OR =1.03; 95% confidence interval, CI 1.00–1.05). At severe OSA levels, a 10 and 4% increase in odds of nondipping DBP per 1-unit increase in AHI and ODI were observed, respectively. A 6% [OR =1.06; 95% CI (1.01–1.10)] increase in nondipping HR odds was observed with each increase in ODI until the upper quartile of ODI.
In patients at cardiovascular risk and moderate-to-severe OSA, increasing AHI and/or ODI were associated with increased odds of nondipping SBP and nondipping MAP. More severe levels of AHI and ODI also were associated with nondipping DBP. These results support progressive BP burden associated with increased OSA severity even in patients managed by cardiology specialty care.
PMCID: PMC4096765  PMID: 24351803
cardiovascular disease; hypertension; hypoxia; sleep apnea
6.  A Simple Tool to Predict ESRD Within 1 Year in Elderly Patients with Advanced CKD 
Chronic kidney disease (CKD) is common in older patients; currently, no tools are available to predict the risk of end-stage renal disease (ESRD) within 1 year. The goal of this study was to develop and validate a model to predict the 1 year risk for ESRD in elderly subjects with advanced CKD.
Retrospective study
Veterans Affairs Medical Center
Patients over 65 years of age with CKD with an estimated (eGFR) less than 30mL/min/1.73m2.
The outcome was ESRD within 1 year of the index eGFR. Cox regression was used to develop a predictive model (VA risk score) which was validated in a separate cohort.
Of the 1,866 patients in the developmental cohort, 77 developed ESRD. Risk factors for ESRD in the final model were age, congestive heart failure, systolic blood pressure, eGFR, potassium, and albumin. In the validation cohort, the C index for the VA risk score was 0.823. The risk for developing ESRD at 1 year from lowest to highest tertile was 0.08%, 2.7%, and 11.3% (P<0.001). The C-index for the recently published Tangri model in the validation cohort was 0.780.
A new model using commonly available clinical measures shows excellent ability to predict the onset of ESRD within the next year in elderly subjects. Additionally, the Tangri model had very good predictive ability. Patients and physicians can use these risk models to inform decisions regarding preparation for renal replacement therapy in patients with advanced CKD.
PMCID: PMC3711593  PMID: 23617782
chronic renal insufficiency; aging; chronic kidney failure; hypertension
7.  The Relationship between Fuchs' Endothelial Corneal Dystrophy Severity and Glaucoma and/or Ocular Hypertension 
Archives of ophthalmology  2012;130(11):1384-1388.
To investigate if Fuchs' Endothelial Corneal Dystrophy (FECD) severity is associated with glaucoma and/or ocular hypertension (G/OHTN).
A subset of eyes (n=1610) from the FECD Genetics Multi-Center Study were examined to estimate the association between FECD severity (grades 0–6 based on guttae confluence) and G/OHTN. Logistic regression models were fit that accounted for the correlation between eyes and adjusted for age, sex, central corneal thickness, intraocular pressure, presence of diabetes, and time of day of initial evaluation.
107 eyes (6.6%) had G/OHTN based on the study definition. The prevalence of G/OHTN in the control group was 6%. Prevalence was lower in index cases with an FECD grade of 1 through 3 and family members with a grade of 0 or 1 through 3 (0% and 2%, respectively) but higher in index cases and family members with a grade of 4 through 6 (11% and 9%, respectively). Adjusting for covariates, eyes with a grade of 4 through 6 were more likely to have concurrent G/OHTN than eyes with no FECD (index cases vs. controls: OR=2.10, p=0.04; affected vs. unaffected family: OR=7.06, p=0.07). Age (OR=1.06 per 1 year increase, p<0.001) and intraocular pressure (OR=1.15 per 1 mmHg increase, p<0.001) were also associated with an increased prevalence of G/OHTN. Sex, diabetes, time of day of evaluation, and central corneal thickness were not associated with the prevalence of G/OHTN (p>0.15).
Glaucoma and/or ocular hypertension occurs more often in eyes affected with severe FECD compared to unaffected eyes. Therefore, it may be beneficial to monitor for the development of glaucoma in these patients.
PMCID: PMC3954552  PMID: 22777534
8.  Relationship of Fuchs’ Endothelial Corneal Dystrophy Severity to Central Corneal Thickness 
Archives of ophthalmology  2012;130(4):10.1001/archophthalmol.2011.1626.
To define the relationship between Fuchs’ endothelial corneal dystrophy (FECD) severity and central corneal thickness (CCT).
Eyes from a subset of index cases, family members, and unrelated controls with normal corneas from the FECD Genetics Multi-Center Study (n=1610) were examined. To estimate the association between FECD severity grade (7-point severity scale based on guttae confluence) and CCT measured by ultrasonic pachymetry, a multivariable model was used that adjusted for eye, age, race, gender, glaucoma or ocular hypertension history, diabetes, contact lens wear, intraocular pressure and familial relationship to index case. An interaction between FECD severity grade and edema (stromal or epithelial) on slit lamp examination was used to investigate if the effect of FECD severity grade on CCT differed between those with and without edema.
Average CCT was thicker in index cases for all FECD grades compared to unaffected controls (p ≤ 0.003) and in affected family members with an FECD grade of 4 or greater compared to unaffected family members (p ≤ 0.04). Similar results were observed for subjects without edema. Average CCT of index cases was greater than that of affected family members for grades 4, 5 and 6 (p ≤ 0.02). Intraocular pressure was also associated with CCT (p<0.01).
An increase in CCT occurs with increasing severity of FECD, including at lower FECD grades where clinically observable edema is not present. Monitoring corneal thickness changes serially could be a more sensitive measure of disease progression with surgical therapeutic implications.
PMCID: PMC3859299  PMID: 22491913
9.  Effect of Nadir CD4+ T Cell Count on Clinical Measures of Periodontal Disease in HIV+ Adults before and during Immune Reconstitution on HAART  
PLoS ONE  2013;8(10):e76986.
The contribution of HIV-infection to periodontal disease (PD) is poorly understood.  We proposed that immunological markers would be associated with improved clinical measures of PD.
We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART) <2 years. PD was characterized clinically as the percent of teeth with ≥1 site with periodontal probing depth (PPD) ≥5.0mm, recession (REC) >0mm, clinical attachment level (CAL) ≥4.0mm, and bleeding on probing (BOP) at ≥4 sites/tooth and microbiologically as specific periodontopathogen concentration. Linear mixed-effects models were used to assess the associations between immune function and PD.
Forty (40) subjects with median 2.7 months on HAART and median nadir CD4+ T-cell count of 212 cells/μl completed a median 3 visits. Over 24 months, CD4+ T-cell count increased by a mean 173 cells/µl (p<0.001) and HIV RNA decreased by 0.5 log10 copies/ml (p<0.001); concurrently, PPD, CAL and BOP decreased by a mean 11.7%, 12.1%, and 14.7% respectively (all p<0.001). Lower nadir CD4+ T-cell count was associated with worse baseline REC (-6.72%; p=0.04) and CAL (9.06%; p<0.001). Further, lower nadir CD4+ T-cell count was associated with a greater relative longitudinal improvement in PPD in subjects with higher baseline levels of Porphyromonas gingivalis (p=0.027), and BOP in subjects with higher baseline levels of Porphyromonas gingivalis or Treponema denticola (p=0.001 and p=0.006 respectively). Longitudinal changes from baseline in CD4+ T-cell count and level of HIV RNA were not independently associated with longitudinal changes in any clinical markers of PD.
Degree of immunosuppression was associated with baseline gingival recession. After HAART initiation, measures of active PD improved most in those with lower nadir CD4+ T-cell counts and higher baseline levels of specific periodontopathogens. Nadir CD4+ T-cell count differentially influences periodontal disease both before and after HAART in HIV-infected adults.
PMCID: PMC3795634  PMID: 24146949
10.  Relation Between Sleep Duration and BMI Varies by Age and Sex in Youth Age 8–19 
Pediatric Obesity  2011;7(1):53-64.
The objectives of this study were to 1) compare the strength of associations between sleep duration and BMI in middle childhood, early and late adolescence; 2) determine whether sleep duration in middle childhood predicts BMI in early or late adolescence; 3) examine the consistency of these associations by sex.
Subjects included 313 children/adolescents aged 8–19 participating in a longitudinal cohort study on sleep and health. Participants were assessed at three time points approximately 4 years apart: ages 8–11, 12–15 and 16–19. BMI z-score (BMIz) was calculated using age and sex normative data from the Centers for Disease Control. Sleep duration was reported by the parent (ages 8–15) or the adolescent (ages 16–19).
Half of the participants were male and 79% were Caucasian. Sleep duration had a negative linear association with BMIz for boys but not girls, and the magnitude of this association decreased with age. Sleep duration at age 8–11 predicted BMIz in early and late adolescence for boys but not girls, and associations were largely attenuated after adjusting for BMIz at age 8–11. The strongest predictor of adolescent BMIz was BMIz at age 8–11 for both boys and girls.
We conclude that the association between sleep duration and BMIz varies by sex and age, with stronger associations in boys and in middle childhood compared to adolescence.
PMCID: PMC3313079  PMID: 22434739
Adolescents; BMI; Children; Obesity; Sleep
11.  Metabolic Complications are Common in Elderly Patients with Chronic Kidney Disease 
Significant controversy exists as to the meaning of a low glomerular filtration rate (GFR) in the elderly. The goal of the study was to evaluate whether elderly patients with low GFR are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia.
Retrospective study
Veterans Affairs Medical Center
All patients over 65 years of age with chronic kidney disease (CKD) and a GFR between 15 and 60 mL/min/1.73m2.
Anemia was defined as a hemoglobin <10g/dL, hyperkalemia as a potassium >5.5mEq/L, acidosis as a bicarbonate <21mEq/L, and hyperphosphatemia as a phosphorus >4.6mg/dL. Multivariable logistic regression was used to evaluate whether age modifies the effect of low GFR on metabolic complications by including an interaction term between age and GFR in each model.
13874 veterans were included in the study. The average age was 79, the average GFR was 46.5; 3.1% had anemia, 2.5% hyperkalemia, 2.3% acidosis, and 4.4% had hyperphosphatemia. Lower GFR was associated with increased rates of metabolic complications across all age groups (odds ratio per 5mL/min/1.73m2 decrease in GFR in multivariable models was 1.21 for anemia, 1.26 for hyperkalemia, 1.45 for acidosis, and 1.72 for hyperphosphatemia). There was no significant interaction between age and GFR in models including only age and GFR or in multivariable models (p values for the age X GFR interaction term: 0.66 for anemia, 0.19 for hyperkalemia, 0.54 for acidosis, and 0.22 for hyperphosphatemia).
Elderly patients with CKD are at risk for anemia, hyperkalemia, acidosis, and hyperphosphatemia; age does not modify the relationship between GFR and development of metabolic complications. Elderly patients with low GFR should be monitored for metabolic complications, regardless of age.
PMCID: PMC3527008  PMID: 22283563
chronic renal insufficiency; aging; anemia; hyperkalemia; acidosis; hyperphosphatemia
12.  A Prospective Cohort Study of Periodontal Disease Measures and Cardiovascular Disease Markers in HIV-Infected Adults 
AIDS Research and Human Retroviruses  2011;27(11):1157-1166.
The determinants of HIV-associated cardiovascular disease (CVD) are not well understood. Periodontal disease (PD) has been linked to CVD but this connection has not been examined in HIV infection. We followed a cohort of HIV-infected adults to ascertain whether PD was associated with carotid artery intima media thickness (IMT) and brachial artery flow-mediated dilation (FMD). We performed a longitudinal observational study of HIV-infected adults on HAART for <2 years with no known heart disease. PD was characterized clinically and microbiologically. Cardiovascular disease was assessed by IMT/FMD. Linear mixed models assessed cross-sectional and longitudinal associations between PD and FMD/IMT. Forty three HIV+ adults completed a median of 24 (6–44) months on the study. Defining delta to be the change in a variable between baseline and a follow-up time, longitudinally, on average and after adjusting for change in time, CVD-specific and HIV-specific potential confounding covariates, a 1-log10 increase in delta Porphyromonas gingivalis was associated with a 0.013 mm increase in delta IMT (95% CI: 0.0006–0.0262; p=0.04). After adjusting for the same potential confounding covariates, a 10% increase in delta gingival recession was associated with a 2.3% increase in delta FMD (95% CI: 0.4–4.2; p=0.03). In a cohort of HIV-infected adults, an increase in subgingival Porphyromonas gingivalis, a known periodontal pathogen, was significantly associated with longitudinal increases in IMT, while increased gingival recession, which herein may represent PD resolution, was significantly associated with longitudinal improvement in FMD. In the context of HIV infection, PD may contribute to CVD risk. Intervention studies treating PD may help clarify this association.
PMCID: PMC3206743  PMID: 21443451
13.  Sleep-disordered Breathing and Prothrombotic Biomarkers 
Rationale: Individuals with sleep-disordered breathing (SDB) are at increased cardiovascular risk, possibly due to SDB-related stresses contributing to atherosclerosis.
Objectives: We postulate that pathways associated with a prothrombotic potential are up-regulated in SDB.
Methods: Morning and evening plasminogen activator inhibitor-1 (PAI-1), morning fibrinogen, and morning D-dimer were measured in 537 Cleveland Family Study adults. Piecewise multivariable linear mixed models estimated relative mean change or mean change in the biomarker per 5-unit increase in apnea-hypopnea index (AHI) in two groups: AHI less than 15 and AHI greater than or equal to 15, and hypoxia defined as percentage of sleep time with SaO2 less than 90% (< 2%, ≥ 2%).
Measurements and Main Results: Nonlinear associations were demonstrated: morning and evening PAI-1 increased by 12% (95% confidence interval [CI], 5–20%; P < 0.001) and 11% (95% CI, 2–20%; P = 0.01), respectively per 5-unit AHI increase until an AHI of 15, when no further increase in PAI-1 was demonstrated. The association between AHI and morning PAI-1 remained significant after adjusting for evening PAI-1 level (10%; 95% CI, 3–17%; P < 0.01). Morning fibrinogen increased on average by 8.4 mg/dl (95% CI, 3.12–13.65; P = 0.002) per five-unit AHI increase until an AHI of 15. There was no association between AHI and morning D-dimer. Hypoxia severity was not associated with thrombotic marker levels.
Conclusions: PAI-1 and fibrinogen levels increase monotonically with AHI at degrees of SDB considered mildly to moderately abnormal, suggesting that even mild SDB levels may increase prothrombotic processes. There may be a plateau in this effect, occurring at levels considered to reflect only moderate SDB severity. These relationships with mild-to-moderate SDB were not observed with D-dimer.
PMCID: PMC2949407  PMID: 20508215
sleep apnea; thrombosis; cardiovascular disease

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