Sumitra Balasubramanian

Association of anxiety disorders and depression with incident heart failure.

Objective Depression has been associated with increased risk of heart failure (HF). Because anxiety is highly comorbid with depression, we sought to establish if anxiety, depression, or their co-occurrence is associated with incident HF. Methods A retrospective cohort (N = 236,079) including Veteran’s Administration patients (age, 50–80 years) free of cardiovascular disease (CVD) at baseline was followed up between 2001 and 2007. Cox proportional hazards models were computed to estimate the association between anxiety disorders alone, major depressive disorder (MDD) alone, and the combination of anxiety and MDD, with incident HF before and after adjusting for sociodemographics, CVD risk factors (Type 2 diabetes, hypertension, hyperlipidemia, obesity), nicotine dependence/personal history of tobacco use, substance use disorders (alcohol and illicit drug abuse/dependence), and psychotropic medication. Results Compared with unaffected patients, those with anxiety only, MDD only, and both disorders were at increased risk for incident HF in age-adjusted models (hazard ratio [HR] = 1.19 [ 95% confidence interval {CI} = 1.10–1.28], HR = 1.21 [95% CI = 1.13–1.28], and HR = 1.24 [95% CI = 1.17–1.32], respectively). After controlling for psychotropics in a full model, the association between anxiety only, MDD only, and both disorders and incident HF increased (HRs = 1.46, 1.56, and 1.74, respectively). Conclusions Anxiety disorders, MDD, and co-occurring anxiety and MDD are associated with incident HF in this large cohort of Veteran’s Administration patients free of CVD at baseline. This risk of HF is greater after accounting for protective effects of psychotropic medications. Prospective studies are needed to clarify the role of depression and anxiety and their pharmacological treatment in the etiology of HF.

Peer substance involvement modifies genetic influences on regular substance involvement in young women

AIMS Peer substance involvement (PSI) is a robust correlate of adolescent substance use. A small number of genetically informative studies suggest that shared genetic and environmental factors contribute to this association. We examine mechanisms by which PSI influences the etiology of regular substance involvement (RSI), particularly in women. DESIGN Population-based cohort study of twin women from the US Midwest. PARTICIPANTS 2176 twin women. MEASUREMENTS To examine the relationship between self-reported PSI during adolescence and a composite RSI representing regular tobacco, alcohol and cannabis use during young adulthood, using genetically informative correlation, moderation and joint correlation-moderation models. FINDINGS There was evidence for a significant additive genetic X environment interaction. PSI was moderately heritable (h(2) = 0.25). Genetic, shared and non-shared influences on RSI overlapped with influences on PSI (genetic correlation of 0.43). Even after controlling for these shared genetic influences, RSI was more heritable in those reporting greater PSI. CONCLUSIONS While young women may select peers based on certain dispositional traits (e.g. permissiveness towards substance use), the social milieu constructed by PSI does modify the architecture of increased RSI in those individuals with increasing levels of PSI being associated with stronger expression of heritable influences.

Greater variability in kidney function is associated with an increased risk of death

Intra-individual variability in kidney function is a common phenomenon; however, predictors of kidney function variability and its prognostic significance are not known. To examine this question, we assembled a cohort of 51,304 US veterans with an estimated glomerular filtration rate (eGFR) <60 ml/min at the end of the study period and who had at least two eGFR measurements during the previous 3 years. Variability in kidney function was defined for each patient as the coefficient of variation of the regression line fitted to all outpatient measures of eGFR during this time frame. In adjusted analyses, blacks, women, and those with Current Procedural Terminology and ICD-9-CM diagnostic codes for hypertension, diabetes, cardiovascular disease, peripheral artery disease, chronic lung disease, hepatitis C, dementia, acute kidney injury, and those with a greater number of hospitalizations had greater variability in eGFR. After a median follow-up of 4.9 years, there were 23.66%, 25.68%, and 31.23% deaths among patients in the lowest, intermediate, and highest tertiles of eGFR variability, respectively. Compared with the referent (those in the lowest tertile), patients in the highest tertile had a significantly increased risk of death with a hazard ratio of 1.34 (1.28-1.40), an association consistently present in all sensitivity analyses. Thus, our results demonstrate that greater variability in kidney function is independently associated with increased risk of death.

High Density Lipoprotein Cholesterol and the Risk of All-Cause Mortality among U.S. Veterans

BACKGROUND AND OBJECTIVES The relationship between HDL cholesterol and all-cause mortality in patients with kidney disease is not clear. We sought to characterize the relationship of HDL cholesterol and risk of death and examine the association by eGFR levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We built a cohort of 1,764,986 men who were United States veterans with at least one eGFR between October of 2003 and September of 2004 and followed them until September of 2013 or death. RESULTS Patients with low HDL cholesterol and low eGFR had a higher burden of comorbid illnesses. Over a median of 9.1 years (interquartile range, 7.7-9.4 years), 26,247 (40.1%), 109,222 (32.3%), 152,625 (29.2%), 113,785 (28.5%), and 139,803 (31.8%) participants with HDL cholesterol ≤25, >25 to <34, ≥34 to ≤42, >42 to <50, and ≥50 mg/dl died. In adjusted survival models, compared with the referent group of patients with low HDL cholesterol (≤25 mg/dl), intermediate HDL cholesterol levels (>25 to <34, ≥34 to ≤42, and >42 to <50 mg/dl) were associated with lower risk of death across all levels of eGFR. The lower risk was partially abrogated in those with high HDL cholesterol (≥50 mg/dl), and the risk of death was similar to the referent category among those with eGFR<30 or ≥90 ml/min per 1.73 m2. Analysis by HDL cholesterol deciles and spline analyses suggest that the relationship between HDL cholesterol and death follows a U-shaped curve. There was a significant interaction between eGFR and HDL cholesterol in that lower eGFR attenuated the salutary association of HDL cholesterol and risk of death (P for interaction <0.01). Presence of coronary artery disease attenuated the lower risk of high HDL cholesterol and all-cause mortality in those with eGFR≥60 ml/min per 1.73 m2 (P for interaction <0.05). CONCLUSIONS Our results show a U-shaped relationship between HDL cholesterol and risk of all-cause mortality across all eGFR categories. The risk is modified by eGFR and cardiovascular disease.

Rate of Kidney Function Decline and Risk of Hospitalizations in Stage 3A CKD

BACKGROUND AND OBJECTIVES Risk of hospitalizations is increased in patients with CKD. We sought to examine the association between rate of kidney function decline and risk of hospitalization in a cohort of patients with early CKD. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS We built a cohort of 247,888 United States veterans who had at least one eGFR measurement between October 1999 and September 2003 and an additional eGFR between October 2003 and September 2004. We selected patients whose initial eGFR was between 45 and 59 ml/min per 1.73 m2. Rate of eGFR change (in milliliters per minute per 1.73 m2 per year) was categorized as no decline (>0), mild (0 to -1, and served as the referent group), moderate (-1 to -5), or severe (>-5) eGFR decline. We built survival models to examine the association between the rate of kidney function decline and the risk of hospitalization and readmission and linear regression to estimate length of hospital stay. RESULTS Over a median observation of 9 years (interquartile range, 5.28-9.00), patients with moderate and severe eGFR decline exhibited a higher risk of hospitalizations (hazard ratio [HR], 1.22; 95% confidence interval [95% CI], 1.19 to 1.26; and HR, 1.33; 95% CI, 1.28 to 1.39, respectively). Among patients with moderate and severe eGFR decline, the association between the rate of decline and the risk of hospitalizations was more pronounced with an increased number of hospitalizations (P<0.01). Patients with moderate and severe eGFR decline had a higher risk of readmission (HR, 1.19; 95% CI, 1.13 to 1.26; and HR, 1.53; 95% CI, 1.43 to 1.63, respectively). Among patients with severe eGFR decline, the association between the rate of kidney function decline and the risk of readmission was stronger with an increased number of readmissions (P<0.01). Patients with moderate and severe eGFR decline experienced an additional length of stay of 1.40 (95% CI, 0.88 to 1.92) and 5.00 days per year (95% CI, 4.34 to 5.66), respectively. CONCLUSIONS The rate of kidney function decline is associated with a higher risk of hospitalizations, readmissions, and prolonged length of hospital stay.

Renal Function Trajectories in Patients with Prior Improved eGFR Slopes and Risk of Death

Background Multiple prior studies demonstrated that patients with early Chronic Kidney Disease (CKD) and positive estimated Glomerular Filtration Rate (eGFR) slopes experience increased risk of death. We sought to characterize patients with positive eGFR slopes, examine the renal function trajectory that follows the time period where positive slope is observed, and examine the association between different trajectories and risk of death. Methods and Findings We built a cohort of 204,132 United States veterans with early CKD stage 3; eGFR slopes were defined based on Bayesian mixed-effects models using outpatient eGFR measurements between October 1999 and September 2004; to build renal function trajectories, patients were followed longitudinally thereafter (from October 2004) until September 2013. There were 41,410 (20.29%) patients with positive eGFR slope and they exhibited increased risk of death compared to patients with stable eGFR slope (HR = 1.33, CI:1.31–1.35). There was an inverse graded association between severity of albuminuria and the odds of positive eGFR slope (OR = 0.94, CI:0.90–0.98, and OR = 0.76, CI:0.69–0.84 for microalbuminuria and albuminuria; respectively). Following the time period where positive eGFR slope is observed, we characterized 4 trajectory phenotypes: high eGFR intercept and positive trajectory (HIPT) (12.42%), intermediate intercept and mild negative trajectory (IIMNT) (60.04%), low intercept and fast negative trajectory (LIFNT)(23.33%), and high intercept and fast negative trajectory (HIFNT) (4.20%). Compared to IIMNT (reference group), HIPT is associated with younger age, dementia, HIV, chronic lung disease, peripheral artery disease, weight loss, and inversely associated with albuminuria; LIFNT and HIFNT were associated with diabetes, hypertension, cardiovascular disease, peripheral artery disease, and albuminuria. The risk of death at 9 years was lowest in IIMNT (HR = 1.12, CI:1.09–1.14), highest in HIPT (HR = 1.71, CI:1.63–1.79), and intermediate in LIFNT (HR = 1.36, CI:1.32–1.40) and HIFNT (HR = 1.56, CI:1.45–1.68). Conclusions Our results demonstrate that patients with positive eGFR slopes, when followed over longer period of time, follow 4 distinct trajectory phenotypes that have distinct demographic and clinical correlates and are differentially associated with risk of death.