Publications

Glutathione S-transferase mu 1 ( encodes an enzyme that catalyzes the conjugation of electrophilic compounds with glutathione to facilitate their degradation or excretion. The loss of one or both copies of is common in many populations and has been associated with CKD progression. With the hypothesis that the loss of is also associated with incident kidney failure and heart failure, we estimated copy number using exome sequencing reads in the Atherosclerosis Risk in Communities (ARIC) Study, a community-based prospective cohort of white and black participants. Overall, 51.2% and 39.8% of white participants and 25.6% and 48.5% of black participants had zero or one copy of , respectively. Over a median follow-up of 24.6 years, 256 kidney failure events occurred in 5715 participants without prevalent kidney failure, and 1028 heart failure events occurred in 5368 participants without prevalent heart failure. In analysis adjusted for demographics, diabetes, and hypertension, having zero or one copy of associated with higher risk of kidney failure and heart failure (adjusted hazard ratio [95% confidence interval] for zero or one versus two copies of : kidney failure, 1.66 [1.27 to 2.17]; heart failure, 1.16 [1.04 to 1.29]). Risk did not differ significantly between participants with zero and one copy of (>0.10). In summary, the loss of was significantly associated with incident kidney and heart failure, independent of traditional risk factors. These results suggest function is a potential treatment target for the prevention of kidney and heart failure.

INTRODUCTION

Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFβ1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure.

HYPOTHESIS

We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure.

METHODS AND RESULTS

In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1 mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and β-myosin heavy chain were increased similarly in Alk1 and WT mice after TAC. Alk-1 mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 collagen mRNA and protein levels were higher in Alk1 mice. LV fractional shortening was lower in Alk1 mice after TAC.

CONCLUSIONS

Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

OBJECTIVES

Smoking is associated with adverse health outcomes among drug users, including those in treatment. To date, however, there has been little evidence about smoking patterns among people receiving opioid-dependence treatment in developing countries. We examined self-reported nicotine dependence and associated factors in a large sample of opioid-dependent patients receiving methadone maintenance treatment (MMT) in northern Vietnam.

SETTING

Five clinics in Hanoi (urban area) and Nam Dinh (rural area).

PARTICIPANTS

Patients receiving MMT in the settings during the study period.

PRIMARY AND SECONDARY OUTCOME MEASURES

We collected data about smoking patterns, levels of nicotine dependence and other covariates such as socioeconomic status, health status, alcohol use and drug use. The Fagerström test was used to measure nicotine dependence (FTND). Logistic regression and Tobit regression were employed to examine relationships between the smoking rate, nicotine dependence and potentially associated variables.

RESULTS

Among 1016 drug users undergoing MMT (98.7% male), 87.2% were current smokers. The mean FTND score was 4.5 (SD 2.4). Longer duration of MMT (OR 0.98, 95% CI 0.96 to 0.99) and being HIV-positive (OR 0.46, 95% CI 0.24 to 0.88) were associated with lower likelihood of smoking. Being employed, older age at first drug injection and having long duration of MMT were inversely related with FTND scores. Higher age and continuing drug and alcohol use were significantly associated with higher FTND scores.

CONCLUSION

Smoking prevalence is high among methadone maintenance drug users. Enhanced smoking cessation support should be integrated into MMT programmes in order to reduce risk factors for cigarette smoking and improve the health and well-being of people recovering from opiate dependence.

BACKGROUND

The Literature on rhabdomyolysis in the HIV-positive population is sparse and limited. We aimed to explore the incidence, patient characteristics, etiologies and outcomes of rhabdomyolysis in a cohort of HIV-positive patients identified through the Johns Hopkins HIV clinical registry between June 1992 and April 2014.

METHODS

A retrospective analysis of 362 HIV-positive patients with non-cardiac CK elevation ≥1000 IU/L was performed. Both inpatients and outpatients were included. Incidence rate and potential etiologies for rhabdomyolysis were ascertained. The development of acute kidney injury (AKI, defined as doubling of serum creatinine), need for dialysis, and death in the setting of rhabdomyolysis were determined. Logistic regression was used to evaluate the association of peak CK level with the development of AKI.

RESULTS

Three hundred sixty two cases of rhabdomyolysis were identified in a cohort of 7079 patients with a 38,382 person years follow-up time. The incidence rate was nine cases per 1000 person-years (95% CI: 8.5-10.5). Infection was the most common etiology followed by compression injury and drug/alcohol use. One-third of cases had multiple potential etiologies. AKI developed in 46% of cases; 20% of which required dialysis. Thirteen percent died during follow-up. After adjustment, AKI was associated with higher CK (OR 2.05 for each 1-log increase in CK [95% CI: 1.40-2.99]), infection (OR 5.48 [95% CI 2.65-11.31]) and higher HIV viral load (OR 1.22 per 1-log increase [95% CI: 1.03-1.45]).

CONCLUSION

Rhabdomyolysis in the HIV-positive population has many possible causes and is frequently multifactorial. HIV-positive individuals with rhabdomyolysis have a high risk of AKI and mortality.