Females present higher dose-adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males.

Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10-4 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.

An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites.

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid-lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross-sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

A genetic association study of heart failure: more evidence for the role of BAG3 in idiopathic dilated cardiomyopathy.

AIMS: Few investigations have been conducted to identify genetic determinants of common, polygenetic forms of heart failure (HF), and only a limited number of these genetic associations have been validated by multiple groups. METHODS AND RESULTS: We performed a case-control study to further investigate the potential impact of 14 previously reported candidate genes on the risk of HF and specific HF sub-types. We also performed an exploratory genome-wide study. We included 799 patients with HF and 1529 controls. After adjusting for age, sex, and genetic ancestry, we found that the C allele of rs2234962 in BAG3 was associated with a decreased risk of idiopathic dilated cardiomyopathy (odds ratio 0.42, 95% confidence interval 0.25-0.68, P = 0.0005), consistent with a previous report. No association for the other primary variants or exploratory genome-wide study was found. CONCLUSIONS: Our findings provide independent replication for the association between a common coding variant (rs2234962) in BAG3 and the risk of idiopathic dilated cardiomyopathy.

Cardiopulmonary, biomarkers, and vascular responses to acute hypoxia following cardiac transplantation.

Previous studies have suggested good adaptation of cardiac transplant (CTx) recipients to exposure to a high altitude. No studies have investigated the cardiopulmonary and biomarker responses to acute hypoxic challenges following CTx. Thirty-six CTx recipients and 17 age-matched healthy controls (HC) were recruited. Sixteen (16) patients (42%) had cardiac allograft vasculopathy (CAV). Cardiopulmonary responses to maximal and submaximal exercise at 21% O2 , 20-minutes hypoxia (11.5% O2 ), and following a 10-minute exposure to 11.5% O2 using 30% of peak power output were completed. Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), suppression of tumorigenicity 2 (ST2) were measured at baseline and at peak stress. Endothelial peripheral function was assessed using near-infrared spectroscopy. Compared with HC, CTx presented a lesser O2 desaturation both at rest (-19.4 ± 6.8 [CTx] vs -24.2 ± 6.0% O2 [HC], P < 0.05) and following exercise (-23.2 ± 4.9 [CTx] vs -26.2 ± 4.7% O2 [HC], P < 0.05). CTx patients exhibited a significant decrease in peak oxygen uptake. IL-6 and VEGF levels were significantly higher in CTx recipients in basal conditions but did not change in response to acute stress. CTx patients exhibit a favorable ventilatory and overall response to hypoxic stress. These data provide further insights on the good adaptability of CTx to exposure to high altitude.

Genetic markers associated with cutaneous adverse drug reactions to allopurinol: a systematic review.

Pharmacogenomic markers in the HLA coding genes have been associated with drug hypersensitivity of multiple drugs, including allopurinol. In this systematic review, we summarize the pharmacogenomic evidence available regarding allopurinol-induced cutaneous adverse drug reactions (cADRs). We found that the HLA-B*5801 allele was significantly associated with the risk of severe cADRs in the Han Chinese, Korean, Thai, Japanese and European populations. The association between less severe cADRs and HLA-B*5801 was less consistent. All SNPs identified in genome-wide association studies of common variants were also located in or nearby HLA-B*5801. Future studies should focus on more common but less severe allopurinol-induced cADRs, as well as the potential role of rare variants as predictors of these cADRs.

Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits.

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10(-7)) and WBC count (P = 3.1 × 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

Long-term evolution, secular trends, and risk factors of renal dysfunction following cardiac transplantation.

Recent reports suggest that individuals who underwent heart transplantation in the last decade have improved post-transplant kidney function. The objectives of this retrospective study were to describe the incidence and to identify fixed and time-dependent predictors of renal dysfunction in cardiac recipients transplanted over a 25-year period (1983-2008). To illustrate temporal trends, patients (n = 306) were divided into five groups based on year of transplantation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at year 1. Secondary endpoints were time to moderate (eGFR <60 ml/min/1.73 m(2) ) and severe renal dysfunction (eGFR <30 ml/min/1.73 m(2) ). Risk factor analyses relied on multivariable regression models. Kidney function was mildly impaired before transplant (median eGFR=61.0 ml/min/1.73 m(2) ), improved at discharge (eGFR=72.3 ml/min/1.73 m(2) ; P < 0.001), decreased considerably in the first year (eGFR = 54.7 ml/min/1.73 m(2) ; P < 0.001), and deteriorated less rapidly thereafter. At year 1, 2004-2008 recipients exhibited a higher eGFR compared with all other patients (P < 0.001). Factors independently associated with eGFR at year 1 and with moderate and severe renal dysfunction included age, gender, pretransplant eGFR, blood pressure, glycemia, and use of prednisone (P < 0.05). In summary, kidney function worsens constantly up to two decades after cardiac transplantation, with the greatest decline occurring in the first year. Corticosteroid minimization and treatment of modifiable risk factors (hypertension, diabetes) may minimize renal deterioration.

Oral ferrous sulfate does not increase preoperative hemoglobin in patients scheduled for hip or knee arthroplasty.

BACKGROUND: Low hemoglobin (Hb) concentrations before lower limb joint replacement are associated with the need for blood transfusions and increased mortality. To optimize preoperative Hb, blood conservation protocols often recommend oral iron supplements, even in nonanemic patients. OBJECTIVE: To investigate the impact of ferrous sulfate on the change in Hb prior to hip or knee arthroplasty and evaluate the effect of oral iron on hematocrit, mean corpuscular volume (MCV), ferritin, and transferrin saturation, as well as its tolerability and treatment adherence. METHODS: We conducted a prospective, observational cohort study of adults with Hb concentrations between 10 and 15 g/dL who received iron supplementation prior to hip or knee arthroplasty. Systemic inflammatory diseases, vitamin B(12) or folate deficiency, and current use of iron supplements, intravenous iron, or erythropoietin were exclusion criteria. All participants were prescribed ferrous sulfate 300 mg 3 times daily for a minimum of 3 weeks. Complete blood cell counts and iron studies were performed before therapy and surgery. RESULTS: Eighty-seven patients with a mean (SD) Hb of 13.47 (0.84) g/dL were included in the study. Preoperative Hb decreased after treatment with iron (-0.14 [0.53] g/dL, p = 0.015). Hematocrit also declined (-0.6% [1.8%], p = 0.002), whereas ferritin increased (25.8 [38.6] ng/mL, p < 0.001). No significant change was seen in MCV and transferrin saturation. The most common adverse effects were constipation (33.3%), heartburn (13.8%), and abdominal pain (12.6%). The adherence rate was 67.1%. CONCLUSIONS: Oral ferrous sulfate supplementation is not an effective method to increase preoperative Hb in patients scheduled for hip or knee arthroplasty, and its use is associated with adverse effects.

Association between renal function and CYP3A5 genotype in heart transplant recipients treated with calcineurin inhibitors.

BACKGROUND: The renal expression of the cytochrome P450 3A5 (CYP3A5) isoenzyme and of the adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporter P-glycoprotein is inversely associated with calcineurin-induced nephrotoxicity. The aim of this study was to evaluate the association between polymorphisms of the genes encoding these proteins and the long-term renal function of heart transplant recipients treated with calcineurin inhibitors. METHODS: We performed a retrospective cohort study of 160 heart transplant recipients from two institutions who were discharged alive after transplant and who received a calcineurin inhibitor during follow-up. The aim of this study was to evaluate the impact of common variants of the genes encoding this isoenzyme (CYP3A5*1 and *3) and the transporter (ABCB1 G2677T/A and C3435T) on the renal function of these patients after heart transplantation. The primary end-point of the study was changes in the estimated glomerular filtration rate (eGFR) at hospital discharge; at 3, 6, 12, 18 and 24 months after heart transplant; and then every year for up to 9 years. RESULTS: After adjusting for independent predictors of eGFR during follow-up, CYP3A5 was significantly associated with eGFR after transplantation (p = 0.0002), with carriers of the CYP3A5*1 allele exhibiting a higher eGFR. None of the ABCB1 variants or haplotypes were associated with eGFR after transplantation. CONCLUSION: The CYP3A5*1 genetic polymorphism is a promising marker to identify heart transplant recipients least likely to develop renal dysfunction during long-term treatment with a calcineurin inhibitor.

Management of anemia and iron deficiency in heart failure.

OPINION STATEMENT: Anemia is independently associated with an increased risk of mortality and morbidity in patients with heart failure (HF). The diagnosis of anemia should prompt assessment of the underlying cause(s), first by using routine laboratory measurements (i.e., serum creatinine and estimated glomerular filtration rate [eGFR], serum iron, transferrin saturation, ferritin, vitamin B12, folic acid, and thyroid stimulating hormone). In clinical practice, it remains unclear whether using levels of the soluble transferrin receptor in HF patients to assess iron deficiency is warranted. Further investigation should follow these simple tests when judged appropriate (e.g., if occult gastrointestinal blood losses are suspected). Hemodilution may contribute significantly to anemia in patients with advanced HF and may be suspected when signs of hypervolemia are present. Euvolemia should be the first goal in such cases (as always), followed by optimization of the disease-modifying therapies used in HF (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, ß-blockers, or aldosterone antagonists and cardiac resynchronization therapy in selected cases). Erythropoiesis-stimulating agents (ESA) can be used to improve functional capacity in patients with significant chronic kidney disease (CKD), a frequent comorbidity in HF patients. ESA and iron therapy is recommended in patients with moderate-to-severe CKD (eGFR < 60 mL/min/1.73 m(2)), with a target hemoglobin level of 11.0 g/dL. In a recent randomized, placebo-controlled clinical trial, weekly administration of intravenous iron significantly improved symptoms, New York Heart Association class, quality of life, and exercise capacity in both anemic and non-anemic HF patients. A trend toward fewer hospitalizations was seen in the group treated with intravenous iron. The rates of adverse events were similar in the treatment and the placebo groups. Larger-scale and longer-term studies are needed to establish the safety and efficacy profile of intravenous iron in non-CKD HF patients and in HF patients without anemia. Studies designed to further unravel the pathophysiology of anemia in HF are essential in order to determine 1) novel treatment targets and 2) whether and how the treatment of anemia could improve outcomes.