The Hedgehog Signaling Pathway in Ischemic Tissues.

Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in the ischemic condition is also presented.

A gene risk score using missense variants in SLCO1B1 is associated with earlier onset statin intolerance.

BACKGROUND AND AIMS: The efficacy of statin therapy is hindered by intolerance to the therapy, leading to discontinuation. Variants in SLCO1B1, which encodes the hepatic transporter OATB1B1, influence statin pharmacokinetics, resulting in altered plasma concentrations of the drug and its metabolites. Current pharmacogenetic guidelines require sequencing of the SLCO1B1 gene, which is more expensive and less accessible than genotyping. In this study, we aimed to develop an easy, clinically implementable functional gene risk score (GRS) of common variants in SLCO1B1 to identify patients at risk of statin intolerance. METHODS AND RESULTS: A GRS was developed from four common variants in SLCO1B1. In statin users from Tayside, Scotland, UK, those with a high-risk GRS had increased odds across three phenotypes of statin intolerance [general statin intolerance (GSI): ORGSI 2.42; 95% confidence interval (CI): 1.29-4.31, P = 0.003; statin-related myopathy: ORSRM 2.51; 95% CI: 1.28-4.53, P = 0.004; statin-related suspected rhabdomyolysis: ORSRSR 2.85; 95% CI: 1.03-6.65, P = 0.02]. In contrast, using the Val174Ala genotype alone or the recommended OATP1B1 functional phenotypes produced weaker and less reliable results. A meta-analysis with results from adjudicated cases of statin-induced myopathy in the PREDICTION-ADR Consortium confirmed these findings (ORVal174Ala 1.99; 95% CI: 1.01-3.95, P = 0.048; ORGRS 1.76; 95% CI: 1.16-2.69, P = 0.008). For those requiring high-dose statin therapy, the high-risk GRS was more consistently associated with the time to onset of statin intolerance amongst the three phenotypes compared with Val174Ala (GSI: HRVal174Ala 2.49; 95% CI: 1.09-5.68, P = 0.03; HRGRS 2.44; 95% CI: 1.46-4.08, P < 0.001). Finally, sequence kernel association testing confirmed that rare variants in SLCO1B1 are associated with the risk of intolerance (P = 0.02). CONCLUSION: We provide evidence that a GRS based on four common SLCO1B1 variants provides an easily implemented genetic tool that is more reliable than the current recommended practice in estimating the risk and predicting early-onset statin intolerance.

The cholesterol-lowering effect of statins is modified by LILRB5 intolerance genotype: Results from a recruit-by-genotype clinical trial.

Background/Aims: Statin intolerance leads to poor adherence to statin therapy, resulting in a failure to achieve desired cholesterol reduction and adverse outcomes. The LILRB5 Asp247Gly genotype has been identified as being associated with statin intolerance and statin-induced myalgia. We conducted a randomized clinical trial to examine its role in immune response through T regulatory cell aggregation and in achieving cholesterol reduction targets. Methods: A double-blind, cross-over, recruit-by-genotype trial was undertaken. A total of 18 participants who had either the Asp247Asp (T/T) genotype or the Gly247Gly (C/C) genotype were recruited to the study. Participants were randomised to receive placebo or atorvastatin 80 mg daily for 28 days. Following a washout period of 3 weeks, they were then switched to the opposite treatment. Biochemical and immunological measurements as well as interviews were performed prior to and after both treatment periods. Within genotype group comparisons were performed using repeated measures Wilcoxon tests. Two-way repeated measures ANOVA with genotype and treatment as factors were used to compare changes in biochemical parameters between groups during placebo and atorvastatin periods. Results: Individuals with the Asp247Asp genotype had a greater increase in creatine kinase (CK) compared to those with Gly247Gly genotype in response to atorvastatin (p = 0.03). Those with Gly247Gly genotype had a mean non-HDL cholesterol reduction of 2.44 (95% CI:1.59 - 3.29) mmol/L while in Asp247Asp genotype group the mean reduction was 1.28 (95%CI: 0.48 - 2.07) mmol/L. The interaction between the genotype and atorvastatin treatment for total cholesterol (p = 0.007) and non-HDL cholesterol response was significant (p = 0.025). Immunological assessment showed no significant changes in aggregation of T regulatory cells by genotype. Conclusion: The Asp247Gly variant in LILRB5, previously associated with statin intolerance, was associated with differential increases in creatine kinase and total cholesterol and non-HDL cholesterol-lowering response to atorvastatin. Taken together, these results suggest that this variant could have utility in precision cardiovascular therapy.

A Single Center Retrospective Cohort Study Comparing Different Anticoagulants for the Treatment of Catheter-Related Thrombosis of the Upper Extremities in Women With Gynecologic and Breast Cancer.

Background: Catheter-related thrombosis (CRT) of the upper extremities is a frequent complication among cancer patients that carry a central venous catheter (CVC) and may lead to pulmonary embolism (PE) and loss of CVC function. Despite its clinical impact, no anticoagulant treatment scheme has been rigorously evaluated in these patients. In addition, there is no proven evidence that direct oral anticoagulants (DOACs) are efficacious and safe in this setting because cancer patients with CRT of the upper extremities were not included in the clinical trials that led to the approval of DOACs for the treatment of cancer-associated venous thromboembolism (VTE). Methods: We performed a single center retrospective cohort study on women with gynecologic or breast cancer treated with either low-molecular-weight heparin, fondaparinux, or DOACs for CRT of the upper extremities. Only patients who received anticoagulation at the proper therapeutic dose and for at least 3 months were included in the analysis. Effectiveness was evaluated in terms of preservation of line function, residual thrombosis, and recurrence of VTE (including PE). Safety was evaluated in terms of death, major bleeding (MB), and clinically relevant non-major bleeding (CRNMB). Results: We identified 74 women who fulfilled the criteria to be included in the analysis. Of these, 31 (41.9%) had been treated with fondaparinux, 21 (28.4%) with enoxaparin, and 22 (29.7%) with the DOAC edoxaban. We found no differences between patients treated with the three different therapeutic approaches, in terms of preservation of line function, incidence of residual thrombosis, and VTE recurrence (including PE). Safety was similar as well, with no MBs recorded in any treatment group. Conclusion: These results, although retrospective and based on a relatively small sample size, indicate that, in women with gynecologic or breast cancer, CRT of the upper extremities may be treated with similar effectiveness and safety with fondaparinux, enoxaparin, and edoxaban. Further studies are needed to substantiate these findings.

Common Statin Intolerance Variants in ABCB1 and LILRB5 Show Synergistic Effects on Statin Response: An Observational Study Using Electronic Health Records.

Background: Statin intolerance impacts approximately 10% of statin users, with side effects ranging from mild myalgia to extreme intolerance resulting in myopathy and rhabdomyolysis. Statin intolerance results in poor adherence to therapy and can impact statin efficacy. Many genetic variants are associated with statin intolerance. The effect of these variants on statin efficacy has not been systematically explored. Methods: Using longitudinal electronic health records and genetic biobank data from Tayside, Scotland, we examined the effect of seven genetic variants with previously reported associations with simvastatin or atorvastatin intolerance on the outcome of statin response. Statin response was measured by the reduction achieved when comparing pre- and post-statin non-high-density lipoprotein-cholesterol (non-HDL-C). Post-treatment statin response was limited to non-HDL-C measured within 6months of therapy initiation. Univariate and multivariable linear regression models were used to assess the main and adjusted effect of the variants on statin efficacy. Results: Around 9,401 statin users met study inclusion criteria, of whom 8,843 were first prescribed simvastatin or atorvastatin. The average difference in post-treatment compared to pre-treatment non-HDL-cholesterol was 1.45 (±1.04) mmol/L. In adjusted analyses, only two variants, one in the gene ATP-binding cassette transporter B1 (ABCB1; rs1045642), and one in leukocyte immunoglobulin like receptor B5 (LILRB5; rs12975366), were associated with statin efficacy. In ABCB1, homozygous carriers of the C allele at rs1045642 had 0.06mmol/L better absolute reduction in non-HDL-cholesterol than carriers of the T allele (95% CI: 0.01, 0.1). In LILRB5 (rs12975366), carriers of the C allele had 0.04mmol/L better absolute reduction compared to those homozygous for the T allele (95% CI: 0.004, 0.08). When combined into a two-variant risk score, individuals with both the rs1045642-CC genotype and the rs12975366-TC or CC genotype had a 0.11mmol/L greater absolute reduction in non-HDL-cholesterol compared to those with rs1045642-TC or TT genotype and the rs12975366-TT genotype (95% CI: 0.05, 0.16; p<0.001). Conclusion: We report two genetic variants for statin adverse drug reactions (ADRs) that are associated with statin efficacy. While the ABCB1 variant has been shown to have an association with statin pharmacokinetics, no similar evidence for LILRB5 has been reported. These findings highlight the value of genetic testing to deliver precision therapeutics to statin users.