Radiologic assessment of HeartMate II position: Minimal pump migration after long-term support.

BACKGROUND: Surgical positioning of the HeartMate II (HMII) left ventricular assist device assuring an unobstructed blood flow path is essential for optimal device function and hemodynamic support. We report a non-invasive radiologic assessment of HMII position after implant and long-term follow-up. METHODS: We reviewed 132 consecutive patients (age 64 ± 14 years; 86% male; 60% destination therapy) implanted with an HMII from January 2009 to December 2012 and followed for them for up to 4 years. A radiologist measured pump position, pocket depth and cannula angles using chest radiography. Changes over time were determined in 64 of these patients with pairs of radiographs immediately after implant and at an average of 2.0 ± 0.7 years of follow-up. RESULTS: The axis of the pump relative to the spine was 92 ± 10° at baseline and 94 ± 9° at 2 years (n = 64, p = 0.02), and inflow cannula angles averaged 21 ± 13° from vertical at baseline and 20 ± 12° at 2 years (p = not statistically significant). More than 90% of angle measurements showed <15° movement over the follow-up duration. There was a small but significant superior pump migration from a depth of 12.7 ± 2.7 cm to 10.4 ± 2.6 cm (p < 0.001). There were no cannula obstructions or instances of right ventricular assist device use. The 30-day operative mortality was 3.0%. Prolonged inotrope dependence occurred in 5.3% (7 of 126) of patients, and low rates of pump thrombosis of 0.018 event/patient-year (0 at 3 months) and stroke 0.074 event/patient-year were noted. CONCLUSION: Non-invasive radiographic measurements of surgical pump placement designed to avoid pump and cannula malposition demonstrate stable position with minimal pump migration.

Exposure to non-therapeutic INR in a high risk cardiovascular patient: potential hazard reduction with genotype-guided warfarin (Coumadin) dosing.

A case to illustrate the utility of genetic screening in warfarin (Coumadin) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/ day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively-far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. The patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2,*3,*4,*5,*6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G > A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. The results highlight the potential for warfarin genetic testing to improve patient care.

Physiogenomic comparison of edema and BMI in patients receiving rosiglitazone or pioglitazone.

BACKGROUND: The thiazolidinediones (TZDs) improve tissue sensitivity to insulin in patients with type II diabetes, resulting in reduced levels of fasting blood glucose and glycated hemoglobin. However, TZDs unpredictably demonstrate adverse effects of increased body weight, fluid retention, and edema. The balance of efficacy and safety of TZD varies widely from patient to patient. Genetic variability may reveal pathophysiological pathways underlying weight gain associated with TZD therapy and due to adiposity and/or edema. METHODS: We analyzed 384 single nucleotide polymorphisms (SNPs) from 222 cardiovascular and metabolic genes in 87 outpatients with type 2 diabetes receiving thiazolidinedione therapy. Physiogenomic analysis was used to discover associations with body mass index (BMI) and edema. RESULTS: The 5 most significant gene associations found between BMI and SNPs were ADORA1, adenosine A1 receptor (rs903361, p<0.0003), PKM2, pyruvate kinase-muscle (rs2856929, p<0.002); ADIPOR2, adiponectin receptor 2 (rs7975375, p<0.007); UCP2, uncoupling protein 2 (rs660339, p<0.008); and APOH, apolipoprotein H (rs8178847, p<0.010). For edema, the 5 most significant gene associations were NPY, neuropeptide Y (rs1468271, p<0.006); GYS1, glycogen synthase 1-muscle (rs2287754, p<0.013); CCL2, chemokine C-C motif ligand 2 (rs3760396, p<0.015); OLR1, oxidized LDL receptor 1 (rs2742115, p<0.015); and GHRH, growth hormone releasing hormone (rs6032470, p<0.023). After accounting for multiple comparisons, ADORA1 was significantly associated with BMI at a false discovery rate (FDR) of <10%. CONCLUSION: Physiogenomic associations were discovered suggesting mechanistic links between adenosine signaling and BMI, and between vascular permeability and drug-induced edema.

Integrating genomic based information into clinical warfarin (Coumadin) management: an illustrative case report.

Warfarin is a well established oral anticoagulant for the treatment of thromboembolic disorders. Warfarin therapy is complicated by a narrow therapeutic index and marked inter-individual dose variability with therapeutic doses ranging from 1 mg to 10 mg/day. Recently genetic variation and resultant drug metabolizing polymorphisms have been found to contribute to warfarin dose variability with resultant hemorrhagic or thromboembolic complications. Cytochrome P4502C9 alters the rate of warfarin metabolism and clearance. A second enzyme, Vitamin K Epoxide Reductase Complex (VKORC) binds and reduces Vitamin K which is necessary for activation of clotting Factors II, VII, IX and X. The VKORC1 gene encodes for Vitamin K Epoxide Reductase Complex subunit 1, a key component of VKORC. The combination of physiologic factors (30%), CYP2C9 variations (20%) and VKORC1 variants (25%) accounts for approximately 75% of warfarin dose variability. This illustrative case report demonstrates the clinical importance of this new information. Clinicians need to incorporate these new genomic findings into appropriate management of warfarin dose anticoagulation.

High carrier prevalence of combinatorial CYP2C9 and VKORC1 genotypes affecting warfarin dosing.

BACKGROUND: Polymorphisms in the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes significantly alter the effective warfarin dose. The CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C) and VKORC1 -1639 G>A polymorphisms affect warfarin dose through altered metabolism (CYP2C9) and sensitivity (VKORC1). OBJECTIVE: We determined the frequencies of SNPs in the CYP2C9 and VKORC1 genes in a clinical outpatient population and the carrier prevalences for a variety of genotype combinations to gauge the impact of these polymorphisms on warfarin dosage using published algorithms. METHOD: A total of 127 patients from an outpatient clinic at Hartford Hospital (Hartford, CT, USA) were genotyped for five SNPs in the CYP2C9 gene and seven SNPs in the VKORC1 gene using Luminex® technology. RESULTS: The polymorphism frequencies were 10.2, 7.9 and 37.4% for the functionally deficient CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms, respectively. Combining prevalence of combinatorial genotypes, 18% were carriers of both CYP2C9 and VKORC1 polymorphisms, 13% were CYP2C9 polymorphism carriers only, 42.5% were VKORC1 carriers only, and the remaining 27% were noncarriers for either gene. Based on published warfarin dosing algorithms, carriers of 1, 2, 3 and 4 functionally deficient polymorphisms predict reductions of 1.0 to 1.6, 2.0 to 2.9, 2.9 to 3.7, and 3.6 to 4.4 mg/day, respectively, in warfarin dose. CONCLUSION: Overall, 73% of the population carried at least one polymorphism predicting deficient warfarin metabolism or responsiveness and 18% were carriers for polymorphisms in both genes studied. Combinatorial genotyping of CYP2C9 and VKORC1 can allow for individualized dosing of warfarin amongst patients with gene polymorphisms potentially reducing the risk of accentuated responses and bleeding.

Increased carrier prevalence of deficient CYP2C9, CYP2C19 and CYP2D6 alleles in depressed patients referred to a tertiary psychiatric hospital.

OBJECTIVE: This study compared the types and carrier prevalences of clinically significant DNA polymorphisms in the cytochrome P450 (CYP450) genes CYP2C9, CYP2C19 and CYP2D6 in major depressive disorder patients with a control group of nonpsychiatrically ill, medical outpatients. METHOD: We conducted a case-control study using 73 psychiatric outpatients diagnosed with depression and referred to a tertiary center, The Institute of Living (Hartford, CT, USA), for treatment resistance or intolerable side-effects to psychotropic drugs. The controls were 120 cardiovascular patients from Hartford Hospital being treated for dyslipidemia but otherwise healthy and not psychiatrically ill. DNA typing to detect polymorphisms in the genes CYP2C9, CYP2C19 and CYP2D6 was accomplished with the Tag-It™ mutation detection assay and the Luminex xMAP® system. RESULTS: The percentage of individuals in psychiatric versus control groups with two wild-type alleles for CYP2C9, CYP2C19 and CYP2D6 genes, were 50 versus 74% (p < 0.001), 71 versus 73% (not statistically significant) and 36 versus 43% (trend, p < 0.2), respectively. Within the psychiatric population, 57% of individuals were carriers of non-wild-type alleles for 2-3 genes, compared with 36% in the control population (p < 0.0001). The balance, 43% in the psychiatric population and 64% in the control, were carriers of non-wild-type alleles for none or one gene. CONCLUSIONS: These findings reveal that clinically relevant CYP2C9 polymorphisms occur more frequently in depressed psychiatric patients than in nonpsychiatric controls. The same trend was found for polymorphisms in the CYP2D6 gene. We found a significant cumulative metabolic deficiency in the psychiatric population for combinations of the CYP2C9, CYP2C19 and CYP2D6 genes. The significant enrichment of CYP2C9-deficient alleles in the psychiatric population validates a previously reported association of this gene with the risk for depression disorders. The high prevalence of carriers with deficient and null alleles suggests that CYP450 DNA typing may play a role in the management of psychiatric patients at tertiary care institutions.

Somatic complications of psychotropic medications in a patient with multiple CYP2 drug metabolism deficiencies.

A 54-year-old woman presented with severe anxiety, multiple somatic complaints, medication intolerance and adverse drug reactions (ADRs) to numerous prescribed psychotropic medications. Multiple drug metabolizing deficiencies were suspected. Molecular analysis was performed for the CYP2 family of Cytochrome P450 (CYP450) drug metabolism isoenzymes by DNA typing CYP2D6, CYP2C9, and CYP2C19 genes. A multiple deficiency in CYP2 drug metabolism was discovered. The patient was a double carrier of null alleles for CYP2D6, a carrier of a null allele for CYP2C19 and a carrier of a deficient allele for CYP2C9. These alleles were confirmed by Mendelian inheritance in her nuclear family, where her brother had a similar multigene CYP2 deficiency. The patient improved clinically with discontinuation of psychotropic medications, suggesting that much of her symptomatology was drug-induced. DNA typing for multigene CYP2 deficiencies is diagnostically useful in individuals with histories of multiple ADRs, which could be avoided by DNA-guided individualized prescription.

High carrier prevalence of deficient and null alleles of CYP2 genes in a major USA hospital: implications for personalized drug safety.

Many drugs are metabolized by highly polymorphic cytochrome P450 (CYP) enzymes. Among these enzymes, members of the CYP2 family coded by the CYP2D6, CYP2C9 and CYP2C19 genes are best amenable to the precise prediction of an individual's innate capacity to metabolize drugs by DNA typing of inherited null and deficient alleles. We determined the frequency of these alleles and the prevalence of their carriers in a New England, USA, tertiary care center to assess underlying population genetic features for the practice of personalized medicine. We determined that 54, 25 and 27% are carriers of at least one deficient or null allele for the CYP2D6, CYP2C9 and CYP2C19 genes, respectively. Furthermore, 6% of individuals are carriers of two null alleles for CYP2D6 and are predicted to have no biochemical activity for this isoenzyme. These results support the implementation of DNA typing of CYP2 genes to diagnose adverse drug reactions and to prevent a substantial number of patients being prescribed drugs they cannot adequately metabolize.