Jeffrey Rollo

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background— Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results— A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ⩽1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions— These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study.

BACKGROUND Atrial fibrillation (AF) diminishes quality of life and accounts for approximately one-third of all strokes. Studies have associated mitochondrial dysfunction with both AF and telomere length (TL). OBJECTIVE The purpose of this study was to test the hypothesis of a relationship between AF and TL. METHODS Blood was collected from consenting participants in the Intermountain Heart Collaborative Study (n = 3576) and DNA extracted. TL was determined by multiplex quantitative polymerase chain reaction, normalized to a single copy gene, and reported as telomere/single gene ratio (t/s). Patient information was extracted from Intermountain Healthcares electronic records database. Prevalent AF was determined by discharge ICD-9 code. AF subtype (paroxysmal [Px], persistent [Ps], long-standing persistent/permanent [Pm]) was determined by chart review. RESULTS The t/s decreased with age (P <.00001). Subjects with a history of AF (n = 379 [10.6%] had shorter telomeres (mean t/s ± SD = 0.87 ± 0.29) compared to subjects without AF (mean t/s 0.95 ± 0.32, P <.0001). The association remained after adjustment for age (P = .017) and cardiovascular risk factors (P = .016). AF subtype was determined for 277 subjects; 110 (39.7%) had Px AF, 65 (23.5%) Ps, and 102 (36.8%) Pm AF. Mean t/s did not differ between Ps, Pm, and subjects without AF (0.94 ± 0.40, 0.94 ± 0.27, and 0.95 ± 0.32, respectively). However, the mean t/s for Px (0.81 ± 0.22) was significantly shorter than for Ps (P = .026), Pm (P = .004), or subjects without AF (P <.0001). CONCLUSION The present study supports an association between Px AF and TL. Short TL may be a previously unrecognized risk factor for AF with potential applications in diagnosis and therapy.

Validation and Quantification of Genetic Determinants of Lipoprotein-a Levels and Predictive Value for Angiographic Coronary Artery Disease

Lipoprotein(a) (Lp[a]) has gained attention as a heritable coronary artery disease (CAD) risk factor and therapeutic target. Two genetic variants in the LPA gene have been reported to influence Lp(a) levels and increase CAD risk. The aim of this study was to prospectively test these variants for their associations with Lp(a) and CAD risk. Participants (n = 1,400) in the Intermountain Heart Collaborative Study Registry who had Lp(a) cholesterol levels determined at coronary angiography were genotyped for rs3798220 and rs1045587 in LPA. Variants were detected by Taqman polymerase chain reaction. Chi-square and linear and logistic regression tests were used as appropriate among genotypes for Lp(a) and angiographic CAD. Age averaged 63 years; 65% were men; and severe CAD was present in 57%, mild CAD in 12%, and no CAD in 31%. Minor allele frequencies were 0.023 for rs3798220 and 0.090 for rs10455872. In multivariate modeling, only rs10455872 (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.67 to 3.33, p = 1.75 × 10⁻⁹) and rs3798220 (OR 1.99, 95% CI 0.99 to 4.00, p = 0.065) contributed to the prediction of elevated Lp(a) cholesterol. Lp(a) cholesterol was weakly associated with CAD (OR 1.17, 95% CI 1.00 to 1.37, p = 0.055). Rs10455872 strongly predicted prevalent CAD (per allele OR 1.43, 95% CI 1.07 to 1.91, p = 0.0172); the effect size for the rare rs3798220 variant was similar (dominant OR 1.47, 95% CI 0.81 to 2.67, p = 0.20), but power was limited to demonstrate significance. The combined genotype explained only a small percentage (≤4%) of variability in Lp(a) cholesterol and prevalence of angiographic CAD. In conclusion, heritable contributions of LPA rs10455872 and rs3798220 to Lp(a) cholesterol levels and to angiographic CAD were prospectively assessed in this study. The percentage of intersubject variability in Lp(a) cholesterol and the percentage of prevalent CAD explained were small.

GLYCA AND GLYCB, NOVEL NMR BIOMARKERS OF INFLAMMATION, STRONGLY PREDICT FUTURE CARDIOVASCULAR EVENTS, BUT NOT THE PRESENCE OF CORONARY ARTERY DISEASE (CAD), AMONG PATIENTS UNDERGOING CORONARY ANGIOGRAPHY: THE INTERMOUNTAIN HEART COLLABORATIVE STUDY

GlycA and GlycB are novel nuclear magnetic resonance spectroscopy (NMR) signals in plasma arising from the glycosylation of circulating acute phase proteins, especially fibrinogen, a1-antichymotrypsin, haptoglobin-1, a1-antitrypsin, complement C3 and a1-acid glycoprotein. These acute phase proteins

Utility of high density lipoprotein particle concentration in predicting future major adverse cardiovascular events among patients undergoing angiography

BACKGROUND HDL-C is recognized to be inversely associated with cardiovascular (CV) risk. However, attenuation of the association of HDL-C with CV risk may occur after adjustment for other lipoprotein parameters and in various disease states, especially in the setting of acute coronary syndrome (ACS). Recently, the number of HDL particles (HDL-P) has been suggested to improve CV risk prediction. METHODS AND RESULTS Patients (n=2999) in the Intermountain Heart Collaborative Study who underwent angiography and had lipoprotein particle measurements determined by nuclear magnetic resonance (NMR) spectroscopy were studied. Multivariable Cox hazard regression was utilized to evaluate the association of HDL-C, HDL-P, and HDL-P subclasses with future major adverse CV events (MACE: death, myocardial infarction, heart failure, and stroke). Patients averaged 64±12years, 66% male, 26% diabetic, and 42% ACS. At angiography, 65% of patients were diagnosed with coronary artery disease (CAD). HDL-C and HDL-P averaged 41±13mg/dL and 28±8μmol/L, respectively. HDL-P (HR=0.903, p=0.001), but not HDL-C (HR=0.947, p=0.102) was significantly associated with MACE. In a model that included all HDL-P subclasses, both small (HR=0.862, p<0.0001) and medium (HR=0.922, p=0.020) were associated with CV risk, but not large HDL-P (HR=1.0042, p=0.185). Small HDL-P continued to be associated with all of the individual components of MACE, but not stroke. CONCLUSION In this study of patients undergoing angiography, HDL-P was a strong, independent predictor of future MACE, with the smaller HDL-P accounting for this association.

INCIDENCE OF DEMENTIA IN RELATION TO GENETIC VARIANTS AT 4Q25 AND APOE ɛ4 IN ATRIAL FIBRILLATION PATIENTS

Genetic predisposition to dementia has been strongly sought, but risk loci remain elusive. Atrial fibrillation (AF), a known risk factor for cerebrovascular accidents (CVA), was recently linked with dementia, especially in a younger population. Two chromosomal loci, 4q25 and 16q22, are associated

DIFFERENTIAL ASSOCIATION OF HIGH-DENSITY LIPOPROTEIN PARTICLE SUBCLASSES AND GLYCA, A NOVEL INFLAMMATORY MARKER, IN PREDICTING CARDIAC DEATH AMONG PATIENTS UNDERGOING ANGIOGRAPHY: THE INTERMOUNTAIN HEART COLLABORATIVE STUDY

HDL particle (HDL-P) concentrations are comprised of particles that vary in size and composition, and potentially, in risk prediction. Inflammation is known to modulate HDL function. Whether increased inflammation alters associations of HDL subclasses with CAD needs further study. Pts (N=2,848) of

METHADONE-INDUCED QTC PROLONGATION IS ASSOCIATED WITH CYP2C19 GENOTYPE AND WITH PLASMA ETHYLIDENE-1,5-DIMETHYL-3,3-DIPHENYLPYRROLIDENE (EDDP) CONCENTRATION: A POSSIBLE MECHANISTIC LINK

Methadone-associated sudden arrhythmic death is due to polymorphic ventricular fibrillation arising from QT prolongation associated with perturbations in the delayed potassium rectifier current. Risk for QT prolongation has been independently associated with both increased formation of the methadone

QTC PROLONGATION CORRELATES WITH PLASMA ETHYLIDENE-1.5-DIMETHYL-3.3-DIPHENYLPYRROLIDENE (EDDP) AMONG SUBJECTS INITIATING METHADONE MAINTENANCE THERAPY

methods: Consenting participants (n=31) initiating methadone maintenance therapy were enrolled in the MEMORIES Trial (Clinical Trials.gov NCT01191242). Peak (4 hr post-oral dose) and trough (24 hr) plasma samples obtained on days 1, 7 and 21 were analyzed for methadone and EDDP (the principal methadone metabolite) by liquid chromatographic tandem mass spectrometry. Pre-treatment and d21 rate-corrected QT interval (QTc) was measured by ECG.