Vitamin D recently has been proposed to play an important role in a broad range of organ functions, including cardiovascular (CV) health; however, the CV evidence-base is limited. We prospectively ...analyzed a large electronic medical records database to determine the prevalence of vitamin D deficiency and the relation of vitamin D levels to prevalent and incident CV risk factors and diseases, including mortality. The database contained 41,504 patient records with at least one measured vitamin D level. The prevalence of vitamin D deficiency (≤30 ng/ml) was 63.6%, with only minor differences by gender or age. Vitamin D deficiency was associated with highly significant (p <0.0001) increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Also, those without risk factors but with severe deficiency had an increased likelihood of developing diabetes, hypertension, and hyperlipidemia. The vitamin D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, and stroke (all p <0.0001), as well as with incident death, heart failure, coronary artery disease/myocardial infarction (all p <0.0001), stroke (p = 0.003), and their composite (p <0.0001). In conclusion, we have confirmed a high prevalence of vitamin D deficiency in the general healthcare population and an association between vitamin D levels and prevalent and incident CV risk factors and outcomes. These observations lend strong support to the hypothesis that vitamin D might play a primary role in CV risk factors and disease. Given the ease of vitamin D measurement and replacement, prospective studies of vitamin D supplementation to prevent and treat CV disease are urgently needed.
Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials.
Consenting patients (n=206) being initiated on ...warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic = 30.7%, standard = 33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic = 29%, standard = 39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of > or = 4 (P=0.03).
An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.
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.
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.
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.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.
The aim of this study was to assess the effect of testosterone replacement therapy (TRT) on cardiovascular outcomes. Men (January 1, 1996, to December 31, 2011) with a low initial total testosterone ...concentration, a subsequent testosterone level, and >3 years of follow-up were studied. Levels were correlated with testosterone supplement use. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death, nonfatal myocardial infarction, and stroke at 3 years. Multivariate adjusted hazard ratios (HRs) comparing groups of persistent low (<212 ng/dl, n = 801), normal (212 to 742 ng/dl, n = 2,241), and high (>742 ng/dl, n = 1,694) achieved testosterone were calculated by Cox hazard regression. A total of 4,736 men were studied. Three-year rates of MACE and death were 6.6% and 4.3%, respectively. Subjects supplemented to normal testosterone had reduced 3-year MACE (HR 0.74; 95% confidence interval CI 0.56 to 0.98, p = 0.04) compared to persistently low testosterone, driven primarily by death (HR 0.65, 95% CI 0.47 to 0.90). HRs for MI and stroke were 0.73 (95% CI 0.40 to 1.34), p = 0.32, and 1.11 (95% CI 0.54 to 2.28), p = 0.78, respectively. MACE was noninferior but not superior for high achieved testosterone with no benefit on MI and a trend to greater stroke risk. In conclusion, in a large general health care population, TRT to normal levels was associated with reduced MACE and death over 3 years but a stroke signal with high achieved levels suggests a conservative approach to TRT.
Intermittent fasting (IF) has been connected with health benefits such as weight loss, lower risk of coronary artery disease (CAD) and diabetes, increased longevity, and improved quality of life. ...However, the mechanisms of these IF benefits in humans require further investigation. This study sought to elucidate some of these mechanisms through secondary analyses of the Fasting and ExprEssion of Longevity Genes during fOOD abstinence (FEELGOOD) trial, in which apparently healthy participants were randomized in a Latin square design to a 24-h water-only fast and a 24-h ad libitum fed day. Two pathways were investigated, with trimethylamine
-oxide (TMAO) levels measured due to their association with elevated risk of CAD, along with conductance of a broad panel of metabolic analytes. Measurements were made at baseline, at the end of the fasting day, and at the end of the fed day. A fasting mean of 14.3 ng in TMAO was found versus the baseline mean of 27.1 ng with
= 0.019, although TMAO levels returned to baseline on refeeding. Further, acute alterations in levels of proline, tyrosine, galactitol, and urea plasma levels were observed along with changes in 24 other metabolites during the fasting period. These acute changes reveal short-term mechanisms which, with consistent repeated episodes of IF, may lead to improved health and reduced risk of CAD and diabetes.
By guiding initial warfarin dose, pharmacogenetic (PGx) algorithms may improve the safety of warfarin initiation. However, once international normalised ratio (INR) response is known, the ...contribution of PGx to dose refinements is uncertain. This study sought to develop and validate clinical and PGx dosing algorithms for warfarin dose refinement on days 6-11 after therapy initiation. An international sample of 2,022 patients at 13 medical centres on three continents provided clinical, INR, and genetic data at treatment days 6-11 to predict therapeutic warfarin dose. Independent derivation and retrospective validation samples were composed by randomly dividing the population (80%/20%). Prior warfarin doses were weighted by their expected effect on S-warfarin concentrations using an exponential-decay pharmacokinetic model. The INR divided by that "effective" dose constituted a treatment response index . Treatment response index, age, amiodarone, body surface area, warfarin indication, and target INR were associated with dose in the derivation sample. A clinical algorithm based on these factors was remarkably accurate: in the retrospective validation cohort its R(2) was 61.2% and median absolute error (MAE) was 5.0 mg/week. Accuracy and safety was confirmed in a prospective cohort (N=43). CYP2C9 variants and VKORC1-1639 G→A were significant dose predictors in both the derivation and validation samples. In the retrospective validation cohort, the PGx algorithm had: R(2)= 69.1% (p<0.05 vs. clinical algorithm), MAE= 4.7 mg/week. In conclusion, a pharmacogenetic warfarin dose-refinement algorithm based on clinical, INR, and genetic factors can explain at least 69.1% of therapeutic warfarin dose variability after about one week of therapy.
Background Depression is associated with cardiovascular (CV) disease, and it has been hypothesized that vitamin (vit)D deficiency may be associated with depression and a contributing factor to excess ...CV events. Therefore, we evaluated whether there is an association between vitD and incident depression among a CV population. Methods Patients (N = 7,358) ≥50 years of age, with a CV diagnosis (coronary artery disease, myocardial infarction, congestive heart failure, cerebrovascular accident, transient ischemic accident, atrial fibrillation, or peripheral vascular disease), no prior depression diagnosis, and a measured vitD level were studied. Vitamin D (ng/mL) was stratified into 4 categories: >50 (optimal O n = 367), 31 to 50 (normal N n = 2,264), 16 to 30 (low L n = 3,402), and ≥15 (very low VL n = 1,325). Depression was defined by International Classification of Diseases, Ninth Edition , codes: 296.2 to 296.36, 311. VitD categories were evaluated by Cox hazard regression with adjustment by standard CV risk factors. Results Age averaged 73.1 ± 10.2 years, and 58.8% were female. When compared to O, VL, L, and N were associated with depression (adjusted: VL, hazard ratio HR 2.70 1.35-5.40, P = .005; L, HR 2.15 1.10-4.21, P = .03; N, HR 1.95 0.99-3.87, P = .06). This association remained even after adjustment by parathyroid hormone levels. Parathyroid hormone was significantly associated with depression, however, became nonsignificant after adjustment by vitD. Winter (December-February) enhanced this association. Significant associations remained when stratifications were made by age (<65, ≥65), sex, and diabetes, although the associations among those age ≥65 and male sex were enhanced. Conclusion Among a CV population ≥50 years with no history of depression, vitD levels were shown to be associated with incident depression after vitD draw. This study strengthens the hypothesis of the association between vitD and depression.
Red cell distribution width (RDW) is associated with morbidity and mortality in coronary artery disease (CAD), but the connection of RDW with chronic inflammation is equivocal.
In 1,489 patients with ...CAD and 8.4–15.2years of follow-up all-cause mortality and RDW were studied using Cox regression. RDW and its associations with inflammation, liver function, renal function, and body mass were assessed. A population of 449 normal (No-CAD) patients also was evaluated.
RDW predicted all-cause mortality in a step-wise manner (HR=1.37 per quintile; 95% CI=1.29, 1.46; p-trend<0.001). A significant but meaningless correlation between RDW and high-sensitivity C-reactive protein (hsCRP) was identified (r=0.181; p<0.001). With full adjustment, RDW remained significant (p-trend<0.001) and the strongest predictor of mortality among all factors included in the model. RDW also strongly predicted all-cause mortality in the normal control population (HR=1.33 per quintile, CI=1.15, 1.55; p-trend<0.001), but hsCRP did not predict mortality among normal controls.
RDW was associated with mortality in patients with CAD and may provide clinically useful prognostication. Although RDW was correlated with hsCRP, they were independent predictors of mortality. RDW has been incorporated into risk prediction tool using data from basic chemistries available at: http://intermountainhealthcare.org/IMRS.
► Red cell distribution width (RDW) is associated with mortality in CAD patients. ► The etiology of RDW elevation is unknown. ► Elevation of RDW is not due to chronic inflammation as measured by hsCRP. ► RDW is also associated with mortality in controls and is not a coronary disease-specific or heart failure-specific marker. ► Despite an unknown pathophysiology, elevated RDW is a strong predictor of mortality.
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).
...The purpose of this study was to test the hypothesis of a relationship between AF and TL.
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 Healthcare's 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.
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).
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.
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