Tami L. Bair

Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population.

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.

Plasma Homocysteine Predicts Mortality Independently of Traditional Risk Factors and C-Reactive Protein in Patients With Angiographically Defined Coronary Artery Disease

BackgroundPlasma homocysteine (tHCY) has been associated with coronary artery disease (CAD). We tested whether tHCY also increases secondary risk, after initial CAD diagnosis, and whether it is independent of traditional risk factors, C-reactive protein (CRP), and methylenetetrahydrofolate reductase (MTHFR) genotype. Methods and ResultsBlood samples were collected from 1412 patients with severe angiographically defined CAD (stenosis ≥70%). Plasma tHCY was measured by fluorescence polarization immunoassay. The study cohort was evaluated for survival after a mean of 3.0±1.0 years of follow-up (minimum 1.5 years, maximum 5.0 years). The average age of the patients was 65±11 years, 77% were males, and 166 died during follow-up. Mortality was greater in patients with tHCY in tertile 3 than in tertiles 1 and 2 (mortality 15.7% versus 9.6%, P =0.001 [log-rank test], hazard ratio [HR] 1.63). The relative hazard increased 16% for each 5-&mgr;mol/L increase in tHCY (P <0.001). In multivariate Cox regression analysis, controlling for univariate clinical and laboratory predictors, elevated tHCY remained predictive of mortality (HR 1.64, P =0.009), together with age (HR 1.72 per 10-year increment, P <0.0001), ejection fraction (HR 0.84 per 10% increment, P =0.0001), diabetes (HR 1.98, P =0.001), CRP (HR 1.42 per tertile, P =0.004), and hyperlipidemia. Homozygosity for the MTHFR variant was weakly predictive of tHCY levels but not mortality. ConclusionsIn patients with angiographically defined CAD, tHCY is a significant predictor of mortality, independent of traditional risk factors, CRP, and MTHFR genotype. These findings increase interest in tHCY as a secondary risk marker and in secondary prevention trials (ie, with folate/B vitamins) to determine whether reduction in tHCY will reduce risk.

Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation.

Outcomes in Patients With AF. Introduction: Atrial fibrillation (AF) adversely impacts mortality, stroke, heart failure, and dementia. AF ablation eliminates AF in most patients. We evaluated the long‐term impact of AF ablation on mortality, heart failure (HF), stroke, and dementia in a large system‐wide patient population.

Usefulness of high-sensitivity C-Reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction

High-sensitivity C-reactive protein (CRP), proposed as a new coronary risk marker, may reflect either an acute phase reaction or the level of chronic inflammation. Thus, CRP may be less predictive of long-term outcomes when measured after acute myocardial infarction (AMI) than after unstable angina pectoris (UAP) or stable angina pectoris (SAP). A total of 1,360 patients with severe coronary artery disease (>/=1 stenosis >/=70%) had CRP levels obtained at angiography. Presenting diagnoses were SAP (n = 599), UAP (n = 442), or AMI (n = 319). During follow-up (mean 2.8 years), death or nonfatal AMI (D/AMI) occurred in 19.5%, 16.1%, and 17.2% (p = NS) with SAP, UAP, and AMI, respectively. Corresponding median CRP levels were 1.31, 1.27, and 2.50 mg/dl (p <0.001). For the overall cohort, increasing age, low ejection fraction, revascularization, and elevated CRP were the strongest of 6 independent predictors for D/AMI. Among those presenting with SAP, CRP levels above the first tertile were associated with an adjusted hazard ratio of 1.8 (95% confidence interval [CI] 1.2 to 2.8, p <0.009) for D/AMI. After UAP, the hazard ratio was 2.7 (95% CI 1.4 to 5.0, p <0.002). However, when measured during hospitalization for AMI, CRP was not predictive of long-term outcome (hazard ratio 1.0 [95 % CI 0.5 to 1.7] p = 0.86). In conclusion, predischarge CRP levels are higher after AMI than after UAP or SAP. However, whereas CRP is strongly predictive of long-term D/AMI for patients presenting with SAP or UAP, it is not predictive shortly after AMI, suggesting that measurements should be delayed until the acute phase reaction is over and levels have returned to baseline.

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.

Atrial fibrillation is independently associated with senile, vascular, and Alzheimer's dementia

BACKGROUND The aging population has resulted in more patients living with cardiovascular disease, such as atrial fibrillation (AF). Recent focus has been placed on understanding the long-term consequences of chronic cardiovascular disease, such as a potential increased risk of dementia. OBJECTIVE This study sought to determine whether there is an association between AF and dementia and whether their coexistence is an independent marker of risk. METHODS A total of 37,025 consecutive patients from the large ongoing prospective Intermountain Heart Collaborative Study database were evaluated and followed up for a mean of 5 years for the development of AF and dementia. Dementia was sub-typed into vascular (VD), senile (SD), Alzheimers (AD), and nonspecified (ND). RESULTS Of the 37,025 patients with a mean age of 60.6 +/- 17.9 years, 10,161 (27%) developed AF and 1,535 (4.1%) developed dementia (179 VD, 321 SD, 347 AD, 688 ND) during the 5-year follow-up. Patients with dementia were older and had higher rates of hypertension, coronary artery disease, renal failure, heart failure, and prior strokes. In age-based analysis, AF independently was significantly associated with all dementia types. The highest risk was in the younger group (<70). After dementia diagnosis, the presence of AF was associated with a marked increased risk of mortality (VD: hazard ratio [HR] = 1.38, P = .01; SD: HR = 1.41, P = .001; AD: HR = 1.45; ND: HR = 1.38, P <.0001). CONCLUSION AF was independently associated with all forms of dementia. Although dementia is strongly associated with aging, the highest risk of AD was in the younger group, in support of the observed association. The presence of AF also identified dementia patients at high risk of death.

Cytomegalovirus Seropositivity and C-Reactive Protein Have Independent and Combined Predictive Value for Mortality in Patients With Angiographically Demonstrated Coronary Artery Disease

BackgroundThe role of inflammation in coronary artery disease (CAD) is being increasingly recognized. Markers of inflammation (eg, C-reactive protein [CRP]) and infection (eg, seropositivity to Chlamydia pneumoniae, cytomegalovirus [CMV], and Helicobacter pylori) have been proposed as risk factors for CAD, but these associations require further evaluation. Methods and ResultsWe prospectively tested whether CRP levels and IgG seropositivity to C pneumoniae, CMV, and H pylori are predictors of subsequent mortality in 985 consecutive patients with angiographically demonstrated CAD (stenosis ≥70%). Patients were followed for an average of 2.7 years (range 1.5 to 4.0 years). Patients averaged 65 years of age; 77% were men; and 110 (11.2%) died during follow-up. CRP levels were significantly elevated in nonsurvivors compared with survivors (mean CRP 3.1 mg/dL versus 1.5 mg/dL, P =0.003). After controlling for all known baseline variables, the 2nd and 3rd tertiles of CRP compared with the 1st produced a Cox hazard ratio (HR) for mortality of 2.4 (P =0.001). Of the 3 infectious markers tested, only seropositivity to CMV (HR=1.9, P <0.05) was predictive of mortality. The majority of mortality risk associated with elevated CRP or CMV seropositivity occurred when both risk factors were present (P for trend <0.0001). Other independent predictors of increased risk of mortality were age (HR=1.07 per year, P <0.0001), left ventricular ejection fraction (HR=0.97 per percent, P <0.0001), and diabetes mellitus (HR=1.7, P =0.02). ConclusionsCMV seropositivity and elevated CRP, especially when in combination, are strong, independent predictors of mortality in patients with CAD. This suggests an interesting hypothesis that a chronic, smoldering infection (CMV) might have the capacity to accelerate the atherothrombotic process.

Statin therapy, lipid levels, C-reactive protein and the survival of patients with angiographically severe coronary artery disease.

OBJECTIVES The joint predictive value of lipid and C-reactive protein (CRP) levels, as well as a possible interaction between statin therapy and CRP, were evaluated for survival after angiographic diagnosis of coronary artery disease (CAD). BACKGROUND Hyperlipidemia increases risk of CAD and myocardial infarction. For first myocardial infarction, the combination of lipid and CRP levels may be prognostically more powerful. Although lipid levels are often measured at angiography to guide therapy, their prognostic value is unclear. METHODS Blood samples were collected from a prospective cohort of 985 patients diagnosed angiographically with severe CAD (stenosis > or =70%) and tested for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and CRP levels. Key risk factors, including initiation of statin therapy, were recorded, and subjects were followed for an average of 3.0 years (range: 1.8 to 4.3 years) to assess survival. RESULTS Mortality was confirmed for 109 subjects (11%). In multiple variable Cox regression, levels of TC, LDL, HDL and the TC:HDL ratio did not predict survival, but statin therapy was protective (adjusted hazard ratio [HR] = 0.49, p = 0.04). C-reactive protein levels, age, left ventricular ejection fraction and diabetes were also independently predictive. Statins primarily benefited subjects with elevated CRP by eliminating the increased mortality across increasing CRP tertiles (statins: HR = 0.97 per tertile, p-trend = 0.94; no statins: HR = 1.8 per tertile, p-trend < 0.0001). CONCLUSIONS Lipid levels drawn at angiography were not predictive of survival in this population, but initiation of statin therapy was associated with improved survival regardless of the lipid levels. The benefit of statin therapy occurred primarily in patients with elevated CRP.

Effect of fasting glucose levels on mortality rate in patients with and without diabetes mellitus and coronary artery disease undergoing percutaneous coronary intervention

BACKGROUND Diabetes mellitus (DM) is predictive of increased mortality for patients with coronary artery disease (CAD). To what extent this risk extends below the diabetic threshold (fasting glucose level [FG] <126 mg/dL) is uncertain. METHODS The study objective was to determine the risk associated with FG in a prospectively assembled cohort of 1612 patients with CAD who were undergoing percutaneous coronary intervention (PCI) and had a FG measured or a clinical diagnosis of DM (CDM). Patients were grouped as: CDM; no CDM, but FG > or =126 mg/dL (ADA-DM); impaired FG, 110-125 mg/dL (IFG); or normal FG, <110 mg/dL (NFG). Survival was assessed for 2.8 +/- 1.2 years. RESULTS The average patient age was 62 +/- 12 years; 74% of the patients were men. Diagnostic frequencies were: CDM, 24%; ADA-DM, 18%; IFG, 19%; and NFG, 39%. Mortality rates were greater for patients in the CDM (44/394 [11.2%], P <.0001), ADA-DM (27/283 [9.5%], P <.001), and IFG (20/305 [6.6%], P =.04) groups than patients in the NFG group(12/630 [1.9%]). Independent receiver operating characteristic analysis chose FG > or =109 mg/dL as the best cutoff for increased risk (sensitivity, 81%; specificity, 51%). After adjustment with Cox regression analysis, CDM (hazard ratio [HR] = 5.0; 95% CI, 2.6-9.6; P <.001), ADA-DM (HR, 4.1; 95% CI, 2.1-8.2; P <.001), and IFG status (HR, 3.2; 95% CI, 1.5-6.5; P =.002) remained independent predictors of mortality. CONCLUSIONS Prognostically significant abnormalities of FG are much more prevalent (61%) than expected in patients with CAD who are undergoing PCI. Despite revascularization, the associated mortality risk of even mild elevations in FG is substantial, emphasizing the importance of early detection and treatment of glycemia-related risk.

Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients.

OBJECTIVES This study evaluated the effect of statin therapy on mortality in individuals with significant coronary artery disease (CAD) stratified by age. BACKGROUND Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) significantly reduce morbidity and mortality in individuals with CAD. Unfortunately, the large statin trials excluded individuals over 80 years old, and it is therefore unknown whether very elderly individuals benefit from statins as do younger individuals. METHODS A cohort of 7,220 individuals with angiographically defined significant CAD (> or =70%) was included. Statin prescription was determined at hospital discharge. Patients were followed up for 3.3 +/- 1.8 years (maximum 6.8). Patients were grouped by age (<65, 65 to 79, and > or =80 years) to determine whether statin therapy reduced mortality in an age-dependent manner. RESULTS Average age was 65 +/- 12 years; 74% were male; and 31% had a postmyocardial infarction status. Overall mortality was 16%. Elderly patients were significantly less likely to receive statins than younger patients (> or =80 years: 19.8%; 65 to 79 years: 21.1%; <65 years: 28.0%; p < 0.001). Mortality was decreased among statin recipients in all age groups: > or =80 years: 29.5% among patients not taking a statin versus 8.5% of those taking a statin (adjusted hazard ratio [HR] 0.50, p = 0.036); 65 to 79 years: 18.7% vs. 6.0% (HR 0.56, p < 0.001); and <65 years: 8.9% vs. 3.1% (HR 0.70, p = 0.097). CONCLUSIONS Statin therapy is associated with reduced mortality in all age groups of individuals with significant CAD, including very elderly individuals. Although older patients were less likely to receive statin therapy, they received a greater absolute risk reduction than younger individuals. More aggressive statin use after CAD diagnosis may be indicated, even in older patients.