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Background: Atrial fibrillation (AF) is associated with a risk for cognitive impairment and dementia, which is more pronounced in patients with a history of clinical stroke. Anticoagulation use and efficacy impact long‐term risk of dementia in AF patients in observational trials. Methods: The cognitive decline and dementia in patients with non‐valvular atrial fibrillation (CAF) Trial was a randomized, prospective, open‐label vanguard clinical study with blinded endpoint assessment involving patients with moderate‐ to high‐risk (CHADS2 or CHA2DS2‐Vasc scores of ≥2) non‐valvular AF assigned to dabigatran etexilate or warfarin. The primary endpoint was incident dementia or moderate cognitive decline at 24 months. Results: A total of 101 patients were enrolled [mean age:73.7 ± 6.0 years, male: 54(53.5%)]. Prior stroke and stroke risk factors were similar between groups. Average INR over the study was 2.41 ± 0.68 in the warfarin group. No patient experienced a stroke or developed dementia. Mini‐Mental Status Evaluation, Hachinski Ischemic scale, cognitive subscale of the Alzheimer's Disease Assessment Scale, Disability Assessment for Dementia, Quality of Life Improvement as assessed by Minnesota Living with Heart Failure Scale and the Anti‐Clot Treatment Scale Quality of Life Survey scores did not vary at baseline or change over 2 years. Biomarker analysis indicated a similar efficacy of anticoagulation strategies. Conclusion: Use of dabigatran and well‐managed warfarin therapy were associated with similar risks of stroke, cognitive decline, and dementia at 2 years, suggestive that either strategy is acceptable. The results of this Vanguard study did not support the pursuit of a larger formally powered study. [ABSTRACT FROM AUTHOR]

Background: Flecainide is a useful antiarrhythmic for atrial fibrillation (AF). However, because of ventricular proarrhythmia risk, a history of myocardial infarction (MI) or coronary artery disease (CAD) is a flecainide exclusion, and stress testing is used to exclude ischemia. We assessed whether absent/mild coronary artery calcium (CAC) can supplement or avoid the need for stress testing.Methods: We assessed ischemic burden using regadenoson Rb-82 PET/CT in 1372 AF patients ≥50 years old without symptoms or signs of clinical CAD. CAC was determined qualitatively by low dose attenuation computed tomography (CT) (n = 816) or by quantitative CT (n = 556). Ischemic burden and clinical outcomes were compared by CAC burden.Results: Patients with CAC absent or mild (n = 766, 57.2%) were younger, more frequently female, and had higher BMI but lower rates of diabetes, hypertension, and dyslipidemia. Average ischemic burden was lower in CAC-absent/mild patients, and CAC-absent/mild patients showed greater coronary flow reserve, had fewer referrals for coronary angiography, and less often had obstructive CAD. Revascularization at 90 days was lower, and the rate of longer-term major adverse cardiovascular events was favorable.Conclusions: An easily administered, inexpensive, low radiation CAC scan can identify a subset of flecainide candidates with a low ischemic burden on PET stress testing that rarely needs coronary angiography/intervention and has favorable outcomes. Absent or mild CAC-burden combined with other clinical information may avoid or complement routine stress testing. However, additional, ideally randomized and multicenter trials are indicated to confirm these findings before replacing stress testing with CAC screening in selecting patients for flecainide therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The Charlson and Elixhauser comorbidity indices are mortality predictors often used in clinical, administrative, and research applications. The Intermountain Mortality Risk Scores (IMRS) are validated mortality predictors that use all factors from the complete blood count and basic metabolic profile. How IMRS, Charlson, and Elixhauser relate to each other is unknown. Methods: All inpatient admissions except obstetric patients at Intermountain Healthcare's 21 adult care hospitals from 2010–2014 (N = 197,680) were examined in a observational cohort study. The most recent admission was a patient's index encounter. Follow-up to 2018 used hospital death records, Utah death certificates, and the Social Security death master file. Three Charlson versions, 8 Elixhauser versions, and 3 IMRS formulations were evaluated in Cox regression and the one of each that was most predictive was used in dual risk score mortality analyses (in-hospital, 30-day, 1-year, and 5-year mortality). Results: Indices with the strongest mortality associations and selected for dual score study were the age-adjusted Charlson, the van Walraven version of the acute Elixhauser, and the 1-year IMRS. For in-hospital mortality, Charlson (c = 0.719; HR = 4.75, 95% CI = 4.45, 5.07), Elixhauser (c = 0.783; HR = 5.79, CI = 5.41, 6.19), and IMRS (c = 0.821; HR = 17.95, CI = 15.90, 20.26) were significant predictors (p<0.001) in univariate analyses. Dual score analysis of Charlson (HR = 1.79, CI = 1.66, 1.92) with IMRS (HR = 13.10, CI = 11.53, 14.87) and of Elixhauser (HR = 3.00, CI = 2.80, 3.21) with IMRS (HR = 11.42, CI = 10.09, 12.92) found significance for both scores in each model. Results were similar for 30-day, 1-year, and 5-year mortality. Conclusions: IMRS provided the strongest ability to predict mortality, adding to and attenuating the predictive ability of the Charlson and Elixhauser indices whose mortality associations remained statistically significant. IMRS uses common, standardized, objective laboratory data and should be further evaluated for integration into mortality risk evaluations. [ABSTRACT FROM AUTHOR]

Impact of Age After Atrial Fibrillation Catheter Ablation Background Catheter ablation of atrial fibrillation (AF) is an established therapeutic rhythm approach in symptomatic patients. Many studies have shown that age has little to no impact on outcomes during the first year after ablation. However, AF is a disease of aging and age-based substrate for arrhythmia is likely to progress. To this regard, we examined patients with 5-year outcome data following an index AF ablation procedure to define the impact of age on long-term outcomes. Methods A total of 923 patients that underwent their index AF ablation and had 5 years of follow-up were studied. Patients were followed up for atrial flutter/AF recurrence, heart failure, stroke, death, and cardiac function. Patients were separated and compared in 5 age-based groups (<50, 51-60, 61-70, 71-80, >80). Results The average age of the population was 66 ± 11 years and 59% were male. The AF was paroxysmal in 55%, persistent in 27%, and longstanding persistent in 18%. Older patients were more likely female and had higher rates of cardiovascular diseases. For every 10-year increase in age there was a higher multivariate-adjusted risk of atrial flutter/AF recurrence (HR: 1.13, P = 0.01), death (HR:1.91, P < 0.0001), and major adverse cardiac events (HR: 1.09, P = 0.07). Although atrial flutter/AF recurrence rates by age were similar at 1 year, at 5 years, younger patients had significantly lower rates of recurrences. Conclusion Age significantly impacts outcomes after AF ablation when analyzed with long-term follow-up. These data highlight the progressive nature of AF and the need to consider interventions early. [ABSTRACT FROM AUTHOR]

Background: There are a paucity of data about the long-term natural history of adult Wolff-Parkinson-White syndrome (WPW) patients in regard to risk of mortality and atrial fibrillation. We sought to describe the long-term outcomes of WPW patients and ascertain the impact of ablation on the natural history.Methods and Results: Three groups of patients were studied: 2 WPW populations (ablation: 872, no ablation: 1461) and a 1:5 control population (n=11 175). Long-term mortality and atrial fibrillation rates were determined. The average follow-up for the WPW group was 7.9±5.9 (median: 6.9) years and was similar between the ablation and nonablation groups. Death rates were similar between the WPW group versus the control group (hazard ratio, 0.96; 95% confidence interval, 0.83-1.11; P=0.56). Nonablated WPW patients had a higher long-term death risk compared with ablated WPW patients (hazard ratio, 2.10; 95% confidence interval: 1.50-20.93; P<0.0001). Incident atrial fibrillation risk was higher in the WPW group compared with the control population (hazard ratio, 1.55; 95% confidence interval, 1.29-1.87; P<0.0001). Nonablated WPW patients had lower risk than ablated patients (hazard ratio, 0.39; 95% confidence interval, 0.28-0.53; P<0.0001).Conclusions: Long-term mortality rates in WPW patients are low and similar to an age-matched and gender-matched control population. WPW patients that underwent the multifactorial process of ablation had a lower mortality compared to nonablated WPW patients. Atrial fibrillation rates are high long-term, and ablation does not reduce this risk. [ABSTRACT FROM AUTHOR]

Antiplatelet and Warfarin Use and Risk of Dementia in Atrial Fibrillation Patients Background Patients with atrial fibrillation (AF) are at higher risk of developing dementia. AF patients treated with warfarin with poor time in therapeutic ranges are significantly more likely to develop dementia. AF patients are also frequently treated with antiplatelet agents due to coexistent vascular disease. We hypothesize that AF patients with anticoagulation and antiplatelet therapies will be at higher risk of dementia, particularly with chronic exposure to over-anticoagulation. Methods Chronically anticoagulated patients receiving warfarin (target INR 2-3) for AF and managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service (CPAS) on concurrent antiplatelet agents with no history of dementia or stroke/TIA were included. The primary outcome was the presence of dementia defined by neurologist determined ICD-9 codes. Percent time with an INR>3.0 was determined and then compared by 3 strata <10% (n = 340), 10-24% (n = 417), ≥25% (n = 235). Multivariable Cox hazard regression was utilized to determine dementia incidence by percent time. Results A total of 992 patients were studied. Patients with an INR>3 more than 25% of the time were 2.40 times more likely to develop dementia (P = 0.04). A comparison between < 10% group and 10-24.9% group with INR>3 indicated no difference in risk for the development of dementia (P = 0.74). The risk was significantly increased in patients using triple antithrombotic therapy, although the number of patients within this group was small. Conclusion In AF patients receiving antiplatelet and anticoagulant therapies, the percent of time exposed to over-anticoagulation increased dementia risk. These data support the possibility of chronic cerebral injury from microbleeds as a mechanism underlying the association of AF and dementia. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pulmonary function testing parameters predict cardiovascular and mortality outcomes. Previously, risk scores were created using the basic metabolic profile and complete blood count, including the Intermountain Risk Score (IMRS). This study sought to develop similar pulmonary-specific risk scores for mortality prediction. METHODS: Subjects evaluated by spirometry at 5 Intermountain Healthcare hospitals (females: n = 2,943; males: n = 2,495) were randomly assigned to risk score derivation (70% of subjects) or an independent validation set (the remaining 30%). Sex-specific scores used spirometry, age, and metabolic and blood count laboratory data. Cox regression β-coefficients formed the basis of risk score weightings. RESULTS: Among females, pulmonary IMRS was strongly associated with 5-y mortality in the validation set (hazard ratio = 1.24 per +1 risk score, CI 1.16-1.33, P trend < .001), with C-statistics of C = 0.835 and C = 0.757 for derivation and validation, respectively. Among males, validation results were similarly significant (hazard ratio = 1.20 per +1 risk score value, CI 1.11-1.28, P trend < .001), with C = 0.755 and C = 0.699 in derivation and validation sets, respectively. Results were stronger for pulmonary basic metabolic profile risk score, with females having C = 0.815 (derivation) and C = 0.806 (validation), whereas males had C = 0.734 and C = 0.731. CONCLUSIONS: Pulmonary-specific IMRS and pulmonary-specific basic metabolic profile risk score provided excellent discrimination of mortality among pulmonary subjects. These risk stratification tools combine familiar, relatively inexpensive, commonly-measured, standardized laboratory parameters with spirometry data. They may be electronically calculated and delivered at the point of care, providing meaningful risk information to assist clinicians in patient evaluations. [ABSTRACT FROM AUTHOR]

Background: Intermittent fasting, alternate-day fasting, and other forms of periodic caloric desistance are gaining popularity in the lay press and among animal research scientists. Whether clinical evidence exists for or is strong enough to support the use of such dietary regimens as health interventions is unclear. Objective: This review sought to identify rigorous, clinically relevant research studies that provide high-quality evidence that therapeutic fasting regimens are clinically beneficial to humans. Design: A systematic review of the published literature through January 2015 was performed by using sensitive search strategies to identify randomized controlled clinical trials that evaluated the effects of fasting on either clinically relevant surrogate outcomes (e.g., weight, cholesterol) or actual clinical event endpoints [e.g., diabetes, coronary artery disease (CAD)] and any other studies that evaluated the effects of fasting on clinical event outcomes. Results: Three randomized controlled clinical trials of fasting in humans were identified, and the results were published in 5 articles, all of which evaluated the effects of fasting on surrogate outcomes. Improvements in weight and other risk-related outcomes were found in the 3 trials. Two observational clinical outcomes studies in humans were found in which fasting was associated with a lower prevalence of CAD or diabetes diagnosis. No randomized controlled trials of fasting for clinical outcomes were identified. Conclusions: Clinical research studies of fasting with robust designs and high levels of clinical evidence are sparse in the literature. Whereas the few randomized controlled trials and observational clinical outcomes studies support the existence of a health benefit from fasting, substantial further research in humans is needed before the use of fasting as a health intervention can be recommended. [ABSTRACT FROM AUTHOR]

Introduction Mechanisms underlying atrial fibrillation (AF) and dementia are unknown. Some genetic risk factors convey risk for AF and cerebral ischemic events. These markers may identify AF patients at risk for dementia either directly or through a gene-gene interaction with the ApoE ε4 variant, a known marker of dementia risk. Methods Caucasian patients with AF and a subsequent dementia diagnosis (n = 112) were matched 1:2 on sex, AF onset age, and follow-up period to AF patients without dementia. AF patients with dementia and AF patients without dementia were matched 1:1 on sex and age at dementia diagnosis (n = 112). Genotyping employed Taqman real-time polymerase chain reaction. Multivariable conditional logistic regression was used to examine associations between AF/dementia groups and single nucleotide polymorphism (SNP), as well as gene-gene interactions. Results In dementia patients, there was an association between the PITX2 loci and AF (rs2634073: odds ratio [OR] = 2.11; P = 0.025 and rs2200733: OR = 2.27; P = 0.029). In patients with AF, there was an association between PITX2 loci, rs2200733, and dementia (OR = 2.15, P = 0.008). There was no association between ApoE ε4 allele and AF in patients with dementia, although confirmation of the association between the carriage of ApoE ε4 allele and dementia was found (OR = 1.79; P = 0.026) in patients with AF. There were no significant interactions between ApoE ε4 allele and both the PITX2 loci and ZFHX3. Conclusions These findings support prior studies of ApoE risk of noncerebral vascular accident-related dementia/Alzheimer's risk in the Caucasians and provide support to suggest an association between PITX2-related SNPs and dementia, which may in part be attributed to silent cerebral ischemic events, a hypothesis deserving further testing. [ABSTRACT FROM AUTHOR]

Background: There are limited options for patients who present with antiarrhythmic-drug (AAD)-refractory ventricular tachycardia (VT) with recurrent implantable cardioverter defibrillator (ICD) shocks. Ranolazine is a drug that exerts antianginal and antiischemic effects and also acts as an antiarrhythmic in isolation and in combination with other class III medications. Ranolazine may be an option for recurrent AAD-refractory ICD shocks secondary to VT, but its efficacy, outcomes, and tolerance are unknown. Methods and Results: Twelve patients (age 65 ± 9.7 years) were treated with ranolazine. Eleven (92%) were male, and 10 (83%) had ischemic heart disease with an average ejection fraction of 0.34 ± 0.13. All patients were on a class III AAD (11 amiodarone, one sotalol), with six (50%) receiving mexilitene or lidocaine. Five patients had a prior ablation and two were referred for a VT ablation at the index presentation. The QRS increased nonsignificantly from 128 ± 31 ms to 133 ± 31 ms, and the QTc increased nonsignificantly from 486 ± 32 ms to 495 ± 31 ms after ranolazine initiation. Over a follow-up of 6 ± 6 months, 11 (92%) patients had a significant reduction in VT and no ICD shocks were observed. VT ablation was not required in those referred. In two patients, gastrointestinal side effects limited long-term use. Of these two patients, one died due to progressive heart failure. In one patient, severe hypoglycemia limited dosing to 500 mg daily, but this was sufficient for VT control. Conclusion: Ranolazine proved effective in reducing VT burden and ICD shocks in patients with AAD-refractory VT. Ranolazine should be further tested for this indication and considered for clinical application when other options have proven ineffective. (PACE 2011; 34:1600-1606) [ABSTRACT FROM AUTHOR]

Background: Previous studies have observed that short-term exposure to elevated concentrations of particulate matter (PM) air pollution increases risk of acute ischemic heart disease events and heart failure hospitalization, alters cardiac autonomic function, and increases risk of arrhythmias. This study explored the potential associations between short-term elevations in PM exposure and atrial fibrillation (AF). Methods and Results: A case-crossover study design was used to explore associations between fine PM (PM2.5, particles with an aerodynamic diameter ≤2.5 μm) and 10,457 AF hospitalizations from 1993 to 2008 of patients who lived on Utah's Wasatch Front. Patients were hospitalized at Intermountain Healthcare facilities with a primary diagnosis of AF. Concurrent day exposure and cumulative lagged exposures for up to 21 days were explored and the data were stratified by sex, age, and previous or subsequent admission for myocardial infarction. Although the estimated associations between PM2.5 and AF hospitalizations for the various lag structures and strata were consistently positive suggestive of risk, they were not statistically significant and they were extremely small compared to previously observed associations with ischemic heart disease events and heart failure hospitalizations. Further, we observed no additive risk between PM2.5 and AF hospitalization in those with respiratory disease or sleep apnea. Conclusions: Unlike previously observed associations with ischemic heart disease events and heart failure hospitalizations using similar study design and approaches, this study found that hospitalization for AF was not significantly associated with elevations in short-term exposure to fine PM air pollution. (PACE 2011; 34:1475-1479) [ABSTRACT FROM AUTHOR]

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. Methods: A total of 4,212 consecutive patients who underwent AF ablation were compared (1:4) to 16,848 age/gender matched controls with AF (no ablation) and 16,848 age/gender matched controls without AF. Patients were enrolled from the large ongoing prospective Intermountain AF study and were followed for at least 3 years. Results: Of the 37,908 patients, mean age 65.0 ± 13 years, 5,667 (14.9%) died, 1,296 (3.4%) had a stroke, and 1,096 (2.9%) were hospitalized for HF over >3 years of follow-up. AF ablation patients were less likely to have diabetes, but were more likely to have hypertension, HF, and significant valvular heart disease. AF ablation patients had a lower risk of death and stroke in comparison to AF patients without ablation. Alzheimer's dementia occurred in 0.2% of the AF ablation patients compared to 0.9% of the AF no ablation patients and 0.5% of the no AF patients (P < 0.0001). Other forms of dementia were also reduced significantly in those treated with ablation. Compared to patients with no AF, AF ablation patients had similar long-term rates of death, dementia, and stroke. Conclusions: AF ablation patients have a significantly lower risk of death, stroke, and dementia in comparison to AF patients without ablation. AF ablation may eliminate the increased risk of death and stroke associated with AF. (J Cardiovasc Electrophysiol, Vol. 22, pp. 839-845, August 2011) [ABSTRACT FROM AUTHOR]

Strategy of Rapid Cardioversion. Background: The significance of early recurrent atrial tachyarrhythmias after atrial fibrillation (AF) ablation is unclear. Atrial remodeling driven by these tachyarrhythmias can result in electrical, contractile, and structural changes that may impair long-term therapy success. Aggressive attempts to restore sinus rhythm in the temporal period of healing after ablation might improve outcomes. Methods: A total of 1,759 AF ablations were performed at Intermountain Medical Center or LDS Hospital. A total of 455 of those were among patients requiring repeat ablations. Patients were instructed to take their pulse daily and, if greater than 100 bpm or irregular, present the following business day fasting to the clinic for evaluation and cardioversion if AF or atrial flutter (AFL) were present. Results: Of the ablations performed, a total of 515 (29%, age: 65.6 ± 11.2 years, male: 57.9%) developed AF/AFL that required cardioverison. The majority of these arrhythmias first occurred in the initial 90 days (63.7%) postablation. During this period, 62.8% were on an antiarrhythmic drug (AAD). Only 25.1% were using an AAD at 3 months. The majority of ablations (75.6%) who experienced AF/AFL within the first 90 days after ablation were in sinus rhythm with no AAD at 1 year. Further, 48% of those with the first recurrence from 90 to 180 days were in sinus rhythm with no AAD at 1 year. Conclusions: The time at which the first recurrence of AF/AFL occurs impacts long-term outcomes. An aggressive strategy of rapid cardioversion postablation reduces the significance of recurrent AF/AFL during the first 6 months. (J Cardiovasc Electrophysiol, Vol. 22, pp. 761-766, July 2011) [ABSTRACT FROM AUTHOR]

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins., (© 2021. The Author(s).)

Low vitamin D (serum or plasma 25-hydroxyvitamin D (25(OH)D)) is a global pandemic and associates with a greater prevalence in all-cause and cardiovascular mortality and morbidity. Open-heart surgery is a form of acute stress that decreases circulating 25(OH)D concentrations and exacerbates the preponderance of low vitamin D in a patient population already characterized by low levels. Although supplemental vitamin D increases 25(OH)D, it is unknown if supplemental vitamin D can overcome the decreases in circulating 25(OH)D induced by open-heart surgery. We sought to identify if supplemental vitamin D protects against the acute decrease in plasma 25(OH)D propagated by open-heart surgery during perioperative care. Participants undergoing open-heart surgery were randomly assigned (double-blind) to one of two groups: (a) vitamin D (n = 75; cholecalciferol, 50,000 IU/dose) or (b) placebo (n = 75). Participants received supplements on three separate occasions: orally the evening before surgery and either orally or per nasogastric tube on postoperative days 1 and 2. Plasma 25(OH)D concentrations were measured at baseline (the day before surgery and before the first supplement bolus), after surgery on postoperative days 1, 2, 3, and 4, at hospital discharge (5-8 days after surgery), and at an elective outpatient follow-up visit at 6 months. Supplemental vitamin D abolished the acute decrease in 25(OH)D induced by open-heart surgery during postoperative care. Moreover, plasma 25(OH)D gradually increased from baseline to day 3 and remained significantly increased thereafter but plateaued to discharge with supplemental vitamin D. We conclude that perioperative vitamin D supplementation protects against the immediate decrease in plasma 25(OH)D induced by open-heart surgery. ClinicalTrials.gov Identifier: NCT02460211., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The red cell distribution width (RDW) is associated with health outcomes. Whether non-RDW risk information is contained in RBC sizes is unknown. This study evaluated the association of the percentage of extreme macrocytic RBCs (%Macro, RBC volume > 120 fl) and microcytic RBCs (%Micro, RBC volume < 60 fl) and the RDW-size distribution (RDW-sd) with mortality and morbidity., Methods: Patients (females, n = 165,770; males, n = 100,210) at Intermountain Healthcare were studied if they had a hematology panel between May 2014 and September 2016. Adjusted sex-specific associations of %Macro/%Micro and RDW-sd with mortality and 33 morbidities were evaluated., Results: Among females with fourth-quartile values of %Macro quartile and %Micro (referred to throughout as 4/4), there was an average of 7.2 morbidities versus 2.9 in the lowest risk (LR1) categories, 1/1, 1/2, 2/1, and 2/2 (P < 0.001). Among males, those in the 4/4 category had 8.0 morbidities, while those in the LR1 had 3.4 (P < 0.001). Cox regressions found %Macro/%Micro (4/4 vs. LR1, females: hazard ratio [HR] = 1.97 [95% CI = 1.53, 2.54]; males: HR = 2.17 [CI = 1.72, 2.73]), RDW-sd (quartile 4 vs. 1, females: HR = 1.33 [CI = 1.04, 1.69]; males: HR = 1.41 [CI = 1.10, 1.80]), and RDW (quartile 4 vs. 1, females: HR = 1.59 [CI = 1.26, 2.00]; males: HR = 1.23 [CI = 0.99, 1.52]) independently predicted mortality. Limitations include that the observational design did not reveal causality and unknown confounders may be unmeasured., Conclusions: Concomitantly elevated %Macro and %Micro predicted the highest mortality risk and the greatest number of morbidities, revealing predictive ability of RBC volume beyond what is measured clinically. Mechanistic investigations are needed to explain the biological basis of these observations., Funding: This study was supported by internal Intermountain Heart Institute funds and in-kind support from Sysmex America Inc.

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Air pollution is associated with greater cardiovascular event risk, but the types of events and specific persons at risk remain unknown. This analysis evaluates effects of short-term exposure to fine particulate matter air pollution with risk of acute coronary syndrome events, including ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina, and non-ST-segment elevation acute coronary syndrome., Methods and Results: Acute coronary syndrome events treated at Intermountain Healthcare hospitals in urban areas of Utah's Wasatch Front were collected between September 1993 and May 2014 (N=16 314). A time-stratified case-crossover design was performed matching fine particulate matter air pollution exposure at the time of each event with referent periods when the event did not occur. Patients served as their own controls, and odds ratios were estimated using nonthreshold and threshold conditional logistic regression models. In patients with angiographic coronary artery disease, odds ratios for a 10-μg/m(3) increase in concurrent-day fine particulate matter air pollution >25 μg/m³ were 1.06 (95% CI 1.02-1.11) for all acute coronary syndrome, 1.15 (95% CI 1.03-1.29) for ST-segment elevation myocardial infarction, 1.02 (95% CI 0.97-1.08) for non-ST-segment elevation myocardial infarction, 1.09 (95% CI 1.02-1.17) for unstable angina, and 1.05 (95% CI 1.00-1.10) for non-ST-segment elevation acute coronary syndrome events. Excess risk from fine particulate matter air pollution exposure was not observed in patients without angiographic coronary artery disease., Conclusions: Elevated fine particulate matter air pollution exposures contribute to triggering acute coronary events, especially ST-segment elevation myocardial infarction, in those with existing seriously diseased coronary arteries but not in those with nondiseased coronary arteries., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Catheter ablation of atrial fibrillation (AF) is an established therapy for symptomatic patients. The long-term efficacy and impact of catheter ablation among patients with severe systolic heart failure (SHF) requires additional study to understand if outcomes achieved at 1 year are maintained and mechanisms of AF recurrence., Methods: Three groups with SHF and 5 years of follow-up were matched 1:4:4 by age (±5 years) and sex: AF ablation patients receiving their first ablation (n = 267), AF patients that did not receive an ablation (n = 1,068), and SHF patient without AF (n = 1,068). SHF was based upon clinical diagnosis and an ejection fraction (EF) ≤35%. Patients were followed for 5-year primary outcomes of AF recurrence, heart failure, stroke, death, and cardiac function., Results: At 5 years, 60.7% of patients had clinical recurrence of AF. Diabetes and a prior heart attack were significant predictors of long-term risk of AF recurrence. Long-term mortality rates were 27%, 55%, 50%, in the AF ablation, AF, and no AF groups, respectively (P < 0.0001), with the lower rates attributed to lower cardiovascular mortality. At 5 years, there was no difference in EF, yet HF hospitalizations were lower following AF ablation compared to patients with AF and no ablation. Stroke rates at 5 years trended to be lower in the AF ablation group, but the difference was not statistically significant., Conclusion: Recurrence rates of AF in patients with SHF after ablation are common at 5 years with an anticipated ongoing increase. Long-term AF-related comorbidities tended to be less in the AF ablation group., (© 2014 Wiley Periodicals, Inc.)

Stroke prevention in atrial fibrillation (AF) is guided by clinical factors with inadequate predictive power. Most thrombi observed in AF are observed in the left atrial appendage (LAA). This study was designed to determine (1) the association between LAA and the incidence of AF-related stroke and (2) the power of LAA to predict stroke. Patients (n = 48) with a history of AF and stroke were compared with control subjects (n = 48) with a history of AF but no history of stroke. Magnetic resonance images from both case and control populations were manually segmented to determine LAA volume. Patients with a history of stroke had larger LAA mean volumes than control subjects (28.8 ± 13.5 cm(3) vs 21.7 ± 8.27 cm(3), p = 0.002). Stroke risk is highest in patients with a LAA volume >34 cm(3) (multivariable OR 7.11, p = 0.003). In conclusion, larger LAA volume is associated with stroke in the setting of AF, and this measure can potentially improve risk stratification for stroke risk management in AF patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Survivors of acute myocardial infarction (MI) are at high risk for death from both sudden cardiac death and progressive heart failure., Objective: This study sought to determine mortality trends, identify markers of risk, and determine whether outcomes in high-risk patients are altered by revascularization during the implantable cardioverter-defibrillator candidacy observation period., Methods: We included 16,793 patients that presented to the catheterization laboratory for acute management of an MI. All patients had 3 years of follow-up to define short- and long-term mortality., Results: Across the demographics studied there were no significant differences in baseline characteristics over time, with exception of an observed decline in patients with an ejection fraction (EF) ≤0.35. Nonetheless, at study closure 16.3% of all cases had an EF ≤ 0.35. There was a gradual increase in use of percutaneous coronary intervention and coronary artery bypass graft; however, at the end of the study, the highest level of revascularization use was slightly >50%. For the composite, right and left bundle branch block or QRS > 120, the death rates at 1 and 5 years were 31.8% and 46.8%, respectively. These 1- and 5-year mortality rates were increased with an EF ≤ 0.35 (36.0%, 60.2%). Mortality in those with EF ≤ 0.35 exceeded 20% in all groups with conduction system disease at 90 days and was not significantly impacted by percutaneous coronary intervention., Conclusion: The highest risk for death after MI is in patients with an EF ≤ 0.35 and/or conduction system disease. The mortality risk is most pronounced in the early observation period after MI when patients must wait to be considered for an implantable cardioverter-defibrillator., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D (Vit D) deficiency has been associated with prevalent and incident cardiovascular (CV) disease, suggesting a role for bioregulators of bone and mineral metabolism in CV health. Vitamin D deficiency leads to secondary hyperparathyroidism, and both primary and secondary hyperparathyroidism are associated with CV pathology. Parathyroid hormone (PTH) is an important regulator of calcium homeostasis, and its impact on CV disease risk is of interest. We tested whether elevated PTH is associated with CV disease and whether risk associations depend on Vit D status and renal function., Methods: Patients in the Intermountain Healthcare system with concurrent PTH and Vit D as 25-hydroxy-vitamin D (25[OH]D) levels were studied (N = 9,369, age 63 ± 16 years, 36% male). Parathyroid hormone levels were defined as low (<15 pg/mL), normal (15-75 pg/mL), or elevated (>75 pg/mL). Prevalence and incidence of hypertension, diabetes, hyperlipidemia, coronary artery disease/myocardial infarction, heart failure, stroke, and peripheral vascular disease were determined by the International Classification of Diseases, Ninth Revision codes documented in electronic medical records at baseline and, for incident events, during an average of 2.0 ± 1.5 years (maximum 7.5 years) of follow-up., Results: Parathyroid hormone elevation at baseline was noted in 26.1% of the study population. Highly significant differential CV prevalence/incidence rates for most CV risk factors, disease diagnoses, and mortality were noted for PTH >75 pg/mL (by 1.25- to 3-fold). Parathyroid hormone correlated only weakly (r = -0.15) with 25(OH)D and moderately with glomerular filtration rate (r = -0.36). 25(OH)D, standard risk factors, and renal dysfunction variably attenuated PTH risk associations, but risk persisted after full multivariable adjustment., Conclusions: Elevated PTH is associated with a greater prevalence and incidence of CV risk factors and predicts a greater likelihood of prevalent and incident disease, including mortality. Risk persists when adjusted for 25(OH)D, renal function, and standard risk factors. Parathyroid hormone represents an important new CV risk factor that adds complementary and independent predictive value for CV disease and mortality., (Copyright © 2011 Mosby, Inc. All rights reserved.)

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) > or =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 > or =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, > or =65), sex, and diabetes, although the associations among those age > or =65 and male sex were enhanced., Conclusion: Among a CV population > or =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., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Some components of the complete blood count and basic metabolic profile are commonly used risk predictors. Many of their components are not commonly used, but they might contain independent risk information. This study tested the ability of a risk score combining all components to predict all-cause mortality., Methods: Patients with baseline complete blood count and basic metabolic profile measurements were randomly assigned (60%/40%) to independent training (N = 71,921) and test (N = 47,458) populations. A third population (N = 16,372) from the Third National Health and Nutrition Examination Survey and a fourth population of patients who underwent coronary angiography (N = 2558) were used as additional validation groups. Risk scores were computed in the training population for 30-day, 1-year, and 5-year mortality using age- and sex-adjusted weights from multivariable modeling of all complete blood count and basic metabolic profile components., Results: Area under the curve c-statistics were exceptional in the training population for death at 30 days (c = 0.90 for women, 0.87 for men), 1 year (c = 0.87, 0.83), and 5-years (c = 0.90, 0.85) and in the test population for death at 30 days (c = 0.88 for women, 0.85 for men), 1 year (c = 0.86, 0.82), and 5 years (c = 0.89, 0.83). In the test, the Third National Health and Nutrition Examination Survey, and the angiography populations, risk scores were highly associated with death (P <.001), and thresholds of risk significantly stratified all 3 populations., Conclusion: In large patient and general populations, risk scores combining complete blood count and basic metabolic profile components were highly predictive of death. Easily computed in a clinical laboratory at negligible incremental cost, these risk scores aggregate baseline risk information from both the popular and the underused components of ubiquitous laboratory tests.

Background: Inflammation has been shown to have a direct role in the initiation, maintenance, and recurrence of atrial fibrillation (AF) although the underlying mechanisms are unknown. Similarly, it is unclear if inflammatory markers are elevated due to the AF alone or the coexisting cardiovascular diseases that increase the risk of AF., Methods: Consecutive patients who underwent angiography for suspicion of coronary artery disease, but without a myocardial infarction, were studied. Serum was analyzed to determine high-sensitivity C-reactive protein (hs-CRP) level. Patients' AF status was determined through ICD-9 codes, review of hospital discharge summaries, clinical evaluations, and electrocardiograms., Results: A total of 2,340 patients were studied (64+/-12 years). Comorbid diseases included 1,438 (61%) coronary artery disease, 1,309 (56%) hypertension, 433 (19%) diabetes, 345 (15%) congestive heart failure, and 43 (2%) a prior stroke. The hs-CRP level was significantly higher in patients with AF (n = 238) compared to those without (14.0 mg/L vs 9.1 mg/L, P < 0.001). Greater CHADS2 score was also significantly associated with higher hs-CRP in a linear fashion (medians [mg/L], 0: 1.99, 1: 2.91, 2: 3.49, 3: 3.89, 4-5: 4.82, P <0.001). The presence of AF was associated with higher hs-CRP level across all scores (medians [mg/L], 0: 2.22 vs 1.98, P = 0.83, 1: 3.85 vs 2.86, P = 0.057, 2: 4.96 vs 3.29, P = 0.021, 3: 6.29 vs 3.17, P = 0.09, 4-5: 4.82 vs 4.50, P = 0.87)., Conclusion: Risks factors associated with AF were associated with higher hs-CRP in an incremental manner. The presence of AF increased hs-CRP across the CHADS2 score strata is supportive of the concept that AF is an inflammatory process and may convey independent risk.

Background: Recent evidence suggests that long-term exposure to particulate air pollution contributes to pulmonary and systemic oxidative stress, inflammation, progression of atherosclerosis, and risk of ischemic heart disease and death. Short-term exposure may contribute to complications of atherosclerosis, such as plaque vulnerability, thrombosis, and acute ischemic events. These findings are inconclusive and controversial and require further study. This study evaluates the role of short-term particulate exposure in triggering acute ischemic heart disease events., Methods and Results: A case-crossover study design was used to analyze ischemic events in 12,865 patients who lived on the Wasatch Front in Utah. Patients were drawn from the cardiac catheterization registry of the Intermountain Heart Collaborative Study, a large, ongoing registry of patients who underwent coronary arteriography and were followed up longitudinally. Ambient fine particulate pollution (particles with an aerodynamic diameter < or = 2.5 microm; PM2.5) elevated by 10 microg/m3 was associated with increased risk of acute ischemic coronary events (unstable angina and myocardial infarction) equal to 4.5% (95% confidence interval, 1.1 to 8.0). Effects were larger for those with angiographically demonstrated coronary artery disease., Conclusions: Short-term particulate exposures contributed to acute coronary events, especially among patients with underlying coronary artery disease. Individuals with stable presentation and those with angiographically demonstrated clean coronaries are not as susceptible to short-term particulate exposure.

A recent European case-control study suggested that statins increase the risk for polyneuropathy, a rare but serious neurologic condition. This risk was assessed in 272 patients with idiopathic polyneuropathy and 1,360 matched controls in the Intermountain Health Care electronic database. It was found that statin use before diagnosis was not significantly greater in patients than controls (odds ratio 1.30, 95% confidence interval 0.3 to 2.1, p = 0.27), nor were doses different between patients and controls.

Background: Seropositivity to cytomegalovirus (CMV) and elevated C-reactive protein (CRP) may jointly predict increased mortality rates in patients with coronary artery disease (CAD). Therapy with statins reduces lipid levels but may also have other beneficial (eg, antiinflammatory) effects. This study prospectively evaluated the effect of statins on CMV-and CRP-associated death among patients with significant, angiographically defined CAD., Methods and Results: We monitored 2315 patients with angiographically significant CAD (stenosis > or =70%) for an average of 2.4 years (maximum, 5.8 years). Anti-CMV IgG antibody levels and CRP concentrations were measured at baseline, and statin prescription was recorded. As previously reported, mortality rate was higher for CMV seropositivity (+) with high CRP (hazard ratio [HR], 2.0) and lower for statins (HR, 0.50). Compared with CMV(-)/low CRP (mortality rate, 5% with statin versus 4% without statin), the protective effect of statin therapy was markedly greater for CMV(+)/low CRP (mortality rate, 2% versus 7%; HR, 0.44; 95% CI, 0.16 to 1.3), CMV negative (-)/high CRP (mortality rate, 1% versus 8%; HR, 0.16), and CMV(+)/high CRP (mortality rate, 6% versus 17%; HR, 0.42; 95% CI, 0.25 to 0.70). After adjustment, interactions were found for statin therapy with CMV(+)/low CRP (P for interaction=0.065), CMV(-)/high CRP (P for interaction=0.051), and CMV(+)/high CRP (P for interaction=0.024)., Conclusions: The survival benefit of statins interacted with CMV seropositivity and high CRP to significantly reduce mortality rates among patients with CAD. This finding supports the hypothesis that statins have beneficial, "lipid-independent," antiinflammatory effects. The mechanism of statin benefit associated with CMV seropositivity remains to be determined.