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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. 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. 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. 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. 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.

Background: Despite recent advances in the treatment and prevention of cardiovascular disease, a treatment gap for secondary prevention medications still exists. Objective: To develop and implement a program ensuring appropriate prescription of aspirin, statins, [beta]-blockers, angiotensin-converting enzyme inhibitors, and warfarin at hospital discharge. Design: A nonrandomized before-after study comparing patients hospitalized before (1996-1998) and after (1999-2002) implementation of a discharge medication program (DMP). Patients were followed for up to 1 year. Setting: The 10 largest hospitals in the Utah-based Intermountain Health Care system. Patients: In the pre-DMP and DMP time periods, 26 000 and 31 465 patients, respectively, were admitted to cardiovascular services (n = 57 465). Measurements: Prescription of indicated medications at hospital discharge; postdischarge death or readmission. Results: By 1 year, the rate of prescription of each medication increased significantly to more than 90% (P < 0.001); this rate was sustained. At 1 year, unadjusted absolute event rates for readmission and death, respectively, were 210 per 1000 person-years and 96 per 1000 person-years before DMP implementation and 191 per 1000 person-years and 70 per 1000 person-years afterward. Relative risk for death and readmission at 30 days decreased after DMP implementation; hazard ratios (HRs) for death and readmission were 0.81 (95% CI, 0.73 to 0.89) and 0.92 (CI, 0.87 to 0.99) (P < 0.001 and P = 0.017, respectively). At 1 year, risk for death continued to decrease (hazard ratio, 0.79 [CI, 0.75 to 0.84]; P< 0.001) while risk for readmission stabilized (hazard ratio, 0.94 [CI, 0.90 to 0.98]; P = 0.002), probably because survivors had more opportunities to be readmitted. Limitations: The study design was observational and nonrandomized, and the authors could not control for potential con-founders or determine the extent to which secular trends accounted for the observed improvements. Conclusions: A relatively simple quality improvement program aimed at enhancing the prescription of appropriate discharge medications among cardiovascular patients is feasible and can be sustained within an integrated multihospital system. Such a program may be associated with improvements in cardiovascular readmission rates and mortality.

Pharmacogenomics is a field dedicated to exploring the contribution of genetics to interindividual variability in drug response. A goal of cardiovascular pharmacogenomics is to guide cardiovascular drug development and selection [...]

Graphical Abstract

To apply the practical parsimonious modeling method of the Intermountain Mortality Risk Score in a primary care environment to predict chronic disease (ChrD) onset.

Introduction: The apolipoprotein A1 (apoA1) remnant ratio has been identified as an independent cardiovascular (CV) risk factor. Higher apoA1 remnant ratios may predict lower CV risk in some patients. This analysis aimed to evaluate the effects of evolocumab on the change from baseline in the apoA1 remnant ratio compared with placebo. Methods: This pooled post hoc analysis included 2464 patients with mixed dyslipidemia treated with evolocumab 140 mg every 2 weeks (Q2W) or 420 mg once monthly (QM) in three phase 3 evolocumab trials. The apoA1 remnant ratio was calculated by dividing apoA1 by the difference between non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoA1 remnant ratio strata were generated using previously published tertile (&lt; 4.7, 4.7–6.8, and > 6.8) and partitioning categories (&lt; 3.6, 3.6–6.0, and > 6.0). Results: The baseline apoA1 remnant ratio in evolocumab and placebo treatment arms was 7.1 and 7.3, respectively. At week 12, evolocumab 140 mg Q2W and 420 mg QM increased the apoA1 remnant ratio by 25.0% and 33.6%, respectively, versus placebo (p&lt; 0.0001 for both groups). When patients were categorized by week 12 apoA1 remnant ratio thresholds (&lt; 3.6 vs. > 3.6, and &lt; 4.7 vs. > 4.7), those with higher week 12 apoA1 remnant ratios were significantly more likely to have also achieved a target non-HDL-C level of &lt; 100 mg/dl. In the subset of women > 50 years of age, the proportion of patients at apoA1 remnant ratio thresholds &lt; 3.6, 3.6–6.0, and > 6.0 at baseline shifted toward or remained at higher thresholds at week 12. Conclusions: This post hoc analysis suggests that evolocumab increases the apoA1 remnant ratio. Funding: Amgen Inc. Plain Language Summary: Plain language summary available for this article.

Intermittent fasting may increase longevity and lower cardiometabolic risk. This study evaluated whether fasting modifies clinical risk scores for mortality [i.e., Intermountain Mortality Risk Score (IMRS)] or chronic diseases [e.g., Pooled Cohort Risk Equations (PCRE), Intermountain Chronic Disease score (ICHRON)].

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Potent P2Y12inhibitors might offer enhanced benefit against thrombotic events in complex percutaneous coronary intervention (PCI). We examined prasugrel use and outcomes according to PCI complexity, as well as analyzing treatment effects according to thienopyridine type.

Depression is a risk factor for cardiovascular (CV) diseases, incident CV events, and mortality. Among individuals who experience a CV diagnosis or event, whether a subsequent diagnosis of depression is associated with a greater risk of mortality is unknown. Among patients with existing coronary artery disease (CAD), this study evaluated the association of a subsequent depression diagnosis with all-cause mortality.

Background Dyslipidemia plays a significant role in the progression of cardiovascular disease. The apolipoprotein (apo) A1 remnant ratio (apo A1/VLDL3-C + IDL-C) has recently been shown to be a strong predictor of death/myocardial infarction risk among women >50 years undergoing angiography. However, whether this ratio is associated with coronary heart disease risk among other populations is unknown. We evaluated the apo A1 remnant ratio and its components for coronary heart disease incidence.Design Observational.Methods Participants (N= 4722) of the Jackson Heart Study were evaluated. Baseline clinical characteristics and lipoprotein subfractions (Vertical Auto Profile method) were collected. Cox hazard regression analysis, adjusted by standard cardiovascular risk factors, was utilized to determine associations of lipoproteins with coronary heart disease.Results Those with new-onset coronary heart disease were older, diabetic, smokers, had less education, used more lipid-lowering medication, and had a more atherogenic lipoprotein profile. After adjustment, the apo A1 remnant ratio (hazard ratio = 0.67 per 1-SD, p= 0.002) was strongly associated with coronary heart disease incidence. This association appears to be driven by the IDL-C denominator (hazard ratio = 1.23 per 1-SD, p= 0.007). Remnants (hazard ratio = 1.21 per 1-SD, p= 0.017), but not apo A1 (hazard ratio = 0.85 per 1-SD, p= 0.121) or VLDL3-C (hazard ratio = 1.13 per 1-SD, p= 0.120) were associated with coronary heart disease. Standard lipids were not associated with coronary heart disease incidence.Conclusion We found the apo A1 remnant ratio to be strongly associated with coronary heart disease. This ratio appears to better stratify risk than standard lipids, apo A1, and remnants among a primary prevention cohort of African Americans. Its utility requires further study as a lipoprotein management target for risk reduction.

Introduction:Recently there has been a much-needed focus on disparity and inequity in cardiovascular disease (CVD) care. Race, ethnicity, sex, and geography are shown to impact CVD care and outcomes. Perhaps one of the reasons for this is the lack of diversity and representation in CVD research studies, especially in non-sponsored research studies. Here we examine three investigator-initiated clinical CVD trials to describe current enrollment patterns and compare them to the comparable populations.Methods:Three Intermountain Healthcare, internally funded, CVD clinical trials were examined. These studies include a pragmatic trial, a randomized unblinded treatment trial, and a biobanking registry. Basic study characteristics and the comparison populations are shown in Table 1.Results:Demographic comparisons are shown in Table 2. Females were equally or slightly more represented in the studies. Minority races were under-represented in the pragmatic trial and the biobank registry. Rural or frontier counties were under-represented in the pragmatic trial and randomized trial. Hispanic/Latino patients were under-represented in all studies.ConclusionsFemales were well represented in all studies, but other minority groups were under-represented. The largest under-representation was for Hispanic/Latino patients. The reasons and mechanisms that may lead to under-representation and the impact on research results are unknown and deserve further study. While addressing these disparities may increase research costs (e.g., translation costs), future studies will benefit from the development of new resources and processes, and ultimately could lead to better care.

Introduction:When patients (pts) are diagnosed with HFrEF, it is hoped that medical therapy will improve their left ventricular ejection fraction (LVEF). However, which baseline clinical characteristics may predict an improvement in LVEF after medical treatment remains unclear.Methods:Pts with a baseline LVEF ≤35% and a follow-up LVEF ≥180 days later were categorized according to the change in LVEF identified between the baseline and follow-up LVEF’s (Increased [ΔLVEF ≥+10%]; No change [ΔLVEF=-9% to +9%]; Decreased [ΔLVEF ≥-10%]). Baseline characteristics and follow-up death rates were collected. Independent predictors of an improved LVEF were determined by logistic regression.Results:Qualifying HFrEF pts totaled 5,632 and were categorized by ΔLVEF as follows: Increased = 3,074 (54.6%); No change = 2,193 (38.9%); Decreased = 365 (6.5%). Baseline characteristics and independent predictors of an increase in LVEF are shown in the figure. During a median follow-up of 6.2 years, the death rate was 35.3%, 60.0%, and 72.6% (p<0.0001) in patients with an increase, no change, or decrease in LVEF, respectively.Conclusions:In patients diagnosed with HFrEF and initiated on medical therapy, an increase in LVEF predicted a lower death rate. The strongest predictors of an increase in LVEF included female gender, the absence of ASCVD, a low initial BNP, a narrow QRS duration, and the presence of atrial fibrillation, pulmonary hypertension, and statin use. Explanations for these findings remain to be determined.

Introduction:The clinical spectrum of COVID-19 can range from asymptomatic to severe, with severe resulting in part from an intense inflammatory response. Selective serotonin reuptake inhibitor (SSRI) is the most commonly prescribed class of antidepressants and has anti-inflammatory and anti-platelet effects. Recent studies reported greater survival and lesser COVID severity in patients taking SSRIs, specifically fluoxetine/fluvoxamine. Recently, application was made to the FDA for emergency use of fluvoxamine to prevent severe COVID-19, but it was denied based on insufficient data.Methods:Patients (n=33,088) testing positive for SARS-CoV-2 between March 14, 2020-December 31, 2021 as outpatients were studied. Patients were matched 3:1 by SSRI prescription at the time of a positive test by propensity score (±0.001). Patients were evaluated for COVID-19 hospitalization within 14-days and death within 3-months of positive SARS-CoV-2 test.Results:A total of 8,272 SSRI patients were well-matched to 24,816 no SSRI patients (Table 1). Hospitalization and death were significantly greater in the SSRI group compared to the no SSRI group (Table 1). A total of 2,067 (25.0%) of SSRI patients were taking fluoxetine or fluvoxamine. While attenuated, no SSRI remained associated with a lower 14-day COVID-19 hospitalization risk when compared to fluoxetine or fluvoxamine use, but not with 3-month death (Table 2).Conclusion:This study did not find a lower risk of progression of COVID-19 severity with the use of any SSRI or fluoxetine/fluvoxamine alone. Results from this study support the FDA’s decision to not recommend their use at an early stage of a COVID-19 infection.

Introduction:There has been considerable discussion regarding the value of follow-up LDL-C measurements in secondary prevention of major adverse cardiac events (MACE). We therefore set out to determine in a large healthcare system whether measurement of LDL-C after an ASCVD event was associated with a difference in MACE during follow-up and whether differences in outcomes could be attributed to differences in statin use.Methods:The Intermountain Enterprise Data Warehouse was searched to identify all adults with a first encounter for ASCVD-including coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD)—between January 1, 1995 and December 31, 2016 who survived the index event and were followed for ≥3 years or until death.Results:Patients (N=68,411) had an average age of 66±14 years; 65% were men; 70.3%, 21.0%, and 8.6% entered with CAD, CVD, and PAD, respectively. A statin was prescribed to 52% of patients during follow-up. A total of 33,698 (49%) did not have and 34,713 (51%) did have a follow-up LDL-C test prior to a subsequent MACE (death, MI, CVA, and revascularization) or end of follow-up. By 3 years, MACE occurred in 14,835 (37.4%) vs. 5,770 (20.1%) of those without vs. with an LDL-C measurement, respectively (Figure top). The multivariable hazard ratio for 3 year MACE based on measuring LDL-C was 0.47. The increased MACE rate associated with not measuring LDL-C was partially mitigated by statin use (Figure bottom). Only 44.7% vs. 58.9% of patients without vs. with LDL-C measurement were taking statins.Conclusion:These data indicate that there is a significant and clinically meaningful difference in MACE based on a follow-up measurement of LDL-C. Statin administration partially, but not completely mitigated the increased MACE rate. While these results are limited in that they are from a retrospective registry, they indicate that LDL-C should be measured, and statin should be administered after an initial ASCVD event.

Introduction:Statins traditionally have been contraindicated during pregnancy because of a theoretical risk of teratogenicity. However, emerging evidence to suggest relative safety and potential harm in contraindicating statins in high cardiovascular (CV)-risk pregnancies have led the FDA in 2021 to remove the “Pregnancy Category X” label. This has placed a heavy burden on physician-patient (pt) shared decision making in that statins “should be discontinued in most pregnant patients or consider the ongoing therapeutic needs of the individual pt, particularly those at very high risk for CV events during pregnancy”.Methods:The objective of this study was to describe the current real-world characteristics of pts prescribed a statin during pregnancy and pregnancy outcomes in a large US healthcare system. Pregnant pts taking a statin were identified by a search of the electronic medical records (eMR) of Intermountain Healthcare, a system of 24 hospitals and 215 clinics in Utah, Idaho, and Nevada, between 1997 and 2021, and pregnancy outcomes determined electronically. Statin pts were matched 1:10 by age (+/- 1 y) with non-statin pts. Characteristics and outcomes were determined, and adjusted odds ratios (aOR) were calculated.Results:A total of 63 statin-user pregnancies were matched to 630 controls. Stain pts had more co-morbidities and higher baseline lipids (Table 1). Adverse pregnancy outcomes were more frequent in statin users (Table 2A). However, statin use did not contribute significantly to multivariable risk prediction of miscarriage or congenital anomalies although possibly it did to eclampsia/preeclampsia (Table 2B).Conclusions:In a current real-world US experience, pts prescribed statins during pregnancy had more comorbidities and more adverse outcomes, including fetal anomalies. However, after adjustment, statin use did not contribute to multivariable risk prediction of miscarriage or congenital anomalies.

Introduction:Health, wellness, and healthcare are most effectively and efficiently managed when health status is quantitatively measured. The Intermountain Mortality Risk Score (IMRS) is a well-validated low-cost decision tool calculated from the complete blood count and basic metabolic profile that can be electronically deployed to inform clinician or patient actions. This study evaluated if 3 serial IMRS measurements improved mortality prediction.Methods:In 119,379 Intermountain Healthcare outpatients, inpatients, and emergency patients, baseline (BL) IMRS was calculated in 1999-2005. Of those, the following were excluded: 22,678 who died prior to having 3 IMRS measurements and 38,228 survivors who at 5 years (y) post-BL did not have 3 IMRS. In the study cohort of 58,473 patients, a 1stfollow-up (1F) IMRS was available 1.49±0.79 y post-BL (range 1-4 y), and a 2ndfollow-up (2F) IMRS at 3.75±0.80 y post-BL (range 2-5 y). Patients had 13.4±1.7 y of follow-up after 2F (range: 9.3-18.7 y), with total follow-up post-BL of 17.2±1.5 y (range: 14.3-20.7 y).Results:Overall, 26,693 patients died (45.7%) after 2F. In females, IMRS for decedents vs. survivors was, respectively, 11.3±3.9 vs 6.3±4.0 at BL, 11.1±3.9 vs 5.7±4.0 at 1F, and 12.2±4.2 vs 6.1±4.0 at 2F; differences in males were similar to those results (all p<0.001). Relative risks for IMRS categories are shown in the Table. C-statistics for females were c= 0.815, 0.834, 0.858 for BL, 1F, and 2F, with 0.872 for a sum of the 3 IMRS (results were similar for males, with absolute c 0.06-0.08 lower).Conclusions:IMRS predicted substantial risk differences at each of 3 timepoints, but the IMRS trajectory (including declines in IMRS) revealed by the sequence of IMRS measurements better personalized risk assessment. When risk level and direction are considered together, critical junctures in a person’s health journey may be revealed, empowering earlier or more intensive prevention, diagnostic testing, and interventions.

Introduction:Statins play a critical role in primary and secondary ASCVD prevention. Although uncommon, myalgias and abnormal liver function tests (LFTs) may limit statin use. Alcohol consumption also is a common cause of LFT elevations. It is unknown whether or to what extent concurrent alcohol and statin use may alter elevated LFT risk and impact management.Methods:Patients (pts) enrolled in the Intermountain INSPIRE registry who completed a health questionnaire for alcohol and other socioeconomic, dietary, and physical activity data were studied. Demographics, anthropometrics, cardiac risk factors, comorbidities, medication use, and laboratory results were obtained from electronic health records. Associations of alcohol and statin use with high ALT (females, >40 U/L; males, >55 U/L) were tested. Alcohol categories were: non-drinkers (ND; n=2797), moderate drinkers (MD; ≤7 drinks/week, n=980), and heavy drinkers (HD; >7 drinks/week, n=164).Results:High ALT was found in 18.9%, 12.6%, and 10.5% of HD, MD, and ND respectively (p=0.002) and in 11.3% of both statin (n=2154) and non-statin users (n=1787) (p=0.97). After adjustment, HD vs. ND had OR=2.19 (CI: 1.44, 3.33; p<0.001), and MD vs ND had OR=1.09 (CI: 0.86, 1.37; p=0.49). Pts not on statins had high ALT in 15.4% of HD (OR=1.47, CI: 0.73, 2.95; p=0.28) and 12.0% of MD (OR=1.10, CI: 0.79, 1.54; p=0.57) compared to 11.0% of ND. In parallel, pts on statins had high ALT in 21.2% of HD (OR=2.58, 95% CI: 1.52, 4.36; p<0.001) and 13.0% of MD (OR=1.16, CI: 0.85, 1.59; p=0.34) vs. 10.2% of ND. Despite these trends, no formal interaction was found between statin use with HD (p-interaction=0.27) or with MD (p-interaction=0.43). Results for high AST (>40 U/L) and low ALP (<40 U/L) were similar to the ALT findings.Conclusions:In this prospective database, statin use was not associated with abnormal LFT findings, whereas risk was higher with increasing alcohol consumption. Concurrent statin and alcohol use was associated with a modestly elevated risk of abnormal LFT, but the interaction was not significant. Reducing alcohol consumption rather than reducing or discontinuing statins may reverse abnormal LFT while preserving the preventive benefit of statins. This hypothesis deserves further prospective testing.

Introduction:Recent interest has focused on STEMI patients (pts) without standard modifiable risk factors (SMuRF-less), noting that they are surprisingly common (14-27%). These studies have reported them to have a worse, or at best similar, in-hospital/short-term prognosis. However, relatively little attention has been paid to the prevalence and prognosis of SMuRF-less patients with non-ST elevation myocardial infarction (NSTEMI). The aim of our study was to identify the proportion and outcomes of SMuRF-less NSTEMI pts in a large US healthcare population.Methods:Pts with NSTEMI between 2001-2021 presenting to Intermountain Healthcare catheterization laboratories were included. SMuRF included a clinical diagnosis of, or treatment for, hypertension, hyperlipidemia, diabetes, and/or smoking. 60-day and long-term major adverse cardiovascular event (MACE) outcomes were defined as death, myocardial infarction, and heart failure hospitalization and were tested using Cox proportional hazard regression.Results:NSTEMI pts totaled 8196, of which1458 (17.8%) were SMuRF-less. SMuRF-less pts were younger, more frequently male, had fewer comorbidities, and were slightly less likely to have PCI/CABG than NSTEMI pts with SMuRF (Table 1). 60-day MACE for SMuRF-less pts were lower (adj HR 0.55, p<0.0001), and this persisted for long-term MACE outcomes (adj HR 0.64, p<0.0001) and for each of its components (Table 2).Conclusions:In this large US healthcare population, SMuRF-less NSTEMI presentation, as with STEMI presentation, was found to be common (17.8%). However, unlike STEMI reports, short- and long-term outcomes were generally more favorable for SMuRF-less status. Further studies to increase understanding of risk factors and preventive measures for NSTEMI in SMuRF-less pts are indicated.

AbstractObjective: To evaluate soluble (s) ST2 as a biomarker of rejection, allograft vasculopathy and mortality after orthotopic heart transplantation (OHT).Methods: sST2 concentrations were measured in 241 patients following OHT.Results: Elevated sST2 was associated with cellular rejection (CR) 1R, with highest rates of CR in the 4th sST2 quartile (p  0.003). No significant association between sST2 and antibody-mediated rejection or allograft vasculopathy was found. sST2 30 ng/mL independently predicted death over 7-year follow-up (HR  2.01; 95 CI 1.15–3.51; p  0.01).Conclusion: Concentrations of sST2 are associated with the presence of CR and predict long-term mortality following OHT.

Peripartum (PP) cardiomyopathy (CM) is a rare condition of unknown etiology that occurs in late pregnancy or early postpartum. Initial evidence suggests that genetic factors may influence PPCM. This study evaluated and replicated genome-wide association of single nucleotide polymorphisms with PPCM.

It is proposed that contrast-induced nephropathy (CN) correlates with the use of increasing contrast volumes during coronary angiography. This supposition has led to the current recommendation to limit the dose of contrast in patients at high risk for renal dysfunction. Limits in contrast dosing may negatively impact the evaluation of patients undergoing cardiac catheterization for myocardial infarction and acute coronary syndrome. The objective of this study was to empirically assess, in a large population, the presence and strength of this correlation.

Coronary artery disease (CAD) is the leading cause of death in the United States. Increasing evidence suggests involvement of inflammation in the atherosclerotic process. We examined cytokines and other inflammatory markers in 865 patients with chest pain in whom coronary angiography revealed no evidence of CAD or CAD with or without concomitant myocardial infarction (MI). We developed a multiplexed immunoassay to simultaneously assess the plasma concentrations of 8 cytokines (interferon gamma, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor alpha), IL-2r, and soluble CD40 ligand in the patient groups. Concentrations of C-reactive protein (CRP) and IL-18 also were determined. Significant differences (P < .05) between no CAD and combined CAD groups were found for IL-2, IL-4, IL-6, IL-12, and IL-18. When the no CAD group was compared with the group with CAD with subsequent MI, significant differences were found for proinflammatory markers IL-6 (P pound .001), IL-8 (P = .017), and CRP (P pound .001). Cytokine profiles may have a role in differentiating patients with CAD with MI from those with chest pain due to other disorders and in deciphering the role of inflammation in the pathogenesis of CAD.

Several lines of evidence have demonstrated an association between a variety of chronic bacterial infections and atherosclerotic cardiovascular disease. This has led to the proposal that antibiotic therapy might be helpful in the secondary prevention of atherosclerosis. A variety of smaller pilot studies have been reported testing this hypothesis and several large multicenter trials are also underway. The purpose of this review is to summarize the results of these studies and comment on their implications for the treatment of atherosclerosis.

Restenosis after percutaneous transluminal coronary intervention (PCI) remains a serious complication in the treatment of coronary artery disease. Although β-adrenergic receptor blockers (BBs) effectively reduce many cardiac events, no large prospective studies have examined the association of BBs with restenosis.

BackgroundRestenosis after percutaneous coronary intervention (PCI) constitutes a serious complication in the treatment of cardiovascular disease, but known risk factors do not fully account for the observed restenosis risk. Preliminary studies of infection or inflammation in restenosis report varied results. We tested whether C-reactive protein (CRP) or pathogen burden (seropositivity to 0, 1, 2, or 3 pathogens, of Chlamydia pneumoniae[Cpn], cytomegalovirus [CMV], or Helicobacter pylori[Hpy]) predict clinical restenosis after percutaneous coronary intervention (PCI). MethodsBlood samples were collected from 415 patients undergoing PCI, and levels of plasma CRP and antibodies to Cpn, CMV, and Hpy were measured. The patient's medical history, demographics, and procedural data were recorded. Patient end points were determined for as long as 6 months as a means of evaluating the incidence of clinical restenosis and major adverse cardiac events. ResultsThe average patient age was 62 years, and 80% of patients were male. Fifty-eight patients (14%) experienced clinical restenosis, whereas 17 patients (4%) died or had an acute myocardial infarction. After adjusting for 19 possible predictors, we found the pathogen burden (P-trend =.04, adjusted odds ratio [OR] 1.5 per number of pathogens) and minimum luminal diameter (P=.003, OR 1.8 per mm decrease) to be significant predictors of clinical restenosis. Male sex was a nonsignificant predictor of restenosis (P=.06, OR 2.2), but CRP was not significant after adjustment (P-trend =.10, OR 0.73 per tertile). ConclusionPathogen burden was associated with clinical coronary restenosis, an association that deserves further exploration and evaluation. CRP, a marker of inflammation, was not associated with an increased risk of restenosis. (Am Heart J 2002;144:491-500.)

OBJECTIVES

In patients with coronary artery disease (CAD), azithromycin therapy is associated with decreased cytokine levels and overall reduction of inflammation. Chlamydia pneumoniae(C.Pn) is a common pathogen that may be an important factor in the development and progression of atherosclerosis. Cell-adhesion molecules have an important role in recruitment of inflammatory cells during plaque development and are expressed by endothelial cells on activation. We sought to define the effect of treatment with azithromycin on circulating levels of soluble vascular cell-adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and E-selectin in patients with CAD. Plasma concentrations of VCAM-1, ICAM-1, and E-selectin were measured in 40 patients with documented CAD and a positive (≥1:16) immunoglobulin G (IgG) titer against C.Pn, 20 subjects with normal coronary arteries, and 14 healthy volunteers. Patients were assigned randomly to receive either 500 mg/wk of azithromycin or placebo for 3 months. Serum samples were obtained at baseline, at 3 months, and during the follow-up visit at 6 months. Patients with documented CAD exhibited elevation of VCAM-1 (535 ± 227 ng/ml; p = 0.0001) and E-selectin (69 ± 29 ng/ml; p = 0.006), but not ICAM-1 (321 ± 65 ng/ml) concentrations as compared with the patients with angiographically proven normal coronary arteries (252 ± 80; 50 ± 22; and 311 ± 40 ng/ml) and healthy controls (110 ± 18; 29 ± 2; and 238 ± 47 ng/ml, respectively). Prolonged treatment with azithromycin did not significantly affect the plasma levels of soluble VCAM-1, ICAM-1, and E-selectin. Soluble markers of endothelial activation are markedly increased in patients with documented CAD as compared with those with normal coronary arteries and healthy controls. Despite substantial heterogeneity in plasma E-selectin, ICAM-1, and VCAM-1 levels, long-term azithromycin treatment did not affect plasma levels of these adhesion molecules, indicative of endothelial activation, over a period of 6 months.

OBJECTIVE

Background:Dealing with statin intolerance represents a major clinical challenge. Controlled clinical trials suggest that a large percentage of statin intolerance may be due to a “nocebo effect”, wherein adverse reactions are linked to pill ingestion irrespective of actual pill content (e.g., SAMSON trial). We tested whether statin intolerance was associated with intolerance to other medications in a large real-world experience. We hypothesized that statin intolerance would be associated with multiple drug intolerances.Methods:We searched Intermountain Healthcare medical records between January 2002 and February 2021 for patients (pts) with a listed intolerance or allergy to 1 or more statins. We compared these to a control group of randomly selected pts not exposed to statins but taking one or more other oral medications. A second control group included all patients taking and tolerating statin therapy. We compared the number of recorded drug allergies/intolerances in the statin intolerant group with those in the 2 control groups.Results:Characteristics of patients in the 3 groups are shown in the Table. On average, statin intolerant patients had 3.64 additional listed drug allergies/intolerances (beyond statins), compared to 1.31 in non-statin exposed controls and 1.81 in the statin tolerant population (both p<.001).Conclusion:In this large real-world experience, statin intolerance was strongly associated with intolerance to multiple other medications. Although some patients may have a true intolerance to multiple medications, including statins, patients with multiple drug intolerances may also suffer from a generalized nocebo effect. In either case, noting a patient’s tendency toward multiple drug intolerances can alert clinicians to an increased intolerance risk when initiating a statin and can lead to preemptive medical and educational interventions aimed at reducing this risk.

Introduction:The use of statins in patients (pts) with heart failure (HF) is controversial. In patients without HF, statins reduce the risk of atherosclerotic cardiovascular disease (ASCVD), including HF-related events. In contrast, no benefit was observed in statin-treated HF pts in the CORONA and GISSI-HF trials. However, issues with generalizability may limit the applicability of these trial results in clinical practice. Therefore, we analyzed the impact of statin therapy in systolic HF pts in a large real-world experience.Methods:We searched Intermountain Healthcare medical records for pts with a diagnosis of HF and a reported ejection fraction of <=40%. We compared outcomes (MACE=death, MI, stroke) at a median of 4.5 years follow-up in those who were and were not prescribed a statin. Statin use was defined as use at or after a HF diagnosis but prior to 60-days before MACE or end of follow-up. Cox hazard regression analysis was used to determine hazard ratios.Results:A total of 15,010 pts were studied. Baseline demographics and outcomes are shown in the Table. Statin use was associated with more frequent ASCVD risk factors yet a lower MACE risk during follow-up. Benefit was similar for primary and secondary prevention pts and for prior and new statin prescriptions. By time-varying hazard ratio (HR) analysis, the longer the pt was on a statin, the greater the reduction in risk of MACE (p<0.0001).Conclusion:These results suggest a potential benefit of selective statin use in the real-world management of HF pts with ASCVD or at high-ASCVD risk. These novel observations deserve validation in additional real-world experiences.

Background:The COVID-19 pandemic has affected nearly every aspect of daily life. The interpersonal loss due to quarantining and social distancing, compounded with societal disruption has negatively affected mental health. Once established, mental health conditions can become chronic with having subsequent effects on additional risk factors and disease incidence, such as cardiovascular disease (CVD).Methods:Patients who completed a PHQ-9 in a primary care setting in the year prior to the COVID pandemic (Mar 1, 2019 to Feb 29, 2020) and during the COVID pandemic (Mar 1, 2020 to Apr 20, 2021) were studied. Patients were stratified into 2 groups: no depression/no longer depressed and remained depressed/became depressed. Patients were assessed for follow-up emergency department (ED) visits for anxiety and chest pain (CP) after PHQ-9 completion during the pandemic.Results:A total of 4,633 patients were studied, with 2,848 (61.5%) being never/no longer depressed and 1,785 (38.5%) remaining/became depressed. PHQ-9 scores during the pandemic were higher than prior to the pandemic among those depressed. A total of 2,171 (46.6%) received a COVID test, with more depressed patients tested compared to non-depressed (Table), but with positivity for SARS-CoV-2 (n=362 [16.7%]) being similar (p=0.18). The table shows baseline characteristics and outcomes. Depression was associated with increased ED visits for anxiety (Table). Those with depression, visited the ED at 3.5 times and 2.7 times greater rate for anxiety and anxiety with CP compared to non-depressed, respectively.Conclusions:Depression was highly prevalent among patients who receive routine primary care, with depressive symptoms increasing during the pandemic. Since depression and anxiety are associated with an increased risk of CVD and associated risk factors, identifying and treating patients early who exhibit such symptoms will be important in reducing the risk of future CVD and risk factor incidence.

Background:Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor remains standard treatment for patients undergoing PCI, and clopidogrel remains the most used agent. Many patients (pts) are genetically resistant to clopidogrel and may not receive its full benefit. However, the use of platelet function testing to provide individualized management of P2Y12 inhibitor therapy remains controversial. Therefore, we analyzed the impact of the use of platelet function testing after PCI in a large real-world experience.Methods:We searched Intermountain Healthcare medical records for pts who underwent PCI followed by DAPT. We compared 1-year outcomes (MACE=death, MI, stroke; and repeat revascularization and major bleeding) in those who did, or did not, receive P2Y12 platelet function testing within 90 days. Cox hazard regression analysis was used to determine multivariable hazard ratios.Results:A total of 11,561 pts were included, of which 650 (5.6%) received P2Y12 platelet function testing. Baseline demographics, discharge P2Y12 inhibitor and outcomes are shown in the Table.Conclusion:In this real-world analysis of patients undergoing PCI, a small proportion of the patients received P2Y12 platelet function testing. Platelet function testing was associated with increased utilization of prasugrel or ticagrelor and a statistically lower incidence of 1-year MACE (10.8% vs. 12.4%, adjusted odds ratio = 0.69, p=0.03), with a very low incidence of major bleeding. Further investigation regarding the potential benefits of individualized management of DAPT therapy through P2Y12 platelet function testing may be justified.

Background:In the presence of comorbid conditions, COVID-19 infections are known to require more advanced treatment, poorer outcomes and have longer-term sequelae. New-onset atrial fibrillation (AF) during COVID-19 infection has been associated with worse cardiovascular outcomes but not mortality. However, it remains unclear whether a prior history (hx) of atrial fibrillation is a cardiovascular risk factor predicting a worse outcome in COVID-19 patients. As such, we examined, using propensity matching accounting for possible confounders, the need for advanced treatment and subsequent major cardiovascular events (MACE) in patients with a prior hx of AF with COVID-19 infection.Methods:From March 2020 to May 2021, patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n=3119) were propensity matched for age, gender, race/ethnicity, prior coronary artery disease (CAD), prior heart failure (HF), prior stroke and hypertension to non-AF SARS-CoV-2 positive patients. Cox hazard regression analysis with multivariable adjustment was used to determine risk of subsequent MACE (all-cause death, myocardial infarction, HF and stroke).Results:Baseline characteristics, treatments, and outcomes stratified by AF status are shown in the Table. While the groups had similar baseline characteristics, AF COVID-19 patients were more likely to require hospitalization, ICU care, and ventilator support. Consistent with our hypothesis, composite MACE event rates were higher in the AF patients (HR=1.60, p<0.0001) secondary to increases in heart failure and all-cause mortality rates.Conclusions:These data support AF as a cardiovascular risk factor predicting worse outcomes in COVID-19 patients. Specifically, AF increases the need for advanced treatments such as hospitalization, ICU care and ventilator support resulting in an increase in subsequent heart failure and all-cause mortality.

Background:As SARS-CoV-2 vaccines are being administered on an unprecedented scale, it is critical to carefully assess risks to aid clinicians in the early detection and treatment of potential side effects. Here we examine increases in the risk of pericarditis following SARS-CoV-2 vaccination.Methods:We examined pericarditis cases from December 15, 2020, to April 15, 2021 seen within Intermountain Healthcare, an integrated healthcare system. Pericarditis was defined by at least two of the following criteria: chest pain, EKG changes, pericardial effusion, and pericardial rub; excluded cases secondary to non-infectious causes (e.g., AF ablation). We determined vaccination within 60 days prior to pericarditis diagnosis using Intermountain and Utah Department of Health vaccination information. Rates of pericarditis per 10 million patient days for vaccinated patients compared to unvaccinated patients were compared. We also examined a case-crossover design with 4 control dates for each pericarditis case.Results:Of the 29 identified pericarditis cases, 13 (44.8%) had a SARS-Cov-2 vaccination within 60 days before the onset of pericarditis. During the same period, 743,774 individuals in the Intermountain Healthcare system had received at least one dose of the SARS-CoV-2 vaccine. Thus, 1.7 per 100,000 vaccinated individuals were diagnosed with acute pericarditis. Within a 60-day post-vaccination window, the rate of acute pericarditis per 10-million patient-days was 3.90 in the vaccinated group and 0.84 in the unvaccinated group. Thus, there was a 4.49 times higher rate of acute pericarditis in vaccinated patients compared to the unvaccinated individuals (p=0.0002). Case-crossover analysis showed the odds of acute pericarditis was 3.33 higher (95% CI: 1.29, 10.14) in the vaccinated versus the unvaccinated group (p=0.01).Conclusions:We found acute pericarditis to be a rare post-SARS-CoV-2 vaccination event, but the risk was significantly higher than in comparable unvaccinated subjects. This risk of pericarditis post-SARS-CoV-2 vaccine is eclipsed by the risk of contracting COVID-19 and its associated, commonly seen severe outcomes. Nevertheless, clinicians should be informed of this risk to facilitate earlier recognition and treatment.

Introduction:Intermittent fasting reduces weight and cardiometabolic risk factors. In the WONDERFUL Trial (NCT02770313), intermittent fasting reduced homeostatic model assessment of insulin resistance (HOMA-IR) and the Metabolic Syndrome Score (MSS), with insulin having the largest decline. The red cell distribution width (RDW) measures the dispersion of red blood cell size, is strongly predictive of mortality and major adverse events, and may be a biomarker of general health. This post hocstudy of subjects from the WONDERFUL Trial examined the interactive effect of intermittent fasting and baseline RDW on changes in insulin, glucose, HOMA-IR, and MSS.Methods:Subjects aged 21-70 years who had pre-diabetes, diabetes, or ≥1 other metabolic syndrome factor and modestly elevated LDL-C were enrolled if they were not taking anti-diabetic or statin medications and were free of chronic diseases (N=71; n=38 intermittent fasting, n=33 controls). Subjects were randomized to 24-hour water-only fasting (twice-weekly for 4 weeks followed by once-weekly for 22 weeks) or ad libitumeating (control) for 26 weeks.Results:Age averaged 49.1±11.1 years and 64.8% were female. Change scores stratified by RDW size distribution (RDW-SD) are shown in the Table. Results were similar when the RDW coefficient of variation (RDW-CV) was used. Intermittent fasting did not change RDW-SD (1.27±9.6 fL vs. control: -0.37±1.76 fL, p=0.34) or RDW-CV (-0.15%±0.55% vs. control: -0.11%±0.45%, p=0.76) over the 26-week trial.Conclusions:Compared to controls, intermittent fasting significantly decreased insulin more in subjects with higher baseline RDW than those with RDW ≤median. This differential effect may also apply to changes in HOMA-IR, glucose, and MSS. These findings should be validated and expanded in larger studies since RDW may identify people who would derive the most cardiometabolic benefit from engaging in intermittent fasting.

Introduction:Intermittent fasting decreases cardiometabolic risk factors, heart failure (HF) risk, and type 2 diabetes risk. Sodium-glucose transport 2 (SGLT-2) inhibitors reduce diabetes and HF risk and a study of canagliflozin reported that it raised galectin-3 levels (Januzzi 2017). Previously in the WONDERFUL trial (NCT02770313), intermittent fasting caused declines in the Metabolic Syndrome Score (MSS) and homeostatic model assessment of insulin resistance (HOMA-IR). This study evaluated intermittent fasting’s effects on galectin-3 in a post hocanalysis of the WONDERFUL Trial.Methods:People aged 21-70 years were enrolled who had ≥1 metabolic syndrome feature or type 2 diabetes, were free of anti-diabetic and statin medications, and had elevated LDL-C. Subjects had 26-week galectin-3 data (N=67; n=36 intermittent fasting, n=31 controls). Subjects were randomized to a 24-hour water-only fasting intervention (fasting twice per week for 4 weeks, then once each week for 22 weeks) or a parallel control arm (ad libitumeating). This study evaluated the 26-week galectin-3 change score and other changes in HF biomarkers.Results:At 26 weeks, the galectin-3 change score was increased in intermittent fasting (0.575±2.63 ng/mL) vs control (-0.624±2.79 ng/mL; p=0.021). Changes in galectin-3 were inversely correlated with HOMA-IR change score (r= -0.288, p=0.018) and MSS change score (r= -0.238, p=0.052). Changes in galectin-3 at 4 weeks (intermittent fasting: 0.345±2.68 ng/mL; control: -0.465±3.18 ng/mL; p=0.27) and 13 weeks (fasting: 0.917±4.96; control: -0.097±2.83 ng/mL; 0.15) were not significantly different. B-type natriuretic peptide went down in intermittent fasting (-0.328±12.29 pg/mL) but this was not significant compared to controls (15.50±75.34 pg/mL, p=0.23). Other HF biomarkers were unchanged.Conclusions:Water-only 24-hour intermittent fasting increased galectin-3. This rise in galectin-3 was correlated with declining HOMA-IR and MSS and may be similar to reported effects of SGLT-2 inhibitors. Increased galectin-3 may be an adaptive response that could prevent chronic disease by decreasing inflammation, ameliorating insulin resistance, or modifying related mechanisms.

Introduction:Mitochondrial DNA copy number (mtDNA-CN) is associated with cardiovascular disease (CVD) and mortality. Here we examine, in a high-risk CVD population, the association with prevalent coronary artery disease (CAD) and subsequent major adverse events (MACE) at 1-,5- and 10-year follow-up of mtDNA-CN.Methods:Consecutive subjects (n=2267) consenting to a blood sample drawn for the Intermountain INSPIRE biorepository at the time of a coronary angiogram from July 1994 to Sept 2003 were included. The mtDNA-CN was determined by multiplexed real-time polymerase chain reaction coamplifying a stable site of mt D- Loop and a region of a single copy genomic β-2-microglobulin gene(β2M). MtDNA-CN is given as the ratio of Mt to β2M DNA. The presence of severe CAD (>70% stenosis) was analyzed using multivariate logistic regression. The subsequent MACE (including all-cause mortality and non-fatal MI) outcomes were studied using multivariate Cox proportional hazard regression.Results:The average age of subjects was 62.3 ± 13.8, 35% were female, and 50% had prior CAD. Over half (55%) had severe CAD at the angiogram. As the mtDNA-CN increased, severe CAD decreased (58% for 1stquartile vs. 51% for 4thquartile). After adjustment for baseline differences, subjects with mtDNA-CN in the 1stquartile were 1.31 times more likely to have severe CAD than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.01, 1.71; p=0.04). A total of 902(39.8%) had a subsequent MACE event within 10-years (193[8.5%] in 1-year and 548[24.2%] in 5-years). There was no association between mtDNA-CN and 1-year MACE. However, mtDNA-CN was associated with 5-year (p=0.006) and 10-year (p=0.003) MACE. After adjustment, subjects with mtDNA-CN in the 1stquartile were at 1.29 increased risk of 10-year MACE than subjects with mtDNA-CN in the 4thquartile (95% CI: 1.07, 1.56; p=0.008).Conclusions:In a coronary angiographic population, mtDNA-CN was associated with severe CAD and the risk of subsequent long-term MACE. These findings suggest that mtDNA-CN could be used as a clinical biomarker for risk. Moreover, understanding the factors impacting mtDNA-CN may also help in the prevention of secondary CVD outcomes.

Introduction:Adults <40-yrs (20-39) may have elevated cardiovascular risk based on higher LDL-C (e.g., ≥160 mg/dL). We sought to compare the risk of MACE (all-cause death, MI, ischemic stroke, heart failure hospitalization, and peripheral vascular disease [PVD]) in adults <40-yrs and LDL-C ≥160 to 189 compared with LDL-C <160 mg/dL.Hypothesis:Adults <40-yrs with LDL-C ≥160-189 mg/dL are minimally addressed in the current cholesterol management guidelines but may have a higher risk of MACE compared to other healthy controls.Methods:Patients (pts) from 20- 39 yrs of age with at least three lipid labs and outpatient primary care encounters at Intermountain Healthcare, a large integrated healthcare system, prior to January 2010 and an LDL-C measurement between January and December of 2020 (n=14,570) were included and followed for MACE until June 2021. Pts with LDL-C >190 or <160 on statin in 2010 but previously ≥160 were excluded. Pts were identified using MDClone (ADAMS self-service analytics platform). Outcome of interest was MACE during 10-yr follow-up, LDL-C was stratified as ≥160-189 vs <160 mg/dL. Baseline characteristics were compared by either a chi-squared or t-test, as appropriate. Multivariate logistic regression was used to identify the role of LDL-C as a predictor of outcome. A p-value of <0.05 was considered statistically significant.Results:Baseline characteristics are presented in the Table. MACE for LDL-C ≥160-189 mg/dL was not statistically significant compared to LDL-C <160 (OR 1.28, 95% CI 0.94 - 1.74, p<0.115).Conclusions:The risk of 10-yr MACE in adults <40 yrs of age with LDL-C ≥160-189 mg/dL did not confer a statistically significant elevated risk. Our findings are consistent with current guidelines that statin therapy is not mandated in these individuals.

Background:Rates of morbidity and mortality after interventional procedures are reported to be inversely associated with institutional volume. Methods:This study assessed both procedural volume and academic status at the 82 US centers that participated in the IMPACT-IItrial. Interventional volumes at the sites ranged from 90 to 3300 cases per year. Patients were randomly assigned to a platelet glycoprotein IIb/IIIa inhibitor (eptifibatide) or placebo during procedures done by experienced operators. The primary end point was the composite of death, myocardial infarction, nonelective repeat coronary intervention, or nonelective coronary artery bypass surgery at 30 days, or placement of an intracoronary stent for abrupt closure during the initial procedure. Results:Baseline patient characteristics and median length of stay were similar between the academic and nonacademic centers. In univariable analysis, volume as a continuous variable had a nonlinear relation with the incidence of the composite end point, with better outcomes noted at the highest volume institutions. Academic status did not predict outcome. When added to a predictive model that contained the variables unstable angina, weight, prior coronary artery bypass grafting, heart rate, and platelet count, procedural volume continued to be associated with the composite outcome (P= .04). Conclusions:We conclude that among hospitals participating in this trial, there is a nonlinear relation between annual interventional volume and outcomes. This relation is complex, involving variations in periprocedural infarction rates and additional, undefined institutional differences (other than academic status) that result in differences in procedural outcome. (Am Heart J 1999;138:976-82.)

OBJECTIVES

OBJECTIVES

OBJECTIVES

Objectives. We tested the hypothesis that an emergency department-based protocol for rapidly ruling out myocardial ischemia would reduce hospital time and expense but maintain diagnostic accuracy.