Intermountain Heart Research Articles

Multimarkers of metabolic malnutrition and inflammation and their association with mortality risk in cardiac catheterisation patients: a prospective, longitudinal, observational, cohort study

Complex and incompletely understood metabolic dysfunction associated with inflammation and protein-energy wasting contribute to the increased mortality risk of older patients and those with chronic organ diseases affected by cachexia, sarcopenia, malnutrition, and frailty. However, these wasting syndromes have uncertain relevance for patients with cardiovascular disease or people at lower risk. Studies are hampered by imperfect objective clinical assessment tools for these intertwined metabolic malnutrition and inflammation syndromes. We aimed to assess, in two independent cohorts of patients who underwent cardiac catheterisation, the mortality risk associated with the metabolic vulnerability index (MVX), a multimarker derived from six simultaneously measured serum biomarkers plausibly linked to these dysmetabolic syndromes. In this prospective, longitudinal, observational study, we included patients aged ≥18 years recruited into the CATHGEN biorepository (Jan 2, 2001, to Dec 30, 2011) and the Intermountain Heart Collaborative Study (Sept 12, 2000, to Sept 21, 2006) who underwent coronary angiography and had clinical nuclear magnetic resonance metabolomic profiling done on frozen plasma obtained at catheterisation. We aggregated six mortality risk biomarkers (GlycA, small HDL, valine, leucine, isoleucine, and citrate concentrations) into sex-specific MVX multimarker scores using coefficients from predictive models for all-cause mortality in the CATHGEN cohort. We assessed associations of biomarkers and MVX with mortality in both cohorts using Cox proportional hazards models adjusted for 15 clinical covariates. We included 5876 participants from the CATHGEN biorepository and 2888 from the Intermountain Heart study. Median follow-up was 6·2 years (IQR 4·4-8·9) in CATHGEN and 8·2 years (6·9-9·2) in the Intermountain Heart study. The six nuclear magnetic resonance biomarkers and MVX made strong, independent contributions to 5-year mortality risk prediction in both cohorts (hazard ratio 2·18 [95% CI 2·03-2·34] in the CATHGEN cohort and 1·67 [1·50-1·87] in the Intermountain Heart cohort). CATHGEN subgroup analyses showed similar MVX associations in men and women, older and younger individuals, for death from cardiovascular or non-cardiovascular causes, and in patients with or without multiple comorbidities. MVX made a dominant contribution to mortality prediction in patients with cardiovascular disease and in low-risk subgroups without pre-existing disease, suggesting that metabolic malnutrition-inflammation syndromes might have a more universal role in survival than previously thought. Labcorp.

Abstract 271: Mitochondrial DNA Copy Number in Peripheral Blood Cells is Associated With All -Cause Mortality in Older Cardiovascular Patients

Background: Mitochondrial DNA copy number (Mt CN) is a surrogate marker of mitochondrial function. Variations in Mt CN have been associated with several age-related diseases. Lower Mt CN may indicate impaired cellular energy production whereas higher Mt CN may compensate for energy disbalance but also may lead to cellular damage through oxidative stress. This study evaluated the association of Mt CN and all-cause mortality in older cardiovascular patients (Pt). Methods: The study was approved by the Intermountain Healthcare Institutional Review Board. Consenting subjects (n=2,253) were participants in the INSPIRE registry undergoing cardiac catheterization at the Intermountain Heart Institute. Total DNA was extracted from EDTA stabilized blood with either Puregene (Qiagen) or Reliaprep (Promega) reagents. Relative Mt CN measurements were performed with multiplexed real-time polymerase chain reaction coamplifying a stable site of Mt D- Loop and a region of a single copy nuclear β-2-microglobulin gene(β2M) and calculated as a ratio of Mt to β2M DNA. Cox regression was used to evaluate the association of Mt CN with all-cause mortality, with adjustment considering 32 covariables. Further adjustment entered the Intermountain Risk Score (IMRS), a validated mortality risk predictor. Results: Mean Pt age was age 62.3±13.8 yrs.; 65.2% were male; 1,122 (50%) died during 25.4 years of follow-up. Mt CN was lower for males (539±449 vs 654 ± 1053 for females; p=0.004). Mt CN was 616±917 in decedents and 542±438 in survivors (p=0.014). In univariable Cox regression, Quartile 1 versus Quartile 4 of Mt CN was associated with the highest mortality risk (hazard ratio [HR]=1.45, CI=1.22, 1.71, p<0.001). This association remained significant after multivariable adjustment (HR=1.30, CI=1.10, 1.54, p=0.003). There was minimal correlation between IMRS and Mt CN continuous values (r= -0.09 for males, r= -0.13 for females). In Cox regression, adjustment for IMRS and covariables showed Mt CN remained associated with mortality (HR=1.30, CI=1.08, 1.57, p=0.006). Conclusions: Low Mt CN is independently associated with higher risk of all-cause mortality. Further studies validating this finding and examining potential underlying physiologic protective mechanisms may prove to be of therapeutic and prognostic value.

Safety and Efficacy of Periprocedural Heparin Plus a Short-Term Infusion of Tirofiban Versus Bivalirudin Monotherapy in Patients Who Underwent Percutaneous Coronary Intervention (from the Intermountain Heart Institute STAIR Observational Registry)

Glycoprotein IIb/IIIa inhibitors, used as a standard intravenous bolus followed by a prolonged infusion for 12 to 18 hours, reduces ischemic complications during percutaneous coronary interventions (PCI) but often at a cost of increased bleeding. Today, when dual oral antiplatelet therapy is routine, heparin use plus short-term (bolus alone or with a <6 hours infusion) glycoprotein IIb/IIIa inhibitors, or bivalirudin monotherapy, have been proposed as potentially superior alternatives. This observational study evaluated the safety and efficacy of heparin plus short-term tirofiban versus bivalirudin monotherapy during PCI. Patients with successful PCI and no cardiogenic shock who were anticoagulated with either of the above regimens were followed for 30-day major bleeding and major adverse cardiovascular events (death, nonfatal myocardial infarction, and urgent target vessel revascularization) at 30 days, 1 year, and long term. A total of 727 patients receiving tirofiban (age = 63 ± 13 years, males = 76%, ACS presentation = 75%, radial access = 51%) and 459 patients receiving bivalirudin, (age = 65 ± 13 years, males = 71%, ACS presentation = 78%, radial access = 18%) were included. Thirty-day major bleeding was 0.7% and 4.1% for tirofiban and bivalirudin, respectively (adjusted odds ratio = 0.17 [0.06, 0.46], p = 0.001). During 30-day, 1-year, and long-term (1.7 ± 0.9 years) follow-up, major adverse cardiovascular events risk did not differ significantly between tirofiban and bivalirudin. However, long-term death was significantly lower in those receiving tirofiban (adjusted hazard ratio = 0.58 [0.34, 1.00], p = 0.05). In conclusion, in this observational study, PCI patients receiving heparin plus short-term tirofiban experienced significantly lower 30-day major bleeding, and improved long-term survival, than those receiving bivalirudin monotherapy.

Extreme erythrocyte macrocytic and microcytic percentages are highly predictive of morbidity and mortality.

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. 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. 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. 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. This study was supported by internal Intermountain Heart Institute funds and in-kind support from Sysmex America Inc.

GlycA and hsCRP are independent and additive predictors of future cardiovascular events among patients undergoing angiography: The intermountain heart collaborative study

BackgroundGlycA is an inflammatory marker that is raised in patients with cardiometabolic diseases and associated with cardiovascular (CV) events. We sought to determine if GlycA adds independent value to hsCRP for CV risk prediction. MethodsPatients in the Intermountain Heart Collaborative Study who underwent coronary angiography and had plasma GlycA and hsCRP levels were studied (n = 2996). Patients were followed for 7.0 ± 2.8 years. GlycA and hsCRP were moderately correlated (r = 0.46, P < .0001). GlycA and hsCRP concentrations were stratified into high and low categories by their median values. Multivariable cox hazard regression was utilized to determine the associations of GlycA quartiles, as well as high and low categories of GlycA and hsCRP, with major adverse cardiovascular events (MACE) defined as the composite of death, myocardial infarction (MI), heart failure (HF) hospitalization, and stroke. ResultsThe highest GlycA quartile was associated with future MACE [HR: 1.43; 95% CI: 1.22–1.69; P < .0001]. Patients with high GlycA and high hsCRP had more diabetes, hyperlipidemia, hypertension, HF, renal failure and MI, but not coronary artery disease. High GlycA and hsCRP (H/H) versus low GlycA and hsCRP (L/L) was associated with MACE, death and HF hospitalization, but not MI or stroke. Combined MACE rates were 33.5%, 41.3%, 35.7% and 49.1% for L/L, L/H, H/L and H/H categories of GlycA/hsCRP, respectively (P-trend < .0001). The interaction between GlycA and hsCRP was significant for the outcome of death (P = .03). ConclusionIn this study, levels of GlycA and hsCRP were independent and additive markers of risk for MACE, death and HF hospitalization.

Abstract 12443: Incident Heart Failure Risk After Acute Myocardial Infarction is Stratified by the Intermountain Major Adverse Cardiovascular Events (IMACE) Risk Scores

Introduction: Previously, the Intermountain Mortality Risk Scores (IMRS) were created to predict all-cause mortality, but also predicted incident heart failure (HF) in unselected catheterization laboratory patients. The Intermountain Major Adverse Cardiovascular Events (IMACE) risk scores were created using IMRS principles to predict MACE (CV mortality, recurrent myocardial infarction [MI], stroke) for acute MI patients. Hypothesis: IMACE stratifies the risk of HF in acute MI patients free of HF at baseline. Methods: Acute MI patients (females: 1,846; males: 4,720) hospitalized at the Intermountain Heart Institute (9/1993-4/2015) were included if they were free from a clinical HF diagnosis and (if available) had LVEF &gt;40%. Incident HF was monitored electronically in Intermountain’s 22 hospitals. A composite of HF and all-cause mortality was also examined. IMACE was computed from previously-derived weightings for age, complete blood count and comprehensive metabolic panel factors, and B-type natriuretic peptide. Results: Mean age at MI was 65.1±13.6 years in females and 59.8±12.3 in males. Cumulative HF-free survival was 90.2% during follow-up of 8.8±5.9 years (max: 21.6 years). Median time to HF diagnosis was 6.0 years, with a stable annual hazard (median 0.4%/year; interquartile range: 0.4%-0.6%). IMACE risk scores (high- vs. low-risk) predicted HF (Figure) in females (HR=3.72, CI=1.68, 8.27) and males (HR=6.90, CI=3.82, 12.48). IMACE predicted mortality/HF for females (HR=6.39, CI=4.83, 8.42) and males (HR=6.34, CI=5.12, 7.85). Other HF predictors were 16 of 53 clinical and treatment variables. Conclusions: IMACE effectively stratified HF incidence after acute MI in patients initially free from HF. Data suggested high-risk females died prior to HF diagnosis. IMACE is a clinically feasible tool for efficiently identifying MI patients for whom additional evaluation and more aggressive therapeutic management may improve long-term prognosis.

Abstract 12529: The Association of the Different Vitamin D Metabolites to Death, Myocardial Infarction, Heart Failure, and Stroke: Results From the Intermountain Heart Collaborative Study

Introduction: Many epidemiological studies have shown that total circulating levels of 25-hydroxyvitamin D (VitD) are strongly associated with poor cardiovascular (CV) outcomes. However, 85-90% of circulating VitD is bound to vitamin D binding protein (BP) or albumin, and levels obtained may not be truly reflective of the VitD available to act on target cells. Whether more direct markers of VitD activity such as bioavailable VitD (BIO) or free VitD (FREE) are more effective in predicting future CV risk is not known. Hypothesis: The more direct markers of VitD activity are more strongly associated with adverse CV outcomes. Methods: Patients (N=4285) undergoing angiography for CAD determination were studied. Levels of VitD, BP and albumin were directly measured and BIO and FREE were calculated using standard formulae. Multivariable Cox hazard regression was utilized to determine quartile (Q) associations with death (all-cause, CAD, and cardiac), MI, HF hospitalization, and stroke. Median length of follow-up was 10.9 years. Results: Patients averaged 64±12 years, 66% male, 23% diabetic, 90% Caucasian, and 70% diagnosed with CAD. Median and interquartile ranges of VitD, BP, BIO, and FREE were 24.9 (20.0, 28.7) ng/mL, 168.3 (103.7, 245.9) ug/mL, 7.1 (3.9, 15.2) ng/mL, and 15.7 (9.2, 33.3) pg/mL, respectively. Multivariable hazard ratios for the various metabolites with each of the outcomes are shown in Table. BP was not associated with any of the outcomes. VitD, BIO, and FREE were all associated with death (all-cause, CAD, and cardiac). VitD continued to be significantly associated with HF hospitalization and stroke, with its association to MI being attenuated. Conclusion: Among this predominately Caucasian population, VitD was found to consistently be the strongest predictor of all of the outcomes over BP, BIO, and FREE. Future studies are needed to evaluate whether obtaining thresholds of VitD levels are associated with a reduction in CV risk.

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

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

Case-Only Survival Analysis Reveals Unique Effects of Genotype, Sex, and Coronary Disease Severity on Survivorship.

Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs—rs1462845 and rs6788787—using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01–1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69–0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08–1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05–1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype (‘A/A’) fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.

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

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

Antithrombotic therapy in patients with acute coronary syndrome in the intermountain heart collaborative study.

Objective. To determine factors associated with single antiplatelet (SAP) or dual antiplatelet (DAP) therapy and anticoagulants (AC) use in hospital and after discharge among patients with acute coronary syndrome (ACS). Methods. We evaluated 5,294 ACS patients in the Intermountain Heart Collaborative Study from 2004 to 2009. Multivariable logistic regressions were used to determine predictors of AC or AP use. Results. In hospital, 99% received an AC, 79% DAP, and 19% SAP; 78% had DAP + AC. Coronary stents were the strongest predictors of DAP use in hospital compared to SAP (P < 0.001). After discharge, 77% received DAP, 20% SAP, and 9% AC; 5% had DAP + AC. DAP compared to SAP was less likely for patients on AC (odds ratio [OR] = 0.30, P < 0.0001) after discharge. Placement of a stent increased the likelihood of DAP (bare metal: OR = 54.8, P < 0.0001; drug eluting: OR = 59.4, P < 0.0001). 923 had atrial fibrillation and 337 had a history of venous thromboembolism; these patients had increased use of AC (29% and 40%, resp.). Conclusion. While in-hospital use of AC was nearly universal, postdischarge AC use was rare. Concern for providing the best antithrombotic therapy, while maintaining an acceptable bleeding risk, may explain the selection decisions.

Abstract 12691: The Combination of Depression and Diabetes is Associated With Short-Term Risk of Death and Myocardial Infarction Among Patients Undergoing Angiography for Acute Coronary Syndrome

Background: Depression and diabetes have been shown to be associated with adverse cardiovascular (CV) events. However, whether there is an increased risk when both conditions are present is unknown. Methods: Patients of the Intermountain Heart Collaborative Study were studied if they underwent angiography for acute coronary syndrome (ACS) and had no prior history of CV disease (no CAD [coronary artery disease], MI [myocardial infarction], stroke, or heart failure). Patients were stratified based on their diabetes and depression status: none, diabetes only, depression only, and diabetes and depression. Multivariable Cox hazard regression was utilized to evaluate the association of diabetes/depression groups to death and MI at 30 days, 6 months, and 1 year. Results: A total of 4,321 (62.7% male; 61.3±12.9 years) patients were studied. The distribution of patients within each diabetes/depression category was: no depression or diabetes: 74.9% (3,236), diabetes only: 18.5% (800), depression only: 4.4% (192), diabetes and depression: 2.2% (93). A total of 46.2% presented with an MI and 61.4% were diagnosed with CAD. Those with both a diabetes and depression diagnosis were at greater risk of short-term death and, in particular, MI (Table). Conclusion: Among those without a history of CV disease undergoing angiography for ACS, the presence of both diabetes and depression indicated a higher risk of short-term death and, in particular, incident MI, than either one alone or neither diagnosis. Such patients may need greater care and evaluation following angiography for ACS in an effort to reduce short-term morbidity and mortality.

Abstract 14994: How Low Should You Go in Secondary Prevention Treatment of LDL Cholesterol: Observational Insights from the Intermountain Heart Collaborative Study

Introduction: Epidemiologic studies have identified high LDL cholesterol levels as an independent risk factor for cardiovascular (CV) disease, and randomized trials with statin therapy have demonstrated added clinical benefit when LDL levels are reduced to at least 70 mg/dL. However, whether targeting significantly lower secondary prevention LDL levels is beneficial, or perhaps actually may be unsafe, is not known. Methods: Patients undergoing coronary angiography who were documented to have significant (≥50% stenosis) coronary artery disease (CAD), discharged on statin therapy with an LDL level &lt;100 mg/dL and had ≤3y clinical follow-up were studied. Patients were stratified, according to on-statin LDL levels, into ultra low (&lt;40 mg/dL [n=221]), very low (40-69 mg/dL [n=1,684]) and low (70-99 mg/dL [n=3,317]) categories and followed for the long-term endpoints of all-cause death, cardiac death, non-cardiac death, MI, stroke, coronary revascularization (CR) and MACE (death, MI, stroke, CR). Hazard ratios (HRs) comparing the three LDL groups were calculated by Cox regression, adjusting for 17 baseline variables. Results: A total of 5,222 patients (age = 66±12 yrs, men = 72%, hypertension = 69%, diabetes = 30%, smokers = 29%, ACS presentation = 69%) were studied. Follow-up for the ultra low, very low and low LDL categories was 6.1±4.3, 6.4±3.9 and 7.3±4.1 yrs respectively. Event rates and adjusted HRs are shown in the Table. Conclusions: In a large secondary prevention population with significant CAD on statin therapy, treating LDL cholesterol levels to &lt;70 mg/dL compared to 70-99 mg/dL was not associated with superior long-term CV outcomes. From a non-CV standpoint, LDL levels down to 40 mg/dL appeared to be safe, but ultra low LDL levels (&lt;40 mg/dL) were associated with a significantly increased risk of non-CV death. Based on this information, very aggressive secondary prevention treatment of LDL cholesterol to levels below 40 mg/dL may require further study.

Abstract 12842: Both Hyponatremia and Elevated Plasma Renin Activity Are Independent and Additive Cardiovascular Risk Factors in Patients With Angiographically Proven Coronary Artery Disease (CAD): The Intermountain Heart Collaborative Study

Background: Several studies have documented an increased risk of future major adverse cardiovascular events (MACE) among CAD patients with elevated baseline plasma renin activity (PRA). One of the proposed mechanisms of elevated PRA is sodium depletion - hyponatremia. However, the relationship between PRA and hyponatremia is not well defined. Methods: A total of 1,781 pts with angiographic CAD (&gt;50% stenosis) enrolled in the Intermountain Heart Collaborative Study were evaluated. Pts were excluded if they had a history of myocardial infarction (MI), heart failure (HF), left ventricular ejection fraction (EF) &lt;45% or were discharged on beta blocker therapy. Baseline sodium levels were stratified between low (&lt;135 mm/L) and normal (≥135 mm/L), and PRA between elevated (&gt;2.3 ng/ml/h) and low (≤2.3 ng/ml/h) risk categories. The independent associations between these categories and MACE (death, MI, HF hospitalization, stroke and new onset renal failure) at five years were determined by multivariable Cox hazard regression analysis. Results: The mean pt age was 65.5 years; most pts were men (73.2%) and hypertensive (70.4%). Overall, PRA was elevated in 940 (52.8%) of the pts and sodium was low in 42 (2.4%) of the pts. The prevalence of elevated PRA was greater among pts with low sodium (66.7% versus 52.4% [p=0.07]). Five-year incidence of MACE was higher among pts with low sodium (61.9% versus 40.7%, p=0.006) and also among those with elevated PRA (43.7% versus 38.3%, p=0.02). After adjustment for baseline characteristics, among pts with low sodium, elevated PRA did not predict an increase in MACE (adjusted hazard ratio (HR)=0.72, p=0.53). However, among those with normal sodium, elevated PRA trended toward an association with MACE (HR=1.14, p=0.08). Conclusion: Among stable pts with angiographically documented CAD, both hyponatremia and elevated PRA are independently associated with future adverse cardiovascular events, although much of the adverse effect of elevated PRA may be explained by the concomitant presence of hyponatremia. The underlying physiology of these findings and its potential implications to future medical management of these pts deserves further study.

Abstract 17014: The Impact of Risk Score (CHADS2 versus CHADS2-Vasc) on Long-term Outcomes After Atrial Fibrillation Ablation

Background: Risk stratification tools are needed to better select candidates for catheter ablation of atrial fibrillation (AF). Both the CHADS2 and CHADS2-VASC scores have utility in predicting AF-related outcomes and guiding anticoagulation treatment. We sought to determine if these risk scores predict long-term outcomes after AF ablation and if one risk score provides comparative superior performance. Methods: CHADS2 and CHADS2-VASC scores were calculated in 2179 AF ablation patients enrolled into Intermountain Heart Collaborative Study. CHADS2 and CHADS2-VASC were categorized by recursive partitioning categories as CHADS2: 0-1, 2-4, and &gt;4 and CHADS2-VASC: 0-2, 2-5, &gt;5. Patient outcomes were analyzed over 5 years for AF/Aflutter recurrence and MACE (death, stroke, heart failure hospitalization and AF/Aflutter recurrence). Results: Average age was 65.7±10.5 years and 61.1% were male. Both scores incrementally predicted risk of AF recurrence, stroke, heart failure, and death at 5 years (Figure). Increasing CHADS2 (hazard ratio [HR] =1.19, p&lt;0.001) and CHADS2-VASC (HR=1.15, p&lt;0.0001) scores were both associated with AF/Aflutter recurrence. Results were similar for MACE: with increasing CHADS2 (HR=1.20, p&lt;0.0001) and CHADS2-VASC (HR=1.15, p&lt;0.0001) scores associated with risk. When CHADS2 and CHADS2-VASC were modeled simultaneously, only CHADS-VASC significantly predicted AF recurrence (HR=1.13, p=0.001) and MACE (HR=1.13, p=0.001). Conclusion: Both the CHADS2 and CHADS2-VASC scores were excellent in stratifying patients for 5-year outcomes after AF ablation. However, the CHADS2-VASC score was superior to CHADS2 when accounting for all baseline variables for predicting both AF recurrence and AF-related morbidities.

Abstract 14819: The Red Cell Distribution Width Predicts Mortality among Patients Free from Systemic Inflammation

Background: The causal mechanism is unknown for why the red cell distribution width (RDW) predicts mortality and morbidity outcomes. One explanation is an inflammatory process: statistically significant, weak magnitude correlations (r&lt;0.30) have been found between RDW and markers of inflammation. This study evaluated the association of RDW with mortality in patients with normal levels of inflammation, as indicated by normal high-sensitivity C-reactive protein (hsCRP) and white blood cell count (WBC). Methods: Intermountain Heart Collaborative Study patients undergoing coronary angiography (N=650) from 1994-2000 were evaluated if they never smoked, were free of acute myocardial infarction (MI), and had baseline hsCRP≤3 mg/L, WBC&gt;4 K/μL, and WBC≤10.6 K/μL. RDW and WBC were tested clinically at index hospitalization via the complete blood count; hsCRP testing used stored research samples. Subjects were followed until December, 2013, and all-cause mortality was determined from hospital records, Utah death certificates, and US Social Security data. Results: Age averaged 66.7±11.6 years, 31.1% were female, and 62.9% died during a mean follow-up of 15.2±1.6 years (range:12.6-19.6 years). Continuous RDW predicted mortality after adjustment for demographics, risk factors, comorbidities, and baseline treatments (hazard ratio [HR]=1.15 per +1%, 95% CI=1.06, 1.26; p=0.002). In quartiles, this was significant for Q4 vs. Q1 (survival 23.6% vs. 43.4%, HR=1.56, CI=1.17, 2.08; p=0.003), but not Q2 (HR=1.18, p=0.29) or Q3 (HR=1.08, p=0.60) vs.Q1. In subjects with hsCRP&lt;1 mg/L (n=259), RDW (adj. HR=1.13 per +1%, CI=0.99, 1.29, p=0.08) and RDW quartiles [Q2: adj. HR=1.70 (p=0.036), Q3: HR=1.88 (p=0.020), Q4: HR=1.97 (p=0.013) vs. Q1] predicted mortality. Among subjects free from heart failure (LVEF≥40%), diabetes, prior or current coronary disease, prior MI, stroke, renal failure, COPD, and depression (n=66), RDW had adjusted HR=1.70 per +1% (CI=1.06, 2.75; p=0.029). Conclusions: RDW predicted mortality in patients with normal hsCRP and WBC. This suggests that RDW marks the risk of a breadth of health concerns, likely including but not limited to inflammation. Further investigation is required to explain the causes of RDW elevation.

Outcomes of Donor Hearts Offered for Transplantation, Declined by a Single Center and Transplanted at a Secondary Institution

Background: Many predictors to assess risk of heart failure (HF) readmissions have been suggested, yet a broad-based approach to using models is lacking. The purpose of this analysis was to use clinical predictors for readmissions found in a univariate analysis in an urban, tertiary care center to create and propose a clinically useful model for HF readmissions derived from a multivariate analysis. Methods: The enterprise data warehouse and the database registry of the Intermountain Heart Collaborative Study were queried for patients discharged from Intermountain Medical Center with a primary diagnosis of HF between January 1, 2012 and December 31, 2012. Assessment of 30-day all-cause (AC) readmissions extended through January 31, 2013. Patients were grouped into those who were, or were not, readmitted within 30 days of discharge. In a previous parallel study, we considered 71 variables in a univariate analysis, 25 of which reached statistical significance for readmissions. Themes from these variables included demographic and clinical data, clinical treatments, comorbidities, and measures of acuity. These variables were then used to perform a multivariate logistic regression analysis to create a risk prediction model for 30-day AC readmissions. Results: Of 586 eligible HF patients identified, 103(17.6%) were readmitted within 30-days; mean time to readmission 13.5 days ( 8.7). The multivariate analysis resulted in 5 variables that remained significant and were predictive of 30-day AC readmissions: longer length of stay, other admissions within the prior year, lower systolic blood pressure on admission, use of pressors or inotropes, and ever having a diagnosis of pneumonia. The final model showed good discrimination for 30-day all-cause readmission with an area under the curve c-statistic of 0.75, see Figure. Conclusions: Given national pressures to improve HF care and reduce readmissions, assessing variables associated with an increased risk in a meaningful manner is not only timely, but of clinical importance. Defining areas of higher acuityseen in longer lengths of stay and previous hospital encounters -should trigger heightened awareness of risk. Creating useful predictive models that may be tested and validated in larger populations will be the next step in making a difference in HF care.

A Predictive Model of Heart Failure Readmissions: Results of a Multivariate Analysis

Background: Many predictors to assess risk of heart failure (HF) readmissions have been suggested, yet a broad-based approach to using models is lacking. The purpose of this analysis was to use clinical predictors for readmissions found in a univariate analysis in an urban, tertiary care center to create and propose a clinically useful model for HF readmissions derived from a multivariate analysis. Methods: The enterprise data warehouse and the database registry of the Intermountain Heart Collaborative Study were queried for patients discharged from Intermountain Medical Center with a primary diagnosis of HF between January 1, 2012 and December 31, 2012. Assessment of 30-day all-cause (AC) readmissions extended through January 31, 2013. Patients were grouped into those who were, or were not, readmitted within 30 days of discharge. In a previous parallel study, we considered 71 variables in a univariate analysis, 25 of which reached statistical significance for readmissions. Themes from these variables included demographic and clinical data, clinical treatments, comorbidities, and measures of acuity. These variables were then used to perform a multivariate logistic regression analysis to create a risk prediction model for 30-day AC readmissions. Results: Of 586 eligible HF patients identified, 103(17.6%) were readmitted within 30-days; mean time to readmission 13.5 days ( 8.7). The multivariate analysis resulted in 5 variables that remained significant and were predictive of 30-day AC readmissions: longer length of stay, other admissions within the prior year, lower systolic blood pressure on admission, use of pressors or inotropes, and ever having a diagnosis of pneumonia. The final model showed good discrimination for 30-day all-cause readmission with an area under the curve c-statistic of 0.75, see Figure. Conclusions: Given national pressures to improve HF care and reduce readmissions, assessing variables associated with an increased risk in a meaningful manner is not only timely, but of clinical importance. Defining areas of higher acuityseen in longer lengths of stay and previous hospital encounters -should trigger heightened awareness of risk. Creating useful predictive models that may be tested and validated in larger populations will be the next step in making a difference in HF care.

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

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

Insulin Growth Factor 1 and Cardiac Allograft Vasculopathy

Purpose Cardiac Allograft Vasculopathy (CAV) is major comorbidity after heart transplantation (OHT) with no definitive therapy besides re-transplantation. Its pathophysiology is not well defined and non-invasive markers of early disease are lacking. Low Insulin Growth Factor 1 (IGF1) and high Insulin Growth Factor Binding protein 3(IGFBP3) have been implicated in the development of atherosclerosis and native coronary artery disease (CAD). The purpose of this study is to evaluate the role of IGF1 and IGFBP3 in CAV. Methods and Materials The Intermountain Heart Collaborative Study Registry was queried for stored blood samples for heart transplant recipients (1995-2010). IGF1 and IGFBP3 plasma levels were done by ELISA and measured at baseline before the diagnosis of CAV in the CAV group and at similar time points after transplantation in the control group (±2 years) which was matched by gender and age. Demographic, clinical and laboratory data were collected at the time of the sample collections. CAV was defined CAV1-3 per International Society for Heart and Lung Transplantation. A non-parametric analysis for comparing the IGF1 and IGFBP3 for the CAV and non-CAV matched patients was done. Results 41 matched CAV and control pairs were analyzed. Average age was 53 ±12 years, 83% were male, and 96% were Caucasian. There was no difference in IGF1 and IGFBP3 serum levels between the two groups at baseline (see Table). Conclusions Although low serum IGF1 is a risk factor of development of CAD, this association was not found in patients with CAV post-transplant. This observation likely reflects differences in pathophysiology between the two diseases as immunologic process plays a major role in the CAV compare to native atherosclerosis. Larger studies are needed to further explore the role of IGF1 in CAV. CAV(n=41) Control (n=41) P value DM % 7.8 (9.8 0.69 HTN % 48.8 36.6 0.37 Average IGF1 (ng/ml)±std 116.66 ±55.73 105±39.02 0.61 Average IGFBP3 (ng/ml))±std 1670.14 ±513.28 1623.75 ±1026.93 0.82 DM: Diabetes Mellitus, HTN: Hypertension, std: standard deviation