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Background: Atherosclerotic cardiovascular disease (ASCVD) often affects > 1 arterial location (polyvascular disease, PVD). The risk of adverse outcomes increases with the number of arterial territories involved. The genetic susceptibility to PVD is unknown. Hypothesis: We hypothesized that a genetic risk score representing cumulative effects of susceptibility variants to ASCVD is associated with presence of PVD. Methods: We searched genome-wide association study (GWAS) catalog to identify genetic variants associated with coronary heart disease (CHD), ischemic stroke, peripheral arterial disease (PAD) or abdominal aortic aneurysm (AAA). No variants were reported to be associated with PVD in ≥ 3 arterial territories at GWAS significance. 10 loci were associated with PVD in 2 arterial territories. We calculated a multi-locus GRS using 10 lead single nuclear polymorphisms (SNP) from these distinct loci (1 per each loci) in 7486 participants in Mayo Vascular Disease Biorepository (age 68±10 years, 61% men, 31% with CHD; 27% carotid artery stenosis; 39% PAD; 14% AAA; 38% without any of these vascular diseases). Results: Of all participants 34% had PVD (2%, 10% and 22% with exact 4, 3 and 2 arterial territories involved respectively). A higher GRS was associated with greater number of arterial territories involved (P for trend of ANOVA <0.001). Patients with PVD in ≥ 3 arterial locations had higher GRS compared to those with 2 arterial locations involved after adjustment for age, sex and cardiovascular risk factors (P =0.008). One unit increase in GRS was associated with 9% higher likelihood for each additional arterial territory involved after adjustment for all covariates (odds ratio from ordinal regression model= 1.09, P <0.001). The result remained significant after further adjustment for combinations of AAA, CHD, carotid arterial stenosis and PAD (all P ≤ 0.01). 5 Of the 10 SNPs were each associated with presence of PVD after adjustment for all covariates (all P <0.01). None of them remained significant after further adjustment for combinations of PVD in different arterial territories (all P ≥ 0.4). Conclusions: A GRS derived from 10 SNPs of ASCVD is associated with PVD,suggesting genetic contribution to the dimension of PVD that may lead to adverse outcome.

Introduction: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. The genetic contribution to mortality in patients with ASCVD is unknown. Hypothesis: Abdominal aortic aneurysm (AAA) often co-exists with ASCVD and two with shared genetic susceptibility underlying disease development. We hypothesiz that a genetic risk score (GRS) for susceptibility variants to AAA and ASCVD increases the risk for all-cause mortality in patients with ASCVD. Methods: We analyzed high-density genotyping data in 3053 participants (age 71 ±10 years, 72% men) with ASCVD in Mayo Vascular Disease Biorepository. We used 4 single nucleotide polymorphisms (SNPs) (rs2383207, rs7025486, rs599839, rs1466535) previously shown to be associated with AAA and ASCVD at GWAS significance (P ≤10^-8) in the NHGRI GWAS catalog to build the GRS. We defined ASCVD as a history of myocardial infarction / coronary revascularization / ischemic stroke / peripheral arterial disease with revascularization. Results: Patients with GRS > median level had similar age (70±10 vs. 71±10), prevalence of men (72% vs. 73%), hypertension (83% vs. 82%), diabetes (32% vs. 31%) and smokers (74% vs. 72%) compared to those with GRS ≤ median (all P>0.2), except for dyslipidemia (91% vs. 88%, P =0.02). After a median follow-up of 4.56 years (interquartile: 3.07-6.26), 620 patients died. Patients with GRS > median had poorer survival compared to those with GRS ≤ median (Figure: Kaplan-Meier curve); and with 23% higher risk for death after adjustment for age, sex and cardiovascular risk factors (hazard ratio HR, 95% CI: 1.23, 1.05-1.45). The association of GRS with all-cause mortality remained significant after excluding patients with known AAA (n=672) (HR, 95%CI: 1.22, 1.01-1.48). Conclusions: A GRS for susceptibility variants of AAA and ASCVD is a prognostic marker in patients with ASCVD.

Introduction: For patients with atrial fibrillation (AF), novel oral anticoagulants (NOACs) provide effective alternatives to warfarin. However, a better understanding is needed of how the introduction of NOAC therapy has improved use of any oral anticoagulation (OAC) for patients with AF. Methods: Within the NCDR PINNACLE registry, we identified 447,770 patients comprising 1,428,660 outpatient encounters with non-valvular AF and CHADS-VASc >1 between April 1, 2008 and September 30, 2014. We examined use of any OAC, any NOAC, and of dabigatran, rivaroxaban, and apixaban individually over time. Multivariable logistic regression was performed to identify factors associated with any OAC and NOAC use at the end of the study period, including CHADS-VASc score, age, weight, CAD, PAD, dyslipidemia, stroke/TIA, heart failure, gender, hypertension, and diabetes. Results: Use of any OAC increased from 52.1 to 61.2% during the study period among patients without a documented contraindication (p for trend <0.01) (Figure). Although warfarin use decreased from 52.1% to 36.8% (p for trend <0.01), use of NOACs increased from 0% to 24.4% (p for trend <0.01). Rivaroxaban was the most frequently prescribed NOAC at the end of the study period (12.1%), followed by dabigatran (6.6%), and apixaban (5.7%). Patient factors associated with use of OAC and NOACs are presented in the Table. Conclusions: In a large U.S. outpatient registry, introduction of NOACs into clinical practice has improved the use of any OAC for AF patients at high risk for stroke. However, more than 1 in 3 high risk patients without a documented contraindication were not treated with any OAC.

Background: The first pediatric appropriate use criteria (PAUC) were recently published for initial outpatient transthoracic echocardiography (TTE). We sought to determine the effect of release of the PAUC on the appropriateness of TTE ordering patterns of pediatric cardiologists. Methods: Data were prospectively collected from patients having initial outpatient TTE ordered prior to (Phase I, 6 mo) and 3 months after release (Phase II, 4 mo) of PAUC. Site-investigators determined the indication of the study and assigned appropriateness rating based on the PAUC document [Appropriate (A), May Be Appropriate (M), or Rarely Appropriate (R)] or "Unclassifiable" (U). Results: A total of 4562 TTEs (2655 Phase I, 1907 Phase II) were ordered by 103 physicians at 6 sites. Overall comparison of appropriateness rating for Phase I and II showed no change in the rate for A or M, but a decline in the rate of R and increase in U. Similar results were noted when comparisons were made for physicians that ordered at least 20 TTEs during each phase (N = 30/103, 29%), Table 1. There was no change in any appropriateness rating at 3 sites, a decline in R at 2, an increase in A at 1, and an increase in U at 2 sites. Overall and site-specific comparisons of rate of R TTEs are shown in Fig 1. Conclusions: The release of PAUC document had only a small impact on physician ordering behavior for initial TTEs, including a small decrease in R. Overall, these data suggest that more focused interventions are required to fully implement guideline recommendations and improve the appropriate use of pediatric TTE. This information should be helpful in designing educational interventions to reduce the rate of TTEs ordered for R indications.

Introduction: The subcutaneous implantable cardioverter defibrillator (S-ICD) is an attractive option for patients with congenital heart disease (CHD) in whom a transvenous system is contraindicated. However, more than 10% of adult patients with CHD fail S-ICD screening due to a large T- to R-wave ratio. We hypothesized right-sternal electrodes may permit S-ICD placement in patients who fail left-sternal screen. Methods: We prospectively screened 40 patients with CHD for S-ICD using the standard proprietary approach. We also screened with right sternal electrodes (with left can electrode position). Results: The mean age of the cohort was 46+/-15 years; 24 males were enrolled. CHD anomalies consisted of tetralogy of Fallot (n=11), Ebstein’s anomaly (n=7), atrial septal defect (n=6), dextro-looped transposition of the great artery (n=5) and other (n=11). Left side screening ECG failed in 9 patients (23%), five of whom passed with right sternal electrodes, increasing the pass rate from 77% to 90%. Figure shows the screening ECG and chest x-ray of a patient who failed in all three vectors on the left side but passed in the alternative vector on the right side and underwent right sided implantation. Conclusions: The addition of right sternal electrodes during screening increases S-ICD eligibility and may avoid thoracotomy for high risk patients with CHD.

Introduction: Among those hospitalized with heart failure, diabetes (DM) is a common comorbid condition and the population characteristics and natural history of those with preserved EF (HFpEF) versus those with reduced EF (HFrEF) remain undefined. Hypothesis: To determine the epidemiologic profile and natural history among those hospitalized with acute heart failure (AHF) with DM and compare outcomes of those with reduced versus preserved EF. Methods: A retrospective chart analysis of adults hospitalized with primary ICD diagnosis of AHF from Olmsted County hospitalized from 2005 - 2008, with follow up until 2013. Demographic, clinical and lab data were collected. Results: Of 912 subjects hospitalized with AHF, 381 (42%) had DM. Among subjects with AHF and DM, those with HFrEF were similar in age to those with HFpEF (76.3±11.7 years vs 78.3±11.2 years, p=0.12), but were more likely to be male (58% vs 37%, p<0.001). Those with DM and HFrEF compared to HFpEF had less hypertension (95% vs 99%, p=0.046), but more coronary artery disease (89% vs 75%, p<0.001), prior myocardial infarction (65% vs 33%, p<0.001), and higher BNP values (1155±906 pg/mL vs 676±568 pg/mL, p<0.001). E/e’ ratio was similar in those with DM and HFrEF versus HFpEF (22.6±10.4 vs 21.7±10.9, p=0.49), suggesting both groups had increased filling pressures. There was no difference in mortality between the HFrEF and HFpEF groups up to 5 years in either the DM group (p=0.46) or the non-DM group (p=0.11). However, those hospitalized with AHF and DM demonstrated a higher rate in those with HFrEF versus HFpEF groups in all cause rehospitalization (p=0.019) and heart failure rehospitalization (p=0.008). This was different from the non-DM group, where there was no difference between HFrEF and HFpEF in all cause hospitalization (p=0.31) or heart failure rehospitalization (p=0.19). Conclusions: In patients hospitalized for AHF with DM, those with HFrEF had increased all cause and heart failure hospitalization as compared to HFpEF. In contrast, subjects without DM had no differences in rehospitalization between the HFrEF and HFpEF groups. Further studies are warranted to define pathophysiological mechanism for this observation.

Background: Epidemiologic studies have demonstrated that the incidence of heart failure varies by race and ethnicity, with the highest incidence occurring in blacks. However, whether these racial and ethnic variations extend to commercially insured populations and whether differences in early outcomes after diagnosis exist requires further exploration. Methods: We utilized administrative claims data from a large U.S. commercial insurance database to retrospectively identify privately insured and Medicare Advantage patients who were diagnosed with heart failure between 2006 and 2014. Published claims-based algorithms were used to identify patients with incident HF and categorize reasons for hospitalization after diagnosis. Results: Among 148,827 patients with incident heart failure (mean age 72.2 years, 51% women), 70% were white, 15% black, 6% Hispanic, 3% Asian and 6% had unknown race/ ethnicity. The incidence of heart failure during the study period was 3.7 per 1000 person-years and was highest among blacks, followed by whites, Hispanics and Asians (9.9, 3.6, 2.5, and 2.0 per 1000 person-years, respectively). In total, 37% of patients were hospitalized at least once in the first year after diagnosis for a total of 93,358 hospitalizations. HF was the most common reason for hospitalization (13% of all hospitalizations), followed by arrhythmia (5%), sepsis (5%), pneumonia (4%), COPD (3%) and acute renal failure (3%). Reasons for hospitalization were similar across racial and ethnic groups. The rate of hospitalizations was highest the first month after diagnosis and then gradually declined. Black patients had the highest rates of hospitalization, while Asians had the lowest (Figure). Conclusions: Even among a commercially insured population that likely have fewer barriers to care, black patients had a higher incidence of HF and higher rates of hospitalization after initial diagnosis compared with other racial and ethnic groups.

Introduction: Insulin-like growth factor-binding protein 7 (IGFBP7) was previously found to be associated with diastolic function in heart failure (HF) with reduced ejection fraction (EF), but it is unclear whether such associations exist in HF with preserved EF (HFpEF), where diastolic function is of pivotal importance. Hypotheses: Baseline (BL) and change (Δ) in IGFBP7 will be significantly associated and correlated with BL and Δ in diastolic indices as well as peak oxygen consumption (VO2 max ) in patients with HFpEF. IGFBP7 will decrease with sildenafil therapy. Methods: At BL and 6 months (6M), IGFBP7, imaging studies, and VO2 max were obtained and compared in 160 HFpEF patients randomized to sildenafil or placebo. Results: Patients with supramedian BL IGFBP7 concentrations (>219 ng/mL) were more likely to be older, to have more congestion and worse renal function, and to have elevated concentrations of several emerging or established HF biomarkers including amino-terminal pro-B-type natriuretic peptide, cystatin C, and highly sensitive troponin (all P<0.05). Higher BL IGFBP7 was correlated with indices of worse diastolic function, including higher E velocity (ρ=0.395, P<0.001), E/e’ (ρ=0.398, P<0.001), left atrial volume index (ρ=0.386, P<0.001), right ventricular systolic pressure (RVSP; ρ=0.413, P<0.001), and transmitral E/A (ρ=0.258, P=0.006). IGFBP7 was also inversely correlated with aortic distensability (ρ= -0.301, P=0.02). There was no association or correlation with measures of systolic function. Notably, in analyses adjusted for respective baseline variables, ΔIGFBP7 was significantly correlated with Δ in E (ρ=0.114), E/A (ρ=0.225), E/e’ (ρ=0.174), and RVSP (ρ=0.282; all P<0.03). Elevated BL IGFBP7 was associated with lower BL VO2 max (13.2 versus 11.1 mL/min/kg; P<0.001) and ΔIGFBP7 was inversely correlated with ΔVO2 max (ρ=-0.19, P=0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 6M in contrast to placebo-treated patients (median ΔIGFBP7 -1.5 versus +13.6 ng/mL; P<0.001). Conclusions: In patients with HFpEF, concentrations of IGFBP7 have unique relationships with measures of diastolic dysfunction and VO2 max . Rise in IGFBP7 may reflect worsening diastology and deteriorating VO2 max .

Background: Treatment of progressive heart failure, due to left ventricular (LV) outflow tract obstruction has been a major component of hypertrophic cardiomyopathy (HCM) disease management for 50 years. Septal myectomy has been the primary treatment option to abolish gradients and relieve heart failure symptoms. The role of myectomy in HCM management has depended on effectiveness in relieving heart failure symptoms, but also an acceptable operative risk. Methods: Over the most recent 15-year period, we reviewed 3,700 consecutive isolated myectomy operations performed at major North American HCM institutions. Composite operative mortality (first 30 days) was only 0.4%. Seventeen operative deaths were at ages 24 to 82 (≥70 years), and only 6 occurred after 2010. Notably, 2 of the 4 Mayo Clinic deaths were in patients with prior alcohol septal ablation. Septal myectomy, when performed in experienced HCM centers, was much safer when compared to operative mortality with coronary artery bypass grafting (2.3%); valve replacement (3.5%); mitral valve replacement specifically (5.7%) (STS Database), similar to atrial or ventricular septal defect closure and 15-fold less than myectomy in community hospital or low volume surgical settings. Conclusions: Surgical myectomy performed in dedicated HCM centers with experienced surgeons and staff is one of the safest open-heart procedures currently practiced, with a mortality rate as low as 0.4%. The large mortality discrepancy for myectomy between community hospitals and dedicated HCM centers underscores that this operation should be considered a specialized procedure best performed in high volume HCM institutions.

Introduction: Hydrochlorothiazide (HCTZ) is among the most commonly prescribed antihypertensives in the US, yet <50% of HCTZ treated patients achieve blood pressure (BP) control. Hypothesis: Integrating metabolomic and genomic profiles of HCTZ treated patients could identify novel pathways/biomarkers for optimizing the use of HCTZ. Methods: Primary analysis included 228 white hypertensives treated with HCTZ from the Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) study. Genotyping was determined via Illumina Omni 1M-Quad Chip and untargeted metabolomics was performed on baseline fasting plasma samples using a GC-TOF MS platform. Pathway analysis was used to integrate metabolites significantly associated with HCTZ BP response (FDR<.05) and genetic signals at p<5x10-5 from HCTZ BP genome-wide analysis. Replication was conducted in another 212 white HCTZ treated patients. Replicated genetic signals were used to create a BP response score by summing their BP lowering alleles. We validated this score by testing it in 196 white HCTZ treated patients in the Genetic Epidemiology of Responses to Antihypertensives (GERA) study. Results: Thirteen metabolites were significantly associated with HCTZ systolic BP (SBP) and diastolic BP (DBP) responses (FDR<.05). Metabolomics-genomics integration revealed significant metabolites along with rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2, in the netrin signalling pathway (p=1x10-5), as potential markers significantly influencing HCTZ BP response. We successfully replicated those 3 genetic signals and added their alleles to create a response score which explained 11.3% and 11.9% of the variability to HCTZ SBP and DBP responses, respectively. We found that patients carrying one “response” allele had a significantly worse response than carriers of six alleles (ΔSBP/ΔDBP: -1.5/1.2 vs -16.3/-10.4 mmHg, respectively, SBP score p=1x10-8 and DBP score p=3x10-9). We further validated this response score by testing it in the GERA (DBP score p=0.03, SBP score p=0.07). Conclusion: This study highlights the power of using different omics to identify novel pathways/biomarkers of drug response, and suggests that PRKAG2, DCC and EPHX2 might be important determinants of HCTZ BP response.