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Introduction:Trimethylamine N-oxide (TMAO) is a systemic molecule generated from gut microbial metabolism that appears to have pro-atherogenic and pro-thrombotic properties. We examined the association of circulating TMAO levels with major adverse CV events (MACE) and the benefit of the antiplatelet drug ticagrelor in the PEGASUS-TIMI 54 trial.Methods:In PEGASUS-TIMI 54, patients with an MI 1-3 years prior were randomized to ticagrelor or placebo (median follow-up 33 months). TMAO levels were measured in a nested case-control study of 597 cases who experienced CV death, MI or stroke (MACE) and 1206 controls matched for age, sex and eGFR. Logistic regression was used to assess the association between TMAO quartiles and MACE, adjusting for baseline characteristics (age, sex, eGFR, region, BMI, hypertension, hypercholesterolemia, diabetes, smoking, PAD, and qualifying index event) as well as the interaction with treatment group.Results:Patients with higher TMAO levels were more likely to be older and female, have higher BMI and lower eGFR, and have a history of hypertension, diabetes, smoking, and PAD. Higher TMAO levels were associated with greater risk of MACE: odds ratios (OR; all for Q4 vs. Q1) was 1.43 (95% confidence intervals (CI) 1.06-1.93, P-trend=0.015). The association was primarily driven by CV death (OR 2.25, 95% CI 1.28-3.96, P-trend = 0.003) and stroke (OR 2.68, 95% CI 1.39-5.17, P-trend < 0.001). After adjustment, the association persisted for CV death (adj-OR 1.89, 95% CI 1.04-3.45, P-trend = 0.029) and stroke (adj-OR 2.03, 95% CI 1.02-4.04, P-trend = 0.019) (Figure). The reduction in MACE with ticagrelor was similar across systemic TMAO quartiles (adjusted P-interaction=0.93).Conclusion:Higher systemic TMAO levels are associated with higher risk of CV death and stroke in patients with prior MI. The benefit of ticagrelor on CV outcome was consistent regardless of TMAO levels.

Background:Patients with diabetes have an increased risk of MI. The prognostic value of a genome-wide polygenic risk score (GPS) developed in the general population for CAD compared with traditional cardiovascular and metabolic risk factors in diabetic patients is unknown.Methods:We studied 6,764 diabetic patients without prior MI from the SAVOR-TIMI 53 trial. The 6.6 million SNP GPS was calculated using the genotype dosage for each allele, multiplied by its weight, and then summed across all variants. Genetic risk categories were defined as low (Q1), intermediate (Q2-4), and high risk (Q5). The primary endpoint was a composite of MI or coronary heart death (CHD). Median follow up was 2 yrs. Cox proportional hazard regression analysis was performed adjusting for age, sex, and principle components 1-4 (ancestry). Similar analyses were done for traditional cardiovascular risk factors and all covariates were entered into a multivariable model to assess their independent strength.Results:There were 156 patients who had an MI or CHD during the trial. Compared with patients at low genetic risk, patients with high genetic risk were at a >2-fold (HR 2.15, 95% CI 1.25-3.71, p=0.006) and patients with intermediate risk were at a 68% higher risk (HR 1.68 [1.03-2.72], p=0.036) of MI or CHD. Of traditional clinical risk factors, GFR <60 mL/min/1.73m2and UACR >30 mg/g were the strongest predictors with approximately 2-fold increased risk of MI or CHD (HR 2.05, 95% CI 1.47-2.86, p<0.0001 & HR 1.98, 95% CI 1.44-2.74, p<0.0001, respectively). In a multivariable regression model (Figure), elevated genetic risk remained an independent predictor of a coronary event on par or above traditional risk factors.Conclusion:In patients with diabetes without prior myocardial infarction, a polygenic risk score is an independent predictor of MI that has prognostic value beyond established risk features, with patients in the top 20% of the risk score having a nearly 2.5-fold higher risk of MI or CHD.

Background:Despite anticoagulation, patients with atrial fibrillation (AF) remain at risk of stroke. Whether a novel genetic risk score (GRS) can help identify patients at increased risk beyond CHA2DS2VASc is not known.Methods:We analyzed all patients with genetic samples from ENGAGE AF-TIMI 48, a randomized trial of edoxaban vs. warfarin. A recently published set of stroke-associated SNPs were used to create a novel 32-SNP GRS. The score was calculated using the genotype dosage for each allele, multiplied by its weight, and then summed across all variants. Patients were divided into low, intermediate, and high genetic risk based on tertiles. The endpoint was ischemic stroke and median follow-up was 2.8 years. Cox proportional hazards model was used to calculate hazard ratios across genetic risk categories, adjusted for age, sex, principal components 1-5 (ancestry), and components of CHA2DS2VASc.Results:A total of 11,187 patients were included in the analysis. Of these, 380 (3.4%) had an ischemic stroke. Using the 32-SNP GRS, even after adjusting for all the component of CHA2DS2VASc, patients in the high genetic risk category were at 31% higher risk of an embolic stroke (adjusted HR 1.31 [1.02-1.68], p=0.037) compared to low genetic risk (Figure). The magnitude of risk was similar to CHF, HTN, and age 65-74, and beyond that of diabetes, gender, and vascular disease. The predictive ability of the genetic risk score appeared even stronger in patients with lower clinical risk CHA2DS2VASc ?5, with an adjusted HR of 1.50 (95% CI 1.10-2.04, p=0.01).Conclusion:In patients anticoagulated for AF, a novel GRS is an independent predictor of ischemic stroke, with prognostic value equivalent to or beyond many established risk factors, and potentially heightened value in those at apparent lower clinical risk.

Introduction:In pts stabilized during hospitalization (hosp) for acute decompensated heart failure (ADHF), initiation of sacubitril/valsartan (sac/val) compared with enalapril (enal) decreases the risk of hosp for HF (HHF) or cardiovascular death (CVD) without increasing the risk of adverse events. It is unknown whether high-risk subpopulations have a similar risk-benefit profile.Methods:PIONEER-HF was a multicenter, randomized, double-blind trial of in-hospital initiation of sac/val (n=440) vs. enal (n=441) in pts stabilized during hosp for ADHF. The composite of HHF/CVD was adjudicated. Key safety outcomes included symptomatic hypotension, hyperkalemia, and worsening renal function. We evaluated heterogeneity of the treatment effect of sac/val on these safety and efficacy outcomes in selected high-risk subgroups?baseline SBP ?118 mmHg (median), eGFR <60 ml/min/1.73 m2(n=455), LVEF ?25% (n=307), baseline NT-proBNP >2701 pg/ml (median), NYHA class III/IV (n=627), ?1 additional hosp for HF within the prior year (n=343), time from presentation to randomization ?67.7 hours (median) (n=439), and ICU admission during the index hosp (n=96).Results:The relative risk reduction in HHF/CVD with sac/val vs. enal was consistent across all high-risk subgroups (p-interaction=NS for each). Furthermore, pts with more high-risk indicators had a greater absolute reduction of HHF/CVD with sac/val (Fig). In addition, there was no significant difference in the risks of symptomatic hypotension, hyperkalemia, or worsening renal function with sac/val vs. enal in each of the high-risk vs. low-risk subgroups (p-interaction=NS for each), including in the risks of symptomatic hypotension in pts with low SBP and hyperkalemia or worsening renal function in pts with low eGFR (Fig).Conclusions:In high-risk subpopulations with ADHF, treatment with sac/val after initial stabilization was well tolerated and conferred a large absolute reduction in HHF/CVD.