Mitral regurgitation attenuates thrombotic risk in nonrheumatic atrial fibrillation: a new CHA2DS2-VASc score risk modifier?

Funding Acknowledgements Type of funding sources: None. Background/Introduction: Atrial fibrillation (AF) carries a thrombotic risk related to left atrial blood stasis. Many risk scores, such as the CHA2DS2-VASc score, have been developed to guide physicians in initiating anticoagulant therapy. However, the risk prediction with these models is modest at best (C-statistic = 0.6). The presence of mitral regurgitation (MR) has been shown to reduce thrombotic risk in patients with rheumatic AF. In nonrheumatic AF, direct evidence of a lower thrombotic risk in patients with MR is still controversial. Purpose The current study assessed the effect of MR on thrombotic risk in nonrheumatic AF patients. Methods The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus (LAAT) and/or left atrial spontaneous echo contrast (LASEC) grade >2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transoesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA2DS2-VASc score. The independent predictors of atrial thrombosis were assessed by stepwise multiple logistic regression analysis. Results A total of 103 (15%) patients had severe MR, 210 (31%) had moderate MR, and 373 (54%) had no-mild MR; the median CHA2DS2-VASc score was 3.0 (IQR 2.0-4.0). Atrial thrombosis (LAAT and/or LASEC grade >2) was observed in 118 patients (17%). The prevalence of atrial thrombosis decreased with increasing MR severity: 19.9% versus 15.2% versus 11.6% for no-mild, moderate, and severe MR, respectively (p for trend = 0.03) (Figure 1). Patients with moderate and severe MR had a lower risk of atrial thrombosis than patients with no-mild MR, with adjusted odds ratios (ORs) of 0.51 (95% CI 0.31-0.84) and 0.24 (95% CI 0.11-0.49), respectively. The other independent predictors of atrial thrombosis were: the CHA2DS2-VASc score with an adjusted OR of 1.25 (95% CI 1.10-1.42), poor left ventricular ejection fraction (LVEF, <40%) with an adjusted OR of 4.08 (95% CI 2.56-6.50), and large left atrial volume index (LAVI, >37 ml/m²) with an adjusted OR of 1.90 (95% CI 1.19-3.03) (Figure 1, upper right corner). The C-statistic of the regression model increased significantly (p = 0.0003) from 0.62 to 0.75 by adding MR grade, LVEF, and LAVI to the univariate CHA2DS2-VASc score model. The protective effect of MR was present across all levels of the CHA2DS2-VASc score and the presence of moderate-severe MR in patients with an intermediate CHA2DS2-VASc score (2-3) lowered the atrial thrombotic risk to the level of patients with a low CHA2DS2-VASc score (0-1). Conclusion Our data show that the presence of MR attenuated the atrial thrombotic risk by more than 50% in patients with nonrheumatic AF, independent of the CHA2DS2-VASc risk score. Moderate to severe MR can therefore be considered a new risk modifier of the CHA2DS2-VASc score, which might help refine the indication of anticoagulants in AF patients. Abstract Figure 1. Thrombotic risk per MR grade.

Admission blood glucose level as an ischemic stroke risk modifier in patients with new-onset non-valvular atrial fibrillation

Background Several scores have been proposed to assess the stroke risk in patients with non-valvular atrial fibrillation (NVAF). However, type 2 diabetes mellitus (T2DM) is considered a major stroke risk factor regardless of glycemic control. Whether basal blood glucose level modifies the risk of stroke in NVAF is still unclear. Purpose To evaluate the risk of ischemic stroke according to the presence of T2DM and admission blood glucose (ABG) level in patients with new-onset NVAF starting direct oral anticoagulants (DOACs). Methods We analyzed all consecutive patients with NVAF at our outpatient clinic from January to December 2018. The study population was constituted by 1014 patients with new-onset NVAF starting DOACs. Baseline characteristics were evaluated in the overall cohort whereas outcomes were assessed for 915 patients. The median follow-up time was 19.6±12.9 months. Results Overall, 50.3% were male with a mean age of 73.9±12.5 years. Diabetic NVAF patients were more frequently male (p=0.04) with higher prevalence of dyslipidemia (p<0.001), hypertension (p<0.001), severe renal impairment (p=0.02), peripheral vasculopathy (p=0.007) and history of myocardial infarction (p<0.001) compared to non-diabetic NVAF. Conversely, no differences were observed between subgroups in terms of age (p=0.8). Baseline blood glucose level was significantly higher in the diabetic NVAF population (160±67 mg/dL vs 119±39 mg/dL; p<0.001). As expected, the mean CHA2DS2-VASc score was significantly higher in diabetic NVAF compared to non-diabetic group (4.7±1.4 vs 3.2±1.5; p<0.001). During a 2 year-follow up period, we collected 27 (3.0%) ischemic stroke. As expected, the rates of stroke were significantly higher in diabetic NVAF (7.6% vs 2.3%, p<0.001). Also, the ABG was significantly greater in NVAF who had an ischemic stroke compared to others (160±68 mg/dL vs 119±39 mg/dL, p=0.005). The incidence of stroke was almost five-time greater in NVAF with ABG level major than 150 mg/dl (9.8% vs 1.9%, p<0.001). At multivariate Cox-regression model adjusted for age, sex and presence of T2DM, blood glucose level at admission was the only independent predictor of ischemic stroke at follow up (HR 1.01, 95% CI 1.001–1.02; p=0.03). Finally, another multivariate Cox-regression model, adjusted for the mean CHA2DS2-VASc score, showed that the ABG level still remained a strong independent predictor of ischemic stroke at follow up (HR 1.012, 95% CI 1.003–1.02; p=0.01). Conclusions Diabetic NVAF had a worse baseline profile and higher stroke risk compared to non-diabetic NVAF. Baseline blood glucose level was an independent predictor of stroke regardless of the presence of T2DM or stroke risk profile. These findings underline the role of basal blood glucose level as a potential stroke risk modifier and therefore emphasize the importance of its routine determination to better stratify the stroke risk in NVAF starting DOACs. Funding Acknowledgement Type of funding source: None

Risk modifiers and mortality in patients with high platelet reactivity to Adenosine-diphosphate (ADP) in the LURIC study

Background Increased platelet reactivity (PR) is an established predictor of cardiovascular (CV) and all-cause mortality. However, therapeutic targeting of PR by tailored antiplatelet therapy (APT) failed to show significant clinical benefit. It remains unclear whether increased PR constitutes a risk-modifier that identifies patients that benefit from risk-factor adjustment. Purpose To identify risk factors that allow modification and/or elimination of increased CV and all-cause mortality in patients with altered PR. Methods ADP- and TRAP-induced PR was measured by CD62P and CD63 expression in 1780 patients who were referred for coronary angiography between 1997 and 2000 and participated in the LURIC study. Statistical analysis was performed by SPSS v25.0 and R v3.6.1 Results ADP-induced PR was an excellent predictor of CV-mortality and risk-equivalent to the presence of coronary artery disease (Figure 1A). Stratification of platelet ADP-response into tertiles demonstrated that patients with high-PR (HPR) and low-PR (LPR) were at increased risk for CV-mortality when compared to the reference group (HPR: HR 1.7 [95% CI: 1.3–2.3]; LPR: HR 1.4 [95% CI: 1.0–1.8]) (Figure 1B). Multivariable-adjustment did not change the association of PR with CV-mortality. Using a relative weight analysis, we identified HbA1c and estimated glomerular filtration rate (eGFR) as potential risk-modifiers. In addition, presence of APT appeared to be an exclusive risk-modifier in the HPR-group. In an multivariable-adjusted risk assessment, we verified that in the HPR group (i) treatment of PR by APT reduced CV-mortality with a HR of 0.5 (95% CI: 0.3–0.7) p=0.0004), (ii) HbA1c of >7.0% in patients with diabetes increased CV-mortality with a HR of 2.0 (95% CI: 1.2–3.2 p=0.004) and (iii) eGFR <60ml/min increased CV-mortality with a HR 1.7 (95% CI: 1.1–2.6 p=0.013). Other risk-factors including blood pressure (<140mmHg), LDL-C (<100mg/dL) and hs-CRP (<2mg/dL) did not alter the mortality risk. None of the risk-modifiers tested affected CV-mortality risk of patients in the LPR group. In the HPR group, risk modification by APT and HbA1c <7.0% in patients with diabetes independently reduced CV-mortality risk to a level that was no longer statistically different to the reference group (p>0.05). Risk modification by an eGFR >60ml/min led to a profound risk reduction in the HPR group but remained statistically different from the reference group (Figure 1C). Conclusion Here, we demonstrate that HPR and LPR are predictors for CV mortality in the LURIC study. Treatment of platelet hyperreactivity by APT, HbA1c of ≤7% in patients with diabetes and an eGFR ≥60ml/min were associated with a reduced CV-mortality in HPR patients and might constitute adjustable risk factors in this group. In addition, we were unable to identify any significant risk factors for patients with LPR underlining a high-risk patient group with insufficient therapeutic options. Figure 1 Funding Acknowledgement Type of funding source: None

A Quantitative Phytochemical Comparison of Olive Leaf Extracts on the Australian Market

Olive leaf extract (OLE), prepared from the fresh or dried leaves of Olea europaea L., is generating interest as a cardiovascular and metabolic disease risk modifier. Positive effects for the leaf extract and its key phytochemical constituents have been reported on blood pressure, respiratory infections, inflammation, and insulin resistance. A variety of OLE products are available both over-the-counter and for professional dispensing. The aim of this research was to quantitatively explore the phytochemical profile of different OLE products on the Australian market. Ten OLE products available on the Australian market (five over-the-counter products and five products for professional compounding and dispensing) were quantitatively analyzed for oleuropein, hydroxytyrosol, oleacein, oleocanthal, total biophenols, maslinic acid, and oleanolic acid, using high-performance liquid chromatography (HPLC). Substantial variation in oleuropein and hydroxytyrosol levels was noted between extracts, with a trend towards higher oleuropein and lower hydroxytyrosol levels being noted in products produced using the fresh olive leaf as opposed to dry olive leaf. These results suggest that OLE products on the Australian market vary substantially in their phytochemical profiles. Products for professional compounding and dispensing in many cases contained less oleuropein than over-the-counter products, but more hydroxytyrosol and comparable total biophenol levels.

Female Sex as a Risk Modifier for Stroke Risk in Atrial Fibrillation: Using CHA2DS2-VASc versus CHA2DS2-VA for Stroke Risk Stratification in Atrial Fibrillation: A Note of Caution

Stroke prevention is a key clinical concern in the management of patients with atrial fibrillation. Oral anticoagulation treatment reduces the risk of disabling stroke, but the treatment increases the risk of bleeding. For decades, the decision to initiate oral anticoagulation has been guided by clinical risk scoring systems such as the CHADS2 and CHA2DS2-VASc scores. In this narrative review, we focus on the recent discussion of the “Sc” (Sex Category) criterion in the CHA2DS2-VASc score. Epidemiological considerations when assessing stroke rates in cohorts are discussed, and the implications of different methodological approaches are outlined. Next, we review studies investigating the association of the “Sc” criterion on the stroke rates under various approaches. Lastly, we discuss potential consequences of implementing the recently suggested sex-less CHA2DS2-VA score, which leaves out female sex from stroke risk assessment in atrial fibrillation.

Use of local genetic ancestry to assess TOMM40-523′ and risk for Alzheimer disease

ObjectiveHere, we re-examine TOMM40-523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) ε4 haplotypes.MethodsThe TOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε3 and APOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.ResultsThe TOMM40-523′ length did not modify risk for LOAD in APOE ε4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523′ was associated with a significantly reduced risk for LOAD in EUR APOE ε3 haplotypes.ConclusionsAdjustment for LGA confirms that TOMM40-523′ cannot explain the strong differential risk for LOAD between APOE ε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-523′ repeat is associated with decreased risk for LOAD in carriers of homozygous APOE ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE ε3 allele haplotype.