The Beneficial Effects of a Direct Thrombin Inhibitor, Dabigatran Etexilate, on the Development and Stability of Atherosclerotic Lesions in Apolipoprotein E-deficient Mice

Kadoglou, Nikolaos P.E.; Moustardas, Petros; Katsimpoulas, Michalis; Kapelouzou, Alkistis; Kostomitsopoulos, Nikolaos; Schäfer, Katrin; Kostakis, Alkiviadis; Liapis, Christos D.

doi:10.1007/s10557-012-6411-3

Cited by 65 publications

(65 citation statements)

References 33 publications

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“…Furthermore, both valvular and arterial calcification have been reported in animals on warfarin treatment 17. By contrast, limited data from experimental animal studies have indicated a potentially beneficial effect of novel, direct‐acting anticoagulants on the development and progression of atherosclerosis 18, 19, 20…”

Section: Discussionmentioning

confidence: 99%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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BackgroundPreclinical data have indicated a link between use of vitamin K antagonists (VKA) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population.Methods and ResultsClinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P<0.0001), intima‐media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P<0.0001), E/E′ (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m2.7 [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro‐atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro‐adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N‐terminal pro B‐type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C‐reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP2C9,CYP4F2, and VKORC1 were modulating effects of VKA on subclinical markers of cardiovascular disease.ConclusionsThese data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

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Section: Discussionmentioning

confidence: 99%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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“…Interestingly, pharmacological treatment of mice on an apoE 2/2 background with the selective thrombin inhibitor dabigatran or with 1 of the factor Xa inhibitors melagatran or rivaroxaban clearly indicates that targeting 1 coagulation protease diminishes atherogenic features of vascular endothelium and reduces plaque burden. 29,[32][33][34] Collectively, one may postulate that in the case of hemophilia, where the lack of factor VIII reduces basal levels of thrombin generation, this may (favorably) affect the plaque phenotype rather than the plaque load, which is driven by stronger factors including hypertension. Both the strength and the direction of the effect of hypocoagulability will be influenced by age, gender, genetic background, and cardiovascular risk factors.…”

Section: Atherosclerosis In Patients With Hemophiliamentioning

confidence: 99%

Cardiovascular risk in patients with hemophilia

Kamphuisen

Cate

2014

Blood

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Patients with hemophilia, who have a lifelong hypocoagulability, seem to have a lower cardiovascular mortality than the general population. Nevertheless, the prevalence of cardiovascular risk factors in patients with hemophilia is as prevalent as in the general population, and hypertension is even more common. Furthermore, hemophiliacs have the same degree of atherosclerosis as the general population. The reduced cardiovascular mortality may be explained by reduced thrombus formation resulting from hypocoagulability. On the other hand, hemophilia, which is associated with reduced thrombin generation, may also increase atherosclerotic plaque stability, as has been shown in mice. Because treatment of these events is extremely challenging in patients with increased bleeding tendency, detection and aggressive treatment of risk factors is mandatory.

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“…In the context of atherogenesis and atherosclerosis, TG is linked to early atherosclerosis, likely one of the drivers of this complex process 75. This model is strongly supported by experimental studies 22, 23, 24, 25…”

Section: Biochemical Mechanisms Linking Thrombin To Atherothrombosismentioning

confidence: 72%

Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?

Cate

Hemker

2016

JAHA

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The Beneficial Effects of a Direct Thrombin Inhibitor, Dabigatran Etexilate, on the Development and Stability of Atherosclerotic Lesions in Apolipoprotein E-deficient Mice

Abstract: DE attenuates arterial thrombosis, reduces lesion size and may promote plaque stability in ApoE-/- mice. The plaque-stabilizing effects of chronic thrombin inhibition might be the result of the favorable modification of inflammatory mechanisms.

Cited by 65 publications

References 33 publications

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Cardiovascular risk in patients with hemophilia

Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?

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