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Vitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup. Female Apoe−/−mice (age 12 weeks) were fed Western‐type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18F]‐NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitroeffects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed. Short‐term treatment with warfarin promoted formation of atherosclerotic lesions with a pro‐inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long‐term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran. Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

Vitamin K antagonists (VKA) and non‐vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off‐target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.

After myocardial infarction, several neurohumoral systems become activated to maintain systemic perfusion pressure. We evaluated whether this leads to alterations of wall structure and contractile reactivity in the thoracic aorta, coronary septal artery, and mesenteric resistance arteries. In male Wistar rats, myocardial infarction (MI) was induced by permanent ligation of the left coronary artery. At 5 weeks after MI or sham operation, vessel segments were isolated, chemically sympathectomized, and mounted in a myograph for recording of isometric force development. Contractile reactivity to high potassium, norepinephrine, phenylephrine, serotonin, and Arg-vasopressin was determined. At the end of the experiments, vessels were fixed for morphometric analysis (cross-sectional area, media thickness, radius, and wall-to-lumen ratio). At 5 weeks after myocardial infarction, no alterations of contractile reactivity or wall structure were observed in the thoracic aorta of MI rats. In mesenteric resistance arteries, a nonselective reduction of maximal active wall tension and of active wall stress in response to vasoconstrictors was observed, whereas vessel wall structure and sensitivity to stimuli were not modified. On the other hand, coronary septal arteries displayed hyperreactivity to all strong contractile stimuli. These observations demonstrate a heterogeneity of arterial reactivity changes at 5 weeks after MI in the rat: (a) no alterations in thoracic aorta, (b) hyporeactivity of mesenteric resistance arteries despite maintenance of media mass, and (c) hyperreactivity of coronary vessels obtained from the hypertrophic remnant myocardium. This could result from the complex regional hemodynamic and neurohumoral changes associated with heart failure and may contribute to the further deterioration of cardiovascular function in this setting.

To investigate the effects of long-term treatment with blockers of the renin–angiotensin system on capillarization and growth of fibers in ischemic hind-limb muscles and in muscles under normal growth conditions.

Objectives: We studied the effects of chronic left coronary artery ligation on cardiac structure and function in the mouse. Methods: Morphometric studies of the left ventricle were performed in coronary artery-ligated and sham-operated animals at one, two, three and five weeks after surgery. The fraction of DNA-synthesizing cells was determined as the fraction of cells incorporating 5-bromo-2-deoxyuridine, which was infused by osmotic minipumps one week before sacrifice. Collagen content of the septum was determined morphometrically. Left ventricular pressure and its derivatives were measured in separate groups of animals at one and three weeks after surgery. Results: Ligation of the main left coronary artery resulted in antero-apical infarction of the left ventricular wall, involving 40% of left ventricular circumference. Infarction resulted in thinning of the infarcted area and left ventricular dilatation. DNA synthesis increased, peaking between one and two weeks in the border-zone of the infarct (22-fold), septum (ten-fold) and right ventricle (five-fold). At five weeks, DNA synthesis was still increased in the border zone of the infarct. Septal collagen content increased ~eight-fold in infarcted mice at two weeks, and decreased thereafter; it was still significantly elevated at five weeks. Left ventricular systolic pressure, and maximal positive and negative dP/dt decreased following infarction; left ventricular end-diastolic pressure was elevated at three weeks, but this effect was not statistically significant. Conclusion: These data provide basic information on changes in cardiac structure and function in mice following chronic coronary artery ligation. They indicate the feasibility of induction of chronic myocardial infarction in this species. Furthermore, they show the similarity of cardiac structural and functional consequences of chronic myocardial infarction in mice to those previously described in rats.