BackgroundMany patients treated with Vitamin K antagonists (VKA) for anticoagulation have concomitant vascular or valvular calcification. This meta-analysis aimed to evaluate a hypothesis that vascular and valvular calcification is a side-effect of VKA treatment.MethodsWe conducted a systematic literature search to identify studies that reported vascular or valvular calcification in patients treated with VKA. The associations between VKA use and calcification were analyzed with random-effects inverse variance models and reported as odds ratios (OR) and 95% confidence intervals (95% CI). In addition, univariate meta-regression analyses were utilized to identify any effect moderators.ResultsThirty-five studies were included (45,757 patients; 6,251 VKA users). The median follow-up was 2.3 years [interquartile range (IQR) of 1.2–4.0]; age 66.2 ± 3.6 years (mean ± SD); the majority of participants were males [77% (IQR: 72–95%)]. VKA use was associated with an increased OR for coronary artery calcification [1.21 (1.08, 1.36), p = 0.001], moderated by the duration of treatment [meta-regression coefficient B of 0.08 (0.03, 0.13), p = 0.0005]. Extra-coronary calcification affecting the aorta, carotid artery, breast artery, and arteries of lower extremities, was also increased in VKA treated patients [1.86 (1.43, 2.42), p < 0.00001] and moderated by the author-reported statistical adjustments of the effect estimates [B: −0.63 (−1.19, −0.08), p = 0.016]. The effect of VKA on the aortic valve calcification was significant [3.07 (1.90, 4.96), p < 0.00001]; however, these studies suffered from a high risk of publication bias.ConclusionVascular and valvular calcification are potential side effects of VKA. The clinical significance of these side effects on cardiovascular outcomes deserves further investigation.

Background Obesity has become a prevalent public health issue, increasing the risk of cardiovascular diseases which are the leading cause of death in the US. A major contributor to the obesity epidemic is the chronic consumption of diets rich in saturated fat and sugar, known as western diet (WD). During obesity, PVAT loses its vasculo‐protective properties and becomes inflamed negatively impacting vascular function. Cx3cr1GFP/WT transgenic fluorescent mice that express a GFP reporter in microglia/macrophages, were utilized in this study to visualize macrophage infiltration in the PVAT from mice chronically exposed to a WD. Methods Adult homozygous male Cx3cr1GFP/WT mice were randomized to the control group (n=4) fed a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) and the WD group (n=9) fed a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 52 weeks. Metabolic cage studies were performed to determine food and water intake, along with feces and urine output. Glucose metabolism was assessed by intraperitoneal glucose tolerance test (IPGTT). At the terminal experiments, direct measurements of arterial blood pressure were obtained by carotid catheterization, and aortas containing PVAT were collected for further histological analysis. Macrophage labeled by GFP in PVAT was visible by fluorescence microscopy and scored in a blind fashion. Results As expected, after over one year under WD conditions, Cx3cr1GFP/WT mice exhibited increased body weight (40.82 ± 2.09 vs. 33.83 ± 1.77g controls, p<0.05) and intolerance to glucose as demonstrated by increased blood glucose area under the curve during IPGTT (51828 ± 4562 vs. 28333 ± 3182 a.u, p<0.05). While the WD group showed decreased daily food consumption (1.36 ± 0.24 vs. 2.17 ± 0.10g controls, p<0.05), no differences in caloric consumption was observed between the groups (5.56 ± 2.78 vs 5.36 ± 1.37 kcals controls). Interestingly, the WD group exhibited decreased water intake (2.90 ± 0.92 vs. 5.13 ± 1.96 mL, p<0.05), urine output (0.56 ± 0.32 vs.1.69 ± 0.63 ml, p<0.01), and feces output (0.34 ± 0.10 vs.1.66 ± 0.30g, p<0.0001) compared to controls. Chronic exposure to WD also resulted in increased systolic blood pressure (119.1 ± 5 vs. 102.9 ± 4 mmHg, p<0.05) along with increased heart rate (481.2 ± 11.7 vs. 429.1 ± 24.6 bpm, p<0.05). Interestingly, PVAT from the WD group exhibited a white‐like adipose tissue feature comprising enlarged adipocytes, in contrast to their native brown‐like adipose tissue, characterizing a phenotypic modulation. Strikingly, GFP signal in the PVAT from the WD group was significantly augmented by 70% compared to controls (Figure 1), showing a robust infiltration of macrophages in the PVAT. Conclusion Our results suggest that increased infiltration of macrophages in PVAT after chronic consumption of a WD promotes inflamed PVAT which in turn may contribute to dysregulation of blood pressure. Further studies will be needed to fully characterize the negative impact of a WD in the PVAT and its cons...

Introduction: The level of homoarginine (hArg) in plasma correlates inversely with cardiovascular and renal disease. However, the cardioprotective mechanism of hArg in renal disease is currently unknown. In this study, we assessed hArg’s effects on cardiovascular function in mice with chronic kidney disease (CKD). Hypothesis: We have previously reported that hArg reduces fibrosis and helps preserve ejection fraction in a model of coronary artery disease. We now hypothesize that hArg supplementation will 1) decrease cardiac and renal fibrosis and inflammation in a model of CKD, 2) preserve cardiac geometry and function, 3) increase renal artery blood flow, and 4) increase survival. Methods: The mice used in this study had a mutation in the low density lipoprotein receptor on the C57BL/6 genetic background. Mice of both sexes (n=28) were fed a standard rodent diet supplemented with 0.1% (F) and 0.2% (M) adenine to induce CKD. Mice were randomly assigned to 14 μg/ml hArg (in drinking water) or placebo (PBO). Cardiac structure and function as well as renal blood flow were measured via high frequency ultrasound (Vevo 3100, VisualSonics). Results: LV geometry data of hArg treated male mice showed increased left ventricular (LV) mass (p<0.05) with normal LV internal diameter and increased LV wall thickness (p<0.01). In terms of cardiac function, ejection fraction (EF, p<0.05), fractional shortening (p<0.01), and cardiac output (p<0.01) were also increased in hArg treated male mice compared to placebo. No differences in renal blood flow were observed. Survival was not affected by hArg. Additionally, we observed decreased food consumption (p<0.01) and fecal output (p<0.001) in hArg treated mice with no difference in urine output compared with placebo. Conclusion: hArg treated male mice developed physiologic cardiac hypertrophy with preserved EF in the absence of LV dilation. Additionally, hArg affected the metabolic state of treated mice reflected in food consumption.

BackgroundAtherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD.MethodsWe combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks.ResultsCo-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight.ConclusionThe adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.

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