Fabrice Mac-Way

Intermittent PTH(1–84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites†

Intermittent parathyroid hormone (PTH) is anabolic for bone. Our aims were to determine (1) whether PTH stimulates bone angiogenesis and (2) whether vascular endothelial growth factor (VEGF A) mediates PTH‐induced bone accrual. Male Wistar rats were given PTH(1–84) daily, and trabecular bone mass increased 150% and 92% after 30 and 15 days, respectively. The vascular system was contrasted to image and quantify bone vessels with synchrotron radiation microtomography and histology. Surprisingly, bone vessel number was reduced by approximately 25% and approximately 40% on days 30 and 15, respectively. PTH redistributed the smaller vessels closer to bone‐formation sites. VEGF A mRNA expression in bone was increased 2 and 6 hours after a single dose of PTH and returned to baseline by 24 hours. Moreover, anti‐VEGF antibody administration (1) blunted the PTH‐induced increase in bone mass and remodeling parameters, (2) prevented the relocation of bone vessels closer to bone‐forming sites, and (3) inhibited the PTH‐induced increase in mRNA of neuropilin 1 and 2, two VEGF coreceptors associated with vascular development and function. In conclusion, PTH(1–84) is osteoanabolic through VEGF‐related mechanism(s). Further, PTH spatially relocates blood vessels closer to sites of new bone formation, which may provide a microenvironment favorable for growth.

Determinants of Progression of Aortic Stiffness in Hemodialysis Patients A Prospective Longitudinal Study

Aortic stiffness is associated with increased cardiovascular mortality in patients with chronic kidney disease. However, the rate of progression of arterial stiffness and the role of cardiovascular risk factors in the progression of arterial stiffness has never been established in a longitudinal study. In a prospective, longitudinal, observational study, carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were assessed in 109 hemodialysis patients at baseline and after a mean follow-up of 1.2 years. We examined the impact of age, atherosclerotic cardiovascular disease, diabetes mellitus, dialysis vintage, and pentosidine (a well-characterized, advanced glycation end products) on the rate of progression of aortic stiffness. The annual rate of changes in carotid-femoral pulse wave velocity and carotid-radial pulse wave velocity were 0.84 m/s per year (95% confidence interval, 0.50–1.12 m/s per year) and −0.66 m/s per year (95% confidence interval, −0.85 to −0.47 m/s per year), respectively. Older subjects, and patients with diabetes mellitus or atherosclerotic cardiovascular disease had higher aortic stiffness at baseline, however, the rate of progression of aortic stiffness was only determined by plasma pentosidine levels (P=0.001). The degree of baseline aortic stiffness was a significant determinant of the regression of brachial stiffness (P<0.001) suggesting that the regression of brachial stiffness occurs in response to central aortic stiffness. These findings suggest that traditional cardiovascular risk factors may play some role in the progression of aortic stiffness before development of advanced chronic kidney disease, and that the enhanced rate of progression of aortic stiffness in chronic kidney disease patients on dialysis are probably determined by more specific chronic kidney disease–related risk factors such as advanced-glycation end products.

Aortic-Brachial Stiffness Mismatch and Mortality in Dialysis Population

We hypothesized that increased aortic stiffness (central elastic artery) combined with a decrease in brachial stiffness (peripheral muscular artery) leads to the reversal of the physiological stiffness gradient (ie, mismatch), promoting end-organ damages through increased forward pressure wave transmission into the microcirculation. We, therefore, examined the effect of aortic-brachial stiffness mismatch on mortality in patients in need of dialysis. In a prospective observational study, aortic-brachial arterial stiffness mismatch (pulse wave velocity ratio) was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity in 310 adult patients on dialysis. After a median follow-up of 29 months, 146 (47%) deaths occurred. The hazard ratio (HR) for mortality related to PWV ratio in a Cox regression analysis was 1.43 (95% confidence interval [CI], 1.24–1.64; P<0.001 per 1 SD) and was still significant after adjustments for confounding factors, such as age, dialysis vintage, sex, cardiovascular disease, diabetes mellitus, smoking status, and weight (HR, 1.23; 95% CI: 1.02–1.49). The HRs for changes in 1 SD of augmentation index (HR, 1.35; 95% CI, 1.12–1.63), carotid-femoral pulse wave velocity (HR, 1.29; 95% CI, 1.11–1.50), and carotid-radial pulse wave velocity (HR, 0.80; 95% CI, 0.67–0.95) were statistically significant in univariate analysis, but were no longer statistically significant after adjustment for age. In conclusion, aortic-brachial arterial stiffness mismatch was strongly and independently associated with increased mortality in this dialysis population. Further studies are required to confirm these finding in lower-risk groups.

Change in fracture risk and fracture pattern after bariatric surgery: nested case-control study

Objective To investigate whether bariatric surgery increases the risk of fracture. Design Retrospective nested case-control study. Setting Patients who underwent bariatric surgery in the province of Quebec, Canada, between 2001 and 2014, selected using healthcare administrative databases. Participants 12 676 patients who underwent bariatric surgery, age and sex matched with 38 028 obese and 126 760 non-obese controls. Main outcome measures Incidence and sites of fracture in patients who had undergone bariatric surgery compared with obese and non-obese controls. Fracture risk was also compared before and after surgery (index date) within each group and by type of surgery from 2006 to 2014. Multivariate conditional Poisson regression models were adjusted for fracture history, number of comorbidities, sociomaterial deprivation, and area of residence. Results Before surgery, patients undergoing bariatric surgery (9169 (72.3%) women; mean age 42 (SD 11) years) were more likely to fracture (1326; 10.5%) than were obese (3065; 8.1%) or non-obese (8329; 6.6%) controls. A mean of 4.4 years after surgery, bariatric patients were more susceptible to fracture (514; 4.1%) than were obese (1013; 2.7%) and non-obese (3008; 2.4%) controls. Postoperative adjusted fracture risk was higher in the bariatric group than in the obese (relative risk 1.38, 95% confidence interval 1.23 to 1.55) and non-obese (1.44, 1.29 to 1.59) groups. Before surgery, the risk of distal lower limb fracture was higher, upper limb fracture risk was lower, and risk of clinical spine, hip, femur, or pelvic fractures was similar in the bariatric and obese groups compared with the non-obese group. After surgery, risk of distal lower limb fracture decreased (relative risk 0.66, 0.56 to 0.78), whereas risk of upper limb (1.64, 1.40 to 1.93), clinical spine (1.78, 1.08 to 2.93), pelvic, hip, or femur (2.52, 1.78 to 3.59) fractures increased. The increase in risk of fracture reached significance only for biliopancreatic diversion. Conclusions Patients undergoing bariatric surgery were more likely to have fractures than were obese or non-obese controls, and this risk remained higher after surgery. Fracture risk was site specific, changing from a pattern associated with obesity to a pattern typical of osteoporosis after surgery. Only biliopancreatic diversion was clearly associated with fracture risk; however, results for Roux-en-Y gastric bypass and sleeve gastrectomy remain inconclusive. Fracture risk assessment and management should be part of bariatric care.

Vascular remodeling and media calcification increases arterial stiffness in chronic kidney disease

Abstract Background: Cardiovascular disease is the most common cause of death in patients with chronic kidney disease (CKD). Arterial stiffness and calcification are non-traditional risk factors of cardiovascular disease in CKD. In CKD rats, we investigated the involvement of smooth muscle cells differentiation to osteoblast-like cells and blood vessel wall remodeling, associated with media calcification, in arterial stiffness. Method: CKD with vascular calcification was induced by subtotal nephrectomy followed by treatment with a high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). At week 3–6, hemodynamic parameters and pulse wave velocity (PWV) were assessed. Vascular media calcification and remodeling were determined by histological von Kossa staining and confocal immunofluorescence analysis of osteocalcin, elastin, α-smooth muscle actin (α-SMA) and collagen-1. Results: Treatment of CKD rats with Ca/P/VitD, but not normal animals, induced a significant increase in pulse pressure and PWV (p < 0.05) and marked calcification in the media. In calcification areas, de novo expression of osteocalcin was observed, whereas α-SMA immunofluorescence levels were reduced (p < 0.01). The immunofluorescence levels of elastin were also reduced, which was related to disruption of elastic lamella. In contrast, collagen-1 immunofluorescence levels in areas of calcification were increased (p < 0.01). Changes in both α-SMA and elastin inversely correlated with the PWV. Conclusion: This study indicate that smooth muscle cells differentiation to osteoblast-like cells and the associated media remodeling, which includes disruption of elastic lamellas and deposition of collagen are, at least in part, associated with the increased arterial stiffness observed in CKD rats with vascular calcification.

Effects of acute variation of dialysate calcium concentrations on arterial stiffness and aortic pressure waveform

Background. Abnormal mineral metabolism in chronic kidney disease plays a critical role in vascular calcification and arterial stiffness. The impact of presently used dialysis calcium concentration (DCa) on arterial stiffness and aortic pressure waveform has never been studied. The aim of the present study is to evaluate, in haemodialysis (HD) patients, the impact of acute modification of DCa on arterial stiffness and central pulse wave profile (cPWP). Method. A randomized Latin square cross-over study was used to evaluate the three different concentrations of DCa (1.00, 1.25 and 1.50 mmol/L) during the second HD of the week for 3 consecutive weeks. Subjects returned to their baseline DCa for the following two treatments, allowing for a 7-day washout period between each experimental HD. cPWP, carotido-radial (c-r) and carotido-femoral (c-f) pulse wave velocities (PWV), plasma level of ionized calcium (iCa) and intact parathyroid hormone (PTH) were measured prior to and immediately after each experimental HD session. Data were analysed by the general linear model for repeated measures and by the general linear mixed model. Results. Eighteen patients with a mean age of 48.9 ± 18 years and a median duration of HD of 8.7 months (range 1–87 months) completed the study. In post-HD, iCa decreased with DCa of 1.00 mmol/L (−0.14 ± 0.04 mmol/L, P < 0.001), increased with a DCa of 1.50 mmol/L (0.10 ± 0.06 mmol/L, P < 0.001) but did not change with a DCa of 1.25 mmol/L. Tests of within-subject contrast showed a linear relationship between higher DCa and a higher post-HD Δc-f PWV, Δc-r PWV and Δmean BP (P < 0.001, P = 0.008 and P = 0.002, respectively). Heart rate-adjusted central augmentation index (AIx) decreased significantly after HD, but was not related to DCa. The timing of wave refection (Tr) occurred earlier after dialysis resulting in a linear relationship between higher DCa and post-HD earlier Tr (P < 0.044). In a multivariate linear-mixed model for repeated measures, the percentage increase in c-f PWV and c-r PWV was significantly associated with the increasing level of iCa, whereas the increasing level of ΔMBP was not significant. In contrast, the percentage decrease in Tr (earlier wave reflection) was determined by higher ΔMBP and higher ultrafiltration, whereas the relative change in AIx was inversely determined by the variation in the heart rate and directly by ΔMBP. Conclusion. We conclude that Dca and acute changes in the serum iCa concentration, even within physiological range, are associated with detectable changes of arterial stiffness and cPWP. Long-term studies are necessary to evaluate the long-term effects of DCa modulation on arterial stiffness.

The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study

BACKGROUND Accelerated progression of aortic stiffness in patients with advanced chronic kidney disease is not well explained by the traditional cardiovascular risk factors. We hypothesized that vitamin K deficiency may result in an accelerated progression of aortic stiffness in the pro-calcifying uremic milieu. METHOD Eighteen hemodialysis (HD) patients on warfarin were matched to 54 HD patients without warfarin (control). Aortic stiffness was determined by carotid-femoral pulse wave velocity (cf-PWV) at baseline and after a mean follow-up of 1.2 years. In the control group, spontaneous vitamin K deficiency was defined as proteins induced by vitamin K deficiency/absence-II >median. RESULTS At baseline, clinical characteristics and cf-PWV were similar. Adjusted cf-PWV increased by 0.86 ± 1.87 m/s in control and by 2.24 ± 2.68 m/s in warfarin group (P = 0.024). After adjustments for confounders, warfarin therapy was independently associated with progression of aortic stiffness (P = 0.016). The rate of progression of aortic stiffness showed a linear trend in response to vitamin K status and warfarin therapy, suggesting that at least part of the effects are mediated through reduced availability of vitamin K. The unadjusted and adjusted hazard ratio (HR) of warfarin therapy on mortality were, respectively, 2.40 (P = 0.006) and 2.53 (P = 0.006). In a forward conditional Cox regression analysis, age, albumin, augmentation index (AIx) and a cf-PWV > 13.8 m/s at the time of follow-up (HR: 2.11, P = 0.05) were independent determinants of mortality, whereas warfarin use was not retained as an independent factor. Finally, control patients with poor vitamin K status had an intermediate survival as compared with controls with better vitamin K status and patients with warfarin (P = 0.01). CONCLUSION This is the first study to show a temporal association between warfarin, functional vitamin K deficiency and progression of aortic stiffness in HD patients. These findings suggest that the net cardiovascular benefit of long-term warfarin therapy may need to be reevaluated in this population.

Impact of an obesogenic diet program on bone densitometry, micro architecture and metabolism in male rat

BackgroundThe relationships between fat mass and bone tissue are complex and not fully elucidated. A high-fat/high-sucrose diet has been shown to induce harmful effects on bone micro architecture and bone biomechanics of rat. When such diet leads to obesity, it may induce an improvement of biomechanical bone parameters in rodent.Here, we examined the impact of a high-fat/high-sucrose diet on the body composition and its resulting effects on bone density and structure in male rats. Forty three Wistar rats aged 7 months were split into 3 groups: 1 sacrificed before diet (BD, n = 14); 1 subjected to 16 weeks of high-fat/high-sucrose diet (HF/HS, n = 14); 1 subjected to standard diet (Control, n = 15). Abdominal circumference and insulin sensitivity were measured and visceral fat mass was weighed. The bone mineral density (BMD) was analyzed at the whole body and tibia by densitometry. Microcomputed tomography and histomorphometric analysis were performed at L2 vertebrae and tibia to study the trabecular and cortical bone structures and the bone cell activities. Osteocalcin and CTX levels were performed to assess the relative balance of the bone formation and resorption. Differences between groups have been tested with an ANOVA with subsequent Scheffe post-hoc test. An ANCOVA with global mass and global fat as covariates was used to determine the potential implication of the resulting mechanical loading on bone.ResultsThe HF/HS group had higher body mass, fat masses and abdominal circumference and developed an impaired glucose tolerance (p < 0.001). Whole body bone mass (p < 0.001) and BMD (p < 0.05) were higher in HF/HS group vs. Control group. The trabecular thickness at vertebrae and the cortical porosity of tibia were improved (p < 0.05) in HF/HS group. Bone formation was predominant in HF/HS group while an unbalance bone favoring bone resorption was observed in the controls. The HF/HS and Control groups had higher total and abdominal fat masses and altered bone parameters vs. BD group.ConclusionsThe HF/HS diet had induced obesity and impaired glucose tolerance. These changes resulted in an improvement of quantitative, qualitative and metabolic bone parameters. The fat mass increase partly explained these observations.

Impact of dialysate calcium concentration on the progression of aortic stiffness in patients on haemodialysis

BACKGROUND Higher dialysate calcium (DCa) can result in an acute and transient increase in arterial stiffness. The aim of the present study is to evaluate the impact of DCa on the progression of arterial stiffness, calcium balance and bone metabolism in haemodialysis (HD) patients over a 6-month period. Method. We randomly assigned 30 patients on chronic HD to be dialysed with a DCa of 1.12 or 1.37 mmol/L for a period of 6 months. Aortic stiffness and brachial stiffness were respectively measured by carotid-femoral pulse wave velocities (cf-PWV) and carotid-radial pulse wave velocity (cr-PWV) at baseline and at 3 and 6 months. Central pulse pressure (PP) and augmentation index were determined by radial artery tonometry. Dialysis calcium balance and parathyroid hormone (PTH) were measured monthly. Procollagen type-1 amino-terminal propeptide (P1NP) and C-terminal telopeptide of type-I collagen (CTX) were measured as markers of bone formation and resorption, respectively. Data was analysed by linear mixed model. RESULTS Twenty-seven patients (66 ± 13 years old) with a mean duration of HD of 5.8 ± 3.6 months completed the study. At baseline, the groups were similar with respect to age, serum levels of calcium, phosphate and PTH, blood pressure (BP), cf-PWV and cr-PWV. The cf-PWV at baseline and 3 and 6 months were, respectively, 13.4 ± 4.2, 14.7 ± 3.31 and 13.6 ± 2.5 m/s in the DCa 1.12 group and 14.6 ± 5.9, 15.8 ± 7.8 and 17.0 ± 7.0 m/s in the DCa 1.37 group. After correction for mean BP, cf-PWV increased with DCa 1.37 as compared to DCa 1.12 (Time-DCa interaction P = 0.002). However, there were no significant effects of DCa on progression of cr-PWV, central PP or augmentation index. During the intervention period, the mean PTH was slightly higher in the DCa 1.12 group as compared to the DCa 1.37 group (325 ± 185 versus 211 ± 128 ng/L, P = 0.054), and dialysis calcium balance was -8.1 ± 4.4 versus -0.2 ± 4.7 mmol/session, respectively, in groups with DCa 1.12 and DCa 1.37 (P = 0.0001). Treatment with DCa 1.12 mmol/L resulted in increasing levels of CTX as compared to DCa 1.37 (P = 0.02), whereas the P1NP levels did not change significantly in either group. CONCLUSIONS In this study, aortic stiffness progressed with DCa 1.37, while it remained stable with DCa 1.12 over a 6-month period. These results suggest that higher DCa concentrations could be a risk factor for the progression of aortic stiffness in HD patients. In the context of limited oral calcium, the long-term safety of DCa 1.12 on bone metabolism remains to be established.

Aortic-Brachial Pulse Wave Velocity Ratio: A Blood Pressure-Independent Index of Vascular Aging.

Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV (R2=0.10 and 0.08; P<0.001 and P=0.003) and MAP and carotid–radial PWV (R2=0.22 and 0.12; P<0.001 and P<0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio (R2=0.0002 and 0.0001; P=0.8 and P=0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging.Aortic stiffness, a cardiovascular risk factor, depends on the operating mean arterial pressure (MAP). The impact of aortic stiffness on cardiovascular outcomes is proposed to be mediated by the attenuation or the reversal of the arterial stiffness gradient. We hypothesized that arterial stiffness gradient is less influenced by changes in MAP. We aimed to study the relationship between MAP and aortic stiffness, brachial stiffness, and arterial stiffness gradient. In a cross-sectional study of a dialysis cohort (group A, n=304) and a cohort of hypertensive or kidney transplant recipient with an estimated glomerular filtration rate of >45 mL/min/1.73 m2 (group B, n=114), we assessed aortic and brachial stiffness by measuring carotid–femoral and carotid–radial pulse wave velocities (PWV). We used aortic–brachial PWV ratio as a measure of arterial stiffness gradient. Although there was a positive relationship between MAP and carotid–femoral PWV ( R 2=0.10 and 0.08; P <0.001 and P =0.003) and MAP and carotid–radial PWV ( R 2=0.22 and 0.12; P <0.001 and P <0.001), there was no statistically or clinically significant relationship between MAP and aortic–brachial PWV ratio ( R 2=0.0002 and 0.0001; P =0.8 and P =0.9) in group A and B, respectively. Dialysis status and increasing age increased the slope of the relationship between MAP and cf-PWV. However, we found no modifying factor (age, sex, dialysis status, diabetes mellitus, cardiovascular disease, and class of antihypertensive drugs) that could affect the lack of relationship between MAP and aortic–brachial PWV ratio. In conclusion, these results suggest that aortic–brachial PWV ratio could be considered as a blood pressure–independent measure of vascular aging. # Novelty and Significance {#article-title-24}