Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum.

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. METHODS: we analyzed whether long-term exposure of Abcc6-/- mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6-/- and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. RESULTS: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6-/- mice. CONCLUSIONS: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model.

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth. We analyzed whether long-term exposure of Abcc6-/- mice (a murine model of Randall's plaque) to vitamin D supplementation, with or without a calcium-rich diet, would accelerate the formation of Randall's plaque. Eight groups of mice (including Abcc6-/- and wild type) received vitamin D alone (100,000 UI/kg every 2 weeks), a calcium-enriched diet alone (calcium gluconate 2 g/L in drinking water), both vitamin D supplementation and a calcium-rich diet, or a standard diet (controls) for 6 months. Kidney calcifications were assessed by 3-dimensional microcomputed tomography, µ-Fourier transform infrared spectroscopy, field emission-scanning electron microscopy, transmission electron microscopy, and Yasue staining. At 6 months, Abcc6-/- mice exposed to vitamin D and calcium supplementation developed massive Randall's plaque when compared with control Abcc6-/- mice (P < 0.01). Wild-type animals did not develop significant calcifications when exposed to vitamin D. Combined administration of vitamin D and calcium significantly accelerates Randall's plaque formation in a murine model. This original model raises concerns about the cumulative risk of vitamin D supplementation and calcium intakes in Randall's plaque formation.

Early arterial calcification does not correlate with bone loss in pseudoxanthoma elasticum.

BACKGROUND AND AIMS: Pseudoxanthoma elasticum (PXE; OMIM 264800, prevalence 1/25,000 to 1/50,000) is an autosomal recessive multisystem disease due to deficiency in ABCC6, an ATP-binding cassette, sub-family C transporter. The PXE phenotype is mainly characterized by progressive ectopic calcification of connective tissues (namely skin, retinal Bruch's membrane and peripheral arteries) but the impact of PXE on bone structure is currently unknown. The present study sought to investigate bone mineralization and its potential link with vascular calcification in a large cohort of PXE patients with inherited mutations of the ABCC6 gene. METHODS AND RESULTS: 96 patients (61 women) matching the PXE criteria participated in this study. Their clinical history and status and bone biological markers were collected. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and expressed as T- and Z-scores. Osteoporotic fractures were identified by X-ray, and coronary (CAC) and lower limb arterial calcification (LLAC) scores were determined by CT scan. RESULTS: 44% of the women were menopausal. Osteopenia was disclosed in 46% (17 women) while 23% (9 women) exhibited osteoporosis, 3 with severe osteoporosis. Fractures of an osteoporotic nature were authenticated in 3 patients (1 woman). Markers of bone remodelling processes (CTX, BSAP and osteocalcin) were within the normal range for our laboratory standards. Severe vitamin D deficiency (<25nmol/L) was found in 15%, while 51% exhibited no vitamin D deficiency (vitamin D≥50nmol/L). LLAC and CAC scores were significantly higher in the patients with a low T- and/or Z-score, although this difference disappeared in multivariate analysis with age as a confounding factor. There was no significant difference in LLAC and CAC between PXE patients with and without osteoporotic fractures. There was no statistically significant association between BMD, LLAC and CAC and any of the bone remodelling factors. CONCLUSIONS: This is the first report on the bone mineralization process in PXE patients. Our data shows that PXE patients are not markedly prone to exaggerated bone demineralization and fracture risk, and prevalence of osteoporosis remains within the normal range for the general population. Furthermore, the relationships between LLAC, but not CAC, and BMD with age are similar to those observed in the general population. Therefore, despite its pivotal role in ectopic calcification, ABCC6 deficiency does not interfere with the bone-vascular axis. The lack of PXE-related disturbances between BMD and arterial calcification also supports vitamin D supplementation in PXE patients with vitamin D deficiency. ClinicalTrials.gov Identifier: NCT01446393.

Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact?

With the discovery that vitamin K-dependent matrix Gla-protein (MGP) is a strong and modifiable factor in the prevention of arterial calcification, vitamin K was put forward as novel treatment option in cardiovascular disease. The vasculoprotective properties of vitamin K are in part based on the ability to improve gamma-glutamylcarboxylation of MGP, which is a prerequisite for MGP as a calcification inhibitor. Data from experimental animal models reveal that high intake of vitamin K can prevent and even reverse vascular calcifications. In addition, clinical data demonstrate that prescription of vitamin K antagonists for long-term oral anticoagulant therapy accelerates vascular calcification. However, controlled data from randomized prospective vitamin K interventional trials are lacking, thereby weakening a general recommendation for supplementation. The present article summarizes our current knowledge on the association between vitamin K and cardiovascular health. Additionally, we focus on an outlook on important ongoing prospective vitamin K intervention studies. These studies address the issues whether vitamin K substitution helps modifying relevant cardiovascular surrogates such as vascular calcification and whether non-vitamin K oral anticoagulants provide an alternative to support cardiovascular health benefits. So research about cardiovascular protection by vitamin K is an evolving field in which we expect a boost of novel and relevant evidence shortly.

Calf muscle stimulation with the Veinoplus device results in a significant increase in lower limb inflow without generating limb ischemia or pain in patients with peripheral artery disease.

OBJECTIVE: Increase in arterial inflow to the lower limbs is important to obtain functional improvement in peripheral artery disease (PAD) patients with claudication. The aim of this study was to assess the effect of electrical stimulation of calf muscles on arterial inflow and tissue oxygen content in PAD in the area of stimulation. METHODS: Fifteen adult patients [mean (standard deviation) age, 62 (12 ) years; height, 165 (8)cm; weight, 76 (13) kg; lowest ankle-brachial index 0.66 (0.19)] with stable arterial claudication were recruited. All patients performed a treadmill test (3.2 km/h, 10% slope) associated with a transcutaneous oximetry test expressed as decrease from rest of oxygen pressure (DROP) index values (calf changes minus chest changes from rest) with a maximum walking distance (median [25th/75th percentiles]) of 295 [133-881] m. The DROP index on the symptomatic side was -25 [-18/-34] mm Hg. On another day the patients underwent electrical stimulation in the seated position on the leg that was the most symptomatic on the treadmill. After resting values were recorded, the gastrocnemius was stimulated for 20minutes at increasing contraction rates at 5-minute steps of 60, 75, 86, and 100bpm on the most symptomatic side. Arterial blood inflow with duplex Doppler ultrasound scanning of the femoral artery, DROP transcutaneous oxygen pressure value, and oxygen concentration (O2Hb) from the near-infrared spectroscopic signal of the calf were recorded on both sides. Patients were instructed to report eventual contraction-induced pain in the stimulated calf. Results are given as mean (standard deviation) or median [25th/75th percentiles] according to distribution, and the level of statistical significance was set at P < .05 on two-tailed tests. RESULTS: Lower limb inflow (mL/min) was 64 [48/86] vs 63 [57/81] (P> .05) before stimulation, 123 [75/156] vs 57 [44/92] (P < .01) at 60bpm, 127 [91/207] vs 49 [43/68] (P < .01) at 75bpm, 140 [84/200] vs 57 [45/71] (P < .01) at 86bpm, and 154 [86/185] vs 55 [46/94] (P < .01) at 100bpm on the stimulated vs nonstimulated limb, respectively. No apparent decrease or significant leg difference was observed in DROP index or O2Hb values. None of the patients reported contraction-induced pain in the leg. CONCLUSIONS: Electrical stimulation of calf muscle with the Veinoplus device results in a significant increase of arterial inflow without measurable muscle ischemia or pain. Potential use of this device as an adjuvant treatment to improve walking capacity in PAD patients remains to be evaluated.

Measurement of the local aortic stiffness by a non-invasive bioelectrical impedance technique.

Aortic stiffness measurement is well recognized as an independent predictor of cardiovascular mortality and morbidity. Recently, a simple method has been proposed for the evaluation of the local aortic stiffness (AoStiff) using a non-invasive bioelectrical impedance (BI) technique. This approach relies on a novel interpretation of the arterial stiffness where AoStiff is computed from the measurement of two new BI variables: (1) the local aortic flow resistance (AoRes) exerted by the drag forces onto the flow; (2) the local aortic wall distensibility (AoDist). Herein, we propose to detail and compare these three indices with the reference pulse wave velocity (PWV) measurement and the direct assessment of the aortic drag forces (DF) and distensibility (DS) obtained by the magnetic resonance imaging technique. Our results show a significant correlation between AoStiff and PWV (r = 0.79; P < 0.0001; 120 patients at rest; mean age 44 ± 16 years), and also between AoRes and DF (r = 0.95; P = 0.0011) and between AoDist and DS (r = 0.93; P = 0.0022) on eight patients at rest (mean age 52 ± 19 years). These first results suggest that local aortic stiffness can be explored reliably by the BI technique.

Programming optimal atrioventricular delay in dual chamber pacing using peak endocardial acceleration: comparison with a standard echocardiographic procedure.

Optimization of programmed atrioventricular delay in dual chamber pacing is essential to the hemodynamic efficiency of the heart. Automatic AV delay optimization in an implanted pacemaker is highly desirable. Variations of peak endocardial acceleration (PEA) with AV delay at rest correlate well with echocardiography derived observations, particularly with end-diastolic filling and mitral valve closure timings. This suggests the possibility of devicing a procedure for the automatic determination of the optimal AV delay. The aim of this study was to compare a proposed algorithm for optimal AV delay determination with an accepted echocardiographic method. Fifteen patients with high degree AV block received BEST-Living pacing systems. Automatic AV delay scans were performed at rest (60-300 ms in 20-ms steps with 60 beats per step) in DDD at 90 ppm, while simultaneously recording cycle-by-cycle PEA values, which were averaged for each AV delay to obtain a PEA versus AV delay curve. Nonlinear regression analysis based on a Boltzmann sigmoid curve was performed, and the optimal AV delay (OAVD) was chosen as the sigmoid inflection point of the regression curve. The OAVD was also evaluated for each patient using the Ritter echocardiographic method. Good sigmoid fit was obtained in 13 of 15 patients. The mean OAVD obtained by the PEA sigmoid algorithm was 146.9 +/- 32.1 ms, and the corresponding result obtained by echocardiography was 156.4 +/- 34.3 ms (range 31.8-39.7 ms). Correlation analysis yielded r = 0.79, P = 0.0012. In conclusion, OAVD estimates obtained by PEA analysis during automatic AV delay scanning are consistent with those obtained by echocardiography. The proposed algorithm can be used for automatic OAVD determination in an implanted pacemaker pulse generator.