Aortic Dilatation in Children and Young People With ADPKD.

Introduction: Aortic root dilatation is a reported cardiovascular sequela seen in children and young people (CYP) with chronic kidney disease (CKD) but has yet to be described in those with autosomal dominant polycystic kidney disease (ADPKD). Methods: Single center, cross-sectional study in a dedicated ADPKD clinic. Echocardiograms were evaluated for the presence of dilatation (defined by a z-score ≥2 [≥99th percentile] SDs from the mean) at 4 standardized locations, namely the aortic valve annulus, sinuses of Valsalva (SoV), sinotubular junction (STJ), and the ascending aorta. Measurements were compared with a control group to assess prevalence, severity, and determinants of aortic dilatation. Results: Ninety-seven children, median age (interquartile range) of 9.3 (6.1, 13.6) years were compared with 19 controls without ADPKD or other CKD. The prevalence of dilatation ranged from 5.2% to 17% in ADPKD, depending on anatomical location with no aortic dilatation identified in the control group. In multivariable regression, aortic root dilatation was significantly associated with cyst burden at the aortic valve annulus and SoV (ß = 0.42 and ß = 0.39, both P < 0.001), with age at SoV (ß = -0.26, P = 0.02), systolic blood pressure (SBP) z-score at SoV (ß = -0.20, P = 0.04) and left ventricular mass index (LVMI) at SoV and STJ (ß = 0.24, P = 0.02 and ß = 0.25, P = 0.03, respectively) following adjustment for age, sex (male or female), body mass index (BMI) z-score, estimated glomerular filtration rate (eGFR), SBP z-score, and LVMI. Conclusion: Our data suggests increased prevalence of aortic root and ascending aortic dilatation in CYP with ADPKD compared with controls. Further studies are needed to understand the pathogenesis and its contribution to the high cardiovascular morbidity in ADPKD.

Association of Cross-Sectional and Longitudinal Change in Arterial Stiffness With Gene Expression in the Twins UK Cohort.

We investigated whether expression of genes previously implicated in arterial stiffening associates with cross-sectional and longitudinal measures of arterial stiffness. Women from the Twins UK cohort (n=470, aged 39-81 years) had gene expression in lymphoblastoid cell lines measured using an Illumina microarray. Arterial stiffness was measured by carotid-femoral pulse wave velocity and carotid distensibility. A subsample (n=121) of women had repeat vascular measures after a mean±SD follow-up of 4.3±1.4 years. Associations of arterial phenotypes with gene expression levels were examined for 52 genes identified from previous association studies. The gene transcript most closely associated with pulse wave velocity in cross-sectional analysis was ectonucleotide pyrophosphatase/phosphodiesterase (P=0.012). Pleiotropic genetic effects accounted for 14% of the phenotypic correlation between ectonucleotide pyrophosphatase/phosphodiesterase expression and pulse wave velocity. Progression of pulse wave velocity during the follow-up period best related to expression of ectonucleotide pyrophosphatase/phosphodiesterase (ß=0.19, P=0.008) and collagen type IV α 1 (ß=0.32, P<0.0001). Gene transcripts most closely related to change in carotid distensibility during the follow-up period were endothelial nitric oxide synthase (ß=-0.20, P=0.005), angiotensin-converting enzyme (ß=-0.15, P=0.035), and B-cell CLL/lymphoma11B (ß=0.18, P=0.010). Expression levels of angiotensin-converting enzyme also related to progression in carotid diameter (ß=0.21, P=0.012). Expression levels of ectonucleotide pyrophosphatase/phosphodiesterase, involved in arterial calcification, and collagen type IV α 1, involved in collagen formation, correlate with aortic stiffening. These genes may be functional mediators of arterial stiffening.

Arterial stiffening relates to arterial calcification but not to noncalcified atheroma in women. A twin study.

OBJECTIVES: Our aim was to examine the relationship of arterial stiffness to measures of atherosclerosis, arterial calcification, and bone mineral density (BMD); the heritability of these measures; and the degree to which they are explained by common genetic influences. BACKGROUND: Arterial stiffening relates to arterial calcification, but this association could result from coexistent atherosclerosis. A reciprocal relationship between arterial stiffening/calcification and BMD could explain the association between cardiovascular morbidity and osteoporosis. METHODS: We examined, in 900 women from the Twins UK cohort, the relationship of carotid-femoral pulse wave velocity (cfPWV) to measures of atherosclerosis (carotid intima-media thickening; carotid/femoral plaque), calcification (calcified plaque [CP]; aortic calcification by computed tomography, performed in subsample of 40 age-matched women with low and high cfPWV), and BMD. RESULTS: The cfPWV independently correlated with CP but not with intima-media thickness or noncalcified plaque. Total aortic calcium, determined by computed tomography, was significantly greater in subjects with high cfPWV (median Agatston score 450.4 compared with 63.2 arbitrary units in subjects with low cfPWV, p = 0.001). There was no independent association between cfPWV and BMD. Adjusted heritability estimates of cfPWV and CP were 0.38 (95% confidence interval: 0.19 to 0.59) and 0.61 (95% confidence interval: 0.04 to 0.83), respectively. Shared genetic factors accounted for 92% of the observed correlation (0.38) between cfPWV and CP. CONCLUSIONS: These results suggest that the association between increased arterial stiffness and the propensity of the arterial wall to calcify is explained by a common genetic etiology and is independent of noncalcified atheromatous plaque and independent of BMD.

Relationship of calcification of atherosclerotic plaque and arterial stiffness to bone mineral density and osteoprotegerin in postmenopausal women referred for osteoporosis screening.

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.