CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events.

BACKGROUND: Novel ways of determining cardiovascular risk are needed as a consequence of population ageing and the increased prevalence of chronic kidney disease (CKD), both of which favour vascular calcification. Since the formation of arterial calcium deposits has a genetic component, single nucleotide polymorphisms (SNPs) could predict cardiovascular events. METHODS: A selection of 1927 CKD patients and controls recruited by the NEFRONA study were genotyped for 60 SNPs from 22 candidate genes. A calcium score was calculated from the echogenicity of arterial atherosclerotic plaques and the presence of cardiovascular events during a 4-year period was recorded. Association of SNPs with the calcium score was identified by multiple linear regression models and their capacity to predict events was assessed by means of Cox proportional hazards regression and receiver operating characteristics curves. RESULTS: Two variants, rs2296241 of CYP24A1 and rs495392 of KL, were associated with the calcium score. Despite this, only heterozygotes for rs495392 had a lower risk of suffering an event compared with homozygotes for the major allele {hazard ratio (HR) 0.67 [95% confidence interval (CI) 0.48-0.93]}. Of note, the calcium score was associated with an increased risk of cardiovascular events [HR 1.71 (95% CI 1.35-2.17)]. The addition of the rs495392 genotype to classical cardiovascular risk factors did not increase the predictive power [area under the curve (AUC) 71.3 (95% CI 61.1-85.5) versus 71.4 (61.5-81.4)]. CONCLUSIONS: Polymorphisms of CYP24A1 and KL are associated with the extent of calcification but do not predict cardiovascular events. However, the echogenic determination of the extent of calcium deposits seems a promising non-irradiating method for the scoring of calcification in high-risk populations.

Regulation of miR-29b and miR-30c by vitamin D receptor activators contributes to attenuate uraemia-induced cardiac fibrosis.

BACKGROUND: Uraemic cardiomyopathy, a process mainly associated with increased myocardial fibrosis, is the leading cause of death in chronic kidney disease patients and can be prevented by vitamin D receptor activators (VDRAs). Since some microRNAs (miRNAs) have emerged as regulators of the fibrotic process, we aimed to analyse the role of specific miRNAs in VDRA prevention of myocardial fibrosis as well as their potential use as biomarkers. METHODS: Wistar rats were nephrectomized and treated intraperitoneally with equivalent doses of two VDRAs: calcitriol and paricalcitol. Biochemical parameters, cardiac fibrosis, miRNA (miR-29b, miR-30c and miR-133b) levels in the heart and serum and expression of their target genes collagen I (COL1A1), matrix metalloproteinase 2 (MMP-2) and connective tissue growth factor (CTGF) in the heart were evaluated. RESULTS: Both VDRAs attenuated cardiac fibrosis, achieving a statistically significant difference in the paricalcitol-treated group. Increases in RNA and protein levels of COL1A1, MMP-2 and CTGF and reduced expression of miR-29b and miR-30c, known regulators of these pro-fibrotic genes, were observed in the heart of chronic renal failure (CRF) rats and were attenuated by both VDRAs. In serum, significant increases in miR-29b, miR-30c and miR-133b levels were observed in CRF rats, which were prevented by VDRA use. Moreover, vitamin D response elements were identified in the three miRNA promoters. CONCLUSIONS: VDRAs, particularly paricalcitol, attenuated cardiac fibrosis acting on COL1A1, MMP-2 and CTGF expression, partly through regulation of miR-29b and miR-30c. These miRNAs and miR-133b could be useful serum biomarkers for cardiac fibrosis and also potential new therapeutic targets.

IL6 gene polymorphism association with calcific aortic valve stenosis and influence on serum levels of interleukin-6.

Aortic valve stenosis is the most frequent valve disease in developed countries and its prevalence will increase with population aging. There is still no pharmaceutical treatment nor biomarker to determine the susceptibility to develop aortic stenosis. Therefore, we analyzed the association of polymorphisms in risk loci with calcific aortic stenosis. Patients with aortic valve disease were genotyped for PALMD rs6702619, LPA rs10455872, and IL6 rs1800795 polymorphisms and circulating levels of interleukin-6 (IL-6) were measured. Calcium content of leaflets obtained in valve replacement surgeries was determined by micro-computed tomography. In the genotyping of 578 individuals, we found significant association between PALMD and IL6 polymorphisms and aortic stenosis in patients with tricuspid aortic valve, independently of other potentially confounding variables such as age and dyslipidemia. There was no association of these polymorphisms with valve calcium content, but this value correlated with the mean aortic pressure gradient (r = 0.44; P < 0.001). The CC genotype of IL6 polymorphism was associated with higher levels of serum IL-6 compared to other genotypes (23.5 vs. 10.5 pg/ml, respectively; P = 0.029). Therefore, patients carrying the CC genotype of IL6 rs1800795 polymorphism present higher levels of circulating IL-6 and this could contribute to the severity of the aortic valve stenosis. Our results agree with the identification of IL6 as a locus risk for stenosis and also with the intervention of this cytokine in aortic valve calcification. A more exhaustive follow-up of those patients carrying risk genotypes is therefore recommended.

Bicuspid aortic valve: what should I know? Updated review of its clinical and pathophysiological aspects. / Válvula aórtica bicúspide: ¿qué debo conocer? Revisión actualizada de sus aspectos clínicos y fisiopatológicos.

La válvula aórtica bicúspide es la cardiopatía congénita más frecuente en la población general. Lejos de ser solo una malformación valvular inocua, supone una enfermedad compleja y heterogénea. A menudo es identificada como un hallazgo incidental en personas sanas, cursando de manera asintomática. Sin embargo, en un alto porcentaje de pacientes conduce a lo largo de su vida a complicaciones valvulares (estenosis, insuficiencia, endocarditis) o aórticas (dilatación o disección). Con frecuencia estas manifestaciones suceden a una edad temprana y causan una elevada morbimortalidad. A pesar de que en los últimos años se ha producido una intensa investigación en este campo, la fisiopatogenia de la enfermedad no es del todo conocida y muchas preguntas siguen abiertas. En este artículo se revisan de forma actualizada los aspectos clínicos y fisiopatológicos más novedosos y relevantes sobre esta cardiopatía congénita.The most common congenital heart disease in the general population is the bicuspid aortic valve. Far from being just a harmless valve malformation, it is a complex and heterogeneous disease. It is often identified as an incidental finding in healthy people. However, in a high percentage of patients it leads throughout their life towards valvular (stenosis, insufficiency, endocarditis) or aortic (dilatation or dissection) complications. Frequently, manifestations occur at an early age, being responsible for high morbidity and mortality. Even though in recent years intense research has been carried out in this field, the pathophysiogenesis of the disease is not fully known and many questions remain open. In this article, we review the most innovative and relevant clinical and pathophysiological aspects of this congenital heart disease.

Correlation of Micro-Computed Tomography Assessment of Valvular Mineralisation with Histopathological and Immunohistochemical Features of Calcific Aortic Valve Disease.

Aortic valve stenosis is a serious disease with increasing prevalence in developed countries. Research aimed at uncovering the molecular mechanisms behind its main cause, aortic valve calcification, is thus crucial for the development of future therapies. It is frequently difficult to measure the extent of mineralisation in soft tissues and some methods require the destruction of the sample. Micro-computed tomography (µCT), a non-destructive technique, was used to quantify the density and volume of calcium deposits on cusps from 57 explanted aortic valves. Conventional and immunostaining techniques were used to characterise valve tissue degeneration and the inflammatory and osteogenic stage with several markers. Although most of the analysed cusps came from severe stenosis patients, the µCT parameter bone volume/tissue volume ratio distinguished several degrees of mineralisation that correlated with the degree of structural change in the tissue and the amount of macrophage infiltration as determined by CD68 immunohistochemistry. Interestingly, exosomal markers CD63 and Alix co-localised with macrophage infiltration surrounding calcium deposits, suggesting that those vesicles could be produced at least in part by these immune cells. In conclusion, we have shown that the ex vivo assessment of aortic valve mineralisation with µCT reflects the molecular and cellular changes in pathological valves during progression towards stenosis. Thus, our results give additional validity to quantitative µCT as a convenient laboratory tool for basic research on this type of cardiovascular calcification.

Válvula aórtica bicúspide: ¿qué debo conocer? Revisión actualizada de sus aspectos clínicos y fisiopatológicos / Bicuspid aortic valve: what should I know? Updated review of its clinical and pathophysiological aspects

Resumen La válvula aórtica bicúspide es la cardiopatía congénita más frecuente en la población general. Lejos de ser solo una malformación valvular inocua, supone una enfermedad compleja y heterogénea. A menudo es identificada como un hallazgo incidental en personas sanas, cursando de manera asintomática. Sin embargo, en un alto porcentaje de pacientes conduce a lo largo de su vida a complicaciones valvulares (estenosis, insuficiencia, endocarditis) o aórticas (dilatación o disección). Con frecuencia estas manifestaciones suceden a una edad temprana y causan una elevada morbimortalidad. A pesar de que en los últimos años se ha producido una intensa investigación en este campo, la fisiopatogenia de la enfermedad no es del todo conocida y muchas preguntas siguen abiertas. En este artículo se revisan de forma actualizada los aspectos clínicos y fisiopatológicos más novedosos y relevantes sobre esta cardiopatía congénita.

Abstract The most common congenital heart disease in the general population is the bicuspid aortic valve. Far from being just a harmless valve malformation, it is a complex and heterogeneous disease. It is often identified as an incidental finding in healthy people. However, in a high percentage of patients it leads throughout their life towards valvular (stenosis, insufficiency, endocarditis) or aortic (dilatation or dissection) complications. Frequently, manifestations occur at an early age, being responsible for high morbidity and mortality. Even though in recent years intense research has been carried out in this field, the pathophysiogenesis of the disease is not fully known and many questions remain open. In this article, we review the most innovative and relevant clinical and pathophysiological aspects of this congenital heart disease.