Hypercalcemia: High calcium levels and what to do
New Genetic Links To Coronary Artery Calcification Uncovered, Offering Treatment Insights
A recent research letter published in the journal Nature Cardiovascular Research describes two new genetic loci associated with coronary artery calcification (CAC).
CAC is a measure of atherosclerosis and predicts coronary artery disease (CAD) events. Coronary calcification is a manifestation of atherosclerotic plaque. It is suggested to contribute to plaque rupture when present as microcalcifications, while more extensive calcification sheets are associated with stabilizing the plaque.
Vascular calcification is characterized by the contractile-to-osteogenic phenotype switch of vascular smooth muscle cells (VSMCs). The osteogenic phenotype is characterized by the expression of markers, including the master regulator of the switch, Runt-related transcription factor 2 (RUNX2), and others such as alkaline phosphatase (ALPL) and bone gamma-carboxyglutamate protein (BGLAP).
Genome-wide association studies (GWASs) have identified more than 200 loci associated with CAD events and only four for CAC. The four CAC loci are also associated with CAD events, and their effects are mainly related to the progression of atherosclerosis. Identifying additional loci for CAC will provide insights into the pathogenic mechanism of atherosclerotic cardiovascular disease.
Letter: Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification. Image Credit: sciencepics / Shutterstock
In the present study, researchers performed a GWAS to identify CAC loci. Around 22,400 individuals from 10 studies, with whole-genome sequencing and CAC data, were included and stratified based on race/ethnicity. Participants were an average age of 58, 53% male and 47% female. Half the population had detectable CAC. In single-variant analyses, over 28.5 million variants with minor allele count ≥ 50 were tested for associations with CAC.
Genetic variants showing a significant association with CAC were detected at six loci – 9p21, matrix metallopeptidase 16 (MMP16), apolipoprotein B (APOB), APOE, arylsulfatase E (ARSE), and phosphatase and actin regulator 1/endothelin 1 (PHACTR1/EDN1). Next, rare variants (minor allele frequency < 1%) were tested for associations with CAC using gene-based variant aggregation and filtering. This resulted in a genome-wide significant aggregation unit for CAC mapping to APOB.
However, the associations were insignificant when adjusted for the index variant identified at that locus in the single-variant analysis. Genetic variants in MMP16 and ARSE were not previously reported to be associated with CAD or CAC at a genome-wide significance level. The inverse association between CAC and the G allele of the ARSE index variant (rs5982944) followed a recessive mode of inheritance.
Further, the index variant at ARSE was associated with carotid plaque, low- (LDL-C) and high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure. It was also associated with thoracic ascending and descending aorta calcification. On the other hand, the MMP16 index variant (rs13268080) showed nominal associations with CAD events and was not significantly associated with any other atherosclerotic phenotypes.
Moreover, the credible set analysis suggested that the ARSE index variant was the causal variant with an 85% posterior probability. This variant was also associated with ARSE gene expression levels in various cells and tissues, such as the aorta and cultured fibroblasts. The G allele of the ARSE index variant was associated with lower ARSE expression in cultured fibroblasts, suggesting that increased ARSE levels might stimulate arterial calcification.
Likewise, the MMP16 index variant was associated with MMP16 gene expression. The G allele of this variant in the aorta was associated with reduced MMP16 messenger RNA (mRNA) levels. Further analyses suggested that increased MMP16 expression might inhibit calcification. Next, functional perturbation analyses were performed in coronary artery VSMCs to examine whether ARSE and MMP16 regulate the phenotypic switch and calcification.
MMP16 expression in VSMCs was reduced by 75% when grown in osteogenic media relative to normal media. Silencing MMP16 had no effect on the osteogenic phenotype or calcification of VSMCs. By contrast, ARSE expression increased five-fold (mRNA) and 1.7-fold (protein) when VSMCs were grown in osteogenic media compared to normal media.
Silencing ARSE decreased the expression of osteogenic phenotype markers (RUNX2, ALPL, and BGLAP) and increased that of calponin (contractile phenotype marker). It also reduced calcium deposition by cells in osteogenic media by 60% and increased cellular contractility. Increasing ARSE levels in VSMCs in normal media caused a seven-fold increase in RUNX2 and a 70% reduction in calponin levels.
Further, coronary VSMC calcification increased four-fold, and coronary artery contractility declined by 70%. When experiments were performed using aortic VSMCs, results were similar to those in coronary artery VSMCs. Next, ARSE expression was examined in the coronary arteries of ischemic CAD patients and controls.
ARSE expression was low in coronary arteries from controls but significantly higher in patients. RUNX2 expression was also higher in calcified ischemic arteries, and it co-localized with ARSE. Additional experiments revealed that the ARSE index variant could influence ARSE gene expression in HEK293 cells and human aortic and coronary artery smooth muscle cells.
ConclusionsTogether, six loci associated with CAC were identified. The ARSE index variant was restricted to populations with African ancestry. The findings implicate ARSE as a regulator of the phenotype switch and calcification. ARSE silencing increased VSMC contractility but decreased osteogenic phenotype markers and calcification, while its overexpression induced opposite effects. Overall, the results underscore ARSE as a potential drug target for vascular calcific disease.
Dr. Roach: Very High CAC Score Might Require More Aggressive Treatment
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Calcium Channel Blockers Effective For Pregnant Patient With Vasospastic Angina
A woman with hopes to conceive was diagnosed with severe vasospastic angina (VSA); however, she was able to carry a healthy baby to full term without angina attacks after starting treatment of a calcium channel blocker, according to a case published in a special Cardio-Obstetrics issue of JACC: Case Reports.
Vasospastic angina is an abnormality of the coronary artery. It presents as chest pain that is caused by coronary artery spasm. It can result in recurrent episodes of angina, including at rest, and can progress into coronary microvascular disfunction, acute myocardial infarction, ventricular arrythmias and even sudden cardiac death. VSA can be triggered during pregnancy when hormonal and nervous system changes occur.
This case presents a patient with no medical history who was in the process of trying to conceive. VSA is often overlooked in patients presenting with chest pain but can result in acute myocardial infarction (heart attack) in pregnant women. Due to its risks on pregnancy, it is important for clinicians to make a definitive diagnosis of VSA, determine its severity and provide proper treatment.
People with VSA are usually treated with calcium channel blockers, however, there is some concern of their safety when prescribed to pregnant people.
"Pregnant patients with vasospastic angina may require special management," said Kota Murai, MD, Ph.D., a cardiologist at the Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan and an author of the study. "Clinicians must be able to accurately assess the advantages and disadvantages of certain VSA treatments and determine which is most beneficial to the health of both the mother and child. This case offers clear evidence of the advantages of the careful management of calcium channel blockers for people who are pregnant or trying to get pregnant."
Calcium channel blockers are under speculation for pregnant patients due to reports of teratogenicity in animal studies. They are unlicensed for use in pregnancy in many countries. However, study authors conclude that calcium channel blockers—such as diltiazem—should be considered under certain conditions. Conditions include prior consultation with the patient, family, obstetricians and cardiologists, invasive catheterization and testing.
To achieve the patient's diagnosis and determine perinatal cardiovascular risk, doctors performed invasive coronary catheterization and vasospasm provocation testing, which resulted in sub-occlusion in the left main trunk (LMT) with chest pain, ST segment depression in the V4–6 leads and hypotension. She was then administered an infusion of isosorbide mononitrate and nicorandil, which alleviated her symptoms. After testing, the patient was confirmed to have severe vasospastic angina and was administered a calcium channel blocker.
The patient was prescribed Diltiazem 200 mg daily and successfully conceived shortly after treatment. The effectiveness of diltiazem was confirmed when she experienced chest pain after treatment was temporarily discontinued due to hyperemesis gravidarum.
Her pregnancy progressed without VSA symptoms after the second trimester and there were no signs of abnormal development of the fetus. After delivery, the patient continued treatment with no recurrence of symptoms and the child obtained no disabilities.
This paper was published in a special cardio-obstetrics issue of JACC: Case Reports, an open access journal serving as a forum for promoting clinical cases and clinical problem solving. It accepts everyday educational or rare clinical cases, well described and with clear learning objectives. Furthermore, the journal aims to serve as a publication vehicle for early career cardiologists and members of the cardiovascular care team, and as a forum for mentorship on the review and publication process.
Other manuscripts published in the special issue include:
Learn more about JACC: Case Reports at www.Jacc.Org/journal/case-reports.
For a copy of any of the papers in JACC: Case Reports, contact Olivia Walther at owalther@acc.Org.
The American College of Cardiology (ACC) is the global leader in transforming cardiovascular care and improving heart health for all. As the preeminent source of professional medical education for the entire cardiovascular care team since 1949, ACC credentials cardiovascular professionals in over 140 countries who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. Through its world-renowned family of JACC Journals, NCDR registries, ACC Accreditation Services, global network of Member Sections, CardioSmart patient resources and more, the College is committed to ensuring a world where science, knowledge and innovation optimize patient care and outcomes. Learn more at www.ACC.Org or follow @ACCinTouch.
The ACC's family of JACC Journals rank among the top cardiovascular journals in the world for scientific impact. The flagship journal, the Journal of the American College of Cardiology (JACC) — and family of specialty journals consisting of JACC: Advances, JACC: Asia, JACC: Basic to Translational Science, JACC: CardioOncology, JACC: Cardiovascular Imaging, JACC: Cardiovascular Interventions, JACC: Case Reports, JACC: Clinical Electrophysiology and JACC: Heart Failure — pride themselves on publishing the top peer-reviewed research on all aspects of cardiovascular disease. Learn more at JACC.Org.
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JournalJACC Case Reports
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