Because the elderly population continues to grow, calcific aortic valve disease (CAVD) is becoming an increasingly prevalent cardiovascular disease. Calcific aortic valve disease is characterized by calcium deposits on the arterial aspect of the aortic valve, which leads to stiffness of the valve cusps and narrowing of the valve orifice; this is diagnosed as aortic valve stenosis (AVS), the clinical manifestation of CAVD. Treatment options are limited to surgical or catheter-based aortic valve replacement for severe disease. Because prevalence is an estimated 2% to 7% in individuals older than 65 years,1 investigations of effective medical therapies to slow or halt the progression of disease are vital.
The aortic valve is composed of an extracellular matrix interspersed with valve interstitial cells that are surrounded by a single layer of valve endothelial cells. Although CAVD was once considered a degenerative disease process that occurred with aging, recent studies2 have implicated numerous pathophysiologic mechanisms related to the dysfunction of valve endothelial cells, inflammatory and immune cell infiltration, and the downregulation of calcification inhibitors. These culminate in the initiation of an osteogenic gene program directed by activated valve interstitial cells that display a myofibroblast phenotype, and the process results in the deposition of calcium-phosphate complexes.2 Risk factors for CAVD include increasing age, hypercholesteremia, hypertension, diabetes, tobacco use, and male sex; these are similar to those of coronary atherosclerosis. In addition, the most common congenital cardiac malformation, bicuspid aortic valve, is a recognized risk factor for CAVD and is thought to be the result of increased biomechanical stress.1 While important insights into the underlying molecular mechanisms for CAVD have been made, to my knowledge, novel pharmacologic therapies remain elusive.
In 2013, Thanassoulis et al3 described the association of nucleotide variant rs10455872, located within intron 25 of LPA, with aortic valve calcium, as measured by cardiac computed tomography, in individuals of white European, African American, and Hispanic American ancestry. Genetic variation in LPA, which is related to the number of kringle IV type 2 repeats,4 correlates with increased serum levels of lipoprotein(a) [Lp(a)], a known risk factor for coronary artery disease, stroke, and CAVD.5 Hepatocytes express apolipoprotein(a) encoded by LPA, and it binds to apolipoprotein B100 to form the cholesterol-rich particle Lp(a), which is proinflammatory and proatherogenic.
In this issue of JAMA Cardiology, Chen et al6 report what is, to our knowledge, the largest case-control study to date to investigate how 2 single-nucleotide variants in the LPA gene are associated with clinical AVS. The investigators used the Genetic Epidemiology Research on Aging cohort data set, which is one of the nation’s largest and most diverse genomics projects. The data set is composed of genetic information and electronic health records of 44 703 individuals who received care in the Kaiser Permanente Health system. In this population, 3469 individuals had been diagnosed as having AVS, as determined by International Classification of Diseases, Ninth Revision (ICD-9) codes for AVS or by Current Procedural Terminology codes for aortic valve replacement. They found that the LPA variants rs10455872 and rs3798220 were each associated with an approximate 30% increase in the risk of developing AVS, even after adjustment for clinical risk factors (eg, coronary artery disease). The minor allele frequencies for rs10455872 and rs3798220 are only 0.07 and 0.02, respectively, but the large cohort size allowed investigators to test if harboring more than 1 risk allele increased AVS risk. Interestingly, they found the risk increased 2-fold with homozygosity for the rs10455872 risk allele or with compound heterozygosity for both risk alleles. Homozygosity for the risk allele rs3798220 increased the risk nearly 4-fold, but this finding was based on a small study subpopulation. Taking advantage of the large cohort size, the investigators found that, in the population with the rs10455872 variant, the risk of AVS decreased with aging. They also found that, among those harboring the rs3798220 variant, only men had an increased likelihood of AVS.
While previous reports have supported an association between these 2 risk alleles in LPA, the strength of the study by Chen et al6 is that their cohort included nearly 3500 affected individuals, of whom 400 required aortic valve replacement. The innovative use of electronic health records allowed the investigators to probe clinically relevant end points, as opposed to relying on aortic valve calcium levels determined by cardiac computed tomography. The demonstration that individuals who harbor these LPA risk alleles are more likely to have AVS or to have had aortic valve replacement provides additional evidence to solidify the association between Lp(a) and calcific AVS (a subset of CAVD cases in which hemodynamic stenosis or narrowing of the valve orifice is noted). While the use of a variant score and incorporation of clinical risk factors for AVS allowed the investigators to identify the select populations who might be at highest risk, other risk factors, such as bicuspid aortic valve, were not included. The study cohort was also only of persons of European ancestry, and because racial/ethnic differences in LPA variants have been described,7 findings might not be applicable to other populations. Additional studies are required to determine if the association of these LPA risk alleles with clinically relevant AVS will hold for other racial/ethnic groups, potentially studies that use other genotyped cohorts derived from electronic health records.
The findings by Chen et al6 provide further genetic evidence supporting a role for Lp(a) in clinically relevant CAVD. The mechanisms by which Lp(a) causes CAVD are active areas of investigation. For example, Lp(a) is a critical carrier of oxidized phospholipids, which, along with its proinflammatory properties, has been shown to be a mediator of osteogenic differentiation and calcification in vascular cells.8 Additionally, lipoprotein-associated phospholipase A2 uses oxidized phospholipids as a substrate to generate free oxidized fatty acids and lysophosphatidylcholine, both of which are proinflammatory. In support of this, oxidized phospholipids, lipoprotein-associated phospholipase A2, and lysophosphatidylcholine have all been linked to CAVD.5 In 2017, 1 study reported9 that Lp(a) can directly induce to calcification in cultured vitro human aortic valve interstitial cells, suggesting yet another alternative mechanism.
While the mechanism by which Lp(a) leads to valve calcification remains elusive, new therapies that target Lp(a) are being developed. Last year, Viney et al10 reported the successful completion of phase 2 clinical trials of apoliprotein(a)-lowering therapies using antisense oligonucleotide approaches. The study by Chen et al6 identifies potential populations who might benefit the most from this new class of drugs. Ultimately, it will be important to increase our understanding of the molecular pathways by which elevated Lp(a) levels lead to CAVD, because this may allow these therapies to be beneficial to other patient populations who are predisposed to CAVD, such as people with bicuspid aortic valve.
Corresponding Author: Vidu Garg, MD, Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, Room WB4221, Columbus, OH 43205 (email@example.com).
Published Online: November 12, 2017. doi:10.1001/jamacardio.2017.4267
Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Vidu Garg. The Role of Lipoprotein(a) in Calcific Aortic Valve DiseaseInsights from a Large-Cohort Genetic Study. JAMA Cardiol. Published online November 12, 2017. doi:10.1001/jamacardio.2017.4267