Journal of the American College of Cardiology Ó 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
Chronic Kidney Disease The “Perfect Storm” of Cardiometabolic Risk Illuminates Genetic Diathesis in Cardiovascular Disease* Dwight A. Towler, MD, PHD Orlando, Florida
A fact well known to the readers of the Journal: heart disease is the number 1 killer in our society, contributing to 600,000 deaths annually (1). Coronary heart disease (CHD) is responsible for approximately two-thirds of these deaths, and 935,000 Americans experience myocardial infarction (MI) each year (1). Hypertension, elevated low-density lipoprotein cholesterol levels, smoking, and diabetes are well appreciated as risk factors. However, a particularly ominous risk for CHD arises in the setting of chronic kidney disease (CKD) (2). As renal function declines below a glomerular ﬁltration rate of 60 ml/min/1.73 m2, the relative risk for cardiovascular mortality progressively increases by 3-fold, as compared with those without CKD (3), and almost 10-fold in the setting of CKD with diabetes (4). Indeed, the cardiovascular risk conveyed by CKD exceeds that conveyed by diabetes (5,6). See page 789
The relationship between mineral metabolism and cardiovascular risk has been increasingly appreciated over the past 2 decades, now codiﬁed in the Kidney Disease: Improving Global Outcomes (KDIGO) designation of CKD-MBD, for “chronic kidney disease–mineral and bone disorder” (7). The CKD-MBD designation only partially captures the clinical implications; the underlying recognition that vascular calcium deposition and skeletal bone mass are reciprocally and functionally coupled in CKD is somewhat reﬂected in the “MBD,” but the appellation does not fully capture the cardiovascular risk associated with perturbation in this relationship. London et al. (8) have nicely demonstrated that the presence and extent of arterial intimal and medial calciﬁcation is a strong predictor of cardiovascular mortality. The fortunate minority of those *Editorials published in the Journal of the American College of Cardiology reﬂect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, Translational Research Institute at Florida Hospital, Orlando, Florida. Dr. Towler is supported by National Institutes of Health grants HL69229, HL81138, and HL114806 and by the Sanford-Burnham Medical Research Institute; and serves on an advisory board for Merck & Co.
Vol. 62, No. 9, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.04.063
with CKD on renal replacement therapy who do not exhibit overt arterial calciﬁcation enjoy much greater longevity (8). The elegant histomorphometric studies by London’s group identiﬁed that dialysis patients with the most severe lowturnover bone disease had the most extensive arterial calcium load (9). Although hypercholesterolemia, hypertension, and hypercoagulability in CKD all certainly contribute, coronary artery disease (CAD) morbidity and mortality stubbornly persist in this high-risk population even when aggressive therapeutic regimens targeting these risk factors are implemented (10,11). Of note, the cardiovascular consequences of perturbations in mineral metabolism (viz., phosphate and calcium metabolism) appear to be emerging in patients with normal renal function as well. For example, at every level of renal function, patients with type 2 diabetes (T2DM) experience increased vascular calcium loads (12), and CKD and T2DM synergistically enhance the risk for MI. Moreover, serum calcium and phosphate levels portend allcause cardiovascular mortality at every level of renal function (13). Thus, a role for calciotropic hormone signaling and mineral metabolic in cardiovascular disease is increasingly apparent. The prevailing metabolic and mechanical insults that most frequently cause CKD (14) also promote cardiovascular calciﬁcation (15)ddisease that is worsened by declining renal function that globally perturbs mineral metabolism, including the bone–vascular axis (16). As such, CKD represents a metabolic “perfect storm” for cardiovascular disease. In this issue of the Journal, Ferguson et al. (17) successfully explore the enhanced CAD risk in the CRIC (Chronic Renal Insufﬁciency Cohort) study to reveal novel insights into the molecular genetics of cardiovascular disease. They implement the working hypothesis that the high-risk milieu of CKD would amplify the negative impact of genetic diathesis, functioning as a metabolic magnifying glass to help identify genes conveying CHD risk. As such, this strategy is somewhat, but imperfectly, analogous to the “sensitized screening” used in genetic studies of lower eukaryotes (18). Coronary artery calciﬁcation (CAC) scores obtained by multislice computed tomography were used to quantify the aberrant vascular mineral metabolism that demarcates and contributes to arterial disease in the CRIC cohort. The ITMAT/Broad/ CARe (IBC) cardiometabolic single nucleotide polymorphism (SNP) array (Illumina, San Diego, California) (19) was then used to interrogate genetic variability at approximately 2,100 loci known to inﬂuence biologically plausible and proven risk pathways in CHD. Because of the relatively small CRIC cohort size (N ¼ 1,509), 2 other sets of CACphenotyped patient populationsdthe PennCAC (Penn Coronary Artery Calciﬁcation) study (N ¼ 2,560) and the AFCS (Amish Family Calciﬁcation Study) (N ¼ 784)dwere used as independent “ﬁlters” to help further validate initial ﬁndings from CRIC. Importantly, these latter groups were not enriched for patients with CKD. This strategy helped identify 23 gene loci that were correlated with CAC scores in the CRIC and PennCAC cohort and/or the CRIC and
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Towler Kidney Disease Illuminates Genetic Diathesis in Coronary Disease
AFCS cohort. Importantly, chr9p21dthe premier locus identiﬁed as conveying both CAC and CHD risk in genomewide association studies applied to the general population (20)dwas identiﬁed by this methodology. Finally, to provide robust evidence for the “hard” primary clinical endpoint of MI, these loci were used to interrogate the PROMIS (Pakistani Risk of Myocardial Infarction Study) cohort. Following this analysis, 4 locidchr9p21, COL4A1, ATP2B1, and ABCA4dwere identiﬁed as contributing to MI risk. Both chr9p21 and COL4A1 had been previously identiﬁed as contributing to CAC scores in genome-wide association studies (20). At this stage, even when correcting for multiple comparisons (not done at earlier stages of discovery), ATP2B1 and COL4A1 genetics signiﬁcantly portended increase risk for MI in the PROMIS cohort lacking enrichment for CKD (17). Why is this study so signiﬁcant? It is enlightening on several levels. First, the impact of CKD speciﬁcally upon CAC load before renal replacement therapy has needed assessment in an adequately sized, well-phenotyped cohort, and CRIC has provided this information (12,17). Moreover, it conﬁrms and extends the association of chr9p21 and COL4A1 genotype with coronary calcium load (17,20). Type IV collagen is vital to basement membrane function and vascular integrity, and alterations contribute to tissue calciﬁcation risk in other venues (21,22). Indeed, type IV collagen protein accumulation is more intense around sites of calciﬁcation in patients with CKD (23). This suggests that additional research into the biological role of type IV collagen in vascular calciﬁcation is warranted. Additionally, when viewed in the context of other recent observations, this study suggests that low-cost focused genotyping may yet provide important, cost-effective risk stratiﬁcation in patients with equivocal CAD risk. CAC arises primarily from atherosclerotic calciﬁcation versus medial artery calciﬁcation (24), and for individuals at intermediate CHD risk by Framingham criteria, CAC scoring helps better assess the probability for MI (25,26). Thus, given these new results, genotyping for CAC risk could be envisioned in an algorithm that augments the implementation of computed tomography imaging to stratify individual clinical CAD risk (27). Moreover, the loci identiﬁed once again implicate mineral metabolism in the pathogenesis of cardiovascular disease. The most intriguing is ATP2B1, alias PMCA1. Via alternative splicing, this gene encodes several different protein isoforms of plasma membrane calcium ATPase 1 (PMCA1), a plasma membrane ATPase that pumps cytosolic calcium across the membrane and out of cells; via this action in vascular smooth muscle cells (VSMCs), PMCA1 regulates vascular tone and blood pressure (28). However, PMCA1 also plays global “housekeeping” functions that are critical to cell viability, and it would be interesting to know whether VSMC’s propensity for apoptotic cell death (29) is altered by PMCA1 insufﬁciency (30) is relevant to acute coronary events. Compensatory upregulation of VSMC PMCA4 with PMCA1 deﬁciency may mitigate some of this risk. Moreover, PMCA1 also plays a critical role in regulating bone-resorbing osteoclast
activation by receptor activator of nuclear factor kappa-B ligand (RANKL) (31). This tumor necrosis factor superfamily member is not only necessary for osteoclast differentiation, function, and survival (15,31), but is also implicated in the pathobiology of vascular calciﬁcation (32). The ATP2B1 rs11105354A allele tracked both lower CAC score and blood pressure, and it may be that global calcium homeostasis is also altered in this genetic setting (17). Of note, the ATP2B1 rs11105354A allele was signiﬁcantly associated with increased serum calcium levels (17). Finally, as the authors point out (17), this type of sensitized screening (18) may be useful in the identiﬁcation of new signaling pathways that contribute to the pathogenesis of CAD through a focus on atherosclerosis phenotypes in patients with CKD. It’s interesting to note that the TLL1 genetic variant identiﬁed by Cresci et al. (33) as signiﬁcantly associated with the extent of CAD appears speciﬁc to the setting of T2DM; similar examples of selective interactions between genotype, metabolic milieu, and CAD risk may also arise in the setting of CKD. Nevertheless, given the clinical management challenges we face with our increasingly aged and dysmetabolic patient populationsdoften with concomitant reductions in renal functiondthe insights afforded by genomics combined with multidisciplinary phenotyping of patients with CKD will no doubt provide novel strategies for assigning and mitigating cardiovascular disease risk. Reprint requests and correspondence: Dr. Dwight A. Towler, Cardiovascular Pathobiology Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute at Lake Nona, 6400 Sanger Road, Orlando, Florida 32827. E-mail: [email protected]
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