Role of Non-High-Density Lipoprotein Cholesterol in Predicting Cerebrovascular Events in Patients Following Myocardial Infarction

Mahajan, Nitin; Ference, Brian А.; Arora, Natasha Purai; Madhavan, Ramesh; Bhattacharya, Pratik; Sudhakar, Rajeev; Sagar, Amit; Wang, Yun; Sacks, Frank M.; Afonso, Luís

doi:10.1016/j.amjcard.2012.02.010

Cited by 19 publications

(14 citation statements)

References 27 publications

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“…Recent work shows that among patients treated with statins, the strength of associations of LDL cholesterol, non-HDL cholesterol, and ApoB with future MCVE is greatest for non-HDL cholesterol 323. In addition, non-HDL cholesterol is an independent predictor of cardiovascular disease in patients following myocardial infarction, with the largest effect of all lipid fractions,324 and an independent risk factor for stroke in healthy women. Finally, non-HDL cholesterol shows a close relationship with small dense LDL levels compared with other lipid parameters.…”

Section: Non-hdl Cholesterol and Reduction Of Residual Riskmentioning

confidence: 99%

Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes

Kones¹

2013

VHRM

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Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the ...

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Section: Non-hdl Cholesterol and Reduction Of Residual Riskmentioning

confidence: 99%

Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes

Kones¹

2013

VHRM

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“…[1][2][3] There is increasing recognition that reductions in nonhigh-density lipoprotein cholesterol (non-HDL-C) may be even better than LDL-C as a predictor of benefit. [4][5][6] Increasingly, guidelines recommend non-HDL-C as an additional therapeutic target to reduce cardiovascular risk. 5,7,8 Each doubling of statin dose has been shown to result in an approximately 5-6% greater reduction in LDL-C, 9 and as statin doses increase, a greater percentage of high-risk patients achieve recommended LDL-C goals, 10 as defined by the 2011 European Society of Cardiology/European Atherosclerosis Society guidelines.…”

Section: Introductionmentioning

confidence: 99%

Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis

Karlson

Palmer

Nicholls

et al. 2015

Eur J Prev Cardiolog

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“…The absence of genetic analysis using NHDL as a phenotype may in part result from its relatively recent recognition as an important, independent and superior predictor of cardiovascular outcomes relative to other atherogenic measures (Robinson 2009; Robinson 2010; Mahajan et al 2012; ERFC 2009; Liu et al 2006). In this analysis, we identified five suggestive common loci influencing NHDL levels; one locus for the baseline within a region of LD in RHOQ-PIGF-CRIPT was replicated at neighboring SNPs in the FamHS, two loci (near LOC100419812 , near LOC100288337 ) for the baseline, and two loci for the PPL response (near LOC100420502 , within CDH13 ) were not replicated in the available studies.…”

Section: Discussionmentioning

confidence: 99%

“…NHDL represents a superior predictor of cardiovascular risk in contrast to other lipid measures, even LDL cholesterol (Robinson 2009; Robinson 2010; Mahajan et al 2012; ERFC 2009; Liu et al 2006). Further, NHDL is an independent predictor of cardiovascular disease among other lipid measures, even among patients with normal triglyceride and LDL levels (Mahajan et al 2012). A possible explanation is NHDL's well-established role in accelerating coronary atherosclerosis (Mahajan et al 2012).…”

Section: Introductionmentioning

confidence: 97%

“…Further, NHDL is an independent predictor of cardiovascular disease among other lipid measures, even among patients with normal triglyceride and LDL levels (Mahajan et al 2012). A possible explanation is NHDL's well-established role in accelerating coronary atherosclerosis (Mahajan et al 2012). According to a recent report, NHDL also can be a biomarker for nonalcoholic fatty liver disease, specifically, nonalcoholic steatohepatitis (Corey et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

An¹,

Straka

Pollin

et al. 2014

Hum Genet

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Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to LDL alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) to identify loci influencing baseline NHDL and its postprandial lipemic (PPL) response. We carried out GWAS in 4,241 participants of European descent. Our discovery cohort included 928 subjects from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study. Our replication cohorts included 3,313 subjects from the Heredity and Phenotype Intervention (HAPI) Heart Study and Family Heart Study (FamHS). A linear mixed model using the kinship matrix was used for association tests. The best association signal was found in a tri-genic region at RHOQ-PIGF-CRIPT for baseline NHDL (lead SNP rs6544903, discovery p = 7e-7, MAF = 2%; validation p = 6e-4 at 0.1 kb upstream neighboring SNP rs3768725, and 5e-4 at 0.7 kb downstream neighboring SNP rs6733143, MAF = 10%). The lead and neighboring SNPs were not perfect surrogate proxies to each other (D′ = 1, r2 = 0.003) but they seemed to be partially dependent (likelihood ration test p = 0.04). Other suggestive loci (discovery p < 1e-6) included LOC100419812 and LOC100288337 for baseline NHDL, and LOC100420502 and CDH13 for NHDL PPL response that were not replicated (p > 0.01). The current and first GWAS of NHDL yielded an interesting common variant in RHOQ-PIGF-CRIPT influencing baseline NHDL levels. Another common variant in CDH13 for NHDL response to dietary high fat intake challenge was also suggested. Further validations for both loci from large independent studies, especially interventional studies, are warranted.

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Role of Non-High-Density Lipoprotein Cholesterol in Predicting Cerebrovascular Events in Patients Following Myocardial Infarction

Cited by 19 publications

References 27 publications

Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes

Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes

Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis

Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

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