Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction

Jørgensen, Anders; Frikke‐Schmidt, Ruth; West, Anders Sode; Grande, Peer; Nordestgaard, Børge G.; Tybjærg‐Hansen, Anne

doi:10.1093/eurheartj/ehs431

Cited by 390 publications

(275 citation statements)

References 57 publications

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“…We have previously demonstrated that elevated remnant cholesterol is causally associated with increased risk of IHD and that this association is independent of low high-density lipoprotein cholesterol levels. 1,2 The causal association of nonfasting remnant cholesterol with low-grade inflammation observed in this study could be explained by remnant cholesterol causing atherosclerosis, a disease with a known inflammatory element. 14 Randomized, clinical trials have found that statin therapy prevents cardiovascular disease when CRP levels are increased, even if LDL cholesterol levels are below traditional intervention levels.…”

Section: Discussionmentioning

confidence: 76%

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

et al. 2013

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Background-Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown. Methods and Results-We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. Conclusions-Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation. (Circulation. 2013;128:1298-1309.)

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Section: Discussionmentioning

confidence: 76%

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

et al. 2013

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“…In a cohort of >50 000 Danish participants, Jorgensen et al identified genetic variants that contributed to extreme elevations in TG levels 29. The investigators showed that these genetic elevations in calculated RLP‐C based on nonfasting TG levels were associated with an 87% increased odds of MI.…”

Section: Discussionmentioning

confidence: 99%

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies

Joshi

Khokhar

Massaro

et al. 2016

JAHA

143

102

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BackgroundRemnant lipoproteins (RLPs), the triglyceride‐enriched precursors to low‐density lipoprotein, are an emerging risk factor for coronary heart disease (CHD). We sought to determine the association of RLP cholesterol (RLP‐C) levels with incident CHD in 2 diverse, prospective, longitudinal observational US cohorts.Methods and ResultsWe analyzed cholesterol levels from serum lipoprotein samples separated via density gradient ultracentrifugation in 4114 US black participants (mean age 53.8 years, 64% women) from the Jackson Heart Study and a random sample of 818 predominantly white participants (mean age 57.3 years, 52% women) from the Framingham Offspring Cohort Study. Multivariable‐adjusted hazard ratios (HRs) for RLP‐C (the sum of very low‐density lipoprotein3 cholesterol and intermediate‐density lipoprotein cholesterol) were derived to estimate associations with incident CHD events consisting of myocardial infarction, CHD death, and revascularizations for each cohort separately and as a combined population. There were 146 CHD events in the combined population. After adjustments for age, sex, body mass index, smoking, blood pressure, diabetes, and lipid‐lowering therapy for the combined population, RLP‐C (HR 1.23 per 1‐SD increase, 95% CI 1.06–1.42, P<0.01) and intermediate‐density lipoprotein cholesterol (HR 1.26 per 1‐SD increase, 95% CI 1.08–1.47, P<0.01) predicted CHD during an 8‐year follow‐up. Associations were attenuated by high‐density lipoprotein cholesterol and ultimately lost significance with inclusion of real low‐density lipoprotein cholesterol, which excludes Lp(a) and IDL cholesterol fractions. Similar associations were seen in multivariable analyses within each cohort.Conclusion RLP‐C levels are predictive of incident CHD in this diverse group of primary prevention subjects. Interventions aimed at reducing RLP‐C to prevent CHD warrant further intensive investigation.Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00415415.

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“…96,97 Furthermore, recent genetic data support the contention that elevated TG levels are a direct cause of CV disease. 76,88 Recent studies suggest that non-fasting TGs may carry information regarding remnant lipoproteins associated with increased risk. 76,86,98,99 For general screening and risk evaluation, non-fasting…”

Section: Triglyceridesmentioning

confidence: 99%

“…76,88 Recent studies suggest that non-fasting TGs may carry information regarding remnant lipoproteins associated with increased risk. 76,86,98,99 For general screening and risk evaluation, non-fasting…”

Section: Triglyceridesmentioning

confidence: 99%

ESC/EAS Guidelines for the management of dyslipidaemias

Catapano¹,

Reiner²,

Backer³

et al. 2011

Atherosclerosis

565

189

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Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction

Abstract: These data are consistent with a causal association between elevated levels of remnant cholesterol in hypertriglyceridaemia and an increased risk of MI. Limitations include that remnants were not measured directly, and that APOA5 genetic variants may influence other lipoprotein parameters.

Cited by 390 publications

References 57 publications

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation

Remnant Lipoprotein Cholesterol and Incident Coronary Heart Disease: The Jackson Heart and Framingham Offspring Cohort Studies

ESC/EAS Guidelines for the management of dyslipidaemias

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