Lipids and other measures available from plasma are well established to predict coronary heart disease (CHD) in general. Much less is known about associations between plasma biomarkers and premature CHD, often defined as occurring before age 55 in men and before age 65 in women.
By reviewing data from a long-term prospective study of U.S. women, researchers at Brigham and Women’s Hospital identified 12 biomarkers specifically associated with premature CHD. In Clinical Chemistry, they discuss the potential implications of biomarker screening and therapeutic strategies.
The authors are Sagar B. Dugani, MD, PhD, formerly a resident in the Center for Lipid Metabolomics at the Brigham, M. Vinayaga Moorthy, PhD, a researcher in the Center and the Divisions of Preventive Medicine, Samia Mora, MD, MHS, a director of the Center and a cardiovascular medicine specialist in the Divisions of Preventive Medicine, Cardiovascular Medicine, and Women’s Health, and colleagues.
Methods
Between April 1993 and January 1996, in the Women’s Health Study, 39,876 healthy women ≥45 were randomly assigned to receive low-dose aspirin, vitamin E, and β-carotene or a matching placebo. This original portion of the trial ended in 2004 with no effects of any treatment on cardiovascular and cancer outcomes. Since then, participants have been followed on an observational basis.
At baseline, 28,024 participants had metabolic, inflammatory, and lipid biomarkers measured from a blood sample. The current analysis investigated 44 biomarkers and followed participants for CHD through 2016. CHD was defined as first myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, or CHD-related death.
Results
During overall median follow-up of 21.6 years, two groups of women were identified by age < or ≥65 years at baseline:
- 25,042 women <65 years old at baseline—447 developed premature CHD, and 24,595 did not develop CHD during follow-up
- 2,982 women ≥65 years old at baseline—351 developed non-premature CHD, and 2,631 did not develop CHD during follow-up
In adjusted analyses, 12 biomarkers showed associations with premature CHD and non-premature CHD. By far, the most substantial risk factor was the lipoprotein insulin resistance (LPIR) score, a novel weighted combination of six lipoprotein measures. A one–standard deviation increase in LPIR score was linked to a 92% higher relative risk of premature CHD, much greater than the relative risk with a one-SD increment in standard tests such as low-density lipoprotein (LDL) cholesterol (40%), lipoprotein(a) (29%), or hemoglobin A1c (8%).
High-density lipoprotein (HDL) cholesterol (relative risk, 0.66) had the strongest protective relationship against premature CHD.
As for the other 32 biomarkers:
- 11, including apolipoprotein B, were associated with both premature and non-premature CHD, but more strongly with premature CHD
- 12 were similarly associated with premature and non-premature CHD
- Nine weren’t significantly associated with either category of CHD
Of the clinical cardiovascular risk factors, diabetes was associated with the greatest risk of premature CHD (>10-fold increase in the risk of premature CHD events and >3-fold increase in non-premature CHD events in women). To a lesser extent, other clinical risk factors also predicted the risk of premature CHD, including metabolic syndrome, overweight, obesity, hypertension, family history, and current smoking.
Opportunities to Improve Care
As the prevalence of obesity in the U.S. increases, so too does the risk of insulin resistance and diabetes. These study findings may guide the development of more targeted biomarker panels to improve screening and identify adults under 65 who need lifestyle and/or pharmacologic interventions. This is particularly relevant for younger and middle-aged women as they have had worrisome increases in cardiovascular mortality recently.
Preventing and managing clinical risk factors, in particular for diabetes, should improve the biomarker profile and reduce the risk of premature CHD.