The findings are drawn from longitudinal data on 4,512 participants in the Multi-Ethnic Study of Atherosclerosis and 2,078 participants in the Dallas Heart Study, all of whom were free of clinical atherosclerosis at baseline. Both studies tracked incident atherosclerotic cardiovascular disease (ASCVD) events, defined as coronary heart disease-related death, nonfatal myocardial infarction, or fatal or nonfatal stroke. The mean follow-up in both cohorts was more than a decade.
Participants of the two studies were analyzed separately because Lp(a) was measured using different assays. Levels of this protein are primarily genetically determined by the age of five; American College of Cardiology/American Heart Association guidelines set 50 mg/dL as the threshold for elevated Lp(a).
In the MESA study, compared to subjects with CAC scores of 0 and normal Lp(a), participants with moderately high CAC scores (i.e., 100 or higher) and Lp(a) in the highest quintile had a hazard ratio for ASCVD of 4.71 over a ten year period. In comparison, for patients in the lower quintiles of Lp(a) with CAC scores of at least 100, the hazard ratio was 2.99, Dr. Anurag Mehta of Emory University in Atlanta, Georgia and colleagues reported in the Journal of the American College of Cardiology.
Quintiles were race-specific, with Lp(a) ranges in the highest quintile of 38-236 mg/dL in whites, 73-314 mg/dl in Blacks, 35-316 mg/dL in Hispanics, and 29-131 mg/dL in Chinese patients. Overall, the quintiles were similar in some respects; in each, the mean age was 62, mean systolic blood pressure was 126 mmHg, and 52% in each quintile had a CAC score of 0. Mean low density lipoprotein rose from 110 mg/DL in the lowest quintile to 131 mg/dL in the highest. Quintile 5 was 41% male, as compared to quintile 1 with 52% males. The independent associations of continuous Lp(a) level and CAC score with ASCVD events remained significant when Lp(a), CAC and traditional risk factors were analyzed together in Cox models, the researchers said.
Ten-year event rates in the MESA study for patients with a CAC score of 100 or higher were 14.91% for those with Lp(a) <50, versus 23.24% for those with higher Lp(a). By comparison, patients with CAC scores of 0 (referent) had a ten year event rate of <3%, with an insignificant rate increase in patients with elevated Lp(a) levels. Patients with CAC scores of 1-99 had a 10-year event rate of about 8%; in this group, with a non-statistical higher rate in patients with the highest Lp(a) levels, but significantly elevated over the referent events rate.
Similar findings were observed among DHS participants, the researchers said.
In considering how to explain the additive effect of CAC to Lp(a), the researchers note that "Lp(a) not only has atherogenic properties related to its low-density-lipoprotein-like composition, but it also possesses unique characteristics secondary to its apolipoprotein (a) component." Effects of the latter include promoting inflammation and endothelial dysfunction through oxidized phospholipid levels and promoting thrombosis. "CAC score, on the other hand, captures the burden of coronary atherosclerosis that has developed over the lifespan in response to continued exposure to measured and unmeasured atherogenic risk factors," the authors write.
The curves between the lower and higher risk group began to diverge at the two year mark, they found.
The implication of the data, said Dr. Sotirios Tsimikas of the University of California, San Diego in La Jolla in an accompanying editorial, is that when a patient without clinical cardiovascular disease is found to have either a moderately high CAC score or or Lp(a) >50 mg/dL, "the next step in the risk evaluation should be to measure (the other parameter)... to identify the patients at highest risk."
The researchers and Dr. Tsimikas agree that treatment options now are limited. High-dose statins remain the initial treatment for high-risk patients to drive LDL to a low level, even if these drugs have limited impact on Lp(a). In patients with elevated Lp(a), the powerful PCSK9 inhibitors only reduce Lp(a) by 15-25%, despite their powerful reduction of LDL by more than 50%. The ongoing phase III HORIZON trial is testing the impact of lowering Lp(a) with monthly subcutaneous injections of TQJ230 (pelacarsen) on the risk of major cardiovascular events in patients with established cardiovascular disease; study completion is expected in 2025.
SOURCE: https://bit.ly/3p6XvOW and https://bit.ly/3IaZBVg Journal of the American College of Cardiology, online February 21, 2022.
By Austin Kutscher MD FACC
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