HDL-Associated Proteoforms and Incident Myocardial Infarction in the Dallas Heart Study

Coronary heart disease (CHD) is the leading cause of death globally. Dysfunctional lipoproteins may contribute to this excess risk but are challenging to measure. Crude circulating levels of protein markers often do not adequately reflect protein function or dysfunction. A proteoform is a specific molecular form of a protein that includes information on the type, location, and combinations of post-translational modifications, which directly affect function and downstream phenotype. While HDL-associated apolipoproteins (apo), particularly apoA-I, mediate cardioprotective functions, it remains unknown whether apoA-I proteoforms are linked to CHD events. Our prior work linking apoA-I proteoforms to cardiometabolic traits supports uncovering proteoform-CHD relationships for mechanistic insight into CHD. The goal of this study was to explore the spectrum of apoA-I proteoforms linked with incident CHD events, a novel approach to identifying CV risk.

At #AHA24, we presented our study investigating apoA-I proteoforms in participants enrolled in the Dallas Heart Study (a community-based multiethnic cohort, more than 3,000 participants without prevalent CVD at baseline). We measured apoA-I proteoforms in baseline samples in 33 incident MI cases during follow-up and 32 controls that remained free from CVD who were matched for age, sex, and race/ethnicity (mean age 56 years, 45% women, 66% Black, and 9% Hispanic). We used a top-down proteomics workflow to quantify apoA-I proteoforms.

We detected 15 apoA-I proteoforms, and their overall abundances were similar between incident MI cases and controls. The associations between some of the apoA1 proteoforms and cardiometabolic traits varied substantially in incident MI cases versus controls. One striking example involved acylated apoA-I proteoforms that showed differential patterns of association with cholesterol, triglyceride, and oxidized LDL in controls vs. incident MI. In addition, when we separated the HDL-associated proteins by size, we found a striking increase in three apoA-I proteoforms in those with incident MI in only the large HDL size fractions.

These findings suggest that lipid proteoforms may be involved in CHD risk. In future studies, we will validate these findings in larger cohorts and explore the role of size-based lipid proteoforms as potential risk markers and therapeutic targets for CHD, with the goal of ultimately improving patient outcomes.

Note: This work was funded by an AHA Postdoctoral Research Fellowship Award.