Conclusions from a new population-based cohort study suggest a significant association between elevated lipoprotein(a) [Lp(a)] levels and both interstitial and replacement myocardial fibrosis. Published Monday online and in the Dec. 12 issue of the Journal of the American College of Cardiology, the findings also demonstrate an association between Lp(a) increase and left atrial (LA) remodeling, emphasizing the role of Lp(a) in the onset and progression of cardiac fibrosis. “In our study, however, after excluding participants who experienced interim myocardial infarction or had myocardial scars defined by CMR LGE [cardiac magnetic resonance and late gadolinium enhancement], the association between elevated Lp(a) and fibrosis remained significant, even after controlling for total coronary calcium score,” the paper’s authors said. “This finding suggests that the link between Lp(a) and interstitial fibrosis is largely independent of coronary artery disease or LV [left ventricular] remodeling secondary to myocardial infarction.” Secondary effects Led by Omar Chehab, MD, from the Johns Hopkins University, Baltimore, the U.S.-based team also suggested that the association between Lp(a) and interstitial myocardial fibrosis (IMF) was not significantly confounded by myocardial remodeling induced by aortic valve stenosis (AVS) and was possibly secondary to a direct effect of Lp(a) on myocardial fibrogenesis. Results from the investigation show that higher Lp(a) levels were associated with increased extracellular volume (ECV fraction [ECV%]) (per log-unit Lp[a]; β=0.2%; P=0.007) and native T1 time (per log-unit Lp[a]; β=4%; P<0.001). Similar associations were noted between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (odds ratio [OR]: 1.20; 95% confidence interval [CI]: 1.04-1.43) and native T1 (OR: 1.2; 95% CI: 1.1-1.4) equal to 30% and 955 ms, respectively. Further findings revealed a greater prevalence of myocardial scar (OR: 1.85; 95% CI:1.1-3.2) at the clinically used Lp(a) cutoff of 30 mg/dL and also at the 50 mg/dL cutoff (OR: 1.9; 95% CI:1.1-3.4). The research team concluded that higher Lp(a) levels were associated with LA enlargement and dysfunction. Oxidative stress pathway “The mechanisms linking Lp(a) to IMF can at least in part be attributed to the oxidative stress pathway combined with inflammation, which is a critical factor in the development of diffuse cardiac fibrosis,” the paper says. “Oxidized phospholipids present on Lp(a) particles can activate various proinflammatory pathways, thereby leading to the recruitment of inflammatory cells to the myocardium. In turn, these inflammatory cells may produce reactive oxygen species and cytokines that promote fibroblast activation and ECM synthesis.” Writing in an accompanying editorial comment, Gilles Lambert, PhD, Kévin Chemello, PhD, and Antonio Gallo, MD, PhD, all from the Université de La Réunion in Sainte-Pierre, France, called for the systematic noninvasive imaging of myocardial fibrosis in patients at risk of heart failure with Lp(a) above 30 mg/dL. “The positive findings of the present study, after excluding subjects with AVS, underscore the significance of considering AVS as more than just an isolated valve disease and point toward the possibility that early myocardial tissue dysfunction contributes to the development of AVS, a process in which Lp(a) may play a substantial role,” the experts said. Role of the TGF-β pathway Discussing possible mechanisms of action, the commentators identified the proinflammatory effects of Lp(a)-associated oxidized phospholipids via the TGF-β pathway as the most plausible underlying cause of these associations. However, they acknowledged that it seems unlikely that the observations might possibly be linked with an impairment of the fibrinolytic system, given that Lp(a) had recently been proven not to be a risk factor for thromboembolism. The commentators described the link between Lp(a) and LA volume and dysfunction as “intriguing,” adding that the parameters eventually induced atrial fibrillation and consequently increased the risk of ischemic stroke. “Of note, the present study does not provide left atrial strain rate peak during relaxation (left atrial strain), an important parameter of left atrial myocardial function,” they pointed out. Study methodology The population-based cohort study included 2,826 participants who had both Lp(a) and complete CMR data from MESA visit 5. Of this population, 2,040 participants (48% female patients, mean age of 69±9 years) had baseline Lp(a) measurements and T1 mapping for IMF evaluation. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50 mg/dL. In addition, multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of ECV%, native T1 time and myocardial scar, as well as parameters of cardiac remodeling in the 2,826 participants. Sources: Chehab O, Abdollahi A, Whelton SP, et al. Association of Lipoprotein(a) Levels With Myocardial Fibrosis in the Multi-Ethnic Study of Atherosclerosis. J Am Coll Cardiol. 2023;82:2280–2291. Lambert G, Chemello K, Gallo A. Lipoprotein(a): More Than Just a Biomarker of Myocardial Fibrosis. J Am Coll Cardiol. 2023;82:2292 – 2295 Image Credit: luchschenF – stock.adobe.com