Lp(a) Appears Tied to Myocardial Fibrosis: Observational Data

Inflammation might be one way that higher Lp(a) levels influence fibrosis formation, but causation and clinical impact are unclear.

Lp(a) Appears Tied to Myocardial Fibrosis: Observational Data

Elevated levels of lipoprotein(a) seem to be associated with greater subclinical interstitial myocardial fibrosis (IMF), increased myocardial scar prevalence, and left atrial remodeling by cardiac magnetic resonance (CMR), according to a new analysis of data from the Multi-Ethnic Study of Atherosclerosis.

Myocardial infarction is the leading cause of fibrosis, which in turn can result in cardiac remodeling, heart failure, and atrial fibrillation. When detected on CMR, such fibrosis is tied to worse cardiovascular outcomes. The idea that an elevated blood marker might be linked to fibrosis formation opens the door to potentially using Lp(a) to guide and develop treatment strategies for heart failure patients, especially those who have heart failure with preserved ejection fraction (HFpEF), according to the authors.

“Lipoprotein(a) is the new, novel risk factor that is pretty much taking over our field [and] has been found to be linked with atherosclerotic disease, plaque in the coronaries, but little has been known on its effect outside of the blood vessels,” lead author Omar Chehab, MD (Johns Hopkins University, Baltimore, MD), told TCTMD. “We were able to shed light on this crucial link between elevated lipoprotein(a) and cardiac remodeling.”

An accompanying editorial agrees with the importance of the findings. The results “provide indisputable evidence of a significant and independent association between elevated Lp(a) concentrations and both interstitial and replacement myocardial fibrosis,” write Gilles Lambert, PhD (Université de La Réunion, Sainte-Pierre, France), and colleagues. Awareness of this link may open “new avenues for mechanistic investigations” looking at whether Lp(a) “contributes to the onset and to the progression of cardiac fibrosis toward HF and atrial fibrillation.”

Steven Nissen, MD (Cleveland Clinic, OH), who wasn’t involved in the study, was more cautious, calling the study findings, interesting but “not definitive” in terms of proving causation between Lp(a) and myocardial fibrosis. “I'm not sure what people are going to do with the information,” he said. “I'm certainly not going to be doing magnetic resonance on my patients with high lipoprotein(a) unless they have symptoms and reasons to do it.”

Relationships Identified

For the study, published in the December 12, 2023, issue of the Journal of the American College of Cardiology, Chehab and colleagues included 2,040 MESA participants (48% female; mean age 69 years) who had baseline Lp(a) measurements and T1 mapping for IMF evaluation in 2010.

Most patients (70%) had Lp(a) levels lower than 30 mg/dL, 12% measured between 30 and < 50 mg/dL, and 18% had elevated Lp(a) of at least 50 mg/dL. Those with Lp(a) levels > 50 mg/dL were more likely to also have higher levels of LDL and HDL cholesterol as well as lower triglyceride levels, and they were more likely to be receiving lipid-lowering drugs.

Lp(a) levels increased with both extracellular volume and native T1 time. Additionally, on adjusted analysis, elevated Lp(a) levels were linked to a higher risk of clinically significant IMF both at an extracellular volume threshold of at least 30% (OR 1.2; 95% CI 1.04-1.43) and at a native T1 threshold of at least 955 ms (OR 1.2; 95% CI 1.1-1.4). These findings were maintained in a model excluding patients with myocardial scar, interim myocardial infarction, and severe aortic stenosis.

Myocardial scar was more likely to be seen when patients’ Lp(a) levels met the cutoffs of both ≥ 30 mg/dL (OR 1.85; 95% CI 1.1-3.2) and ≥ 50 mg/dL (OR 1.9; 95% CI 1.1-3.4). Left atrial enlargement and dysfunction also increased with heightened Lp(a).

The mechanisms behind these findings deserve further exploration, but it’s likely that increased Lp(a) “places us in a very high inflammatory position,” Chehab said. “[It activates] the same pathways that are linked with interstitial myocardial fibrosis.” That may be particularly important in HFpEF, the authors note, since interstitial fibrogenesis can lead to myocardial stiffness and dysfunction, which in turn trigger left atrial enlargement and dysfunction.

Ongoing studies of treatments suppressing Lp(a) to low levels will likely bring greater understanding of these mechanisms, especially if they use CMR, he said. “Once these trials come out, I think it's going to open the door for so many other questions.”

‘Preliminary’ Evidence

Nissen said while the associations identified between Lp(a) and both myocardial fibrosis and myocardial scar are significant, they are “fairly modest.”

“The mechanism is not entirely clear,” he added. “It may be just secondary to the other bad things that Lp(a) does. I don't think they made the case here that there's a direct relationship between lipoprotein(a) and myocardial fibrosis. I think they've shown an association with more research to come.”

Future randomized controlled trials will be better poised to answer questions related to how lowering Lp(a) might reduce the incidence of development of myocardial fibrosis, if it does at all, Nissen said. “All you can say [here] is that there is a weak association between a high Lp(a) and the presence of fibrosis on MRI. It's very preliminary.”

Sources
Disclosures
  • This work was supported by the National Heart, Lung, and Blood Institute, the National Center for Advancing Translational Sciences, and by a grant from Bayer Healthcare for the use of gadolinium contrast agent.
  • Chehab reports no relevant conflicts of interest.
  • Lambert reports receiving consulting fees from Nyrada and Amgen.
  • Nissen reports serving as an investigator for a variety of studies on drugs designed to lower lipoprotein(a).

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