Rise in CV Risk Factors Tied to Vulnerable Plaque in ACS Patients

A greater number of cardiovascular risk factors in patients with acute coronary syndromes equals greater plaque vulnerability, according to a study that used optical coherence tomography to tease out the mechanisms driving disease.

The association was particularly strong—though not exclusive to—culprit lesions, Marco Covani, MD (Massachusetts General Hospital, Boston, and University Hospital of Parma, Italy), and colleagues report in a paper published in the July 15, 2025, issue of JACC.

It’s intuitive that risk factors would, by definition, predict disease, but, as senior author Ik-Kyung Jang, MD, PhD (Massachusetts General Hospital, Boston, and Kyung Hee University, Seoul, Republic of Korea), pointed out to TCTMD, what’s less certain is how the cumulative burden of numerous factors impacts risk. The question is clinically relevant given that cardiology clinics rarely see patients with just one risk factor.

“We know patients with multiple risk factors are at higher risk for future adverse events [like CV death and MI], so everybody assumed the mechanism is related to vascular instability or vulnerability,” he said. “But nobody really has tried to bridge this gap [before].”

The fact that vulnerable plaques were less directly tied to risk factors in nonculprit lesions is somewhat surprising given that CVD tends to be systemic, said Jang. The difference could relate to hemodynamic factors like shear stress, he suggested, or to the fact that atherosclerosis is a dynamic process where, with time, stable plaques can become vulnerable and vice versa.

Ori Ben-Yehuda, MD (University of California-San Diego, La Jolla), in an editorial, also highlights the challenge of identifying which specific plaque will become “culprit.”

“The advent of intravascular imaging has allowed not only the in vivo quantification of the extent of plaque throughout the coronaries, but also the characterization of plaque morphology,” he says, also citing the advances in epidemiology that have added to the understanding of CV risk factors.

The new study findings, Ben-Yehuda notes, “provide important mechanistic insights into plaque vulnerability and . . . emphasize the importance of modifiable risk factors in the pathogenesis not only of atherosclerosis in general, but in plaque vulnerability itself.”

At a clinical level, the results emphasize the additive nature of CV risk factors as well as the need to intensively manage them, he adds.

Underlying Pathology

Covani and colleagues analyzed data on 1,581 ACS patients (median age 66 years; 80% male) who had undergone preintervention OCT as part of registries in the US, Japan, China, Italy, Belgium, India, and Germany. Patients were divided into five groups based on their number of risk factors: hyperlipidemia (68.9% of the cohort), hypertension (64.4%), current smoking (37.6%), and diabetes (32.5%).

The study included 1,581 culprit plaques as well as 606 nonculprit plaques.

For the culprit lesions, an increasing risk factor burden was linked to a higher likelihood of lipid-rich plaques (P for trend = 0.027), thin-cap fibroatheromas (P for trend = 0.006), macrophages (P for trend < 0.001), microvessels (P for trend < 0.001), and cholesterol crystals (P for trend = 0.032). Additionally, each of these vulnerable features apart from lipid-rich plaque was more common in patients with two or more risk factors, as compared to those with fewer.

Plaque rupture in culprit lesions rose in prevalence alongside a greater risk factor burden (P for trend = 0.015). In contrast, plaque erosion grew less common in the presence of more risk factors (P for trend < 0001). Rupture was more common in STEMI versus NSTE ACS patients, while the opposite was true for erosion.

“Although clinical manifestations are similar, the underlying pathology between rupture and erosion is distinctly different,” said Jang. “ Plaque rupture is primarily due to vascular inflammation,” he specified. “Plaque erosion is a complex process. . . . The level of vascular inflammation is much lower in erosion compared to rupture, and there’s an endothelial component, a coagulation component, and also a blood-flow problem.”

For nonculprit plaques, the only characteristics to increase in conjunction with risk factors were macrophages, cholesterol crystals, and the cumulative number of vulnerable features.

Additionally, the study authors found that white blood cell count positively correlated with risk factor burden. This suggests “patients with multiple risk factors are likely to have higher systemic inflammation and greater coronary vulnerability,” they write. “These findings reinforce the connection between traditional risk factors and vascular inflammation, emphasizing that risk factors may promote plaque vulnerability by amplifying both local and systemic inflammatory processes, ultimately contributing to a more vulnerable phenotype.”

Jang cautioned that OCT, in this context,  is used “as a research tool to study vascular biology,” not as a routine screening tool. Thus, he said, the imaging they did here isn’t something to replicate in day-to-day practice.

The next step will be looking at whether addressing modifiable risk factors associated with vulnerable plaque can improve plaque phenotype, Jang added. One day it may be possible, through better understanding of pathobiology, to “ propose tailored therapy or precision medicine depending on the mechanism of ACS,” he suggested.