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Meds Target, Tame Vulnerable Plaque

MedpageToday

While prospectively detecting and treating vulnerable plaque remains a challenge, some medications, current and emerging, can help stabilize plaque for secondary prevention, according to a European Society of Cardiology (ESC) position paper.

The ESC Working Group of Atherosclerosis and Vascular Biology noted in the paper that strong clinical evidence has shown the ability of statins to stabilize plaque, along with positive results for aspirin and other antiplatelet agents, beta-blockers, and renin-angiotensin-aldosterone system inhibitors.

Researchers also noted the existence of some evidence showing plaque stabilization abilities for peroxisome proliferator activated receptor (PPAR) agonists, niacin, omega-3 fatty acids, and some HDL-raising therapies, according to the paper published online in Thrombosis and Haemostasis.

Vulnerable Plaques

Led by Seppo Ylä-Herttuala, MD, chairman of the ESC position paper task force, researchers noted that at least 75% of symptomatic coronary thrombi are caused by plaque rupture.

They described vulnerable plaques as those with thin fibrous caps, large lipid cores, and outward, or positive, remodeling.

A further categorization divides vulnerable plaque into two major types: rupture-prone and erosion-prone.

Rupture-prone plaques are homogenous, characterized by large and soft lipid-rich necrotic cores, with thin and inflamed fibrous caps. They have neovascularization properties and spotty calcification.

Erosion-prone plaques are heterogeneous, with no known distinct morphological features. However, they are rarely associated with expansive remodeling and only sparsely inflamed.

"So, irrespective of the plaque type, it is a misconception that vulnerable plaques are globally inflamed," researchers wrote.

The fibrous caps of vulnerable plaques contain abundant blood-derived leukocytes, including monocytes, macrophages, and T-lymphocytes.

Preclinical evidence suggests that some T-cells promote atherosclerosis, while others reduce atherosclerosis. "Thus, immunomodulation, which aims to change the T-helper cell milieu and promote Tregs [regulatory T-cells], seems an attractive possibility," the authors wrote.

Since T-cells promote plaque vulnerability locally through their effects on macrophages, research has focused on PPAR agonists and liver X receptor agonists, which have been shown in preclinical studies to positively affect macrophage inflammatory response.

An atheroprogressive immune response can also be counterbalanced by atheroprotective cytokines. For example, inhibiting transforming growth factor-β accelerated atherosclerosis and induced a vulnerable plaque phenotype in mice. Drugs that favor the expression of cytokines might help stabilize vulnerable plaque.

Chemokines, a large family of small, related cytokines that regulate cell trafficking of leukocytes to areas of injury, also have been shown to be integral players in the pro-inflammatory response. Inhibiting certain chemokines could help transform vulnerable to stable plaques.

Extracellular proteases including matrix metalloproteinases and cathepsins from macrophages promote many of the adverse structural changes associated with plaque vulnerability. "Inhibiting proteases directly or preventing their secretion into the plaque extracellular matrix appear attractive pathways to new plaque stabilizing treatments," Ylä-Herttuala and colleagues suggested.

Endothelial dysfunction is linked to activation of oxidative stress pathways, which aggravate atherosclerotic plaque formation. In preclinical models, it's been shown that up-regulating the nitric oxide pathway attenuates the atherosclerosis process. New drugs could potentially target this pathway, thus limiting endothelial dysfunction, which is "as an independent predictor of major adverse cardiac events."

Plaque Stability

The authors noted the difficulty of establishing dietary factors related to plaque stabilization. However, the effect of the Mediterranean diet, which has been shown to significantly reduce cardiovascular mortality by 9%, "seems to be related to increased consumption of nutrients, such as folates, omega-3 acids, polyphenols and vitamin D."

They pointed to only one study with direct evidence of nutrients on plaque stability (Lancet 2003; 361: 477–485). The study of 162 patients awaiting endarterectomy found that the inclusion of fish oil in the diet reduced the content of macrophages in the excised carotid arteries.

The ESC position paper noted the use of biomarkers, particularly high-sensitivity C-reactive protein, a marker of inflammation, to gauge one's risk of adverse cardiovascular events.

It also pointed to other "promising" biomarker targets such as chemokines and cytokines, tissue metalloproteinases, hemostatic factors, and myeloperoxidase. But all of these potential biomarker targets need validation and confirmation, the authors stated.

"A good biomarker needs to be specific for disease development or progression, to have a high predictive value for events and, if possible, should reflect successful treatment," the authors wrote, adding that there is a "pressing need for more specific and prognostic biomarkers to be added to the established risk factors to optimize risk prediction."

Genetic research has identified certain genes associated with cardiovascular disease. However, no data yet point to a specific genetic signature of the vulnerable plaque. "Although a specific (single) genetic test to identify a patient who carries rupture prone plaques is the ultimate goal, this seems currently unlikely," researchers wrote.

Catheter-based imaging modalities such as intravascular ultrasound (IVUS), virtual histology (VH)-IVUS, and optical coherence tomography (OCT), have added to the understanding of vulnerable plaque.

IVUS has validated that positive remodeling is associated with ruptured plaques. VH-IVUS, which characterizes plaque composition, has linked positive remodeling with a necrotic core.

OCT, which has higher resolution than IVUS, has added to the understanding of the thin fibrous cap on vulnerable plaques. OCT may one day be used to assess the effect of statins in plaque stabilization, Ylä-Herttuala and colleagues posited.

"Techniques emerging for future use include coronary CT, MRI and imaging techniques using markers of metabolic activity of certain cell types (e.g., macrophages) such as 18-FDG-PET," they wrote.

Studies of statins or statins plus other drugs (such as niacin) have demonstrated reductions in cardiovascular events, suggesting the hypothesis that these strategies lead to plaque stabilization. "However, current knowledge is still limited," the authors said.

They noted two statin studies that showed an effect on inflammation and plaque stability.

Crisby et al. showed that lesions from patients receiving pravastatin had significantly higher collagen content and less inflammatory cells, "suggesting that these plaques were more stable than plaques from untreated patients" (Circulation 2001; 103: 926–933).

Cortellaro et al. demonstrated that lesions from patients given atorvastatin exhibited fewer macrophages and inflammatory cells (Thromb Haemost 2002; 88: 41–47).

"Plaque rupture and subsequent thrombotic occlusion of the coronary artery account for as many as three quarters of myocardial infarctions," Ylä-Herttuala and colleagues wrote.

While the concept of plaque stabilization is two decades old, more recent research has lead to a better understanding of the pathophysiology of vulnerable plaque. Ultimately, this knowledge will help in the development of drugs to target specific atheroprogressive pathways.

Disclosures

The authors had no conflicts of interest to disclose.

Primary Source

Thrombosis and Haemostasis

Ylä-Herttuala S, et al "Stabilization of atherosclerotic plaques: Position paper of the European Society of Cardiology (ESC) Working Group of Atherosclerosis and Vascular Biology" Thomb Haemost 2011; DOI: 10.1160/TH10-12-0784.