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Vulnerable Plaques

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Proposed Treatment of Vulnerable Plaque

Conceptual Basis for Treatment

Based on the current concept of the vulnerable plaque (VP), clinical strategies for preventing acute coronary syndrome (ACS) can now be framed as promoting plaque stability. In a literature review, Forrester (2002) identified 5 stages of plaque destabilization, including:

  1. Endothelial activation
  2. LDL entry into vessel wall
  3. LDL activation.
  4. Breakdown of the fibrous cap.
  5. Thrombus formation.

In the same review, he proposed six mechanisms by which anti-atherosclerotic therapies may exert their therapeutic effects:

  1. Improve endothelial function.
  2. Decrease LDL levels.
  3. Inhibit LDL oxidation.
  4. Increase reverse cholinesterase transport.
  5. Reduce inflammation.
  6. Inhibit thrombosis.

Proposed Treatments for Vulnerable Plaque

Endothelial dysfunction is believed to promote inflammation, and inflammatory cell activity can contribute to "VP"; therefore lipid-lowering drugs, including statins, are recommended to reduce inflammation and improvement of endothelial function. Matrix metalloproteinase (MMP) activity may also contribute to the plaque rupture. Statin therapy may reduce this risk by decreasing collagen degradation (Corti, Farkouh, and Badimon 2002; Corti and Badimon 2002).

ACE inhibitors such as ramipril may have direct or indirect effects on plaque stability (Corti 2002). Ambrose (2002) suggests using ACE inhibitors and beta-blockers to stabilize plaques by reducing the circumferential stress on the fibrous caps. ACE inhibitors improve endothelial function, reduce inflammation of the vascular wall, and may induce the synthesis and release of interleukin-6 from macrophages. Antithrombotic agents such as aspirin were recommended to reduce platelet aggregability. Other agents that may promote plaque stability include antioxidants and macrolide antibiotics. Anti-inflammatory agents, including inhibitors of MMP, were also suggested.

Rabbani (1999) reviewed single agent and combination therapies, including statins alone or in conjunction with anti-lipemic agents, niacin and/or diet, diet alone or with exercise and stress management, partial ileal bypass, beta-blockers, ACE inhibitors, and anti-oxidants. Other theoretical therapies include: gene therapy, MMP inhibition, reduction in inflammatory cell infiltration, and macrolide antibiotics.

Zaman et al. (1999), suggested drug interventions such as: lipid-lowering and antioxidants agents (to help stabilize the plaques by reducing the lipid content, harden the fibrous tissue, and reduce MMP activity in the plaque), ACE inhibitors (to improve endothelial dysfunction), antibiotics (for the anti-chlamydial or anti-inflammation properties), beta-blockers (to reduce cap fatigue by the reduction of stresses in the arterial walls).

Treatment modalities such as phototherapy, cryotherapy, or thermotherapy have been discussed as potential therapies along with drug-eluting stents by Baim (The Gray Sheet, Sept 29, 2003). A multifaceted approach described by Corti (2002) includes lifestyle modifications and medications, such as statins and ACE inhibitors. Kereiakes (2003) advocated a systemic approach that includes statins, clopidogrel, ACE inhibitors, fibrates, thiazolidinediones, low molecular weight heparins, platelet glycoprotein IIb/IIIa receptor antagonists, and cyclooxygenase 2 inhibitors.

On the basis of two studies of plaque morphology in carotid arteries, endarterectomy (AbuRahma 1998; Lal 2002) was suggested to manage stenosis once the "VP" had been identified. A review article indicated that, in selected cases, "high-risk zones of vulnerable plaque" may be treated by "invasive/catheter-based strategies, including photodynamic or sonodynamic activation of photosensitizer/sonosensitizer agents." These agents ". localize within plaque inflammatory/smooth muscles cells or by targeted site-specific drug delivery." This author also speculated about the future potential of "novel drug-eluting stent platforms" for treating certain types of stenoses (Kereiakes 2003).

Mechanical interventions, including stenting, were not mentioned as potential therapeutic approaches to VP in the review articles we examined for this report, including those articles that focused primarily on therapeutic strategies (Rabbani 1999; Zaman 1999; Libby 2001; Forrester 2002). The use of invasive treatment modality for "VP" appears to be at most only a minor theme in the current literature.

Review of Articles Reporting Treatments Related to "VP"

Review of the literature identified four articles that assessed treatments related to potential therapeutic mechanisms of "VP." Three articles, including one case report, examined the effect of treatments on the progression of carotid artery plaques. One randomized controlled trial examined the effectiveness of antibiotics for the prevention of a secondary event for the patients who had MI. There were no primary prevention studies for CAD.

Thies (2003) studied the effect of fish oil on 53 subjects in a 3-arm randomized controlled trial. All 162 patients were scheduled for carotid endarterectomy and the morphology of the excised plaques was evaluated. Fewer plaques from patients who took fish oil (long chain omega-3 fatty acids) had a thin fibrous cap and signs of inflammation compared with the controls.

Another study examined five hypercholesterolemic subjects with carotid artery plaques verified by ultrasound. After a 1-year intervention of cerivastatin, their plaque stability index (percentage of total plaque lesion on echogram as a high intensity region) improved significantly (Kurata 2001).

A case report of a hyperlipidemic, hyperhomocysteinemic, 78 year- old male showed a regression of the carotid plaque area following the use of folate, pyridoxine, and cyanocobalamin. Ultrasound was employed to evaluate the stability of the carotid plaque (Spence 2002).

The recently completed WIZARD trial (Weekly Intervention with Zithromax (azithromycin) for Atherosclerosis and its Related Disorders) tested the hypothesis that chronic infection may contribute to the pathogenesis of atherosclerosis. Thus, the elimination of chronic infection with an antibiotic will lead to reduced systemic inflammation and lower the risk of future ACS events. Survivors of AMI were treated with an antibiotic, azithromycin, for 11 weeks and followed for approximately 3 years. Among stable patients with previous MI and with evidence of C-pneumoniae exposure, azithromycin did not significantly reduce the clinical sequelae of CAD (O'Connor 2003).

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