TREATMENT OF HYPERTENSION

The ability to find vulnerable plaques will make it possible to test the hypothesis that vulnerable patients require lower blood pressure, e.g., 120/70 mm Hg. As noted earlier, ACE inhibitors not only reduce blood pressure, stroke risk, and mortality in congestive heart failure, but also reduce the risk of reinfarction and of progressive atherosclerosis. Several mechanisms may contribute, including the anti-inflammatory action of ACE inhibitors. Related and equally promising drugs are the angiotensin receptor blockers, which have the putative benefits of blocking angiotensin-II formed by the action of tissue chymases and of increasing the stimulation of the type 2 receptor of angiotensin-II.207,208 However, limited clinical information, to date, suggests that the benefits are similar to those of ACE inhibitors, albeit with a lower incidence of angioneurotic edema and cough.209 β-adrenergic blockade reduces blood pressure, cardiac contractility, increases diastolic filling time, and decreases vulnerability to arrhythmias. It also reduces the risks of reinfarction and of mortality in congestive heart failure. The mechanism(s) by which beta-blockers reduce the risk of infarction are not clear, but may simply relate to the reduced number of heart beats and the reduced rate of pressure rise in the coronary arteries. The recently released Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) suggested that the benefits of diuretics are essentially equal to that of ACE inhibitors and beta-blockers, but the caveat is that most ALLHAT patients did not have coronary atherosclerosis.

Thus, the multiple demonstrated benefits of ACE inhibitors and beta-blockers in patients with known coronary disease should not be ignored. Inhibition of Neovascularization Inhibition of neovascularization is another potential method for stabilizing plaques and reducing plaque growth. Folkman’s lab 212 used recombinant murine angiogenesis inhibitors (endostatin and TNP-470) in apolipoprotein E–deficient (apoE−/−) mice and showed that these drugs significantly reduce plaque progression (by 85% and 70%, respectively) without affecting cholesterol levels.

Local and Regional Therapies Stenting, clopidogrel, and GPIIb/IIIa inhibitors reduce the incidence of acute complications with angioplasty. New drug-eluting stents, in particular, have been shown to markedly reduce restenosis rates. Together with the recent recognition that percutaneous coronary intervention (PCI) serves mainly to reduce angina and increase walking distance some 20% to 30%, whereas most MIs and coronary deaths are precipitated by thrombosis of a plaque less than 50% diameter stenosis (DS), and that most patients with MI have a second or even a third vulnerable lesion, interventional cardiologists are now planning trials of stenting for hot plaques. Despite their cost, drug-eluting stents are particularly attractive for treatment of vulnerable plaques because macrophage content has repeatedly been shown to predispose to restenosis.214 Moreover, Stefanadis . 100 found that warmer lesions post–percutaneous transluminal coronary angioplasty (PTCA) had a higher rate of subsequent events. Interventionalists have also noted that plaque vulnerability could help decide whether to intervene on a 50% to 70% DS lesion, or influence stent selection. For example, if a 20% stenosis that is 10 mm downstream of the ischemia-causing culprit is hot or otherwise vulnerable, the interventionalist may select a stent that is long enough to treat both lesions.

Balloon Angioplasty with Drug-Eluting Stents Balloon angioplasty has been used in humans since 1977, and the advent of coronary stenting in 1986 led to a marked reduction in the postangioplasty restenosis rate. Further improvement has been achieved with stents coated with antiproliferative drugs (such as sirolimus and paclitaxel), which can potentially abolish in-stent restenosis. The concept of local drug delivery via coated stents offers both the biologic and the mechanical means of preventing such restenosis. Several drugs are being used for this purpose. Paclitaxel- and sirolimus-eluting stents have been studied extensively with major success in minimizing the risk of in-stent restenosis.

Newer stent designs and new molecatheroscl erotic vulner abl e plaque s 633 ular and cellular stents including those covered with stem cells are under development and may confer major improvements in the field. The potential benefit of stenting hemodynamically nonsignificant but vulnerable (e.g., hot, remodeled) plaques remains to be investigated in randomized clinical trials. Several drugs with different mechanisms of action (antiproliferative, anticoagulant, antiinflammatory, gene transferring, etc.) are being investigated for use in these stents. Better characterization and classification of each lesion with new detection techniques will help investigators decide which coated stent is best suited for treating a specific lesion. Use of antiproliferative drugs in oral form after stent implantation is another promising therapy for preventing restenosis. Farb and ,coworkers223 used oral everolimus (amacrolide of the same family as sirolimus) to inhibit in-stent neointimal growth in the iliac arteries of rabbits. This drug reduced in-stent neointimal growth significantly (42% to 46%). The safety and efficacy of such treatment in humans.