The central role of the unstable plaque and disturbed endothelial function in acute coronary syndromes is described in Chapters 6 and 17 . This chapter briefly reviews these mechanisms and the potential for reversing them in patients with acute coronary syndromes. Several therapies proven to be beneficial in improving outcomes in acute coronary syndromes may act by acute stabilization of the unstable plaque and reversal of endothelial dysfunction and likely future therapies are discussed.
The Concept of Plaque Passivation
The pathophysiologic processes that contribute to instability of the coronary atherosclerotic plaque are now well described, , and there has been considerable progress in understanding the causes of inflammation and its consequences. A vulnerable plaque is characterized by an increased lipid pool, an increased macrophage, foam cell and T-lymphocyte content, and reduced collagen and smooth muscle cell population. , This can lead to rupture or erosion at the margins or shoulder region of the plaque where the overlying fibrous cap is thinnest and infiltrated by macrophages and exposed to the greatest shear stress. , Current practice employs aggressive antithrombotic strategies to stabilize the patient with an acute coronary syndrome by targeting platelet adhesion, aggregation, and thrombosis in the coronary arteries. In contrast to the relatively advanced state of antithrombotic therapies, there is at present a paucity of validated diagnostic tools to identify the unstable plaque and only a few clearly identified therapeutic targets for preventing plaque rupture and enhancing plaque stabilization (see Chapter 18 ). Nevertheless, there is a huge potential to improve clinical outcomes in acute coronary syndromes if the balance of the complex processes within the unstable plaque can be tipped toward endothelial stabilization and passivation of the unstable plaque.
Multiple factors determine the balance between instability and stability of the atherosclerotic plaque and define the potential therapeutic targets. The factors affecting the balance between stability and instability of the plaque are summarized in Box 26-1 .
BOX 26-1
Thickness of the overlying fibrous cap
Synthetic role of vascular smooth muscle cells
Extent of the inflammatory process
Size of the lipid pool
Matrix degeneration by metalloproteinases
These include the thickness of the overlying fibrous cap, the function of the vascular smooth muscle cells, the extent of the inflammatory process, the size of the lipid pool, and matrix degeneration by metalloproteinases.
Thickness of the Overlying Fibrous Cap
Histopathologic observations confirm that a thin overlying cap is a typical feature of the unstable plaque, leading to rupture and erosion. Both rupture and erosion are important and shear stresses may mechanically damage the endothelium without rupture occurring. Therefore, plaque will be strengthened by deposition of collagen in the fibrous cap, and vice versa. Controlling this process in the unstable plaque without encouraging adverse vascular remodeling and without affecting matrix synthesis in other tissues and organs is a significant challenge.
Function of Vascular Smooth Muscle Cells
Smooth muscle cells have the capacity to modulate their phenotype from normal contractile cells to a synthetic phenotype capable of proliferation and enhanced matrix synthesis. Transition to the synthetic phenotype of smooth muscle cells is associated with an increase in collagen secretion, a key process in enhancing plaque stabilization. In contrast, the unstable atherosclerotic plaque is typically characterized by reduced numbers of vascular smooth muscle cells and reduced collagen content, and an increase in the rate of smooth muscle cell apoptosis. The rate of apoptosis is a major determinant of the numbers of vascular smooth muscle cells in the atherosclerotic plaque and is governed by complex cell, cell matrix, and cell cytokine interactions. There is evidence of increased apoptosis of vascular smooth muscles in the atherosclerotic plaque of unstable angina patients compared with stable angina patients, and apoptosis has been detected in the shoulder region of plaques at the sites that appear most likely to rupture. The expression of nitric oxide (NO), enhanced by cytokines such as interleukin-1 beta, interferon gamma, and tumor necrosis factor involved in the inflammatory process and acting via the production of peroxynitrite in combination with superoxide radicals, is a key determinant of the rate of smooth muscle cell apoptosis. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) may have a role modulating the apoptotic processes that lead to plaque instability by stimulating macrophage apoptosis and encouraging the ingrowth of vascular smooth muscle. TRAIL levels are reduced in acute coronary syndromes and human recombinant TRAIL has been shown to ameliorate atherosclerosis in mice.
Extent of the Inflammatory Process
Atherosclerosis has been recognized as an inflammatory process, and unstable plaques in particular are characterized by a dense inflammatory cell infiltrate. Atherectomy specimens from patients with acute coronary syndromes show an increased frequency of macrophages and T lymphocytes compared with atherectomy specimens of patients with refractory unstable angina. Control of the inflammatory cell infiltrate into an unstable atherosclerotic plaque by modulation of cell adhesion molecules and migration factors is a potential approach to stabilizing the unstable plaque.
Size of the Lipid Pool
In addition to the thickness of the overlying cap and the degree of cellular infiltration, the degree of stability of the plaque is determined by the size of the lipid pool. Davies and coworkers established that the critical threshold of vulnerability to rupture was a 50% volume of extracellular lipids. Computer modeling of plaques has identified the circumferential tensile strength on the fibrous cap as the most important mechanical stress factor involved in plaque rupture. , Therefore, any intervention that can reduce the size of the lipid pool is likely to stabilize the plaque.
Matrix Degeneration by Metalloproteinases
Matrix degradation leading to plaque rupture appears to be primarily due to the action of matrix metalloproteinases (MMPs). MMPs expression by vascular smooth muscle cells and macrophages is increased in human atherosclerotic plaques. The activity of MMPs is inhibited by naturally occurring tissue inhibitors of metalloproteinases (TIMPs). Exogenously administered TIMPs are readily metabolized and denatured.
Role of Endothelium and Endothelial Dysfunction
The vascular endothelium is the most widely distributed but largest “organ” in the body equivalent in area to a football field and in mass to five normal-sized hearts. Endothelial cells line the cardiovascular system and provide an interface between blood and tissues linked by tight junctions allowing intercellular communication and exchange of solutes and ions. In addition, the endothelium has complex functions, which modulate smooth muscle tone, mediate hemostasis, cellular proliferation, and inflammatory and immune mechanisms in the vessel wall. Furchgott’s seminal observations established that normal vasoregulation requires the presence of the endothelium. The modulation of vascular tone is dependent on relaxing and contracting factors derived from the endothelium. These are summarized in Box 26-2 .
BOX 26-2 Endothelium-Dependent Vasodilation
This is dependent on at least three endothelium-derived vasodilators, each of which represents a potential therapeutic target. The first is the potent endothelium-derived vasoactive substance prostacyclin (PGI 2 ) , discovered in the late 1970s. A more labile, diffusible substance which mediated endothelium-dependent vasorelaxation, was discovered in the 1980s, referred to initially as endothelium-derived relaxation factor (EDRF) , is now well established as nitric oxide. , Nitric oxide is synthesized from its precursor, l -arginine, with the enzyme nitric oxide synthase. There are three isoforms of nitric oxide synthase, neuronal n-NOS, inducible i-NOS, and endothelial e-NOS, of which e-NOS is expressed ubiquitously in endothelial cells, and differing genotypes offer some potential for gene therapy. The activity of nitric oxide is dependent on an intracellular rise in calcium which is signaled through stimulation with neurotransmitters such as acetylcholine or substance P, circulating hormones such as bradykinin, or shear stress. A third vasodilating factor referred to as endothelium-derived hyperpolarizing factor (EDHF), which leads to hyperpolarization of smooth muscle cells via activation of potassium channels, has been identified.
Endothelium-Dependent Vasoconstriction
Vasoconstriction is mediated by two directly acting endothelium-derived contracting factors, the eicosanoid family, predominantly thromboxane A 2 , and the endothelins. The endothelin most active in the vasculature is endothelin-1, stimulated by numerous endogenous agents including interleukin-1, transforming growth factor beta, shear stress, and hypoxia. Vasoconstriction is also enhanced by the final stage of production of angiotensin II by the angiotensin-converting enzyme at the luminal surface of endothelial cells.
In addition to its role in vasoregulation, the endothelium secretes a range of prothrombotic and antithrombotic factors including tissue plasminogen activator (TPA) and plasminogen activator inhibitor (PAI1). The endothelium helps prevent spontaneous platelet aggregation adhesion by production of prostacyclin and nitric oxide.
The endothelium contains important mechanoreceptors that sense changes in shear stress and hydrostatic pressure; flow-induced vessel dilatation requires an intact functional endothelium and is the basis of the widely used flow-mediated dilatation test of endothelial function.
The concept of endothelial dysfunction has been intensively studied. Endothelial cells are activated by the inflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor-α, and interferon-γ. Activated endothelial cells express leukocyte adhesion molecules and produce tissue factor, creating a procoagulant environment. Endothelial cell injury results in a dysfunctional endothelium, which can no longer maintain a thromboresistant state and promotes vasoconstriction by diminished production of nitric oxide and synthesis of endothelin-1. The production of reactive oxygen species as a consequence of endothelial injury potentiates endothelial dysfunction by depleting available NO and reacting to form peroxynitrite, which causes further oxidative injury to the endothelium. The production of lipid peroxides further depletes NO. Oxidized low-density lipoprotein (LDL) acts as chemoattractant for macrophages, which in turn promote the expression of adhesion molecules on the endothelial surface. Reversal of endothelial dysfunction is an important future target of therapy in patients with acute coronary syndromes (ACS), while some of the interventions currently used for ACS achieve their benefit by reversing endothelial dysfunction. These are discussed later.
Therapies Directed to Plaque Stabilization and Correction of Endothelial Dysfunction
Reduction of Low-Density Lipoproteins (LDL)—Hydroxy-methylglutaryl Coenzyme A Reductase Inhibitors (Statins)
Statins have been demonstrated to influence a number of other mechanisms independent of their lipid-lowering effects that are thought to be potentially important in the treatment of acute coronary syndromes. Animal studies have revealed potential roles for statins in plaque stabilization, by increase in collagen content of the unstable plaque, reduced macrophage activation and expression of matrix metalloproteinases, and modulation of immune function. Reductions in plasma fibrinogen and thrombogenic factors have been demonstrated in hypercholesterolemic patients. , A tendency for enhanced platelet thrombus formation in subjects with hypercholesterolemia can be reversed with only 2.4 months of treatment with pravastatin. Early improvements in endothelial-dependent vasodilation have been demonstrated in hypercholesterolemic patients, and these benefits have been confirmed within 6 weeks of commencing statin therapy in patients who are recovering from an acute coronary syndrome.
Clinical trials in patients stabilized after a coronary event have demonstrated beyond doubt that treatment with statins reduces the risk of future cardiovascular events and reduces mortality in patients with cardiovascular disease. While it would seem logical to initiate secondary preventive treatment as soon as possible after the acute event, the “evidence gap” to judge whether there is truly an early effect of statins in acute coronary syndromes has recently narrowed.
Small-scale clinical trials showed that statins started 2 to 10 days after acute myocardial infarction (AMI) or unstable angina pectoris (UAP) were well tolerated and associated with reductions in total and LDL cholesterol and improvements in endothelial function. , These early studies did not assess long-term outcomes.
Retrospective analyses of databases suggested a beneficial short-term effect of statin therapy prior to or immediately following admission to hospital with AMI. Despite the use of sophisticated matching techniques for assessing the propensity for being prescribed lipid-lowering therapy in these observational studies, the possibility of bias in the decision to treat could not be excluded, and the effect of statins could not be separated from the effect of other lipid-lowering therapies. Randomized trial data to fully assess the impact of early statin therapy has recently become available.
The randomized clinical trials of early commencement of statins after a coronary event and the meta-analyses of these trials are summarized in Table 26-1 .
| Trial | Time of Commencement | N | Drugs | Patients |
|---|---|---|---|---|
| MIRACL | 24-96 hours | 3086 |
| NSTEMI |
| PACT | <24 hours | 3408 | Pravastatin 20-40 mg vs. placebo | STEMI and NSTEMI |
| A to Z | <5 days, mean 3.7 days | 4497 | Tirofiban then simvastatin 40 mg vs. placebo | NSTEMI |
| PROVE-IT | <10 days median 7 days | 4162 | Pravastatin 40 mg vs. atorvastatin 80 mg | NSTEMI |
| FLORIDA | Median 8 days | 540 | Fluvastatin 80 mg vs. placebo | AMI |
The MIRACL study was the first large-scale clinical trial completed to investigate whether early treatment with a statin in patients with UAP or a non–Q-wave AMI is beneficial. MIRACL enrolled 3086 patients with UAP or non–Q-wave acute MI within 24 to 96 hours of hospital admission for randomization to atorvastatin 80 mg per day or placebo. The primary efficacy parameter was time at the first occurrence of death, resuscitated cardiac arrest, non-fatal MI, or angina pectoris with evidence of myocardial ischemia requiring re-hospitalization. The relative risk (RR) of the primary efficacy measure was 0.84 ( P = .048, 95% confidence interval [CI], 0.701-0.999), and for re-hospitalization for UAP (a component of the primary efficacy measure) was 0.74 ( P = .02, 95% CI, 0.57-0.95). There was no effect on death, non-fatal myocardial infarction, or resuscitated cardiac arrest. An unexpected halving of the stroke rate from 1.6 to 0.8 ( P = .05, 95% CI, 0.026-0.99) was observed. The primary efficacy measure in the MIRACL trial only just achieved its statistical significance, and the results were not definitive evidence of an early benefit for statins in the modern treatment of acute coronary syndromes.
The PROVE-IT trial compared the effect of a moderate statin regimen of pravastatin 40 mg with aggressive regimen of atorvastatin 80 mg, in 4162 patients who had been hospitalized for an ACS within the preceding 10 days. The trial showed a significant benefit of the more aggressive statin regimen with a 16% reduction in the hazard ratio (HR) in favor of atorvastatin ( P = .005, 95% CI, 5%-26%).
The A to Z study studied the effect of statin therapy (simvastatin) in stabilizing the postcoronary course in patients who had received a glycoprotein (GP) IIb/IIIa inhibitor (tirofiban) in the early treatment of their ACS. The trial compared 2265 ACS patients who received 40 mg/day of simvastatin for 1 month followed by 80 mg/day thereafter with 2232 patients receiving placebo for 4 months followed by 20 mg/day of simvastatin. There was not a statistically significant difference in the composite primary end point of cardiovascular death, nonfatal myocardial infarction, readmission for ACS, and stroke during the first 4 months between the groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P = .89), but from 4 months through the end of the study the primary end point was significantly reduced in the higher dose simvastatin group (HR, 0.75; 95% CI, 0.60-0.95; P = .02). The results of this trial were confounded by a relatively high incidence of myopathy in patients receiving simvastatin 80 mg/day, compared with patients receiving lower doses of simvastatin ( P = .02).
Two studies have commenced the statin within 24 hours of onset of an acute coronary syndrome. The FLORIDA trial compared very early fluvastatin 80 mg daily with placebo. In 545 patients, the statin did not affect ischemia on ambulatory electrocardiography (AECG), nor the occurrence of any major clinical events as compared to placebo, but the trial was underpowered because the prevalence of unstable ischemia was low. The PACT trial initiated statin therapy even earlier, within 24 hours after the onset of the acute coronary syndrome, and its primary end point was the frequency of events within the first month. The trial was stopped before the anticipated 10,000 patients were enrolled, but a total of 3408 patients were randomly assigned to treatment with pravastatin or matching placebo. Treatment was continued for 4 weeks; a relative risk reduction of 6.4% favored allocation to pravastatin but was not statistically significant (95% CI, 13.2%-27.6%).
The timing of commencement of therapy in the published trials of statins after acute coronary syndromes is summarized in Figure 26-1 .
Meta-analysis of the trials of early statins in acute coronary syndromes did not show any benefit on early outcomes. Death, stroke, cardiovascular death, fatal or nonfatal myocardial infarction, or revascularization procedures were not reduced in the first 4 months ; however, there were effects on extended follow-up, which started to appear at 4 months and continued for at least 2 years. The dose of statin required to achieve benefit is high, as demonstrated in the PROVE-IT trial, which showed that the benefit of 80 mg atorvastatin was superior to 40 mg of pravastatin. A meta-analysis of safety data for high dose versus low dose statin has not shown any adverse effect. On the basis of these recent trials, the evidence that early initiation of statins is regarded as level A and in recent guidelines, initiation in hospital is recommended. In summary, there are valid reasons, including convenience and no evidence of an adverse effect, for initiating aggressive LDL-lowering therapy with a statin in hospital after an acute coronary syndrome.
Further evidence that statins may have a direct plaque-stabilizing effect independent of their lipid-lowering effects comes from studies that have shown improved outcomes with statin pre-loading , and re-loading immediately prior to percutaneous coronary intervention.
Raising High-Density Lipoprotein (HDL)
The possibility that the benefits of LDL reduction by statins could be potentiated by raising endogenous HDL levels or with HDL mimetics has been explored, but to date has not reached the point of clinical application. The ILLUMINATE trial of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib was aborted because of an increase in all-cause mortality, and this has stimulated debate on whether raising HDL will be beneficial in acute coronary syndromes, or whether the adverse effects in the ILLUMINATE trial were due to a molecule-specific effect on raising blood pressure. Several alternative methods of raising HDL are under investigation. A trial of infusion of APO A-1 Milano in acute coronary syndrome patients resulted in a significant reduction in atherosclerosis volume measured by intravascular ultrasound. A trial of recombinant HDL in acute coronary syndromes has been completed and showed no benefit on atherosclerosis volume. Further trials are underway in acute coronary syndromes with recombinant HDLs and HDL mimetics and alternative targets for raising HDL.
Angiotensin Converting Enzyme (ACE) Inhibitors
The presence of an important tissue renin-angiotensin system is now well recognized, and it is estimated that less than 10% of ACE is found circulating in the plasma. The central role of the system in the vascular wall is summarized in Figure 26-2 .
Angiotensin II can have a wide range of deleterious effects in the vascular wall, including vasoconstriction by stimulating the production of norepinephrine and enhancing the production of endothelin-1, which further facilitates the conversion of angiotensin I to angiotensin II. It also promotes the release of inflammatory cytokines, thrombotic factors, and metalloproteinases. The endothelial-based receptor that binds oxidized LDL (lectin-like Old receptor type 1, [LOX]) interacts with angiotensin II. Angiotensin II upregulates the receptor effects, which can be blocked with angiotensin receptor blockers and angiotensin converting enzyme inhibitors. ACE inhibitors can block these effects, shifting the balance in favor of vasodilatation, anti-inflammatory, and antiproliferative effects.
These effects have been demonstrated to be clinically significant. , Several clinical trials of ACE inhibitors have shown improvements in coronary endothelial dysfunction in patients with coronary artery disease. Quinapril 40 mg per day partly reversed the vasoconstricting effects of intra-coronary acetylcholine in patients with coronary artery disease ; however, the effects on atherosclerotic progression were less impressive.
The benefits of ACE inhibitors on improving ischemic outcomes has been the subject of detailed study in patients with stable coronary artery disease and those at high risk, but have not been tested directly in the setting of acute coronary syndromes. A benefit on ischemic events in chronically treated patients suggests mechanisms of benefit on coronary atherosclerosis independent of the well established benefits in hypertension and cardiac failure and left ventricular dysfunction. This was initially suspected in retrospective analyses of the cardiac failure and postinfarction trials, which showed effects consistent with a benefit on myocardial ischemia, in addition to the hypothesized effect on left ventricular dysfunction. Randomized trials of ACE inhibitors in patients with preserved left ventricular function have shown a reduction in the rates of mortality and vascular events in high-risk patients including many diabetics (HOPE trial) and in high-risk postinfarction patients (EUROPA trial). There was no benefit demonstrated in lower risk patients (PEACE trial). A subsequent meta-analysis of these three major trials supported benefit of ACE inhibition even in patients at low risk. There are no modern data in acute coronary syndromes, and extrapolations from stable patients may not be relevant. It is not yet clear if these benefits of ACE inhibitors on endothelial function will be mimicked by the angiotensin II receptor antagonists (AIIRAs, ARBs). A preliminary study with irbesartan suggests that it has effects on cytokines and adhesion molecules in patients with premature atherosclerosis, which may be of potential benefit in plaque passivation and restoration of endothelial dysfunction.
The CHARM Preserved study of inpatients with preserved left ventricular function showed no effect on mortality or on composite outcomes, which included nonfatal myocardial infarction and nonfatal stroke, and a large scale trial (ONTARGET) in stable patients with coronary heart disease showed no difference in effect between the ACE inhibitor ramipril and the angiotensin receptor blocker telmisartan. The use of ACE inhibitors during acute coronary syndromes and myocardial infarction is well supported by randomized clinical trials but the benefit is less dramatic in those without left ventricular dysfunction, and the current data does not necessarily support the routine use of ACE inhibitors in patients with acute coronary syndromes. Caution in the use of ACE inhibitors early in acute coronary syndromes is necessary and it should be recalled that the first trial of an ACE-I in acute myocardial infarction had an adverse effect due to hypotension.
Aspirin–Angiotensin Converting Enzyme (ACE) Inhibitor Interaction?
Several studies have suggested that patients taking aspirin concomitantly with ACE inhibitors will have a reduced effectiveness of the ACE inhibitor benefit because of the inhibition of prostaglandins by the aspirin. , However, there was no evidence of a clinically significant interaction potential in overviews of all the large postinfarction trials. , In view of this evidence in large scale trials, it seems unlikely that this interaction would be significant in the setting of combined aspirin and ACE inhibitor use in ACS. However, an analysis of the combination in patients in acute coronary reperfusion studies and trials of antiplatelet therapy in patients undergoing percutaneous coronary intervention have suggested an interaction. After adjusting for confounders, combined use of aspirin and ACE inhibitors was associated with increased mortality compared with aspirin alone. Despite the reassuring findings from the large trials in stable patients, the possibility of an interaction during the intensive therapy phase of an acute coronary syndrome cannot be discounted.
Immunomodulation for Plaque Stabilization
Directly targeting the inflammatory process in the unstable plaque is a logical approach, but not yet a proven therapeutic strategy.
The role of C-reactive protein (CRP) in provoking instability in atherosclerosis remains a hotly disputed area of research. CRP has been identified in the unstable plaque and can upregulate cytokine, cell adhesion molecule, and matrix metalloproteinase expression, all factors that are implicated in instability of the atherosclerotic plaque, and can also activate the CD40/CD40 ligand, an important link between atherosclerosis and thrombosis. Because of these observations, there has been keen interest in identifying inhibitors of CRP, which may have a role in stabilization of the unstable atherosclerotic plaque. There are many potential CRP inhibitors, but it is worth noting that the demonstration that circulating CRP levels are lowered by an intervention does not necessarily imply an inhibition of the molecular action of CRP nor does it necessarily imply benefits on atherosclerosis. CRP may simply be a marker that inflammation is present. For instance, rofecoxib lowers hs-CRP significantly, and was suggested as a possible candidate for trial of the atherosclerosis/inflammatory hypothesis only weeks before the worldwide withdrawal of rofecoxib because of adverse vascular effects. A molecule that directly targets CRP has been developed and recently reported. 1,6-Bis(phosphocholine)-hexane is a specific small-molecule inhibitor of CRP, which has been shown in rats undergoing acute myocardial infarction to abrogate the increase in infarct size and cardiac dysfunction produced by injection of human CRP. There are no data yet on effects on atherosclerosis, and its role in stabilizing the atherosclerotic plaque will depend on the outcome of the debate on whether CRP has a direct adverse effect on the vascular wall.
Specific inhibitors of cytokines involved in the inflammatory cascade “upstream” from CRP release from the liver are available for patients with inflammatory conditions such as rheumatoid arthritis.
Inhibitors of tumor necrosis factor (TNF-α), which have been shown to reduce inflammation are in clinical use in rheumatoid arthritis, but examination of their role in atherosclerotic vascular disease has been limited. The TNF-α inhibitor etanercept has shown a clear effect on CRP in metabolic syndrome but trials of the effect on modulating the inflammatory state in cardiac failure patients resulted in adverse effects and early termination of the trials. Furthermore, TNF-α inhibition has other non-vascular effects on inflammation, which may limit the suitability for use in atherosclerosis. A meta-analysis of the effect in 3493 patients with rheumatoid arthritis who received anti-TNF-α antibody treatment and 1512 patients who received placebo showed worrying increases in malignancy (odds ratio [OR] 3.3; 95% CI, 1.2-9.1) and serious infection (OR 2.0; 95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher doses. The role of selective inhibitors of IL-6 has been examined in inflammatory diseases , but to date, not in atherosclerosis. IL-1 is released early in the process of plaque instability and may be amenable to inhibition by a specific blocker, and a trial to test the effect on inflammatory markers in ACS is currently underway.
Since MMPs have been implicated in the process of plaque destabilization, TIMPs may have a future role. A specific inhibitor of MMP 9 has been shown to be ineffective in preventing adverse remodeling post myocardial infarction, but its role in plaque stabilization has not been evaluated. The role of CD40 ligand (also known as CD154) in contributing to plaque instability has been well studied. The CD40 pathway is a key signaling mechanism through which macrophages and vascular smooth muscle cells in atheroma can express matrix-degrading proteinases leading to plaque rupture.
Interruption of the CD40-CD40 ligand interaction raises the intriguing therapeutic possibility that interruption of CD40 signaling by a CD40 ligand antibody could result in plaque stabilization, , but clinical trials directed to this target have not yet been conducted.
Lipoprotein-associated phospholipase 2 (PL-PLA2) is produced primarily by macrophages and lymphocytes and is bound to LDL; it has been shown to be proinflammatory and atherogenic. A promising immunomodulating approach to plaque instability may be to inhibit LP-PLA2 by a selective inhibitor (darapladib). Darapladib has been shown to reduce LP-PLA2 and inflammatory markers and is currently being trialed to assess its effects on outcomes in ACS.
The antitubulin agent colchicine lowers hs-CRP in patients with stable coronary artery disease and has direct intracellular effects on the cells involved in atherosclerosis and may be a low cost, widely applicable method of lowering CRP without the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs). A trial to assess the effect on coronary artery disease is currently underway.
Even further upstream in the inflammatory cascade are the cell signaling transcription factors that trigger the release of proinflammatory cytokines and cell adhesion molecules. The most important of these is NFκB. Potential inhibitors of the NFκB pathways have been described, including a number of naturally occurring substances.
Plaque Stabilizing Potential of Interventions Used in Acute Coronary Syndromes (ACS)
Beta-Adrenergic Blockers
Beta-adrenergic blockers are widely used in acute coronary syndromes. While there is no evidence that the standard beta blockers exert their benefit on acute coronary syndromes through an effect on the unstable plaque or on endothelial function, a reduction in shear stress and flexion stress has been thought to be important. A third-generation beta blocker, nebivolol, was shown to have some effects on in vitro markers of endothelial function, but there is no firm data that this is of relevance to the management of the patient with an ACS. Of the more widely used beta adrenergic blockers, it has been shown that atenolol has no effect on endothelial-dependent forearm blood flow in hypertensive patients when compared to an ACE inhibitor, nor was any effect on endothelial-dependent coronary vasomotion shown in patients with coronary disease.
Calcium Channel Blockers
There is still uncertainty as to whether calcium channel blockers are effective or otherwise in acute coronary syndromes , and they are recommended only for symptom relief rather than for improving prognosis. There is no convincing evidence that any of the effects observed in clinical trials are due to an effect on plaque passivation or on endothelial dysfunction although the results with third-generation calcium channel blockers suggest a possible role.
Organic Nitrates
Organic nitrates are commonly used in acute coronary syndromes. Their action is similar to those of nitric oxide, causing vasodilatation via an increase in intracellular concentrations of cyclic guanosine monophosphate, resulting in smooth muscle cell relaxation and antiplatelet effects. Exogenously administered nitrates can act in the presence of a damaged endothelium. The effects of nitrates have been studied in acute myocardial infarction, but no convincing benefits have been shown in patients with unstable angina or non–ST-segment elevation.
Antioxidants
Since the production of reactive oxygen species (ROS) in the vascular wall has several deleterious effects, the potential for potent antioxidant therapies could be considered as a plaque-stabilizing strategy. A large number of epidemiologic observational studies have shown an association between atherosclerotic disease and low levels of antioxidant vitamins, but well-conducted studies have failed to show a clear benefit. To date, there are no studies of the effect of antioxidant therapy administered in the early phases of acute coronary syndromes.
Estrogens
The effects of estrogens on the vascular wall are mediated by nongenomic and genomic mechanisms and any of these effects are potentially beneficial. , Despite that, there is clear evidence that estrogen therapy is unhelpful in the post coronary patient. Obviously, further research is required to explain the discrepancy between the apparently beneficial biological effects of estrogen on the vascular wall and the adverse effects in clinical trials, and whether alternative methods of utilizing the effects of estrogen on the vascular wall will deliver better clinical outcomes in acute coronary syndromes.
Blood Sugar Control
Disturbed endothelial function is well documented in diabetes. The mechanisms by which diabetes affects endothelial function is not well understood, but advanced glycation end products, glycated and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been implicated. Intensive blood glucose control with sulfonylureas or insulin is associated with a reduction in microvascular, though not macrovascular, complications in type 2 diabetes, and intensive control with metformin in overweight patients with type 2 diabetes is associated with reduced vascular endpoints. The mechanism of this improvement over a 20-year follow-up period is not clear, but improved metabolic control in diabetic patients, whatever the treatment used, is associated with reversal of endothelial dysfunction. The thiazolidinediones may exert specific effects on endothelial function by their ability to bind to peroxisome proliferator-activated receptors, which have been shown to be present in the vessel wall ; however, the safety of thiazolidinediones (glitazones) remains to be established.
Smoking Cessation
There is some evidence that the deleterious effects of smoking are mediated by an effect on endothelial dysfunction. This may also occur with passive smoking. The effects in acute coronary syndromes have not been documented for obvious reasons, but the available data support the universal clinical recommendation that a patient with an acute coronary syndrome should immediately and permanently desist from smoking.
Dietary Intervention
There is evidence that dyslipidemia is associated with disturbed endothelial function. High fat meals accompanied by postprandial rise in serum triglycerides can impair endothelial function within hours. These effects were minimized when the high-fat meal contained antioxidant-rich foods. Animal experiments have shown that hypercholesterolemic rabbits fed a low-fat diet show a reduction in cellular infiltrate and MMP activity and an increase in collagen accumulation in the fibrous cap compared with animals fed a high-fat diet. This demonstrates a likely mechanism by which a low-fat diet can contribute to plaque stabilization in ACS. It has been hypothesized that the postprandial state can precipitate unstable coronary syndromes because of effects on the vascular wall leading to plaque instability.
Inhibition of Neovascularization
Since the unstable atherosclerotic plaque is characterized by infiltration of vasa vasorum with the potential for rupture and leakage of inflammatory cells, the possibility of limiting neo-vascularization has been investigated.
The Role of Percutaneous Coronary Intervention (PCI) in Plaque Passivation
The use of PCI in acute coronary syndromes is widespread, and the convincing results of recent trials of acute coronary intervention in acute coronary syndromes confirm the validity of this approach. Until now, the target lesion for PCI in ACS patients has been the critical lesion, which is assumed to be the cause of the acute reduction in coronary blood flow. It is not clear if the benefits of coronary stenting in ACS are achieved by plaque stabilization or by other mechanisms. The use of PCI with drug eluting stents to treat plaques that are unstable but not critically obstructing the vessel is a potential future strategy for management of the patient with an ACS. There is no clinical trial data to support this approach, although serial angioscopic study shows that stenting can seal the unstable plaque by encouraging neointimal proliferation.
Cyclooxygenase-2 (COX-2) Inhibitors and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Acute Coronary Syndromes
Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors have potent anti-inflammatory effects and reduce hs-CRP and have even been suggested as potential candidates for stabilization of the unstable plaque. However, reports that patients on COX-2 inhibitors have a higher risk of acute vascular thrombotic events has led to the withdrawal of rofecoxib and caution in the use of celecoxib. There is evidence that the adverse effects of the COX-2 inhibitors may be due to an effect on endothelial function and enhancement of thrombosis by inhibiting the production of prostacyclin. Recent reports indicate that the risks may be as high with all NSAIDs. , Until more observations become available, limited use of COX-2 inhibitors and NSAIDs in ACS is a sensible precaution.
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