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CARDIOLOGY CASEBOOK |
Atherosclerosis leads to hardening, weakening, or occlusion of the arteries. The fundamental lesion is the atheroma (Greek: gruel, athere, meal, tumor). Atheroma is a discrete plaque containing lipid deposits that arises in the intima of an artery and has a predilection for areas of tortuosity and turbulence of blood flow. The aorta, the most frequently affected, is followed by the coronary, cerebral, and peripheral lower extremity arteries.
Atherosclerosis and its complications are the leading cause of death in North America and Western Europe.1 The mortality rates of men 55 to 59 years of age have been 3 times greater than the mortality rate in the general population. Statin therapy and surgical intervention have favorably influenced these statistics. The evidence of atherosclerotic disease, generally absent or rare before puberty, increases with age and becomes moderate to high in patients reaching age 70. Mortality rates of coronary heart disease show that men are more prone to the disease than are women. Atheromatosis begins early in men, as was shown by the high degree (40%) of atherosclerotic involvement of the coronary arteries in American soldiers 20 to 30 years old who were killed in the Korean War.2 Atherosclerosis is a disease of multiple causes; a variety of factors from both the host and his (or her) environment contribute to the production of the vascular lesion and the vascular complications. Diabetes mellitus, hereditary hyperlipidemia, and hypertension greatly increase the probability of coronary atherosclerosis in both men and women.
The benefits of the statin drugs in the management of hyperlipidemia and its clinical consequences have been just short of miraculous. Their reported pleiotropic effects may have pushed the envelope of drug benefits beyond belief. In order to help understand statin pleiotropy, leading questions are presented with discussion of the answers.
QUESTIONS
ANSWERS
1. b. the effects of statin therapy other than those due to lowering LDL levels
d. second answer here
The advances made in the management of hyper-cholesterolemia were primarily due to the lipid-lowering effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as the "statins." Statin is the generic suffix universally used to classify the HMG-CoA reductase inhibitors. The prefix is specific for and identifies the pharmaceutical company that developed and distributes the drug: eg, lovastatin, atorvastatin, pravastatin, simvastatin, fluvastatin, rosuvastatin. The use of statins in long prospective clinical trials has provided unequivocal evidence that cholesterol-lowering therapy reduces major coronary events in primary and secondary prevention, and it reduces all-cause mortality in secondary prevention. In addition, a number of studies have reported on the beneficial effects of statins that were unrelated to those due to LDL lowering; these are referred to as the pleiotropic effects of statins. Pleiotropy (Greek: "pleio" or many, and "tropos" manner), a term used to indicate diverse properties, is used to describe the clinical benefits of statin therapy that extend beyond lipid modification and are independent of reduction in levels of LDL cholesterol.3 Pleiotropic effects are reported as directly benefiting coronary and cerebrovascular tissue, bone, kidney, and glucose metabolism (reduces progression of nephropathy and development of type II diabetes); decreasing the incidence of dementia, Alzheimer’s disease (AD), allograft rejection; and reducing fracture risk and the incidence of osteoporosis.4
The distinction between the clinical benefits of lowering levels of LDL cholesterol and the pleiotropic effects of statin therapy may actually not be dissociated (as reported in current literature) because the effects of hyperlipidemia and of statin therapy on small arteries and arterioles have not been reported. Should investigations reveal that the pathological changes due to hyperlipidemia that are observed in the coronary arteries also occur in the small arteries and arterioles, then it follows that the improvements in the wide diversity of diseases and pathological states attributed to statin therapy would not necessarily be effects of pleiotropy, but rather a result of the beneficial lipid-lowering effects of statins on diseased hyperlipidemic arterioles. Studies of arterioles in hyperlipidemic states before and after statin therapy could help determine if "pleiotropy" is appropriate terminology when it can be shown that atheromatous changes also occur in the very small arteries and arterioles and will improve with statin therapy. The importance of knowing the pathology of the arterioles in hyperlipidemic states are patently evident because the pleiotropic effects of statins are attributed to diseases that result from small vessel pathology.
2. n. all of the above
a. reduction in osteoporosis and risks of fractures
Osteoporosis is endemic and is associated with an increase in low trauma fractures of the vertebral spine, femur, and distal radius, especially in elderly white and Asian women. Risk factors for osteoporosis include the postmenopausal state, family history of hip fracture, smoking, inadequate calcium and vitamin D intake, sedentary lifestyle. Osteoporosis and atherosclerosis share the tendency to accelerate after menopause; both are promoted by inflammatory processes.3 Pharmacological agents used in the treatment of osteoporosis inhibit bone resorption (the nitrogen-containing bisphosphonates exert a cytotoxic effect on osteoclasts). Statins may lessen osteoporosis by preventing bone resorption and stimulating bone formation and production. In animals, statins increased the number of osteoblasts and new bone formation.4 Clinical studies showed that patients with osteoporosis who were being treated with statins had a 20% lower risk of fracture.5 Several studies have shown that statins increase the bone mineral density of the spine and hip. However, there is still insufficient evidence to justify the use of only statins for the prevention or treatment of osteoporosis instead of established therapy. The combined use of conventional therapy and statins would be acceptable.
b. reduced incidence of dementia Dementia, including AD, is a complex and overlapping pathological condition and is characterized by persistent and usually progressive impairment of multiple cognitive functions. The progressive decline in cognitive function observed with dementia may arise from several pathologies. However, vascular disease and multi-infarct dementia may mimic AD. As a result, one of the most widely discussed emerging roles for statin therapy is the prevention and treatment of dementia and AD. The reduced risk of AD with statin therapy may reflect a reduction in embolic and ischemic stroke, as well as direct effects on the AD process. AD has been associated with an inflammatory response to neuronal injury, raising the possibility that anti-inflammatory drugs may have a role in its therapy. AD is said to result from the effects of accumulated peptide amyloid B, which causes neurotoxicity and neurodegeneration. Clinical studies suggest a relationship between amyloid B and cholesterol levels. When the plasma cholesterol level is high, an increase in sterol turnover in the brain may increase the rate of amyloid B production and apolipoprotein levels to promote the formation of neuritic plaques that are characteristic of AD. In animal studies, statins reduce the levels of 2 precursor peptides necessary for amyloid B processing. The relationship between cholesterol and amyloid B suggests that statins may reduce the development of AD by a lipid-lowering mechanism.5 Another study revealed that patients with hyperlipidemia treated with statins had a lower relative risk for dementia. Statin therapy has reduced the risk of dementia in patients older than 50 who did not have elevated lipid levels.5 A cross-sectional analysis from a group of 56000 revealed a 60% to 73% lower incidence of confirmed or probable AD in patients treated with statins.5 Statins may also affect the development of dementia by modulating endothelial function and inflammation.
c. improved psychological well-being Chronic statin therapy in patients with coronary artery disease was associated with improved psychological well-being.6 A cumulative reduction was seen in the levels of depression, anxiety, and hostility after a prolonged period of statin use. These findings were independent of the serum cholesterol level at baseline and of the degree of serum cholesterol reduction at follow-up.
d. regression of tumor cells Observations have been made on the influence of statins on cancer growth and an antineoplastic potential of statins in cancer patients has been reported. The influence of statin therapy on cellular proliferation and tumor reduction is currently under study.7
e. improved endothelial function The vascular endothelium serves as an important autocrine and paracrine organ that regulates the contractile state and cellular composition of the vascular wall. Risk factors such as dyslipidemia, cigarette smoking, diabetes, hypertension, and physical inactivity initiate and potentiate endothelial dysfunction. Evidence suggests that elevations in total cholesterol and LDL levels adversely affect endothelial function, especially endothelium-dependent vasodilatation.
Dysfunctional endothelium impairs the synthesis, release, and control of endothelial-derived nitric oxide (NO). In addition to mediating vascular relaxation, endothelial NO inhibits several components of the atherogenic process, such as platelet aggregation, vascular smooth muscle proliferation, and endothelial-leukocyte interactions. An impaired endothelium allows a vascular environment that promotes atherogenesis through sustained vasoconstriction, inflammation, smooth muscle cell proliferation, and the breakdown of collagen. Reduction in NO levels is associated with increased production of the powerful vasoconstrictor, endothelin-1.
f. reduced incidence of type II diabetes Endothelial dysfunction is a hallmark of diabetes and insulin-resistant states and is characterized by reduced effective NO action. Hyperglycemic states trigger a cascade of events that lead to an increase in vascular tone. Statins improve endothelial function often before significant reductions in serum cholesterol levels are apparent.8,9 The exact mechanisms by which statins improve endothelial function are not completely clear, but what is known is that statins diminish the abnormal vascular relaxation, partially restoring NO production. In diabetic patients, statins not only increase endothelial cell NO production, but modulate the release and action of vasoconstrictors.4 A retrospective analysis of the East of Scotland Coronary Prevention Study (WOSCOPS) revealed that pravastatin therapy reduced the risk of developing diabetes by 30%.10 This prevention of diabetes was originally thought to be related to reductions in triglyceride levels. However, advances in understanding the cellular actions of statins link their effect to either changes in substrate delivery to insulin-sensitive tissues or to modulation of insulin-activated signals that mediate glucose uptake. Statins, like insulin, activate factors that are instrumental to glucose uptake and inhibit the cellular cascades that inactivate insulin receptors and signaling.4
g. reduction of allograft organ rejection Statins exert their beneficial effects on coronary artery disease by a host of pleiotropic effects that involve immunomodulation. In an early investigation, pravastatin not only reduced cardiac allograft rejection associated with hemodynamic compromise and coronary vasculopathy, but subsequently improved 1-year survival.11,12 Statins may act as modulators of allograft outcome; they can inhibit expression of monocyte tissue factor and reduce the hypercoagulability seen in transplant recipients. This immunomodulation may be protective against late allograft vasculopathy. Other reports suggest that statins (pravastatin) act synergistically with cyclosporine to reduce levels of cytotoxic T-lymphocytes and cytokine activation (simvastatin).11
h. reduction in blood pressure In a recent animal study, a new statin agent, rosuvastatin, was shown to exert beneficial cardiovascular effects in hypertensive mice. These effects included lowering of arterial pressure and peripheral vascular resistance, probably due to an improvement in endothelial function. These pleiotropic hemodynamic effects of rosuvastatin were independent of its lipid-lowering actions.13
i. reduce oxidation The intimal formation of foam cells from modified LDL-cholesterol is a key step in the development of mature atheromas. Statins provide an antioxidant effect that prevents LDL-cholesterol modification. The antioxidative properties of statins also prevent the development of cardiac and smooth muscle cell hypertrophy.
j. reduce thrombogenicity Acute thrombus formation at the site of plaque rupture or vascular injury is the cause of most acute coronary events. The potential of a specific atherosclerotic plaque to produce a thrombus is determined by the interactions between platelets, coagulation parameters, local coronary flow characteristics, inherent thrombogenicity of the plaque, and vessel wall composition.5 Platelets play a fundamental role in atherogenesis and in the pathophysiology of acute coronary syndromes. Hyper-cholesterolemia is associated with both hypercoagulability and enhanced platelet activation. High LDL levels increase platelet reactivity and thromboxane A2 (TXA2) levels. Several studies show that statins reduce TXA2 and platelet reactivity, as well as increasing the synthesis of prostacycline, the antagonist of TXA2. Different statins (lipophilic versus hydrophilic) demonstrate various effects on prothrombotic factors, such as tissue factor, platelet aggregation, blood and plasma viscosity, fibrinogen, plasminogen activator inhibitor, and lipoprotein(a).4 Statins normalize thrombin generation and reduce platelet aggregation in hypercholesterolemic patients.
k. reduce the rate of vascular events
Coronary Artery
A meta-analysis of cholesterol-lowering trials indicates that the risk of myocardial infarction in persons treated with statins was significantly lower than the risk in persons treated with other cholesterol-lowering agents or modalities. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, statins were effective in reducing recurrent ischemic events as early as 16 weeks after acute coronary ischemia.14
Cerebrovascular
Ischemic stroke, the third leading cause of death in the United States, is a major cause of long-term disability. Ischemic stroke may be caused by intracranial artery thrombosis or by embolism from the cardiac chambers or from disrupted plaques in the carotid artery or aorta. As with coronary atheromas, statins prevent cerebrovascular plaque rupture by decreasing vascular inflammation, enhancing plaque stability and endothelial function; these salutory statin effects occur with or without lipid lowering. Antiplatelet agents reduce the incidence of ischemic strokes, but do not affect the size of a cerebral infarct. Before the advent of statins, lowering cholesterol levels through diet, niacin, colestipol, or gemfibrozil did not reduce the incidence of stroke.3 In several large clinical trials, statin therapy reduced the risk of stroke and other ischemic events in patients with coronary artery disease. Statin induced a reversal of carotid intimalmedial thickening in patients who had no clinical coronary artery disease.5,15 The decreased incidence of ischemic stroke is due to a statin-induced up-regulation of endothelial NO expression. Statins have a few additional beneficial effects in ischemic stroke: (1) the reduction of oxidized LDL levels with statin therapy provides protection against ischemic stroke; and (2) an anti-inflammatory effect (40% decrease in macrophage/T-lymphocyte content) decreases immunoreactivity to oxidized LDL cholesterol on carotid artery intima, which could translate to a decrease in the incidence of carotid embolism.5
In the MIRACL trial, early treatment with statins in acute coronary syndromes dramatically reduced recurrent ischemic cardiac events. In a subgroup analysis, the early use of high doses of statins reduced the incidence of nonfatal stroke by 50%.3 When these findings were compared with those in patients in whom nonstatin, lipid-lowering therapy had been used and who had achieved comparable lipid levels, the results and benefits of statins on endothelial function and vascular structure were reported to be independent of any changes in serum levels of cholesterol.8 Animals pretreated with statins showed an increase in cerebral blood flow and a smaller infarct following cerebrovascular occlusion.9
Renal
Glomerular injury initiates several inflammatory cascades that involve cellular events similar to those seen in vascular tissue. Statins inhibit key events in this process and can alter the progression of renal disease.
l. improved ventricular function in HF
Short-term statin therapy improves cardiac function, neurohormonal imbalance, and symptoms associated with idiopathic dilated cardiomyopathy; all of these effects are unrelated to baseline cholesterol levels. A study of patients with class II and III HF (New York Heart Association) randomly assigned to statin or placebo therapy revealed that the statin-treated group had a 40% improvement in functional class and also an improved left ventricular ejection fraction of 34% to 41%. Similarly, plasma concentrations of tumor necrosis factor-
, interleukin-6, and brain natriuretic peptide were significantly lower in the statin-treated group.6
m. diminish vascular inflammation
Atherosclerosis is a complex inflammatory process that leads to thrombus formation, neointimal thickening, and angiogenesis. Vascular inflammation is characterized by the presence of monocytes or macrophages and T lymphocytes within the vessel wall. Inflammatory cells are pivotal to the progression of the athero-sclerotic lesion as they can alter endothelial function, smooth muscle cell proliferation, collagen degradation, and thrombosis. Markers of inflammation, such as high-sensitivity C-reactive protein (hs-CRP), interleukin-6, tumor necrosis factor- and others, have been proposed as risk factors for cardiovascular disease. Statins decrease CRP levels in 6 weeks of treatment independent of reduction in LDL cholesterol levels, supporting the anti-inflammatory action of statin therapy. hs-CRP is an acute-phase reactant that is produced by the liver in response to proinflammatory cytokines. Increased hs-CRP levels reflect low-grade systemic inflammation and when elevated in patients with atherosclerotic heart disease are predictive of increased risk of acute coronary events. Statins reduce the number of inflammatory cells and matrix metalloproteinase activity within the atherosclerotic plaque and lower hs-CRP levels (13–50%). These results were independent of their lipid-lowering effects.
SUMMARY
Accumulating evidence from clinical trials and basic research indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of LDL cholesterol levels and effects independent of the lowering of LDL cholesterol levels. The latter effects are referred to as pleiotropic. The full potential of this exciting class of drugs in vascular and nonvascular protection is only just being realized. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, and stabilize unstable plaques. Statins reduce glomerular injury, renal disease progression, insulin resistance, and bone resorption. Ezetimibe, a recently approved medication, enhances the lipid-lowering effects of the statins by lowering LDL and increasing HDL levels through its property of inhibiting absorption of cholesterol in the small intestine. These salutary effects of ezetimibe on statin levels presumably enhance the beneficial effects attributed to statin pleiotropy.
It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. No other therapeutic agent can claim equally stellar results in such a wide variety of diseases. The common denominator in all of the diseases that have been shown to improve with statin pleiotropy could be arteriolar pathology due to hyperlipidemia, which improves in response to statins by a return of arteriolar function to normal rather than through statin pleiotropy. Recent reports indicate that higher doses of statins reverse atheromatous changes in the coronary artery when the LDL cholesterol level is lowered to well below 2.59 mmol/L (100 mg/dL). These results lend additional support to the probability that similar pathological changes that may be present in the small arteries and arterioles also can respond to adequate statin therapy. Statin pleiotropy: fact or fiction?
ACKNOWLEDGMENT
This work was supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.
To purchase reprints, contact Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), PO Box 016960, Miami, FL 33101.
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