Calcium channel blockers and coronary atherosclerosis: From the rabbit to the real world

Calcium channel blockers and coronary atherosclerosis: From the rabbit to the real world

Many calcium channel blockers have been shown to retard the development of atherosclerosis in cholesterol-fed rabbits. The mechanisms that may contribute to this effect include Stimulation of choiesteryi ester hydroiase activity in smooth muscle ceils, ameiiii of hypercholesteroiemic- induced endotheiiai dysfunction, or inhibition of smooth muscle ceil proliferation and migration. The effect of calcium channel blockers on the evolution of coronary atherosclerosis in humans has been assessed in three clinical trials. in the Montreal Heart institute trial, nicardipine did not influence the overall rate of progression and regression; however, patients treated with nicardipine experienced significantly less progression of minimal lesions, deftned as stenoses of less than or equal to 20% severity. in the international Niiedipine Trial on Antiatherosclerotic Therapy (INTACT), nifedipine had no effect on overall progression and regression but, by one method of analysis, reduced the rate of appearance of new coronary iesions. in a prefiminary report, diitiazem prevented the development of coronary atherosclerosis in heart tmnsplant recipients. These studies indicate that calcium channel blockers retard the development of early atherosclerosis not only in animal models but also in human coronary arteries. Other studies recently completed or now under way will help to clarify the clinical role of calcium channel blockers in antiatherosclerotic therapy. (AM HEART J 1994;128:1309-16.)

David Waters, MD,” and Jacques Lesperance, MDb Hartford, Conn., and Montreal, Quebec, Canada

Progression of coronary atherosclerosis leads to unstable angina, myocardial infarction, congestive heart failure, and sudden coronary death. Treatments di- rected at preventing these consequences of coronary disease progression have led to reduced rates of morbidity and mortality; however, a more direct approach would be preferable. Interventions that could prevent the appearance of the atherosclerotic plaque, slow its progression, stabilize its fibrous cap to reduce the risk of plaque fissure, or induce regression of established lesions would obviously have a major im- pact on the incidence of coronary events.

To date, lipid-lowering therapy has appeared to be the most promising intervention to accomplish these objectives. l-6 However, favorable modifications of lipid levels do not solve the problem entirely. For ex- ample, in the Familial Atherosclerosis Treatment

From the aDivision of Cardiology, Hartford Hospital and the University of Connecticut School of Medicine, and the “Department of Radiology, Mon- treal Heart Institute and the University of Montreal Medicel School,

Reprint requests: David Waters, MD, Division of Cardiology, Hartford Hospital, 80 Seymour St., Hartford, CT 06102-5037.

Copyright !L 1994 by Mosby-Year Book, Inc. 000%8703/94/$3.00 + 0 4/O/59821

Study (FATS),i one quarter of patients treated with colestipol plus niacin experienced coronary progression in only 2.5 years, despite a reduction of 32% in low-density lipoprotein (LDL) cholesterol and an increase of 43 % in high-density lipoprotein cholesterol. Other approaches need to be explored. This paper reviews a large body of experimental evidence and three completed clinical trials suggesting that calcium channel blockers exert a favorable effect on the development of coronary atherosclerosis.

CALCIUM CHANNEL BLOCKERS IN ANIMAL MODELS

OF ATHEROSCLEROStS

The model that has been used most extensively to investigate the antiatherosclerotic effects of calcium channel blockers is the cholesterol-fed rabbit. Rab- bits fed a 1% to 2 % cholesterol diet for 8 to 12 weeks develop total serum cholesterol levels in the range of 2000 mg/dl, massive hepatic lipid accumulation, and diffuse aortic atherosclerosis. Histologically, this atherosclerosis is characterized by an abundance of lipid-laden foam cells and is quite dissimilar to advanced human atherosclerotic plaques. A further limitation of this experimental model is that the development of atherosclerosis is variable and is influ-

1309

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American Heart Journal

Table I. Potential explanations for the antiatherogenic effect of calcium channel blockers

Reduction of arterial pressurelg Antithrombotic and antiplatelet activity20, 21 Preservation of endothelial functionQ Antioxidant activityis, 2g Reduction of intracellular lipid accumulation by stimulating

cholesteryl ester hydrolase activitysQ-32 Inhibition of SMC proliferation in response to growth

factors22-24 Inhibition of SMC migration33s 34 Promotion of cholesterol efIlux26 and preventing cholesteryl

ester deposition in macrophages25

enced by many factors, including the season of the year.

Kramsch et al7 reported in the early 1980s that the calcium channel blocker lanthanum suppressed experimental atherosclerosis. A beneficial effect on the development of atherosclerosis in the cholesterol- fed rabbit was subsequently demonstrated with the dihydropyridines nifedipine,8 isradipine,g nisoldipine,lO nilvadipine,ll and nicardipine,i2 as well as with diltiazem13 and verapamil.14 The study of Henry and Bentley8 that used nifedipine is typical of these reports. For 8 weeks a 2 % cholesterol diet was fed to 13 rabbits given a placebo and 13 rabbits treated with nifedipine 10 mg twice daily. The aortic intimal surface covered with lipid-stainable lesions averaged 40% of: 5% in placebo-treated rabbits and 17 % f 3 % in nifedipine-treated rabbits @ < O.OOl), in spite of similar high serum cholesterol levels in both groups.

However, several studies have failed to demonstrate a beneficial effect of calcium channel blockers on experimental atherosclerosis. Potential reasons for this discrepancy include an inadequate sample size, given the wide variability in atherosclerosis development among rabbits, and poor drug bioavail- ability.15 Felodipine has recently been reported to retard aortic atherosclerosis in the cholesterol-fed rat.i6 Nifedipine17 and amlodipine la have also been shown to suppress atherogenesis in monkeys, a model more analogous to human atherosclerosis.

MECHANISM OF ACTlON

of the animal experiments, and the benefit could thus be explained by a lowering of arterial pressure. How- ever, Habib et a1.g used low doses of isradipine, within the range used in humans, and demonstrated that the antiatherogenic effect was still present even in the absence of changes in arterial pressure. On the other hand, in the clinical trial with nicardipine (discus- sion to follow), lowering of arterial systolic pressure and lower systolic pressure at baseline were significant predictors of prevention of minimal lesion progression.ig

Increased platelet aggregation is associated with coronary progression and a higher risk of coronary eventszO Calcium channel blockers exert only a weak antiaggregatory effect on platelets; however, recent data indicate that verapamil inhibits platelet thrombus formation in humans.21 Platelet-derived growth factor (and other growth factors) plays a key role in atherogenesis by stimulating smooth muscle cell (SMC) proliferation. Nifedipine,22 isradipine,23 and verapami124 have been shown to block this response. The antiatherosclerotic effect of calcium channel blockers could therefore be related to their antiplatelet activities.

Macrophages and endothelial cells do not contain voltage-dependent calcium channels; however, calcium channel blockers inhibit cholesteryl ester deposition and promote cholesterol ef?lux from macrophages. 26 The calcium channel blocker isradipine has been shown to partially reverse the endothelial dysfunction associated with hypercholesterolemia in rabbits9 In patients with risk factors including hypercholesterolemia but without angiographic evidence of coronary atherosclerosis, endothelial function is already abnormal, as indicated by its vasocon- strictive response to acetylcholine.27 The antiathero- genie effects of calcium channel blockers may be related to their beneficial effects on endothelial function.

Oxidation of LDL cholesterol greatly increases its atherogenic potential. 28 The process of LDL oxidation can probably occur in the subendothelial microenvironment where antioxidant levels may be 10w.s~ Several recent reports indicate that some calcium channel blockers behave as weak antioxidants in membrane systems. 2g They could thus shift the balance away from LDL oxidation and block the

The antiatherogenic effects of calcium channel generation of foam cells. In a recent preliminary re- blockers are important because they act indepen- p0rt,18 amlodipine-treated hypercholesterolemic dently of serum lipid lowering and thus provide an monkeys had less circulating oxidized LDL choles- alternate approach to influencing the evolution of terol and less coronary and aortic atherosclerosis human coronary atherosclerosis. Various mecha- than did control animals with comparable plasma nisms of action advanced to account for this benefit levels of total and LDL cholesterol. are listed in Table I. High doses were used in many Intracellular lipid accumulation is an important

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feature of the atherosclerotic plaque that can be favorably influenced by nifedipine30 or verapamiL31 As shown by Etingin and Hajjar,30 nifedipine increases cholesteryl ester hydrolase activity and thus reduces cholesterol and cholesteryl ester levels in lipid-laden, cultured SMCs from rabbits. This mechanism has been proven to be relevant to human atherosclero- sis32: in 35 patients undergoing coronary bypass surgery, aortic tissue samples were obtained and stripped of endothelium and adventitia. In the 23 patients who had been treated for several months with calcium channel blockers, cholesteryl ester hydrolase activity was significantly higher in the tissue samples and cholesterol and cholesteryl ester levels were significantly lower compared with the 12 patients who did not receive pretreatment with a calcium channel blocker. These differences were independent of serum cholesterol levels, age, and other medica- tions. The mechanism by which calcium channel blockers stimulate cholesteryl ester hydrolase activity is by increasing intracellular cyclic adenosine monophosphate.2g

In addition to SMC proliferation, migration of SMCs from the media to the intima is another com- ponent of atherogenesis that is favorably influenced by calcium channel blockers. Nakao et a1.33 demonstrated that nicardipine can block SMC migration. In a recent preliminary report,34 amlodipine, nitren- dipine, and verapamil each inhibited SMC migration induced by platelet-derived growth factor, with amlodipine being somewhat superior to the other two drugs. A possible explanation for this superiority has been provided by the work of Mason.35 The charged dihydropyridine amlodipine remains in contact with the calcium channel longer and has almost no loss of activity when the cholesterol content of the cell membrane is increased, as has been shown to occur with increasing blood cholesterol levels. In contrast, the membrane concentrations of uncharged dihydropyridines such as nimodipine or isradipine may decrease up to fourfold in the presence of an increased membrane cholesterol content.

CLINICAL TRIALS OF CALCIUM CHANNEL BLOCKERS

AND CORONARY ATHEROSCLEROSIS

The results of three randomized, placebo-controlled clinical trials assessing the effect of calcium channel blockers on the evolution of coronary atherosclerosis have been reported.lgp 36, 37

The Montreal Heart Institute Nicardipine Trial. The purpose of this study was to determine whether chronic treatment with nicardipine could influence the progression of coronary atherosclerosis.ig Pa- tients 65 years of age or younger with less than 75%

stenoses in at least four coronary artery segments were randomized within 1 month of baseline coronary arteriography to double-blind therapy with placebo or nicardipine, 30 mg three times per day. The following patients were excluded: those with previous or planned bypass surgery or angioplasty; those with an ejection fraction less than 0.40, severe triple vessel disease, or left main stenosis; and those with a heart condition requiring treatment with a calcium channel blocker. Of the 383 patients en- rolled, 335 (87 % ) underwent repeat coronary arteriography at 24 months, with coronary lesions mea- sured quantitatively.

Coronary events (five deaths, 22 myocardial infarctions, and 28 episodes of unstable angina) occurred in 28 of 192 patients treated with nicardipine and 23 of 191 patients who received placebo (p = 0.21). Progression, defined as a worsening of minimum diameter by at least 0.4 mm, was detected in 44 % of patients receiving nicardipine and 43 % of patients receiving placebo; 23% of patients treated with nicardipine and 19% of placebo recipients experienced regression of one or more lesions. None of these differences approached statistical significance.

Among the 217 patients with 411 stenoses of less than or equal to 20% at the first arteriogram, such minimal lesions progressed in only 15 of 99 patients treated with nicardipine compared with 32 of 118 patients who received a placebo (15% vs 27 % , p = 0.046). In this subgroup, 16 of 178 minimal lesions in patients treated with nicardipine and 38 of 233 minimal lesions in patients who received a placebo progressed (p = 0.038). Progression of a minimal lesion is illustrated in Fig. 1. By stepwise lo- gistic regression analysis, baseline systolic blood pressure (p = 0.04) and the change in systolic blood pressure between baseline and 6 months (p = 0.002) correlated with progression of minimal lesions. This finding suggests that blood pressure reduction might account for the beneficial effect of nicardipine on minimal lesions.

Overall, the results of this trial indicate that nicardipine has no effect on advanced coronary atherosclerosis but may retard the progression of minimal lesions, defined as those less than 20 % in stenosis diameter on the first arteriogram. This effect of the drug is compatible with the experimental animal data discussed previously. Although “new” lesions, or minimal lesions that progress, are rarely severe enough to cause myocardial ischemia, they are dan- gerous because they increase the risk of a coronary event. Coronary lesions that rupture and cause myocardial infarction are usually in the range of 30% to

1312 Waters and Lespbrance December 1994


Fig. 1. Development of a new coronary lesion. A, This segment of the left anterior descending coronary artery contains only minimal irregularities (arrows). B, The quantitative measurement system calculates a diameter stenosis of 13.5 % . Stenoses within this range can be classified as measurement noise. C, Repeat arteriography 2 years later reveals a mild but definite lesion (arrows) at the same site. D, The minimum lumen diameter has decreased from 2.41 to 1.55 mm and the diameter stenosis is now 36 % . Although this lesion is not severe enough to causeischemia, the patient is at risk for occlusion and myocardial infarction.

70% diameter stenosis,38 and new lesions in this range are more likely to be at higher risk than older, more fibrotic stenoses.

The International Nifedipine Trial on Antiatheroscle- rotic Therapy (INTACT). The purpose of INTACT was to assess whether treatment with nifedipine retarded the angiographic progression of coronary atherosclerosis.36 In nine European centers, 425 patients with “mild” coronary artery disease were randomly allo- cated to double-blind therapy with placebo or nifedipine, 80 mg per day in divided doses. Inclusion cri- teria included age of less than 65 years and the presence of at least one coronary risk factor. Patients previously treated with calcium channel blockers for at least 6 months, those with diffuse or severe coronary disease, and patients requiring extensive revas- cularization procedures were excluded. A second coronary arteriography was planned after 3 years and all films were interpreted quantitatively.

The two groups were well matched for clinical variables, and 282 (82 % ) of the patients had a second arteriography. Progression and regression were defined as a change of greater than or equal to 20% in diameter stenosis or of greater than or equal to 0.4 mm in minimum diameter. Progression, using the latter criterion, was seen in 35% of patients who received a placebo and 29% of patients treated with nifedipine; 21% of patients in the placebo group and 16% of patients in the nifedipine group had regression. These differences were not statistically significant.

New coronary lesions, defined as stenoses of less than 20% on the first arteriogram and greater than 20 % on the second arteriogram, developed in 49 % of patients receiving placebo and 40% of patients treated with nifedipine. This difference, which rep- resents the statistically more appropriate method for evaluating a treatment effect, was not statistically

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American Heart Journal Waters and Lesptkance 1313

significant. However, the authors also reported new lesions on a per-patient basis: 0.82 new lesions per patient in the placebo group and 0.59 in the nifedipine group. Expressed this way, as a 28% reduction in new lesions per patient with active treatment, the difference was statistically significant (p = 0.034).

Although clinical events were not an endpoint of the trial, it is disturbing to note that mortality was higher in the nifedipine group. Two patients who received placebo and eight patients treated with nifedipine died from cardiac causes, and four additional noncardiac-related deaths were reported in the nifedipine group. No differences between treatment groups were seen for new myocardial infarctions or unstable angina. The pattern of mortality in INTACT is consistent with two other studies in survivors of myocardial infarction, in which more deaths were reported in patients treated with nifedipine compared with those receiving placebo.3gy 4o Some dihydropyridine calcium channel blockers have occasionally shown “proischemic” effects41; how long-term treatment with these drugs will influence coronary events and overall mortality is not certain.

Coronary atherosclerosis after heart transplantation. A form of accelerated coronary atherosclerosis de- velops after heart transplantation that limits the long-term prognosis of these patients. This process is manifest angiographically as progressive distal vessel obliteration associated with more typical proximal atherosclerotic lesions. 42 Intracoronary ultrasonography shows that by 1 year after transplantation all patients have developed at least some degree of intimal thickening, the initial atherosclerotic abnormality.43

Preliminary results from an ongoing study indicate that diltiazem may prevent this type of atherosclerosis. 37 Coronary arteriograms were obtained soon after heart transplantation and at 1 and 2 years after transplantation in 57 of 104 consecutive eligible patients who were randomized to unblinded treatment with or without diltiazem. The average coronary arterial diameter decreased in the control group (p < 0.001) but remained unchanged in patients treated with diltiazem. Coronary stenoses greater than 50% of luminal diameter have developed in seven untreated and two diltiazem-treated patients. Coronary death or retransplantation has occurred in five patients, none of whom was in the diltiazem group. Further follow-up will reveal whether the small improvements seen within 2 years in coronary dimensions will presage a reduction in future coronary events in these patients.

The importance of immunologic mechanisms in the pathogenesis of atherosclerosis after heart trans-

plantation and its similarity to ordinary atherosclerosis in terms of etiology have not been well defined. The mechanism by which diltiazem appears to prevent atherosclerosis after heart transplantation and the mechanism by which dihydropyridines appear t,o prevent the development of new lesions may be similar but are as yet undefined.

Other trials. A small study that was neither randomized nor blinded reported that patients treated with nifedipine had less coronary progression and more regression than did patients treated with isosorbide dinitrate or propranoloi.44 These results with nifedipine were not confirmed by the much larger INTACT study.

A salutary effect of nifedipine on the development of atherosclerosis in coronary bypass grafts, as assessed in a randomized, double-biind, placebo-controlled trial, was reported in preliminary form in 1989.45 In another study of the effect of drug therapy on the evolution of atherosclerosis in bypass grafts and native vessels, the Frankfurt Isoptin Progression Study (FIPS) randomized patients after coronary bypass surgery to verapamil or placebo. The trial was hampered by avery high dropout rate, and the results have not yet been published.

The effect of isradipine on the development of carotid atherosclerosis has been assessed with use of ultrasonography in the recently completed Multi- center Isradipine Diuretic Atherosclerosis Study (MIDAS). This trial did not observe an antiathero- genie effect of isradipine (Curt D. Furberg, personal communication, August 1994). The Prospective Ran- domized Evaluation of the Vascular Effects of Nor- vast Trial (PREVENT) is currently randomizing 720

patients with mild coronary atherosclerosis to amlodipine or placebo. Patients will undergo a second coronary arteriography after 3 years; a subset of patients will also be assessed by carotid ultrasonography. The results of these two trials will help clarify what clinical role calcium channel blockers will have as antiatherosclerotic therapy.

FUTURE DIRECTIONS

A major limitation of angiographic trials is that coronary arteriography provides limited informa- tion. Although quantitative techniques can more ac- curately assess changes in the severity of arterial narrowings than could older methods,46 the arterial wall and its pathology are not directly visualized. Newer techniques, specifically angioscopy47 and intravascular ultrasonography,48 circumvent this limitation and will eventually yield data on lesion changes to complement coronary arteriography. Although both of these techniques are now in their infancy, in-

1314 Waters and Lespkrance December 1994


Fig. 2. In this segment that appeared normal on coronary arteriography, intracoronary ultrasonography (A) demonstrates extensive intramural disease. The white arrow denotes a large echo-dense plaque that was not apparent on any of the angiographic views. The underlying junction of plaque and intima is clearly seen (black arrow). The corresponding pathology cross-section (B) reveals a large, lipid-rich plaque (arrow). This case illustrates that intracoronary ultrasonography is capable of defining intramural atherosclerosis that is not appreciated by arteriography.

travascular ultrasonography is superior to angioscopy because it does not require a blood-free field of vision and displays the entire thickness of the vessel wall, not just the surface. Intracoronary ultrasonography is likely to be more useful than coronary arteriography, particularly in the assessment of early coronary lesions. As illustrated by Fig. 2, intramural coronary atherosclerosis can be detected by intracoronary ultrasonography early in its evolution, be- fore a lesion is seen on coronary arteriography.

In spite of their limitations, the clinical trials completed to date demonstrate that calcium channel blockers do not influence the evolution of established coronary atherosclerosis but appear to prevent the progression of early lesions. This conclusion is tenta-

tive, pending completion of ongoing clinical trials. Whether this beneficial effect is a feature of all calcium channel blockers or whether some of these drugs are more potent than others in this regard is as yet not known.

The combined effect of lipid-lowering therapy and a calcium channel blocker on human coronary atherosclerosis has yet to be investigated. In the recently published Canadian Coronary Atherosclerosis Inter- vention Trial (CCAIT),6 lovastatin significantly reduced the appearance of new coronary lesions. Add- ing a calcium channel blocker to a 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor might add no additional benefit with respect to the development of new lesions, or the combination might

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produce an additive or synergistic effect because the mechanisms of action of the two classes of drugs dif- fer. Further studies can be expected to yield an array of drugs that exert a favorable influence on the evolution of coronary atherosclerosis by acting on different components of the atherosclerotic process.

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Antiatherogenic effects of ,8-adrenergic blocking agents: Theoretical9 experimental, and epidemiologic considerations

Theoretical considerations and results from experimental studies in animal models suggest that long-term P-adrenergic blockade should be antiatherogenic. Some of these experimental results indicate that &blockers could inhibit atherogenesfs and thus prevent clinical events independently of any effects on blood pressure through concomitant reductions in heart rate, blood velocity and energy, endothelial permeability to lipoproteins, and the likelihood of plaque rupture. Any such independent inhibition of atherogenesis implies, in turn, that &blockers might be more desirable than alternative antihypertensive therapies in persons at high risk for atherosclerotic diseases. Results of the three major trials directly comparing &blockers to diuretics in the primary prevention of coronary heart disease among patients with hypertension were largely inconclusive. However, ancillary data from these and other trials are consistent in demonstrating that &adrenergic blockade is associated with anti-coronary heart disease effects and, thus, is perhaps antiatherogenic. A definitive evaluation of the antiatherogenic effects of ,&blockers is not forthcoming because no large clinical trials directly assessing the effect of these drugs on atherosclerosis have been done or are planned. (AM HEART J 1994;128:1316-28.)

Jay R. Kaplan, PhDF and Stephen B. Manuck, PhDar b Winston-Salem, N.C., and

Pittsburgh, Pa.

From the BDepartment of Comparative Medicine, Bowman Gray School of Medicine of Wake Forest University, and the bDepartment of Psychology,

&Adrenergic blocking agents (@-blockers) are widely

University of Pittsburgh. prescribed after myocardial infarction (MI) and for

Supported in part by grant Nos. MH-47234, HL-45666, and HL-40962 from the treatment of hypertension, angina pectoris, and the National Institutes of Health. arrhythmia.l Hypertension, which affects at least Reprint requests: Jay R. Kaplan, PhD, Department of Comparative Med- 25 % of adult Americans,2 is the most prevalent of the mine, Bowman Gray School of Medicine of Wake Forest University, Med- ical Center Blvd., Winston-Salem, NC 27X7-1040.

disorders for which @-blockers are indicated.3 How-

Copyright @ 1994 by Mosby-Year Book, Inc. ever, ,&blockers comprise only one of several classes OOOZ-8703/94/$3.00 + 0 4lOf89822 of drugs that are useful in treating hypertension;

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Calcium channel blockers and coronary atherosclerosis: From the rabbit to the real world

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