The myocardial renin-angiotensin system: Existence, importance, and clinical implications

PROGRESS

IN CARDIOLOGY

The myocardial renin-angiotensin system: Existence, importance, and clinical implications W. Carter

Grinstead,

MD, and James B. Young, MD. Houston,

Evidence is growing that angiotensin II is produced in multiple tissues, including the heart. Cardiac-derived angiotensin II may enhance myocardial contractility, stimulate deleterious hypertrophy, worsen ischemia, and promote dysrhythmias. An understanding of cardiac angiotensin II may profoundly impact the treatment of ventricular hypertrophy and arrhythmias, congestive heart failure, and coronary artery disease. This review examines evidence for the existence of a cardiac renin-angiotensin system (RAS), the effects of locally generated cardiac angiotensin II, and possible therapeutic implications. EVIDENCE SYSTEM

FOR A CARDIAC

RENIN-ANGIOTENSIN

The search for local angiotensin II production arose from a lack of correlation between the efficacy of angiotensin-converting enzyme (ACE) inhibitors and plasma renin activity.l For example, ACE inhibitors may control systemic hypertension despite normal plasma renin activity, suggesting an effect independent of circulating renin and angiotensin levels. Second, angiotensin I and II are extensively cleared by peripheral tissues, but venous angiotensin II concentrations are higher than expected from clearance data.2 This finding suggests nonrenal tissue as a major source of angiotensin II. Dzau3 proposed that the function of the circulating RAS is preservation of short-term cardiorenal homeostasis, while the longterm control of vascular resistance and local tissue function is influenced by the tissue RAS. An additional function of the circulating RAS could be delivery of renin and angiotensinogen to tissues for local production of angiotensin I, which is subsequently converted to angiotensin II by tissue ACE.2

From Baylor Received Reprint 77030. ‘ml35483

the Multi-Organ Transplant College of Medicine. for publication requests:

James

Aug.

Center 15, 1991;

B. Young,

MD,

of The Methodist accepted 6565 Fannin,

Hospital

and

Houston,

TX

Oct. 1, 1991. SM491,

Texas

The regulation of tissue angiotensin II production could primarily depend on tissue ACE concentrations and be independent of circulating renin and angiotensinogen levels. To prove the existence of a cardiac RAS, one needs to show that cardiac tissue contains renin, angiotensinogen, and ACE; that angiotensin II is locally produced; and that the heart possessesangiotensin II receptors.4 Table I outlines the following evidence. Ganten et a1.5identified renin and angiotensinogen messenger ribonucleic acid (RNA) expression in the rat heart. They used complementary deoxyribonucleic acid (DNA) fragments of renin and angiotensinogen genesfrom a rat genomic bank. Expression of the genes in all four heart chambers was demonstrated by Northern blotting and liquid hybridization assay. Dzau6 using similar methods, confirmed the presence of renin and angiotensinogen messenger RNA in mouse and rat hearts. Sodium-depleted rodents possessed increased cardiac renin activity, which rose in parallel with the quantity of renin messenger RNA.6 These findings have been confirmed by others. 7-gThe demonstration that genesfor renin and angiotensinogen are expressed in cardiac tissue strongly suggests that these proteins are synthesized in the mammalian heart.1° Renin activity in mammalian hearts was first demonstrated in the dog by Hayduk et al.‘l in 1970. Nephrectomy had no effect, but sodium depletion enhanced cardiac renin activity. Re and Ravigatt? measured renin activity in isolated rat left ventricular myocytes. Mean renin activity was 39.2 pg of angiotensin I produced per hour per 10 pg of cells. Specific antirenin antibodies inhibited 80 5%of renin activity. Jin et al.” detected angiotensins in the rhesus monkey heart. Concentrations were highest in the right atrium, followed by the right ventricle, left atrium, septum, and left ventricle.lO Elevated myocardial angiotensin II in nephrectomized rats with absent plasma angiotensin II provides evidence against a transfer of angiotensin II from the circulation into heart tissue.13 1039

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Table

I. Evidence for a cardiac renin-angiotensin system

American

Renin and angiotensinogen messenger RNA detected in rodent atria and ventricles Cardiac renin activity, angiotensin, and ACE activity detected in multiple mammalian species Intracardiac production of angiotensin I and conversion of angiotensin I to angiotensin II demonstrated Cardiac angiotensin II receptors found in numerous species, including man RNA, Ribonucleic

acid; ACE, angiotensin-converting

enzyme

ACE has been localized in rat cardiac endothelium using an iodine-labelled enalapril analog as a marker.4 ACE was particularly concentrated in and around the mitral and tricuspid valves and the sinoatrial node. Welsch et a1.i4detected cardiac ACE activity in rat hearts using fluorimetric assays and tritiumlabelled ramiprilat. Evidence for the intracardiac conversion of angiotensin I to angiotensin II was first presented by Neddleman et a1.15and by Nakashima et al., who used bioassay systems to show activation of exogenously infused angiotensin I during passage through the rabbit coronary circulation. Ganten et al., from the University of Heidelberg, have performed extensive animal studies analyzing the dynamics of a cardiac RAS. First, local conversion of angiotensin I to angiotensin II was shown in the isolated perfused rat heart. When angiotensin I was added to the perfusate, angiotensin II appeared in the coronary sinus effluent. This conversion was attenuated in a dosedependent manner when the ACE inhibitors captopril, ramiprilat, and cilazaprilat were added to the perfusate.iO Oral ACE inhibition had the same effect. Rats fed cilazapril monoethyl ester 15 minutes and 1 hour before sacrifice showed reduced angiotensin II coronary sinus concentrations upon perfusion with angiotensin I. This effect waned in rats fed ACE inhibitor 4 hours and 8 hours before being put to death.” When renin was perfused into isolated rat hearts, both angiogensin I and II appeared in the coronary sinus. The addition of a renin inhibitor caused reduced angiotensin I production, while the addition of an ACE inhibitor attenuated the conversion of angiotensin I to angiotensin II.17 Further evidence that angiotensin can be locally produced comes from a study of nephrectomized rabbits that had very low levels of circulating angiotensin II. At baseline, cardiac angiotensin II was detectable, but 4 hours after the ingestion of ramipril, atria1 angiotensin II was significantly reduced. In a separate study, spontaneously hypertensive rats were fed the ACE inhibitor ramipril for 4 weeks. After the

April 1992 Heart Journal

animals were put to death, ACE activity was det,ermined in heart homogenates by fluorimetric assay. Ramipril decreased cardiac converting enzyme activity by 83 So.ls This was the first direct evidence of cardiac converting enzyme inhibition following chronic ACE inhibitor therapy. Finally, abundant evidence points to the presence of angiotensin II receptors in cardiac tissue. Numerous mammalian studies have demonstrated approximately 50 fmol of angiotensin II receptors per milligram of myocardium. Animals studied include the rabbit,1g,20 guinea pig,“] calf,“2 chick,23 and rat.24 When stimulated, this membrane-bound receptor activates phospholipase C and the subsequent hydrolysis of phosphatidylinositol biphosphate to diacyl glycerol and inositol triphosphate, resulting in modulation of calcium-sensitive protein kinases. By this mechanism, angiotensin II may regulate cytosolic calcium concentrations directly. Urata et a1.“5 extended these observations to humans. Diseased hearts from 14 patients undergoing transplantation and six normal hearts from organ donors were dissected and angiotensin II receptor sites were determined in the midventricular portions of the left and right ventricles. IJtilizing autoradiographic techniques, angiotensin II receptors were found on myocardial membranes and adrenergic nerves in both normal and diseased hearts.*” That angiotensin II receptors are present on adrenergic nerve fibers is important, in that one method by which angiotensin II exerts its cardiac effects may be the modulation of sympathetic nervous transmission. EFFECTS

OF CARDIAC

ANGIOTENSIN

II (Table

II)

Numerous studies have shown a positive inotropic effect of angiotensin II. In 1964,26 isolated kitten papillary muscles responded to angiotensin II with a consistent concentration-dependent improvement in inotropic state. In 1971, Dempsey et a1.27perfused isolated whole cat hearts with angiotensin II and noted increased contractility that was independent of endogenous catecholamines or intact adrenergic nerves. Similar results have been found in the rabbit,2s dog,2g and calf.sO Animal models have consistently shown that angiotensin II increases the rate of myocardial tension development and maximum developed tension, but time to peak tension is not sh0rtened.l The positive inotropic effect of angiotensin II is not observed in intact animals, probably because the vasoconstrictive effect of angiotensin II increasesventricular afterload and overwhelms the inotropic effect.6 The positive inotropic response to angiotensin II in mammalian models appears to be mediated by activation of voltage-sensitive slow cal-

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Table

123 4, Part

Myocardial renin-angiotensin system

1

II. Effects of cardiac angiotensin II

Positive inotropic effect in isolated hearts and myocardial strips Enhanced sympathetic nerve activity Myocardial growth Coronary artery constriction Ventricular arrhythmias

cium channels. This effect is independent of the p-adrenergic system and cyclic adenosine monophosphate accumulation. 31 However, angiotensin II also directly facilitates cardiac sympathetic nervous system activity and therefore has an indirect inotropic effect.l Most studies conclude that this effect results from enhanced neurotransmitter release from presynaptic nerve terminals. 32 Angiotensin II also depresses prejunctional neurotransmitter reuptake,33 stimulates sympathetic ganglia,34 and elevates catecholamine biosynthesis.s5 Xiang et a13” studied isolated rabbit hearts that had intact sympathetic cardiac nerves. Sympathetic stimulation increased heart rate and contractility and depressed coronary blood flow. In animals treated with the ACE inhibitor ramipril 1 hour before death, sympathetic nerve effects were attenuated. Rabbits not receiving pre-sacrifice ramipril did not show this attenuation. This study showed that ACE inhibition blocks angiotensin-induced facilitation of cardiac sympathetic nerve activity.“6 In contrast to the inotropic benefit, cardiac angiotensin II may have detrimental effects on cardiac function. Angiotensin is a growth factor and may induce ventricular hypertrophy. Khairallah et a1.37 demonstrated that angiotensin II enters atria1 cells and localizes in nuclei, where it stimulates production of DNA, RNA, and protein. Owens38 demonstrated that angiotensin II produces a hypertrophic response in cultures of rat arterial smooth muscle cells. Similar growth-enhancing effects have been shown in fibroblast cultures.3g As with the inotropic effects, angiotensin II’s induction of myocardial growth may be a direct effect or may be secondary to enhanced sympathetic neurotransmission.3 Angiotensin II intensely increases coronary vascular resist,ance. In 1964,40 in a dog model, angiotensin II increased coronary vascular resistance 6 % to 92 % . Coronary vasoconstriction may diminish oxygen supply, with resultant ischemia. For example, in a rabbit model, 10 out of 10 animals that received angiotensin infusions developed extensive multifocal myocardial necrosis, whereas control animals were without lesions.41 Angiotensin II may also induce arrhythmias. In the isolated perfused heart in the presence of calcium

Table

111.Clinical implications

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of cardiac ACE inhibition

Hypertension and aortic stenosis Regression of myocardial hypertrophy Congestive heart failure Reduced sympathetic nerve activity Improved coronary blood flow Prevention/regression of myocardial hypertrophy Enhancement/depression of contractility Coronary artery disease Improved coronary blood flow Prevention of nitrate tolerance (sulfhydryl group-containing ACE inhibitors) Reduced infarction size Attenuated postinfarction ventricular remodeling Prevention of ventricular arrhythmias

chloride, angiotensin II induced runs of extrasystoles.4 The ACE inhibitor ramiprilat abolished this effect. The mechanisms by which angiotensin II may cause arrhythmias include decreased coronary blood flow, afterload elevation with increased oxygen demand, and enhancement of sympathetic neurotransmission.42 CLINICAL IMPLICATIONS INHIBITION

OF CARDIAC

ACE

ACE inhibition clearly benefits patients with systemic hypertension and congestive heart failure. Traditionally, clinicians are taught that these benefits result from a reduction in circulating angiotensin II and possibly from enhanced bradykinin activity. Because of the strong evidence that a cardiac RAS exists and the possible detrimental effects of cardiacgenerated angiotensin II, inhibition of locally derived angiotensin may be of clinical benefit (Table III). Long-standing elevated ventricular afterload, such as in systemic hypertension or aortic stenosis, induces ventricular hypertrophy. As previously discussed, angiotensin II may act as a growth factor. Several studies show that ACE inhibition causes regression of cardiac hypertrophy separate from an antihypertensive effect, and this regression may be the result of an attenuation of angiotensin II’s growth factor activity. For example, a group of rats with experimental aortic stenosis had a 34 ?;I increase in left ventricular mass after 6 weeks, and when subsequently fed the ACE inhibitor quinapril, showed 78% regression of this additional left ventricular mass. Since afterload was fixed, regression of left ventricular hypertrophy appeared to result from an attenuation of angiotensin II’s action.43 A similar study of rats with aortic stenosis compared the ACE inhibitor ramipril with nifedipine and dihydralazine. Control rats showed a 29 % increase in left ventricular mass. Ramipril decreased total heart weight, ven-

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and Young

tricular wall thickness, and heart protein content to levels equal to those in normotensive control groups, while the groups given nifedipine and dihydralazine showed no reduction in these parameters.44 Finally, in the model of Pfeffer et a1.,45captopril was given for 10 months to hypertensive rats, beginning at 14 months of age. Mean left ventricular weight at 24 months of age was 3.01 mg per gram of body weight, significantly lower than the control group’s 4.37 mg per gram of body weight, and equal to that of 6-month-old hypertensive rats. This finding implies that captopril induced regression of left ventricular hypertrophy. 45 Since other antihypertensive agents have not consistently shown this same effect (for example, minoxidil increases left ventricular weight in hypertensive rats), regression in left ventricular mass may be agent-specific and independent of antihypertensive effects.45 These animal studies have been confirmed in humans. Eight hypertensive patients treated with enalapril for 12 weeks showed a reduction in left ventricular mass index by echocardiography. In a separate study of seven patients with hypertension and left ventricular hypertrophy, enalapril was given for 7 months and left ventricular mass was measured at 5 days, and at 1, 3, and 7 months. After 3 months of therapy, left ventricular mass fell by 10% and at 7 months it fell by 12 m 10.47 Since an ACE inhibitor’s blood pressure-lowering effect probably reflects its action on the classic circulating RAS, a separate antihypertrophy effect that does not correlate with this pressure effect may indicate that ACE inhibition acts on a cardiac RAS to produce this phenomenon. The benefit of ACE inhibition in congestive heart failure has clearly been shown. Enalapril improves survival in moderate48 and severe4g heart failure. Most of the survival benefit is a result of fewer pump failure deaths, but a trend toward fewer myocardial infarction deaths has also been noted.4a750 Both enalapril and captopril improve exercise tolerance and the quality of life. 51,52A beneficial response to ACE inhibition has been seen in the presence of normal plasma renin activity and angiotensin II concentration, which implies ACE inhibition at the tissue leve1.53Patients in heart failure may have augmented myocardial RAS activity. Hirsch et a1.54discovered an elevation in cardiac ACE activity in rats with experimental compensated congestive heart failure. Plasma renin and ACE activity were normal. In a separate model, sodium-depleted animals showed elevated cardiac angiotensinogen and renin messenger RNA.6 Since patients with clinical congestive heart failure often ingest diuretics and restrict their dietary sodium, a similar state of sodium depletion may be present, leading to elevation of cardiac RAS compo-

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nents. If the myocardial RAS is activated, increased local angiotensin II could depress coronary blood flow through vasoconstriction, augment norepinephine release from sympathetic nerve terminals, and induce myocardial hypertrophy.53 Thus in congestive heart failure cardiac ACE inhibition may improve coronary blood flow, depress sympathetic nerve input, and prevent deleterious hypertrophy. On the other hand, a decrease in cardiac angiotensin II activity could depress myocardial contractility. Interestingly, Urata et a1.55have suggested that myocardial angiotensin II formation may not be suppressed in the presence of ACE inhibition. In 8 normal and 24 failing hearts obtained at donor harvesting and transplantation, respectively, captopril inhibited the conversion of radioactive iodine-labeled angiotensin I to angiotensin II by only 4 S, to 115;, , while a different serine proteinase inhibitor reduced this conversion by 80%. Urata et a1.55speculated that cardiac conversion of angiotensin I to angiotensin II may be caused by one or more membrane-bound serine proteinases and not by ACE. When ACE inhibitor is utilized in congestive heart failure, circulating angiotensin I concentrations should elevate and, according to this model, could increase cardiac angiotensin II levels via a separate conversion pathway. By this mechanism, angiotensin II’s inotropic activity could be augmented in heart failure under the influence of ACE inhibition. In patients with coronary atherosclerosis, the vasoconstricting properties of local angiotensin II may reduce coronary blood flow and worsen ischemia. The conceivable benefit of ACE inhibition acting at the cardiac level is attenuation of the vasoconstricting effect of angiotensin II and subsequent improvement in oxygen supply. In a study of 12 patients with documented coronary artery disease and stable effort angina, atria1 pacing was performed to invoke ischemia. Before the stress test, patients received intravenous captopril or placebo. All subjects had normal resting plasma renin activity. At peak stress, coronary blood flow was 296 t 259 ml/min in the captopril group, versus only 229 -+ 154 ml/min in the placebo group (p = 0.11). Coronary vascular resistance was lower in the group receiving captopril but this difference was not of statistical significance.56 Angina began in 14 minutes (mean) in the placebo group, compared with 19 minutes in the group given captopril. Apparently, captopril improved the myocardial oxygen supply-demand balance. Of importance, the authors did not see alterations in systemic hemodynamics, a finding consistent with the hypothesis that ACE inhibitor acted locally. Foult et a1.57 infused the ACE inhibitor enalaprilat into patients’ coronary arteries and noted increased coronary blood

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flow (181 + 73 ml/min at baseline, which increased to 214 2 79 ml/min with enalaprilat, p < 0.001). No changes were detected in the blood pressure-pulse product, systemic vascular resistance, myocardial oxygen consumption, plasma renin activity, or plasma aldosterone level. This study also suggests local ACE inhibition separate from a systemic effect. ACE inhibition may cause coronary vasodilatation by angiotensin II-independent mechanisms. Potential pathways include inhibition of bradykinin metabolism and subsequent increase in vasodilatory prostaglandins (for example, PGIz).~ In addition, ACE inhibitors containing sulfhydryl groups may contribute by replenishing tissue thiol and preventing tolerance to nitrate therapy.58 ACE inhibition may reduce the size of myocardial infarction. Linz et a1.5goccluded the left anterior descending artery of rat hearts for 15 minutes. Following a 30-minute reperfusion period, coronary sinus effluent was analyzed for creatine kinase (CK) and lactate dehydrogenase (LDH), and myocardium was analyzed for glycogen, lactate, creatine phosphate, and adenosine triphosphate (ATP).5g In rats that received a single dose of oral ramipril before coronary occlusion, a significant decrease in coronary sinus CK and LDH, a decrease in tissue lactate, and an increase in tissue ATP, creatine phosphate, and glycogen stores strongly implied a reduction in myocardial necrosis. DeGraeff et al.“O occluded the left coronary artery of closed-chest pigs for 1 hour and measured serum CK and coronary sinus norepinephrine and inosine (an ATP metabolite). Compared with control animals, pigs receiving captopril had a significant drop in CK release and coronary sinus norepinephrine and inosine. DeGraeff et a160 speculated this apparent reduction in infarct size resulted from improved coronary blood flow (secondary to reduction in local angiotensin II or an increase in bradykinin levels), attenuation of sympathetic cardiac neurotransmission, or removal of free radicals by captopril’s sulfhydryl group. Additional animal studies with captopri161 and enalaprilic acid62 also conclude that ACE inhibition reduces infarct size. After myocardial infarction, ACE inhibition, possibly via reduced cardiac angiotensin II, influences ventricular remodeling. Pfeffer et al. 63administered captopril to rats 3 weeks after left ventricular artery ligation and noted a reduction in left ventricular mass and volume after 3 months compared with control animals. In patients with anterior myocardial infarction and depressed ejection fraction (545 % ), 1 year of captopril attenuated ventricular enlargement and reduced filling pressures.64 Finally, inhibition of cardiac angiotensin II may prevent malignant arrhythmias. In the isolated per-

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fused rat heart, reperfusion arrhythmias worsened after the addition of either angiotensin I or angiotensin II to the perfusate. Ventricular fibrillation was completely eliminated after ramipril was added.65 Van Gilst et a1.66 perfused rat hearts with captopril during 15 minutes of coronary artery ligation, and noted that all 10 control rats developed reperfusion ventricular fibrillation, while only 4 of 10 receiving captopril fibrillated. Further studies in rats67 and in dogs68 verified these findings. In the closed-chest pig model of DeGraeff et a1.,42 with coronary artery occlusion and reperfusion, both captopril-treated and control pigs developed an idioventricular rhythm during reperfusion. However, none of the captopriltreated animals developed ventricular tachycardia at electrophysiologic study 2 weeks later, while six of eight control pigs were inducible.42 Angiotensin II induces coronary vasoconstriction and augments sympathetic neurotransmission; both effects are potentially arrhythmogenic. Thus ACE inhibition may reduce ventricular arrhythmias by suppressing cardiac angiotensin II activity. Arrhythmia suppression may also be the result of non-angiotensin pathways. Van Gilst et a1.6g noted that the pronounced effect of captopril in alleviating reperfusion ventricular fibrillation in the rat heart was completely abolished when indomethacin was added to the perfusate, a finding that suggests that local prostaglandin plays a rhythmstabilizing role. ACE inhibition enhances bradykinin activity, which may alleviate arrhythmias by directly dilating coronary arteries or by promoting prostaglandin production.5g SUMMARY

Major components of the renin-angiotensin system have been localized to cardiac tissue. Cardiac-derived angiotensin II may benefit myocardial contractility but may promote detrimental myocardial hypertrophy, coronary vasoconstriction, and arrhythmias. The benefits of ACE inhibition probably extend beyond the classic circulating RAS to include the heart directly. We thank Barbara assistance in preparing

Bond and Kathryn the manuscript.

Pruitt-Bruun

for their

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49. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35. 50. Braunwald E. ACE-inhibitors-a conerstone of the treatment of heart failure. N Engl J Med 1991;325:351-3. 51. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study. Circulation 1984;70:271-8. 52. Captopril-Digoxin Multicenter Research Group. Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988;259:539-44. 53. Dzau VJ, Hirsch AT. Emerging role of the tissue reninangiotensin systems in congestive heart failure. Eur Heart J 199O;II(suppl B):65-71. 54. Hirsch AT, Talsness C, Lage A, Dzau VJ. The effect of experimental myocardial infarction and chronic captopril treatment on plasma and tissue angiotensin converting-enzyme activity [Abstract]. Clin Res 1989;37:266A. 55. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II-forming pathways in normal and failing human hearts. Circ Res 1990;66:883-90. 56. Ikram H, Low CJS, Shirlaw T, Webb CM, Richards AM, Crozier IG. Antianginal, hemodynamic and coronary vascular effects of captopril in stable angina pectoris. Am J Cardiol 1990;66:164-7. 57. Foult JM, Tavolaro 0, Antony I, Nitenberg A. Coronary vasodilation induced by intracoronary enalaprilat: an argument for the role of a local renin-angiotensin system in patients with dilated cardiomyopathy. Eur Heart J 1998; lO(supp1 F):97-100. 58. Dzau VJ. Tissue renin-angiotensin system: physiologic and pharmacologic implications. Circulation 1988;77(suppl I):I1-3. 59. Linz W, Schoelkens BA, Jin M, Wilhelm M, Ganten D. The heart as a target for converting enzyme inhibitors: studies in ischaemic isolated working rat hearts. J Hyperten 1986;4(suppl 6):S477-9.

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