1380
immunological assessment. We have avoided this problem by assessing dogs owned by patients with well-characterised SLE. All of the dogs were household pets and had been owned by the patients for a number of years. Sharp19 suggested that viral or mycoplasmal infection might explain many features of the arthritides, and Kallick et al20 proposed organisms of the haemobartonellaeperythrozoon-anaplasma group as the cause of human SLE. Several infections
known to be transmitted from in households and some viral dogs (and cats) infections have reciprocal modes of transmission.21 In this context, dog ownership may be a risk factor for scleroderma, because of the proposed infectious aetiology of the condition.22 It is notable that when increased concentrations of anti-dsDNA antibody were found in the serum of laboratory technicians who routinely handled blood from SLE patients," this was the only autoantibody recorded, a are
man to
finding similar to ours. Evidence that transmissible agents are a cause of canine SLE has been sought with variable results,6,23 but there is compelling evidence for a viral mode of transmission.6,24 The immunological abnormalities found in pet dogs owned by SLE patients lend support to the view that common environmental factors or transmissible agents are important in the cause and pathogenesis of SLE. We are currently extending this study to substantiate these findings and, in particular, to relate them to autoantibody concentrations in other groups in pet dogs. We thank Ms N. Richards for the serum protein electrophoresis, Mrs S. Bishop for the immunofluoresence assays, and Mr G. Young from the People’s Dispensary for Sick Animals (PDSA), Dunkirk, Nottingham, for collecting blood samples from the SLE patients’ dogs. We also thank Dr J. G. Bowen (The Boots Company) and Dr J. Wills (Pedigree Petfoods) for supplying blood samples from normal dogs, Dr T. J. Gruffydd-Jones (Department of Veterinary Medicine, University of Bristol) for samples from dogs with autoimmune disorders, and Mr B. Trow (Department of Clinical Veterinary Medicine, University of Cambridge) for the canine positive-
control
Jones DRE, Stokes CR, Gruffydd-Jones TJ, Bourne FJ. An enzymelinked antiglobulin test for the detection of erythrocyte-bound antibodies in canine autoimmune haemolytic anaemia. Vet Immunol Immunopathol 1987; 16: 11-21. 14. Wallington TB, Gooi HC. Non-organ-specific autoantibodies. In: Gooi HC, Chapel H, eds. Clinical immunology. A practical approach.
13.
Oxford: IRL Press, 1990: 212-14. 15. Kristensen S, Flagstad A, Jansen H, et al. The absence of evidence suggesting that systemic lupus erythematosus is a zoonosis of dogs. Vet Rec 1979; 105: 422-23. 16. Lewis RM. Animal model of human disease: canine systemic lupus erythematosus. Am J Pathol 1972; 69: 537-40. 17. Bennett D. Canine systemic lupus erythematosus. Vet Annu 1987; 27: 350-60. 18. Costa O, Fournel C, Lotchouang E, Monier JC, Fontaine M. Specificities of antinuclear antibodies detected in dogs with systemic lupus erythematosus. Vet Immunol Immunopathol 1984; 7: 369-82. 19. Sharp JT. Infectious agents in the arthritides: current status. Hosp Pract 1971; 6: 142-51. 20. Kallick CA, Levin S, Reddi KT, Landau WL. Systemic lupus
erythematosus associated with haemobartonella-like organisms. Nature 1972; 236: 145-46. 21. Mayr A. Infektionen, die vom Menschen in Haushalten auf Hund und Katze übertragen werden. (Infections transmitted from man to dogs and cats in the 187: 508-26.
household). Zentralbl Bakteriol Mikrobiol Hyg [B] 1989;
22. Silman AJ, Jones S. Pet ownership: a possible risk factor for scleroderma. Br J Rheumatol 1990; 29: 494. 23. Lewis RM, Schwartz RS. Canine systemic lupus erythematosus. J Exp Med 1971; 134: 417-38. 24. Lewis RM, Tannenberg W, Smith C, Schwartz RS. C-type viruses in systemic lupus erythematosus. Nature 1974; 252: 78-79.
SHORT REPORTS Side-branch occlusion during percutaneous transluminal coronary
angioplasty
serum.
REFERENCES 1. Wallace DJ, Dubois EL. Dubois’ lupus erythematosus. Philadelphia: Lea & Febiger, 1987. 2. Fessel WJ. Epidemiology of systemic lupus erythematosus. Rheum Dis Clin N Am 1988; 14: 15-23. 3. Deapen DM, Weinrib L, Langholz B, Horvitz DA, Mack TM. A revised estimate of twin concordance in SLE: a survey of 138 pairs. Arthritis Rheum 1986; 29: S26 (abstr). 4. Shanley KJ. Lupus erythematosus in small animals. Clin Dermatol 1985; 3: 131-38. 5. Frye FL. Observations on systemic lupus erythematosus accompanying lymphoreticular neoplasia in poikilothermic species. Theriogenology 1976; 6: 127-29. 6. Lewis RM, André-Schwartz J, Harris GS, Hirsch MS, Black PH, Schwartz RS. Canine systemic lupus erythematosus. Transmission of serologic abnormalities by cell-free filtrates. J Clin Invest 1973; 52: 1893-907. 7. Monier JC, Dardenne M, Rigal D, Costa O, Fournel C, Lapras M. Clinical and laboratory features of canine lupus syndromes. Arthritis Rheum 1980; 23: 294-301 8. Beaucher WN, Garman RH, Condemi JJ. Familial lupus erythematosus. Antibodies to DNA in household dogs. N Engl J Med 1977; 296:
982-84. 9. Clair D, DeHoratius RJ, Wolfe J, Halliwell R. Autoantibodies to human contacts of SLE dogs. Arthritis Rheum 1980; 23: 251-53. 10. Reinertsen JL, Kaslow RA, Kippel JH, Hurvitz AI, Lewis RM. An epidemiologic study of households exposed to canine systemic lupus erythematosus. Arthritis Rheum 1980; 23: 564-68. 11. Zambinski M, Messner R, Mandel J. Anti-DNA antibodies in technicians handling lupus blood. Proceedings of the 53rd Annual General Meeting, American College of Rheumatology; June 1989; Cincinnati: S25. 12. Thoburn R, Hurvitz AI, Kunkel HG. A DNA-binding protein in the serum of certain mammalian species. Proc Nat Acad Sci USA 1972; 69: 3327-30.
Concentrations of creatine kinase (CK) MB mass troponin T were measured in serial peripheral venous blood samples from 21 patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Angiography showed sidebranch occlusion during PTCA without clinical signs of myocardial injury in 5 patients. After PTCA, CKMB mass concentrations were substantially higher than normal in all 5 patients with side-branch occlusion, and troponin T concentrations were high in 3. By contrast, only 2 patients and 1 patient, respectively, without side-branch occlusion had slight rises in CKMB and troponin T. Release of the contractile protein troponin T reflects more severe damage to myocytes than simple leakage of CKMB. Therefore, myocardial damage induced by side-branch occlusion can be graded by measurement of and cardiac
troponin T in plasma.
is
Percutaneous transluminal coronary angioplasty (PTCA) widely used to dilate stenoses of coronary arteries.
1381
Inflation of the balloon
at the site of stenosis sometimes occlusion of smaller side visible causes angiographically clinical branches’2 without signs of myocardial ischaemia. It is not clear whether myocardial damage occurs in these circumstances. The widely used measurement of creatine kinase (CK) MB activity or total CK activity is less sensitive in the diagnosis of myocardial injury than measurements of the mass concentrations in plasma of CKMB or cardiacspecific troponin T. 3-5 We have assessed myocardial damage due to side-branch occlusion by measurement of these mass
concentrations. We studied 21 patients (16 men, 5 women; aged 33-79 years, 59 years) who were undergoing routine PTCA for stable (in 14) or unstable (in 7) angina pectoris. 7 patients had a history of previous myocardial infarction. 1 stenosis was dilated in each patient; 9 stenoses were in the left anterior descending coronary artery, 5 in the left circumflex artery, and 7 in the right coronary artery. After balloon deflation no patient complained of chest pain or had ST-T changes on electrocardiography or signs of a new myocardial infarction. Blood samples were taken before PTCA and 6 h, 24 h, and 48 h afterwards. CKMB mass concentrations were measured by a microparticle enzyme immunoassay (Abbott, Chicago, Illinois, USA) and troponin T by the enzyme immunoassay (Boehringer Mannheim, Germany) of Katus et al.4 We compared changes in plasma concentrations from baseline to 48 h after PTCA between the groups by means of the MannWhitney test with Bonferroni’s correction. mean
PTCA was successful in all patients. The procedure resulted in angiographically visible side-branch occlusion without concomitant chest pain or ST-T changes in 5 patients. The affected vessels were side branches of the right coronary artery in 2, of the left anterior descending (ramus diagonalis) in 1, and the circumflex artery (ramus marginalis) in 2. At the end of the procedure angiography documented absence both of anterograde flow in the side branch and of anterograde or retrograde filling via collaterals from the ipsilateral vessel in all 5 patients. The duration of documented closure ranged from 24 min to 60 min. In all 5 patients, CKMB mass concentrations were above the normal range from 6 h to 48 h after PTCA. 3 also had high troponin T concentrations 48 h after PTCA. By contrast, among the patients without side-branch occlusion, only 2 had high CKMB concentrations at 6 h and 24 h (only slightly above normal) and only 1 patient had a borderline raised troponin T concentration at 48 h (see figure). The mean increases in CKMB mass from baseline to 24 h and to 48 h were significantly greater in the group with side-branch occlusion than in the patients without occlusion (p 0-0078 and p 0-039, respectively). For troponin T, the difference between the groups in increase from baseline achieved significance only at 48 h (p 0-045). Uncomplicated PTCA did not cause a significant rise in CKMB mass or troponin T plasma concentration, which =
=
=
confirms
previous fmdings.6 However, angiographically documented, symptomless side-branch occlusion led to myocardial injury in all cases reflected by an increase of CKMB mass and troponin T (3 cases) plasma concentrations. Increases in CKMB do not necessarily reflect necrosis of myocardial tissue.7,8 There are at least two different but linked mechanisms that mediate protein efflux and the destruction of the contractile apparatus.9 Cardiac troponin T is a contractile protein with only a small soluble cytoplasmic precursor pool.l0 The long duration of high troponin T concentrations in 3 patients with side-branch occlusion shows that the contractile apparatus was degraded and the plasma membrane was leaky; thus the damage to the heart muscle was greater in these patients than in those with
Median (.) and interquartile range (boxes) of CKMB mass and cardiac troponin T concentrations in patients undergoing PTCA.
= patients with symptomless side-branch occlusion during PTCA; 0= patients without such occlusion. Broken lines= 97-5percentile of range in healthy controls.
release of cytoplasmic proteins such as CKMB. Positron emission tomographic studies of myocardial viability could be used to identify jeopardised regions of myocardium and could further elucidate the consequences of side-branch occlusion. PTCA-induced side-branch occlusion, though it does not cause symptoms, leads to myocardial damage and to an increase in at least one of the markers we measured. Measurement of troponin T concentrations is a simple and less invasive way of assessing the damage incurred; it may discriminate between reversible injury and necrosis.
only
We thank Mr M. Falk for helpful statistical advice.
REFERENCES 1. Morimoto
S, Hiramitsu S, Yamada K, Uemura A, Kubo N, Mizuno Y. Lesions in side branches of arteries having undergone percutaneous transluminal coronary angioplasty: a histopathologic study. Am Heart J 1990; 120: 864-72. LW, Kramer BL, Howard E, Lesch
2. Klein
M. Incidence and clinical
significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty. JACC 1991; 17: 621-26. 3. Mair J, Artner-Dworzak E, Dienstl A, et al. Early detection of acute myocardial infarction by measurement of mass concentration of CKMB. Am J Cardiol 1991; 68: 1545-50.
1382
MAXIMUM NIFEDIPINE CONCENTRATIONS
HA, Rcmppis A, Neumann FJ, et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation
4. Katus
1991; 83: 902-12. 5. Gerhardt W, Katus H, Ravkilde J, et al. S-troponin T in suspected ischemic myocardial injury compared with mass and catalytic concentrations of S-creatine kinase isoenzyme MB. Clin Chem 1991; 37: 1405-11. 6. Hunt AC, Chow SL, Shiu MF, Chilton DC, Cummins B, Cummins P. Release of creatine kinase-MB and cardiac specific troponin-I following percutaneous transluminal coronary angioplasty. Eur Heart J 1991; 12: 690-94. 7. Heyndrickx GR, Amano J, Kenna T, et al. Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons. JACC 1985; 6: 1299-303. 8. Piper HM, Schwartz P, Spahr R, Hütter JF, Spieckermann PG. Early enzyme release from myocardial cells is not due to irreversible cell damage. J Mol Cell Cardiol 1984; 16: 385-88 9. Duncan CJ, Jackson MJ. Different mechanisms mediate structural changes and intracellular enzyme efflux following damage to skeletal muscle. J Cell Sci 1987; 87: 183-88. 10. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991; 67: 1360-67.
Departments of Medical Chemistry and Biochemistry (H. Talasz, MD, N. Genser, MD, J. Mair, MD, E. Artner Dworzak, MD, Prof B. Puschendorf, MD) and Internal Medicine (G. Friedrich, MD, N. Moes, MD, V. Muhlberger, MD), University of Innsbruck Medical School, Innsbruck, Austria. Correspondence
ADDRESSES:
Prof B. Puschendorf, Institut fur Medizinische Chemie und Biochemie, Fritz-Preglstrasse 3, A-6020 Innsbruck, Austria.
to
Gingival sequestration of nifedipine in nifedipine-induced gingival overgrowth
The mechanism of gingival overgrowth associated with long-term use of nifedipine and of other drugs that affect calcium homoeostasis, such as cyclosporin and phenytoin, is unknown. With an ultrasensitive we measured the assay, in and of pharmacokinetics nifedipine plasma gingival crevicular fluid (GCF) of nine patients receiving this drug for angina and hypertension. In seven patients, the maximum nifedipine concentration was in the range 15-316 (mean 84 [SD 105]) times greater in GCF than in plasma. The two patients with low (undetectable) GCF nifedipine did not have overgrowth. We propose that gingival tissues sequester nifedipine and that the very high nifedipine concentrations predispose the tissues to overgrowth.
Gingival overgrowth is phenytoin, cyclosporin,
a common
feature of the
use
*Highest value from two sites sampled N D not detected =
( < 80 pg/I)
m
any of 12
samples analysed
plasma concentration for phenytoin and cyclosporin4,5 but there are no data on the disposition of nifedipine in relation to the incidence of gingival overgrowth. We have studied the pharmacokinetics of nifedipine in plasma and in the gingival crevicular fluid (GCF), a serum-derived tissue transudate, production of which is directly related to the extent of gingival related
to
inflammation. Nine men with angina and hypertension, who had been receiving nifedipine (40-80 mg/day) for at least 6 months, took part in the study, which was approved by the local ethics committee. Patients 1-5 had substantial (up to 30%) gingival enlargement and were labelled "responders". Patients 6-9 were labelled "nonresponders", according to established periodontal criteria.1-3 There was no significant difference between responders and nonresponders in the duration of treatment. Each patient had at least eight upper and lower anterior teeth. Any concomitant antihypertensive or antianginal drug therapy was not taken into account for our classification. Each patient took his first daily dose of nifedipine as normal, and venous blood for nifedipine analysis was sampled via an indwelling cannula at baseline and 0-h,1 h, 2 h, 4 h, and 8 h after the dose. After periodontal examination, the teeth were thoroughly cleaned, washed, and dried with a stream of air. For each patient, we selected two gingival pockets with probing depths of at least 4
mm
associated with the upper and lower anterior teeth for
sampling of GCF. The sites were isolated with cottonwool rolls, and high-volume aspiration ensured that the area was kept free of saliva. At the same time as each blood sampling, GCF was collected from these sites by means of special paper strips (Periopaper, Pro Flow, Amityville, New York, USA), and the volume collected on each strip was determined with a calibrated Periotron machine (Pro Flow). Strips (two from each site at each time) were placed in amber 10000-
of
and
calcium-channel-blocking drugs.l Of the last group, nifedipine is the agent most frequently implicated, perhaps because it is so widely used.2 As many as 10% of dentate patients treated with nifedipine undergo substantial gingival changes.3 There is no satisfactory explanation as to why these apparently unrelated drugs produce an indistinguishable adverse reaction in the gingivae. The severity of overgrowth is
Steady-state plasma and GCF nifedipine concentrations patient 3 after 20 mg nifedipine.
in
immunological assessment. We have avoided this problem by assessing dogs owned by patients with well-characterised SLE. All of the dogs were household pets and had been owned by the patients for a number of years. Sharp19 suggested that viral or mycoplasmal infection might explain many features of the arthritides, and Kallick et al20 proposed organisms of the haemobartonellaeperythrozoon-anaplasma group as the cause of human SLE. Several infections
known to be transmitted from in households and some viral dogs (and cats) infections have reciprocal modes of transmission.21 In this context, dog ownership may be a risk factor for scleroderma, because of the proposed infectious aetiology of the condition.22 It is notable that when increased concentrations of anti-dsDNA antibody were found in the serum of laboratory technicians who routinely handled blood from SLE patients," this was the only autoantibody recorded, a are
man to
finding similar to ours. Evidence that transmissible agents are a cause of canine SLE has been sought with variable results,6,23 but there is compelling evidence for a viral mode of transmission.6,24 The immunological abnormalities found in pet dogs owned by SLE patients lend support to the view that common environmental factors or transmissible agents are important in the cause and pathogenesis of SLE. We are currently extending this study to substantiate these findings and, in particular, to relate them to autoantibody concentrations in other groups in pet dogs. We thank Ms N. Richards for the serum protein electrophoresis, Mrs S. Bishop for the immunofluoresence assays, and Mr G. Young from the People’s Dispensary for Sick Animals (PDSA), Dunkirk, Nottingham, for collecting blood samples from the SLE patients’ dogs. We also thank Dr J. G. Bowen (The Boots Company) and Dr J. Wills (Pedigree Petfoods) for supplying blood samples from normal dogs, Dr T. J. Gruffydd-Jones (Department of Veterinary Medicine, University of Bristol) for samples from dogs with autoimmune disorders, and Mr B. Trow (Department of Clinical Veterinary Medicine, University of Cambridge) for the canine positive-
control
Jones DRE, Stokes CR, Gruffydd-Jones TJ, Bourne FJ. An enzymelinked antiglobulin test for the detection of erythrocyte-bound antibodies in canine autoimmune haemolytic anaemia. Vet Immunol Immunopathol 1987; 16: 11-21. 14. Wallington TB, Gooi HC. Non-organ-specific autoantibodies. In: Gooi HC, Chapel H, eds. Clinical immunology. A practical approach.
13.
Oxford: IRL Press, 1990: 212-14. 15. Kristensen S, Flagstad A, Jansen H, et al. The absence of evidence suggesting that systemic lupus erythematosus is a zoonosis of dogs. Vet Rec 1979; 105: 422-23. 16. Lewis RM. Animal model of human disease: canine systemic lupus erythematosus. Am J Pathol 1972; 69: 537-40. 17. Bennett D. Canine systemic lupus erythematosus. Vet Annu 1987; 27: 350-60. 18. Costa O, Fournel C, Lotchouang E, Monier JC, Fontaine M. Specificities of antinuclear antibodies detected in dogs with systemic lupus erythematosus. Vet Immunol Immunopathol 1984; 7: 369-82. 19. Sharp JT. Infectious agents in the arthritides: current status. Hosp Pract 1971; 6: 142-51. 20. Kallick CA, Levin S, Reddi KT, Landau WL. Systemic lupus
erythematosus associated with haemobartonella-like organisms. Nature 1972; 236: 145-46. 21. Mayr A. Infektionen, die vom Menschen in Haushalten auf Hund und Katze übertragen werden. (Infections transmitted from man to dogs and cats in the 187: 508-26.
household). Zentralbl Bakteriol Mikrobiol Hyg [B] 1989;
22. Silman AJ, Jones S. Pet ownership: a possible risk factor for scleroderma. Br J Rheumatol 1990; 29: 494. 23. Lewis RM, Schwartz RS. Canine systemic lupus erythematosus. J Exp Med 1971; 134: 417-38. 24. Lewis RM, Tannenberg W, Smith C, Schwartz RS. C-type viruses in systemic lupus erythematosus. Nature 1974; 252: 78-79.
SHORT REPORTS Side-branch occlusion during percutaneous transluminal coronary
angioplasty
serum.
REFERENCES 1. Wallace DJ, Dubois EL. Dubois’ lupus erythematosus. Philadelphia: Lea & Febiger, 1987. 2. Fessel WJ. Epidemiology of systemic lupus erythematosus. Rheum Dis Clin N Am 1988; 14: 15-23. 3. Deapen DM, Weinrib L, Langholz B, Horvitz DA, Mack TM. A revised estimate of twin concordance in SLE: a survey of 138 pairs. Arthritis Rheum 1986; 29: S26 (abstr). 4. Shanley KJ. Lupus erythematosus in small animals. Clin Dermatol 1985; 3: 131-38. 5. Frye FL. Observations on systemic lupus erythematosus accompanying lymphoreticular neoplasia in poikilothermic species. Theriogenology 1976; 6: 127-29. 6. Lewis RM, André-Schwartz J, Harris GS, Hirsch MS, Black PH, Schwartz RS. Canine systemic lupus erythematosus. Transmission of serologic abnormalities by cell-free filtrates. J Clin Invest 1973; 52: 1893-907. 7. Monier JC, Dardenne M, Rigal D, Costa O, Fournel C, Lapras M. Clinical and laboratory features of canine lupus syndromes. Arthritis Rheum 1980; 23: 294-301 8. Beaucher WN, Garman RH, Condemi JJ. Familial lupus erythematosus. Antibodies to DNA in household dogs. N Engl J Med 1977; 296:
982-84. 9. Clair D, DeHoratius RJ, Wolfe J, Halliwell R. Autoantibodies to human contacts of SLE dogs. Arthritis Rheum 1980; 23: 251-53. 10. Reinertsen JL, Kaslow RA, Kippel JH, Hurvitz AI, Lewis RM. An epidemiologic study of households exposed to canine systemic lupus erythematosus. Arthritis Rheum 1980; 23: 564-68. 11. Zambinski M, Messner R, Mandel J. Anti-DNA antibodies in technicians handling lupus blood. Proceedings of the 53rd Annual General Meeting, American College of Rheumatology; June 1989; Cincinnati: S25. 12. Thoburn R, Hurvitz AI, Kunkel HG. A DNA-binding protein in the serum of certain mammalian species. Proc Nat Acad Sci USA 1972; 69: 3327-30.
Concentrations of creatine kinase (CK) MB mass troponin T were measured in serial peripheral venous blood samples from 21 patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Angiography showed sidebranch occlusion during PTCA without clinical signs of myocardial injury in 5 patients. After PTCA, CKMB mass concentrations were substantially higher than normal in all 5 patients with side-branch occlusion, and troponin T concentrations were high in 3. By contrast, only 2 patients and 1 patient, respectively, without side-branch occlusion had slight rises in CKMB and troponin T. Release of the contractile protein troponin T reflects more severe damage to myocytes than simple leakage of CKMB. Therefore, myocardial damage induced by side-branch occlusion can be graded by measurement of and cardiac
troponin T in plasma.
is
Percutaneous transluminal coronary angioplasty (PTCA) widely used to dilate stenoses of coronary arteries.
1381
Inflation of the balloon
at the site of stenosis sometimes occlusion of smaller side visible causes angiographically clinical branches’2 without signs of myocardial ischaemia. It is not clear whether myocardial damage occurs in these circumstances. The widely used measurement of creatine kinase (CK) MB activity or total CK activity is less sensitive in the diagnosis of myocardial injury than measurements of the mass concentrations in plasma of CKMB or cardiacspecific troponin T. 3-5 We have assessed myocardial damage due to side-branch occlusion by measurement of these mass
concentrations. We studied 21 patients (16 men, 5 women; aged 33-79 years, 59 years) who were undergoing routine PTCA for stable (in 14) or unstable (in 7) angina pectoris. 7 patients had a history of previous myocardial infarction. 1 stenosis was dilated in each patient; 9 stenoses were in the left anterior descending coronary artery, 5 in the left circumflex artery, and 7 in the right coronary artery. After balloon deflation no patient complained of chest pain or had ST-T changes on electrocardiography or signs of a new myocardial infarction. Blood samples were taken before PTCA and 6 h, 24 h, and 48 h afterwards. CKMB mass concentrations were measured by a microparticle enzyme immunoassay (Abbott, Chicago, Illinois, USA) and troponin T by the enzyme immunoassay (Boehringer Mannheim, Germany) of Katus et al.4 We compared changes in plasma concentrations from baseline to 48 h after PTCA between the groups by means of the MannWhitney test with Bonferroni’s correction. mean
PTCA was successful in all patients. The procedure resulted in angiographically visible side-branch occlusion without concomitant chest pain or ST-T changes in 5 patients. The affected vessels were side branches of the right coronary artery in 2, of the left anterior descending (ramus diagonalis) in 1, and the circumflex artery (ramus marginalis) in 2. At the end of the procedure angiography documented absence both of anterograde flow in the side branch and of anterograde or retrograde filling via collaterals from the ipsilateral vessel in all 5 patients. The duration of documented closure ranged from 24 min to 60 min. In all 5 patients, CKMB mass concentrations were above the normal range from 6 h to 48 h after PTCA. 3 also had high troponin T concentrations 48 h after PTCA. By contrast, among the patients without side-branch occlusion, only 2 had high CKMB concentrations at 6 h and 24 h (only slightly above normal) and only 1 patient had a borderline raised troponin T concentration at 48 h (see figure). The mean increases in CKMB mass from baseline to 24 h and to 48 h were significantly greater in the group with side-branch occlusion than in the patients without occlusion (p 0-0078 and p 0-039, respectively). For troponin T, the difference between the groups in increase from baseline achieved significance only at 48 h (p 0-045). Uncomplicated PTCA did not cause a significant rise in CKMB mass or troponin T plasma concentration, which =
=
=
confirms
previous fmdings.6 However, angiographically documented, symptomless side-branch occlusion led to myocardial injury in all cases reflected by an increase of CKMB mass and troponin T (3 cases) plasma concentrations. Increases in CKMB do not necessarily reflect necrosis of myocardial tissue.7,8 There are at least two different but linked mechanisms that mediate protein efflux and the destruction of the contractile apparatus.9 Cardiac troponin T is a contractile protein with only a small soluble cytoplasmic precursor pool.l0 The long duration of high troponin T concentrations in 3 patients with side-branch occlusion shows that the contractile apparatus was degraded and the plasma membrane was leaky; thus the damage to the heart muscle was greater in these patients than in those with
Median (.) and interquartile range (boxes) of CKMB mass and cardiac troponin T concentrations in patients undergoing PTCA.
= patients with symptomless side-branch occlusion during PTCA; 0= patients without such occlusion. Broken lines= 97-5percentile of range in healthy controls.
release of cytoplasmic proteins such as CKMB. Positron emission tomographic studies of myocardial viability could be used to identify jeopardised regions of myocardium and could further elucidate the consequences of side-branch occlusion. PTCA-induced side-branch occlusion, though it does not cause symptoms, leads to myocardial damage and to an increase in at least one of the markers we measured. Measurement of troponin T concentrations is a simple and less invasive way of assessing the damage incurred; it may discriminate between reversible injury and necrosis.
only
We thank Mr M. Falk for helpful statistical advice.
REFERENCES 1. Morimoto
S, Hiramitsu S, Yamada K, Uemura A, Kubo N, Mizuno Y. Lesions in side branches of arteries having undergone percutaneous transluminal coronary angioplasty: a histopathologic study. Am Heart J 1990; 120: 864-72. LW, Kramer BL, Howard E, Lesch
2. Klein
M. Incidence and clinical
significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty. JACC 1991; 17: 621-26. 3. Mair J, Artner-Dworzak E, Dienstl A, et al. Early detection of acute myocardial infarction by measurement of mass concentration of CKMB. Am J Cardiol 1991; 68: 1545-50.
1382
MAXIMUM NIFEDIPINE CONCENTRATIONS
HA, Rcmppis A, Neumann FJ, et al. Diagnostic efficiency of troponin T measurements in acute myocardial infarction. Circulation
4. Katus
1991; 83: 902-12. 5. Gerhardt W, Katus H, Ravkilde J, et al. S-troponin T in suspected ischemic myocardial injury compared with mass and catalytic concentrations of S-creatine kinase isoenzyme MB. Clin Chem 1991; 37: 1405-11. 6. Hunt AC, Chow SL, Shiu MF, Chilton DC, Cummins B, Cummins P. Release of creatine kinase-MB and cardiac specific troponin-I following percutaneous transluminal coronary angioplasty. Eur Heart J 1991; 12: 690-94. 7. Heyndrickx GR, Amano J, Kenna T, et al. Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons. JACC 1985; 6: 1299-303. 8. Piper HM, Schwartz P, Spahr R, Hütter JF, Spieckermann PG. Early enzyme release from myocardial cells is not due to irreversible cell damage. J Mol Cell Cardiol 1984; 16: 385-88 9. Duncan CJ, Jackson MJ. Different mechanisms mediate structural changes and intracellular enzyme efflux following damage to skeletal muscle. J Cell Sci 1987; 87: 183-88. 10. Katus HA, Remppis A, Scheffold T, Diederich KW, Kuebler W. Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction. Am J Cardiol 1991; 67: 1360-67.
Departments of Medical Chemistry and Biochemistry (H. Talasz, MD, N. Genser, MD, J. Mair, MD, E. Artner Dworzak, MD, Prof B. Puschendorf, MD) and Internal Medicine (G. Friedrich, MD, N. Moes, MD, V. Muhlberger, MD), University of Innsbruck Medical School, Innsbruck, Austria. Correspondence
ADDRESSES:
Prof B. Puschendorf, Institut fur Medizinische Chemie und Biochemie, Fritz-Preglstrasse 3, A-6020 Innsbruck, Austria.
to
Gingival sequestration of nifedipine in nifedipine-induced gingival overgrowth
The mechanism of gingival overgrowth associated with long-term use of nifedipine and of other drugs that affect calcium homoeostasis, such as cyclosporin and phenytoin, is unknown. With an ultrasensitive we measured the assay, in and of pharmacokinetics nifedipine plasma gingival crevicular fluid (GCF) of nine patients receiving this drug for angina and hypertension. In seven patients, the maximum nifedipine concentration was in the range 15-316 (mean 84 [SD 105]) times greater in GCF than in plasma. The two patients with low (undetectable) GCF nifedipine did not have overgrowth. We propose that gingival tissues sequester nifedipine and that the very high nifedipine concentrations predispose the tissues to overgrowth.
Gingival overgrowth is phenytoin, cyclosporin,
a common
feature of the
use
*Highest value from two sites sampled N D not detected =
( < 80 pg/I)
m
any of 12
samples analysed
plasma concentration for phenytoin and cyclosporin4,5 but there are no data on the disposition of nifedipine in relation to the incidence of gingival overgrowth. We have studied the pharmacokinetics of nifedipine in plasma and in the gingival crevicular fluid (GCF), a serum-derived tissue transudate, production of which is directly related to the extent of gingival related
to
inflammation. Nine men with angina and hypertension, who had been receiving nifedipine (40-80 mg/day) for at least 6 months, took part in the study, which was approved by the local ethics committee. Patients 1-5 had substantial (up to 30%) gingival enlargement and were labelled "responders". Patients 6-9 were labelled "nonresponders", according to established periodontal criteria.1-3 There was no significant difference between responders and nonresponders in the duration of treatment. Each patient had at least eight upper and lower anterior teeth. Any concomitant antihypertensive or antianginal drug therapy was not taken into account for our classification. Each patient took his first daily dose of nifedipine as normal, and venous blood for nifedipine analysis was sampled via an indwelling cannula at baseline and 0-h,1 h, 2 h, 4 h, and 8 h after the dose. After periodontal examination, the teeth were thoroughly cleaned, washed, and dried with a stream of air. For each patient, we selected two gingival pockets with probing depths of at least 4
mm
associated with the upper and lower anterior teeth for
sampling of GCF. The sites were isolated with cottonwool rolls, and high-volume aspiration ensured that the area was kept free of saliva. At the same time as each blood sampling, GCF was collected from these sites by means of special paper strips (Periopaper, Pro Flow, Amityville, New York, USA), and the volume collected on each strip was determined with a calibrated Periotron machine (Pro Flow). Strips (two from each site at each time) were placed in amber 10000-
of
and
calcium-channel-blocking drugs.l Of the last group, nifedipine is the agent most frequently implicated, perhaps because it is so widely used.2 As many as 10% of dentate patients treated with nifedipine undergo substantial gingival changes.3 There is no satisfactory explanation as to why these apparently unrelated drugs produce an indistinguishable adverse reaction in the gingivae. The severity of overgrowth is
Steady-state plasma and GCF nifedipine concentrations patient 3 after 20 mg nifedipine.
in
