- Email: [email protected]
Magnesium deficiency detected by intravenous loading test in variant angina pectoris
Magnesium Deficiency Detected by Intravenous Loading Test in Variant Angina Pectoris Kazuo Goto, MD, Hirofumi Yasue, MD, Ken Okumura, MD, Koshi Matsuyama, MD, Kiyotaka Kugiyama, MD, Hiroo Miyagi, MD, and Toshinobu Higashi, MD
To study whether magnesium (Mg) deficiency is present in patients with variant angina, 24-hour Mg retention of low dose Mg (0.2 mEq/kg lean body weight) administered intravenously over 4 hours in 20 patients with variant angina was examined. No patient had received calcium antagonists before or during the study. All had attacks of chest pain associated with ST elevation on electrocardiograms. Twenty-one subjects without ischemic heart disease were studied as control subjects. Ten patients with variant angina were restudied 10 to 525 days (mean 235 f 30) after the treatment with calcium antagonists (diltiazem 120 to 240 or nifedipine 40 to 60 mg/day), which resulted in complete suppression of angina1 attacks. The mean serum Mg concentrations in the patients with variant angina and the control subjects were 2.1 f 0.05 and 2.1 f 0.03 mg/dl, respectively (difference not significant). However, 24-hour Mg retention in the patients with variant angina was 60 f 5%, while that in the control subjects was 36 f 3% (p
From the Division of Cardiology, Kumamoto University Medical School, Kumamoto, Japan. This study was supported in part by a grantin-aid for scientific research (B62480218) from the Ministry of Education and a research grant (61C-4) from the Ministry of Health and Welfare, Japan. Manuscript received August 7, 1989; revised manuscript received and accepted November 27, 1989. Address for reprints: Hirofumi Yasue, MD, Division of Cardiology, Kumamoto University Medical School, l-l-l Honjo, Kumamoto City, Kumamoto 860, Japan.
I
t is now established that coronary spasm plays an important role in the pathogenesis of not only variant anginalm3 but also ischemic heart disease in generaL3m7However, the precise mechanism(s) by which coronary spasm occurs still remains unknown. Although previous studies have suggested that magnesium (Mg) deficiency may be involved in the pathogenesis of coronary spasm, no systematic clinical study of Mg metabolism in patients with variant angina has been performed. The present study was designed to use the intravenous Mg loading test to examine whether Mg deficiency is present in patients with variant angina, and if so, whether this deficiency can be corrected by treatment with calcium antagonists that suppress variant angina. METHODS Patients: We studied 20 patients with variant angina
(17 men and 3 women) whose ages ranged from 38 to 72 years (mean 57). All patients had attacks of chest pain associated with ST elevation on the electrocardiogram occurring at rest, usually from midnight to early morning. In all of them, coronary spasm was documented by coronary arteriography during spontaneous or induced angina1 attacks (induced by intracoronary injection of acetylcholine8m10 or intravenous administration of ergonovine maleate) in the cardiac catheterization laboratory. Clinical data including age, sex, electrocardiographic changes during attacks and coronary arteriographic findings are listed in Table I.” Ten of them (1 to 10) were restudied 10 to 529 days (mean 235 f 30) after the treatment with calcium antagonists (diltiazem 120 to 240 mg or nifedipine 40 to 80 mg/day), which resulted in complete suppression of angina1 attacks. Twenty-one subjects without ischemic heart disease, matched for age and sex with the variant angina patient group (17 men and 4 women ranging in age from 3 1 to 72, with a mean age of 51 years), were studied as control subjects. Six of them had atypical chest pain, 4 had valvular heart disease, 4 permanent pacemaker implantation, 3 arrhythmias, 1 patent ductus arteriosus and 3 were normal volunteers. None of the study patients in either group had previous myocardial infarction, heart failure, intestinal malabsorption, loss of body fluids, chronic excessive alcohol ingestion or liver cirrhosis, renal disease or diabetes mellitus. None of them had received calcium antagonists, diuretics, digitalis or other agents affecting Mg metabolism (such as gentamycin or carbenicillin) within at least 3 months before the study. This study was approved by the ethics committee of our institution and informed consent was obtained from each patient. THE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15, 1990
709
TABLE
I Electrocardiographic
and
Coronary
Arteriographic
Findings
in 20 Patients
with
Variant
Coronary Patient No.
Age Ws),
1
Sex
48. M
ST Elevation During Attack
During
II III aVF or Vz-5
s1 loo, Sll
2 3 4
50. M 55, M 57, M
5 6 7 8 9
60. 61, 63, 63, 72.
M M F F M
10 11 12 13 14 15 16 17 18
72, 38, 46, 48, 49, 53, 56, 57. 57.
M M M M M F M M M
19 20
58, M 67. M
S, to SIS refer to the segment NTG = nitroglycerin.
arteries
defined
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Attack
(%)
s, 90,
After NTG (%) Normal
100
s190, s7 loo s, loo, se loo SI loo, sg 90
ST 75 S, 25, S, 25 Normal
S? loo St 99, se 90 s, 99 s3 loo, s, 75 s, loo
V1-a, aVL II Ill aVF. Vs.6 I aVL, !I-6 II Ill aVF II Ill aVF II Ill aVF
s3
SJ 75 s7 50 Normal s3 50 4AV. 4PD 75 s13 75 Normal Normal Normal Normal Normal Normal Normal Normal S13 90,4AV 90
by the Amewan
VOLUME
65
sg s5 Sl s2 Sl
loo. se loo loo loo 100 99, s7 99 loo, sg loo
s,j100 s2 100, s13 S13 100.4AV
v2-6 s, loo s, 99 Heart Association
Magnesium loading test: The .^test ~ was based on the method proposed by Ryzen et al.lL For this test, dietary Mg intake and fecal Mg excretion were ignored, and patients were allowed to eat their regular diet during the study. Twenty-four-hour urine samples were collected to determine Mg excretion and creatinine clearance. After completion of baseline 24-hour urine collection, patients were given 0.2 mEq/kg lean body weight of intravenous Mg in 50 ml of 5% glucose over 4 hours. This dose was chosen so as not to exceed greatly the maximal renal tubular reabsorption of Mg.t3 The blood pressure, heart rate and deep tendon reflex were monitored during the Mg infusion. Blood specimens were obtained for determination of serum Mg, calcium, potassium and creatinine concentrations before and immediately after completion of the infusion. Twenty-four-hour urine samples beginning with the infusion were collected again for determination of urine Mg. The adequacy of 24-hour urine collection was checked by determining 24-hour urine creatinine excretion. Measurements: Serum and urine Mg concentrations were determined by atomic absorption spectrophotometry (Perkin Elmer 403). Serum calcium, potassium and creatinine concentrations, as well as urine creatinine concentrations, were determined by autoanalyzer (Technicon SMAC-1). The amount of Mg in 24-hour urine collection before the Mg infusion was considered as a basal urinary Mg excretion. This value was then subtracted from the amount of Mg in the postinfusion 24-hour urine collection. The difference of pre- and postinfusion 24-hour urinary Mg excretions was compared with the total amount of Mg infused and ex710
Arteriogram
VI-4 II Ill aVF, Vs.6 II III aVF, V5,6 or I, aVL. V5.6 I, aVL. V2-e II III aVF or V2-6 II Ill aVF II Ill aVF, Vs.6 il Ill aVF
V14 II III aVF II Ill aVF or 1 avL, II III aVF II III aVF
of the coronary
Angina
Commwx
loo 100
Normal S, 25
Report.”
pressed as a percent of loaded Mg retention at 24 hours after the infusion. Twenty-four-hour Mg retention (%) was calculated according to the formula: 24-hour Mg retention (%) = 1 _ Postinfusion U-Mg - Preinfusion U-Mg x 1oo Total elemental Mg infused where U-Mg is 24-hour urinary Mg excretion. Statistical analysis: All data were expressed as mean f standard error of the mean. The Student paired and unpaired t tests were used for the statistical analysis. A p value <0.05 was considered statistically significant.
1
RESULTS Magnesium retention in patients with variant angina: Serum calcium, potassium and creatinine concen-
trations were within normal ranges for all the study patients in both groups and there were no significant differences between the variant angina group and the control group (9.1 f 0.09 vs 9.3 f 0.09 mg/dl for calcium, 4.3 f 0.06 vs 4.1 f 0.07 mEq/liters for potassium, 1.1 f 0.03 vs 1.l f 0.04 mg/dl for creatinine, respectively). Serum Mg concentrations increased significantly after Mg infusion in both the variant angina group and the control group (from 2.1 f 0.05 to 2.8 f 0.06, p
the value between the 2 groups (90 f 3.9 ml/min for the variant angina group vs 88 f 3.8 ml/min for the control group). However, the patients with variant angina retained significantly greater amounts of Mg load than did the control subjects (60 f 5 vs 36 f 3%, p
mean serum Mg concentration before and after calcium antagonist treatment in 10 patients with variant angina (2.1 f 0.09 vs 2.1 f 0.07 mg/dl). There were also no significant changes in the mean serum calcium, potassium and creatinine concentrations before and after the treatment (9.2 f 0.04 vs 9.2 f 0.08 mg/dl for calcium, 4.3 f 0.09 vs 4.5 f 0.06 mEq/liters for potassium, 1.1 f 0.04 vs 1.1 f 0.07 mg/dl for creatinine, respectively). However, the retention of Mg load was significantly decreased after the treatment with calcium antagonists as compared with before the treatment (60 f 6 vs 34 f 7%, p
Mg has been shown to compete with calcium for the membrane and intracellular binding sites, eventually affecting the availability of calcium for development of tension.14,‘5 Previous in vitro studies have shown that
Mg deficiency constricts isolated dog lb and human” coronary arteries and Mg repletion dilates them. Epidemiologic studies have indicated that the mortality from ischemic heart disease has an inverse correlation with the intake of Mg. 18.iy Also, Mg deficiency has been found in patients with ischemic heart disease and an important role for Mg in ischemic heart disease has been postulated.20 Moreover, previous clinical studies?’ ~23have shown that the intravenous infusion of Mg suppresses attacks of variant angina. Thus, it is possible that Mg deficiency is involved in the pathogenesis of coronary spasm in patients with variant angina. Since only 1% of total body Mg is in the extracellular space,24serum Mg concentrations may not accurately reflect total body Mg content. The Mg loading test has been used to assessMg deficiency.‘2J5m’7 The reliability of this test as a true estimate of an intracellular Mg deficiency has been demonstrated in previous studies 25.28
The present study indicates that many patients with variant angina have Mg deficiency. Although there was some overlap of Mg retention between the variant angina group and the control group, 9 (45%) of the 20 patients with variant angina had increased Mg retention greater than the range for the control subjects. The clinical conditions that may lead to Mg depletion were not found in any of the patients with variant angina in the present study. Reduced intake due to inadequate dietary habits could not be excluded as a possible cause of Mg deficiency in these patients. Acute stress of the attacks with elevated levels of catechol-
p (0.001
100
I
p (0.01
I
100
l
f l
: :e
40
l@ iP
60
r”
1 T P
l
mean
l
20
80
.-: +;
l
8
1 N
s V
0
:
I
r
f 3 l
- P:
I
k.SEM
; @e
00 Variant
Angina (n=20>
Control (n=21)
FIGURE 1. Twenty-four-hour magnesium (Mg) retention (%) in patients with variant angina and control subjects. Mean retention of Mg was signifkantly highsr in patients with variant angina than control subjects. SEM = standard errar of the mean.
mean
+SEM
0 before
after
FIGURE 2. Twenty-four-hour magnesium (Mg) retention (%) bsfore and after cakiim antagonist treatment in 10 patients with variant angina. Mg ret&ion decreased significanUy after treatment with cakium antagonists. SEM = standard error of ths mean.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15, 1990
711
amines and subsequent changes in the renal handling of Mg or an increased intracellular precipitation of insoluble Mg soaps could also lead to Mg deficiency in these patients as in patients with acute myocardial infarction 29,30 Because Mg deficiency is known to cause coronary vasoconstriction, the present study indicates that Mg deficiency is involved in or predisposed to the production of coronary spasm in at least some patients with variant angina. However, Mg deficiency may not be the sole cause of variant angina because not all patients with variant angina are associated with Mg depletion. Thus, pathogenesis of coronary spasm may be multifactorial. The present study also showed that increased Mg retention in patients with variant angina decreased to the levels of control subjects after the attacks were completely suppressed with treatment with calcium antagonists. This may be because the calcium antagonists corrected Mg deficiency or because Mg deficiency was secondary to the stress of angina1 attacks as in acute myocardial infarction and was improved after disap pearance of angina1 attacks caused by the treatment with calcium antagonists. 29 Further studies are required to clarify these problems. Acknowledgment: We thank Yoko Shibuya, Umeko Senba and Koichi Nagata for the technical advice for determining Mg concentration.
REFERENCES 1. Yasue H, Touyama M, Kato H, Tanaka S, Akiyama F. Prinzmetal’s variant form of angina as a manifestation of a-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. Am Heart J 1976: 91:148-155. 2. Oliva PB, Potts DE, Plus RG. Coronary arterial spasm in Prinzmetal’s angina. Documentation by coronary arteriography. N Engl J Med 1973;288:745-751. 3. Maseri A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra A, Parcdi 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardioll978;42:10/9-1035. 4. Yasue H, Omote S, Takizawa A, Nagao M. Coronary arterial spasm in ischemic heart disease and its pathogenesis: a review. Circ Res 1983;52(supp/ l):f147-l-152. 5. Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Exertional angina pectoris caused by coronary arterial spasm: effects of various drugs. Am J Cardiol 1979;43:647-652. 6. Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myccardial infarction. Circulation 1977;56:366-374. 7. Maseri A, L’Abbate A, Baloldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi 0, Biagini A, Distante A, Pesola A. Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of “preinfarction” angina. N Engl J Med 1978;299:1271-1277.
712
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
8. Horio Y, Yasue H, Okumura K, Takaoka K, Matsuyama K, Goto K. Minoda K. Effects of intracoronary injection of acetylcholine on coronary arterial hemodynamics and diameter. Am J Cardiol 1988.62:887-891. 9. Yasue H, Horio Y, Nakamura N. Fujii H, lmoto N. Son&a R. Kugiyama K. Obata K, Morikami Y. Kimura T. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nerve system in the pathogenesis of coronary artery spasm. Circulation /986;74:955963. 10. Okumura K, Yasue H, Matsuyama K, Goto K. Miyagi H, Ogawa H. Matsuyama K. Sensitivity and specificity of injection of acetylcholine for the induction of coronary artery spasm. JACC 1988:12:883-888, 11. AHA Committee Report. Circulation 1975;5/:5-9. 12. Ryzen E, Elbaum N, Singer FR, Rude RK. Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium /985;4:/37-147. 13. Rude RK, Bethune JE, Singer FR. Renal tubular maximum for magnesium in normal, hyperparathyroid, and hypoparathyroid man. J C/in Endocrinol Merab 1980;51:1425-1431. 14. Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Hem J 1984;108:188-193, 15. Altura BM, Altura BT. Magnesium, electrolyte transport and coronary vascular tone. Drugs 1984;28(suppl 1):120-142. 16. Turlapaty PDMV, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science 1980:208:198-200. 17. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jogasaki M, Araki H. Effect of magnesium on the tone of isolated human coronary arteries. Comparison with diltiazem and nitroglycerin. Circulation /989:79:/l 18-1124. IS. Karppanen H. Epidemiological studies on the relationship between magnesium intake and cardiovascular diseases. Artery /98/,9:/90-199. 19. Anderson TW, Neri LC, Schteiber GB, Talbot FDF. Zdrojewski A. Ischemic heart disease, water hardness and myocardial infarction. Can Med Assoc J 1975:113:199-203. 20. Rasmussen HS, McNair P, Goransson L. Larson OG, Balslov S, Aurup P. Magnesium deficiency in patients with ischemic heart disease with and without acute myocardial infarction uncovered by an intravenous loading test. Arch In/em Med 1988;148:329-332. 21. Kugiyama K, Yasue H. Okumura K, Goto K. Mincda K. Miyagi H. Matsuyama K, Kojima A, Koga Y, Takahashi M. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina. JACC 1988: 12:1177-1183. 22. Miyagi H, Yasue H, Okumura K, Ogawa H. Goto K, Oshima S. Effect of magnesium on angina1 attack induced by hyperventilation in patients with variant angina. Circulation 1989:79:597-602. 23. Cohen L, Kitzcs R. Magnesium sulfate in the treatment of variant angina. Magnesium 1984;3:46-49. 24. Quamme GA, Dirks JH. Magnesium metabolism. In: Maxwell MH, Kleeman CR, Narins RG, eds. Clinical Disorders of Fluid and Electrolyte Metabolism (Fourth Ed). New York: McGraw-Hill 1987;297-316. 25. Jones JE, Shane SR, Jacobs WH, Flink EB. Magnesium balance studies in chronic alcoholism. Ann NY Acad Sci 1969:162:934-946. 26. Bohmer T, Mathesen B. Magnesiuin deficiency in chronic alcoholic patients uncovered by an intravenous loading test. Stand J C/in Lab Invest 1982;42:633636. 27. Caddell JL, Saier FL, Thomason CA. Parenteral magnesium load tests in postpartum American women. Am J C/in Nurr 1975;28:1099-1104. 28. Martin HE. Clinical magnesium deficiency. Ann NY Acad Sri 1969;/62. 891-900. 29. Rasmussen HS, Aurap P, Hojberg S, Jensen EK. McNair P. Magnesium and acute myocardial infarction: transient myocardial ischemia not induced by renal magnesium loss in patients with acute myocardial infarction. Arch lnrern Med 1986:146:872X+74, 30. Flink EB, Shane SR, Scobbo RR, Blehschmidt NG, McDowell P. Relationship of free fatty acids and magnesium in ethanol withdrawal in dogs. Merabolism 1979:28:858-865.
To study whether magnesium (Mg) deficiency is present in patients with variant angina, 24-hour Mg retention of low dose Mg (0.2 mEq/kg lean body weight) administered intravenously over 4 hours in 20 patients with variant angina was examined. No patient had received calcium antagonists before or during the study. All had attacks of chest pain associated with ST elevation on electrocardiograms. Twenty-one subjects without ischemic heart disease were studied as control subjects. Ten patients with variant angina were restudied 10 to 525 days (mean 235 f 30) after the treatment with calcium antagonists (diltiazem 120 to 240 or nifedipine 40 to 60 mg/day), which resulted in complete suppression of angina1 attacks. The mean serum Mg concentrations in the patients with variant angina and the control subjects were 2.1 f 0.05 and 2.1 f 0.03 mg/dl, respectively (difference not significant). However, 24-hour Mg retention in the patients with variant angina was 60 f 5%, while that in the control subjects was 36 f 3% (p
From the Division of Cardiology, Kumamoto University Medical School, Kumamoto, Japan. This study was supported in part by a grantin-aid for scientific research (B62480218) from the Ministry of Education and a research grant (61C-4) from the Ministry of Health and Welfare, Japan. Manuscript received August 7, 1989; revised manuscript received and accepted November 27, 1989. Address for reprints: Hirofumi Yasue, MD, Division of Cardiology, Kumamoto University Medical School, l-l-l Honjo, Kumamoto City, Kumamoto 860, Japan.
I
t is now established that coronary spasm plays an important role in the pathogenesis of not only variant anginalm3 but also ischemic heart disease in generaL3m7However, the precise mechanism(s) by which coronary spasm occurs still remains unknown. Although previous studies have suggested that magnesium (Mg) deficiency may be involved in the pathogenesis of coronary spasm, no systematic clinical study of Mg metabolism in patients with variant angina has been performed. The present study was designed to use the intravenous Mg loading test to examine whether Mg deficiency is present in patients with variant angina, and if so, whether this deficiency can be corrected by treatment with calcium antagonists that suppress variant angina. METHODS Patients: We studied 20 patients with variant angina
(17 men and 3 women) whose ages ranged from 38 to 72 years (mean 57). All patients had attacks of chest pain associated with ST elevation on the electrocardiogram occurring at rest, usually from midnight to early morning. In all of them, coronary spasm was documented by coronary arteriography during spontaneous or induced angina1 attacks (induced by intracoronary injection of acetylcholine8m10 or intravenous administration of ergonovine maleate) in the cardiac catheterization laboratory. Clinical data including age, sex, electrocardiographic changes during attacks and coronary arteriographic findings are listed in Table I.” Ten of them (1 to 10) were restudied 10 to 529 days (mean 235 f 30) after the treatment with calcium antagonists (diltiazem 120 to 240 mg or nifedipine 40 to 80 mg/day), which resulted in complete suppression of angina1 attacks. Twenty-one subjects without ischemic heart disease, matched for age and sex with the variant angina patient group (17 men and 4 women ranging in age from 3 1 to 72, with a mean age of 51 years), were studied as control subjects. Six of them had atypical chest pain, 4 had valvular heart disease, 4 permanent pacemaker implantation, 3 arrhythmias, 1 patent ductus arteriosus and 3 were normal volunteers. None of the study patients in either group had previous myocardial infarction, heart failure, intestinal malabsorption, loss of body fluids, chronic excessive alcohol ingestion or liver cirrhosis, renal disease or diabetes mellitus. None of them had received calcium antagonists, diuretics, digitalis or other agents affecting Mg metabolism (such as gentamycin or carbenicillin) within at least 3 months before the study. This study was approved by the ethics committee of our institution and informed consent was obtained from each patient. THE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15, 1990
709
TABLE
I Electrocardiographic
and
Coronary
Arteriographic
Findings
in 20 Patients
with
Variant
Coronary Patient No.
Age Ws),
1
Sex
48. M
ST Elevation During Attack
During
II III aVF or Vz-5
s1 loo, Sll
2 3 4
50. M 55, M 57, M
5 6 7 8 9
60. 61, 63, 63, 72.
M M F F M
10 11 12 13 14 15 16 17 18
72, 38, 46, 48, 49, 53, 56, 57. 57.
M M M M M F M M M
19 20
58, M 67. M
S, to SIS refer to the segment NTG = nitroglycerin.
arteries
defined
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Attack
(%)
s, 90,
After NTG (%) Normal
100
s190, s7 loo s, loo, se loo SI loo, sg 90
ST 75 S, 25, S, 25 Normal
S? loo St 99, se 90 s, 99 s3 loo, s, 75 s, loo
V1-a, aVL II Ill aVF. Vs.6 I aVL, !I-6 II Ill aVF II Ill aVF II Ill aVF
s3
SJ 75 s7 50 Normal s3 50 4AV. 4PD 75 s13 75 Normal Normal Normal Normal Normal Normal Normal Normal S13 90,4AV 90
by the Amewan
VOLUME
65
sg s5 Sl s2 Sl
loo. se loo loo loo 100 99, s7 99 loo, sg loo
s,j100 s2 100, s13 S13 100.4AV
v2-6 s, loo s, 99 Heart Association
Magnesium loading test: The .^test ~ was based on the method proposed by Ryzen et al.lL For this test, dietary Mg intake and fecal Mg excretion were ignored, and patients were allowed to eat their regular diet during the study. Twenty-four-hour urine samples were collected to determine Mg excretion and creatinine clearance. After completion of baseline 24-hour urine collection, patients were given 0.2 mEq/kg lean body weight of intravenous Mg in 50 ml of 5% glucose over 4 hours. This dose was chosen so as not to exceed greatly the maximal renal tubular reabsorption of Mg.t3 The blood pressure, heart rate and deep tendon reflex were monitored during the Mg infusion. Blood specimens were obtained for determination of serum Mg, calcium, potassium and creatinine concentrations before and immediately after completion of the infusion. Twenty-four-hour urine samples beginning with the infusion were collected again for determination of urine Mg. The adequacy of 24-hour urine collection was checked by determining 24-hour urine creatinine excretion. Measurements: Serum and urine Mg concentrations were determined by atomic absorption spectrophotometry (Perkin Elmer 403). Serum calcium, potassium and creatinine concentrations, as well as urine creatinine concentrations, were determined by autoanalyzer (Technicon SMAC-1). The amount of Mg in 24-hour urine collection before the Mg infusion was considered as a basal urinary Mg excretion. This value was then subtracted from the amount of Mg in the postinfusion 24-hour urine collection. The difference of pre- and postinfusion 24-hour urinary Mg excretions was compared with the total amount of Mg infused and ex710
Arteriogram
VI-4 II Ill aVF, Vs.6 II III aVF, V5,6 or I, aVL. V5.6 I, aVL. V2-e II III aVF or V2-6 II Ill aVF II Ill aVF, Vs.6 il Ill aVF
V14 II III aVF II Ill aVF or 1 avL, II III aVF II III aVF
of the coronary
Angina
Commwx
loo 100
Normal S, 25
Report.”
pressed as a percent of loaded Mg retention at 24 hours after the infusion. Twenty-four-hour Mg retention (%) was calculated according to the formula: 24-hour Mg retention (%) = 1 _ Postinfusion U-Mg - Preinfusion U-Mg x 1oo Total elemental Mg infused where U-Mg is 24-hour urinary Mg excretion. Statistical analysis: All data were expressed as mean f standard error of the mean. The Student paired and unpaired t tests were used for the statistical analysis. A p value <0.05 was considered statistically significant.
1
RESULTS Magnesium retention in patients with variant angina: Serum calcium, potassium and creatinine concen-
trations were within normal ranges for all the study patients in both groups and there were no significant differences between the variant angina group and the control group (9.1 f 0.09 vs 9.3 f 0.09 mg/dl for calcium, 4.3 f 0.06 vs 4.1 f 0.07 mEq/liters for potassium, 1.1 f 0.03 vs 1.l f 0.04 mg/dl for creatinine, respectively). Serum Mg concentrations increased significantly after Mg infusion in both the variant angina group and the control group (from 2.1 f 0.05 to 2.8 f 0.06, p
the value between the 2 groups (90 f 3.9 ml/min for the variant angina group vs 88 f 3.8 ml/min for the control group). However, the patients with variant angina retained significantly greater amounts of Mg load than did the control subjects (60 f 5 vs 36 f 3%, p
mean serum Mg concentration before and after calcium antagonist treatment in 10 patients with variant angina (2.1 f 0.09 vs 2.1 f 0.07 mg/dl). There were also no significant changes in the mean serum calcium, potassium and creatinine concentrations before and after the treatment (9.2 f 0.04 vs 9.2 f 0.08 mg/dl for calcium, 4.3 f 0.09 vs 4.5 f 0.06 mEq/liters for potassium, 1.1 f 0.04 vs 1.1 f 0.07 mg/dl for creatinine, respectively). However, the retention of Mg load was significantly decreased after the treatment with calcium antagonists as compared with before the treatment (60 f 6 vs 34 f 7%, p
Mg has been shown to compete with calcium for the membrane and intracellular binding sites, eventually affecting the availability of calcium for development of tension.14,‘5 Previous in vitro studies have shown that
Mg deficiency constricts isolated dog lb and human” coronary arteries and Mg repletion dilates them. Epidemiologic studies have indicated that the mortality from ischemic heart disease has an inverse correlation with the intake of Mg. 18.iy Also, Mg deficiency has been found in patients with ischemic heart disease and an important role for Mg in ischemic heart disease has been postulated.20 Moreover, previous clinical studies?’ ~23have shown that the intravenous infusion of Mg suppresses attacks of variant angina. Thus, it is possible that Mg deficiency is involved in the pathogenesis of coronary spasm in patients with variant angina. Since only 1% of total body Mg is in the extracellular space,24serum Mg concentrations may not accurately reflect total body Mg content. The Mg loading test has been used to assessMg deficiency.‘2J5m’7 The reliability of this test as a true estimate of an intracellular Mg deficiency has been demonstrated in previous studies 25.28
The present study indicates that many patients with variant angina have Mg deficiency. Although there was some overlap of Mg retention between the variant angina group and the control group, 9 (45%) of the 20 patients with variant angina had increased Mg retention greater than the range for the control subjects. The clinical conditions that may lead to Mg depletion were not found in any of the patients with variant angina in the present study. Reduced intake due to inadequate dietary habits could not be excluded as a possible cause of Mg deficiency in these patients. Acute stress of the attacks with elevated levels of catechol-
p (0.001
100
I
p (0.01
I
100
l
f l
: :e
40
l@ iP
60
r”
1 T P
l
mean
l
20
80
.-: +;
l
8
1 N
s V
0
:
I
r
f 3 l
- P:
I
k.SEM
; @e
00 Variant
Angina (n=20>
Control (n=21)
FIGURE 1. Twenty-four-hour magnesium (Mg) retention (%) in patients with variant angina and control subjects. Mean retention of Mg was signifkantly highsr in patients with variant angina than control subjects. SEM = standard errar of the mean.
mean
+SEM
0 before
after
FIGURE 2. Twenty-four-hour magnesium (Mg) retention (%) bsfore and after cakiim antagonist treatment in 10 patients with variant angina. Mg ret&ion decreased significanUy after treatment with cakium antagonists. SEM = standard error of ths mean.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15, 1990
711
amines and subsequent changes in the renal handling of Mg or an increased intracellular precipitation of insoluble Mg soaps could also lead to Mg deficiency in these patients as in patients with acute myocardial infarction 29,30 Because Mg deficiency is known to cause coronary vasoconstriction, the present study indicates that Mg deficiency is involved in or predisposed to the production of coronary spasm in at least some patients with variant angina. However, Mg deficiency may not be the sole cause of variant angina because not all patients with variant angina are associated with Mg depletion. Thus, pathogenesis of coronary spasm may be multifactorial. The present study also showed that increased Mg retention in patients with variant angina decreased to the levels of control subjects after the attacks were completely suppressed with treatment with calcium antagonists. This may be because the calcium antagonists corrected Mg deficiency or because Mg deficiency was secondary to the stress of angina1 attacks as in acute myocardial infarction and was improved after disap pearance of angina1 attacks caused by the treatment with calcium antagonists. 29 Further studies are required to clarify these problems. Acknowledgment: We thank Yoko Shibuya, Umeko Senba and Koichi Nagata for the technical advice for determining Mg concentration.
REFERENCES 1. Yasue H, Touyama M, Kato H, Tanaka S, Akiyama F. Prinzmetal’s variant form of angina as a manifestation of a-adrenergic receptor-mediated coronary artery spasm: documentation by coronary arteriography. Am Heart J 1976: 91:148-155. 2. Oliva PB, Potts DE, Plus RG. Coronary arterial spasm in Prinzmetal’s angina. Documentation by coronary arteriography. N Engl J Med 1973;288:745-751. 3. Maseri A, Severi S, De Nes M, L’Abbate A, Chierchia S, Marzilli M, Ballestra A, Parcdi 0, Biagini A, Distante A. “Variant angina”: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardioll978;42:10/9-1035. 4. Yasue H, Omote S, Takizawa A, Nagao M. Coronary arterial spasm in ischemic heart disease and its pathogenesis: a review. Circ Res 1983;52(supp/ l):f147-l-152. 5. Yasue H, Omote S, Takizawa A, Nagao M, Miwa K, Tanaka S. Exertional angina pectoris caused by coronary arterial spasm: effects of various drugs. Am J Cardiol 1979;43:647-652. 6. Oliva PB, Breckinridge JC. Arteriographic evidence of coronary arterial spasm in acute myccardial infarction. Circulation 1977;56:366-374. 7. Maseri A, L’Abbate A, Baloldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi 0, Biagini A, Distante A, Pesola A. Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of “preinfarction” angina. N Engl J Med 1978;299:1271-1277.
712
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
8. Horio Y, Yasue H, Okumura K, Takaoka K, Matsuyama K, Goto K. Minoda K. Effects of intracoronary injection of acetylcholine on coronary arterial hemodynamics and diameter. Am J Cardiol 1988.62:887-891. 9. Yasue H, Horio Y, Nakamura N. Fujii H, lmoto N. Son&a R. Kugiyama K. Obata K, Morikami Y. Kimura T. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nerve system in the pathogenesis of coronary artery spasm. Circulation /986;74:955963. 10. Okumura K, Yasue H, Matsuyama K, Goto K. Miyagi H, Ogawa H. Matsuyama K. Sensitivity and specificity of injection of acetylcholine for the induction of coronary artery spasm. JACC 1988:12:883-888, 11. AHA Committee Report. Circulation 1975;5/:5-9. 12. Ryzen E, Elbaum N, Singer FR, Rude RK. Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium /985;4:/37-147. 13. Rude RK, Bethune JE, Singer FR. Renal tubular maximum for magnesium in normal, hyperparathyroid, and hypoparathyroid man. J C/in Endocrinol Merab 1980;51:1425-1431. 14. Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Hem J 1984;108:188-193, 15. Altura BM, Altura BT. Magnesium, electrolyte transport and coronary vascular tone. Drugs 1984;28(suppl 1):120-142. 16. Turlapaty PDMV, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science 1980:208:198-200. 17. Kimura T, Yasue H, Sakaino N, Rokutanda M, Jogasaki M, Araki H. Effect of magnesium on the tone of isolated human coronary arteries. Comparison with diltiazem and nitroglycerin. Circulation /989:79:/l 18-1124. IS. Karppanen H. Epidemiological studies on the relationship between magnesium intake and cardiovascular diseases. Artery /98/,9:/90-199. 19. Anderson TW, Neri LC, Schteiber GB, Talbot FDF. Zdrojewski A. Ischemic heart disease, water hardness and myocardial infarction. Can Med Assoc J 1975:113:199-203. 20. Rasmussen HS, McNair P, Goransson L. Larson OG, Balslov S, Aurup P. Magnesium deficiency in patients with ischemic heart disease with and without acute myocardial infarction uncovered by an intravenous loading test. Arch In/em Med 1988;148:329-332. 21. Kugiyama K, Yasue H. Okumura K, Goto K. Mincda K. Miyagi H. Matsuyama K, Kojima A, Koga Y, Takahashi M. Suppression of exercise-induced angina by magnesium sulfate in patients with variant angina. JACC 1988: 12:1177-1183. 22. Miyagi H, Yasue H, Okumura K, Ogawa H. Goto K, Oshima S. Effect of magnesium on angina1 attack induced by hyperventilation in patients with variant angina. Circulation 1989:79:597-602. 23. Cohen L, Kitzcs R. Magnesium sulfate in the treatment of variant angina. Magnesium 1984;3:46-49. 24. Quamme GA, Dirks JH. Magnesium metabolism. In: Maxwell MH, Kleeman CR, Narins RG, eds. Clinical Disorders of Fluid and Electrolyte Metabolism (Fourth Ed). New York: McGraw-Hill 1987;297-316. 25. Jones JE, Shane SR, Jacobs WH, Flink EB. Magnesium balance studies in chronic alcoholism. Ann NY Acad Sci 1969:162:934-946. 26. Bohmer T, Mathesen B. Magnesiuin deficiency in chronic alcoholic patients uncovered by an intravenous loading test. Stand J C/in Lab Invest 1982;42:633636. 27. Caddell JL, Saier FL, Thomason CA. Parenteral magnesium load tests in postpartum American women. Am J C/in Nurr 1975;28:1099-1104. 28. Martin HE. Clinical magnesium deficiency. Ann NY Acad Sri 1969;/62. 891-900. 29. Rasmussen HS, Aurap P, Hojberg S, Jensen EK. McNair P. Magnesium and acute myocardial infarction: transient myocardial ischemia not induced by renal magnesium loss in patients with acute myocardial infarction. Arch lnrern Med 1986:146:872X+74, 30. Flink EB, Shane SR, Scobbo RR, Blehschmidt NG, McDowell P. Relationship of free fatty acids and magnesium in ethanol withdrawal in dogs. Merabolism 1979:28:858-865.