Importance of magnesium deficiency in alcohol-induced variant angina

Importance of Magnesium Deficiency in AlcohoClnduced Variant Angina Kunihisa Miwa, MD, Akihiko lgawa, MD, Yuko Miyagi, MD, and Masatoshi Fujita, MD t is well recognized that alcohol is a precipitating fac- out alcohol-induced angina1 attacks, and 9 normal subIAngina1 tor of angina1 attacks in patients with variant angina. 1,2 jects. Protocol 2 included 8 additional patients with alattacks in some patients with variant angina are cohol-induced attacks of variant angina (Table I). In all, closely related to alcohol ingestion.2 The attacks usually occur several hours after alcohol ingestion. Therefore, it is postulated that angina may be induced by a major metabolite, acetaldehyde, rather than the direct action of alcohol.2 Catecholamines released by acetaldehyde may induce coronary spasm through a-adrenergic receptors that are present in large coronary arteries. However, the precise mechanisms responsible for the occurrence of coronary spasm by the ingestion of alcohol have not been elucidated fully. Recent studies indicated that magnesium (Mg) deficiency may be involved in the pathogenesis of coronary spasm. 3,4Because urinary Mg excretion is augmented by alcohol drinking,5 Mg deficiency may be responsible for angina1 attacks related to alcohol ingestion. The present study was designed to examine: (1) whether there is Mg deficiency in patients with alcoholinduced variant angina, and (2) whether intravenously administered Mg is effective in suppressing alcohol-induced variant angina. This study comprised 2 separate protocols. Protocol I included 21 patients with variant angina, with or with-

29 patients (25 men and 4 women; age range 37 to 73 years, mean 5.5) with variant angina were studied. Patients were carefully interviewed to determine the relation between alcohol ingestion and angina1 attacks. Angina1 attacks were considered to be related to alcohol ingestion when I of the following criteria was ful$lled: (I) The attacks occurred only after alcohol ingestion; (2) the attacks occurred 22 times more frequently after alcohol ingestion; or (3) the attacks occurred 22 times more frequently after alcohol ingestion of more than the usual daily consumption. All patients had recurrent angina1 attacks associated with ST elevation occurring at rest, usually from midnight to early morning. In all patients, coronary spasm was documented by coronary arteriography during spontaneous or acetylcholine-induced angina1 attacks.” Twenty-one patients with variant angina and 9 control subjects were studied for the Mg-loading test (protocol I). Patients with variant angina were divided into 2 groups: group A, 10 patients with alcohol-induced angina1 attacks; and group B, 11 with variant angina unrelated to alcohol ingestion. Nine subjects without ischemic heart disease, matched for age and sex with patients with variant angina, were studied as a control. In all control subjects, daily alcohol consumption was ~90 g. The mean daily alcoholic consumption level in group A (65 k 7 glday) was signifi-

From the Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-01, Japan. Manuscript received June 4, 1993; revised manuscript received August 2, 1993, and accepted August 3.

TABLE Protocol

I Clinical

Findings

in Patients

with

Variant

Angina

and Alcohol-Induced

Patient No.

Age (yr) & Sex

1 2

43M 66M

for

Coronary Arteriographic Findings (% stenosis)

Electrocardiographic Changes During Attacks ST t W-4) ST t (II, III, aVF)

Exemse Test

Control

ST t P/z-4) ST t (II, Ill, aVF)

3

65F

ST t (V3m6)

ST 1 (II, Ill, aVF, V3-6)

4

ST? ST? ST1

W-4) (V1-5) W-5)

ST 1 (II, Ill, aVF, V5,6) ST 1 (II, III, aVF, V&6)

6

33M 43M 59M

7 8

51M

ST?

(h,z)

58M

ST t (II, Ill, aVF)

ST?

(Vz-4)

ST?

(V3-5)

ND

ACh

6:90

100%

2:25 7:o IO:99

100%

1l:O 6:90 9:90% 11,

5

Attacks

2

90% 100% 99% 99%

12, 13:75% 7:90 7:90 7~25 4:o 6:75 1:o 4:o 6, 1l:O

100% 100% 90% 99% 90% 90% 99%

100%

13:75% ACh = intracoronary iqecbon of acetylchollne6; coronary artery segment was numbered according to American Heart Association committee report’ ; ND = not done; ST t = ST-segment elevation; ST 1 = ST-segment depression

BRIEF REPORTS 813

TABLE Variant

II Effects Angina

of Alcohol

Intake

and Magnesium

Infusion

on Spontaneous

Day 1 (Control) Patient No.

Sp Attacks (no.)

HV

1

ST?

ST f in V3-5 0.3 mV HV 3’30” ST f in II, III, aVF, V6 0.25 mV ST f in V4-6 0.2 mV HV 5’ ST t in VI-3 0.2 mV ST f in VI-4 0.4 mV ST t in Vz-4 0.35 mV ST t In V3-5 0.2 mV ST t in II, Ill, aVF 0.25 mV

0

in VI-5 0.25 mV in Vi-3 0.25 mV in Vi-5 0.2 mV In%50.2mV in II, Ill, aVF

mV

0.5 * 0.4

2.0 + 0.8*

in Patients

with

Day 3 (Alcohol + Mg)

HV

1

inV1-5

0.3 mV HV 4’30” ST t in II, III, aVF 0.1 mV ST t ST T ST t STJ ST t 0.25

Attacks

Day 2 (Alcohol)

Sp Attacks (no.)

1

and Hyperventilation-Induced

Sp Attacks (no.)

HV

1

STt

0

0.25 mV HV 4’05” -

inV3-5

5

-

1 0 1

ST T in VI-3 0.15 mV -

3 0

ST f in Vl,z 0.15 mV ST t in II, Ill, aVF 0.2 mV

1.4 2 0.6

*p < 0.05 versus day 1 by Wilcoxon’s signed-rank test. Values presented as mean ? SEM. Day 1 = control (no alcohol); Day 2 = alcohol Intake on night before: Day 3 = after alcohol intake on night before, magnesium sulfate was Infused at 7 A.M.: HV = hypewentilatwn test (vigorous hyperventilation was performed for 6 minutes unless otherwise stated); Sp = spontaneous: - = negative; other abbreviations as I” Table I.

cantly higher than in the control group (34 + 11 glday; p ~0.05) and group B (41 f 9 glday; p ~0.05). Eight additional patients with variant angina and alcohol-induced attacks were studied for the alcohol-hyperventilation study (protocol 2) (Table I). Calcium antagonists were never administered before the study, exceptfor temporary use of 13 days, and these drugs were withheld NS

I P-CO.01 -)I

P
’

l l

l

0 Control

Group A

Group

B

RGURE 1. Twenty-four-hour magnesium (Mg) retention in 9 control subjects, and 10 patients with alcoholinduced variant angina (Group A), and 11 with variant angina unrelated to alcohol ingestion (Group B). Mean retention of magnesium was significantly higher in group A than In control subjects (p ~0.01) and group B (p <0.05).

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for 23 days before and during the study. No patient had previous myocardial infarction, heart failure, intestinal malabsorption, loss of body JEuids,liver cirrhosis, renal disease or alcoholism. Alcohol was forbidden for 23 days before the study. The Mg-loading test was based on the method described by Ryzen et a1.8 Twenty-fourhour urine samples were obtained to determine Mg excretion and creatinine clearance. After completion of baseline 24-hour urine collection, patients were administered 0.1 mMlkg of body weight of intravenous Mg sulfate in 50 ml of 5% glucose over 4 hours. Blood specimens were obtained for determination of serum Mg concentration before and immediately after completion of the infusion. Twenty-four-hour urine samples, beginning with the infusion, were obtained again for determination of urine Mg. The adequacy of the 24-hour urine collection was checked by determining the 24-hour urine creatinine excretion. Before protocol 2, all 8patients underwent a control hyperventilation test resulting in an angina1 attack accompanied by ST-segment elevation. The hyperventilation test was then repeated in the early morning (from 6 A.M. to 8 A.M.) successively for 3 days. Patients were asked to peflorm the hyperventilation test in which they vigorously hyperventilated for 6 minutes. If chest pain or ischemic ST-segment changes on the electrocardiogram appeared during hyperventilation, the test was terminated immediately. Sublingual nitroglycerin was administered when the attack was induced. In the evenings of days 1 and 2, all patients drank approximately 56 g of alcohol contained in beer (4.5% alcohol content) or Japanese sake (15%). On days I (control study) and 2 (alcohol study), 1 hour before the hyperventilation test, 100 ml of 5% glucose solution was infused for 20 minutes as a placebo. On day 3 (alcohol + Mg study), I hour before the hyperventilation test, Mg sulfate (0.27 mMlkg of body weight) dissolved in 100 ml of 5% glucose solution was infused for 20 minutes, The degree of ST-segment shif was measured at a point 80

APRIL 15,1994

ms after the nadir of the S wave. The hyperventilation test was considered positive if angina1 attacks associated with ischemic ST-segment changes were provoked by hyperventilation. If a shorter hyperventilation time needed to induce an angina1 attack, greater (>O.l mV) ST-segment elevation or change from negative to positive hyperventilation test was observed after ingestion of alcohol, alcohol was considered to have a detrimental effect on the hyperventilation test. During the 3-day study period, a diary of angina1 attacks was recorded, and oscilloscopic electrocardiographic monitoring was performed continuously in all patients. The number of spontaneous ischemic episodes indicated by angina1 attacks or ST-segment elevation was counted, and daily urinary Mg excretion was estimated each day. All data are presented as mean 5 SEM. In protocol I, serum Mg concentrations increased significantly (p < 0.01) after Mg infusion in both the variant angina (group A: 2.0 + 0.1 to 2.6 * 0.1 mgldl; and group B: 2.1 z!~0.1 to 2.7 f 0.1 mgldl) and control (1.9 -t 0.1 to 2.5 f 0.1 mgldl) groups. Creatinine clearance was within the normal range in all study patients. However, patients with variant angina (groups A and B) retained signiJcantly greater amounts of Mg load than did control subjects (50 + 6% vs 31 * 7%; p ~0.01). Variant angina1 patients with alcohol-induced attacks retained significantly greater amounts of Mg load (60 + 8%) than did those without them (40 + 8%; p ~0.05) and control subjects (31 + 7%; p ~0.01) (Figure I). Twenty-four-hour Mg retention in patients with variant angina unrelated to alcohol ingestion was slightly greater than in control subjects (p = NS). The results of protocol 2 are summarized in Table II. In 7 of 8 patients (88%), the angina1 attack was induced by hyperventilation during the control study on day 1. In 1 patient, the attack occurred during the process of hyperventilation, and in the remaining 6, it occurred a mean of 4 minutes

(range 1 to 7) after the termination of hyperventilation. On day 2 after receiving alcohol (alcohol study), all 8 patients (100%) had angina during the hyperventilation test. The negative result changed to positive in 1 patient (no. 6). A shorter hyperventilation time was needed to induce an angina1 attack in 2 patients (nos. 1 and 3). The extent of ST-segment elevation increased in 2 patients (nos. 2 and 5). Thus, a detrimental effect of alcohol ingestion on the hyperventilation test was observed in 5 of 8 patients (63%). Spontaneous attacks occurred significantly (p ~0.05) more frequently on day 2 than on day 1 (2.0 + 0.8 vs 0.5 f 0.4). On day 3, all patients had transient facialgushing during Mg infusion. Serum Mg concentration increasedfrom 2.2 + 0.2 to 4.6 f 0.4 mgldl, 20 minutes after the infusion of Mg solution. No attacks were provoked by hyperventilation in 4 of 8 patients (50%) after intravenous administration of Mg sulfate (p co.05 vs alcohol study). Spontaneous angina was also completely suppressed in 4 of 8 patients (50%) after administration of Mg sulfate (after 8 A.M. on day 3). The frequency of spontaneous attacks (1.4 + 0.6) tended to decrease on day 3 compared with day 2. Figure 2 shows a representative patient (no. 6). Daily urinary Mg excretion was 0.12 f 0.02 g/day on day 1, 0.15 f 0.02 on day 2 and 0.13 f 0.02 on day 3. There were no significant differences in daily urinary Mg excretion among these 3 days, although it was slightly higher on days 2 and 3 (alcohol study) than on day 1 (Figure 3). The Mg-loading test revealed that Mg deficiency was present in patients with alcohol-induced variant angina. In contrast, patients with variant angina unrelated to alcohol ingestion had only a slightly higher level of Mg retention after intravenous administration of Mg than did control subjects. In patients with alcohol-induced variant angina, the occurrence of hyperventilation-induced coronary spasm was completely prevented in 50% after intravenous Mg infusion. The prevention of spontaneous

Hyperventilation Day

Day

1

BP

147168

Day

2

(Alcohol

(Alcohol)

(Control) CONTROL

Test

HV 135l72

CONTROL

CONTROL

HV

121/70

126164

138/96

3 + Mg) HV 119/66

-+-A,

-v--P-

-p---p

--y-y-

FlGURE 2. Effects of alcohol ingestion and magnesium (Mg) infusion on results of hyperventilation (HV) test in a patient (no. 6) with variant angma. Day 1, neither angina1 attack nor ebctroca rdiographic i8chemic changes were pm voked by hyperventilathm. Day 2, after alcohol ingestion, hyperventilation provoked angina1 attack accompanied by ST+egment elevation in precordial leads. Day 3, after repeated alcohol i~estion, another hyperventilation test was performed. Before hyperventilation procedure, magnesium sulfate (0.27 mm/kg) was infused intravenously. Hyperventilation did not provoke either angina or electrocardiographic ischemic changes. BP = blood pressure.

BRIEF REPORTS

815

Daily

Urinary

Mg

excretion

NS

FIGURE 3. Effects of alcohol ingestion on daily urinary magnesium (Mg) excretion. As compared with day 1, daily magnesium excretion tended to lb crease on days 2 and 3 after alcohol ingestion.

01

I Day1

(Control)

I Day3

I Day2 (Alcohol)

(Alcohol)

attacks was not remarkable, probably owing to rapid excretion of the intravenously infused Mg. Mg deficiency was reported recently to be present in patients with variant angina.4 The serum Mg level is not a sensitive marker for Mg deficiency, which can be better detected by the Mg-loading test. An earlier in vitro study showed that Mg deficiency constricts human coronary arteries and that Mg repletion dilates them9 Moreover, recent clinical studies showed that intravenous infusion of Mg suppresses attacks of variant angina.3J0 When Yasue et al” investigated the long-term prognosis of patients with variant angina and influential factors, alcohol intake was found to be one of the 5 most important factors influencing survival rate. Although alcohol intake had detrimental effects on survival in patients with variant angina,” and alcohol-induced attacks were observed frequently, the mechanisms by which alcohol intake triggers angina1 attacks or coronary spasm have been unclear. The present results suggest that alcohol-induced Mg deficiency may be involved in the underlying pathogenesis predisposing to the alcohol-induced attacks in patients with variant angina. The Mg level in the vascular smooth muscle may be low in these patients, despite serum Mg levels in the normal range. Mg deficiency in chronic alcoholic patients has been noted also and was uncovered by an intravenous Mg-loading test.12The Mg deficiency in alcoholic patients was attributed to reduced food intake, some degree of malabsorption, and increased loss in the urine. It has not been determined whether the increase of Mg in the urine by alcohol is due to increased glomerular filtration of Mg or to a decrease of the tubular reabsorption of Mg. In the present patients with variant angina and latent Mg deficiency induced by habitual drinking, alcohol ingestion probably accelerated urinary Mg excretion with a reduction of the

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 73

tissue Mg content to less than the critical level to facilitate the development of coronary artery spasm the moming after drinking. In conclusion, there is Mg deficiency in patients with alcohol-induced variant angina, and Mg infusion is often effective in suppressing the hyperventilation-induced attacks the morning after alcohol intake, suggesting that chronic alcohol intake could he a risk factor for coronary artery spasm through Mg deficiency.

1. Femandez D, Rosenthal JE, Cohen LS, Hammond G, Wolfson S. Alcohol-induced Prinzmetal variant angina. Am J Cardiol 1973;32:238-239. 2. Takizawa A, Yaw H, Omote S, Nagao M, Hyon H, Nishida S, Horie M. Variant angina induced by alcohol ingestion. Am Heart J 1984;107:25-27. a. 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, Circularion 1989;79:597-602. 4. Goto K, Yasue H, Okumura K, Matsuyama K, Kugiyama K, Miyagi H, Higashi T. Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 1990;65:709-712. 5. Kalbfleisch JM, Lindeman RD, Ginn HE, Smith WO. Effects of ethanol administration on urinary excretion of magnesium and other electrolytes in alcoholic and normal subjects. J Clin Invest 1963;42:1471-1475. 6. Miwa K, Fujita M, Ejiri M, Sasayama S. Comparative sensitivity of intracoronary injection of acetylcholine for the induction of coronary spasm in patients with various types of angina pectcris. Am Hem-r J 1990;120:5~550. 7. Austen WG, Edwards JE, Frye RL, Gemini GG, Gott GL, Griffith LSC, McGoon DC, Murphy ML, Roe RB. A reporting system on patients evaluated for cow nary artery disease. Circularion 1975;5l(suppl IV):IV-5-IV-40. 8. Ryzen E, Elbaum N, Singer FR. Parentemal magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 1985;4:137-147. 9. Turlapaty PDMV, Altura BT. Magnesium deficiency produces spasms of cornnary arteries: relationship to etiology of sudden death in ischemic heart disease. Science 1980;208:198-200. 10. Cohen L, Kitzes R. Magnesium sulfate in the treatment of variant angina. Mugnesium 1984;3:4&49. 11. Yasue H, Takizawa A, Nagao M, Nishida S, Horie M, Kubota 1, Omote S, Takaoka K, Okumura K. Long-term prognosis for patients with variant angina and influential factors. Circulation 1988;78: 1-9. 12. Bohmer T, Mathesen B. Magnesium deficiency in chronic alcoholic patients uncovered by an intravenous loading test. ScandJClin LabInvest 1982;42:633-636.

APRIL 15,1994