Exercise stress-induced changes in systemic arterial potassium in angina pectoris

Exercise Stress-Induced Changes in Systemic Arterial Potassium in Angina Pectoris

Andrew Thomson, MB, PhD, FRACP, and David T. Kelly, MB, FRACP

Large fluctuations in systemic arterial potassium have been found during and after exercise in normal subjects. To determine whether similar changes occur in patients with angina pectoris, arterial potassium levels were measured before, during and immediately after maximal bicycle exercise in 20 patients with exertional angina. In 10 of these patients, leg blood flow and arteriovenous potassium levels also were measured. During exercise, arterial potassium increased significantly both from rest to submaximal exercise (4.3 f 0.1 to 4.7 f 0.1 mmol/liter, p <O.Ol) and from submaximal to maximal exercise (5.4 f 0.1 mmol/liter, p <O.Ol). Within 1 minute of cessation of exercise, arterial potassium had decreased to 4.7 f 0.1 mmol/liter (p <O.OOl) and continued to decrease to a minimum of 4.1 f 0.1 mmol/liter between 3 and 5 minutes after exercise, significantly less than the rest value (p <O.OS). At maximal exercise (99 f 9 watts), the calwlated release of potassium from each leg reached 2.7 f 1.3 mmol/min. Four minutes after exercise, the leg muscles were resorbing potassium at 0.24 mmol/min. In these patients with exertional myocardial ischemia, the magnitude and rapidity of arterial potassium changes during and after exercise resemble those found in normal subjects, but occurred at much lower workloads. Release and resorption of potassium by exercising muscle in patients with angina pectoris may cause potentially arrhythmogenic arterial potassium fluctuations.

(Am J Cardiol 1989;63:1435-1440)

From the Hallstrom Institute of Cardiology, Royal Prince Alfred Hos- pital, Sydney, Australia. This study was sponsored in part by the Aus- tralian National Health and Medical Research Council, Canberra, Australia. Manuscript received January 9, 1989; revised manuscript received March 22, 1989, and accepted March 23.

Address for reprints: A. Thomson, MB, PhD, FRACP, Royal Ho- bart Hospital, GPO Box 1061L, Hobart, Tasmania 7001, Australia.

T he stress of vigorous exercise causes arterial potassium to increase markedly in normal subjects due to potassium release from skeletal muscle

cells.1-6 The release of potassium appears to be propor- tional to the workload,6 although the exercise hyperkalemia may be reduced by physical conditioning.’ After exercise, arterial potassium decreases rapidly, often to levels below rest values, indicating active uptake of the ion.1,3*4,8 At rest, stress hypokalemia increases the incidence and severity of arrhythmias in patients with coronary artery disease.9J0 Similarly, rapid stress-induced changes of arterial potassium in patients with exercise- induced myocardial ischemia may be arrhythmogenic. This study measures the changes in arterial potassium in patients limited by angina pectoris during and after maximal exercise, and documents the changes in release and resorption of potassium by exercising leg muscles.

METHODS Patients: Twenty men, ages 39 to 68 years (mean

58) with angiographically documented coronary artery disease, exertional angina pectoris and positive results on treadmill exercise tests participated in the study. All patients were taking metoprolol (200 mg/day) as routine antianginal medication. No patient had a known history of or a predisposition to arrhythmias. All patients gave written informed consent before participat- ing in the study.

Study protocol: The study had 2 phases. The first phase was designed to document arterial potassium changes from rest to maximal exercise and thence to the immediate recovery period. The second phase was designed to measure potassium release and resorption by exercising muscles.

In both phases, patients exercised on an upright cy- cle ergometer (Siemens-Elma model 380B) until they were limited by chest pain, leg fatigue or both. In phase 1, 10 patients were instrumented with a radial artery cannula. After a rest and an unloaded exercise level (total 6 minutes), the initial load of 30 watts was increased by 30 watts every 3 minutes. In phase 2, 10 different patients were instrumented with a femoral venous thermodilution catheter and an arterial line. In 6 of these patients, a femoral arterial catheter (Seldicath 3Fr) re- placed the radial artery cannula. After measurements at rest, the initial workload of 30 watts was increased by 30 watts every 6 minutes. All rest and exercise studies were performed at least 2 hours after a light meal. Six- minute stages were used to maximize the number of femoral blood flow measurements.

THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 15, 1989 1435

EXERCISE STRESS-INDUCED PDTASSIUM CHANGES

TABLE I Arterial Electrolyte, Blood Gas, Lactate and Hemodynamic Results

Rest Submaximal Exercise

Maximal Exercise

K+ (mmol/liter) Na+ (mmol/liter) Lactate (mmol/liter)

PH so2 (%) HC03 (mmol/liter) HR (beats/min) ST1 (mm)

4.3*0.1* 139f 1 0.5 f 0.1

7.43 f 0.01 98fO 25f 1 64*2+

-0.2fO.l+

4.7f0.1” 140f 1+ 1.4 f 0.2+

7.41 A 0.01+ 98fO 25fl’ 81 f 3*

-1.1 f 0.3’

5.4f0.19 142 f I+ 5.7 f 0.6

7.37 f 0.01 98fO 21 f 1

118f6* -2.4 f 0.5*

Four Minutes After Exercise

4.1 f 0.1 138fl 6.0 f 0.7

7.36 f 0.02 98fO 20f 1 80f4

-1.1 f 0.2

l p <O.Ol; t p <0.05 for comparisons between adjacent levels. HC03 = bicarbonate; HR = heart rate; SO2 = oxygen saturation; ST/ = ST-segment depression.

Measurements: During each stage, heart rate, arterial blood pressure and 3 electrocardiographic leads were continuously monitored (Electronics for Medicine VR12). Pressure measurements were made during the last 30 seconds of each stage. Arterial and venous blood samples were taken during the last 60 seconds of each stage. Femoral blood flow was measured using bolus thermodilution beginning after 1 minute of each stage. ST-segment depression was measured 80 ms after the J point (CASE II, Marquette Electronics).

Particular care was taken in the collection of blood for potassium measurement. Arterial blood was allowed to fill preheparinized syringes under arterial pressure. Venous samples required gentle negative pressure due to the small bore of the sampling catheters. All samples for a particular study, including the recovery samples, were taken in identical fashion by the same investigator. Samples were analyzed for plasma Na+, potassium, Cl+, HCOs- and glucose as soon as feasible (Instru- mentation Laboratories, IL 508). Hemoglobin, oxygen saturation, pH, 02 and CO2 tensions were measured in each sample (Co-oximeter, Instrumentation Laborato- ries model 282, Corning 175 blood gas analyzer). Blood 02 content was calculated as the product of hemoglobin

concentration, 1.39 ml Oz/g of hemoglobin and the oxygen saturation.

In phase 2, femoral blood flow was measured using bolus thermodilution. A 2.4-ml bolus of iced 5% dex- trose was rapidly injected through a 5Fr thermodilution catheter (with the infusion port positioned 1 cm above the pubic ramus and the thermistor 10 cm proximally) and a modified thermodilution computer (American Edwards model 9520A) was used to calculate femoral blood flow as reported previously.” Leg potassium release or resorption was calculated as the arteriovenous potassium difference multiplied by the mean femoral blood flow.

Recovery period: At maximal exercise patients were instructed to stop abruptly. Blood samples and pressure measurements were then taken at the end of each minute for at least 6 minutes. In phase 2, blood flow measurements were commenced immediately and continued for 6 minutes. The mean recovery femoral blood flows were used for calculations.

Statistical analysis: All values are expressed as mean f standard error of the mean. Comparisons between levels were analyzed for statistical significance using an analysis of variance unless otherwise stated.

6.0

EXERCISE RECOVERY

REST SUBYAX MAX 0 1

WORK LEVEL MIN”TES2AF;ER &E&IS;

FIGURE 1. Arterial potasshun levels before, durihg and after exercise.

1436 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63

Potassium values for 1 patient in phase 1 were techni- cally unsuitable for analysis, as were the femoral blood flow values for 1 patient in phase 2.

RESULTS Phases 1 and 2 at rest: At rest, all electrolytes were

within the normal range. The mean arterial potassium was 4.3 f 0.1 mmol/liter (Table I). The arterial lactate was 0.5 f 0.1 mmol/liter and systolic blood pressure 152 f 5 mm Hg. The heart rate was 64 f 2 beats/min (consistent with /3 blockade at rest).

Submaximal exercise: At 30 watts, the arterial potassium had increased significantly to 4.7 f 0.1 mmol/ liter (p <O.Ol), whereas the arterial lactate had increased to 1.4 f 0.2 mmol/liter but still remained within the normal range (<1.5 mmol/liter). The heart rate had reached 81 f 3 beats/min and the ST-segment depression was -1.1 f 0.3 mm (p <0.05).

Maximal exercise: At maximal exercise (mean workload 99 f 9 watts), arterial potassium had increased to 5.4 f 0.1 mmol/liter (p <O.Ol, Figure 1) and was associated with a significant increase in arterial lactate, to 5.7 f 0.6 mmol/liter (p <O.Ol), indicating marked anaerobic metabolism. The maximal heart rate achieved was 118 f 6 beats/min and the systolic blood

0.0,

EXERCISE LEVEL

1 “CST .“.YAX MAY “CCOVLCIV EXERCISE LEVEL

FIGURE 2. ST-m (A) and rate pressure product (B) levels beforo, during and aftor exerciso.

pressure was 177 f 6 mm Hg, with a rate pressure product of 20.8 f 1.6 mm Hg . beats s min-’ * lo3 (Fig- ure 2B). Eighteen patients had angina and mean ST depression was 2.4 f 0.4 mm (p <O.OOl, Figure 2A).

Recovery: Within 1 minute after exercise the arterial potassium had decreased by a mean of 0.7 mmol/ liter, to 4.7 f 0.1 mmol/liter (p CO.001, paired t test), whereas the arterial lactate continued to increase (6.0 f 0.7 mmol/liter, Figure 3A). The hemodynamic parame- ters rapidly returned toward normal, as evidenced by the heart rate (95 f 7 beats/min) and systolic blood pressure (161 f 6 mm Hg).

Arterial potassium continued to decrease steadily for 3 minutes after exercise, reaching a nadir between 3 and 5 minutes after exercise (4.1 f 0.1 mmol/liter), which was significantly lower than the level at rest (p <0.05 paired t test, Figure 1). The arterial lactate did not change significantly during the recovery period.

Source of potassium release and resorption: At rest in phase 2, the leg blood flow was 0.37 f 0.07 liters/ min and there was minimal potassium release from the leg (0.05 f 0.03 mmol/min). During submaximal exercise (30 watts), significant leg potassium release oc-

A o L I

REST SUmWAX WAX RECOVERI

EXERCISE LEVEL

B o “LACTA;: CHANGE PO

(mmol/l) L FlGURE 3. A, arterial lactate levels before, during and efter exorcise. B, cordation ol femoral venous lactate and femoral veneus potassium chenges from rest to fiubmaximal and maximal exercise.


EXERCISE STRESS-INDUCED POTASSIUM CHANGES

curred (0.70 f 0.28 mmol/min) and leg blood flow in- Exercising leg muscle was a major source of the ar- creased to 2.12 f 0.22 liters/min. terial potassium fluctuations. Direct measurement of leg

At maximal exercise (93 f 11 watts), leg potassium blood flow and leg arteriovenous potassium difference release reached 2.7 f 1.3 mmol/min (Figure 4). The showed that, during exercise, potassium release from 1 mean maximal leg blood flow was 3.70 f 0.66 liters/ leg progressively increased to peak at 2.7 mmol/min at min (Figure 5A, p <0.05) and the arteriovenous potassium difference was 0.6 f 0.3 mmol/liter. The mean leg oxygen consumption was 0.53 f 0.09 liters/min (Figure 5B). During exercise, the increase in femoral venous potassium correlated well with the increase in femoral venous lactate (y = 0.16 x + 0.14, standard error of the estimate = 0.27, r = 0.90, Figure 3B).

Within 1 minute after exercise, leg potassium flux had changed from release at maximal exercise to resorption (0.5 f 0.2 mmol/min, p <0.05). Leg potassium resorption continued during the recovery period (Figure 4). The mean recovery leg blood flow was 1.17 f 0.11 liters/min. Resorption of potassium by recover- ing leg muscles contributed to the significant decrease in arterial potassium and the more dramatic reduction in femoral venous potassium (Table II).

Arrhythmias: At rest, 1 patient had atria1 extrasystoles, 1 patient had ventricular extrasystoles and 1 patient had both. During submaximal exercise, 3 patients had ventricular extrasystoles only and 3 had atria1 and ventricular extrasystoles. At maximal exercise, 3 patients had atria1 and 7 had ventricular extrasystoles. During recovery, 2 patients had atria1 and 6 had ventricular extrasystoles. The highest incidence of extrasystoles was in the fourth minute of recovery.

I REsr S”6MAX MAX RECOVERI

EXERCISE LEVEL I

-1 DISCUSSION

This study shows that in these patients with coronary artery disease, despite a low mean maximal workload, there were marked changes in arterial potassium during and immediately after exercise. The arterial potassium increased significantly from rest to submaximal exercise and then to maximal exercise. In all patients

1 666-r *LmHAX “AX RECOVERY

EXERCISE LEVEL

the arterial potassium decreased immediately after ex- FIGURE 5. Leg blood flow (A) and leg oxygen consumption ercise by a mean of 1.3 mmol/liter within 4 minutes. (B) levels before, during and after exercise. 4

EXERCISE RECOVERY

3-

1- 4 :4 cl------ -~---~-~~~---_--__ ----- -_----------------.

-1 REST SUBYAX MAX 0 1

WORK LEVEL hi I N”TES2 AFTER ;XE& I S;

FIGURE 4. Potassbnn release and l.eso@mfrcentbelegbetore, dwlng and after exercise.


TABLE II Leg Blood Flow, Potassium and Oxygen Metabolism I

Submaximal Maximal Four Minutes After

Leg K+ flux (mmol/min) Leg VOZ (ml/min)’ Blood flow (liters/min) Leg a - vK+ (mmol/liter) Leg a - vCI2 (ml/liter)

Rest

-0.05 f 0.03

Exercise

-0.70 f 0.28

Exercise

-2.67 f 1.25*

Exercise

0.24f0.14 36&g* 254 f ia* 532 f 90+ 69f 11

0.37 f 0.07s 2.12f0.228 3.70 f 0.66* 1.17f0.11 -0.14 f 0.09 -0.24 f 0.09 -0.62 f 0.33* 0.20f0.10

96f6* 122 f 6* 149 f 5+ 59f6

* p <0.05; + p <O.Ol for comparisons between adjacent levels. a - vK+ = arteriovenous potassium dierence; a - v02 = arteriovenous oxygen difference: K+ flux = potassium release or resorption; V02 = oxygen consumptnn.

maximal work. Within 1 minute after exercise, potassium release had changed to resorption at 0.5 mmol/min. Potassium resorption continued throughout the recovery period and arterial potassium returned to normal at the end of the sixth minute after exercise.

The increase in femoral venous potassium correlated with the increase in femoral venous lactate during exercise, suggesting that anaerobic metabolism in exercising skeletal muscle is associated with potassium release (Figure 3). Lactic acid production due to ischemia decreases the intracellular pH that inhibits membrane Na+/potassium adenosine triphosphatase (ATPase),12 allowing cellular potassium loss. Opposing potassium release are high levels of circulating catecholamines during exercise,13,21 which stimulate Na+/potassium ATPase14-16 and may limit potassium loss from skeletal muscle. Lactate and potassium release from the leg occurred at low exercise levels, suggesting that anaerobic pathways were recruited early and that poor aerobic fit- ness may have contributed to the magnitude of arterial potassium changes in these patients.

The changes in arterial potassium after exercise in this study were similar to those reported for normal subjects after more strenuous exercise.3J7J8 The high levels of circulating catecholamines during exercise continue to increase for >2 minutes after exerciseI and remain elevated thereafter for several minutes.19-22 The recovery reduction in arterial potassium was probably due to continued catecholamine stimulation of membrane- bound Na+/potassium ATPase14J5 in the absence of muscle ischemia or anaerobic metabolism. In these patients, angina pectoris and ischemic left ventricular dys- function may have further increased sympathetic stimulation contributing to the rapidity of the potassium changes.

Arrhythmias are common during and after exercise in patients with coronary artery disease.23-26 The incidence of arrhythmias in this study was low and the data do not show a direct relation between arterial potassium changes and arrhythmias. However, in patients predisposed to arrhythmias, the rapidity of the arterial potassium changes may influence cardiac impulse formation and conduction,27,28 thereby increasing the likelihood of arrhythmias. Exercise-induced hyperkalemia may re- duce resting membrane potential29 and postexercise hypokalemia may cause hyperpolarization of surrounding nonischemic myocardium, 3o both of which predispose to arrhythmias. The threshold for ventricular fibrillation is

reduced by 58% in the ischemic canine heart subjected to hypokalemia.31

All patients in this study were taking metoprolol as their routine antianginal medication. Nonselective p blockers have been shown to augment the increase in arterial potassium during exercise32 due to the inhibi- tion of Na+/potassium ATPase stimulation.‘4,32 How- ever, p2 adrenoceptors appear to mediate catecholamine-induced hypokalemia,16 and metoprolol, a par- tially selective /?I adrenoceptor blocker, is at least 50 times less potent in blocking cellular potassium uptake.15 Because both the increase in arterial potassium during exercise and the decrease in arterial potassium immediately after exercise are a function of catecholamine stimulation, the use of metoprolol may have aug- mented the increase in arterial potassium during exercise and reduced the sudden decrease in arterial potassium after exercise.

Clinical significance: Significant changes in arterial potassium occur at low levels of exercise in patients with angina pectoris due to potassium release from exercising muscles. More importantly, arterial potassium decreases rapidly within minutes after exercise. Electro- lyte changes of this magnitude and rapidity may con- tribute to the incidence of exercise-induced arrhythmias in predisposed patients.

REFERENCES 1. Hazeyama Y, Sparks HV. A model of potassium ion efflux during exercise of skeletal muscle. Am J Physiol 1979;236:R83-R9f.I. 2. Kilbum AH. Muscular origin of elevated plasma potassium during exercise. J Appl Physiol 1966;21:675-678. 3. Coester N, Elliott JC, Luft UC. Plasma electrolytes, pH, and ECG during and after exhaustive exercise. J Appl Physiol 1973:34:677-682. 4. Van Beaumont W, Strand JC, Petrofsky JS, Hipskind SG, Greenleaf JE. Changes in total plasma content of electrolytes and proteins with maximal exercise. J Appl Physioi 197334:102-106, 5. Tibes U, Hemmer B, Schweigart U, Boning D, Fotescu D. Exercise acidosis as cause of electrolyte changes in femoral venous blood of trained and untrained man. Pjlugers Arch 1974;347:145-158. 6. Wilkerson JE, Horvath SM. Gutin B, Molnar S, Diaz FJ. Plasma electrolyte content and concentration during treadmill exercise in humans. J Appl Physiol 1982;53:1529-1539. 7. Knochel JP, Blanchley JD, Johnson JH, Carter NW. Muscle cell electrical hyperpolarisation and reduced exercise hyperkalemia in physically conditioned dogs. J Clin lmxst 1975;75:740-745. 8. Brown MJ. Hypokalemia from beta*-receptor stimulation by circulating epinephrine. Am J Cardiol 1985;56:3D-90. 9. Hulting J. In-hospital ventricular fibrillation and its relation to serum potassium. Acta Med Stand 1981:(suppl647):109-116. 10. Nordehaug JE. Malignant arrhythmias in relation to serum potassium values in patients with acute myocardial infarction. Acta Med Sand 1981;(supp/ 647):101-107. 11. Thomson A, Fletcher PJ, Harris PJ, Freedman B, Kelly DT. Regional


EXERCISE STRESS-INDUCED POTASSIUM CHANGES

distribution of cardiac output at rest and during exercise in patients with exertional angina pectoris before and after nifedipine therapy. JACC 1988;11:837- 842. 12. Eaton DC, Hamilton KL, Johnson KE. Intracellular acidosis blocks the basolateral Na-K pump in rabbit urinary bladder. Am JPhysio/ 1984;247:F946- F954. 13. Vendsalu A. Studies on adrenaline and noradrenaline in human plasma. Acta Physiol Stand 1960;48(suppI 173):8-l 14. 14. Clausen T, Flatman JA. The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J Physiol 1977;270:383-414. 15. Clausen T, Flatman JA. ,!?z-adrenoceptors mediate the stimulating effect of adrenaline on active elcctrogenic Na-K transport in rat soleus muscle. Br J Pharmacol 1980,68:749-755. 16. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta* receptor stimulation by circulating epinephrine. N Engl J Med 1983;309;1414-1419. 17. Ljunghall S, Joborn H, Rastad J, Akerstrom G. Plasma potassium and phosphate concentrations-influence by adrenaline infusion, fl-blockade and physical exercise. Acta Med Scand 1987;221:83-93. 16. Williams ME, Gervino EV, Rosa RM, Landsberg L, Young JB, Silva P, Epstein FH. Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 1985;312:823-827. 19. Watson RDS, Hamilato CA, Jones DH, Reid JL, Stallard TJ, Littler WA. Sequential changes in plasma noradrenaline during bicycle exercise. Clin Sci 1980;58:37-43. 20. Dearman J, Francis KT. Plasma levels of catccholamines, cortisol, and beta- endorphins in male athletes after running 26.2, 6, and 2 miles. J Sports Med 1983;23:30-38.

21. Dimsdale JE, Hartley H, Guiney T, Ruskin JN, Greenblatt D. Postexercise peril. Plasma catecholamines and exercise. JAMA 1984;251:630-632. 22. Cryssanthopoulos C, Barboriak JT, Fink JN, Stekiel WJ, Maksud MG. Adrenergic responses of asthmatic and normal subjects to submaximal and maximal work loads. .I Al&y Clin Immunol 1978,61:17-22. 23. Goldschlager N, Cake D, Cohn K. Exercise-induced ventricular arrhythmias in patients with coronary artery disease. Am J Cardiol 1973;31:434-440. 24. Gooch AS, McConnell. Analysis of transient arrhythmias and conduction disturbances occurring during submaximal treadmill exercise testing. Prag Car- diouasc Dis 1970;13:293-307. 25. DeMaria AN, Vera Z, Amsterdam EA. Mason DT, Massumi RA. Distur- bances of cardiac rhythm and conduction induced by exercise. Am J Cardiol 1974;33:732-736. 26. Jelinek MV, Low B. Exercise stress testing for exposure of cardiac arrhyth- mia. Prog Cardiovasc Dis 1974;16:497-521, 27. Fisch C. Relation of electrolyte disturbances to cardiac arrhythmias. Circula- tion 1973:47:408-419. 28. Surawicz B. Ventricular fibrillation. Am J Cardiol 1971:28:268-287. 29. Opie LH, Nathan D, Lubbe WF. Biochemical aspects of arrhythmogenesis and ventricular fibrillation. Am J Cardiol 1979;43:131-148. 30. Papademetriou V. Diuretics, hypokalemia, and cardiac arrhythmias. A criti- cal analysis. Am Heart J 1986:111:1217-1224. 31. Hohnloser SH, Verrier RL, Low B, Raeder EA. Effect of hypokalemia on susceptibility to ventricular fibrillation in the normal and ischemic canine heart. Am Heart J 1986;112:32-35. 32. Carlsson E, Fellenius E, Lundborg P, Svensson L. Beta-adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-425.


Documents

Exercise stress-induced changes in systemic arterial potassium in angina pectoris