Author + information
- Received April 27, 1998
- Revision received October 26, 1998
- Accepted December 17, 1998
- Published online March 15, 1999.
- Hans Erik Bøtker, MD, PhD∗,*,
- Helle Sauer Sonne, MD∗,
- Ole Frøbert, MD, PhD∗ and
- Frederik Andreasen, MD, PhD†
- ↵*Reprint requests and correspondence: Hans Erik Bøtker, MD, PhD, Department of Cardiology, Skejby Hospital/University Hospital Aarhus, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark
The purpose of this study was to determine whether patients with syndrome X have altered potassium metabolism.
Patients with syndrome X have angina pectoris and exercise induced ST segment depression on the electrocardiogram despite normal coronary angiograms. Increasing evidence suggests that myocardial ischemia is uncommon in these patients. Altered potassium metabolism causing interstitial potassium accumulation in the myocardium may be an alternative mechanism for chest pain and ST segment depression in syndrome X.
We compared the magnitude of exercise-induced hyperkalemia in 16 patients with syndrome X (12 female and four male, mean ± SD age 53 ± 6 years) and 15 matched healthy control subjects. The participants underwent a bicycle test at a fixed load of 75 W for 10 min, and blood samples were taken for analysis of potassium, catecholamines and lactate before, during and in the recovery period after exercise. In five patients with syndrome X, the test was repeated during alpha1adrenoceptor blockade.
Baseline concentrations of serum potassium, plasma catecholamines and plasma lactate were similar in patients and control subjects. The rate of exercise-induced increment of serum potassium was increased in the patients (70 ± 29 vs. 30 ± 21 μmol/liter/min in control subjects, p < 0.001). Six patients, who stopped before 10 min of exercise, showed very rapid increments in serum potassium concentration. Compared to the control subjects, patients also demonstrated larger increments in rate–pressure product, plasma norepinephrine and lactate concentrations during exercise. The rate of serum potassium increment correlated with the rate of plasma norepinephrine increment in the patients (r = 0.63, p < 0.02), but not in the control subjects (r = 0.01, p = 0.97). Blockade of alpha1adrenoceptors decreased systolic blood pressure at baseline, but did not influence the increment of serum potassium, plasma catecholamines and lactate.
Patients with syndrome X have enhanced exercise induced hyperkalemia in parallel with augmented increases of circulating norepinephrine and lactate. The prevailing mechanisms behind the abnormal potassium handling comprise sources distinct from alpha1-adrenoceptor activation.
The cardiologic syndrome X is characterized by angina pectoris and ST segment depression during exercise testing but normal coronary arteries at angiography. Increasing evidence suggests that myocardial ischemia is uncommon in these patients (1,2). It has been proposed that potassium metabolism is altered in patients with syndrome X (3). Potassium is released from the human myocardium under conditions of stress or increases of heart rate (4). On cessation of tachycardia the small net loss of intracellular potassium is replaced to maintain a steady state. If patients with syndrome X release a greater amount of intracellular potassium or take up potassium more slowly, then potassium could be retained in the myocardium. Such an accumulation would account for features of syndrome X, including chest pain, ST segment changes, modification of coronary (5)and systemic vasoreactivity (6)and a good prognosis (7). However, no confirmatory data exist to support this hypothesis. Potassium regulation during exercise may reflect disturbances of potassium metabolism, because patients with syndrome X in addition to angina pectoris often suffer from generalized fatigue in the skeletal muscles (8). To determine whether there is any evidence of a disturbed potassium metabolism in patients with syndrome X we compared exercise-induced hyperkalemia in patients with syndrome X and matched healthy control subjects.
We studied 16 patients with syndrome X (typical effort angina, ≥0.1 mV ST segment depression on bicycle exercise testing and normal coronary angiograms) (Table 1). Mean duration of symptoms was 4.2 years (range 6 months to 12 years). All patients were otherwise healthy, and none had concomitant cardiovascular or metabolic disease. Epicardial spasm was excluded by a hyperventilation test. Valvular and myocardial diseases were excluded by echocardiography and ventriculography. Ejection fraction was >55% in all patients. Prior to the study 12 patients were treated with calcium channel blocking agents, three with beta-adrenergic blocking agents and 16 with long-acting nitroglycerin.
Healthy control subjects were recruited among the hospital staff and blood donors. They were matched to the patients for age, gender, body mass index, maximal oxygen uptake and blood pressure. None of the volunteers had a history of neurologic, endocrinologic or cardiologic diseases. All were free of medication, and had a normal clinical investigation and a normal exercise electrocardiogram (ECG).
The study was approved by the local Ethics Committee. All medications were discontinued two weeks before the study. Short-acting nitrates, however, were allowed up to 6 h before the study. Investigations were performed on two separate days within one week. At the first visit, participants underwent exercise ECG testing. Maximal aerobic capacity was expressed as peak oxygen uptake (VO2 peak) (9). During a separate visit, the participants underwent a bicycle test at a fixed load of 75 W for 10 min. A computer-connected Schiller ERGOMETRIC 900 bicycle ergometer and a Schiller Cardiovit CS-6/12 Exec mingograph (Geneva, Switzerland) were used. Blood pressure was measured automatically by a BOSCH EBM blood pressure measure unit (Berlin, Germany) connected to the computer. On the basis of the caloric coefficient of oxygen uptake of 13.95 ml/min per watt (10), individual oxygen uptake was extrapolated from workload as: where Wis the workload obtained and 3.5 resting oxygen consumption in ml/kg/min (11). A short catheter was inserted into a large antecubital vein. The system was kept patent by slow infusion of isotonic saline. Serum potassium and albumin were measured at baseline, every 2.5 min during the exercise test and at 1, 2, 3, 5, 7 and 10 min after cessation of the bicycle test. Plasma epinephrine, plasma norepinephrine and plasma lactate were measured before and at the end of exercise. Analysis for serum potassium was done with a standard method on a Kodak Ektachem 700 XR analyzer (Rochester, New York). For determination of epinephrine and norepinephrine 4 ml of blood was collected into glass tubes containing 80 μl ethylene glycol tetraacetic acid (EGTA)/gluthation (76 mg EGTA and 6 mg glutathion in 1 ml water, pH adjusted at 7.3). Samples were centrifuged and stored at −80°C until analysis. Analyses were performed using high performance liquid chromatography (12). Blood samples for determination of lactate were collected into heparinized ice-cooled glass tubes, centrifuged, deproteinized and stored at −80°C until later duplicate analysis. Plasma lactate was determined enzymatically using lactate dehydrogenase at pH = 9.0 (13).
The study was repeated in five patients after administration of an alpha1adrenoceptor antagonist, doxazosin (Carduran) 2 mg orally 2 h before the test.
Data are presented as mean ± SD. Mean values are compared using paired and unpaired ttests. Correlations are assessed by linear regression analysis. A p value <0.05 is considered statistically significant.
Baseline serum potassium, plasma lactate, epinephrine and norepinephrine concentrations were similar in patients and control subjects (Table 2). Six patients with syndrome X terminated exercise testing before 10 min of exercise due to anginal pain. The individual increases of serum potassium during exercise in these patients are depicted in Figure 1, which also shows that the exercise-induced hyperkalemia is enhanced in the remaining syndrome X patients compared to the control subjects.
Absolute values of VO2during exercise did not differ between patients and control subjects (18.7 ± 2.0 and 20.1 ± 2.6 ml/kg/min, p = 0.11). However, the relative value of the actual VO2during the fixed workload in percentage of VO2 peakwas significantly higher in the patients than in the control subjects (76 ± 14% vs. 63 ± 16%, p < 0.05). Correction for variations in relative submaximal effort by calculating the ratio of [rate of serum potassium increment/VO2during fixed workload in proportion to VO2 peak] showed that the difference in the rate of serum potassium increment between patients and control subjects persisted (91 ± 27 vs. 51 ± 34 μmol/liter/min, p < 0.001).
During exercise, patients with syndrome X revealed larger increments in rate–pressure product, plasma norepinephrine and lactate concentrations than control subjects (Table 2). Four patients had ST segment depressions ≥0.1 mV at the termination of exercise. Among these one patient stopped exercise after 5 min and 10 s, whereas the remaining three patients completed the 10-min exercise scheme. No significant correlations were observed between the rate of potassium increment and rate of lactate increment in patients (r = 0.42, p = 0.11) or control subjects (r = 0.08, p = 0.77). In the patient group, the rate of potassium increment correlated with the rate of norepinephrine increment (r = 0.63, p < 0.02), whereas no correlation was found in control subjects (r = 0.01, p = 0.97). In the recovery period, the rate of serum potassium decrease did not differ between patients and control subjects (31 ± 19 and 38 ± 20 mmol/liter/min, p = 0.30).
After doxazosin administration to five of the patients who completed 10 min of bicycling during the first test, systolic blood pressure at baseline was decreased compared to the test without doxazosin (Table 3). Baseline plasma concentrations of potassium, epinephrine, norepinephrine and lactate were unchanged after doxazosin. During exercise the increase in rate–pressure product was unchanged with doxazosin, whereas the increases of plasma catecholamines tended to be higher after doxazosin administration. The increases in potassium and lactate were similar with and without doxazosin.
The present study shows that patients with syndrome X exhibit enhanced exercise-induced hyperkalemia in parallel with augmented increases of circulating norepinephrine and lactate concentrations compared to a matched group of healthy control subjects. The enhanced exercise-induced hyperkalemia in patients with syndrome X is not modulated by the alpha1adrenergic antagonist doxazosin.
Acute potassium homeostasis is controlled by extrarenal tissues and determined by epinephrine, norepinephrine and insulin (14). The abnormal potassium handling in patients with syndrome X is thought to affect the transport of potassium between intracellular and extracellular myocardial compartments and therefore involves components responsible for the acute regulation of potassium balance (15). Assessment of myocardial potassium exchange by determination of potassium concentrations in the coronary sinus is suboptimal because the measured changes may be small (2).
The skeletal muscles contain the largest pool of potassium in the body (75% of total) (14). The regulatory mechanisms of transsarcolemmal exchange of potassium in skeletal muscle and cardiac muscle are similar and appear to involve identical structures (16). Thus, we chose to study the acute regulation of potassium metabolism during exercise. We used a moderate workload (on average 70% of peak VO2) for a limited duration because it represents an integral part of the lifestyle in many adults and produces a predictable yet modest increase in the serum potassium concentration (17). We used the same absolute workload in all participants because the peak concentrations of potassium in plasma during exercise are proportional to exercise intensity, contracting muscle mass and the level of physical capacity (18,19). Syndrome X patients are expected to have compromised physical capacity because exercise induces angina pectoris. Thus, we sought to eliminate these confounders by selecting the control group to match the patient group as closely as possible with respect to body mass index and VO2 peak. Even so, the relative value of VO2during the fixed workload in percentage of VO2 peakwas, on average, higher in the patients than in the control subjects. These findings suggest that this workload is closer to the anaerobic threshold in the patients than in the control subjects (20), so that the enhanced hyperkalemia during exercise may be associated with a reduction of aerobic capacity. However, ratios for rate of potassium increments/VO2during fixed workload in percentage of VO2 peakshowed that the difference in exercise-induced hyperkalemia persisted after correction for individual variations in relative submaximal effort.
Exercise, catecholamines and insulin
The main cellular mechanism regulating exercise-induced hyperkalemia is the Na+,K+, adenosine triphosphatase (ATPase) in skeletal muscle (14). The concentration of Na+,K+,ATPase exceeds the demands for Na+–K+transport under usual physiologic conditions (14), and it is generally accepted that increased activation of the Na+,K+,ATPase is responsible for the reduction of exercise-induced hyperkalemia. Catecholamines increase K+influx and Na+efflux through selective beta2adrenoceptor stimulation (17). Several studies have indicated that sympathetic activity in patients with syndrome X is increased (21–23). The results of the present study show that the enhanced exercise-induced hyperkalemia in patients with syndrome X occurs despite a simultaneously augmented increase in plasma norepinephrine. Moreover, the increase in norepinephrine and the increase in potassium correlated in the patients. This observation, together with previous observations that alpha-adrenergic stimulation causes an elevation of plasma potassium concentration (24,25), which can be reversed by phentolamine, an alpha-receptor antagonist, prompted us to study the influence of doxazosin, a selective alpha1adrenoceptor antagonist, on exercise-induced hyperkalemia. Doxazosin increases the coronary flow reserve in patients with syndrome X (26). Assessed by the significant hemodynamic effect of doxazosin at rest, we achieved sufficient alpha1blockade, but the hyperkalemic response during exercise was not modified. This finding tends to exclude a significant involvement of alpha1adrenoceptor activation in the enhanced exercise-induced hyperkalemia in patients with syndrome X. At present, it is unknown whether the effect of alpha-adrenergic modification of potassium homeostasis is mediated via the alpha1or alpha2receptor. Because unspecific alpha-adrenoceptor blockade with phentolamine diminishes the exercise-induced rise in plasma potassium concentration in healthy subjects (27), we cannot exclude the possibility that an effect is mediated through the alpha2receptor.
Insulin reduces the circulating potassium concentration by stimulation of the Na+,K+,ATPase in skeletal muscle. Patients with syndrome X are characterized by impaired insulin-stimulated glucose uptake in skeletal and cardiac muscle (28), but the actions of insulin on cellular glucose and potassium uptake are independent of one another (29,30). We have recently demonstrated that potassium handling in response to insulin is similar in patients with syndrome X and control subjects (28). Thus, insulin is not likely to be involved in the abnormal potassium handling during exercise in patients with syndrome X.
Although high extracellular concentrations of potassium are associated with ST segment depressions similar to those observed in the present study during exercise, the maximal serum potassium concentrations observed here were far from the serum concentrations of 8 to 12 mmol/liter that cause ST segment depression (31). However, the use of a catheter in the cubital vein may be a relatively insensitive way to characterize myocardial potassium delivery compared with arterial or arteriovenous blood sampling over a specified group of exercising skeletal muscles, for example, in the leg. Since the exercise in the present study was carried out on a bicycle, only a minor part of the work was done by the arm muscles. Thus, the arm muscles may extract rather than release potassium so that the concentration in the cubital vein may be underestimated compared with the central vessels.
Conclusions and implications
So far, we have demonstrated that potassium metabolism during exercise is altered in patients with syndrome X. These findings may account for the high prevalence of generalized fatigue in the skeletal muscles (8), because excessive potassium efflux from skeletal muscle reduces the potassium gradient between the intra- and extracellular compartments and impairs action potential transmission and consequently tension development (32). Potassium acts as a mediator of cardiac pain per se (33,34)and in combination with other chemical mediators such as adenosine (35). Whether the abnormal potassium handling in patients with syndrome X also involves cardiac muscle, causing localized interstitial hyperkalemia, cannot be determined from the present study. In the absence of any demonstrable perfusion abnormality, the uptake and washout of the potassium analog thallium-201 is reduced in patients with syndrome X (36). This may be a result of abnormal myocardial potassium handling.
We thank Ms. Eva Sparrewath, Ms. Bente Jacobsen, Ms. Birthe Baumgarten and the staff of the Department of Biochemical Chemistry, Skejby Hospital for skillful laboratory assistance.
☆ This study was supported by a grant from the Danish Heart Foundation.
- adenosine triphosphatase
- ethylene glycol tetraacetic acid
- VO2 peak
- peak oxygen uptake
- Received April 27, 1998.
- Revision received October 26, 1998.
- Accepted December 17, 1998.
- American College of Cardiology
- Camici P.G,
- Marraccini P,
- Lorenzoni R,
- et al.
- Webb S.C,
- Poole-Wilson P.A
- Opherk D,
- Schuler G,
- Wetterauer K,
- Manthey J,
- Schwarz F,
- Kubler W
- Bass C,
- Wade C,
- Hand D,
- Jackson G
- Åstrand I
- Åstrand P,
- Rodahl K
- Eriksson B,
- Persson B
- Hohorst H.J
- Clausen T
- Castellino P,
- Simonson D.C,
- DeFronzo R.A
- Barlow C.W,
- Qayyum M.S,
- Davey P.P,
- Conway J,
- Paterson D.J,
- Robbins P.A
- Frøbert O,
- Mølgaard H,
- Bøtker H.E,
- Bagger J.P
- Todd E.P,
- Vick R.L
- Ferrannini E,
- Taddei S,
- Santoro D,
- et al.
- Gettes L.S
- Sjøgaard G
- Webb S.C,
- Canepa-Anson R,
- Rickards A.F,
- Poole-Wilson P.A