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Interaction of the sympathetic nervous system and electrolytes in congestive heart failure
Interaction of the Sympathetic Nervous System and Electrolytes in Congestive Heart Failure Gary S. Francis,
Congestive heart failure is characterized by both disturbances in electrolyte homeostasis and neurohormonal regulation. Total body potassium is reduced, and this reduction bears a modest relation to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Patients with decompensated heart faikue show increases in both plasma epinephrine and plasma norepinephrine, whereas patients with chronic stable heart failure usually have an increase only in plasma norepinephrine. High levels of circulating epinephrine may contribute to the development of hypokalemia by activating skeletal muscle and liver membrane &-adrenergic receptors, which in turn stimulate intracellular cyclic adenosine monophosphate to activate the membrane-bound Na+K+adenosine triphosphatase pump. The net result is that potassium flux across the cell membrane from the extracellular to the intracellular space increases, setting the stage for hypokalemia and possibly serious ventricular arrhythmias. Other mechanisms that may contribute to the development of hypokalemia in heart failure inelude the kaliurests brought on by excessive levels of aldosterone. Moreover, it is likely that the activity of the sympathetic nervous system in heart faikrre is facilitated by concomitant activation of the reninangiotensin system. Increased sympathetic nerve activity may then release additional renin from the kidney (by way of a &-adrenergic mechanism). Therefore, both the sympathetic nervous system and the adrenal medulla may interact to cause hypokalemia in patients with heart failure. Because hypokalemia is known to predispose patients to ventricular arrhythmias, it may be prudent to aggressively maintain serum potassium levels in patients with heart failure in the range of 4 to 5 mEq/ liter. (Am J Cardiol 1990;65:24E-27E)
MD
ongestive heart failure is a complex clinical syndrome, characterized by multiple metabolic disturbances, including electrolyte abnormalities.‘*2 Magnesium and potassium (K+) are reduced in both plasma and in skeletal muscle in patients with heart failure.’ The reduction in total body K+ cannot be explained by simple muscle wasting, dosage of diuretic drug, severity of heart failure or changes in renal function.2 Patients with heart failure do, however, demonstrate an inverse and significant (p
C
PLASMA CATECHOLAMINES WITH HEART FAILURE From the Department of Medicine, Veterans Administration Medical Center and the University of Minnesota Medical School, Minneapolis, Minnesota. This study was supported by Grants HL 22977, HL 07 184, HL 32427 and RR-400 from the National Institutes of Health, Bethesda, Maryland and by the Research Service, Veterans Administration, Washington, D.C. Address for reprints: Gary S. Francis, MD, Cardiovascular Research (111 C 1), Veterans Administration Medical Center, Minneapolis, Minnesota 55417.
24E
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
IN PATIENTS
Plasma norepinephrine is increased in patients with congestive heart failure,9v10 although the mechanism by which the sympathetic nervous system is activated in heart failure remains unclear. Nevertheless, plasma norepinephrine does correlate well with directly measured sympathetic neuronal traffic in patients with heart failure,” and plasma levels of this neurotransmitter are believed to be a reasonable estimate of general sympathetic
Vicious Impaired
Cycle of CHF LV Function
FtGURE 1. cengestive heart faihm? (CHF) is a complex clinical syndmmechar~hyactivatlon ofneurohumKal~smsthat maywntrWtefuthertoexpressionofthesyndmme.ttirpossible
t Sympathetic drive t Renin-angiotensin-aldosterone t Arginine vasopressin
bUtblOtplWC+llthd~
nervous system activation, as well as renin-angiotensin activatkm, leads to amllythlas through drect andindiipro&donofhypokalemia. LV = left venbiudar.
Peripheral
vasoconstriction
Na+and H 2 0 retention Hypokalemia, hyponatremia ? Arrhythmias
activity. It is believed that activation of the sympathetic nervous system in heart failure is a “compensatory” responseto a perceivedneedto heighten perfusion pressure to vital organs and enhancemyocardial contractility.‘* It is, however,hypothesizedthat activation of this and other neurohumoral mechanismsin heart failure may ultimateIv lead to further numn dvsfunction, and possibly, to arrhythmias (Fig. i). * *
1200
FtGURE 2. Twenny-itve
In patients with advancing heart failure, plasma norepinephrine progressivelyincreases,whereaspump function remains relatively constant (Fig. 2).13This observation may explain why an elevatedplasma norepinephrine is associatedwith a poor prognosis in patients with advanced heart failure, whereasleft ventricular function is predictive only when a broad spectrum of patients with varying degreesof myocardial dysfunction are studied.I4
r
pa6ents
WlthCOlDgdkheart~W~
followedupforameanof19.6f 2.71nmths.Allpatienb-ent base6nepla!manorepineph’
800
evaha6enwhen6rstrefedZthe dlnkwhlk
t-eaiagdigitalisd
dltmdcs. Pa6mts then began treatmfmtwithcaptopIiloreIudapiland undenventtonowupplawnanorepinephkedetsnnindonsat5.6~ 1.6modvs(n=22)andat16.6f 2.7 manths (n = 26). There was a b?ndforproipS&eincreasein plasma MKepinephrjllc over the. Thesedatahaveinpartkenprevi~tim$~. (Afnnn Am
600
01 Control
I #l 5.6 + 1.5 mo.
I #2 lg.6
5 2.7 mo.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6,199O
25E
A SYMPOSIUM:
HORMONE-ELECTROLYTE
INTERACYIONS
IN CONGESTIVE
HEART FAILURE
Epinephrine 1 adenyl
Na’-K’-
Unlike plasma norepinephrine (which is a neurotransmitter), plasma epinephrine is a true hormone, released from the adrenal medulla. Plasma epinephrine is increased in only a small fraction of patients with heart failure, usually during periods of overt clinical decompensation.t5 These differences between plasma norepinephrine and plasma epinephrine are important with regard to the pathogenesis of hypokalemia. It is the Pz-adrenergic receptor that is operative in initiating the steps necessary to drive potassium into the cell against a gradient, thereby promoting hypokalemia. l6 The Pz-adrenergic receptor, however, has a greater affinity for epinephrine than for norepinephrine. One would therefore expect a stronger relation between increased plasma epinephrine and hypokalemia than between plasma norepinephrine and hypokalemia. Support for this concept is derived from the studies of Nordrehaug et al,” who demonstrated a strong relation between serum potassium and ventricular arrhythmias in patients with acute myocardial infarction, a condition in which plasma epinephrine is known to increase markedly.‘* In this study, serum potassium concentrations correlate inversely with plasma epinephrine but not with plasma norepinephrine. HYPOKALEMIA FROM BETA-ADRENERGIC RECEPTOR STIMULATION Rosa et all9 reported in 1980 that a tolerance to potassium load in humans is enhanced by the continuous infusion of epinephrine (1 pg/min). Brown et all6 demonstrated that epinephrine can cause hypokalemia; this response, however, can be blocked by the selective /?z antagonist ICI 11855 1. Vincent et a120showed that salbutamol, a relatively selective 82 agonist, also reduces serum potassium, and this response can be markedly attenuated by propranolol, a nonselective /3r- and &blocking agent.
26E
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
FlGURE 3. Cehdar medwnism suggesting how &-m
cyclase
ATPase
leadstoincreasd intracehdar cydlladenoslne~ (CAMP). Cydic AMP then stimulates memlwac-beund sodium-ptassiwn adenoshe tipheqhhe (Na+-K+-AYPase), which exchanges intracehlar so&m (Na+) ions far extracellular potassiwn (K+) ions, thuscadnga&iftlromtheextracehdartothe-cempartment. (Adapted from Am J Cart did.9
Taken together, these studies provide strong evidence that activation of Pz-adrenergic receptors decreases extracellular potassium. These p2 receptors are primarily found on skeletal muscle and liver cell membranes, although other locations may also be important. The electrophysiologic studies of Clausen and Flatman21in 1977 were instrumental in providing an explanation for the effects of a & agonist on serum potassium. Based on these data, one can formulate a hypothesis of how epinephrine may increase intracellular potassium and reduce serum potassium (Fig. 3). Epinephrine binds to the membrane &-adrenergic receptor, activating cellular adenyl cyclase. The subsequent increase in intracellular 3’5’-cyclic adenosyl monophosphate activates Na+K+-adenosine triphosphatase, thereby allowing extracellular potassium to be “pumped” into the cell against a substantial gradient. This mechanism becomes particularly important during dynamic exercise. During exercise, potassium leaks from working muscles and enters the extracellular space, acting to increase serum potassium. This increase is partially offset, however, by an increase in plasma epinephrine, which occurs in parallel to the generalized activation of the sympathetic nervous system during exercise. 22 Therefore, after p-adrenergic blockage with propranolol, there may be a striking increase in serum potassium during exercise, possibly related to the fact that the PZ receptor is blocked and cannot operate to maintain potassium homeostasis.23It is possible that in patients with decompensated or advanced congestive heart failure (who have high levels of circulating epinephrine) hypokalemia develops partly because of a propensity to this &adrenergic mechanism, although other factors, including increased aldosterone activity on the distal renal tubule may also play a role. Because ventricular arrhythmias and hypokalemia are highly correlated in patients with heart failure,3 a deficit of extra-
cellular potassium may be important in the genesisof sudden, unexpected death. CONCLUSIONS
In summary, patients with heart failure manifest both neurohumoral and electrolyte abnormalities that are likely to be interrelated.24 The increase in plasma norepinephrine may promote ventricular arrhythmias directly or indirectly by activating the renin-angiotensin-aldosterone system (thereby stimulating the kidney to excrete potassium) and predisposingto hypokalemia. In very advanced or decompensatedheart failure, the increase in plasma epinephrine may activate adrenergic /32receptors to cause a shift of extracellular potassium into skeletal muscle and liver cells, thereby leading to hypokalemia. Although unproven, it is likely that hypokalemia or rapid transmembrane shifts of potassium acrosscells (including the myocardium), or both, can predisposethe patient with heart failure to seriousventricular arrhythmias and sudden death. These observationssuggestthat every effort should be made to maintain serum potassium concentrations in thesepatients, probably within the rangeof 4 to 5 m&l/liter. This strategy may offer a practical and safe opportunity to suppress serious arrhythmias and, possibly, to improve survival. Acknowledgment: The secretarial assistance of Sandy Thiesse is gratefully acknowledged.
REFERENCES 1. Dyckaer T, Wester PO. Plasma and skeletal muscle electrolytes in patients on long-term diuretic therapy for arterial hypertension and/or congestive heart failure. Acta Med Scand 1987:222:231-236. 2. Cleland JGF, Dargie HJ, Robertson I, Robertson JIS, East BW. Total body electrolyte composition in patients with heart failure: a comparison with normal subjects and patients with untreated hypertension. Br Heart J 1987;58;230-238. 3. Dargie HJ, Cleland JGF, Leckie BJ, Inglis CC, East BW, Ford I. Relation of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;75:suppl JVYV-98-W-107. 4. Cohen JD, Neaton JD, Prineas RJ, Daniels KA and the Multiple Risk Factor Intervention Trial Research Group. Diuretics, serum potassium and ventricular
arrhythmias in the multiple risk factor intervention trial. Am J Cardiol 1987$0:548-554. 5. Hollilield JW. Potassium and magnesium abnormalities: diuretics and arrhythmias in hypertension. Am J A4ed 1984:77:suppl 5A:28-32. 6. Hollifield JW. Thiazide treatment for hypertension effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy. Am J Med 1986:80: suppl4A:8-12. 7. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J CardioJ 1986;57:3& 7B. 9. Packer M. Sudden unexpected death in patients with congestive heart failure: a second frontier. Circulation 1985:72:68Jb685. 9. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;4/:233~243. 10. Francis GS. Plasma catccholamincs in patients with congestive heart failure. Cardiwasc Rev Rep 1984,6:444-454. Il. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913-919. 12. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101970-377. 13. Francis GS, Rector T. Sequential neurohumoral measurements in patients with congestive heart failure. Am Heart J 1988;116:1464-1468. 14. Franc&a JA. Why patients with heart failure die: hemodynamic and funo tional determinants of survival. Circulation 1987:75:suppl JVYV-20-W-27. 15. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1666. 16. Brown MJ, Brown DC, Murphy MB. Hypokalemia from betal-receptor stimulation by circulating epinephrine. N Engl J Med 1983;309;1414-1419. 17. Nordrehaug JE, Johanncsscn K-A, van der Lipp G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation 1985:71.645-649. 16. Nordrehaug JE, Johanessen K-A, van der Lipp G, Myking OL. Circulating catecholamine and potassium concentrations early in acute myocardial infarction: effect of intervention with timolol. Am Heart J 1985;J 10~944-948. 19. Rosa RM, Silva P, Young JB, Landsberg L, Brown RS, Rowe JW, Epstein FH. Adrenergic modulation of extra renal potassium disposal. N Eng/ J h4ed 1980;302:431~434. 20. Vincent HH, Man In’t Veld AJ, Bwmsma F, Schalekamp M. Prevention of epinephrine-induced hypokalemia by nonselective beta blockers. Am J Cardiol 1985;56:JOD-140. 21. Clausen T, Flatman JA. The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J PhysioJ (Land) J977;270:383-414. 22. Francis GS, Goldsmith SR, Ziesche SM, Cohn JN. The response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol 1982;49:1152-1156. 23. Carlson E, Fellenius E, Lundborg P, Svensson L. B-adrenergic blocker, plasma potassium, and exercise. hncet 1978;2:424-425. 24. Francis GS, Cohn JN. The autonomic nervous system in congestive heart failure. Annu Rev Med 1986:37:235-247.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6.1990
27E
Congestive heart failure is characterized by both disturbances in electrolyte homeostasis and neurohormonal regulation. Total body potassium is reduced, and this reduction bears a modest relation to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Patients with decompensated heart faikue show increases in both plasma epinephrine and plasma norepinephrine, whereas patients with chronic stable heart failure usually have an increase only in plasma norepinephrine. High levels of circulating epinephrine may contribute to the development of hypokalemia by activating skeletal muscle and liver membrane &-adrenergic receptors, which in turn stimulate intracellular cyclic adenosine monophosphate to activate the membrane-bound Na+K+adenosine triphosphatase pump. The net result is that potassium flux across the cell membrane from the extracellular to the intracellular space increases, setting the stage for hypokalemia and possibly serious ventricular arrhythmias. Other mechanisms that may contribute to the development of hypokalemia in heart failure inelude the kaliurests brought on by excessive levels of aldosterone. Moreover, it is likely that the activity of the sympathetic nervous system in heart faikrre is facilitated by concomitant activation of the reninangiotensin system. Increased sympathetic nerve activity may then release additional renin from the kidney (by way of a &-adrenergic mechanism). Therefore, both the sympathetic nervous system and the adrenal medulla may interact to cause hypokalemia in patients with heart failure. Because hypokalemia is known to predispose patients to ventricular arrhythmias, it may be prudent to aggressively maintain serum potassium levels in patients with heart failure in the range of 4 to 5 mEq/ liter. (Am J Cardiol 1990;65:24E-27E)
MD
ongestive heart failure is a complex clinical syndrome, characterized by multiple metabolic disturbances, including electrolyte abnormalities.‘*2 Magnesium and potassium (K+) are reduced in both plasma and in skeletal muscle in patients with heart failure.’ The reduction in total body K+ cannot be explained by simple muscle wasting, dosage of diuretic drug, severity of heart failure or changes in renal function.2 Patients with heart failure do, however, demonstrate an inverse and significant (p
C
PLASMA CATECHOLAMINES WITH HEART FAILURE From the Department of Medicine, Veterans Administration Medical Center and the University of Minnesota Medical School, Minneapolis, Minnesota. This study was supported by Grants HL 22977, HL 07 184, HL 32427 and RR-400 from the National Institutes of Health, Bethesda, Maryland and by the Research Service, Veterans Administration, Washington, D.C. Address for reprints: Gary S. Francis, MD, Cardiovascular Research (111 C 1), Veterans Administration Medical Center, Minneapolis, Minnesota 55417.
24E
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
IN PATIENTS
Plasma norepinephrine is increased in patients with congestive heart failure,9v10 although the mechanism by which the sympathetic nervous system is activated in heart failure remains unclear. Nevertheless, plasma norepinephrine does correlate well with directly measured sympathetic neuronal traffic in patients with heart failure,” and plasma levels of this neurotransmitter are believed to be a reasonable estimate of general sympathetic
Vicious Impaired
Cycle of CHF LV Function
FtGURE 1. cengestive heart faihm? (CHF) is a complex clinical syndmmechar~hyactivatlon ofneurohumKal~smsthat maywntrWtefuthertoexpressionofthesyndmme.ttirpossible
t Sympathetic drive t Renin-angiotensin-aldosterone t Arginine vasopressin
bUtblOtplWC+llthd~
nervous system activation, as well as renin-angiotensin activatkm, leads to amllythlas through drect andindiipro&donofhypokalemia. LV = left venbiudar.
Peripheral
vasoconstriction
Na+and H 2 0 retention Hypokalemia, hyponatremia ? Arrhythmias
activity. It is believed that activation of the sympathetic nervous system in heart failure is a “compensatory” responseto a perceivedneedto heighten perfusion pressure to vital organs and enhancemyocardial contractility.‘* It is, however,hypothesizedthat activation of this and other neurohumoral mechanismsin heart failure may ultimateIv lead to further numn dvsfunction, and possibly, to arrhythmias (Fig. i). * *
1200
FtGURE 2. Twenny-itve
In patients with advancing heart failure, plasma norepinephrine progressivelyincreases,whereaspump function remains relatively constant (Fig. 2).13This observation may explain why an elevatedplasma norepinephrine is associatedwith a poor prognosis in patients with advanced heart failure, whereasleft ventricular function is predictive only when a broad spectrum of patients with varying degreesof myocardial dysfunction are studied.I4
r
pa6ents
WlthCOlDgdkheart~W~
followedupforameanof19.6f 2.71nmths.Allpatienb-ent base6nepla!manorepineph’
800
evaha6enwhen6rstrefedZthe dlnkwhlk
t-eaiagdigitalisd
dltmdcs. Pa6mts then began treatmfmtwithcaptopIiloreIudapiland undenventtonowupplawnanorepinephkedetsnnindonsat5.6~ 1.6modvs(n=22)andat16.6f 2.7 manths (n = 26). There was a b?ndforproipS&eincreasein plasma MKepinephrjllc over the. Thesedatahaveinpartkenprevi~tim$~. (Afnnn Am
600
01 Control
I #l 5.6 + 1.5 mo.
I #2 lg.6
5 2.7 mo.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6,199O
25E
A SYMPOSIUM:
HORMONE-ELECTROLYTE
INTERACYIONS
IN CONGESTIVE
HEART FAILURE
Epinephrine 1 adenyl
Na’-K’-
Unlike plasma norepinephrine (which is a neurotransmitter), plasma epinephrine is a true hormone, released from the adrenal medulla. Plasma epinephrine is increased in only a small fraction of patients with heart failure, usually during periods of overt clinical decompensation.t5 These differences between plasma norepinephrine and plasma epinephrine are important with regard to the pathogenesis of hypokalemia. It is the Pz-adrenergic receptor that is operative in initiating the steps necessary to drive potassium into the cell against a gradient, thereby promoting hypokalemia. l6 The Pz-adrenergic receptor, however, has a greater affinity for epinephrine than for norepinephrine. One would therefore expect a stronger relation between increased plasma epinephrine and hypokalemia than between plasma norepinephrine and hypokalemia. Support for this concept is derived from the studies of Nordrehaug et al,” who demonstrated a strong relation between serum potassium and ventricular arrhythmias in patients with acute myocardial infarction, a condition in which plasma epinephrine is known to increase markedly.‘* In this study, serum potassium concentrations correlate inversely with plasma epinephrine but not with plasma norepinephrine. HYPOKALEMIA FROM BETA-ADRENERGIC RECEPTOR STIMULATION Rosa et all9 reported in 1980 that a tolerance to potassium load in humans is enhanced by the continuous infusion of epinephrine (1 pg/min). Brown et all6 demonstrated that epinephrine can cause hypokalemia; this response, however, can be blocked by the selective /?z antagonist ICI 11855 1. Vincent et a120showed that salbutamol, a relatively selective 82 agonist, also reduces serum potassium, and this response can be markedly attenuated by propranolol, a nonselective /3r- and &blocking agent.
26E
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65
FlGURE 3. Cehdar medwnism suggesting how &-m
cyclase
ATPase
leadstoincreasd intracehdar cydlladenoslne~ (CAMP). Cydic AMP then stimulates memlwac-beund sodium-ptassiwn adenoshe tipheqhhe (Na+-K+-AYPase), which exchanges intracehlar so&m (Na+) ions far extracellular potassiwn (K+) ions, thuscadnga&iftlromtheextracehdartothe-cempartment. (Adapted from Am J Cart did.9
Taken together, these studies provide strong evidence that activation of Pz-adrenergic receptors decreases extracellular potassium. These p2 receptors are primarily found on skeletal muscle and liver cell membranes, although other locations may also be important. The electrophysiologic studies of Clausen and Flatman21in 1977 were instrumental in providing an explanation for the effects of a & agonist on serum potassium. Based on these data, one can formulate a hypothesis of how epinephrine may increase intracellular potassium and reduce serum potassium (Fig. 3). Epinephrine binds to the membrane &-adrenergic receptor, activating cellular adenyl cyclase. The subsequent increase in intracellular 3’5’-cyclic adenosyl monophosphate activates Na+K+-adenosine triphosphatase, thereby allowing extracellular potassium to be “pumped” into the cell against a substantial gradient. This mechanism becomes particularly important during dynamic exercise. During exercise, potassium leaks from working muscles and enters the extracellular space, acting to increase serum potassium. This increase is partially offset, however, by an increase in plasma epinephrine, which occurs in parallel to the generalized activation of the sympathetic nervous system during exercise. 22 Therefore, after p-adrenergic blockage with propranolol, there may be a striking increase in serum potassium during exercise, possibly related to the fact that the PZ receptor is blocked and cannot operate to maintain potassium homeostasis.23It is possible that in patients with decompensated or advanced congestive heart failure (who have high levels of circulating epinephrine) hypokalemia develops partly because of a propensity to this &adrenergic mechanism, although other factors, including increased aldosterone activity on the distal renal tubule may also play a role. Because ventricular arrhythmias and hypokalemia are highly correlated in patients with heart failure,3 a deficit of extra-
cellular potassium may be important in the genesisof sudden, unexpected death. CONCLUSIONS
In summary, patients with heart failure manifest both neurohumoral and electrolyte abnormalities that are likely to be interrelated.24 The increase in plasma norepinephrine may promote ventricular arrhythmias directly or indirectly by activating the renin-angiotensin-aldosterone system (thereby stimulating the kidney to excrete potassium) and predisposingto hypokalemia. In very advanced or decompensatedheart failure, the increase in plasma epinephrine may activate adrenergic /32receptors to cause a shift of extracellular potassium into skeletal muscle and liver cells, thereby leading to hypokalemia. Although unproven, it is likely that hypokalemia or rapid transmembrane shifts of potassium acrosscells (including the myocardium), or both, can predisposethe patient with heart failure to seriousventricular arrhythmias and sudden death. These observationssuggestthat every effort should be made to maintain serum potassium concentrations in thesepatients, probably within the rangeof 4 to 5 m&l/liter. This strategy may offer a practical and safe opportunity to suppress serious arrhythmias and, possibly, to improve survival. Acknowledgment: The secretarial assistance of Sandy Thiesse is gratefully acknowledged.
REFERENCES 1. Dyckaer T, Wester PO. Plasma and skeletal muscle electrolytes in patients on long-term diuretic therapy for arterial hypertension and/or congestive heart failure. Acta Med Scand 1987:222:231-236. 2. Cleland JGF, Dargie HJ, Robertson I, Robertson JIS, East BW. Total body electrolyte composition in patients with heart failure: a comparison with normal subjects and patients with untreated hypertension. Br Heart J 1987;58;230-238. 3. Dargie HJ, Cleland JGF, Leckie BJ, Inglis CC, East BW, Ford I. Relation of arrhythmias and electrolyte abnormalities to survival in patients with severe chronic heart failure. Circulation 1987;75:suppl JVYV-98-W-107. 4. Cohen JD, Neaton JD, Prineas RJ, Daniels KA and the Multiple Risk Factor Intervention Trial Research Group. Diuretics, serum potassium and ventricular
arrhythmias in the multiple risk factor intervention trial. Am J Cardiol 1987$0:548-554. 5. Hollilield JW. Potassium and magnesium abnormalities: diuretics and arrhythmias in hypertension. Am J A4ed 1984:77:suppl 5A:28-32. 6. Hollifield JW. Thiazide treatment for hypertension effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy. Am J Med 1986:80: suppl4A:8-12. 7. Francis GS. Development of arrhythmias in the patient with congestive heart failure: pathophysiology, prevalence and prognosis. Am J CardioJ 1986;57:3& 7B. 9. Packer M. Sudden unexpected death in patients with congestive heart failure: a second frontier. Circulation 1985:72:68Jb685. 9. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;4/:233~243. 10. Francis GS. Plasma catccholamincs in patients with congestive heart failure. Cardiwasc Rev Rep 1984,6:444-454. Il. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlof G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913-919. 12. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101970-377. 13. Francis GS, Rector T. Sequential neurohumoral measurements in patients with congestive heart failure. Am Heart J 1988;116:1464-1468. 14. Franc&a JA. Why patients with heart failure die: hemodynamic and funo tional determinants of survival. Circulation 1987:75:suppl JVYV-20-W-27. 15. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1666. 16. Brown MJ, Brown DC, Murphy MB. Hypokalemia from betal-receptor stimulation by circulating epinephrine. N Engl J Med 1983;309;1414-1419. 17. Nordrehaug JE, Johanncsscn K-A, van der Lipp G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation 1985:71.645-649. 16. Nordrehaug JE, Johanessen K-A, van der Lipp G, Myking OL. Circulating catecholamine and potassium concentrations early in acute myocardial infarction: effect of intervention with timolol. Am Heart J 1985;J 10~944-948. 19. Rosa RM, Silva P, Young JB, Landsberg L, Brown RS, Rowe JW, Epstein FH. Adrenergic modulation of extra renal potassium disposal. N Eng/ J h4ed 1980;302:431~434. 20. Vincent HH, Man In’t Veld AJ, Bwmsma F, Schalekamp M. Prevention of epinephrine-induced hypokalemia by nonselective beta blockers. Am J Cardiol 1985;56:JOD-140. 21. Clausen T, Flatman JA. The effect of catecholamines on Na-K transport and membrane potential in rat soleus muscle. J PhysioJ (Land) J977;270:383-414. 22. Francis GS, Goldsmith SR, Ziesche SM, Cohn JN. The response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol 1982;49:1152-1156. 23. Carlson E, Fellenius E, Lundborg P, Svensson L. B-adrenergic blocker, plasma potassium, and exercise. hncet 1978;2:424-425. 24. Francis GS, Cohn JN. The autonomic nervous system in congestive heart failure. Annu Rev Med 1986:37:235-247.
THE AMERICAN JOURNAL OF CARDIOLOGY MARCH 6.1990
27E