International Journal of Cardiology 158 (2012) 12–17

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International Journal of Cardiology

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Review

The meaning of hypokalemia in heart failure

Agata Bielecka-Dabrowa a, Dimitri P. Mikhailidis b, Linda Jones c, Jacek Rysz d,Wilbert S. Aronow e, Maciej Banach a,⁎a Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Polandb Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London, London, UKc Division of Gerontology, Geriatric and Palliative Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USAd Department of Nephrology, Hypertension and Family Medicine, Chair of Nephrology and Hypertension, Medical University of Lodz, Polande Department of Medicine, New York Medical College, Valhalla, NY, USA

⁎ Corresponding author at: Department of Hypertensin Lodz, Medical University of Lodz, Poland. ZeromskieTel.: +48 42 639 37 71; fax: +48 42 639 37 71.

E-mail address: maciejbanach@aol.co.uk (M. Banach

0167-5273/$ – see front matter © 2011 Elsevier Irelanddoi:10.1016/j.ijcard.2011.06.121

a b s t r a c t

a r t i c l e i n f o

Article history:Received 9 March 2011Received in revised form 15 June 2011Accepted 25 June 2011Available online 20 July 2011

Keywords:PotassiumHypokalemiaHeart failureDiuretics

Maintenance of normal potassium (K+) homeostasis has become an increasingly important limiting factor inthe therapy of heart failure (HF). With the application of loop diuretics and digoxin, hypokalemia has becomea frequent and feared side effect of treatment. Low serum K+ in HF may be also a marker of increasedneurohormonal activity and disease progression.To gain the maximum benefit from treatment, we need to individualize drug use and carefully monitorelectrolytes. Symptomatic HF patients (New York Heart Association class III–IV) should be prescribed thelowest dose of diuretic necessary to maintain euvolemia. Mild hypokalemia may be corrected by the use ofaldosterone receptor antagonists such as spironolactone or eplerenone. However, a more severe hypokalemiashould preferably be corrected using K+ supplement. Serum K levels should be frequently checked andmaintained between 4.0 and 5.5 mEq/l (mmol/l).

ion, WAM University Hospitalgo 113; 90-549 Lodz, Poland.

).

Ltd. All rights reserved.

© 2011 Elsevier Ireland Ltd. All rights reserved.

1. Epidemiology of hypokalemia in heart failure (HF)

Congestive heart failure carries a grim prognosis. The 5-yearsurvival rate is well below 40% [1], with half of the deaths classified assudden [2,3]. These deaths were probably caused by ventriculararrhythmias or electromechanical dissociation [4–6]. Electrophysio-logical remodeling is associated with the progression of hypertrophyand heart failure (HF) [7].

Potassium (K+) is an important electrolyte essential for a healthynervous system and a regular heart rhythm [7,8]. K+ concentration isimportant in cell metabolism and membrane excitability [8].Hypokalemia has not been well defined in HF, but in the literatureon hypertension, the definition has varied from b3.5 to b4.0 mEq/L(mmol/l) [9]. K+ depletion is commonly seen in patients withcongestive heart failure, a condition that is characterized by severalphysiologic abnormalities predisposing to the development ofelectrolyte disturbances.

2. Etiology and pathophysiology of hypokalemia in HF

The sodium-rich diet of modern humans may produce sodiumoverload and K+ depletion [10]. Hypokalemia contributes to the

pathogenesis of cardiovascular disease, and many cardiovasculardisorders and drugs cause hypokalemia [11,12].

Patients with HF may have difficulty with K+ transport into tissues.In patientswithHF, an increase in oxidative stressmay result in a defectin Na+/K+-ATPase activity and thus in transport of K+ into tissues.Consequently, tissue levels of K+maybe considerably lower than serumlevels, whichwould place them at increased risk formyocardial fibrosis,hypertrophy, and sudden cardiac death. For example, patients with HFhave been found to have a serum K+ level greater than 7.0 mEq/L(mmol/l) without any electrocardiographic changes or clinical mani-festations of hyperkalemia because their tissue K+ level was normal orlow, as reflected by the red-cell K+ concentration [13]. Thus, it has beensuggested that the level of serumK+ should bemaintained between 4.5and 5.5 mEq/L (mmol/l) in patients with HF [14].

Among the pathogenic factors associated with HF are renaldysfunction and neurohormonal activation, which stimulate therenin–angiotensin–aldosterone axis, sympathetic nervous tone, andhypersecretion of catecholamines [15].

Serum K+ is negatively correlated with plasma renin activity andplasma noradrenaline, and patients who respond to treatment showincreases in intracellular K+ concentrations [16,17]. Thus, neurohor-monal activation contributes markedly to K+ depletion in HF. A dropin intravascular volume, such as that which occurs with leftventricular systolic dysfunction, and reduced cardiac output resultsin a pathologically elevated aldosterone level. In patients withcongestive heart failure, aldosterone may reach plasma levels up to60 times higher than those measured in normal subjects [18,19].

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Cardiomyocytes, blood vessels, and adipocytes have also beenshown to synthesize aldosterone [19]. Aldosterone induces sodiumand water reabsorption with concomitant K+ excretion. The adverseeffects attributed to hyperaldosteronism that may influence cardio-vascular function include increased intravascular-fluid retention andvolume overload, endothelial dysfunction, impaired vascular reactiv-ity, sympathetic nervous system activation, decreased baroreceptorsensitivity, increased electrolyte excretion (K+ and magnesium ions),and cardiomyocyte apoptosis [18,20,21] (Fig. 1). Low levels of serumK+ in HF may be a marker of increased neurohormonal activity anddisease progression [21,22].

Hypokalemia is a frequent and feared side effect of the treatmentof HF with loop diuretics and digoxin [23] because the arrhythmo-genic potential of digoxin is enhanced by hypokalemia. The mainclasses of diuretics are the loop diuretics, K+-sparing diuretics, andthiazides. Loop diuretics, the mainstay of acute and chronic therapyfor HF, are “threshold drugs”; therefore, a dose adequate to achieve apharmacodynamic effect must be prescribed [23].

Loop diuretics include the sulfonamide derivatives furosemide,bumetanide, and torsemide, as well as ethacrynic acid, which is usedless often. These drugs inhibit the Na+-K+-2Cl−cotransporter (NKCC)in the thick ascending limb of the loop of Henle, which is responsiblefor reabsorption of 20% to 30% of the filtered sodium [24]. Thiazidediuretics, which are the most commonly used of the diuretic class,inhibit the sodium-chloride transporter in the distal tubule. Becausethis transporter normally reabsorbs only about 5% of filtered sodium,these diuretics are less efficacious than loop diuretics in producingdiuresis and natriuresis [24]. Nevertheless, they are sufficientlypowerful to satisfy most therapeutic needs requiring a diuretic.Their mechanism depends on renal prostaglandin production [24].

Because loop and thiazide diuretics increase sodium delivery tothe distal segment of the distal tubule, K+ loss increases (potentiallycausing hypokalemia). This occurs because the increase in distaltubular sodium concentration stimulates the aldosterone-sensitivesodium pump to increase sodium reabsorption in exchange for K+

and hydrogen ions, which are lost to the urine [25–27].

Fig. 1. The effect of impaired left ventricular (LV) function on aldosterone synthesis. A, A decefferent renal blood flow. B, This stimulates renin secretion from the juxtaglomerular apparatwhich is converted to angiotensin II (AT II) by ACE in the pulmonary artery vasculature (aldosterone. Elevated plasma levels of aldosterone have a number of adverse effects on theeducation), © 1998 William Fridl, dba U-Write; kidney and glomerulus images from Bill CaMcGill Molson Medical Informatics Project, McGill University.

Potentially harmful effects of administration of high doses of loopdiuretics are neurohormonal activation of the renin–angiotensin–aldosterone system and increased levels of norepinephrine andarginine vasopressin, both of which are fundamentally involved inthe progression of HF [25–27]. In patients with HF it is important toachieve euvolemia that improves patients clinical condition, on theother hand physicians should attempt to lower diuretic doses, whenpossible, due to the neurohormonal activation of renin–angiotensin–aldosterone system (RAAS).

Administration of loop diuretics may lead to electrolyte imbal-ances (such as hypokalemia, hyponatremia, and hypomagnesemia)that may exacerbate cardiac arrhythmias and increase the risk ofsudden cardiac death [28,29]. In the Studies of Left VentricularDysfunction (SOLVD) trial, use of a diuretic was associated with a 37%increase in the risk of arrhythmic death after controlling for multipleother measures of disease severity [28,29].

Still, little is known about the effects of hypokalemia on outcomesin patients with chronic heart failure [30].

3. Effect of hypokalemia in HF

Hypokalemia causes cellular hyperpolarity, increases restingpotential, hastens depolarization, and increases automaticity andexcitability [31,32]. Because cardiac repolarization relies on K+ influx,hypokalemia lengthens the action potential and increases QTdispersion reflecting electrical inhomogeneity. Most patients withHF have increased ventricular ectopy, and 50% exhibit nonsustainedventricular tachycardia [33]. A total of 50% of deaths from HF aresudden, presumably due to arrhythmias. In victims of sudden cardiacdeath, the level of myocardial K+ is markedly lower than in controls,and survivors are often hypokalemic [34]. In HF, all-cause and cardiacmortality rates are higher in individuals taking non-K+-sparingdiuretics [35]. The incidence of arrhythmic death is significantly andindependently related to use of non-K+-sparing diuretics [34,35].

Hypokalemia predisposes a patient to digoxin toxicity by reducingrenal clearance and promotingmyocardial binding of the drug. This, in

rease in cardiac output as a result of LV systolic dysfunction is perceived as a decrease inus. C, In the peripheral circulation, renin cleaves angiotensinogen to angiotensin I (AT I),D). E, Angiotensin II stimulates the zona glomerulosa in the adrenal cortex to secretecardiovascular system. NO· indicates nitric oxide. (Heart images from U-Write patientmelet; blood vessel images from John MacNeil; adrenal gland image reproduced from

14 A. Bielecka-Dabrowa et al. / International Journal of Cardiology 158 (2012) 12–17

turn, produces increased automaticity and ventricular arrhythmias[36,37]. K+ depletion exacerbates diastolic dysfunction in animal andhuman models [38].

The negative effect of hypokalemia in patients with HF has beenreported in clinical studies. The researchby Bowling et al. [39] included7788 patients with chronic heart failure in the Digitalis InvestigationGroup trial. Of these, 2793 had chronic kidney disease, defined as anestimated glomerular filtration rate (eGFR)b60 mL/min/1.73 m2.Propensity scores for hypokalemia [serum K+, b4 mEq/L (mmol/l)]were used to assemble a balanced cohort of 522 pairs of patients withhypokalemia and normokalemia. Death due to all causes occurred in48% and 36% of patients with hypokalemia and normokalemia,respectively, during 57 months of follow-up (matched hazard ratiowhen hypokalemia was compared with normokalemia, 1.56; 95%confidence interval [CI], 1.25 to 1.95; Pb0.0001). In patients with HFand chronic kidney disease, death from all causes occurred in 47% and38% of patients with mild hypokalemia [3.5 to 3.9 mEq/L (mmol/l)]and normokalemia, respectively (matched hazard ratio, 1.31; 95% CI,1.03 to 1.66; P=0.027) [39].

The analysis of Ahmed et al. [40] is based on patients followed for32 months in the US-Canadian Digitalis Investigation Group (DIG)trial who had K+ levels b5.5 mEq/L (mmol/l). The DIG trial, whichpredated the recommended use of beta-blockers in HF, enrolledpatients with chronic systolic or diastolic HF of any cause. The cohort's1187 patients with levels of serum K+b4 mEq/L (mmol/l) werematched with the same number who had higher levels based onpropensity scores encompassing a broad range of demographic,clinical, and treatment-related factors. Nearly all of those featuresbecame covariates in an analysis that showed low K+ to beindependently associated with increased cardiovascular and all-cause mortality, as well as death due to progressive HF (Table 1).Similar but insignificant trends were seen for all-cause, cardiovascu-lar, and hospitalization related to myocardial infarction and stroke[40].

Alper et al. [41] studied the effect of low serum K+ levels in apropensity-matched population of elderly patients with heart failure(≥65 years); patients were categorized into groups with low[b4 mEq/L (mmol/l)]; n=590 and normal [4–4.9 mEq/L (mmol/l);n=2684] K+ levels. Low serum K+ was associated with increasedmortality: 37% (rate, 1338/10000 person-years) in patients withnormal K+ and 43% (rate, 1594/10000 person-years) in patients withlow K+ (hazard ratio [HR] for low K+, 1.22; 95% CI, 1.04–1.44;P=0.014). A low serum K+ level (HR, 1.10; 95% CI, 0.96–1.25;P=0.175) was not associated with all-cause hospitalization [41].

According to a post hoc analysis of data from a randomized trial,hypokalemia is associated with an increased mortality risk that isindependent of the New York Heart Association (NYHA) functionalclass, drugs used in therapy, and use of K+ supplements [40,42].

In the Eplerenone Post-Acute Myocardial Infarction Heart FailureEfficacy and Survival Study (EPHESUS), a significant absolute decreaseof 4.7% was found in the incidence of hypokalemia [serum K+

b3.5 mEq/L (mmol/l)], and the incidence of hypokalemia was greaterthan that of hyperkalemia [serum K+ ≥6.0 mEq/L (mmol/l)] [43].

Table 1Mortality risks associated with serum potassium ≤4 mEq/L in heart failure (HF) [40].

End point HR (95% CI)* P

All-cause mortality 1.25 (1.07–1.46) 0.006CV mortality 1.27 (1.06–1.51) 0.009Death from progressive HF 1.36 (1.05–1.75) 0.020

Results are expressed as hazard ration (HR) and 95% confidence interval (CI).*Adjusted for demographics, HF etiology, cardiovascular diseases, diabetes, medications(including digoxin, ACE inhibitors, diuretics), use of potassium-sparing diuretics,potassium supplementation, HF signs and symptoms, NYHA functional class, chest X-ray findings and serum creatinine.

Althoughmany clinicians have become concerned about the risk ofhypokalemia only when the level of serum K+ is b3.5 mEq/L(mmol/l), a recent analysis of the National Heart, Lung, and BloodInstitute's Digitalis Investigation Group trial showed an increased riskof both sudden cardiac death and progressive HF in patients with aserum K+ level b4.5 mEq/L (mmol/l), regardless of the use of K+

supplements [44].This relationship of decreased serum K+ [b4.4 mEq/L (mmol/l)] as

an independent predictor of sudden cardiac death in patients with HFhas been demonstrated in other studies. In the United Kingdom HeartFailure Evaluation and Assessment of Risk Trial, Nolan et al. found thatlow serum K+ levels were related to sudden cardiac death (n=433)[45].

Leier et al. [46] have recommended maintaining serum K+ levelsin the range of 4.5 to 5.0 mEq/L (mmol/l). The importance ofpreventing hypokalemia is underscored by the finding that the risksof dysrhythmias, syncope, cardiac arrest, or death are greater inpatients with HF. This result may be due in part to the cells ofhypertrophied and failing hearts often having prolonged actionpotential duration, which in most cases is caused by a decrease inoutward K+ currents [46].

4. Prevention and treatment of hypokalemia in HF

The combination drug therapy may simultaneously improveclinical outcomes while it enhances the risk of K+-related adverseevents [47]. The K+-sparing diuretics are important in preventinghypokalemia in HF [47].

The K+-sparing diuretics include spironolactone and eplerenone.Unlike loop and thiazide diuretics, these drugs do not act directly onsodium transport. Some drugs in this class antagonize the actions ofaldosterone (aldosterone receptor antagonists) at the distal segmentof the distal tubule, which causemore sodium (andwater) to pass intothe collecting duct and be excreted in the urine. By inhibitingaldosterone-sensitive sodium reabsorption, fewer K+ and hydrogenions are exchanged for sodium by this transporter, and therefore, lessK+ and hydrogen are lost via the urine. Other K+-sparing diureticsdirectly inhibit sodium channels associated with the aldosterone-sensitive sodium pump, and therefore, they have similar effects on K+

and hydrogen ions as aldosterone antagonists [47]. Their mechanismdepends on renal prostaglandin production [47]. Aldosterone block-ade is effective in reducing death from all causes in patients aftermyocardial infarction complicated by left ventricular dysfunction andHF. The use of aldosterone blockade in these patients has beenrecognized as a class 1 indication in both U.S. and European guidelines[47].

The positive influence of these drugs is connectedwith their abilityto inhibit the adverse effect of hyperaldosteronism in patients with HF(Fig. 1) [48,49].

Spironolactone is a nonselective aldosterone receptor antagonistthat is metabolized extensively in the liver to its active metabolite andis structurally similar to progesterone, thereby allowing sex-steroidreceptor cross-reactivity [50]. This phenomenon accounts for theantiprogesterone and antiandrogen effects observed in some patientstreated with spironolactone [50].

In the pre-RALES (The Randomized Aldactone Evaluation Study)pilot study, [51] in 214 patients a dose response in the incidence ofhyperkalemia defined as serum K+N5.5 mEq/l (mmol/l) was assessedin 4 groups treated with spironolactone in doses of 12.5, 25, 50 and75 mg. The incidence of hyperkalemia was 5, 13, 20 and 24%,respectively, and predictors for the development of hyperkalemiawere the use of angiotensin-converting (ACE) inhibitors and abaseline elevation of K+ or creatinine. The treatment was consideredsafe, provided that serum K+ levels were monitored closely [51].

The RALES investigators performed a safety study regarding theuse of spironolactone in patients in NYHA class III to IV with left

Fig. 2. Association of potassium supplement use and all-cause hospitalization. Adoptedfrom [61].

15A. Bielecka-Dabrowa et al. / International Journal of Cardiology 158 (2012) 12–17

ventricular systolic dysfunction. Of note, 10% of the patients in thecontrol group in this study presented with hypokalemia [52].

In contrast, those patients assigned to receive 50 or 75 mg ofspironolactone had no episodes of hypokalemia, and there was justone episode in those receiving 25 mg/day. This study showed asignificant reduction in mortality of approximately 30%. Subgroupanalysis showed similar improvement in mortality rates regardless ofthe creatinine or K+ concentration or the use of K+ supplements [52].

The positive experience in clinical trials contrastswith several reportsof cases of serious hyperkalemia in patients givenwith spironolactone forchronic heart failure in clinical practice, some of which were associatedwith increased hospital admissions and death [53–55].

The occurrence of hyperkalemia in these trialsmay have been relatedto the higher doses used in this study [56] compared to those in thereference trials, EPHESUS and RALES. In clinical practice, patients areoftenolder than in randomized trials andmayhavea reducedeGFR that isnot reflected by the level of serumcreatinine, because serumcreatinine isan inaccurate measure of true kidney function in the elderly [56].

During aldosterone antagonist treatment one should assess renalparameters and electrolyte concentration optimally after 1 week andthen 4 weeks after treatment initiation; after an optimal dosage of thedrug is established, measurements should be obtained at 1, 2, 3 and6 months, and afterwards every 6 months [57]. It is recommendedthat whenever a change in electrolyte status is suspected, such asduring an episode of vomiting or diarrhea or at initiation or dosageadjustment of concomitant diuretic therapy, serum K+ levels shouldbe remeasured or the aldosterone blocker withheld until suchmeasurement is possible [58].

Eplerenone is a selective aldosterone receptor antagonist derivedfrom spironolactone, but because of its limited affinity for theprogesterone and androgen receptors, it lacks sex-related adverse sideeffects [50].

In the EPHESUS trial [56], the selective aldosterone blockereplerenone (25 to 50 mg/d) significantly reduced all-cause mortality(15%; P=0.008) and cardiovascular mortality or hospitalization (13%;P=0.002)whenused in addition to standard therapy inpatientswith leftventricular systolic dysfunction, a left ventricular ejection fraction≤40%,and HF after acute myocardial infarction. Additionally, it reducedhospitalization for HF (15%; P=0.03) and sudden cardiac death (21%;P=0.03). Patients were excluded if the baseline K+ was N5.0 mEq/L orserum creatinine was N2.5 mg/dL (221.0 μmol/l).

A subanalysis of the EPHESUS study examined the relationshipbetween eplerenone, serum K+, and clinical outcomes. These post hocanalyses demonstrated that eplerenone, when administered at a doseof 25 to 50 mg/d, is associated with a 4.4% absolute increase in theincidence of hyperkalemia [N5.5 mEq/L (mmol/l)] and an absoluteincrease of only 1.6% in the incidence of more marked hyperkalemia[≥6.0 mEq/L (mmol/l)]. Overall, less than 1% of patients who wererandomized to eplerenone had to discontinue therapy because ofhyperkalemia [56]. Eplerenone can be used safely in patients with HF,provided they are monitored appropriately, as in the EPHESUS trial.

A positive effect of eplerenone was balanced by a significantreduction in hypokalemia [b3.5 mEq/l (mmol/l)] episodes (8.4% vs13.1%) in the eplerenone and placebo group, respectively [56]. Thiseffect could theoretically lead to a significant reduction in the risk ofarrhythmia in HF, which can be even greater since aldosteroneantagonism reduces renal magnesium excretion [56]. It is likely thatthe reduction in hypokalemia was much more important than thepotentially dangerous risk of hyperkalemia [56]. In this regard, it isinteresting to consider mortality rates according to subgroups. Whendeath rates were analyzed according to K+ concentration [cut-offvalue of 4 mEq/l (mmol/l)], there was no difference in all-causemortality (P=0.29), but the difference was significant whenconsidering cardiovascular death or hospitalization for cardiovascularevents (P=0.02), favoring those patients with a K+ concentra-tionN4 mEq/l (mmol/l) [59].

5. Potassium supplements in HF patients

K+ supplements are commonly used to treat hypokalemia andmaintain normokalemia. However, their long-term effects on out-comes in chronic heart failure are unknown. Ekundayo et al. used apublic-use copy of the Digitalis Investigation Group (DIG) trial datasetto determine the association of K+ supplement use with outcomeswith a propensity-matched design. Although the use of K+ supple-ments in chronic heart failure was not associated with mortality (HRwhen K+ supplement use was compared with non-use, 1.05; 95% CI,0.94–1.18; P=0.390), it was associated with increased hospitaliza-tion due to cardiovascular causes (1.19; 1.08–1.32; P=0.001) andprogressive HF (1.27; 1.12–1.43; Pb0.0001) [60]. Ahmed et al.revealed that K+-supplement use was associated with no reductionin mortality, but with increased hospitalization (Fig. 2) [61].

6. Conclusions

Hypokalemia is common in HF patients, often due to a defect inNa+/K+-ATPase activity and intracellular shift of K caused byoxidative stress and neurohormonal activation. Serum K+ levelshave important therapeutic and prognostic implication for HFpatients. While diuretics, commonly used in HF may cause hypoka-lemia, neurohormonal blockade using ACE inhibitors, angiotensinreceptor blockers, beta-blockers, and aldosterone antagonists maycause hyperkalemia. Hypokalemia is associated with ventriculararrhythmias and sudden cardiac death. Mild hypokalemia may becorrected by the use of aldosterone receptor antagonists such asspironolactone or eplerenone. However, a more severe hypokalemiashould preferably be corrected using K+ supplement. Patients withchronic hypokalemia requiring K+ supplements to maintain normo-kalemia may be treated with aldosterone antagonists instead. SomeHF patients may remain hypokalemic despite therapy with aldoste-rone antagonists and should be treated with K+ supplements. HF inpatients with chronic kidney disease and diabetes mellitus receivingaldosterone antagonists and/or K+ supplements should be monitoredclosely to avoid hyperkalemia (K+ N5.5 mEq/L). Symptomatic HFpatients (NYHA class III–IV) should be prescribed the lowest dose ofdiuretic necessary to maintain euvolemia. Serum K levels should befrequently checked and maintained between 4.0 and 5.5 mEq/l(mmol/l).

Declaration of interest

The authors have not received any payments in connection withthe preparation of this review. No pharmaceutical company sup-ported or was involved with the preparation of this article.

16 A. Bielecka-Dabrowa et al. / International Journal of Cardiology 158 (2012) 12–17

Acknowledgement

The authors of this manuscript have certified that they complywith the Principles of Ethical Publishing in the International Journal ofCardiology [62].

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