Skip to main content
The Journal of Clinical Hypertension logoLink to The Journal of Clinical Hypertension
. 2007 May 31;4(3):198–206. doi: 10.1111/j.1524-6175.2002.01728.x

Importance of Potassium in Cardiovascular Disease

Domenic A Sica 1, Allan D Struthers 2, William C Cushman 3, Mark Wood 4, John S Banas Jr 5, Murray Epstein 6
PMCID: PMC8101903  PMID: 12045369

Abstract

The pivotal role of potassium (K+) in cardiovascular disease and the importance of preserving potassium balance have become clinical hot points, particularly as relates to new and emerging cardioprotective and renoprotective therapies that promote potassium retention. Although clinicians May be aware of the critical nature of this relationship, quite frequently there is some uncertainty as to the best way to monitor potassium levels in the face of a host of pathologic states and/or accompanying drug therapies that affect serum levels and/or total body potassium balance. Moreover, guidelines for monitoring of serum potassium levels are at best tentative and oftentimes are translated according to the level of concern of the respective physician. To address these uncertainties, an expert group was convened that included representatives from multiple disciplines. They attempted to reach consensus on the importance of K+ in hypertension, stroke, and arrhythmias as well as practical issues on maintaining K+ balance and avoiding K+ depletion. Because of the complexity of this topic, issues of hyperkalemia will be addressed in a forthcoming manuscript.


The critical role of potassium (K+) in cardiovascular (CV) disease and the importance of maintaining a normokalemic state are increasingly being recognized, particularly as relates to new and emerging cardioprotective and renoprotective therapies that promote K+ retention. Although clinicians May be aware of the critical nature of this relationship, they often are unsure of the best way to monitor K+ levels in the face of varying pathologic states and drug therapies that affect total body K+ balance or serum levels, or both. To address these uncertainties, an expert group was convened that included representatives from cardiology, electrophysiology, nephrology, pharmacology, hypertension, and endocrinology. They attempted to reach consensus on the importance of K+ in hypertension, stroke, and arrhythmias as well as practical issues on maintaining K+ balance and avoiding K+ depletion. Because of the complexity of the topic discussed, issues on hyperkalemia will be addressed in a subsequent manuscript.

POTASSIUM BALANCE

Potassium Intake

The primary source of K+ is found in the diet; between 40 and 100 mmol are typically ingested on a daily basis. 1 The main sources of dietary K+ are foods of vegetable origin. Fresh and dried fruits, fresh vegetables, milk, and meat are leading sources of K+; processed or refined foods are generally higher in sodium (Na+) (and fat) and lower in K+ (and fiber). Regional, ethnic, and socioeconomic factors influence daily K+ intake with high interindividual as well as day‐to‐day intraindividual variation. In particular, the elderly and African Americans are known to ingest diets lower in K+ content. 2 The K+ found in foodstuffs is typically coupled with phosphate, citrate, or acetate. These salts are less effective in repairing K+ losses associated with chloride depletion, such as occurs with diuretic therapy. K+ chloride is the salt that is generally most effective in correcting diuretic‐induced hypokalemia.

Serum Potassium

The measurement of serum K+ , although easily accomplished, is not always standardized. Indeed, the normal range for K+ values is itself highly variable between laboratories; the lower limit fluctuates between 3.5 and 3.8 mmol/L and the upper limit between 5.0 and 5.5 mmol/L. Thus, interpretation of the value returned from the laboratory requires careful consideration and understanding of the conditions under which the sample was obtained. For example, a serum K+ value measured from a clotted blood sample (red‐top tube) is typically 0.1–0.3 mmol/L higher than that obtained from a plasma sample, a difference that is generally of minimal clinical significance. Blood samples obtained using improper techniques can also result in pseudohyperkalemia. Prolonged use of a tourniquet above a venipuncture site or excessive fist clenching will result in tissue hypoxia and the leaching of K+ from tissue into plasma. Plasma K+ values exhibit a circadian rhythm (average peak‐to‐trough difference =0.60 mmol/L, with lowest values at night) 3 , 4 and also decrease postprandially because of insulin released in response to an ingested carbohydrate load. These are important considerations when evaluating K+ status in diuretic‐treated patients.

A low serum K+ value is one of the most common inpatient electrolyte disturbances observed in clinical practice. As many as 20% of hospitalized patients will be found to be hypokalemic (defined by a serum K+ <3.6 mmol/L) at some time during a hospitalization. 5 The majority of these patients have serum K+ values that fall somewhere between 3.0 and 3.5 mmol/L. The observed hypokalemia is frequently evanescent because of transcellular shifts of K+ , which tend to be readily reversible. On an outpatient basis, hypokalemia is more commonly related to bodily losses. Such bodily losses typically occur as the result of either renal and/or gastrointestinal (GI) abnormalities, which May be related to the disease state or to medication. Under such conditions, the observed level of hypokalemia correlates more closely with the size of the total body deficits.

External Factors

The economy of K+ in the body is typically separated into elements of both external and internal balance. The GI and renal systems influence external K+ balance, with a normally functioning gut typically conserving or eliminating K+ based on total body stores. The GI abnormalities most relevant to external K+ balance include diarrhea and/or vomiting. Diarrheal states are commonly attended by significant K+ and magnesium (Mg++) losses, with stool K+ content reaching values as high as 90 mmol/L. Mg++ losses can be dramatic with sustained diarrhea and are often difficult to quantify because the serum Mg++ concentration poorly reflects the total body balance of this cation. Total body Mg++ deficiency, with or without low serum Mg++ values, can limit the body's ability to conserve administered K+ and is therefore something to be considered in the case of “refractory hypokalemia.” Vomiting is another GI disturbance commonly marked by the presence of hypokalemia, although its origin is not as a consequence of GI losses—gastric fluid typically contains 10 mmol of K+/L—but rather as the result of increased renal K+ losses in association with metabolic alkalosis.

Renal factors influencing K+ balance include urinary flow rate, extracellular fluid volume, diuretic use, Na+ intake, acid‐base balance, mineralocorticoid excess, renal tubular diseases, and Mg++ depletion. 6 Diuretic therapy is the leading drug‐related cause of hypokalemia and directly relates to the dose of the diuretic as well as to the level of dietary Na+ intake. Diuretic therapy as the cause of hypokalemia is fairly straightforward unless diuretics are being surreptitiously ingested; in the case of the latter, determining that diuretic use is occurring is made easier by recognizing the urinary and plasma electrolyte patterns characteristically observed in such settings.

Internal Factors

An average 70‐kg adult maintains a total body K+ content of approximately 3500 mmol, the majority of which (98%) resides intracellularly; accordingly, <2% of total body K+ is located within the extracellular fluid space. The persistence of this relationship results in a very high intracellular‐to‐extracellular ratio (10:1) for K+.

Both insulin and β‐adrenergic active catecholamines encourage intracellular migration of K+ by stimulating cell membrane Na+/K+ adenosine triphosphatase. 7 It remains unclear whether aldosterone affects transcellular K+ distribution; alternatively, aldosterone remains an important determinant of renal K+ handling. 8

Hypokalemia is not always associated with true depletion of body K+ stores. Potassium redistribution is a frequently observed phenomenon, most often seen in stressful situations, such as at the time of an acute myocardial infarction (AMI), when endogenous catecholamine release exerts a β2‐adrenergic‐mediated effect to force intracellular transmigration of K+ . Other clinical situations where intracellular K+ migration May be observed to a sufficient degree so as to be clinically relevant include insulin administration (e.g., in the treatment of hyperglycemia) or during β2 agonist use (i.e., during cardiac arrest, in the course of postoperative blood pressure [BP] support in the cardiothoracic surgery patient, and/or in the course of symptomatic management of acute or chronic asthma). It is important to recognize that redistributional hypokalemia occurs independently of the underlying state of total body K+ balance. Therefore, laboratory values obtained during such situations cannot be used to accurately predict whether a true total body deficit of K+ exists, or in the instance of a mixed picture—a patient with a known basis for a K+ deficit and the presence of factors associated with redistribution—to establish the true level of the deficit. When redistributional hypokalemia is treated, it should be treated cautiously, with an understanding that when the precipitating factor is removed—which can occur rapidly—continued administration of K+ in the absence of a stimulus for transcellular K+ shifts can lead to development of hyperkalemia. Total body K+ can be measured by a number of sophisticated methods, but none are routinely clinically available. Thus, estimation of total body K+ status in the presence of hypokalemia is, at best, a cautious clinical guess.

Potassium and Magnesium Interrelationship

As is the case for K+, Mg++ is one of the principal intracellular cations, and pathologic conditions causing an imbalance in one of these cations typically have some effect on the other. In the congestive heart failure patient, for example, the neurohormonal activation characteristic of congestive heart failure as well as aggressive diuretic therapy, which serves to further stimulate the renin‐angiotensin‐aldosterone system (RAAS), could cause deficiencies in these two important cations.

The clinical problems of hypokalemia and hypomagnesemia largely parallel one another. 9 , 10 Findings from a survey in nearly 1000 patients showed hypokalemia to be present in up to 42% of patients with hypomagnesemia. Isolated perturbations in K+ do not significantly influence Mg++ homeostasis, but abnormalities in Mg++ balance can be accompanied by secondary K+ depletion. When hypomagnesemia and hypokalemia coexist, Mg++ repletion is not uncommonly required before K+ status can be corrected. 10

Mg++ and/or K+ depletion can play a pivotal role in the genesis of cardiac arrhythmias, particularly in patients with underlying ischemic heart disease. 10 Mg++ has important electrophysiologic effects; it plays a critical role in the regulation of energy sources and in the control of ion pumps, and it has a direct membrane stabilizing effect on excitable myocardial membranes without adversely affecting repolarization time.

CARDIAC IMPLICATIONS OF POTASSIUM

K+ is critical to the maintenance of CV health and the normokalemic state is vital to the prevention of potentially serious sequelae, especially in the at‐risk CV patient. In such patients, many factors, such as endogenous and exogenous catecholamine activity, activation of the RAAS, and/or the use of potent K+‐wasting diuretics, May lead to hypokalemia. K+‐wasting diuretics are noteworthy in this regard in that their use can lead to significant K+ or Mg++ deficiency, or both. Diuretic‐related hypokalemia is dose‐dependent, correlated with the level of volume depletion and/or the degree to which circulating serum catecholamine levels rise. However, diuretic therapy has been shown to reduce coronary heart disease events in hypertensive patients, despite the fact that some decreases in K+ levels May occur and that they May have a short‐term adverse effect on glucose and lipid metabolism.

Electrophysiologic Effects of Potassium

Because K+ serves as the primary ion mediating cardiac repolarization, the hypokalemic state is highly arrhythmogenic, particularly in the presence of digoxin or antiarrhythmic drug therapy. Hypokalemic states produce complex effects on myocardial refractory periods and the potential for triggered arrhythmias. In contrast, hyperkalemia causes slowed conduction and conduction block which, if sufficiently progressive, can result in asystole. Hyperkalemia May also attenuate the effects of antiarrhythmic agents and repolarizing K+ currents. 11

Electrocardiographically, hypokalemia produces a flattening or inversion of the T wave with concomitant prominence of the U wave, usually with prolongation of the QT interval. The electrocardiographic pattern of hypokalemia is not specific and is similar to that seen following administration of antiarrhythmic agents, or phenothiazine, or in left ventricular hypertrophy or marked bradycardia. 12 , 13

Potassium and Arrhythmias

Clinically, arrhythmias associated with hypokalemia include atrial fibrillation and multifocal atrial tachycardias. The most concerning and life‐threatening arrhythmias associated with K+ deficiency states are ventricular tachyarrhythmias, which range from an increase in the frequency of premature ventricular contractions, linearly related to the fall in serum K+ concentrations, to nonsustained ventricular tachycardias and triggering of monomorphic and polymorphic ventricular tachycardias, including torsade de pointes and ventricular fibrillation. Low extracellular K+ concentrations also alter the effects of antiarrhythmic drugs.

Data gathered from relatively small studies show a relationship between serum K+ levels and the development of ventricular arrhythmias in patients admitted with AMI (Figure 1). 14 , 15 , 16 , 17 , 18 The catecholamine surge (neurohumoral response) that occurs during an AMI causes a rapid, transient transcellular shift of K+ , resulting in a short‐lived but dramatic fall in serum K+ of approximately 0.5–0.6 mmol/L, although in certain instances the drop May be more extreme (Figure 2). 19 Accordingly, in an autopsy study, myocardial K+ content was significantly lower in subjects who died of cardiac arrest (0.063 mmol/g wet weight) than in those who died from trauma (0.074 mmol/g wet weight; p<0.025). Myocardial Mg++ concentrations were also significantly lower. 20 This latter observation is of some relevance to the arrhythmogenic potential of transcellular K+ shifts.

Figure 1.

Figure 1

Probability of ventricular tachycardia in relation to serum potassium concentration. Dotted lines denote SD. Reproduced with permission from Circulation. 1985;71: 645–649. 15

Figure 2.

Figure 2

Serum potassium (means±SD) during infusion of 5% dextrose, 0.06 µg/kg/min adrenaline, and 5% dextrose again in six patients after pretreatment with placebo or bendrofluazide (5 mg) for 7 days Reproduced with permission from Lancet. 1983;1(8338): 1358–1361. 19

It should be appreciated, though, that the association of low K+ levels with an increased risk of primary ventricular fibrillation in AMI patients is confounded by the size of the infarct. Larger infarctions are typically accompanied by a greater increase in plasma catecholamines and therefore a greater intracellular flux of K+ ; thus, the lower K+ values May not directly relate to arrhythmia risk but rather reflect a larger infarct size with its attendant risk. As shown in the Beta‐Blocker Heart Attack Trial (BHAT) and the Norwegian Timolol Studies, β blocker therapy lessens the catecholamine surge, independently reduces transcellular K+ shifts, and thereby maintains a normokalemic state. 21 , 22

Transcellular K+ shifts in the setting of AMI must always be viewed in the context of the underlying state of K+ balance and/or the prevailing serum K+ value in the affected patient. Thus, a patient who had normal or high‐normal serum K+ values before the AMI would likely experience a drop in serum K+ into a range that would modestly increase their risk for subsequent ventricular arrhythmias. In contrast, a hypertensive patient taking a K+‐wasting diuretic could be subject to a much greater arrhythmogenic risk since they would experience transcellular shifts of K+ in the presence of varying degrees of total body K+ depletion.

Hypokalemia contributes to arrhythmic deaths in cardiac patients, but it is by no means the only cause, and, in fact, diuretic therapy, which May result in some degree of hypokalemia, especially with larger doses, is associated with a decrease in CHD events. Potassium‐wasting diuretics, although shown to reduce mortality and the incidence of strokes, abdominal aortic aneurysms, and hypertensive deaths, have been associated with an increased incidence of sudden cardiac death, although this May not be a dose‐dependent phenomenon. 23 Findings from older trials 24 , 25 and some studies demonstrate the importance of K+ and diuretics on sudden cardiac death. It is of interest to note, however, that these data can be confusing. For example, in the Multiple Risk Factor Intervention (MRFIT) trial24 the lowest CHD mortality was in patients on high‐dose chlorothiazide with the lowest serum potassium levels.

Recently, data from the Systolic Hypertension in the Elderly Program (SHEP) 26 were reanalyzed to specifically examine K+ values and morbidity and mortality end points. At the end of 1 year, 7.2% of patients receiving active diuretic therapy with chlorthalidone (up to 25 mg) had K+ values <3.5 mmol/L. Patients in the treated group who were normokalemic (i.e., K+≥3.5 mmol/L) showed a significant reduction in the hazard ratio for any CV event and stroke and a trend for reduction in coronary heart disease‐related events (Figure 3). Patients in the treated group who were hypokalemic had a similar risk of events as those in the placebo group. In this regard, what May have been observed is not an increased risk with hypokalemia per se but a reduced benefit. Moreover, this analysis reaffirms findings that thiazide diuretic therapy is extremely effective at reducing CV events, but also suggests that such benefit May fade when K+ values fall chronically below 3.5 mmol/L.

Figure 3.

Figure 3

Hazard ratio of cardiovascular (CV) events, coronary heart disease (CHD), stroke, and all‐cause mortality according to potassium status at year 1 in the Systolic Hypertension in the Elderly Program (SHEP). 26 Open bars=placebo (n=2003); solid bars=hypokalemic chlorthalidone‐treated (K+ <3.5 mmol/L; n=151); gray/hatched bars=normokalemic chlorthalidone‐treated (K+≥3.5 mmol/L; n=1951); *indicates a significant reduction in hazard ratio vs. placebo group

In the SHEP analysis, the actual reduction in K+ values after 3 years in the active treatment group was −0.46 mmol/L and −0.16 mmol/L in the placebo group, a difference of only 0.3 mmol/L. Nonetheless, this seemingly small difference translated into significant disparity in clinical benefit. Interestingly, the reduction in serum K+ in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 27 after 4 years was also 0.3 mmol/L (4.3—4.0 mmol/L). The significance of diuretic‐related K+ changes in the ALLHAT study is still unclear and awaits final analysis of study results. In other studies of thiazide diuretic therapy, 28 hypokalemia occurred at a higher rate but in a dose‐dependent fashion; for example, the fall in serum K+ was 0.57 mmol/L (50‐mg hydrochlorothiazide group) vs. 0.17 mmol/L (25‐mg hydrochlorothiazide group). This latter study had only a 24‐week maintenance phase and, because of its short nature, would have been less likely to detect differences in clinical outcome relating to differences in serum K+ values. Diuretic‐related hypokalemia, although for the most part dose‐dependent, does not always result in an increased risk of arrhythmias, even in patients with documented left ventricular hypertrophy. In one carefully done study, patients with and without left ventricular hypertrophy received 100 mg of hydrochlorothiazide for 4 weeks. Hypokalemia was noted, yet no increase in ventricular premature contractions, couplets, or ventricular tachycardia was noted in the patients with left ventricular hypertrophy before and after exercise. 29 , 30 , 31

A final consideration in this issue is that age May independently influence the degree to which hypokalemia develops in an elderly diuretic‐treated population, such as that in the SHEP trial, in part because the RAAS is less reactive in these subjects.

Potassium and BP

K+ depletion and/or low dietary K+ play a pivotal role in BP regulation in patients with essential hypertension as well as in normotensive individuals. 32 , 33 , 34 Numerous epidemiologic studies have shown that hypertension is more prevalent in populations ingesting low‐K+ diets, such as African Americans in the Southeastern United States. 34 , 35 An even more striking correlation between dietary K+ and hypertension is observed when the urinary Na+/K+ ratio is employed as a more comprehensive indicator of dietary preferences, 35 , 36 , 37 with higher values quite obviously favoring a greater prevalence of hypertension. These epidemiologic data, together with a number of other observations, strongly suggest that K+ homeostasis is critically linked to Na+ effects as relates to BP (Table I).

Table I.

Possible Mechanism of the Antihypertensive Effect of Potassium

• Direct natriuretic effect; conversion of salt‐sensitive hypertension to salt‐resistant hypertension
•↑ Renalkallikrein, and eiccdanoid production
•↑ Nitric oxide (↑ vatodibtory response to acetylcholine)
• Attenuation of sympathetic activity
•↓ Amount and effect of platrra renin activity (PRA) and blunted rise in PRA following K+‐related natriures is
• Direct arterial effect—enhanced activity of Na+/K+ adencsine triphoaphatase
• Enhanced vascular compliance
• Conversion of nocturnal nondipping to dipping blood pressure status
Na+=sodium; K+=potassium

Exogenous K+ supplementation lowers BP in hypertensive individuals. 1 , 3 , 38 , 39 In a meta‐analysis of 33 randomized, controlled trials in more than 2600 normotensive and hypertensive adults, the effects of supplemental oral dietary K+ on BP were evaluated. 39 The median value for oral dietary K+ dose was 75 mmol/day. Mean BP was 147/95 mm Hg and mean urinary K+ excretion at baseline ranged from 39–79 mmol/day. Excluding one outlier trial, the overall net changes in systolic BP (−3.11 mm Hg) and diastolic BP (−1.97 mm Hg) were significant (Table II). Many clinicians May not consider these changes of clinical significance, but they are of great importance from a public health perspective. Patients in trials in which antihypertensive medications were not prescribed also had significant reductions in BP after taking oral K+ . BP reductions in hypertensive individuals were larger, but not significantly different than those in normotensive individuals. Studies examining high‐K+ diets replete with fresh fruits and vegetables, such as the Dietary Approaches to Stop Hypertension (DASH) trial, 36 wherein K+ intake increased from 37–71 mmol/day despite Na+ being fixed at 130 mmol/day, also showed significant reductions in BP.

Table II.

Mean Met Systolic and Diastolic Blood Pressure Change in Randomized, Controlled Trial*, of Oral Potassium Supplementation

Trials Ntrials Met A Sep, mm Hg Net A Dep, mm Hg
(35% CI) (95%CI)
All excluding one outlier 31 −3.11* (−1.91 to −4.31) −l.97 (−0,52 to −3.42)
Net A urinary K+≥20 mmd/day 20 −4.91* (−2.69 to −7.12) −2.71 (−0.71 to −4.71)
No antihypertensive drugs administered 20 −4.05* (−2.74 to −6.95) −2.71 (−0.80 to−4.61)
Hypertensive 20 −4.4 (−2.2 to −6.6) −2.5 (−0.l to −4.9)
Normotensive 12 −1.8 (−O.6 to −2.9) −1.0 (−0 to −2.1)
Black 6 −5.6$ (−2.4 to −8.7) −3.0 (−O.7 to −5.3)
White 25 −2.0 (−0.9 to −3.0) −1.1 (−0.1 to −2.1)
CI=confidence interval; SEP=systolic blood pressure; DBP=diastolic blood pressure; K+potassium; *<0.001 vs. baseline; p=0.01 vs. baseline; p=0.07 vs. nonmontensive; $ p=0.03 vs. white Modified with permission from JAMA. 1997;277:1624–1632.*

Accordingly, the epidemiologic and clinical trial evidence for K+ is now as convincing as is the case for Na+ . The population in general and, in particular, those with hypertension, would benefit from not only a reduction in Na+ intake but also an increase in dietary K+ . An increase in dietary K+ can be a gradual and sustained effort concentrating on reducing intake of foodstuffs with a very high salt content and substituting a diet rich in fruits and vegetables. It should be noted that the type of salt given (e.g., K+ chloride, K+ phosphate, K+ citrate, or K+ acetate) appears not to be a determinant of the BP reduction that occurs with dietary K+ administration.

Potassium and Stroke

Elevated BP is a key risk factor in the development of stroke. An independent beneficial effect of dietary K+ (increase of 10 mmol/day) on the risk of stroke in humans was first reported by Khaw and Barrett‐Conner in 1987. 40 More recent findings from the Health Professionals Study, 41 the National Health and Nutrition Examination Survey I (NHANES‐I), 42 and the Nurses' Health Study 43 also show high dietary K+ intake to be inversely and dose‐proportionally related to stroke risk. In the NHANES‐I follow‐up study, 42 a dietary intake of ≤34.6 mmol of K+ over 24 hours was significantly associated with an increased risk of stroke (hazard ratio 1.28; p<0.001). Other studies have shown an inverse relationship between K+ intake and stroke in subgroups such as African American men and hypertensive men, although not having adjusted for other dietary factors that might confound the risk between K+ and stroke, such as dietary intake of fiber, calcium, or vitamin C, might provide alternative explanations for these ethnic and gender‐related findings. 44

The protective mechanism of increased dietary K+ in reducing stroke deaths May be related to even the slight degree of BP lowering, even with a small increase in the amount ingested. It May also be related to a direct endothelial effect wherein macrophages are rendered incapable of adhering to the vascular walls, as has been well described in stroke‐prone spontaneously hypertensive rats. 44 , 45 , 46 , 47 , 48 Although not specifically designed to evaluate K+ intake, studies have clearly shown that diets high in fresh fruits and vegetables reduced the risk of ischemic stroke in men and women, independently of BP. 49 , 50 These natural foods are known to be high in K+ content along with other healthful nutrients such as calcium, fiber, and antioxidants. Recently, the Food and Drug Administration approved a health claim that “diets containing foods that are good sources of K+ and low in Na+ May reduce the risk of high BP and stroke.” Qualifying foods must contain at least 350 mg K+ , <140 mg Na+ , <3 g total fat, ≤1 g saturated fat, and ≤15% of energy from saturated fatty acids. Several low‐fat dairy products meet these criteria, including low‐fat and nonfat milk, and low‐fat yogurt. 51

Potassium and Atherosclerosis

Increased dietary K+ intake and/or exogenous K+ administration May afford a protective influence on vascular and tissue‐based biology as relates to atheromatous disease. In animal models, K+ inhibits free radical formation, proliferation of vascular smooth muscle cells, platelet aggregation, and arterial thrombosis and reduces vessel‐wall cholesterol content. 45 , 46 , 47 , 48 How K+ relates to atherosclerosis in man remains unanswered. This question will prove difficult to answer because K+ interplays with a number of neurohormonal pathways, BP, and aspects of Na+ homeostasis that in and of themselves are known to affect the development of atherosclerosis and/or the atherosclerotic burden.

POTASSIUM MONITORING

As our understanding of the benefits of K+ grows, intolerance for low or low‐normal K+ levels and greater acceptance of high to high‐normal levels emerges. Serum K+ is generally considered to be a more reflective measure of long‐term dietary K+ intake. Serum K+ should be monitored, as a matter of course, in all patients who are newly diagnosed with hypertension, heart failure, or any other illness requiring therapy with a diuretic or agent that inhibits the RAAS, such as β blockers, angiotensin‐converting enzyme inhibitors, angiotensin‐receptor blockers, vasopeptidase inhibitors, or a range of K+‐sparing agents. In fact, the serum Na+/K+ ratio is more closely correlated with BP. Patients at risk for the development of hyperkalemia, such as those with some degree of renal impairment or diabetes, those taking K+‐sparing medications, or those taking exogenous K+ supplements, should have K+ values monitored more regularly at the discretion of the treating physician. Factors that cause transcellular K+ shifts will complicate interpretation of the serum K+ value.

Clinicians can be comforted by the fact that hyperkalemia does not typically occur in patients with normal renal status, because large K+ loads are efficiently and rapidly excreted. 9 , 29 , 52 In the Studies of Left Ventricular Dysfunction (SOLVD) database, severe hyperkalemia due to enalapril therapy was uncommon; only 6.4% of the 1285 patients developed serum K+ levels >5.5 mmol/L. 52

The National Council on Potassium in Clinical Practice suggests that patients with congestive heart failure, cardiac arrhythmias, or hypertension should maintain serum K+ levels of ≥4.0 mmol/L. 2 However, realizing the substantial risks of hypokalemia, perhaps an optimal serum K+ value in patients with these underlying conditions and who are without concurrent renal dysfunction should be slightly higher, in the normal to high‐normal range (4.5–5.0 mmol/L).

MANAGEMENT OF POTASSIUM DISTURBANCES

For patients in whom low K+ levels could prove detrimental to cardiac health, maintenance of serum K+ values in the normal range should be a therapeutic goal. If thiazide‐type diuretics are needed, clinicians should appreciate that the higher the dose, the greater the risk of hypokalemia and therein encourage the patient to reduce Na+ intake and increase intake of K+‐rich foods. If these measures prove unsuccessful, a next step would be oral K+ supplementation or addition of a K+‐sparing therapy, such as a K+‐sparing diuretic, angiotensin‐converting enzyme inhibitor, angiotensin receptor blocker, or aldosterone‐receptor antagonist, if clinically indicated. Serum K+ should be periodically monitored. The frequency with which such monitoring occurs is typically at the prerogative of the treating physician, although at the extremes of K+ values it can be expected that monitoring will be more frequent.

Dietary intake of K+‐rich foods should be encouraged when serum K+ levels are between 3.5 and 4 mmol/L, if for no other reason than the BP reduction, which May occur in the setting of a high K+ intake. If levels fall below 3.5 mmol/L—which typically occurs because of external K+ losses—oral supplementation with a K+ chloride preparation can be initiated at a typical dose of 20–60 mmol/day. A bicarbonate salt May be helpful for K+ depletion in the setting of metabolic acidosis. Some controversy exists regarding which K+ salt is most effective. 32 A more detailed discussion on this issue is available in recently published guidelines on potassium supplementation 2 and will be addressed in a subsequent publication by this consensus group. If increasing dietary K+ or oral K+ supplementation does not correct the hypokalemia or is not acceptable to the patient, addition of K+‐sparing therapy should be considered.

CONCLUSIONS

Abnormalities of K+ homeostasis occur with some regularity in clinical medicine. These abnormalities include hypokalemia and hyperkalemia, with each such disturbance having a specific associated symptom complex. Moreover, it is increasingly recognized that even in the presence of a normal serum K+ concentration, pathophysiologic consequences of reduced dietary K+ intake are important. The arena of K+ homeostasis is replete with recommendations for what represents an optimal range for serum K+ values, although such recommendations are seldom based on fact. Nevertheless, in evaluating existing literature, it would appear that a serum K+ value maintained in the range of 4.0–5.0 mmol/L is both safe and likely to provide stability in a wide range of CV processes. It remains unclear, though, whether there is an increased risk that accompanies K+ values in the 3.5–3.9 mmol/L range in diuretic‐treated patients. In addition, a high K+ intake should be encouraged in most patients; current clinical trial evidence would support a daily intake of K+≥60 mmol/day.

References

  • 1. Young DB, Lin H, McCabe RD. Potassium's cardiovascular protective mechanisms. Am J Physiol. 1995;268(pt 2): R825–R837. [DOI] [PubMed] [Google Scholar]
  • 2. Cohn JN, Kowey PR, Whelton PK, et al. New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice. Arch Intern Med. 2000;160:2429–2436. [DOI] [PubMed] [Google Scholar]
  • 3. Kawano Y, Minami J, Takishita S, et al. Effects of potassium supplementation on office, home, and 24‐h blood pressure in patients with essential hypertension. Am J Hypertens. 1998; 11:1141–1146. [DOI] [PubMed] [Google Scholar]
  • 4. Solomon R, Weinberg MS, Dubey A. The diurnal rhythm of plasma potassium: relationship to diuretic therapy. J Cardiovasc Pharmacol. 1991. ;17:854–859. [DOI] [PubMed] [Google Scholar]
  • 5. Paice BJ, Paterson KR, Onyanga‐Omara F, et al. Record linkage study of hypokalemia in hospitalized patients. Postgrad Med J. 1986;62:187–191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Halperin ML, Kamel KS. Potassium. Lancet. 1998;352: 135–140. [DOI] [PubMed] [Google Scholar]
  • 7. Clausen T, Everts ME. Regulation of the Na, K‐pump in skeletal muscle. Kidney Int. 1989;35;1–13. [DOI] [PubMed] [Google Scholar]
  • 8. Field MJ, Giebisch GJ. Hormonal control of renal potassium excretion. Kidney Int. 1985;27:379–387. [DOI] [PubMed] [Google Scholar]
  • 9. Leier CV, Dei Cas L, Metra M. Clinical relevance and management of the major electrolyte abnormalities in congestive heart failure: hyponatremia, hypokalemia, and hypomagnesemia. Am Heart J. 1994;128:564–574. [DOI] [PubMed] [Google Scholar]
  • 10. Whang R, Whang DD, Ryan MP. Refractory potassium repletion: a consequence of magnesium deficiency. Arch Intern Med. 1992;152:40–45. [PubMed] [Google Scholar]
  • 11. Yang T, Roden DM. Extracellular potassium modulation of drug block of IKr: implications for torsade de pointes and reverse‐use dependence. Circulation. 1996;93:407–411. [DOI] [PubMed] [Google Scholar]
  • 12. Fletcher GF, Hurst JW, Schlant RC. Electrocardiographic changes in severe hypokalemia. A reappraisal. Am J Cardiol. 1967;20:628–631. [DOI] [PubMed] [Google Scholar]
  • 13. Huerta BJ, Lemberg L. Potassium imbalance in the coronary care unit. Heart Lung. 1985;14:193–195. [PubMed] [Google Scholar]
  • 14. Hulting J. In‐hospital ventricular fibrillation and its relation to serum potassium. Acta Med Scand Suppl. 1981;647:109–116. [DOI] [PubMed] [Google Scholar]
  • 15. Nordrehaug JE, Johannessen K‐A, Von Der Lippe G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation. 1985;71:645–649. [DOI] [PubMed] [Google Scholar]
  • 16. Nordrehaug JE. Malignant arrhythmias in relation to serum potassium values in patients with an acute myocardial infarction. Acta Med Scand Suppl. 1981;647:101–107. [DOI] [PubMed] [Google Scholar]
  • 17. Salerno DM, Asigner RW, Elsperger J, et al. Frequency of hypokalemia after successfully resuscitated out‐of‐hospital cardiac arrest compared with that in transmural acute myocardial infarction. Am J Cardiol. 1987;59:84–88. [DOI] [PubMed] [Google Scholar]
  • 18. Solomon RJ, Cole AG. Importance of potassium in patients with acute myocardial infarction. Acta Med Scand Suppl. 1981;647:87–93. [DOI] [PubMed] [Google Scholar]
  • 19. Struthers AD, Whitesmith R, Reid JL. Prior thiazide diuretic treatment increases adrenaline‐induced hypokalaemia. Lancet. 1983;1(8338):1358–1361. [DOI] [PubMed] [Google Scholar]
  • 20. Johnson CJ, Peterson DR, Smith EK. Myocardial tissue concentrations of magnesium and potassium in men dying suddenly from ischemic heart disease. Am J Clin Nutr. 1979; 32:967–970. [DOI] [PubMed] [Google Scholar]
  • 21. Nordrehaug JE, Johannessen K‐A, Von Der Lippe G, et al. Effect of timolol on changes in serum potassium concentration during acute myocardial infarction. Br Heart J. 1985;53:388–393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Valladares BK, Lemberg L. Catecholamines, potassium, and beta‐blockade. Heart Lung. 1986;15:105–107. [PubMed] [Google Scholar]
  • 23. Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first‐line agents: a systematic review and meta‐analysis. JAMA. 1997;277:739–745. [PubMed] [Google Scholar]
  • 24. Cohen JD, Neaton JD, Prineas RJ, et al., For 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;60:548–554. [DOI] [PubMed] [Google Scholar]
  • 25. Medical Research Council Working Party on Mild to Moderate Hypertension . Ventricular extrasystole during thiazides treatment: substudy of MRC mild hypertension trial. BMJ. 1983;287:1249–1253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Franse LV, Pahor M, Di Bari M, et al. Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000;35:1025–1030. [DOI] [PubMed] [Google Scholar]
  • 27. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone: the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2000;283:1967–1975. [PubMed] [Google Scholar]
  • 28. Cushman WC, Khatri I, Materson BJ, et al., For The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents . Treatment of hypertension in the elderly. III. Response of isolated systolic hypertension to various doses of hydrochlorothiazide: results of a Department of Veterans Affairs Cooperative Study. Arch Intern Med. 1991;151:1954–1960. [DOI] [PubMed] [Google Scholar]
  • 29. Papademetriou V, Fletcher R, Khatri IM, et al. Diuretic‐induced hypokalemia in uncomplicated systemic hypertension: effect of plasma potassium correction on cardiac arrhythmias. Am J Cardiol. 1983;52(8):1017–1022. [DOI] [PubMed] [Google Scholar]
  • 30. Papademetriou V, Price M, Notargiacomo A, et al. Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Heart J. 1985;110(3):595–599. [DOI] [PubMed] [Google Scholar]
  • 31. Madias JE, Madias NE, Gavras HP. Nonarrhythmogenicity of diuretic‐induced hypokalemia. Its evidence in patients with uncomplicated hypertension. Arch Intern Med. 1984;144(11): 2171–2176. [PubMed] [Google Scholar]
  • 32. He FJ, MacGregor GA. Beneficial effects of potassium. BMJ. 2001;323:497–501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. He FJ, MacGregor GA. Potassium intake and blood pressure. Am J Hypertens. 1999;12:849–851. [PubMed] [Google Scholar]
  • 34. Krishna GG. Potassium and blood pressure regulation. Drug Ther. March 1993:88–92. [Google Scholar]
  • 35. Watson RL, Langford HG. Weight, urinary electrolytes, and blood pressure—results of several community based studies. J Chronic Dis. 1982;35(12):909–918. [DOI] [PubMed] [Google Scholar]
  • 36. Appel LJ, Moore TJ, Obarzanek E, et al., For The DASH Collaborative Research Group . A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336:1117–1124. [DOI] [PubMed] [Google Scholar]
  • 37. Dyer AR, Elliott P, Shipley M, For The INTERSALT Cooperative Research Group . Urinary electrolyte excretion in 24 hours and blood pressure in the INTERSALT study. II. Estimates of electrolyte‐blood pressure associations corrected for regression dilution bias. Am J Epidemiol. 1994;139:940–951. [DOI] [PubMed] [Google Scholar]
  • 38. Brancati FL, Appel LJ, Seidler AJ, et al. Effect of potassium supplementation on blood pressure in African Americans on a low‐potassium diet: a randomized, double‐blind, placebo‐controlled trial. Arch Intern Med. 1996;156: 61–67. [PubMed] [Google Scholar]
  • 39. Whelton PK, He J, Cutler JA, et al. Effects of oral potassium on blood pressure: meta‐analysis of randomized controlled clinical trials. JAMA. 1997;277:1624–1632. [DOI] [PubMed] [Google Scholar]
  • 40. Khaw K‐T, Barrett‐Connor E. Dietary potassium and stroke‐associated mortality: a 12‐year prospective population study. N Engl J Med. 1987;316:235–240. [DOI] [PubMed] [Google Scholar]
  • 41. Ascherio A, Rimm EB, Hernán MA, et al. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation. 1998;98:1198–1204. [DOI] [PubMed] [Google Scholar]
  • 42. Bazzano LA, He J, Ogden LG, et al. Dietary potassium intake and risk of stroke in US men and women: National Health and Nutrition Examination Survey I epidemiologic follow‐up study. Stroke. 2001;32:1473–1480. [DOI] [PubMed] [Google Scholar]
  • 43. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30:1772–1779. [DOI] [PubMed] [Google Scholar]
  • 44. Fang J, Madhavan S, Alderman MH. Dietary potassium intake and stroke mortality. Stroke. 2000;31:1532–1537. [DOI] [PubMed] [Google Scholar]
  • 45. Ishimitsu T, Tobian L, Sugimoto K, et al. High‐potassium diets reduce vascular and plasma lipid peroxides in stroke‐prone spontaneously hypertensive rats. Clin Exp Hypertens. 1996; 18:659–673. [DOI] [PubMed] [Google Scholar]
  • 46. Ishimitsu T, Tobian L, Sugimoto K, et al. High‐potassium diets reduce macrophage adherence to the vascular wall in stroke‐prone spontaneously hypertensive rats. J Vasc Res. 1995;32:406–412. [DOI] [PubMed] [Google Scholar]
  • 47. Tobian L. High‐potassium diets markedly protect against stroke deaths and kidney disease in hypertensive rats, an echo from prehistoric days. J Hypertens. 1986;4(suppl 4): S67–S76. [PubMed] [Google Scholar]
  • 48. Tobian L, MacNeill D, Johnson MA, et al. Potassium protection against lesions of the renal tubules, arteries, and glomeruli and nephron loss in salt‐loaded hypertensive Dahl S rats. Hypertension. 1984;6(suppl I):I170–I176. [DOI] [PubMed] [Google Scholar]
  • 49. Gillman MW, Cupples LA, Gagnon D, et al. Protective effects of fruits and vegetables on development of stroke in men. JAMA. 1995;273:1113–1117. [DOI] [PubMed] [Google Scholar]
  • 50. Joshipura KJ, Ascherio A, Manson JE, et al. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA. 1999;282:1233–1239. [DOI] [PubMed] [Google Scholar]
  • 51. US Food and Drug Administration Center for Food Safety and Applied Nutrition. Health Claim Notification for Potassium-Containing Foods. Available at: http://vm.cfsan.fda.gov/dms/helm/k.html. Accessed April 20, 2002. [Google Scholar]
  • 52. Schoolwerth AC, Sica DA, Ballermann BJ, et al. Renal considerations in angiotensin‐converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association. Circulation. 2001. ;104:1985–1991. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Clinical Hypertension are provided here courtesy of Wiley

RESOURCES