Heart Fail Rev (2015) 20:493–503

DOI 10.1007/s10741-015-9482-y

Acid–base and electrolyte abnormalities in heart failure:

pathophysiology and implications
Caterina Urso1 • Salvatore Brucculeri1 • Gregorio Caimi1

Published online: 28 March 2015

Ó The Author(s) 2015. This article is published with open access at Springerlink.com

Abstract Electrolyte and acid–base abnormalities are a drugs used in this condition, such as diuretics [2]. These
frequent and potentially dangerous complication in sub- abnormalities reflect the severity of CHF and contribute to
jects with congestive heart failure. This may be due either the functional impairment and to the poor long-term
to the pathophysiological alterations present in the heart prognosis [3].
failure state leading to neurohumoral activation (stimula- The common electrolyte abnormalities are hypona-
tion of the renin–angiotensin–aldosterone system, sympa- tremia, hypokalemia, and hypomagnesemia. The acid–base
thoadrenergic stimulation), or to the adverse events of disturbances generally observed are metabolic alkalosis
therapy with diuretics, cardiac glycosides, and ACE in- pure or combined with respiratory alkalosis [4]. Several
hibitors. Subjects with heart failure may show hypona- mechanisms interact to produce these alterations. The de-
tremia, magnesium, and potassium deficiencies; the latter crease in cardiac output leads directly to a reduction in
two play a pivotal role in the development of cardiac ar- renal blood flow, with impairment of renal excretion of
rhythmias. The early identification of these alterations and water and electrolytes, and it causes the activation of
the knowledge of the pathophysiological mechanisms are several neurohormonal responses which affect both car-
very useful for the management of these patients. diovascular homeostasis and electrolyte balance. The
therapy of CHF subjects includes the discovery and man-
Keywords Acid–base disturbances
Congestive heart agement of these electrolyte abnormalities that have a role
failure
Electrolyte abnormalities in the development of ventricular arrhythmias [5].

Introduction Hyponatremia

Heart failure is a major cause of cardiovascular mortality Hyponatremia is the most common electrolyte abnormality
and morbidity, resulting in more than one million hospi- observed in hospitalized subjects; it is defined as a serum
talizations per year in the USA, and it is the most common sodium concentration lower than 136 mmol/L [6]. Mild-to-
hospital discharge diagnosis among subjects older than moderate hyponatremia is generally present in 10 % of HF
65 years [1]. subjects [7]; however, this frequency seems to be higher in
Subjects with congestive heart failure (CHF) usually different reports. For example, in the OPTIME-CHF trial,
show acid–base and electrolyte disorders, due both to the 27 % of subjects show serum sodium concentrations
activation of several neurohumoral mechanisms and to ranging between 132 and 135 mEq/L [8], while in the
ESCAPE trial, 18 % of the subjects had persistent hy-
ponatremia throughout their hospitalization, defined as
& Caterina Urso serum sodium below 134 mEq/L [3].
[email protected]
Maintenance of total body salt and fluid within normal
1
Dipartimento Biomedico di Medicina Interna e Specialistica, range is under the control of the atrial-renal reflexes, the
Universitá di Palermo, 90127 Palermo, Italy RAAS, and the sympathetic nervous system (SNS) [9].

123
494 Heart Fail Rev (2015) 20:493–503

In a normal heart, any increase in atrial pressure sup- Furthermore, it is well known that heart and kidneys are
presses the release of the antidiuretic hormone, decreases closely interrelated and that disorder of either of the two
the tone of the SNS in the kidneys, and enhances the re- organs may induce dysfunction in the other organ in a
lease of the atrial natriuretic peptide [10]. The latter pro- spiral fashion leading to cardiorenal syndrome (CRS).
motes sodium and water excretion at the distal nephron, These two organs act in tandem to regulate blood pressure,
improves GFR, causes vasodilatation, and decreases the vascular tone, diuresis, natriuresis, intravascular volume
release of the antidiuretic hormone. In HF, these actions are homeostasis, and peripheral tissue perfusion. Changes in
blunted, and therefore sodium and water retention occurs the RAAS, SNS, and inflammation are the cardiorenal
despite elevated atrial pressures [11]. The decrease in connectors to develop CRS [17].
cardiac output and in effective circulating volume leads to As cardiac output drops, renal blood flow and GFR
activation of baroreceptors, which in turn activate the SNS, follow suit, impairing the kidney’s ability to excrete dilute
the RAAS, and the release of arginine vasopressin. The urine. Dilutional impairment occurs due to disturbance of
final effect is an enhanced retention of sodium and water one or more of the following mechanisms: GFR, separation
[12, 13] (Fig. 1). of salt and water at the thick limb of Henle’s loop, and
The SNS activation helps to maintain circulatory ADH action in the collecting duct. The volume of tubule
homeostasis and perfusion to vital organs by increasing fluid that is delivered to the distal nephron determines in
inotropy and chronotropy of the failing myocardium and by large measure the volume of dilute urine that can be ex-
modulating vascular reaction. In the long term, these creted. Thus, if glomerular filtration is decreased or prox-
mechanisms as well as the RAAS activation are maladap- imal tubule reabsorption is greatly enhanced, the resulting
tive and responsible for disease progression [14–16]. diminution in the amount of fluid delivered to the distal

HEART FAILURE

VEC

SNS ACTIVITY AVP

ANGIOTENSIN II ACTIVITY THIRST

RENAL
VASOCONSTRICTION

GFR
PROXIMAL TUBULAR SODIUM AND
WATER REABSORPTION
WATER INTAKE

DISTAL SODIUM AND WATER DELIVERY

IMPAIRED ESCAPE FROM ACTION OF

ALDOSTERONE AND RESISTANCE TO
NATRIURETIC PEPTIDES

WATER EXCRETION

DIURETICS HYPONATREMIA AND EDEMA

Fig. 1 Hyponatremia in heart failure. VEC extracellular fluid volume, SNS sympathetic nervous system, AVP arginine vasopressin, GFR
glomerular filtration rate

123
Heart Fail Rev (2015) 20:493–503 495

tubule itself limits the rate of renal water excretion [18, Hyponatremia may be a marker of neurohormonal ac-
19]. tivation that reflects the severity of heart failure [26], but it
Angiotensin II promotes the retention of sodium and may also result from the HF therapy [7, 27].
water by the stimulation of the release of aldosterone, in- Diuretics are one of the most common causes of drugs
creasing the efferent arteriolar tone, hence promoting induced hyponatremia; Although thiazide diuretics are
sodium and water absorption by the resulting rise in the most often implicated [28], also non-thiazide agents, such
filtration fraction, as well as by a direct effect on proximal as furosemide, spironolactone, and indapamide, have been
tubule [20], by stimulating the thirst center, and by causing associated with hyponatremia [29].
the release of arginine vasopressin [7]. It should also be mentioned that the hydrochlorothiazide
Both adrenergic stimulation and angiotensin II activate and amiloride combination increases the risk of hypona-
receptors on the proximal tubule epithelium, leading to tremia. This increment is probably due to the direct effect
increased sodium reabsorption and decreased sodium and of amiloride on the collecting tubule increasing sodium
water delivery to the renal collecting duct, thus exacer- loss. Moreover, amiloride spares potassium and, therefore,
bating the sodium retaining effect of aldosterone and re- worsens thiazide-induced hyponatremia as a consequence
ducing the diuretic effects of natriuretic peptides [12]. of potassium retention by exchanging it for sodium in the
Furthermore, angiotensin II activates NADPH oxidase, distal tubule [30].
which results in the formation of reactive oxygen species. Several clinical studies have shown that hyponatremia is
The increased oxidative stress enhances negative inotropic associated with adverse prognosis and reduced survival in
effects and induces cardiac remodeling [21]. Therefore, a HF [31]. Serum sodium concentration on admission or dis-
vicious cycle sets in promoting structural and functional charge is a predictor of in-hospital short-term and long-term
damage to both kidneys and heart. Aldosterone, in turn, mortality in subjects hospitalized for HF [32, 33]. Moreover,
causes continuous renal sodium reabsorption and increases hyponatremia is associated with an increased rate of re-
the myocardial fibrosis of the failing heart [22]. hospitalization and major complications [32], as well as a
Hyponatremic subjects with advanced HF often have longer hospital stay in hospitalized HF subjects [34, 35]. In a
inappropriately elevated plasma AVP levels that in turn, study of 355 subjects admitted for HF, a serum sodium
lead to enhanced renal water retention by increasing the concentration\130 mEq/L was associated with a higher in-
number of aquaporin water channels in the collecting duct hospital death rate [36]. In the OPTIME-CHF study, sub-
of the kidney [23]. jects with serum sodium\135 mEq/L had longer lengths of
The actions of AVP are mediated by three AVP receptor hospital stay and a doubling of in-hospital as well as 60-day
subtypes (V1aR, V1bR, and V2R). The V1aR is located in mortality [8]. Finally, serum sodium levels also predict
vascular smooth muscle cells and cardiomyocytes mediat- mortality in outpatients with chronic heart failure [33, 37].
ing vasoconstriction and hypertrophy, platelets aggrega- The treatment of significant hyponatremia in heart fail-
tion, and glycogen metabolism in hepatocytes. The V1bR ure is not easy. The conventional treatments such as fluid
located in the anterior pituitary play a crucial role in restriction, infusion of hypertonic saline, and conventional
regulating hypothalamic–pituitary–adrenal axis activity by diuretic therapies are not usually effective. Vasopressin
stimulating the release of corticotrophin and ACTH. The receptor antagonists have been shown to enhance aquaresis
V2R located in the collecting tubules of the kidney are and correct hyponatremia. However, long-term beneficial
notable in the pathophysiology of HF and mediate the effects of such treatments in chronic heart failure have not
antidiuretic effect of AVP. Binding of AVP to V2R acti- been validated [38].
vates the adenylate cyclase signaling pathway, leading to
phosphorylation of the preformed water channel aquaporin-
2 and their subsequent insertion into the apical membranes Hypokalemia
of the collecting ducts. Furthermore, the urinary excretion
of aquaporin-2 is increased in heart failure subjects with Hypokalemia is commonly observed in CHF subjects, and
elevated AVP [24]. Notably, the elevated plasma AVP it is a strong independent predictor of mortality [39].
levels are not adequately reduced even with acute water Hypokalemia has not been well defined in HF, and even
loading in hyponatremic HF subjects [23]. in the literature, its range varies from 3.5 to 4.0 mEq/L
The AVP cannot be reliably investigated by the current (mmol/L) [40]. Hypokalemia is generally more evident in
laboratory methods; however, copeptin, the C-terminal subjects with advanced CHF receiving pronounced diuretic
segment of the AVP precursor peptide, is secreted in an therapy and with the greatest activation of the renin–an-
equimolar ratio to AVP and is a sensitive and stable sur- giotensin system [41].
rogate marker for its release. Copeptin is also a promising Low levels of serum K? may be a marker of increased
indicator in the differential diagnosis of hyponatremia [25]. neurohormonal activity and disease progression [42];

123
496 Heart Fail Rev (2015) 20:493–503

furthermore, serum K? is negatively correlated with plas- In vitro, high extracellular potassium concentration im-
ma renin activity and plasma noradrenaline [43]. pairs platelet aggregation; moreover, in animal models,
Catecholamines cause hypokalemia and increase the increasing plasma potassium reduces the rate of thrombosis
arrhythmic risk; adrenaline, in fact, stimulates the sodium– on endothelial lesions. Potassium ameliorates oxidative
potassium-ATPase pump via b2-receptors and shifts stress by reducing free-radical formation, diminishing
potassium intracellularly. It seems likely that the observed vascular smooth muscle cell proliferation, and reducing
mortality benefit with beta-blockade in HF is partly monocyte adherence to vessels [56]. Furthermore, potas-
ascribable to the prevention of hypokalemic arrhythmias sium appears to have an antihypertensive effect mediated
[44]. by increased natriuresis, vasodilation, heightened barore-
It is known that potassium depletion is a risk factor for flex sensitivity, and reduced cardiac sensitivity to
increased frequency of ventricular arrhythmias; moreover, catecholamines and angiotensin II [57]. Potassium also
hypokalemia can potentiate the arrhythmias associated seems to retard the progression of atherosclerosis [56]
with CHF therapy (e.g., digitalis) and diminish the efficacy (Fig. 2).
of anti-arrhythmic drugs by altering the electrophysiologic While diuretics and adrenergic stimulation may cause
properties of the myocardium and negating some of the hypokalemia, neurohormonal blockade using ACE in-
antiarrhythmic activity of these agents. The frequency of hibitors, angiotensin receptor blockers, beta-blockers, and
ventricular ectopic beats and the frequency of sudden death aldosterone antagonists may cause hyperkalemia and so the
correlate with both serum and whole body levels of serum K? level should be frequently checked in these
potassium [45]. subjects [58].
A total of 50 % of deaths from HF are sudden, pre- As result of different studies, the myocardiocytes would
sumably due to arrhythmias. In victims of sudden cardiac present mechanisms of adaptation to chronic hypo- or hy-
death (SCD), the level of myocardial K? is often lower per-kalemia. Studies in animal models showed that cardiac
than in controls, and survivors may show hypokalemia muscle was protected against loss of potassium during
apparently caused by a shift of potassium from the in- chronic potassium depletion by an adaptive increase in the
travascular compartment [46]. It is unclear whether hy- density of sodium pump. An increase in the activity and
pokalemia precedes and causes the episode or occurs as a quantity of (Na?–K?) ATPase in the myocardial tissue
result of resuscitation; however, it was found a correlation would protect it against K? loss. It is not yet known
between the decreased serum K? (\4.4 mEq/L) and SCD whether these results can be extrapolated to human beings
[47]. [59–61].
In HF, all-cause and cardiac mortality rates are higher in Bartter’s syndrome offers a opportunity to study clinical
subjects taking non-K?-sparing diuretics; furthermore, the effects of chronic electrolyte disturbances. Although ex-
incidence of arrhythmic death is significantly and inde- tracellular concentrations of potassium were usually very
pendently correlated with the use of non-K?-sparing di- low in these subjects, the electrocardiographic changes
uretics [48]. were slight and arrhythmias were not common. This pattern
In HF subjects, there is evidence that the serum potas- may reflect an adaptation of the myocardium to hy-
sium level should be maintained above 4.5 mEq/L to pokalemia [62].
minimize the risk of SCD [40, 47, 49], while Leier et al. In a study, intracellular K? concentration and ATPase
[50] advise maintaining the level in the range of 4.5 to activity of myocardiocytes were measured in early stage of
5.0 mEq/L. A mild hypokalemia may be corrected by the burn injury. The latter accelerates K? efflux current, but
use of aldosterone receptor antagonists such as spirono- inhibits K? influx current; the reduction in Na?–K?-
lactone or eplerenone, while a more severe hypokalemia ATPase activity may be one reason for decrease in intra-
should preferably be corrected using K? supplement [40]. cellular K? concentration after injury [63].
However, potassium replacement should be routinely
considered in patients with CHF, even if the initial potas-
sium determination appears to be normal [51]. Hypomagnesemia
Potassium depletion causes diastolic dysfunction [52],
while high potassium protects against hypertensive en- Magnesium plays a role in many enzymatic processes, and
dothelial dysfunction [53, 54]. it is an important component in the mitochondrial structure
Potassium mediates vasodilation via strong inwardly and function; it modulates cellular potassium permeability
rectifying potassium channels and the sodium–potassium- and affects calcium uptake and its distribution [64, 65].
ATPase pump of vascular smooth muscle cells, and this Hypomagnesemia (serum magnesium \1.5 mg/dL) is not
may be useful when NO bioavailability is low; potassium infrequently observed in CHF subjects, but its patho-
also reduces angiotensin II-induced vasoconstriction [55]. physiology remains less studied when compared to other

123
Heart Fail Rev (2015) 20:493–503 497

Fig. 2 Hypokalemia in heart

failure. RAAS renin– HEART FAILURE
angiotensin–aldosterone system

CATECHOLAMINES RAAS DIURETICS

HYPOKALEMIA

ARRHYTMIAS ENDOTHELIAL DYSFUNCTION

DIASTOLIC VASOCONSTRICTION
DISFUNCTION

electrolyte alterations. However, there is evidence that It has been demonstrated that potassium depletion in-
early detection and correction of magnesium abnormalities hibits the reabsorption of magnesium in the distal convo-
could remedy potentially dangerous arrhythmogenic ef- luted tubule, thus leading to hypermagnesiuria and
fects. There is also confirmation that the effective correc- hypomagnesemia [70]. However, it is well documented
tion of magnesium disturbances is favorable in CHF that primary disturbances of magnesium balance, par-
subjects [66]. ticularly magnesium deficit, produce secondary cellular
Hypomagnesemia occurs either as an isolated distur- potassium depletion [71] (Fig. 3).
bance or in association with other acid–base and electrolyte Furthermore, it has been hypothesized that the detection
abnormalities; several interrelated mechanisms are impli- of electrolyte disorders, such as hypokalemia, hypona-
cated in its pathogenesis [67]. As magnesium and potas- tremia, hypophosphatemia, hypocalcemia, and especially
sium are mainly intracellular ions, measurements in serum refractory potassium depletion in CHF subjects, should alert
or plasma are of limited value to assess magnesium status. to the possibility of coexisting magnesium depletion [72].
There was no correlation between the intracellular elec- The prevalence of hypomagnesemia in CHF subjects
trolyte content and the electrolyte levels in plasma, either ranges from 7 % of well-compensated ambulatory subjects
for mononuclear cells or erythrocytes or for myocardial to 52 % in more advanced CHF subjects who are treated
and skeletal muscle [68]. aggressively with diuretics [73].
In the setting of CHF, magnesium depletion stems from In animal models, magnesium deficiency leads to the
reduced dietary intake, altered distribution of the ion, and development of mitochondrial alterations with calcium ac-
renal losses. It should also be considered that edematous cumulation, cell death, and multifocal myocardial necrosis
states, involving the intestinal mucosa, might interfere with [74].
the absorption of microelements, such as magnesium. Hypomagnesemia seems to have vasoconstrictor prop-
Respiratory alkalosis may produce a decrease in serum erties, secondary to the inhibition of prostaglandin-induced
magnesium due to a shift of magnesium inside the intra- relaxation and to the enhancement of the activity of the
cellular compartment. Furthermore, it is well documented vasoconstrictor neurohormones through alterations in cal-
that an excessive catecholamine release in decompensated cium uptake. Furthermore, hypomagnesemia can poten-
CHF can significantly influence the trans-cellular magne- tially induce hypercoagulability, via enhanced adenosine
sium shift [69]. diphosphate-induced platelet aggregation [75].
Diuretics (loop-acting diuretics in particular) produce The worsening of CHF secondary to very severe hypo-
most of renal magnesium loss, especially in the volume- magnesemia has been described, and in some cases, mag-
expanded setting of CHF and in associated hyperaldos- nesium supplementation determines the reversal of heart
teronism [69]. failure [76].

123
498 Heart Fail Rev (2015) 20:493–503

Fig. 3 Pathogenesis and effects

of hypomagnesemia in CHF. HEART FAILURE
RAAS renin–angiotensin–
aldosterone system

EDEMA RAAS ALKALOSIS DIURETICS CATECHOLAMINES

IPOKALEMIA

ABSORPTION INTESTINAL RENAL LOSS of Mg 2+ SHIFT INTRACELLULAR of Mg 2+

HYPOMAGNESEMIA

MITOCHONDRIAL VASOCONSTRICTION
ALTERATIONS AND
MYOCARDIAL
PLATELET
ARRHYTHMIAS NECROSIS
AGGREGATION

Moreover, the mortality increase in CHF subjects with cases of hypocalcemia in CHF have been reported and
hypomagnesemia was believed to be related to the devel- these are often in association with hypomagnesemia [4].
opment of ventricular arrhythmias rather than clinical and The clinical setting of hypocalcemia includes hy-
hemodynamic deterioration. Elevated levels of magnesium poparathyroidism, end-stage kidney disease, and respira-
decrease the sensitivity of myocardium to the antiarrhyth- tory alkalosis [79]; in addition, loop diuretics block the
mic action of cardiac glycosides. Digoxin directly limits reabsorption of calcium in the loop of Henle and may play
the renal tubular reabsorption of magnesium, therefore a role in the pathogenesis of hypocalcemia [80].
increasing magnesium excretion; a low magnesium con- It was shown that the correction of calcium disorder
centration increases the action of cardiac glycoside. The could improve CHF [81].
antiarrhythmic action of magnesium is mediated by a re- In CHF subjects, hypophosphatemia is generally due to
duced sensitivity to electrophysiologic changes induced by phosphate loss ascribed to respiratory alkalosis, to hypo-
Ca2?. The prognostic significance of serum magnesium magnesemia, and to phosphaturic effects of diuretics [82].
concentration in CHF subjects is currently under investi- Phosphorus depletion has been associated with re-
gation, although in a retrospective study of subjects with versible cardiomyopathy [83].
moderate-to-severe CHF, an inverse correlation was noted Some research showed an evident association of in-
between mortality and plasma magnesium [77]. creased levels of inorganic phosphate with CHF hospital-
ization even if the nature of this relationships is not clear
[84]; an explanation might be found in features of a my-
Hypocalcemia and hypophosphatemia ocardiocyte metabolism. It has recently been supposed that
inorganic phosphate is both the primary feedback signal for
Hypocalcemia (total serum calcium concentration stimulating oxidative phosphorylation and also the most
\8.6 mg/dL or ionized calcium concentration \1.1 mmol/ significant product of ATP hydrolysis in limiting the heart
L) and hypophosphatemia (serum phosphorus concentration capacity to hydrolyze ATP [85].
\2.7 mg/dL) are less investigated in HF subjects even It is known that inorganic phosphate plays a role in the
though not of minor importance. Despite the pivotal role of down-regulation of myocardial contractile force at the
calcium ions in contraction of cardiac muscle [78], few onset of ischemia [86]. Furthermore, there is a negative

123
Heart Fail Rev (2015) 20:493–503 499

Fig. 4 Metabolic alkalosis in

CHF. CHF congestive heart CHF
failure, VEC extracellular fluid
volume

SODIUM DELIVERY TO
VEC DIURETICS
DISTAL NEPHRON

ANGIOTENSIN II ALDOSTERONE

PROXIMAL TUBULE K+ SECRETION

HYPOKALEMIA
SODIUM REABSORPTION
H+ SECRETION
IN EXCHANGE WITH H+

NH4 + ESCRETION K+
H+
K+
+
H

METABOLIC ALKALOSIS

correlation between inorganic phosphates and systolic proximal tubule, and bicarbonate generation, pre-
blood pressure [87]. dominantly in the distal tubule. Bicarbonate reabsorption is
influenced by an effective circulating volume, glomerular
filtration rate, and serum potassium level, whereas bicar-
Acid–base abnormalities in CHF bonate generation is affected by distal sodium delivery and
reabsorption, aldosterone level, arterial pH, and pCO2 [92].
In CHF, various acid–base disorders can be discovered due In states of volume depletion, the increase in renal
to the renal loss of hydrogen ions and hydrogen ion move- avidity for sodium reabsorption results in an acceleration of
ments into cells, the reduction in the effective circulating the sodium–potassium exchange mechanisms, leading to
volume, hypoxemia, and renal failure. This justifies the oc- the development of negative potassium balance and
currence of metabolic alkalosis, metabolic acidosis, respi- favouring the maintenance of metabolic alkalosis [93]. In
ratory alkalosis, as well as respiratory acidosis alone or in this case, there is a reduction in bicarbonate back leak from
combination. Several studies have systematically evaluated the renal interstitium to the tubular lumen and a consequent
the prevalence of acid–base disturbances in CHF [88–90]. increase in the net tubular bicarbonate reabsorption [94].
About 37 % of CHF subjects show at least one acid–base The renal loss of hydrogen ions in heart failure is related
abnormality, most commonly metabolic alkalosis, alone or to mineralcorticoid excess and to the increased production
associated with respiratory alkalosis. Alkalemia is more of angiotensin II. Mineralcorticoids stimulate the apical
common in subjects with more advanced CHF (36 % in sodium channel and basolateral Na?–K? ATPase and in-
subjects with class IV compared with 11 % of those with creased sodium reabsorption promoting secretion through
class III) [4]. Other studies confirm the trend toward alka- the apical potassium channel. About two-thirds of filtered
lemia of mixed metabolic and respiratory origin in un- sodium is reabsorbed with Cl- or in exchange for H? in the
selected advanced CHF subjects [88, 90]. In addition, proximal tubule. Proximal tubule reabsorption is increased
diuretic therapy increases the prevalence of metabolic alka- by angiotensin II through the constriction of the efferent
losis, although the subjects who improve the circulatory glomerular arteriole and through the increase in filtration
status with diuretic therapy may improve their alkalosis [91]. fraction and in the number of Na?–H? exchangers. The
In normal conditions, the kidney preserves normal acid– final effect is to retain sodium, to deplete potassium, and to
base balance by bicarbonate reabsorption, principally in the produce extracellular alkalosis; furthermore, coexistent

123
500 Heart Fail Rev (2015) 20:493–503

potassium depletion increases plasma renin activity and whereas respiratory alkalosis, mediated by a SNS, inter-
angiotensin II production [95]. feres on blood pressure and cardiac arrhythmias. The latter
Diuretics employed in heart failure are frequently re- are frequently found in metabolic alkalosis associated with
sponsible for metabolic alkalosis due to several possible hypokalemia [102].
mechanisms. Diuretics cause an increase in sodium deliv- In end-stage heart failure, the most common complica-
ery to the distal nephron and accelerate potassium and tion is the pulmonary edema. Positive airway pressure
proton secretion; furthermore, volume contraction stimu- (PAP) therapy represents a potentially beneficial non-phar-
lates renin and aldosterone secretion. Potassium depletion macological approach in this clinical condition [103, 104].
with an aldosterone excess is always accompanied by PAP diminishes systemic venous return and right ven-
metabolic alkalosis. Hypokalemia promotes alkalosis tricular (RV) preload by increasing intrathoracic pressure;
principally through two mechanisms: first, hydrogen shifts it also alters pulmonary total vascular resistance that is the
from the extracellular to the intracellular compartments in major determinant of RV afterload [105]. In ADHF, PAP
exchange for potassium, thereby contributing to the alka- therapy increases oxygenation through the recruitment of
lemia, and second, hypokalemia produces a stimulation of collapsed alveoli, induces fluid shifts back from alveoli and
bicarbonate reabsorption in the proximal tubule and in- interstitial space to the pulmonary circulation, reduces
creases the acid excretion [96] (Fig. 4). respiratory muscle load and the work of breathing, and
Alkalosis seems to be an adverse prognostic factor; in a stabilizes hemodynamics [105].
recent study, the in-hospital mortality rate was higher in the
alkalosis group (14.1 %) than in the normal (4.5 %) and
acidosis groups (9.3 %) of HF subjects [97].
The treatment of metabolic alkalosis is based on chlo- Conclusions
ride and potassium repletion, enhancement of renal bicar-
bonate excretion (such as acetazolamide), or, if CHF subjects develop multiple acid–base and electrolyte
accompanied by kidney failure, low-bicarbonate dialysis. abnormalities due to several pathophysiological mechan-
In CHF, an appropriate management of circulatory failure isms. Their incidence is often correlated with the severity
and the use of aldosterone antagonists in the diuretic of cardiac dysfunction; furthermore, these imbalances are
regimen are useful for its treatment. In end-stage heart associated with a poor prognosis. Many of these metabolic
failure, a progressive reduction in plasma renal flow and in derangements are drug-induced; therefore, these subjects
GFR leads to renal failure with the reduced capacity of the need close monitoring. When treating CHF, one must
kidneys to excrete net acid, which can then induce a consider how to prevent and to correct electrolyte
metabolic acidosis [98]. imbalances.
Light and George [99] evaluated the changes in pul-
Conflict of interest The authors declare no conflict of interest.
monary function in 28 subjects hospitalized for CHF, and
they showed that initially, subjects had both obstructive Open Access This article is distributed under the terms of the
and restrictive ventilatory dysfunction. In another study, Creative Commons Attribution License which permits any use, dis-
Niset et al. evaluated the reversibility of the lung dys- tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
function in 47 patients with severe CHF before and 1 year
after heart transplantation. They affirmed that the restric-
tive ventilatory defect induced by chronic HF was re-
versible, whereas the exception of the reduction in References
diffusion lung capacity for carbon monoxide was not im-
proved, which probably reflected irreversible changes in 1. Ghali JK, Cooper R, Ford E (1990) Trends in hospitalization for
heart failure in the United States, 1973–1986: evidence for in-
the lung vasculature [100]. creasing population prevalence. Arch Intern Med 150:769–773
Subjects with heart failure and with pulmonary edema 2. Oster JR, Preston RA, Materson BJ (1994) Fluid and electrolyte
can develop respiratory alkalosis in the presence of sus- disorders in congestive heart failure. Semin Nephrol 14:485–505
tained alveolar hyperventilation that causes hypocapnia. In 3. Gheorghiade M, Hellkamp AS, Pina IL et al (2005) Hemody-
namic characterization and prognostic value of persistent hy-
fact, the stagnation of liquid in the perivascular and peri- ponatremia in patients with severe heart failure in the ESCAPE
bronchial connective and in the interstitial spaces of the trial. J Am Coll Cardiol 45:145A
alveolar septa stimulates receptors J and produces a reflex 4. Elisaf MS, Siamopoulos KC (1997) Acid–base and electrolyte
hyperventilation [101]. abnormalities in patients with congestive heart failure. Exp Clin
Cardiol 2:140–144
Effects of acid–base disorders on cardiovascular func- 5. Dargie HJ (1990) Interrelation of electrolytes and renin–an-
tion are well known. Depression of the cardiac function is giotensin system in congestive heart failure. Am J Cardiol
observed mainly with respiratory and metabolic acidosis, 65:28E–32E

123
Heart Fail Rev (2015) 20:493–503 501

6. Adrogué HJ, Madias NE (2000) Hyponatremia. N Engl J Med 31. Costache II, Alexandrescu DM, Cimpoeşu D, Petriş OR, Petriş
342:1581–1589 AO (2014) Hyponatremia-risk factor in patients with chronic
7. Sica DA (2005) Hyponatremia and heart failure—patho- heart failure—clinical, evolutive and therapeutic implications.
physiology and implications. Congest Heart Fail 11:274–277 Rev Med Chir Soc Med Nat Iasi 118:315–319
8. Klein L, O’Connor M, Leimberger D, Gattis-Stough W, Piña IL, 32. Chin MH, Goldman L (1996) Correlates of major complications
Felker GM (2005) Lower serum sodium is associated with in- or death in patients admitted to the hospital with congestive
creased short-term mortality in hospitalized patients with heart failure. Arch Intern Med 156:1814–1820
worsening heart failure: results from the Chronic Heart Failure 33. Chen MC, Chang HW, Cheng CI, Chen YH, Chai HT (2003)
(OPTIME-CHF) Study. Circulation 111:2454–2460 Risk stratification of in-hospital mortality in patients hospital-
9. Schrier RW (1990) Body fluid volume regulation in health and ized for chronic congestive heart failure secondary to non-is-
disease: a unifying hypothesis. Ann Inter Med 113:155–159 chemic cardiomyopathy. Cardiology 100:136–142. doi:10.1159/
10. Rademaker MT, Richards AM (2005) Cardiac natriuretic pep- 000073931
tides for cardiac health. Clin Sci 108:23–36 34. Krumholz HM, Chen YT, Bradford WD, Cerese J (1999) Var-
11. Schier RW, Abraham WT (1999) Hormones and hemodynamics iations in and correlates of length of stay in academic hospitals
in heart failure. N Engl J Med 341:577–578 among patients with heart failure resulting from systolic dys-
12. Schrier RW (2006) Water and sodium retention in edematous function. Am J Manag Care 5:715–723
disorder: role of vasopressin and aldosterone. Am J Med 35. Zoghi M, Duygu H, Güngör H, Nalbantgil S, Yilmaz GM,
119:47–53 Tülüce K (2008) The determination of the factors impacting on
13. Dzau VJ (1987) Renal and circulatory mechanisms in congestive in-hospital mortality in patients with acute heart failure in a
heart failure. Kidney Int 31:1402–1415 tertiary referral center. Anadolu Kardiyol Derg 8:255–259
14. Packer M (1995) Evolution of the neurohormonal hypothesis to 36. Wong PS, Davidsson GK, Timeyin Warren A, Watson DJ,
explain the progression of chronic heart failure. Eur Heart J 16:4–6 Vincent R (2002) Heart failure in patients admitted to hospital:
15. Brown JJ, Davies DL, Johnson VW, Lever AF, Robertson JI mortality is still high. Eur J Intern Med 13:304–310
(1970) Renin relationships in congestive cardiac failure, treated 37. Kearney MT, Fox KA, Lee AJ, Brooksby WP, Shah AM, Flapan
and untreated. Am Heart J 80:329–342 A (2004) Predicting sudden death in patients with mild to
16. Packer M, Medina Y, Yushak M (1984) Relationship between moderate chronic heart failure. Heart 90:1137–1143. doi:10.
serum sodium concentration and the hemodynamic and clinical 1136/hrt.2003.021733
responses to converting enzyme inhibition with captopril in 38. Chatterjee K (2009) Hyponatremia in heart failure. J Intensive
severe heart failure. J Am Coll Cardiol 3:1035–1043 Care Med 24:347–351
17. Ronco C, Haapio M, House AA (2008) Cardiorenal syndrome. 39. Cleland JG, Dargie HJ, Robertson I, Robertson JI, East BW
J Am Coll Cardiol 52:1527–1539 (1987) Total body electrolyte composition in patients with heart
18. Schrier RW (1975) Nonosmolar factors affecting renal water failure: a comparison with normal subjects and patients with
excretion. N Engl J Med 292:81–88 untreated hypertension. Br Heart J 58:230–238
19. Cogan MG (1990) Angiotensin II a potent controller of sodium 40. Macdonald JE, Struthers AD (2004) What is the optimal serum
transport in the early proximal tubule. Hypertension 15:451–458 potassium level in cardiovascular patients? J Am Coll Cardiol
20. Schuster VL, Kokko JP, Jacobson HR (1984) Angiotensin II 43:155–161
directly stimulates sodium transport in rabbit proximal convo- 41. Packer M (1990) Potential role of potassium as a determinant of
luted tubules. J Clin Investig 73:507–515 morbidity and mortality in patients with systemic hypertension
21. Heymes C, Bentall JK, Ratajczak P (2003) Increased myocardial and congestive heart failure. Am J Cardiol 6:45–51
NADPH oxidase activity in human heart failure. J Am Coll 42. Williams GH (2005) Aldosterone and heart failure: the rest of
Cardiol 41:2164–2171 the story. Heart Fail Rev 10:5–6
22. Weber K (2001) Mechanisms of disease: aldosterone in chronic 43. Cleland JG, Dargie HJ, Ford I (1987) Mortality in heart failure:
heart failure. N Engl J Med 345:1689–1697 clinical variables of prognostic value. Br Heart J 58:572–582
23. Goldsmith SR, Francis GS, Cowley AW (1986) Arginine va- 44. Brown MJ, Brown DC, Murphy MB (1983) Hypokalemia from
sopressin and the renal response to water loading in congestive beta2-receptor stimulation by circulating epinephrine. N Engl J
heart failure. Am J Cardiol 58:295–299 Med 309:1414–1419
24. Funayama H, Nakamura T, Saito T, Yoshimura A, Saito M, 45. Podrid PJ (1990) Potassium and ventricular arrhythmias. Am J
Kawakami M, Ishikawa SE (2004) Urinary excretion of aqua- Cardiol 65:33–44
porin-2 water channel exaggerated dependent upon vasopressin 46. Salerno DM, Asinger RW, Elsperger J, Ruiz E, Hodges M
in congestive heart failure. Kidney Int 66:1387–1392 (1987) Frequency of hypokalemia after successfully resuscitated
25. Nickel CH, Bingisser R, Morgenthaler NG (2012) The role of out-of-hospital cardiac arrest compared with that in transmural
copeptin as a diagnostic and prognostic biomarker for risk acute myocardial infarction. Am J Cardiol 59:84–88
stratification in the emergency department. BMC Med 10:7 47. Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen
26. De Luca L, Klein L, Udelson JE, Orlandi C, Sardella G, Fedele M, Baig W, Flapan AD, Cowlwy A, Prescott RJ, Neilson JM,
F, Gheorghiade M (2005) Hyponatremia in patients with heart Fox KA (1998) Prospective study of heart rate variability and
failure. Am J Cardiol 96:19–23 mortality in chronic heart failure: results of the United Kingdom
27. Oren RM (2005) Hyponatremia in congestive heart failure. Am J heart failure evaluation and assessment of risk trial (UK-heart).
Cardiol 95:2–7. doi:10.1016/j.amjcard.2005.03.002 Circulation 98:1510–1516
28. Chow KM, Szeto CC, Wong TY, Leung CB, Li PK (2003) Risk 48. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ
factors for thiazide-induced hyponatraemia. QJM 96:911–917 (1999) Diuretics and risk of arrhythmic death in patients with
29. Chapman MD, Hanrahan R, McEwen J, Marley JE (2002) Hy- left ventricular dysfunction. Circulation 100:1311–1315
ponatraemia and hypokalaemia due to indapamide. Med J Aust 49. Pitt B, Remme W, Zannad F (2003) Eplerenone, a selective
176:219–221 aldosterone blocker, in patients with left ventricular dysfunction
30. Van Assen S, Mudde AH (1999) Severe hyponatraemia in an after myocardial infarction. N Engl J Med 348:1309–1321
amiloride/hydrochlorothiazide-treated patient. Neth J Med 50. Leier CV, Dei Cas L, Metra M (1994) Clinical relevance and
54:108–113 management of the major electrolyte abnormalities in

123
502 Heart Fail Rev (2015) 20:493–503

congestive heart failure: hyponatremia, hypokalemia, and hy- 74. Seelig MS, Haddy FJ (1980) Magnesium and the arteries. Ef-
pomagnesemia. Am Heart J 128:564–574 fects of magnesium deficiency on arteries and on the retention of
51. Cohn J, Kowey P, Whelton P, Prisant M (2000) New guidelines sodium, potassium and calcium. In: Cantin M, Seelig MS (eds)
for potassium replacement in clinical practice. Arch Intern Med Magnesium in health and disease. SP Medical and Scientific
160:2429–2436 Books, New York, pp 605–638
52. Srivastava TN, Young DB (1995) Impairment of cardiac func- 75. Stevenson MM, Yoder I (1972) Studies of platelet aggregation,
tion by moderate potassium depletion. J Card Fail 1:195–200 plasma adenosine diphosphate breakdown, and blood coagula-
53. Sudhir K, Kurtz TW, Yock PG, Connolly AJ, Morris RC (1993) tion in magnesium deficient calves and rats. Thromh Diarh
Potassium preserves endothelial function and enhances aortic Herrrorrh 22:299–305
compliance in Dahl rats. Hypertension 22:3 76. Altura BM, Altura BT (1986) Biochemistry and patho-
54. Taddei S, Mattei P, Virdis A, Sudano I, Ghiadoni L, Salvetti A physiology of congestive heart failure: is there a role for mag-
(1994) Effect of potassium on vasodilation to acetylcholine in nesium! Magnesium 5:134–143
essential hypertension. Hypertension 23:485–490 77. Gottlieb SS, Baruch L, Kukin ML, Bemstein JL, Fisher ML,
55. Campbell WB, Schmitz JM (1978) Effect of alterations in di- Packer M (1990) Prognostic importance of the serum magne-
etary potassium on the pressor and steroidogenic effects of an- sium concentration in patients with congestive heart failure.
giotensins II and III. Endocrinology 103:2098–2104 J Am Cardiol 6:827–883
56. Young DB, Lin H, McCabe RD (1995) Potassium’s cardiovas- 78. Levine SN, Rheams CN (1985) Hypocalcemic heart failure. Am
cular protective mechanisms. Am J Physiol 268:R825–R837 J Med 78:1033–1035
57. Barri YM, Wingo CS (1997) The effects of potassium depletion 79. Krapf R, Jaeger P, Hulter HN (1992) Chronic respiratory alka-
and supplementation on blood pressure: a clinical review. Am J losis induces renal PTH resistance, hyperphosphatemia and
Med Sci 314:37–40 hypocalcemia in humans. Kidney Int 42:727–734
58. Bielecka-Dabrowa A, Mikhailidis D, Jones L (2012) The mean- 80. Bourdeau JE, Buss SL, Vurek GG (1982) Inibition of calcium
ing of hypokalemia in heart failure. Int J Cardiol 158:12–17 absorption in the cortical thick ascending limb of Henle’s loop
59. Ward J, Cameron I (1984) Adaptation of the cardiac muscle by furosemide. J Pharmacol Exp Ther 221:815–819
sodium pump to chronic potassium deficiency. Cardiovasc Res 81. Rimailho A, Bouchard P, Aschaison G (1985) Improvement of
18:257–263 hypocalcemic cardiomyopathy by correction of serum calcium
60. Erdmann E, Bolte HD, Luderitz B (1971) The (Na?–K?) level. Am Heart J 109:611–613
ATPase activity of guinea-pig heart muscle in potassium defi- 82. Gaasbeek A, Meinders AE (2005) Hypophosphatemia. An up-
ciency. Arch Biochem Biophys 145:121–125 date on its etiology and treatment. Am J Med 118:1094–1101
61. Shattock M, Matsuura H, Ward J (1994) Sodium pump current 83. Darsee JR, Nutter DO (1978) Reversible severe congestive
measured in cardiac ventricular myocytes isolated from control cardiomyopathy in three cases of hypophosphatemia. Ann Inter
and potassium depleted rabbits. Cardiovasc Res 28:1854–1862 Med 89:867–870
62. Blomstrom-Lundqvist C, Caidahl K, Olsson B, Rudins A (1989) 84. Plischke M, Albrecht C, Bielesz B, Shayganfar S (2011) Inor-
Electrocardiographic findings and frequency of arrhythmias in ganic phosphate and FGF-23 predict outcome in stable systolic
Bartter’s syndrome. Br Heart J 61:274–279 heart failure. Eur J Clin Investig 42:649–656
63. Li M, Xiao J, Yan S (1996) Changes in intracellular K? con- 85. Wu F, Zhang EY, Zhang J, Bache RJ, Beard DA (2008) Phos-
centration and ATPase activity of myocardiocytes in early stage phate metabolite concentrations and ATP hydrolysis potential
of burn injury. Zhonghua Zheng Xing Shao Shang Wai Ke Za normal and ischaemic hearts. J Physiol 586:4193–4208
Zhi 12:177–179 86. He MX, Wang S, Downey HF (1997) Correlation between
64. Rude RK (1989) Physiology of magnesium metabolism and the myocardial contractile force and cytosolic inorganic phosphate
important role of magnesium in potassium deficiency. Am J during early ischemia. Am J Physiol 272:1333–1341
Cardiol 63:31–34 87. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G (2005) Relation
65. Gattlieb SS (1989) Importance of magnesium in congestive between serum phosphate level and cardiovascular event rate in
heart failure. Am J Cardiol 63:39–42 people with coronary disease. Circulation 112:2627–2633
66. Douban S, Brodsky MA, Whang DD, Whang R (1996) Significance 88. Milionis HJ, Alexandrides GE, Liberopoulos EL, Bairaktari ET,
of magnesium congestive heart failure. Am Heart J 132:664–671 Goudevenos J, Elisaf MS (2002) Hypomagnesemia and con-
67. Milionisa HJ, Alexandridesa GE, Liberopoulosa EN, Bairaktarib current acid–base and electrolyte abnormalities in patients with
ET, Goudevenosc J, Elisaf MS (2002) Hypomagnesemia and congestive heart failure. Eur J Heart Fail 4:167–173
concurrent acid–base and electrolyte abnormalities in patients 89. Kuwahara T, Kawai C (1992) Acid–base disturbances in heart
with congestive heart failure. Eur J Heart Fail 4:167–173 failure. Nippon Rinsho 50:2173–2177
68. Schwinger RH, Erdman E (1992) Heart failure and electrolyte 90. Frangiosa A, De Santo LS, De Santo NG, Anastasio P, Favazzi
disturbances. Methods Find Exp Clin Pharmacol 14:315–325 P, Cirillo E, Cotrufo M, Adroguè HJ (2002) Acid–base state in
69. Wester PO (1992) Electrolyte balance in heart failure and the patients after cardiac transplantation. Am J Nephrol 22:332–337
role of magnesium ions. Am J Cardiol 70:44–49 91. Kratky V, Bartonova J, Hrdina R (1990) Nektere metabolicke a
70. Wu X, Ackermann U, Sonnenberg H (1995) Potassium deple- acidobazicke zmeny pri intenzvini diureticke lecbe srdecni sla-
tion and salt-sensitive hypertension in DAHL rats: effect on bosti. Vnitr Lek 36:330–341
calcium, magnesium, and phosphate excretions. Clin Exp 92. Sterns RH (2003) Fluid, electrolyte, and acid–base disturbances.
Hypertens 17:989–1008 NephSAP 2:3–8
71. Solomon R (1987) The relationship between disorders of Kq and 93. Selden DW, Rector FC (1972) The generation and maintenance
Mgq homeostasis. Semin Nephrol 2:253–262 of metabolic alkalosis. Kidney Int 1:306–321
72. Shils ME (1980) Magnesium, calcium and parathyroid interac- 94. Pitts RF, Lotspeich WD (1996) Bicarbonate and the renal
tions. Ann NY Acad Sci 355:165–178 regulation of acid–base balance. Am J Physiol 147:138–154
73. Ralston MA, Mumane MR, Unverferth DV, Leier CV (1990) Serum 95. Kassirer JP, London AM, Goldman DM (1970) On the patho-
and tissue magnesium concentrations in patients with heart failure genesis of metabolic alkalosis in hyperaldosteronism. Am J Med
and serious ventricular arrhythmias. Ann Intern Med 113:841–846 49:306–315

123
Heart Fail Rev (2015) 20:493–503 503

96. Galla JH (2000) Metabolic alkalosis. J Am Soc Nephrol 102. Moster WG, Reirer C, Gardier RW (1969) Cardiac output and
11:369–375 postganglionic sympathetic activity during acute respiratory al-
97. Shirakabe A, Hata N, Kobayashi N (2012) Clinical significance kalosis. Anesthesiology 31:28–34
of acid–base balance in an emergency setting in patients with 103. JCS Joint Working Group (2013) Guidelines for treatment of
acute heart failure. J Cardiol 60:288–294 acute heart failure (JCS 2011). Circ J 77:2157–2201
98. Peixoto Aldo J, Alpern Robert J (2013) Acid–base and elec- 104. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm
trolyte teaching case treatment of severe metabolic alkalosis in a M, Dickstein K (2012) ESC Guidelines for the diagnosis and
patient with congestive heart failure. Am J Kidney 61:822–827 treatment of acute and chronic heart failure 2012: the Task Force
99. Light RW, George RB (1983) Serial pulmonary function in for the Diagnosis and Treatment of Acute and Chronic Heart
patients with acute heart failure. Arch Intern Med 143:429–433 Failure 2012 of the European Society of Cardiology. Developed
100. Niset G, Ninane V, Antoine M, Yernault JC (1993) Respiratory in collaboration with the Heart Failure Association (HFA) of the
dysfunction in congestive heart failure: correction after heart ESC. Eur Heart J 33:1787–1847
transplantation. Eur Respir J 6:1197–1201 105. Kato T, Suda S, Kasai T (2014) Positive airway pressure therapy
101. Paintal AS (1970) The mechanism of excitation of type J re- for heart failure. World J Cardiol 6:1175–1191
ceptors and the J reflex. Ciba Foundation Symposium-Breathing:
Hering-Breuer Centenary Symposium

123