REVIEW

Hypochloraemia in Patients with Heart Failure: Causesand Consequences

Joseph J. Cuthbert . Sunil Bhandari . Andrew L. Clark

Received: July 3, 2020 / Published online: August 9, 2020� The Author(s) 2020

ABSTRACT

Hypochloraemia is a common electrolyteabnormality in patients with heart failure (HF).It has a strong association with adverse outcomeregardless of HF phenotype and independent ofother prognostic markers. How hypochloraemiadevelops in a patient with HF and how it mightinfluence outcome are not clear, and in thisreview we explore the possible mechanisms.Patients with HF and hypochloraemia almostinvariably take higher doses of loop diureticthan patients with normal chloride levels.However, renal chloride and bicarbonatehomeostasis are closely linked, and the latter

may be influenced by neurohormonal activa-tion: it is likely that the etiology of hypochlo-raemia in patients with HF is multifactorial anddue to more than just diuretic-induced urinarylosses. There are multiple proposed mechanismsby which low chloride concentrations may leadto an adverse outcome in patients with HF: byincreasing renin release; by a stimulatory effecton the with-no-lysine kinases which mightincrease renal sodium-chloride co-transporteractivity; and by an adverse effect on myocardialconduction and contractility. None of theseproposed mechanisms are proven in humanswith HF. However, if true, it might suggest thathypochloraemia is a therapeutic target thatmight be amenable to treatment with acetazo-lamide or chloride supplementation.

Keywords: Acetazolamide; Chloride; Diuretics;Diuretic resistance; Heart failure;Hypochloraemia; Metabolic alkalosis;Outcome; Prognosis; Sudden death

Digital features To view digital features for this articlego to https://doi.org/10.6084/m9.figshare.12674555.

J. J. Cuthbert (&) � A. L. ClarkDepartment of Academic Cardiology, Hull YorkMedical School, Hull and East Yorkshire MedicalResearch and Teaching Centre, Castle Hill Hospital,Cottingham, Kingston upon Hull HU16 5JQ, UKe-mail: joe.cuthbert@hey.nhs.uk

S. BhandariDepartment of Academic Nephrology, HullUniversity Teaching Hospitals NHS Trust and HullYork Medical School, Anlaby Road, Kingston uponHull HU3 2JZ, UK

Cardiol Ther (2020) 9:333–347

https://doi.org/10.1007/s40119-020-00194-3

Key Summary Points

Low serum chloride levels are associatedwith adverse prognosis in patients withacute or chronic heart failure (HF)regardless of left ventricular ejectionfraction and independently of otherprognostic markers such as N-terminalpro-B-type natriuretic peptide levels.

It is not clear how hypochloraemiadevelops in patients with HF but it may belinked to neurohormonal activation,high-dose loop diuretic usage, andmetabolic alkalosis.

It is not known whether hypochloraemiais a marker or mediator of adverseoutcome in patients with heart failure,although there are several putativemechanisms that might suggest the latter.For example, hypochloraemia might belinked to increased neurohormonalactivation, diuretic resistance, andincreased risk of sudden cardiac death.

Acetazolamide may increase natriuresisand diuresis while also increasing chloridereabsorption and bicarbonate excretionand thus might be a useful treatment forpatients with HF, hypochloraemia,metabolic alkalosis, and diureticresistance.

INTRODUCTION

A link between low serum chloride concentra-tions, loop diuretics, and risk of death inpatients following a heart attack was firstreported in 1979 [1], and the first reportedassociation between low serum chloride con-centrations and increased risk of death amongstpatients with heart failure (HF) was in 2007 [2].The authors of neither paper made even apassing reference to the chloride findings in thediscussion [1, 2], perhaps owing to a lack of

understanding regarding the importance ofserum chloride: the potential prognostic sig-nificance of low chloride has, until recently, notbeen appreciated.

Hypochloraemia is a common electrolytedisturbance and marker of adverse outcomeamongst patients with HF independent of otherprognostic markers, including hyponatremia(Table 1) [3–12]. The mechanisms are poorlyunderstood. In this review, we will discuss theaetiology of hypochloraemia in patients withHF, explore the possible mechanisms behind itsassociation with adverse outcome, and considerwhat, if anything, might be done about it. Thepresent article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.

HYPOCHLORAEMIA AND HEARTFAILURE

Chloride is the main anion in the plasma andextracellular fluid [13], and is freely filtered inthe glomerulus of the kidney into the urinaryspace (tubular lumen). Renal tubular cells areasymmetric with an apical surface facing theurinary space and a basolateral membrane fac-ing the renal interstitium (peritubular capillar-ies). The majority of chloride reabsorptionoccurs in the proximal convoluted tubule(PCT), paracellularly in the intercellular spacepassively along an electrochemical gradient asthe permeability to chloride anions exceeds thatof other anions such as bicarbonate [14, 15].Active, trans-cellular, reabsorption occurs viaCl-/anion counter transports (antiporters orexchangers) in particular formate amongstothers (sulphate, iodide, oxalate, hydroxyl, andbicarbonate) on the apical membrane, and by asodium-driven Cl-/HCO3

- antiporter and K?/Cl- symporter on the basolateral membrane[16]. In the loop of Henle (LoH), further chlo-ride reabsorption takes place via Na?/K?/2Cl-

co-transporters (NKCC2) on the apical mem-brane (the site of action of loop diuretics) andvoltage-gated chloride channels on the baso-lateral membrane [17]. In the distal convolutedtubule (DCT) and collecting duct (CD)

334 Cardiol Ther (2020) 9:333–347

Table1

Summaryof

reportsof

hypochloraem

iain

patientswithheartfailure

Stud

y(year)

Pop

ulation(N

)Find

ings

Cuthbertet

al.

(2018)

[3]

OutpatientswithHeFREFandHeFNEF(N

=4705)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

moresevere

symptom

sandhigher

NTproB

NPlevelsin

both

HeFREFandHeFNEF

phenotypes

Weremorelikelyto

dieor

beadmittedwithHFregardlessof

HFphenotypeandindepend

ent

ofNTproB

NPandsodium

levels

Patientswithhypochloraem

iaandnorm

alsodium

levelshadhigher

bicarbonateandlower

potassium

levelsthan

thosewithdualhypochloraem

iaandhyponatrem

ia

Therewasno

associationbetweenchloride

andNTproB

NPlevelson

MVanalysisbutboth

were

independ

ently

associated

withadverseoutcom

e,suggesting

they

assessdifferentaspectsof

the

HFsynd

rome

Signaltowards

anassociationbetweenhypochloraem

iaandsudden

death

U-shapedrelationship

betweenchloride

andoutcom

e:therewas

asubstantialincreasedrisk

of

deathin

patientswithchloride

levels\

100mmol/l(higherthan

thearbitrarycut-offthat

defin

eshypochloraem

ia—

\96

mmol/l)

Grodinet

al.

(2015)

[4]

Twodifferentcohortsof

inpatientswithHeFREF(C

leveland

Clin

iccohortN

=1318;Penn

sylvaniacohort:N

=876)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

lower

LVEF,

higher

NTproB

NPandlonger

length

ofhospitalstay

Greater

risk

ofdeathindepend

entof

sodium

levelsin

twodifferentpopulationsof

patients

admittedwithHF

Ter

Maaten

etal.(2016)

[5]

Inpatientsenrolledin

thePR

OTECT

trial(N

=2033)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

lower

diureticresponse

(weightlostper40

mgfurosemide)

despitetaking

higher

dosesof

diuretic,and

weremorelikelyto

have

‘‘residualcongestion’’on

day7

Weremorelikelyto

requireinotropicsupportandhave

worsening

HFsymptom

sduring

admission

Weremorelikelyto

die180days

afterdischarge

Patientswithlowchloride

thathadresolved

bythetimeof

dischargehadasimilarpost-discharge

prognosisto

thosewithnorm

alchloride

levelsthroughout

admission

There

was

nodifference

inadmission

NTproB

NPor

BNPacrossquintilesof

chloride

Cardiol Ther (2020) 9:333–347 335

Table1

continued

Stud

y(year)

Pop

ulation(N

)Find

ings

Grodinet

al.

(2016)

[6]

Outpatients(N

=1673)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Weremorelikelyto

take

loop

diuretics

Weremorelikelyto

dieduring

5-yearfollow-upregardlessof

sodium

levels,

afteradjustmentfor

BNPandLVEF

There

was

nodifference

inbaselin

erenalfun

ction,

LVEF,

orBNPlevelsbetweenpatientswith

lowchloride

levelsandthosewithnorm

alchloride

levels

Testani

etal.

(2016)

[7]

Outpatientsenrolledin

theBEST

trial(N

=2699)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

worse

renalfunction,low

erLVEFandmoresevere

symptom

s

Weremorelikelyto

dieduring

follow-up

Modestassociationbetweenchloride

andsodium

levels(r=

0.53;P\

0.001)

andonlyhalfof

patientswithhypochloraem

iawerealso

hyponatrem

ic

Low

sodium

,was

notassociated

withmortalityaftermultivariableadjustment

Hanberg

etal.

(2016)

[8]

Outpatientswithprogressivesymptom

sattend

ingfordaily

IV

furosemideor

POtorasemide(N

=162)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Werelesslikelyto

take

either

ACEIor

bBbutmorelikelyto

take

digoxinor

high-doseloop

diuretics

Had

worse

renalfunction

Had

greaterfractionalexcretionof

chloride

andpotassium

butsimilarfractionalexcretionof

sodium

pre-diureticbutlower

fractionalexcretionof

allthreeions

post-diuretic

Had

lower

diureticefficiency(m

mol

ofNa?

perdoublin

gof

loop

diureticdose)

Wereat

greaterrisk

ofall-cause

mortalityindepend

entof

sodium

levelsor

renalfunction

There

was

nodifference

inbaselin

eLVEFor

NTproB

NPbetweenpatientswithlowchloride

levelsandthosewithnorm

alchloride

levels

Chlorideandreninlevelswereinverselycorrelated

(r=

-0.46;P=

0.001)

independ

entof

sodium

levelsor

renalfunction

336 Cardiol Ther (2020) 9:333–347

Table1

continued

Stud

y(year)

Pop

ulation(N

)Find

ings

Hanberg

etal.

(2016)

[8]

OutpatientswithstableHFgiven21

glysine

chloride

perday

(115

mmol/lchloride)for3days

(N=

10)

Serum

chloride

increasedby

2.2mmol/lfrom

baselin

e(P

=0.01)buttherewasno

difference

in

urinevolume

Renin

levelswereparadoxically

higher

afterchloride

supplementation

NTproB

NPlevelsdecreasedby

25%

ineightpatients(P

=0.01)

Grodinet

al.

(2017)

[9]

Inpatientsenrolledin

theROSE

-AHFtrial(N

=360)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Weremorelikelyto

take

high-doseloop

diureticon

admission

andhadgreatercumulativedoses

ofloop

diureticduring

admission

Had

lower

diureticefficiencydefin

edas

millilitres

ofurinepassed

per40

mgof

furosemide

Weremorelikelyto

dieor

bereadmittedwithHFduring

60-day

follow-upindepend

entof

sodium

levels

There

was

nodifference

insymptom

severity,N

TproB

NPlevels,

renalfunction,rateof

worsening

HFas

inpatient,or

rate

offreedom

from

congestion

after72

hof

treatm

ent

betweenpatientswithlowchloride

levelsandthosewithnorm

allevels

Average

chloride

change

was-

0.9mmol/lperdayduring

7days

oftreatm

ent,averagediuretic

dose

onadmission

80mgfurosemideequivalents

Changein

chloride

levelswas

notassociated

withoutcom

e

Ferreira

etal.

(2017)

[10]

Patientsenrolledin

theEPH

ESU

SandCAPR

ICORN

trials

(N=

7195)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Wereolder,morelikelyto

have

AF,

worse

renalfunction,and

LVEF

Weremorelikelyto

take

diureticsanddigoxin

Low

serum

chloride

was

onlyassociated

withincreasedmortality(not

hospitalization)

inthe

contextof

lowsodium

Grodinet

al.

(2018)

[11]

OutpatientswithHeFNEFenrolledin

theTOPC

ATtrial

(N=

942from

North

Americawithavailablechloride

data)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

moresevere

symptom

sandmorelikelyto

betaking

diureticatahigher

averagedaily

dose

Had

high

E/e

0ratioindicating

greaterLVfillin

gpressures

Wereatgreaterrisk

ofthecompositeendpoint

ofcardiovasculardeath,hospitalizationwithHF,

orabortedcardiacarrestindepend

entof

sodium

orNTproB

NPlevels

Cardiol Ther (2020) 9:333–347 337

(responsible for * 5% of chloride reabsorption)chloride is reabsorbed by thiazide-sensitive Na?/Cl- co-transporter and Cl-/HCO3

- antiporterand returns to the bloodstream via voltage-gated chloride channels on the basolateralmembrane (Fig. 1) [18].

At first sight, the origin of hypochloraemiaseems likely to be similar to the putative aeti-ology of hyponatremia in patients with HF: lowchloride results from either haemodilution ordepletion due to loop diuretics [19]. However,patients with hypochloraemia appear to fallinto two phenotypes; those with concurrenthyponatremia and those with normal sodiumconcentrations [3]. The group with normalsodium has higher bicarbonate, and lowerpotassium concentrations (and a higher rate ofclinically significant hypokalaemia (defined as aserum K?\3.5 mmol/l) [3].

An Association with Metabolic Alkalosis?

In other disease states, such as severe vomitingor mineralocorticoid excess, hypochloraemia isassociated with metabolic alkalosis(HCO3

-[30 mmol/l) [20, 21]. Metabolic alka-losis is the most common acid-base abnormalityin patients with HF, affecting up to half ofpatients admitted to hospital [22]. While acti-vation of the renin–angiotensin–aldosteronesystem (RAAS) is usually linked to sodiumhomeostasis [23], data from in vitro and in vivoanimal studies suggest that neurohormonalactivation might play a significant role in thedevelopment and maintenance of a metabolicalkalosis in patients with HF (Fig. 2).

In vitro and in vivo studies suggest thatwhen noradrenaline [24], and angiotensin II[25] levels increase, bicarbonate reabsorption inthe first segment of the PCT increases. Addi-tionally, in vivo studies in rats show thataldosterone increases the activity of the H?-ATPase pump in the CD which increases H?

secretion into the urine [26]. The increasedacidification of the urine might result in a netgain of bicarbonate by the body.

Loop diuretics might also contribute to ametabolic alkalosis: a so-called ‘‘contraction-al-kalosis’’ due to decreased extracellular fluid

Table1

continued

Stud

y(year)

Pop

ulation(N

)Find

ings

Marchenko

etal.(2020)

[12]

Consecutive

inpatientsat

asinglecentre

(N=

1241)

Com

paredto

patientswithnorm

alchloride

levels,

patientswithlowchloride:

Had

higher

averagedaily

loop

diureticdose

during

inpatientstay

Had

higheraverageweightlossduring

inpatientstay

—in

contrastto

otherreportsin

patients

admittedwithHFdetailedabove

Had

ahigher

LVEF–in

contrastto

otherreportsdetailedabove

Had

greater30-day

readmission

ordeathrate

and12-m

onth

deathrate

HeFREFheartfailure

dueto

areducedejection

fraction,HeFNEFheartfailure

withanorm

alejection

fraction,HFheartfailure,BNPB-typenatriureticpeptide,NTproBNP

N-terminalpro-B-typenatriureticpeptide,MVmultivariable,L

VEFleftventricularejection

fraction,A

CEIangiotensin-converting

enzymeinhibitor,bBbeta-blocker,m

lsmillilitres,

AFatrialfibrillation,L

Vleftventricular

338 Cardiol Ther (2020) 9:333–347

volume resulting in increased bicarbonate con-centration [27] is well recognized in the litera-ture, but may be an over-simplification. In vivo,increased sodium delivery to the CD (due toapical NKCC2 co-transporter inhibition)increases the activity of the H?-ATPase pump,increasing H? secretion into the urine [28].In vitro studies in rats have found that hy-pokalaemia (a potential complication of loopdiuretic use) promotes bicarbonate reabsorptionin the PCT [29, 30], and hypokalaemia increasesRAAS activation in humans with HF [31, 32],which might further drive bicarbonate reab-sorption (Fig. 2).

In vitro and in vivo studies in both rabbitsand rats suggest that increased bicarbonatereabsorption is accompanied by increasedchloride excretion [33–35]. The same processmay occur in humans [36]. One small study(N = 51) found that patients with HF andhypochloraemia had higher serum bicarbonate,and greater fractional chloride excretion thanthose with normal chloride levels while havingsimilar fractional sodium excretion (Table 1) [8].‘‘Chloride wasting nephropathy’’—persistent

urinary chloride excretion—is seen in patientswith hyperaldosteronism [37] and/or severepotassium depletion [38], and similar metabolicstates have been reported in patients with HF[39].

An additional factor contributing to themaintenance of an alkalosis is that as serumconcentrations of chloride fall (either due toincreased excretion in response to increasedbicarbonate reabsorption, or diuretic use, orboth), there is less and less chloride filtered intoin the urinary space. A threshold of low serumchloride may be reached beyond which bicar-bonate excretion is inhibited as there is lesschloride in the urine to exchange with bicar-bonate [36, 37].

Patients can thus be trapped in a cycle ofhypochloraemia and alkalosis, which is onlypartly due to loop diuretic usage (Fig. 2): forexample, among patients admitted with HF,those with serum bicarbonate concentrationsabove the median (C 28 mmol/l) had moresevere disease (lower left ventricular ejectionfraction, worse renal function, and highernatriuretic peptide levels) but were on lower

Fig. 1 Chloride reabsorption along the nephron. Themajority of renal chloride reabsorption occurs in theproximal convoluted tubule, paracellularly along an

electrochemical gradient although transcellular Cl-/aniontransport also plays a role

Cardiol Ther (2020) 9:333–347 339

doses of loop diuretic than patients with serumbicarbonate below the median [25].

CHLORIDE AND OUTCOME

Whether a low chloride concentration is amarker or a mediator of adverse outcome isunknown although there are possible patho-physiological mechanisms, which might sug-gest the latter (Fig. 3).

Diuretic Resistance

The with-no-lysine (WNK) kinases (WNK1,WNK3, and WNK4) are the first step in an enzy-matic cascade which increases activity of theNa?/K?/2Cl- and Na?/Cl- co-transporters[40–43]. Chloride binds to the catalytic site of thekinases, thus inactivating them [44, 45]. In vitroand in vivo studies suggest that the activity ofWNK1 and WNK4 is reduced at high chlorideconcentrations [44, 46], but increased at lowerconcentrations [47, 48]. Thus, hypochloraemiamay increase the activity of both Na?/K?/2Cl-

and Na?/Cl- co-transporters, meaning greaterdoses of loop diuretic are required to induce a

diuresis. In addition, chronic use of loop diureticleads to an increase in sodium delivery to thedistal tubule with consequent hypertrophy ofcells in the distal nephron. The hypertrophiedcells reabsorb sodiummore avidly, an effect thatcan be mitigated by increasing the dose of loopdiuretic and/or the additional use of a thiazidediuretic [49].

Consistent with this idea, patients withhypochloraemia take higher doses of loopdiuretics than those with normal chloride levels[3–12], but whether a high-dose diuretic is thecause of hypochloraemia or becomes necessarybecause of hypochloraemia-induced diureticresistance is uncertain.

Effect on the RAAS

Renin secretion is controlled by the maculadensa. These specialized cells are sensitive tosodium chloride, low concentrations of whichin the urinary space leads to renin secretionfrom the juxtaglomerular cells of the afferentand efferent arterioles. Increased chloride (butnot increased sodium) delivery to the maculadensa suppresses renin release from the granular

Fig. 2 Possible association between hypochloraemia, meta-bolic alkalosis, and neurohormonal activation in patientswith heart failure. Our proposed theoretical link betweenhypochloraemia, metabolic alkalosis, and neurohormonalactivation in patients with heart failure is based on various

in vivo and in vitro animal experiments. The dotted greyedlines denote that loop diuretics are only a contributingfactor in this proposed model, rather than the driving force

340 Cardiol Ther (2020) 9:333–347

cells in the afferent arteriole and a subsequentfall in angiotensin II levels [50, 51]. Chlorideand renin are inversely related in patients withHF [8]. This is the rate-limiting event in theRAAS.

Sudden Death

Chloride channels play a role in ventricularrepolarization [52, 53], and in regulating thepositive chronotropic effect of cardiac pace-maker activity [54]. Myocyte volume and pH areregulated, in part, by chloride-dependent co-transporters [55, 56]. Abnormalities of thechloride channels and co-transporters may bearrhythmogenic [57, 58] and can impair con-tractility [59]. Consistent with these observa-tions, a large study of outpatients with HFfound that patients with hypochloraemia hadan increased risk of sudden death (Table 1) [3].

A THERAPEUTIC TARGET?

Hypertonic saline (HS) increases diuresis andmay improve outcome when given alongside

intravenous furosemide in patients admittedwith HF [60, 61]. However, data on changes inchloride levels are absent from almost allreports of HS and whether any observed benefitis due a change in chloride levels is pure spec-ulation. A proof-of-concept study of oral chlo-ride supplementation in patients with HF(N = 10) found that lysine chloride increasedchloride levels but required enormous doses toaffect only small changes in serum chloride(Table 1) [8]. Further work is ongoing(NCT03446651) [62].

Acetazolamide

Acetazolamide (ACZ) is a carbonic anhydrase(CA) inhibitor. CA catalyses the interconversionbetween carbon dioxide and water on the onehand, and hydrogen (H?) and bicarbonate ionson the other (Fig. 4). CA on the apical mem-brane of the PCT cell converts free H? andbicarbonate to water and carbon dioxide in theurinary space; the water then diffuses back intothe cell via aquaporin 1 channels, carbondioxide freely diffuses across the apical mem-brane [63, 64]. There, the water and carbon

Fig. 3 Confirmed and possible associations betweenhypochloraemia and adverse outcome in patients withheart failure. The dotted lines denote possible links

demonstrated in animal studies and the thick lines denoteconfirmed links in patients with heart failure

Cardiol Ther (2020) 9:333–347 341

dioxide are converted back to H? and bicar-bonate ions by intracellular CA.

The newly formed H? ions in the cell areexcreted in exchange for urinary sodium viaNa?/H? co-transporters on the apical mem-brane [65, 66], and bicarbonate returns to thecirculation via Na?/HCO3

- and Cl-/HCO3-

antiporters on the basolateral membrane (Fig. 4)[67]. Inhibition of intracellular CA reducesproduction of intracellular H?, thus reducingsodium reabsorption via the Na?/H? antiporterson the apical membrane, and inhibition ofluminal CA reduces production of water andcarbon dioxide, thus increasing urinary bicar-bonate levels (Fig. 4).

ACZ increases bicarbonate excretion andchloride reabsorption in vivo [32, 68], andincreases serum chloride levels in humans[69, 70]. The reasons behind this are not clearbut may result from two potential mechanisms:firstly, increased HCO3

- in the urinary spaceincreases the negative charge thus increasingthe electrochemical gradient along which

chloride is reabsorbed in the PCT. Secondly,in vivo studies suggest that ACZ, separatelyfrom CA inhibition, also inhibits the basolateralCl-/HCO3

- antiporter in the PCT thus reducingmovement of chloride out of the blood and intothe cell (Fig. 4).

There are thus three ways in which ACZmight be beneficial for patients with HF: (1)increasing sodium excretion and increasingdiuresis [71, 72]; (2) increasing bicarbonateexcretion, which may reduce metabolic alkalo-sis [73, 74]; and (3) increasing renal chloridereabsorption, which may reverse hypochlo-raemia [69, 70].

The ADVOR study of ACZ in patientsadmitted with HF is aiming to recruit * 500patients, the largest study of ACZ in patientswith HF to date. The primary endpoint istreatment success (i.e., clinical decongestiondefined as the absence of pleural effusion,ascites, and significant peripheral oedema) after3 days of treatment. Secondary endpointsinclude mortality and morbidity alongside

Fig. 4 Renal carbonic anhydrase and acetazolamide. Inhi-bition of renal carbonic anhydrase with acetazolamidemight increase luminal bicarbonate concentrations, reduceintracellular hydrogen ion concentrations thus reducing

sodium reabsorption via the Na?/H? antiporter, andreduce movement of chloride out of the peritubularcapillaries. ACZ acetazolamide

342 Cardiol Ther (2020) 9:333–347

changes in natriuresis, body weight, and natri-uretic peptide levels [75]. There is no plannedanalysis of either chloride or bicarbonatechanges but the data will give an insight intothe usefulness of ACZ as a treatment for patientswith HF.

FUTURE PERSPECTIVE: ISPREVENTION BETTER THAN CURE?

Amongst patients admitted with HF, those withhypochloraemia that resolves by the time ofdischarge have a similar post-discharge prog-nosis to those with normal chloride concentra-tions throughout admission [5]. Conversely,incident hypochloraemia during admission isassociated with an increased risk of adverseoutcome post-discharge [5]. If hypochloraemiaresults from the inevitable combination of sev-ere HF and high-dose loop diuretics, it may bethat prevention of hypochloraemia, rather thanthe correction of an existing abnormality, mayhave the greater effect on outcome. Whetheracetazolamide might be best employed as apreventative measure is unknown, but shouldbe the focus of future research.

CONCLUSIONS

Hypochloraemia is a common electrolyteabnormality in patients with HF and is animportant marker of poor prognosis. There aremany unknowns as to how hypochloraemiadevelops and whether it has a pathophysiolog-ical effect in patients with HF. If the latter istrue, it may be a therapeutic target. As ever,more work is needed.

ACKNOWLEDGEMENTS

Funding. No funding was received for thisstudy. No Rapid Service Fee was received by thejournal for the publication of this article.

Authorship. All named authors meet theInternational Committee of Medical Journal

Editors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Joseph Cuthbert, Sunil Bhan-dari, and Andrew L. Clark declare that they havenothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analysed during the current study.

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