Journal Of Clinical & Experimental Cardiology

Citation:Kataoka H (2019) Rationale of the “Chloride Theory” as an Explanation for Neurohormonal Activity in Heart Failure Pathophysiology:Literature Review. J Clin Exp Cardiolog 10: 634.Page 3 of 10previous studies deeply examined the association between the serumsodium concentration and neurohormonal systems.Clinical StudiesRenin-angiotensin-aldosterone systemThe RAAS is basically involved in the development and progressionof HF [18-20,35]. Activation of the RAAS ultimately results inincreased afterload and body fluid retention, leading to a vicious cycleof decompensated HF [49-51,54]. Many previous studies concordantlyreported an inverse association between the serum sodiumconcentration and plasma renin activity in populations of HF patientswith various disease severities [51,55-58].Figure 3: Interactions between changes in RAAS activity (greenarrows), plasma volume (blue arrows), and hemodynamics (redarrows) according to changes in the serum chloride concentrationin heart failure pathophysiology. ADH: Antidiuretic Hormone; Cl:Chloride; GFR: Glomerular Filtration Rate; Na: Sodium; RAAS:Renin-Angiotensin-Aldosterone System.Therefore, this literature review mainly includes studies of therelation between sodium and neurohormonal activity in various HFstates. Pathophysiologic differences would exist between HF patientsstratified by the dynamics of sodium and chloride [9], but it is likelythat many of the clinical features, although not all, overlap betweeneach type of worsening of HF.Neurohormonal Activity under Worsening of HF/FluidRetentionHypothesis according to the “chloride theory”According to the “ chloride theory ” , worsening HF patientscomprise those with increased vs. non-increased serum chlorideconcentrations from clinical stability to worsening HF [8,9]. Thepathophysiology of the former type of worsening HF patients issummarized on the left side in Figure 1. Hypothetically, the RAAS inthis type of worsening HF might be inhibited or not so augmented dueto: 1) negative tubuloglomerular feedback resulting from an increasedsupply of filtered chloride to the macula densa [3-6], and 2) chloriderelated preservation of arterial filling [3,40-42]. The latter type ofworsening HF (decrease in the serum chloride concentration) is shownon the right side in Figure 1. In this subtype of worsening HF, inaddition to the response to lower blood pressure, the RAAS tends to beover activated due to positive tubuloglomerular feedback resultingfrom a decreased supply of filtered chloride to the macula densa, butthe RAAS activation to increase reabsorption of filtered solutes wouldbe ineffective because the supply of these solutes is reduced in theurinary tubules of HF patients with no increase in the serum chlorideconcentration. It is speculated that a substantial number of the clinicalfeatures of this type of worsening of HF overlaps with those ofadvanced HF patients with hyponatremia [49-53].J Clin Exp Cardiolog, an open access journalISSN: 2155-9880Enhanced RAAS activation is frequently observed in advanced HF[58,59] and hypovolemia [54], but not in mild to moderate HF,perhaps due to maintenance of arterial filling under such situations. Asshown in Table 1, early studies indicated that plasma renin activity wasnot increased [60,61], and the plasma aldosterone concentration wasnot affected [60] or slightly increased [61] in untreated NYHAfunctional class I-III HF patients. A recent study reported that patientswith acute decompensated HF exhibited lower plasma renin activitycompared with stable HF patients [62]. Body fluid retention inducedby a high sodium diet [63,64] or diuretics withdrawal [65] in mild tomoderate HF patients depressed the plasma renin activity. Thus,according to the studies referenced above, a diagram predicting RAASactivation according to the proposed “ chloride theory ” underworsening HF (Figure 1) seems applicable to the real-world clinicalsetting because 1) the inverse relationship between their interaction[55-57] and 2) decreased renin secretion under the situation of plasmavolume expansion [60-65] and its increase under advanced HF statusand hypovolemia [54,58] support the inhibitory (left side in Figure 1)and excitatory effects of serum chloride on RAAS activity (right side inFigure 1) in each type of HF patient under the “chloride theory”.Very recently, an exciting study by Hanberg et al. [47] demonstratedan independent association between the serum chloride concentrationand serum renin levels. This study included 162 chronic HF patientstaking loop diuretics, of whom 111 had hypochloremia (serumchloride 96 mmol/L) and 51 had normochloremia (serumchloride 96 mmol/L). They observed that the total renin level washigher in patients with hypochloremia compared to those withouthypochloremia. Renin levels were negatively correlated with serumchloride (r 0.46; p 0.001) whereas the serum sodium correlationwas less pronounced (r 0.30; p 0.001). In a multivariable modelcontaining both serum chloride and sodium, chloride remainedsignificantly associated with renin levels (β 0.08; p 0.001), whereassodium was no longer associated with the renin level (β 0.02;p 0.49). These observations by Hanberg et al. [47] strongly support the“chloride theory” for HF pathophysiology.Antidiuretic hormone systemAntidiuretic Hormone (ADH) is a potentially importantneurohormone in HF pathophysiology. This hormone (also calledvasopressin) affects free water reabsorption in the kidney, body fluidosmolality, blood volume, vasoconstriction, and myocardial contractilefunction [66]. The dominant stimulus for ADH secretion is serumosmolality, but nonosmotic factors (e.g., cardiac filling pressure,arterial pressure, and the effects of adrenergic stimuli and angiotensinII in the central nervous system) can modulate the osmotic control ofADH to varying degrees [67]. Lanfear et al. [26] reported that anelevated ADH level in patients hospitalized for worsening chronicVolume 10 Issue 6 1000634

Citation:Kataoka H (2019) Rationale of the “Chloride Theory” as an Explanation for Neurohormonal Activity in Heart Failure Pathophysiology:Literature Review. J Clin Exp Cardiolog 10: 634.Page 4 of 10systolic HF was independently associated with the longer termoutcomes, including death.According to the “chloride theory” (Figure 1), it seems that ADHactivity could not be correctly estimated because its secretion might becounter-balanced, consistent with changes in opposing directionsproduced by the serum osmolality or the nonosmotic factor of thebaroreceptor response in each type of worsening HF. Under the HFtype of increased serum chloride concentration from clinical stabilityto worsening HF, ADH secretion might be enhanced by increasedserum osmolality, but depressed by maintenance of arterial filling, andvice versa in the HF type of non-increased serum chlorideconcentration.In the clinical setting, ADH activity is ordinarily elevated in HFpatients compared with normal subjects [59,68,69]. There is somecontroversies, however, regarding the correlation of ADH activity withhemodynamic parameters, such as a positive association with theright-sided cardiac pressure [68], a significant correlation of thebaseline ADH level with increase in systemic vascular resistance aftervasopressin antagonist infusion [70], a weak association with adifference in the left ventricular ejection fraction [59], and an unclearassociation between them [69]. Vasopressin levels widely vary amongindividual patients and across studies, and not all HF patients in thesestudies had elevated levels compared with the normal reference [71].With regard to a correlation of ADH activity with serum sodiumconcentrations, one study did not demonstrate a significant associationbetween them [69] whereas other studies confirmed ADH elevation inHF patients with hyponatremia [70,72,73]. A positive associationbetween ADH level and plasma renin activity was reported byGoldsmith et al. [69], but not by Creager et al. [70]. Furtherinvestigation is needed to clarify the interaction between changes inthe serum chloride concentration and ADH activity, and its relation tothe “chloride theory” under HF pathophysiology.Sympathetic nervous systemThe “chloride theory” does not incorporate the central nervoussystem because a direct interaction cannot be speculated betweenchloride itself and the central nervous system. The sympatheticnervous system, however, would strongly communicate with the RAASand ADH axis under HF pathophysiology [49,74] in parallel with thehemodynamic severity (see under subheading “ Importance ofhemodynamic effects on neurohormonal activity in HF syndrome”).Besides an interaction between the RAAS and ADH axis, increasedactivity of the sympathetic nervous system would reduce venouscompliance, leading to the mobilization of fluid from the venouscapacitance vessels to the effective circulatory volume, culminating inHF pathophysiology [74,75].In brief, activation of the sympathetic nervous system underworsening HF status induces peripheral and renal vasoconstrictionand renin release via stimulation of renal sympathetic nerves,subsequently activating the RAAS from the macula densa andreleasing ADH from the supraoptic and paraventricular nuclei in thehypothalamus [19,20,23,49,74]. Notably, the action of angiotensin II inthe central nervous system may be deeply involved in HFpathophysiology, including promotion of thirst behaviour and saltappetite, regulation of ADH, regulation of sympathetic outflow, andmodulation of the sensitivity of the arterial baroreflex, as well as manyother important cardiovascular reflexes [74,76].J Clin Exp Cardiolog, an open access journalISSN: 2155-9880As shown in Table 1, in the clinical setting, various types ofsympathetic activity occur in response to the mode of body fluidretention in HF patients: noradrenaline is elevated before decongestiontreatment [60,61], but high sodium intake [64] or diuretic withdrawal[65] do not induce sympathetic activation.Neurohormonal Activity under Resolution of HF/FluidRetentionHypothesis according to the “chloride theory”The working hypothesis of the “chloride theory” during worseningHF (Figure 1) could provide rational pharmacologic strategies forinterrupting the vicious cycle of worsening HF. Considering thehypothesis of the “chloride theory” for worsening HF, manipulation ofthe serum chloride concentration would become an attractivetherapeutic target for HF treatment. Based on the “chloride theory” forworsening HF, hypothetical therapeutic effects on plasma volume andthe RAAS and ADH systems through changes in the serum chlorideconcentration are shown in Figure 2. According to this hypothesis,RAAS activity would be enhanced under conventional diuretic therapyfor natriuresis in worsening HF (Figure 2A). For diuretic treatment ofpatients with worsening HF and decreased serum chlorideconcentrations, therapeutic targeting would focus on correcting thehypochloremia, such as preserving and enhancing the concentration ofserum chloride with aquaresis using a V2-receptor antagonist (Figure2B) [77-82] or supplementing the chloride by dietary salt intake and/orinfusing hyperosmotic saline (Figure 2C) [83-85]. Thoughconcomitant restoration of cardiac functional reserve may be required[10,43-45], presumed favourable effects on diuresis would inducechanges in both plasma volume and blood pressure by: 1) promotingcapillary vascular system refilling, thus inhibiting plasma volumecontraction by chloride-induced enhancement of tonicity [86,87], and2) restoring or preserving arterial pressure by chloride-related vascularexpansion [3,40-42]. Importantly, chloride is a key electrolyte for theregulation of renin release in the macula densa, and thereforepreserving the supply of filtered chloride to the macula densa bychloride-regaining therapy described above is expected to reduceRAAS activation via tubuloglomerular feedback [3-6].Clinical StudiesRenin-angiotensin-aldosterone systemAs presented in Table 2, during decongestive treatment for HFpatients with conventional natriuretic diuretics, almost all studiesindicate enhanced plasma renin activity [58,60,88,89], and anincreased [60] or decreased [89] plasma aldosterone concentration.The main mechanism for the RAAS activity under usage ofconventional diuretics is reported to be diuretic-induced plasmavolume contraction [90], but other potential mechanisms of enhancedRAAS activity due to a decreased supply of chloride into macula densacells and consequent positive tubuloglomerular feedback are asfollows: 1) blockade of the entrance of chloride into the macula densacells by loop diuretics [7], and/or 2) decreased chloride supply tomacula densa cells due to hypochloremia, as predicted by the “chloridetheory” [8].Volume 10 Issue 6 1000634

Citation:Kataoka H (2019) Rationale of the “Chloride Theory” as an Explanation for Neurohormonal Activity in Heart Failure Pathophysiology:Literature Review. J Clin Exp Cardiolog 10: 634.Page 5 of 10Neurohormonal findings in HF patientsFirst(Ref. duration)CommentsdesignTwelveNYHA Frusemidefunctional class amiloride dailyBayliss et al. [60] II-III HF patients month)RAASADHBefore treatment:normal; Renin,(1 aldosterone,normalNA51 controls; 60HF patients, G-126 unlike HF,G-2 15 possibleHF, and G-3 19definite HF (48NYHA class I-IIIand 12 NYHARemes et al. [61] class IV patients) Untreated HF statusOthersVascularexpansionmight depress renin levelat the upper end of theBefore treatment:: normal range in patientswith "moderate HF".noradrenaline Renin activity, notdifferentfromcontrols;aldosterone, widerangevariationand G-3 controls NAPlasma renin activitywas not increased in HFpatientsexcept4ANPG-3 G-2 G-1 contr patients. Activation ofols; adrenaline, G-3, RAAS is uncommon inuntreated HF.G-2 controlsDifferent stages ofHF worseningNijst et al. [62]G-I: 72 ADHFwith REF G-II:72 CHF withREF G-III: 53CHF with NEFCross-sectionalfindingsduringdifferent stages of Renin activity; GHFII G-III G-INAThe RAAS system ishighly activated in stableHF with REF and HFNT-proBNP; G-I with NEF patients, anddownregulated in ADHF.G-II G-IIIHigh sodium dietTenNYHAfunctional class-IstableHFpatients and 10normalvolunteersDrug off. One weakof low sodium (100mmol/d), followed by8-day of a highsodium (250 mmol/d) Renin diet (15 days)aldosterone Volpe et al.[63]Twelvecompensated HFpatients (NYHAclass II and III)Damgaard et al. and 12 agematched controls[64]DiureticswithdrawalGalve et al. [65]One weak of a lowsodium (70 mmol/d)and 1 weak of ahigh-sodiumdiet(250 mmol/d). (14days)Angiotensin II 26 stable CHF(NYHA class II) Withdrawalof Renin patientsdiuretics. (3 months) aldosterone tly fall to asimilar extent in bothgroups in response toincreased salt intake.NAANP ; BNP NAHighsodiumintakeimproves phrine ; hormonesHFEpinephrine ; Pro- compensatedpatients.BNP ; Vasopressin Diuretic withdrawal isassociatedwithanANP ; Endothelin-I improvement in some ; Norepinephrine neurohumoralparameters. Table 1: Clinical studies on the relation between heart failure worsening/fluid retention and neurohormonal systems. ADH: AntidiureticHormone; ADHF: Acute Decompensated Heart Filure; ANP: Atrial Natriuretic Peptide; BNP: B-type Natriuretic Peptide; CHF: Chronic HeartFailure; d: day; G: Group; HF: Heart Failure; NYHA: New York Heart Association; NEF: Normal Ejection Fraction; REF: Reduced EjectionFraction.As shown in Table 2, in concordance with the prediction by the“ chloride theory ” , aquaresis using a V2-receptor antagonist fordecongestive therapy in HF does not induce the activity of renin[79-81] and aldosterone [80,81] in the RAAS. Jujo et al. [81] elegantlydemonstrated different clinical effects on RAAS activity betweenfurosemide and a V2-receptor antagonist, the former having astimulating-effect and the latter having a non-stimulating effect onRAAS activity, as demonstrated in experimental studies [91,92].According to the “chloride theory”, RAAS activity is expected to bereduced or not activated by chloride supplementation therapy. Onestudy reported that salt supplementation for refractory HF did notsignificantly activate serum renin and aldosterone levels, even underconcomitant usage of furosemide [84].J Clin Exp Cardiolog, an open access journalISSN: 2155-9880In another recent study, lysine chloride supplementation [47]induced favourable decongestive effects in 10 HF patients, but theserum renin activity was enhanced after this therapy. In this study,however, furosemide was used concomitantly, which favours RAASactivation and may be a confounding factor for the analysis.In summary, a literature review supports the status of the RAASactivity predicted by the “ chloride theory ” during resolution ofworsening HF based on the successful effects of several specificdecongestion therapies in a real clinical setting.Volume 10 Issue 6 1000634

Citation:Kataoka H (2019) Rationale of the “Chloride Theory” as an Explanation for Neurohormonal Activity in Heart Failure Pathophysiology:Literature Review. J Clin Exp Cardiolog 10: 634.Page 6 of 10Neurohormonal findings in HF patientsHF therapyFirst(Ref. #)Loop diureticsTwelveNYHA Furosemidefunctional class II- amiloridedailyBayliss et al. [60] III HF horSubjectsetal. 56subjectsCommentsdesigncontrolRAASADH (1 Renin ;Aldosterone NAOthersNoradrenaline Diureticsinduceclinical improvement,but stimulate theRAAS.Neurohormonalactivation occurs inpatientswithLVdysfunction and noovert HF, which isfurther increased asovert HF ensues anddiuretics are added totherapy.ReferencevalueReferencevalueReference value151LVdysfunctionwithout overt HF13% diuretic useRenin Vasopressin Norepinephrine 81 overt HFRenin withoutdiuretics;Renin withdiureticsVasopressin Norepinephrine 59% diuretic useJohnson et al.[89]34 advanced CHFHemodynamicallyguidedtherapyoffurosemide vasodilators (mean 3.4 Renin ;days)Aldosterone Norepinephrine ; decreasestherapy.Endothelin Mentz et al. [58]427 ADHFRenin withContinuous (High vs. continuous low dose) vs. bolus Renin withfurosemide i.v. (72-96 bolus;Aldosterone NAhours)NAHigh-doseloopdiuretic therapy didnot result in RAASactivationgreaterthan that with lowdose diuretic therapy.240 CHFTolvaptan (n 120) orplacebo (n 120) (1year)Renin Norepinephrine ; BNP Vasopressinlevelsincrease as expectedduringtolvaptanusage.Tolvaptan(15mg Renin ;p.o./d; n 26) (7 days)Aldosterone NABNP Tolvaptanpreventsactivationpatients.Furosemide (40 mg Renin ;i.v./d; n 30) (5 days)Aldosterone NAAs compared withfurosemide, tolvaptanCatecholamine ; induceslessBNP activation of RAAS.Tolvaptan(7.5mg Renin ;p.o./d; n 30) (5 days)Aldosterone Catecholamine ;BNP 1.7% salt infusion (500mL) furosemide(40 Renin ; Vasopressinmg) (n 22) (24 hours)Aldosterone Contrarytoexpectation, plasmarenin activity was notdifferentbetweengroups. The failure ofreninactivitysuppression might bedue to a repulsiveactivation secondaryNorepinephrine ; to favorable diuresisBNP

of arterial circulatory integrity" as the conceptual core of the established "arterial under-filling theory" for HF pathophysiology [18-20] depends deeply on chloride itself because this electrolyte has a central role in maintaining arterial circulatory integrity [3,40-42]. Additionally, interactions between dynamic changes in the serum