Neurohormonal Activation and Renal Chloride Avidity in Acute Heart Failure: Clinical Evidence Supporting the "Chloride Theory".

INTRODUCTION: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl-]) was recently proposed as the "chloride (Cl) theory" for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the "Cl theory." METHODS: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones. RESULTS: In the 29 patients, urinary Cl concentrations ([uCl-]) inversely correlated with log (plasma renin activity [PRA]) (r = -0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = -0.50, p = 0.006). The [sCl-]‒[uCl-] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl-]‒[uCl-] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (-77 to ‒5 mEq/L; n = 14), the absorption group (1-84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. -0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001). CONCLUSION: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the "Cl theory." A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4-6, 2023.

Estimation of Plasma Renin Activity on the Basis of Serum and Urinary Chloride Concentrations versus Sodium Concentrations.

INTRODUCTION: The present study examined the possible estimation of plasma renin activity (PRA) by serum and urinary concentrations of chloride versus sodium in acute and chronic heart failure (HF). METHODS: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) and 26 patients with recovery of HF after decongestive therapy (50% men; 81.2 ± 12 years) were analyzed. Blood and urine samples were obtained immediately before decongestive therapy in acute HF patients. Clinical tests included peripheral blood tests, serum and spot urinary electrolytes, and plasma neurohormones. Sodium- or chloride-related indices included serum ([sNa+] or [sCl-]) and urinary ([uNa+] or [uCl-]) concentrations, their differences, and their ratio. Linear regression analysis was used for correlation coefficients. RESULTS: PRA levels higher than the normal range were detected in only 5 (17%) of 29 patients with acute HF, but in as many as 11 (42%) of 26 patients with chronic HF. In the 29 patients with acute HF, all the chloride- and sodium-related indices except for [sNa+] were correlated with PRA: the [sCl-]/[uCl-] ratio was best correlated with PRA (R2 = 0.84, p < 0.0001) followed by the [sNa+]/[uNa+] ratio (R2 = 0.64, p < 0.0001). In the 26 patients with chronic HF, however, both the [sCl-] (R2 = 0.36, p = 0.001) and [sNa+] (R2 = 0.22, p = 0.016) were only weakly correlated with PRA. CONCLUSION: In acute HF, chloride-related indices derived from serum and urinary concentrations were firmly associated with PRA or better than sodium-related indices. In chronic HF, either chloride- or sodium-related indices were not firmly associated with PRA, presumably due to influence of cardiovascular medication.

Mechanistic insights into chloride-related heart failure progression according to the plasma volume status.

AIMS: Two types of heart failure (HF) progression were recently proposed on the basis of an increased vs. non-increased serum chloride concentration. The applicability of this concept to real-world HF pathophysiology requires further investigation. The present study evaluated the mechanisms of HF progression to a different type according to changes in the estimated plasma volume status (ePVS). METHODS AND RESULTS: Data from 47 patients (32% men; 78.2 ± 9.7 years of age) with stable to worsening HF (37.5 ± 16 days) were analysed. Physical examination, standard blood tests, and b-type natriuretic peptide (BNP) measurements were conducted. The ePVS was calculated as follows: ePVS (dL/g) = [100 - haematocrit (%)]/[haemoglobin (g/dL)]. For the study subjects as a whole (n = 47), changes in the ePVS correlated positively with changes in the serum chloride concentration from stable to worsening HF (r = 0.398, P = 0.0056). When divided into two groups of worsening HF with an increased (n = 31) vs. non-increased serum chloride concentration (n = 16), no significant baseline differences in body weight, serum logBNP, or ePVS were detected between groups. Under worsening HF, the increase in body weight (2.34 ± 1.12 vs. 2.59 ± 1.56 kg, P = 0.57) and logBNP (0.39 ± 0.30 vs. 0.54 ± 0.31 pg/mL, P = 0.13) did not differ between groups, but the increase in the ePVS was smaller in the group with a non-increased serum chloride concentration compared with that with an increased serum chloride concentration (0.292 ± 0.49 vs. 0.653 ± 0.60 dL/g, P = 0.044). An increase in the %change in ePVS ≥ 10% was less common in patients with a non-increased chloride concentration (37% vs. 71%, P = 0.03). Patients with a non-increased serum chloride concentration had more HF signs (3.31 ± 0.79 vs. 2.65 ± 0.71, P = 0.005) and a higher incidence of pulmonary rales (63% vs. 16%, P = 0.0024) than those with an increased serum chloride concentration. CONCLUSIONS: According to the changes in the ePVS, HF progression may result from a difference between two HF types (i.e. increased vs. non-increased serum chloride concentration) in the cardiac reserve in response to a given cardiac burden by modulating plasma volume status via the possible tonicity potential of chloride.

Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication.

Until recently, most studies of heart failure (HF) focused on body fluid dynamics through control of the sodium and water balance in the body. Chloride has remained largely ignored in the medical literature, and in clinical practice, chloride is generally considered as an afterthought to the better-known electrolytes of sodium and potassium. In recent years, however, the important role of chloride in the distribution of body fluid has emerged in the field of HF pathophysiology. Investigation of HF pathophysiology according to the dynamics of serum chloride is rational considering that chloride is an established key electrolyte for tubulo-glomerular feedback in the kidney and a possible regulatory electrolyte for body fluid distribution. The present review provides a historical overview of HF pathophysiology, followed by descriptions of the recent attention to the electrolyte chloride in the cardiovascular field, the known role of chloride in the human body, and recent new findings regarding the role of chloride leading to the proposed 'chloride theory' hypothesis in HF pathophysiology. Next, vascular and organ congestion in HF is discussed, and finally, a new classification and potential therapeutic strategy are proposed according to the 'chloride theory'.

Arginine Vasopressin as an Important Mediator of Fluctuations in the Serum Creatinine Concentration Under Decongestion Treatment in Heart Failure Patients.

Background: The mechanism underlying serum creatinine (SCr) fluctuations in heart failure (HF) patients remains unclear. This study examined mediators of SCr fluctuations under diuretic treatment in HF patients. Methods and Results: Data from 26 HF patients were analyzed. Clinical tests included measurement of peripheral blood, blood urea nitrogen, SCr, serum and urinary electrolytes, B-type natriuretic peptide (BNP), and plasma neurohormones. Among the 26 patients recovering from worsening HF, changes in SCr were negatively correlated with changes in serum Cl, and positively correlated with changes in plasma arginine vasopressin (AVP). According to the median change in SCr, patients were divided into high (range 0.16-0.79 mg/dL; n=13) and low (range -0.35 to 0.14 mg/dL; n=13) change groups. Plasma AVP concentrations after treatment decreased in the low SCr change group and increased in the high SCr change group (-1.28±2.8 vs. 2.14±4.4 pg/mL, respectively; P=0.027). In both groups, there was no change in plasma volume, plasma BNP and norepinephrine concentrations decreased, and plasma renin activity increased after treatment. Multivariate logistic regression analysis showed a tendency towards an independent association between an increase in SCr and an increase or no change in the plasma AVP after decongestion (odds ratio 4.44; 95% confidence interval 0.81-24.3; P=0.086). Conclusions: Plasma AVP appears to be a physiologically important mediator of SCr fluctuations under decongestion treatment in HF patients.

Proposal for New Classification and Practical Use of Diuretics According to Their Effects on the Serum Chloride Concentration: Rationale Based on the "Chloride Theory".

Currently, diuretic therapy for heart failure (HF) pathophysiology is primarily focused on the sodium and water balance. Over the last several years, however, chloride (Cl) has been recognized to have an important role in HF pathophysiology, as both a prognostic marker and a possible central factor regulating the body fluid status. I recently proposed a unifying hypothesis for HF pathophysiology, called the "chloride theory", during HF worsening and recovery, as follows. Chloride is the key electrolyte for regulating both reabsorption of tubular electrolytes and water in the kidney through the renin-angiotensin-aldosterone system and distributing body fluid in each compartment of the body. As changes between the serum Cl concentration and plasma volume are intimately associated with worsening HF and its recovery after decongestive therapy, modulation of the serum Cl concentration by careful selection and combination of various diuretics and their doses could become an attractive therapeutic option for HF. In this review, I will propose a new classification and practical use of diuretics according to their effects on the serum Cl concentration. Diuretic use according to this classification is expected to be a useful strategy for the treatment of patients with HF.

Enhancement of the serum chloride concentration by administration of sodium-glucose cotransporter-2 inhibitor and its mechanisms and clinical significance in type 2 diabetic patients: a pilot study.

BACKGROUND: Chloride is a key electrolyte that regulates the body fluid distribution. Accordingly, manipulating chloride kinetics by selecting a suitable diuretic could be an attractive strategy for correcting body fluid dysregulation. Therefore, this study examined the effects and contributing factors of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) on the serum chloride concentration in type 2 diabetic (T2DM) patients without heart failure (HF). METHODS: This study was a retrospective single-center observational study that enrolled 10 T2DM/non-HF outpatients for whom the SGLT2i empagliflozin (daily oral dose of 10 mg) was prescribed. Among these 10 patients, 6 underwent detailed clinical testing that included hormonal and metabolic blood tests. RESULTS: Empagliflozin treatment for 1-2 months decreased body weight (- 2.69 ± 1.9 kg; p = 0.002) and HbA1c (- 0.88 ± 0.55%; p = 0.0007). The hemoglobin (+ 0.27 ± 0.36 g/dL; p = 0.04) and hematocrit (+ 1.34 ± 1.38%; p = 0.014) values increased, but the serum creatinine concentration remained unchanged. The serum chloride concentration increased from 104 ± 3.23 to 106 ± 2.80 mEq/L (p = 0.004), but the sodium and potassium concentrations did not change. The spot urinary sodium concentration decreased from 159 ± 43 to 98 ± 35 mEq/L (p < 0.02) and the spot urinary chloride tended to decrease (from 162 ± 59 to 104 ± 36 mEq/L, p < 0.08). Both renin and aldosterone tended to be activated (5/6, 83%). The strong organic acid metabolite concentrations of serum acetoacetate (from 42 ± 25 to 100 ± 45 µmol/L, p < 0.02) and total ketone bodies (from 112 ± 64 to 300 ± 177 µmol/L, p < 0.04) increased, but the actual HCO3 - concentration decreased (from 27 ± 2.5 to 24 ± 1.6 mEq/L, p < 0.008). CONCLUSIONS: The present study demonstrated that SGLT2i enhances the serum chloride concentration in T2DM patients and suggests that the effect is mediated by the possible following mechanisms: (1) enhanced reabsorption of urinary chloride by aldosterone activation due to blood pressure lowering and blood vessel contraction effects, (2) reciprocal increase in the serum chloride concentration by reducing the serum HCO3 - concentration via a buffering effect of strong organic acid metabolites, and (3) reduced NaHCO3 reabsorption and concurrently enhanced chloride reabsorption in the urinary tubules by inhibiting Na+-H+ exchanger 3 in the renal proximal tubules. Thus, the diuretic SGLT2i induces excessive extravascular fluid to drain into the vascular space by the enhanced vascular "tonicity" caused by the elevated serum chloride concentration.

Effusion-Serum Chloride Gradient in Heart Failure-Associated Pleural Effusion　- Pathophysiologic Implications.

Background: There is scant clinical data of electrolyte analyses in the pleural fluid under heart failure (HF) pathophysiology. Methods and Results: This study retrospectively analyzed data from 17 consecutive patients who presented with pleural effusion and underwent thoracentesis. A diagnosis of worsening HF was established by clinical criteria (presentation, echocardiography, serum B-type natriuretic peptide, and response to therapy). Samples of non-heparinized pleural fluid and peripheral venous blood, obtained within 2 h of each other, were subjected to biochemical analysis. The source of pleural effusion was determined as transudate or exudate according to Light's criteria. Fifteen patients (53% men; mean [±SD] age 85±11 years) had HF-associated pleural effusion, 10 of whom had transudative effusion and 5 who had exudative effusion (fulfilling only 1 [n=4] or both [n=1] lactate dehydrogenase criteria). The effusion-serum gradient (calculated by subtracting the serum electrolyte concentration from the effusion electrolyte concentration) was significantly higher for chloride (mean [±SD] 7.4±2.6 mEq/L; range 4-14 mEq/L) than sodium (0.9±1.4 mEq/L; ranging from -1 to 4 mEq/L) and potassium (-0.1±0.3 mEq/L; ranging from -0.8 to 0.2 mEq/L; P<0.001 for each). Conclusions: In HF-associated pleural effusion, the chloride concentration is higher in the pleural effusion than the serum, indicating that chloride may have an important role in the formation and retention of body fluid in the pleural space.

Comparison of Changes in Plasma Volume and Renal Function between Acetazolamide and Conventional Diuretics: Understanding the Mechanical Differences according to the "Chloride Theory".

OBJECTIVE: We compared the effects of the chloride-regaining diuretic acetazolamide with those of conventional diuretics on plasma volume, serum electrolytes, and renal function in acutely decompensated heart failure (HF) patients. METHODS: A retrospective analysis was performed on the data of 13 patients treated with acetazolamide (Group A) and 13 patients with conventional diuretics (Group B) matched based on diuresis-induced weight reduction (≥1 kg) during resolution of worsening HF. Changes in plasma volume (Strauss formula), renal function, and serum electrolytes under treatment were determined by peripheral blood tests. RESULTS: Clinical characteristics at baseline were not different between groups A and B. After diuretic therapy, body weight reduction (-2.23 ± 1.11 vs. -2.22 ± 1.06 kg, p = 0.97) and the number of residual HF-related signs (0.31 ± 0.48 vs. 0.23 ± 0.44, p = 0.67) was not different between groups. After each treatment, the serum chloride concen-tration increased in Group A, but decreased in Group B (+5.31 ± 4.91 vs. - 4.54 ± 4.68 mEq/L, p < 0.0001). Plasma volume (0.63 ± 13.1 vs. -12.1 ± 10.5%, p < 0.01) and renal function determined by changes in serum creatinine concentration (0.048 ± 0.12 vs. 0.21 ± 0.24 mg/dL, p < 0.047) were preserved in Group A compared with Group B. CONCLUSIONS: While both groups exhibited equivalent body weight reduction and resolution of HF-related signs after each diuretic treatment, acetazolamide treatment preserved plasma volume and renal function compared to conventional diuretics.

Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the 'chloride theory' for heart failure pathophysiology.

According to the "chloride theory" for heart failure (HF) pathophysiology, manipulation of the serum chloride concentration is an important therapeutic target. This study determined the short- and long-term effects of acetazolamide (Diamox), a potential chloride-regaining diuretic, on peripheral blood, serum electrolytes, and renal function. Effects of low-dose Diamox (250-500 mg/day) were evaluated in 30 HF patients for whom Diamox was added as de-novo/add-on decongestion therapy for acutely worsening HF (n = 18) or as modification therapy for serum hypochloremia in stable HF ( < 100 mEq/L; n = 12). Peripheral hematologic tests were performed at baseline, and at short- ( ≤ 10 days) and long-term ( ~ 60 days) time-points. In all 30 study patients of both groups, the serum chloride concentration increased in the short-term and even further over the long-term. The serum potassium concentration constantly decreased throughout the study period. Both the blood urea nitrogen and serum creatinine concentrations increased in the short-term, but returned to baseline levels over the long-term. Responders to Diamox (n = 13; defined by HF resolution and body weight loss ≥ 1 kg) in the decongestion group exhibited reduced serum b-type natriuretic peptide levels and a markedly increased serum chloride concentration, but the hemoglobin/hematocrit and serum creatinine concentrations did not change after treatment. In conclusion, acetazolamide is a potent candidate "chloride-regaining diuretic" for treating HF patients under the "chloride theory". Its effect to enhance the serum chloride concentration occurred within 10 days and persisted for at least ~ 60 days. Plasma volume and renal function were preserved under adequate diuretic treatment with acetazolamide.

Biochemical Determinants of Changes in Plasma Volume After Decongestion Therapy for Worsening Heart Failure.

BACKGROUND: Optimal vascular volume is required to avoid organ dysfunction during decongestive therapy for worsening heart failure (HF). This study investigated the relation between changes in serum substance(s) and the vascular volume after diuresis in HF patients. METHODS AND RESULTS: Data from 47 patients with HF undergoing conventional diuretic therapy were analyzed. Blood tests included measurements of hemoglobin, hematocrit, and serum albumin/solutes. The relative changes in the plasma volume (%PV) from worsening HF to recovery were determined with the use of the Strauss formula. When divided into 2 groups based on the median %PV, the group with preserved volume (%PV ≥ -10%, range -10% to 21%; n = 23) exhibited a smaller decrease in body weight (-2.50 ± 1.98 vs -4.29 ± 2.60 kg; P = .012) and serum sodium (Na) (-1.57 ± 3.29 vs -4.13 ± 4.96 mEq/L; P = .04) and chloride (Cl) (-2.0 ± 4.06 vs -6.79 ± 5.21 mEq/L; P = .001) concentrations and a smaller increase in albumin (0.20 ± 0.28 vs 0.41 ± 0.24g/dL; P = .009) compared with the group with nonpreserved volume (%PV < -11%, range -33% to -11%; n = 24) after decongestive therapy. Changes in %PV were positively correlated with changes in body weight (r = 0.406; P = .0047) and serum Na (r = 0.433; P = .0024) and Cl (r = 0.408; P = .0044) concentrations and negatively correlated with changes in albumin (r = -0.492; P = .0004), blood urea nitrogen (r = -0.306; P = .037), and creatinine (r = -0.306; P = .036). Multivariate logistic regression analysis demonstrated an independent association between preserved %PV and an increased or preserved serum Cl concentration after decongestive therapy (odds ratio 8.71, 95% confidence interval 1.20-63.0; P = .032). CONCLUSIONS: Positive and independent association exists between change in the vascular volume and the serum Cl concentration under decongestive HF therapy.

Treatment of hypochloremia with acetazolamide in an advanced heart failure patient and importance of monitoring urinary electrolytes.

Chloride was recently recognized to play an important role in the pathophysiology of heart failure (HF). Chloride manipulation, including the use of acetazolamide, may be a requisite therapeutic target in HF treatment. An 87-year-old male patient with advanced HF and hypertrophic cardiomyopathy was admitted to the hospital due to hypochloremia (94 mEq/L) and hyponatremia (134 mEq/L) under diuretic treatment with azosemide, spironolactone, and tolvaptan. On admission, HF-related signs of overhydration were lacking, but B-type natriuretic peptide was moderately elevated. The etiology of the hypochloremia/natremia state was depletion of both electrolytes based on serum analysis and spot urinary concentrations. Immediately after admission, acetazolamide (500 mg/d) was prescribed to correct the hypochloremia in parallel with cessation of the preceding administration of azosemide and spironolactone, and tapering off of the tolvaptan over 7 days. Under treatment, both serum chloride and sodium concentrations recovered to normal (108 mEq/L and 148 mEq/L, respectively), and the serum potassium concentration decreased from 3.9 mEq/L to 2.4 mEq/L. Urinary concentrations of sodium and potassium increased from 18 mEq/L to 31 mEq/L and from 19 mEq/L to 51.5 mEq/L respectively, in concordance with the changes in serum concentrations, but the chloride concentration decreased from 18 mEq/L to 12 mEq/L, opposite the changes in the serum concentration. .

Changes in red blood cell volume during transition of heart failure status: a reflection of cellular hydration status?

This study examined how changes in heart failure (HF) status induce changes in the index of erythrocyte hydration based on mean red blood cell volume (MCV). Data from 47 HF patients (32% men; 78.2 ± 9.7 years) that experienced worsening and recovery of HF were analysed. Blood tests included measurements of MCV, albumin, serum solutes and b-type natriuretic peptide (BNP). Among a total of 47 worsening HF events, changes in MCV were positively correlated with changes in body weight (r = 0.31, p = .034), serum sodium (r = 0.417, p = .0036), and chloride (r = 0.457, p = .0012), and negatively correlated with changes in blood urea nitrogen (r= -0.389, p = .0069) and creatinine (r= -0.494, p = .0004). At recovery from worsening of HF by conventional diuretic therapy, change in MCV was positively correlated with the change in body weight (r = 0.457, p = .0012), serum sodium (r = 0.466, p = .001) and chloride (r = 0.484, p = .0006). Multivariate regression analysis demonstrated an independent association between the increase in serum chloride and MCV from stability to worsening of HF (odds ratio [OR] 6.02, 95% confidence interval [CI] 1.09-33.2, p = .039) and the increase or absence of change in serum chloride concentration and preserved MCV after decongestion (OR 11.5, 95% CI 1.53-85.9, p = .017). In conclusion, this study demonstrates that the changes in MCV under transition in HF status do not reflect a change that occurs in parallel with changes in HF-related markers, such as body weight and serum BNP level, but is independently associated with a change in the serum chloride concentration. Whether changes in MCV actually reflect the bodily cellular hydration status warrants further research.

Dynamic changes in serum chloride concentrations during worsening of heart failure and its recovery following conventional diuretic therapy: A single-center study.

BACKGROUND AND AIMS: Few data are available regarding the dynamic changes in the serum chloride concentrations in heart failure (HF) pathophysiology. The aim of the present study was to investigate changes in the serum chloride concentration under worsening HF and its recovery following conventional diuretic therapy. METHODS: Blood test data, including measurements of serum albumin/solutes and b-type natriuretic peptide, at both worsening and recovery of HF status, were obtained from 47 patients with definite HF. RESULTS: Ambulatory patients with HF were enrolled and followed up at the outpatient clinic of Nishida Hospital between June 2003 and March 2009. From clinically stable to worsening HF, the serum sodium concentration increased from (mean ± SD) 139 ± 4.1 to 141 ± 5.07 mEq/L (P < 0.05, two-way analysis of variance) and the serum chloride concentration increased from 101 ± 5.36 to 104 ± 5.44 mEq/L (P < 0.01) among all patients. After resolution of worsening HF by treatment with conventional diuretics, both the serum sodium concentration and serum chloride concentration decreased significantly to 138 ± 5.12 and 99.5 ± 5.33 mEq/L, respectively (P < 0.0001 for each). The absolute changes in the serum sodium concentration from clinically stable HF to worsening HF appeared to be lesser than those in the serum chloride concentration (1.70 ± 4.34 vs 2.72 ± 6.02 mEq/L, P = 0.079, t test), but this was not statistically significant. Absolute changes in the serum sodium concentration from worsening HF to its recovery following treatment with conventional diuretics were lesser than those in the serum chloride concentration (-2.87 ± 4.38 vs -4.45 ± 5.23 mEq/L, P = 0.0068, t test). CONCLUSION: Under conventional diuretic therapy, greater changes occur in the serum chloride concentration than in the serum sodium concentration under HF state transitions, suggesting that chloride dynamics might contribute more to HF pathophysiology under such therapeutic circumstance.

Vasopressin antagonist-like effect of acetazolamide in a heart failure patient: a case report.

BACKGROUND: Hyponatraemia is easily corrected by treatment with an oral vasopressin antagonist, but these medications are costly and their use at outpatient clinics is restricted by government-managed insurance in Japan. Acetazolamide could be an alternative diuretic to a vasopressin antagonist. CASE SUMMARY: An 83-year-old dyspnoeic male patient was emergently admitted to the hospital due to decompensated heart failure (HF), hypotension, and hyperkalaemia-associated sinus arrest with a junctional escape rhythm. Urgent treatment with a noradrenaline drip infusion and a beta stimulant adhesive skin patch promptly restored sinus rhythm with conducted normal QRS complex, which resolved the hypotension. Blood tests on admission revealed moderately elevated b-type natriuretic peptide (BNP, 576 pg/mL), hyponatraemia (128 mEq/L), hypochloraemia (95 mEq/L), hyperkalaemia (5.7 mEq/L), and preserved renal function (creatinine, 1.0 mg/dL) under no cardiovascular medications. Immediately after admission, low-dose oral acetazolamide (500 mg/day) and polystyrene sulfonate-Ca jelly (Argamate, 25 g/day for 3 days) were prescribed to correct the decompensated HF status and electrolyte disturbance. Three days later, both the serum sodium and chloride concentrations had recovered to normal levels (136 mEq/L and 104 mEq/L, respectively), and the serum potassium concentration had decreased to 4.5 mEq/L. Two weeks later, the patient's HF status became stable and the serum BNP concentration returned to normal (55 pg/mL). DISCUSSION: The present case indicates that the classic diuretic of acetazolamide would have a vasopressin blockade-like effect and could be an alternative diuretic to vasopressin antagonists for some proportion of HF patients with hyponatraemia.

Proposal for heart failure progression based on the 'chloride theory': worsening heart failure with increased vs. non-increased serum chloride concentration.

AIMS: Chloride (Cl) is an established key electrolyte for the activation of the renin-angiotensin-aldosterone system. Recent studies have shown the serum Cl as a key electrolyte for the regulation of body fluid distribution in heart failure (HF) patients. The clinical differences of worsening HF status according to the changes in serum Cl concentration are unclear. METHODS AND RESULTS: Data from 47 chronic HF patients were analysed. Upon worsening HF, each patient exhibited at least two HF-related signs. Blood tests included haemoglobin (Hb), haematocrit (Ht), mean red blood cell volume (MCV), albumin, serum solutes, and b-type natriuretic peptide. The relative change in the plasma volume (%PV) from stable to worsening HF was estimated as follows: 100 × {Hb (stable) × [1 - Ht (worse)]}/{Hb (worse) × [1 - Ht (stable)]} - 100. When patients were divided into two groups based on changes in serum Cl concentration from stable to worsening HF, the pathophysiologic features of the patients with increased Cl (range 1-23 mEq/L; n = 31) included a greater increase in serum sodium (2.94 ± 4.15 vs. -0.69 ± 3.75 mEq/L, P = 0.005), higher vascular expansion (12 ± 11.1 vs. 4.81 ± 7.94%, P = 0.026), a tendency towards a greater MCV (1.23 ± 2.36 vs. -0.06 ± 1.88 fL, P = 0.065), and preserved renal function defined by the absence of an increase of serum creatinine (-0.24 ± 0.39 vs. -0.05 ± 0.12 mg/dL, P = 0.057) compared to patients with non-increased Cl (range -9 to 0 mEq/L; n = 16). Clinically, the increased Cl group had fewer HF signs (2.65 ± 0.71 vs. 3.31 ± 0.79, P = 0.005) although the change in symptoms did not differ between groups (48% vs. 63%, P = 0.54). CONCLUSIONS: The present study suggests a new clinical entity of worsening HF status, that is, HF with increased vs. non-increased serum Cl concentration from clinical stability to worsening HF.

The "chloride theory", a unifying hypothesis for renal handling and body fluid distribution in heart failure pathophysiology.

Body fluid volume regulation is a complex process involving the interaction of various afferent (sensory) and neurohumoral efferent (effector) mechanisms. Historically, most studies focused on the body fluid dynamics in heart failure (HF) status through control of the balance of sodium, potassium, and water in the body, and maintaining arterial circulatory integrity is central to a unifying hypothesis of body fluid regulation in HF pathophysiology. The pathophysiologic background of the biochemical determinants of vascular volume in HF status, however, has not been known. I recently demonstrated that changes in vascular and red blood cell volumes are independently associated with the serum chloride concentration, but not the serum sodium concentration, during worsening HF and its recovery. Based on these observations and the established central role of chloride in the renin-angiotensin-aldosterone system, I propose a unifying hypothesis of the "chloride theory" for HF pathophysiology, which states that changes in the serum chloride concentration are the primary determinant of changes in plasma volume and the renin-angiotensin-aldosterone system under worsening HF and therapeutic resolution of worsening HF.

Vascular expansion during worsening of heart failure: Effects on clinical features and its determinants.

BACKGROUND: This study investigated the relation of the changes in serum solutes/albumin to the level of vascular expansion and clinical features during worsening HF. METHODS: Data from 47 patients with acute on chronic HF worsening were analyzed. Blood tests included hemoglobin, hematocrit, albumin, solutes (Na/K/Cl/BUN/Cr), and b-type natriuretic peptide (BNP). The relative change in the vascular expansion from stable to worsening HF was estimated based on changes in the plasma volume (%PV). RESULTS: When divided into two groups based on the median %PV, the clinical features of the expansion group (11≤%PV [range 11% to 36%]; n=24) included a lower incidence of crackles (13% vs. 52%, p=0.005) and a tendency toward preserved renal function (83% vs. 57%, p=0.06) compared with the non-expansion group (%PV [range -19% to 11%]<11; n=23), whereas the increase in body weight and log BNP did not differ between groups. The expansion group had a greater increase in serum Na (3.58±4.43 vs. -0.11±3.31mEq/L, p=0.0016) and Cl (5.54±6.24 vs. -0.03±4.18mEq/L, p=0.0006), and a decrease in serum albumin (-0.37±0.3 vs. -0.16±0.3g/dL, p=0.04) and creatinine (-0.28±0.39 vs. -0.06±0.22mg/dL, p=0.027) from stability to worsening HF. Multivariate logistic regression analysis revealed an independent association between the increase in %PV and the increase in the serum Cl concentration from stability to worsening HF (odds ratio: 12.2, 95% confidence interval: 1.78-83.8, p=0.011). CONCLUSIONS: Though this study is observational and does not allow for causal inference, it may nonetheless be speculated that a greater accumulation of Cl in the blood vessels acts to increase or maintain intravascular volume, which induces different clinical features of HF.

Strategy for monitoring decompensated heart failure treated by an oral vasopressin antagonist with special reference to the role of serum chloride: A case report.

Compared with conventional diuretic therapy, monitoring decompensated heart failure (HF) under treatment with a vasopressin antagonist is problematic because (1) use of this medication usually allows the patient free water intake to prevent drug-induced hypernatremia and (2) this medication often induces only minimal changes in the hemodynamics and blood concentration. In a 68-year-old female HF patient, use of tolvaptan did not induce much change in the urine output, presumably because of the low water intake due to a lack of thirst, but she did achieve a profound weight loss. Both the changes in chloride and sodium were negatively correlated with changes in the hemoglobin and serum creatinine, and positively correlated with changes in the mean red blood cell volume, but changes in the serum chloride were better correlated with each variable than were changes in the serum sodium. .