Predictors of Myocardial Sodium Accumulation in Chronic Heart Failure

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Dragunov, Anna V. Sokolova, Ekaterina Pershina, Dmitry Shchekochikhin, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7759682/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To identify clinical, laboratory, and imaging predictors of myocardial sodium accumulation in patients with chronic heart failure (CHF). Methods This was a prospective two-center observational study including 15 patients with decompensated CHF on a high-salt diet and 5 healthy volunteers on a low-salt diet. All participants underwent dual-energy computed tomography (DECT) with generation of material decomposition maps (H₂O|Na, H₂O|NaCl) for quantitative assessment of myocardial sodium and NaCl. Estimated plasma osmolarity (eOSM) was calculated as 2[Na⁺] + 2[K⁺] + [Urea] + [Glucose], followed by calculation of osmolyte fractions (PropNa/eOSM, PropUrea/eOSM, etc.). Between-group comparisons, correlation analysis, ROC analysis, and regression modeling (univariate and multivariate models with FDR correction; internal bootstrap validation of the multivariate model) were performed. Results Compared with healthy controls, CHF patients had higher myocardial relative density (HU: 51.69 ± 5.67 vs. 38.65 ± 4.72; p = 0.004) and sodium concentration (72.24 ± 26.38 vs. 25.49 ± 44.04 mmol/kg; p = 0.025). Myocardial sodium concentration correlated inversely with the sodium fraction of eOSM (R=–0.63; p = 0.0027) and positively with the urea fraction (R = 0.66; p = 0.0014). Similar associations were observed for NaCl (R=–0.54; p = 0.015 and R = 0.66; p = 0.0015, respectively). In ROC analysis, sodium and urea fractions of eOSM demonstrated comparable discrimination for low myocardial sodium (AUC = 0.829 and 0.843; Youden thresholds 45.6% and 2.25%, respectively). In a multivariate linear model, myocardial sodium accumulation was associated with reduced sodium (β=–54; p < 0.001) and glucose fractions of eOSM (β=–27; p = 0.014), as well as increased absolute monocyte count (β = 21; p = 0.047). Internal validation confirmed acceptable calibration of the model. Conclusion Patients with decompensated CHF demonstrate increased myocardial sodium content and higher HU on DECT. The plasma osmometric profile—particularly sodium and urea fractions of eOSM—together with inflammatory markers, are associated with myocardial sodium accumulation and may serve as predictors for risk stratification and personalized therapy. Health sciences/Cardiology Health sciences/Diseases Health sciences/Medical research Biological sciences/Physiology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Chronic heart failure (CHF) is one of the most significant conditions in contemporary cardiology, characterized by high prevalence, poor prognosis, and substantial impact on patients’ quality of life. Epidemiological studies report that the prevalence of CHF reaches 1.5–2% in the general population and rises to over 10% among individuals older than 70 years [ 1 ]. Despite advances in therapeutic strategies, including renin–angiotensin–aldosterone system inhibitors, beta-blockers, and SGLT2 inhibitors, the prognosis for patients with CHF remains unfavorable, with persistently high rates of hospitalizations and mortality [ 2 ]. Accordingly, the search for novel pathophysiological markers and predictors of disease progression is of particular importance. The classical understanding of sodium and water balance regulation is based on Guyton’s two-compartment model, in which the kidneys play a central role in maintaining equilibrium between sodium intake, extracellular fluid volume, and blood pressure [ 3 ]. However, accumulating evidence highlights the limitations of this model: many patients exhibit fluid retention and worsening CHF symptoms without a marked increase in intravascular volume, pointing to more complex mechanisms of sodium homeostasis [ 3 ]. In recent decades, a new line of research has emerged, focusing on the concept of osmotically inactive sodium storage in interstitial tissues. Pioneering studies by J. Titze and colleagues demonstrated that sodium can accumulate in the skin, skeletal muscle, and myocardium by binding to negatively charged glycosaminoglycans of the extracellular matrix [ 4 , 5 ]. This form of deposition does not involve equivalent water retention and creates a so-called “third compartment” of sodium distribution. Excess osmotically inactive sodium is thought to promote inflammatory and fibrotic responses, myocardial remodeling, and progression of CHF [ 6 ]. Several studies suggest that myocardial sodium accumulation may correlate with clinical status and serve as a potential predictor of adverse outcomes. Identified risk factors include high salt intake, chronic activation of the renin–angiotensin–aldosterone and sympathetic nervous systems, and long-term use of diuretics that induce fluctuations in water–electrolyte balance [ 7 , 8 ]. Recently, both laboratory and imaging markers have gained attention: NT-proBNP levels, indices of systemic inflammation (neutrophil-to-lymphocyte ratio, systemic inflammation index, hs-CRP, among others), as well as echocardiographic parameters such as left ventricular ejection fraction, left atrial volume index, and indices of diastolic dysfunction [ 9 ]. Nevertheless, comprehensive studies aimed specifically at identifying predictors of myocardial sodium deposition remain scarce. A recent study by Dragunov et al. (2025) demonstrated that in CHF patients receiving intensive loop diuretic therapy in the context of high salt intake (> 10 g/day), a shift in plasma osmolyte distribution occurs: the relative contribution of urea increases while that of sodium decreases in estimated plasma osmolarity [ 10 ]. This phenomenon has been interpreted within the framework of “aestivation,” a metabolic adaptation designed to preserve water and minimize fluid loss under conditions of sodium excess and forced diuresis. Taken together, these observations underscore the need to identify and validate clinical, laboratory, and imaging markers that may predict myocardial sodium deposition in patients with CHF. Such markers would enhance understanding of disease mechanisms and provide a basis for personalized risk stratification and optimization of therapeutic approaches. Objective of the study To identify clinical, laboratory, and imaging predictors of myocardial sodium accumulation in patients with chronic heart failure. Results Clinical characteristics of the study population A total of 20 individuals were included in the study: 15 patients with decompensated chronic heart failure on a high-salt diet (> 6 g/day) and 5 healthy volunteers adhering to a low-salt diet. Clinical characteristics Patients with decompensated CHF were significantly older than healthy controls (68 ± 12 vs. 37 ± 6 years, p < 0.001), with a higher proportion of men (93% vs. 20%, p = 0.005). They also had greater body weight (95 ± 22 vs. 70 ± 12 kg, p = 0.006), body mass index (30.8 ± 6.4 vs. 24.1 ± 1.7 kg/m², p = 0.002), and body surface area (2.10 ± 0.26 vs. 1.81 ± 0.20 m², p = 0.026) (Table 1). Hemodynamic parameters differed between groups: CHF patients exhibited higher systolic blood pressure (144 ± 34 vs. 119 ± 5 mmHg, p = 0.018), pulse pressure (66 ± 20 vs. 43 ± 1 mmHg, p < 0.001), and respiratory rate (20 ± 3 vs. 14 ± 1 breaths/min, p < 0.001). Heart rate tended to be higher in the CHF group (82 ± 20 vs. 70 ± 3 bpm, p = 0.052). Echocardiographic parameters showed marked differences: left ventricular ejection fraction was lower in CHF patients (39 ± 10 vs. 63 ± 2%, p < 0.001); end-diastolic volume was higher (152 ± 45 vs. 118 ± 6 mL, p = 0.011); and end-systolic volume index was elevated (43 ± 21 vs. 25 ± 3 mL/m², p = 0.004). Right ventricular size (3.67 ± 0.57 vs. 2.64 ± 0.11 cm, p < 0.001), left atrial volume (95 ± 20 vs. 46 ± 2 mL, p < 0.001), and indexed LA volume (46 ± 9 vs. 26 ± 3 mL/m², p < 0.001) were all significantly greater in the CHF group. Significant valvular regurgitation was detected in 73% of CHF patients and in none of the controls (p = 0.008). Laboratory parameters also differed: CHF patients had higher leukocyte counts (9.17 ± 2.24 vs. 5.96 ± 0.34 ×10⁹/L, p < 0.001), lower platelet counts (201 ± 85 vs. 255 ± 11 ×10⁹/L, p = 0.029), markedly elevated NT-proBNP (6488 ± 8773 vs. 40 ± 4 pg/mL, p = 0.013), higher urea (8.57 ± 3.02 vs. 4.94 ± 0.24 mmol/L, p < 0.001), creatinine (119 ± 29 vs. 75 ± 5 µmol/L, p < 0.001), glucose (7.95 ± 3.37 vs. 4.90 ± 0.16 mmol/L, p = 0.004), and AST (38 ± 24 vs. 21 ± 2 U/L, p = 0.014). Plasma potassium tended to be lower in CHF patients (4.00 ± 0.46 vs. 4.24 ± 0.11 mmol/L, p = 0.078). Analysis of pharmacotherapy showed that most CHF patients received standard guideline-directed therapy. All patients were treated with loop diuretics, predominantly furosemide (mean daily dose 50 ± 10 mg). Mineralocorticoid receptor antagonists were prescribed at a mean daily dose of 28.6 mg. All patients received SGLT2 inhibitors (dapagliflozin, 10 mg/day). Anticoagulant therapy was administered in 80% of cases, mainly apixaban (10 mg/day) and rivaroxaban (20 mg/day). Antiplatelet therapy (aspirin 100 mg/day or clopidogrel 75 mg/day) was used in 60%. Beta-blockers (metoprolol, bisoprolol, carvedilol) were prescribed to 70% of patients in low starting doses (metoprolol 6.25 mg/day, bisoprolol 2.5–5 mg/day, carvedilol 6.25 mg/day). RAAS inhibitors included valsartan (50% of patients, 20–40 mg/day) and sacubitril/valsartan (ARNI, 30%). ACE inhibitors (captopril, fosinopril) were used less frequently (25% of patients, typically at low doses: captopril 5 mg/day, fosinopril 5 mg/day). Concomitant therapies included statins (atorvastatin 40–80 mg/day, 70% of patients) and proton pump inhibitors (omeprazole or pantoprazole 20 mg/day, 65%). Less common therapies included calcium channel blockers (amlodipine 5 mg/day, diltiazem 120 mg/day; ~20% of patients) and antiarrhythmics (amiodarone, 25%). Myocardial sodium content In the CHF group (n = 151), myocardial tissue density and sodium concentration were significantly higher compared with the control group (n = 51) (Table 2, Fig. 1 ). Mean myocardial density was 51.69 ± 5.67 HU versus 38.65 ± 4.72 HU in controls (p = 0.004). Myocardial sodium concentration was also higher in CHF patients (72.24 ± 26.38 vs. 25.49 ± 44.04 mmol/kg, p = 0.025). Differences in bound sodium forms were less pronounced. NaCl concentration tended to be higher in CHF patients (18.91 ± 6.99 vs. 9.42 ± 11.92 mmol/kg), but did not reach statistical significance (p = 0.20). A similar trend was observed for Na₂CO₃ (156.47 ± 54.09 vs. 68.65 ± 108.60 mmol/kg, p = 0.14). Metabolic signatures of aestivation in CHF Associations between myocardial sodium content and plasma biochemical parameters are shown in Figure Fig. 2 . Myocardial sodium concentration correlated negatively with the sodium fraction of plasma osmolarity (R = − 0.63; p = 0.0027) and positively with the urea fraction (R = 0.66; p = 0.0014). Similar associations were observed for myocardial NaCl: a negative correlation with plasma sodium (R = − 0.54; p = 0.015) and a positive correlation with plasma urea (R = 0.66; p = 0.0015). No significant associations were found with plasma potassium (R = − 0.04; p = 0.85 for Na; R = 0.003; p = 0.99 for NaCl) or glucose (R = 0.28; p = 0.23 for Na; R = 0.13; p = 0.57 for NaCl). These findings are consistent with the concept of osmotically neutral tissue sodium storage mediated by binding to matrix structures, whereby circulating plasma sodium concentration does not accurately reflect tissue sodium burden. Analysis of mean myocardial sodium concentration identified values < 60 mmol/kg as representing low myocardial sodium content, a threshold observed in most control participants. Accordingly, all subjects were stratified into two subgroups: <60 and ≥ 60 mmol/kg. Associations of these categories with parameters of metabolic aestivation were then assessed. When stratified by myocardial sodium content (< 60 vs. ≥60 mmol/kg), significant differences in plasma osmolyte fractions were observed (Figure Fig. 3 ). Participants with low myocardial sodium had a higher plasma sodium fraction ( p = 0.016) and a lower plasma urea fraction ( p = 0.031) compared with those with high myocardial sodium. No significant differences were detected for potassium ( p = 0.85) or glucose ( p = 0.18). These findings indicate that features of metabolic aestivation are closely linked to myocardial sodium accumulation. Univariable analysis Next, we examined associations of myocardial sodium with factors related to fluid retention in decompensated CHF. In univariable analyses, both logistic and linear regression identified several variables significantly associated with myocardial sodium content. The urea fraction of plasma osmolarity on day 1 was a predictor of higher myocardial sodium (OR 4.65; 95% CI 1.35–29.3; p = 0.011; β = 25; 95% CI 11–39; p = 0.001). Conversely, a higher sodium fraction was associated with reduced myocardial sodium (OR 0.12; 95% CI 0.01–0.58; p = 0.006; β = − 32; 95% CI − 51 to − 13; p = 0.003). Myocardial NaCl content also showed a strong positive association with total myocardial sodium (OR 2.01; 95% CI 1.23–5.80; p < 0.001; β = 3.9; 95% CI 3.3–4.4; p < 0.001). In addition, reduced estimated glomerular filtration rate (eGFR) was linked to myocardial sodium accumulation, reaching statistical significance in linear regression (β = − 0.92; 95% CI − 1.6 to − 0.25; p = 0.010), while in logistic regression the association was borderline (OR 0.96; 95% CI 0.90–1.00; p = 0.072). All these associations remained significant after Benjamini–Hochberg FDR correction (Table 3). In contrast, potassium, glucose, NT-proBNP, water deficit, creatinine dynamics, and inferior vena cava collapsibility showed no significant associations with myocardial sodium content. ROC analysis ROC analysis demonstrated that the sodium fraction of plasma osmolarity was characterized by an AUC of 0.823 (95% ДИ 0.612–1), whereas the urea fraction showed an AUC of 0.792 (95% ДИ 0.576–1). These results indicate that both osmolarity fractions possess comparable diagnostic value for predicting low myocardial sodium content. Comparison of predictive performance using DeLong’s test revealed no statistically significant difference ( p = 0.716) between ROC curves for sodium and urea fractions, further supporting the similar diagnostic informativeness of these parameters in identifying low myocardial sodium levels. Multivariable analysis Clinical and laboratory variables potentially associated with myocardial sodium content (age, sex, eGFR, left ventricular ejection fraction, body mass index, absolute monocyte count, and plasma osmolarity fractions of sodium, potassium, glucose, and urea) were included in the multivariable analysis. A full linear regression model was initially constructed, followed by optimization using backward elimination according to the Akaike information criterion (AIC), with stepwise evaluation of each predictor. At each iteration, variables whose exclusion did not reduce model performance were removed. The final model comprised a minimal set of clinically interpretable predictors, which was used for coefficient interpretation and diagnostic evaluation. Model adequacy was further confirmed through standard regression diagnostics, including assessment of linearity, multicollinearity, and the distribution of residuals. Multivariable Analysis During model diagnostics, one observation was identified as an outlier and excluded from the final analysis. According to the results of the multivariable linear regression model (Table 4), myocardial sodium accumulation was significantly associated with the proportion of plasma osmolarity attributable to sodium and glucose, as well as with the absolute monocyte count. A higher proportion of sodium-derived plasma osmolarity (day 1) was strongly associated with lower myocardial sodium content (β = − 54; 95% CI: − 81 to − 28; p < 0.001). Similarly, an increased proportion of glucose-derived osmolarity (day 1) was associated with a reduction in myocardial sodium (β = − 27; 95% CI: − 48 to − 6.2; p = 0.014). In contrast, a higher absolute monocyte count showed a positive association with myocardial sodium accumulation (β = 21; 95% CI: 0.36 to 42; p = 0.047). Residual analysis indicated an overall satisfactory fit of the model. The assessment of linearity demonstrated that the relationship between predicted and observed values was largely preserved, with minor deviations at the lower range of predicted values, potentially reflecting a non-linear component. Multicollinearity diagnostics confirmed the absence of substantial interdependence among predictors, supporting the stability of the model. The distribution of residuals approximated normality, with only a slight elongation of the right tail. Collectively, these results suggest that the model adequately satisfies the assumptions of linear regression and can be reliably used to interpret predictors of myocardial sodium accumulation. Attempts to describe the relationship between myocardial sodium content and the sodium-derived fraction of plasma osmolarity using a non-linear saturation model did not yield biologically interpretable parameters. Model validation To evaluate the robustness and generalizability of the multivariable linear model, we performed internal bootstrap validation (1,000 resamples). This approach allows assessment of potential model overfitting and agreement between predicted and observed outcomes. The apparent coefficient of determination was R² = 0.63, and after optimism correction it remained R² = 0.51, indicating an adequate level of explained variability without evidence of substantial overfitting. The optimism-corrected calibration slope was 0.99, suggesting preservation of the prediction scale, while the calibration intercept (-0.16) was close to zero, reflecting minimal systematic bias. The bootstrap-corrected calibration curve demonstrated good agreement across most of the prediction range, supporting the adequacy of the model for interpreting determinants of myocardial sodium accumulation. Sodium saturation threshold in the myocardium Figure Fig. 4 shows the associations between myocardial sodium content and the proportions of plasma osmolarity attributable to sodium and urea, together with the corresponding ROC analyses. A higher sodium-derived plasma osmolarity fraction was strongly associated with reduced myocardial sodium accumulation (β = − 54; 95% CI: − 81 to − 28; p < 0.001). The optimal Youden threshold was 45.6% (sensitivity 100%, specificity 62%) ( Fig. 4 A,B). In contrast, a higher urea-derived plasma osmolarity fraction was positively associated with myocardial sodium accumulation (β = 21; 95% CI: 0.36–42; p = 0.047), with an optimal threshold of 2.25% (Fig. 4 C,D). ROC analysis yielded AUC values of 0.829 for sodium and 0.843 for urea, indicating comparable diagnostic performance of both markers in predicting low myocardial sodium content. Principal component analysis (PCA) To reduce dimensionality and address multicollinearity among plasma osmolarity fractions (sodium, urea, glucose, potassium) in relation to myocardial sodium content, we performed principal component analysis (PCA). This method transformed correlated variables into independent components explaining the majority of variance, and provided a visual separation of patients according to salt intake levels. As shown in Figure Fig. 5 , the first two components explained 76.5% of the variance (PC1, 51.3%; PC2, 25.2%). The sodium- and urea-derived fractions of plasma osmolarity contributed most strongly to PC1 and PC2, respectively. Myocardial sodium (M_Na) was aligned with the urea vector, consistent with the positive association between myocardial sodium accumulation and plasma urea fraction. The 68% confidence ellipses illustrate clear group separation according to dietary salt intake. Discussion The principal finding of this study is that patients with decompensated chronic heart failure (CHF) demonstrate significantly greater myocardial sodium accumulation compared with healthy controls. Key predictors of this process were features of metabolic aestivation (reduced sodium contribution and increased urea fraction in plasma osmolarity) as well as absolute monocyte count. These findings are consistent with earlier reports in healthy volunteers showing that dietary sodium intake modulates mononuclear phagocyte networks [ 11 , 12 ]. Monocytes, as precursors of macrophages and dendritic cells, play an important role in regulating chronic inflammation, which may underlie the observed association between immune activation, tissue sodium storage, and CHF progression. Our results further support the concept of osmotically neutral sodium storage in interstitial depots, originally described by Titze and colleagues [ 13 , 14 ]. In contrast to the classical “volume–sodium” model, which links sodium excess to water retention and intravascular volume expansion, our data suggest that sodium can accumulate in tissues independently of plasma sodium levels. This aligns with evidence that negatively charged glycosaminoglycans (GAGs) in the extracellular matrix can bind sodium ions and create osmotically inactive depots [ 15 ]. The positive association between myocardial sodium content and changes in the urea and sodium fractions of plasma osmolarity is consistent with the concept of metabolic aestivation, which describes osmolyte redistribution under chronic sodium overload [ 16 , 17 ]. To our knowledge, these findings provide the first evidence that biochemical markers of plasma osmolarity may reflect tissue sodium storage, opening potential avenues for early diagnosis and prognostic stratification in CHF. The additional link with monocyte counts suggests a contribution of inflammatory mechanisms. This interpretation is in line with contemporary evidence showing that inflammatory activation and extracellular matrix remodeling may enhance tissue sodium-binding capacity [ 18 ]. Previous experimental work from our group demonstrated that myocardial Na⁺ accumulates in the extracellular matrix by binding to GAG structures [ 19 ]. Using high-resolution X-ray fluorescence spectroscopy, we showed that chronic high sodium intake markedly increases interstitial sodium content in animal models. We have also demonstrated in patients that dietary sodium intake is associated with features of metabolic aestivation [ 20 ]. Clinically, the present study is the first to link myocardial sodium accumulation assessed by dual-energy CT with biochemical signatures of metabolic aestivation. This approach may serve as a promising tool to study tissue sodium deposition, particularly in the myocardium of CHF patients, and as an accessible surrogate marker of pathological sodium storage. Such insights open perspectives for individualized diuretic and nutritional therapy. Limitations The main limitations of this study are the relatively small sample size and baseline imbalances in age and sex between the CHF and control groups. Another important factor is the influence of ongoing diuretic therapy, which may modify water–electrolyte balance and complicate interpretation of urinary sodium excretion. Future directions include validation in larger cohorts across different CHF phenotypes (HFrEF, HFmrEF, HFpEF), longitudinal assessment of myocardial sodium dynamics during therapy, and detailed investigation of inflammatory and immune mechanisms regulating sodium storage. Development of prognostic models integrating imaging and laboratory data, along with exploration of novel therapeutic strategies to mitigate osmotically neutral sodium accumulation, represents a crucial next step. Materials and methods Study design Design and participants. This was a prospective two-center observational study conducted at N.I. Pirogov City Clinical Hospital No. 1 and City Clinical Hospital No. 4, Moscow Department of Health, from July 2024 to August 2025. At screening, 130 patients hospitalized with clinical manifestations of decompensated chronic heart failure (CHF) were evaluated at Pirogov Hospital No. 1. A total of 15 patients were included in the final analysis (study group). Upon admission, all patients underwent computed tomography (CT) for quantitative assessment of myocardial sodium content during decompensation. Control group. Additionally, 30 healthy volunteers without chronic cardiovascular or systemic diseases were screened; 5 individuals were included in the final analysis. All controls adhered to a low-salt diet (< 6 g/day), confirmed by questionnaire, dietary interview, and urinary sodium concentration. Participant flow. Of the 130 hospitalized patients, exclusions at screening included: significant comorbidities (e.g., history of cancer, active inflammation, end-stage chronic kidney disease, impaired liver function, prior stroke); inability to undergo CT (n = 51); thiazide diuretic use (n = 43); absence of standard quadruple therapy (n = 31). Fifteen patients were ultimately included. Of 30 volunteers, exclusions were: refusal/contraindication to CT (n = 17); nonadherence to a low-salt diet (n = 8). Five volunteers were included in the final analysis. (The CONSORT flow diagram is presented in Figure Fig. 6 .) Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation and conduct of this study. Data availability The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics statement The study was conducted at City Clinical Hospital No. 1 and City Clinical Hospital No. 4 of the Moscow Healthcare Department. Ethical approval was obtained from the Local Ethics Committee of City Clinical Hospital No. 4 (protocol No. 273, December 2023), which served as the primary approving committee for all participating centers. Written informed consent was obtained from all participants. Consent to Participate Written informed consent was obtained from all patients and healthy volunteers prior to enrollment in the study and the performance of all study procedures, including dual-energy CT. Data collection. All participants completed standardized clinical questionnaires, laboratory testing, and imaging assessments. In the CHF group, concurrent pharmacotherapy during decompensation (diuretics, ACE inhibitors/ARBs, β-blockers, mineralocorticoid receptor antagonists, etc.) was additionally documented. Comparative analysis. The primary comparison between groups was myocardial sodium accumulation (primary endpoint), while secondary endpoints included clinical and laboratory indices reflecting cardiovascular function. Ethics. The study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee, and written informed consent was obtained from all participants. Inclusion and Exclusion Criteria Inclusion criteria (CHF group): - Age ≥18 years. - Hospitalization due to clinical manifestations of decompensated CHF. - Confirmed diagnosis of CHF (per clinical guidelines). - Stable background therapy (ACE inhibitors/ARBs, β-blockers) for ≥3 weeks prior to admission. - Signed informed consent for participation and CT examination. Inclusion criteria (Control group): - Age ≥18 years. - No chronic cardiovascular or systemic disease. - Adherence to a low-salt diet (<6 g/day), confirmed by questionnaire, dietary interview, and urinary sodium concentration. - Signed informed consent. Exclusion criteria (Both groups): - Refusal to participate or contraindications to CT. - Inability to undergo CT for technical reasons. - Low adherence, inability to cooperate, or incapacity. - Any severe decompensated somatic disease affecting prognosis (e.g., severe anemia, autoimmune or endocrine disorders). - Alcohol, drug, or medication abuse. Exclusion criteria (CHF group only): - Significant comorbidities: history of cancer, active inflammation, end-stage CKD, impaired liver function, or prior stroke. - Thiazide diuretic use. - Absence of standard quadruple therapy (ACE inhibitors/ARBs, β-blockers, mineralocorticoid receptor antagonists, loop diuretics). Exclusion criteria (Control group only): - Nonadherence to a low-salt diet (<6 g/day). Calculation of plasma osmolarity Plasma osmolarity was calculated according to Equation 1. Subsequently, the proportion of each osmolyte relative to the estimated plasma osmolarity was determined, yielding the following ratios: Prop Na/eOSM , Prop K/eOSM , Prop Urea/eOSM , and Prop Glucose/eOSM . Assessment of salt intake Salt intake was assessed using a dietary questionnaire in which patients recorded their diet for one week, including any two weekdays and one weekend day prior to hospitalization. The electronic questionnaire was hosted at http://www.saltquest.ru/Sodium_project/. The questionnaire incorporated a precompiled database of food products manufactured in the Russian Federation with known sodium content per 100 g of product or dish. Individual items and recipes were grouped into similar product types (e.g., popcorn, potato chips, crackers) and subsequently aggregated into broader categories (e.g., snacks) that formed the basis of the dietary diary. For each diary entry, meal type (breakfast, lunch, dinner), portion size, and additional salting were recorded. The amount of added salt was estimated as 0.1 g per additional salting [21]. Only patients with stable sodium intake were included. Weekly fluctuations of up to ±2 g/day were permitted, provided they did not exceed the following intake categories: (1) 10 g/day of salt. Dual-energy CT protocol Quantification of myocardial sodium and NaCl was performed using dual-energy computed tomography (DECT). Scanning was conducted on a Revolution GSI scanner (GE Healthcare). The technology employs rapid kV switching between 80 and 140 kV with a 0.25 ms interval, enabling near-simultaneous acquisition at two energy levels. Data collection was performed with a GSI detector, ensuring high measurement accuracy within the short switching interval. Data processing was performed on an AW 4.7 workstation (GE Healthcare) using GSI Viewer software. Material decomposition maps were constructed: sodium with water subtraction (H₂O|Na) and NaCl with water subtraction (H₂O|NaCl). From these maps, mean myocardial sodium and NaCl content were determined. Additionally, myocardial attenuation (HU) was measured. Urinary sodium assessment In the CHF group, quantitative assessment of sodium excretion in 24-hour urine was not performed , as all patients were on diuretic therapy at the time of enrollment, making the results unreliable and not reflective of true dietary sodium intake. In the control group (healthy volunteers), 24-hour urinary sodium excretion was measured using standard urine collection followed by ionometry with an ion-selective electrode (ISE). To verify completeness of collection, creatinine concentration was additionally assessed. Results were expressed as daily sodium excretion (mmol/day) and sodium excretion normalized to creatinine (mmol/mmol Cr). Definition of heart failure CHF diagnosis was established in accordance with the National Clinical Guidelines for the Diagnosis and Treatment of Chronic Heart Failure [22]. CHF stage and functional class were determined by two independent experienced cardiologists; in cases of disagreement, the final decision was made by consensus. Left ventricular ejection fraction (LVEF) was assessed by Simpson’s method in apical four- and two-chamber views, and the mean LVEF was reported. Kidney function and CKD verification Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2011 equation [23]. Albuminuria was assessed using dipstick testing, and the albumin-to-creatinine ratio was measured in a morning urine sample. CKD diagnosis was verified in accordance with national recommendations [24], based on the following criteria: presence of any clinical markers of kidney damage confirmed twice (≥3 months apart); reduction in eGFR (<60 mL/min/1.73 m²), albuminuria, or other markers of renal injury confirmed for ≥3 months; sustained eGFR <60 mL/min/1.73 m² regardless of other markers; irreversible structural abnormalities of the kidney confirmed by biopsy or imaging. Sample size calculation To ensure adequate statistical power, an a priori sample size calculation was performed. The assumed effect size was large (Cohen’s d = 0.8), with a significance level of α = 0.05 and a required power of at least 80%. Based on these parameters, the minimum required sample size for a two-sample Student’s t -test was approximately 16 participants per group, allowing detection of clinically meaningful differences in the primary endpoint with high probability. The observed effect size was 1.42 (Cohen’s d ), consistent with a large effect. The mean difference between groups was 46.75 units, with a pooled standard deviation of 32.84. According to the two-sample Student’s t -test assuming equal variances, the result was t (13) = 2.6, p = 0.022. The 95% confidence interval for the mean difference ranged from 7.89 to 85.61 units. Given the actual group sizes (10 and 5 participants, respectively) and α = 0.05, the achieved study power was approximately 67.1%. References Bozkurt, B. et al. Heart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. Journal of Cardiac Failure 29, 1412–1451 (2023). McDonagh, T. A. et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal 44, 3627–3639 (2023). Bagordo, D., Rossi, G. P., Delles, C., Wiig, H. & Rossitto, G. Tangram of Sodium and Fluid Balance. Hypertension (Dallas, Tex.: 1979) 81, 490–500 (2024). Titze, J. A different view on sodium balance. Current Opinion in Nephrology and Hypertension 24, 14–20 (2015). Titze, J. et al. Long-term sodium balance in humans in a terrestrial space station simulation study. American Journal of Kidney Diseases 40, 508–516 (2002). Mutengo, K. H., Ngalamika, O., Kirabo, A. & Masenga, S. K. Salt sensitivity and myocardial fibrosis: Unraveling the silent cardiovascular remodeling. Frontiers in Pharmacology 16, (2025). Patel, Y. & Joseph, J. Sodium Intake and Heart Failure. International Journal of Molecular Sciences 21, 9474 (2020). Dietary Sodium and Cardiovascular Disease Risk. New England Journal of Medicine 375, 2404–2408 (2016). Chrysohoou, C., Konstantinou, K. & Tsioufis, K. The Role of NT-proBNP Levels in the Diagnosis and Treatment of Heart Failure with Preserved Ejection FractionIt Is Not Always a Hide-and-Seek Game. Journal of Cardiovascular Development and Disease 11, 225 (2024). Dragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. & Arutyunov, G. P. The impact of high-salt diet and diuretics on the development of the aestival phenomenon in patients with chronic heart failure. Frontiers in Nutrition 12, 1–14 (2025). Yi, B. et al. Effects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: a longitudinal study. Translational Research: The Journal of Laboratory and Clinical Medicine 166, 103–110 (2015). Dragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. & Arutyunov, G. P. Impact of salt intake on inflammation markers in cardiovascular disease: a retrospective observational case-control study. Kuban Scientific Medical Bulletin 28, (2021). Titze, J. et al. Reduced osmotically inactive na storage capacity and hypertension in the dahl model. American Journal of Physiology-Renal Physiology 283, F134–F141 (2002). Titze, J. Sodium balance is not just a renal affair. Current opinion in nephrology and hypertension 23, 101–105 (2014). Titze, J. et al. Glycosaminoglycan polymerization may enable osmotically inactive na+ storage in the skin. American Journal of Physiology-Heart and Circulatory Physiology 287, H203–H208 (2004). Kovarik, J. J. et al. Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. Acta Physiologica (Oxford, England) 232, e13629 (2021). Wild, J. et al. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. Acta Physiologica 232, e13628 (2021). Schatz, V. et al. Elementary immunology: Na+ as a regulator of immunity. Pediatric Nephrology 32, 201–210 (2017). Artyukov, I. et al. The first observation of osmotically neutral sodium accumulation in the myocardial interstitium. Scientific Reports 11, (2021). Dragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. & Arutyunov, G. P. The impact of high-salt diet and diuretics on the development of the aestival phenomenon in patients with chronic heart failure. Frontiers in Nutrition 12, 1–14 (2025). Dragunov, D. O., Sokolova, A. V. & Arutjunov, G. P. Development and Validation of a Questionnaire to Assess the Level of Salt Intake in the Adult Population of the Russian Federation Using Machine Learning Methods. The Russian Archives of Internal Medicine 14, 284–297 (2024). Russian Society of Cardiology (RSC), (RSC). 2020 clinical practice guidelines for chronic heart failure. Russian Journal of Cardiology 25, 4083 (2020). Levey, A. S. et al. A New Equation to Estimate Glomerular Filtration Rate. Annals of Internal Medicine 150, 604 (2009). Russian Association of Nephrologists. Clinical recommendations. Chronic kidney disease (CKD). Nephrology (Saint-Petersburg) 25, 10–82 (2021). Tables Tables 1 to 4 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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1","display":"","copyAsset":false,"role":"figure","size":66691,"visible":true,"origin":"","legend":"\u003cp\u003eMyocardial sodium content and relative density in patients with decompensated chronic heart failure and healthy volunteers. (A) Myocardial sodium concentration (mmol/kg) was significantly higher in patients with high salt intake (\u0026gt;6 g/day, red) compared with healthy volunteers on a low-salt diet (blue) (p = 0.025). (B) Relative myocardial density (Hounsfield units, HU), assessed by dual-energy CT, was also significantly higher in decompensated patients compared with controls (p = 0.0039). (C) Myocardial sodium content in the bound form (NaCl, mmol/kg) showed only a trend toward elevation in CHF patients, without reaching statistical significance (p = 0.16).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/5bbd8dc769e9a84486ecbc44.png"},{"id":94860642,"identity":"2d05dab9-5815-4119-a16c-e65f160d8be7","added_by":"auto","created_at":"2025-10-31 13:00:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":129686,"visible":true,"origin":"","legend":"\u003cp\u003eAssociations between myocardial sodium (Na and NaCl) and plasma biochemical parameters in patients with different salt intake levels. Scatter plots with linear regression lines (blue for total sodium, red for NaCl) illustrate correlations with plasma sodium, urea, potassium, and glucose fractions. Each point represents an individual: red markers indicate high salt intake, turquoise markers indicate low salt intake.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/34fdc37d056db5ea75bd4075.png"},{"id":94985713,"identity":"58f57593-f475-4034-a329-eb1e3e56c720","added_by":"auto","created_at":"2025-11-03 06:58:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":73848,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of myocardial sodium content (\u0026lt;60 vs. ≥60 mmol/kg) with plasma composition (% sodium, urea, potassium, glucose). Patients with low myocardial sodium (\u0026lt;60) had significantly higher plasma sodium fraction (p = 0.025) and lower urea fraction (p = 0.019) compared with those with high myocardial sodium (\u0026gt;60 mmol/kg). No significant differences were observed for potassium (p = 0.74) or glucose (p = 0.36). Red diamonds indicate means, horizontal lines in boxes indicate medians, and whiskers represent interquartile ranges.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/50e02b9663f3881ec61a6c38.png"},{"id":94985758,"identity":"6d18450e-75ca-4077-98db-bdee536a63f0","added_by":"auto","created_at":"2025-11-03 06:58:51","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":77088,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between myocardial sodium content and the plasma osmolarity fractions attributable to sodium and urea, along with ROC analysis. (A) Linear regression of myocardial sodium against sodium-derived plasma osmolarity; dashed lines indicate the optimal Youden threshold. (B) ROC curve for sodium-derived plasma osmolarity (AUC = 0.829; optimal threshold 45.6; sensitivity 1.0; specificity 0.62). (C) Linear regression of myocardial sodium against urea-derived plasma osmolarity. (D) ROC curve for urea-derived plasma osmolarity (AUC = 0.843; optimal threshold 2.25; sensitivity 0.75; specificity 0.75).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/de81d53471af7c7049f34fa3.png"},{"id":94860645,"identity":"4cac7ff8-4b85-4349-aa4f-1eb4d4b174dc","added_by":"auto","created_at":"2025-10-31 13:00:51","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67547,"visible":true,"origin":"","legend":"\u003cp\u003ePCA biplot of plasma osmolarity fractions and myocardial sodium content. The first two principal components explained 76.5% of total variance (PC1, 51.3%; PC2, 25.2%). Arrows represent variable loadings; ellipses denote 68% confidence regions by diet group. Myocardial sodium (M_Na) was oriented in the same direction as the urea fraction, indicating a positive association.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/e3ae4c67face63c167009cb0.png"},{"id":94860650,"identity":"5e3cbf5a-d75e-4d3f-82c6-4638e729b6ce","added_by":"auto","created_at":"2025-10-31 13:00:51","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":130210,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT diagram of patient selection\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/903360e71676f7ffcf0703c9.png"},{"id":96711136,"identity":"c3fac0e5-643c-45d0-9af9-23d9d506d1f0","added_by":"auto","created_at":"2025-11-25 10:11:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1349561,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/63081cd5-9f9a-44f4-ae02-da7ba2d1d4c0.pdf"},{"id":94860644,"identity":"36cff978-e911-478a-acd1-76b766c4bffb","added_by":"auto","created_at":"2025-10-31 13:00:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24434,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-7759682/v1/ccfb94cae4df9c65d864550b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors of Myocardial Sodium Accumulation in Chronic Heart Failure","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic heart failure (CHF) is one of the most significant conditions in contemporary cardiology, characterized by high prevalence, poor prognosis, and substantial impact on patients\u0026rsquo; quality of life. Epidemiological studies report that the prevalence of CHF reaches 1.5\u0026ndash;2% in the general population and rises to over 10% among individuals older than 70 years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advances in therapeutic strategies, including renin\u0026ndash;angiotensin\u0026ndash;aldosterone system inhibitors, beta-blockers, and SGLT2 inhibitors, the prognosis for patients with CHF remains unfavorable, with persistently high rates of hospitalizations and mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Accordingly, the search for novel pathophysiological markers and predictors of disease progression is of particular importance.\u003c/p\u003e\u003cp\u003eThe classical understanding of sodium and water balance regulation is based on Guyton\u0026rsquo;s two-compartment model, in which the kidneys play a central role in maintaining equilibrium between sodium intake, extracellular fluid volume, and blood pressure [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, accumulating evidence highlights the limitations of this model: many patients exhibit fluid retention and worsening CHF symptoms without a marked increase in intravascular volume, pointing to more complex mechanisms of sodium homeostasis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn recent decades, a new line of research has emerged, focusing on the concept of osmotically inactive sodium storage in interstitial tissues. Pioneering studies by J. Titze and colleagues demonstrated that sodium can accumulate in the skin, skeletal muscle, and myocardium by binding to negatively charged glycosaminoglycans of the extracellular matrix [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This form of deposition does not involve equivalent water retention and creates a so-called \u0026ldquo;third compartment\u0026rdquo; of sodium distribution. Excess osmotically inactive sodium is thought to promote inflammatory and fibrotic responses, myocardial remodeling, and progression of CHF [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral studies suggest that myocardial sodium accumulation may correlate with clinical status and serve as a potential predictor of adverse outcomes. Identified risk factors include high salt intake, chronic activation of the renin\u0026ndash;angiotensin\u0026ndash;aldosterone and sympathetic nervous systems, and long-term use of diuretics that induce fluctuations in water\u0026ndash;electrolyte balance [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recently, both laboratory and imaging markers have gained attention: NT-proBNP levels, indices of systemic inflammation (neutrophil-to-lymphocyte ratio, systemic inflammation index, hs-CRP, among others), as well as echocardiographic parameters such as left ventricular ejection fraction, left atrial volume index, and indices of diastolic dysfunction [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Nevertheless, comprehensive studies aimed specifically at identifying predictors of myocardial sodium deposition remain scarce.\u003c/p\u003e\u003cp\u003eA recent study by Dragunov et al. (2025) demonstrated that in CHF patients receiving intensive loop diuretic therapy in the context of high salt intake (\u0026gt;\u0026thinsp;10 g/day), a shift in plasma osmolyte distribution occurs: the relative contribution of urea increases while that of sodium decreases in estimated plasma osmolarity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This phenomenon has been interpreted within the framework of \u0026ldquo;aestivation,\u0026rdquo; a metabolic adaptation designed to preserve water and minimize fluid loss under conditions of sodium excess and forced diuresis.\u003c/p\u003e\u003cp\u003eTaken together, these observations underscore the need to identify and validate clinical, laboratory, and imaging markers that may predict myocardial sodium deposition in patients with CHF. Such markers would enhance understanding of disease mechanisms and provide a basis for personalized risk stratification and optimization of therapeutic approaches.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eObjective of the study\u003c/strong\u003e\u003cp\u003eTo identify clinical, laboratory, and imaging predictors of myocardial sodium accumulation in patients with chronic heart failure.\u003c/p\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eClinical characteristics of the study population\u003c/h2\u003e\u003cp\u003eA total of 20 individuals were included in the study: 15 patients with decompensated chronic heart failure on a high-salt diet (\u0026gt;\u0026thinsp;6 g/day) and 5 healthy volunteers adhering to a low-salt diet.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eClinical characteristics\u003c/h3\u003e\n\u003cp\u003ePatients with decompensated CHF were significantly older than healthy controls (68\u0026thinsp;\u0026plusmn;\u0026thinsp;12 vs. 37\u0026thinsp;\u0026plusmn;\u0026thinsp;6 years, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with a higher proportion of men (93% vs. 20%, p\u0026thinsp;=\u0026thinsp;0.005). They also had greater body weight (95\u0026thinsp;\u0026plusmn;\u0026thinsp;22 vs. 70\u0026thinsp;\u0026plusmn;\u0026thinsp;12 kg, p\u0026thinsp;=\u0026thinsp;0.006), body mass index (30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4 vs. 24.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 kg/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.002), and body surface area (2.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26 vs. 1.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20 m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.026) (Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eHemodynamic parameters differed between groups: CHF patients exhibited higher systolic blood pressure (144\u0026thinsp;\u0026plusmn;\u0026thinsp;34 vs. 119\u0026thinsp;\u0026plusmn;\u0026thinsp;5 mmHg, p\u0026thinsp;=\u0026thinsp;0.018), pulse pressure (66\u0026thinsp;\u0026plusmn;\u0026thinsp;20 vs. 43\u0026thinsp;\u0026plusmn;\u0026thinsp;1 mmHg, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and respiratory rate (20\u0026thinsp;\u0026plusmn;\u0026thinsp;3 vs. 14\u0026thinsp;\u0026plusmn;\u0026thinsp;1 breaths/min, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Heart rate tended to be higher in the CHF group (82\u0026thinsp;\u0026plusmn;\u0026thinsp;20 vs. 70\u0026thinsp;\u0026plusmn;\u0026thinsp;3 bpm, p\u0026thinsp;=\u0026thinsp;0.052).\u003c/p\u003e\u003cp\u003eEchocardiographic parameters showed marked differences: left ventricular ejection fraction was lower in CHF patients (39\u0026thinsp;\u0026plusmn;\u0026thinsp;10 vs. 63\u0026thinsp;\u0026plusmn;\u0026thinsp;2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001); end-diastolic volume was higher (152\u0026thinsp;\u0026plusmn;\u0026thinsp;45 vs. 118\u0026thinsp;\u0026plusmn;\u0026thinsp;6 mL, p\u0026thinsp;=\u0026thinsp;0.011); and end-systolic volume index was elevated (43\u0026thinsp;\u0026plusmn;\u0026thinsp;21 vs. 25\u0026thinsp;\u0026plusmn;\u0026thinsp;3 mL/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.004). Right ventricular size (3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57 vs. 2.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 cm, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), left atrial volume (95\u0026thinsp;\u0026plusmn;\u0026thinsp;20 vs. 46\u0026thinsp;\u0026plusmn;\u0026thinsp;2 mL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and indexed LA volume (46\u0026thinsp;\u0026plusmn;\u0026thinsp;9 vs. 26\u0026thinsp;\u0026plusmn;\u0026thinsp;3 mL/m\u0026sup2;, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were all significantly greater in the CHF group. Significant valvular regurgitation was detected in 73% of CHF patients and in none of the controls (p\u0026thinsp;=\u0026thinsp;0.008).\u003c/p\u003e\u003cp\u003eLaboratory parameters also differed: CHF patients had higher leukocyte counts (9.17\u0026thinsp;\u0026plusmn;\u0026thinsp;2.24 vs. 5.96\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34 \u0026times;10⁹/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lower platelet counts (201\u0026thinsp;\u0026plusmn;\u0026thinsp;85 vs. 255\u0026thinsp;\u0026plusmn;\u0026thinsp;11 \u0026times;10⁹/L, p\u0026thinsp;=\u0026thinsp;0.029), markedly elevated NT-proBNP (6488\u0026thinsp;\u0026plusmn;\u0026thinsp;8773 vs. 40\u0026thinsp;\u0026plusmn;\u0026thinsp;4 pg/mL, p\u0026thinsp;=\u0026thinsp;0.013), higher urea (8.57\u0026thinsp;\u0026plusmn;\u0026thinsp;3.02 vs. 4.94\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24 mmol/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), creatinine (119\u0026thinsp;\u0026plusmn;\u0026thinsp;29 vs. 75\u0026thinsp;\u0026plusmn;\u0026thinsp;5 \u0026micro;mol/L, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), glucose (7.95\u0026thinsp;\u0026plusmn;\u0026thinsp;3.37 vs. 4.90\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16 mmol/L, p\u0026thinsp;=\u0026thinsp;0.004), and AST (38\u0026thinsp;\u0026plusmn;\u0026thinsp;24 vs. 21\u0026thinsp;\u0026plusmn;\u0026thinsp;2 U/L, p\u0026thinsp;=\u0026thinsp;0.014). Plasma potassium tended to be lower in CHF patients (4.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46 vs. 4.24\u0026thinsp;\u0026plusmn;\u0026thinsp;0.11 mmol/L, p\u0026thinsp;=\u0026thinsp;0.078).\u003c/p\u003e\u003cp\u003e Analysis of pharmacotherapy showed that most CHF patients received standard guideline-directed therapy. All patients were treated with loop diuretics, predominantly furosemide (mean daily dose 50\u0026thinsp;\u0026plusmn;\u0026thinsp;10 mg). Mineralocorticoid receptor antagonists were prescribed at a mean daily dose of 28.6 mg. All patients received SGLT2 inhibitors (dapagliflozin, 10 mg/day). Anticoagulant therapy was administered in 80% of cases, mainly apixaban (10 mg/day) and rivaroxaban (20 mg/day). Antiplatelet therapy (aspirin 100 mg/day or clopidogrel 75 mg/day) was used in 60%. Beta-blockers (metoprolol, bisoprolol, carvedilol) were prescribed to 70% of patients in low starting doses (metoprolol 6.25 mg/day, bisoprolol 2.5\u0026ndash;5 mg/day, carvedilol 6.25 mg/day). RAAS inhibitors included valsartan (50% of patients, 20\u0026ndash;40 mg/day) and sacubitril/valsartan (ARNI, 30%). ACE inhibitors (captopril, fosinopril) were used less frequently (25% of patients, typically at low doses: captopril 5 mg/day, fosinopril 5 mg/day). Concomitant therapies included statins (atorvastatin 40\u0026ndash;80 mg/day, 70% of patients) and proton pump inhibitors (omeprazole or pantoprazole 20 mg/day, 65%). Less common therapies included calcium channel blockers (amlodipine 5 mg/day, diltiazem 120 mg/day; ~20% of patients) and antiarrhythmics (amiodarone, 25%).\u003c/p\u003e\n\u003ch3\u003eMyocardial sodium content\u003c/h3\u003e\n\u003cp\u003eIn the CHF group (n\u0026thinsp;=\u0026thinsp;151), myocardial tissue density and sodium concentration were significantly higher compared with the control group (n\u0026thinsp;=\u0026thinsp;51) (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Mean myocardial density was 51.69\u0026thinsp;\u0026plusmn;\u0026thinsp;5.67 HU versus 38.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.72 HU in controls (p\u0026thinsp;=\u0026thinsp;0.004). Myocardial sodium concentration was also higher in CHF patients (72.24\u0026thinsp;\u0026plusmn;\u0026thinsp;26.38 vs. 25.49\u0026thinsp;\u0026plusmn;\u0026thinsp;44.04 mmol/kg, p\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e\u003cp\u003eDifferences in bound sodium forms were less pronounced. NaCl concentration tended to be higher in CHF patients (18.91\u0026thinsp;\u0026plusmn;\u0026thinsp;6.99 vs. 9.42\u0026thinsp;\u0026plusmn;\u0026thinsp;11.92 mmol/kg), but did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.20). A similar trend was observed for Na₂CO₃ (156.47\u0026thinsp;\u0026plusmn;\u0026thinsp;54.09 vs. 68.65\u0026thinsp;\u0026plusmn;\u0026thinsp;108.60 mmol/kg, p\u0026thinsp;=\u0026thinsp;0.14).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eMetabolic signatures of aestivation in CHF\u003c/h3\u003e\n\u003cp\u003eAssociations between myocardial sodium content and plasma biochemical parameters are shown in Figure Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Myocardial sodium concentration correlated negatively with the sodium fraction of plasma osmolarity (R = \u0026minus;\u0026thinsp;0.63; p\u0026thinsp;=\u0026thinsp;0.0027) and positively with the urea fraction (R\u0026thinsp;=\u0026thinsp;0.66; p\u0026thinsp;=\u0026thinsp;0.0014). Similar associations were observed for myocardial NaCl: a negative correlation with plasma sodium (R = \u0026minus;\u0026thinsp;0.54; p\u0026thinsp;=\u0026thinsp;0.015) and a positive correlation with plasma urea (R\u0026thinsp;=\u0026thinsp;0.66; p\u0026thinsp;=\u0026thinsp;0.0015). No significant associations were found with plasma potassium (R = \u0026minus;\u0026thinsp;0.04; p\u0026thinsp;=\u0026thinsp;0.85 for Na; R\u0026thinsp;=\u0026thinsp;0.003; p\u0026thinsp;=\u0026thinsp;0.99 for NaCl) or glucose (R\u0026thinsp;=\u0026thinsp;0.28; p\u0026thinsp;=\u0026thinsp;0.23 for Na; R\u0026thinsp;=\u0026thinsp;0.13; p\u0026thinsp;=\u0026thinsp;0.57 for NaCl). These findings are consistent with the concept of osmotically neutral tissue sodium storage mediated by binding to matrix structures, whereby circulating plasma sodium concentration does not accurately reflect tissue sodium burden.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAnalysis of mean myocardial sodium concentration identified values\u0026thinsp;\u0026lt;\u0026thinsp;60 mmol/kg as representing low myocardial sodium content, a threshold observed in most control participants. Accordingly, all subjects were stratified into two subgroups: \u0026lt;60 and \u0026ge;\u0026thinsp;60 mmol/kg. Associations of these categories with parameters of metabolic aestivation were then assessed.\u003c/p\u003e\u003cp\u003eWhen stratified by myocardial sodium content (\u0026lt;\u0026thinsp;60 vs. \u0026ge;60 mmol/kg), significant differences in plasma osmolyte fractions were observed (Figure Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Participants with low myocardial sodium had a higher plasma sodium fraction (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and a lower plasma urea fraction (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.031) compared with those with high myocardial sodium. No significant differences were detected for potassium (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.85) or glucose (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.18). These findings indicate that features of metabolic aestivation are closely linked to myocardial sodium accumulation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eUnivariable analysis\u003c/h3\u003e\n\u003cp\u003eNext, we examined associations of myocardial sodium with factors related to fluid retention in decompensated CHF. In univariable analyses, both logistic and linear regression identified several variables significantly associated with myocardial sodium content.\u003c/p\u003e\u003cp\u003eThe urea fraction of plasma osmolarity on day 1 was a predictor of higher myocardial sodium (OR 4.65; 95% CI 1.35\u0026ndash;29.3; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011; β\u0026thinsp;=\u0026thinsp;25; 95% CI 11\u0026ndash;39; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Conversely, a higher sodium fraction was associated with reduced myocardial sodium (OR 0.12; 95% CI 0.01\u0026ndash;0.58; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006; β = \u0026minus;\u0026thinsp;32; 95% CI \u0026minus;\u0026thinsp;51 to \u0026minus;\u0026thinsp;13; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). Myocardial NaCl content also showed a strong positive association with total myocardial sodium (OR 2.01; 95% CI 1.23\u0026ndash;5.80; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; β\u0026thinsp;=\u0026thinsp;3.9; 95% CI 3.3\u0026ndash;4.4; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003eIn addition, reduced estimated glomerular filtration rate (eGFR) was linked to myocardial sodium accumulation, reaching statistical significance in linear regression (β = \u0026minus;\u0026thinsp;0.92; 95% CI \u0026minus;\u0026thinsp;1.6 to \u0026minus;\u0026thinsp;0.25; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010), while in logistic regression the association was borderline (OR 0.96; 95% CI 0.90\u0026ndash;1.00; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.072). All these associations remained significant after Benjamini\u0026ndash;Hochberg FDR correction (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eIn contrast, potassium, glucose, NT-proBNP, water deficit, creatinine dynamics, and inferior vena cava collapsibility showed no significant associations with myocardial sodium content.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eROC analysis\u003c/h2\u003e\u003cp\u003eROC analysis demonstrated that the sodium fraction of plasma osmolarity was characterized by an AUC of 0.823 (95% ДИ 0.612\u0026ndash;1), whereas the urea fraction showed an AUC of 0.792 (95% ДИ 0.576\u0026ndash;1). These results indicate that both osmolarity fractions possess comparable diagnostic value for predicting low myocardial sodium content. Comparison of predictive performance using DeLong\u0026rsquo;s test revealed no statistically significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.716) between ROC curves for sodium and urea fractions, further supporting the similar diagnostic informativeness of these parameters in identifying low myocardial sodium levels.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMultivariable analysis\u003c/h3\u003e\n\u003cp\u003eClinical and laboratory variables potentially associated with myocardial sodium content (age, sex, eGFR, left ventricular ejection fraction, body mass index, absolute monocyte count, and plasma osmolarity fractions of sodium, potassium, glucose, and urea) were included in the multivariable analysis. A full linear regression model was initially constructed, followed by optimization using backward elimination according to the Akaike information criterion (AIC), with stepwise evaluation of each predictor. At each iteration, variables whose exclusion did not reduce model performance were removed.\u003c/p\u003e\u003cp\u003eThe final model comprised a minimal set of clinically interpretable predictors, which was used for coefficient interpretation and diagnostic evaluation. Model adequacy was further confirmed through standard regression diagnostics, including assessment of linearity, multicollinearity, and the distribution of residuals.\u003c/p\u003e\u003cp\u003eMultivariable Analysis\u003c/p\u003e\u003cp\u003eDuring model diagnostics, one observation was identified as an outlier and excluded from the final analysis. According to the results of the multivariable linear regression model (Table\u0026nbsp;4), myocardial sodium accumulation was significantly associated with the proportion of plasma osmolarity attributable to sodium and glucose, as well as with the absolute monocyte count. A higher proportion of sodium-derived plasma osmolarity (day 1) was strongly associated with lower myocardial sodium content (β = \u0026minus;\u0026thinsp;54; 95% CI: \u0026minus;\u0026thinsp;81 to \u0026minus;\u0026thinsp;28; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, an increased proportion of glucose-derived osmolarity (day 1) was associated with a reduction in myocardial sodium (β = \u0026minus;\u0026thinsp;27; 95% CI: \u0026minus;\u0026thinsp;48 to \u0026minus;\u0026thinsp;6.2; p\u0026thinsp;=\u0026thinsp;0.014). In contrast, a higher absolute monocyte count showed a positive association with myocardial sodium accumulation (β\u0026thinsp;=\u0026thinsp;21; 95% CI: 0.36 to 42; p\u0026thinsp;=\u0026thinsp;0.047).\u003c/p\u003e\u003cp\u003eResidual analysis indicated an overall satisfactory fit of the model. The assessment of linearity demonstrated that the relationship between predicted and observed values was largely preserved, with minor deviations at the lower range of predicted values, potentially reflecting a non-linear component. Multicollinearity diagnostics confirmed the absence of substantial interdependence among predictors, supporting the stability of the model. The distribution of residuals approximated normality, with only a slight elongation of the right tail. Collectively, these results suggest that the model adequately satisfies the assumptions of linear regression and can be reliably used to interpret predictors of myocardial sodium accumulation.\u003c/p\u003e\u003cp\u003eAttempts to describe the relationship between myocardial sodium content and the sodium-derived fraction of plasma osmolarity using a non-linear saturation model did not yield biologically interpretable parameters.\u003c/p\u003e\n\u003ch3\u003eModel validation\u003c/h3\u003e\n\u003cp\u003eTo evaluate the robustness and generalizability of the multivariable linear model, we performed internal bootstrap validation (1,000 resamples). This approach allows assessment of potential model overfitting and agreement between predicted and observed outcomes. The apparent coefficient of determination was R\u0026sup2; = 0.63, and after optimism correction it remained R\u0026sup2; = 0.51, indicating an adequate level of explained variability without evidence of substantial overfitting. The optimism-corrected calibration slope was 0.99, suggesting preservation of the prediction scale, while the calibration intercept (-0.16) was close to zero, reflecting minimal systematic bias. The bootstrap-corrected calibration curve demonstrated good agreement across most of the prediction range, supporting the adequacy of the model for interpreting determinants of myocardial sodium accumulation.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSodium saturation threshold in the myocardium\u003c/h2\u003e\u003cp\u003eFigure Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the associations between myocardial sodium content and the proportions of plasma osmolarity attributable to sodium and urea, together with the corresponding ROC analyses. A higher sodium-derived plasma osmolarity fraction was strongly associated with reduced myocardial sodium accumulation (β = \u0026minus;\u0026thinsp;54; 95% CI: \u0026minus;\u0026thinsp;81 to \u0026minus;\u0026thinsp;28; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The optimal Youden threshold was 45.6% (sensitivity 100%, specificity 62%) ( Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA,B). In contrast, a higher urea-derived plasma osmolarity fraction was positively associated with myocardial sodium accumulation (β\u0026thinsp;=\u0026thinsp;21; 95% CI: 0.36\u0026ndash;42; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047), with an optimal threshold of 2.25% (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC,D). ROC analysis yielded AUC values of 0.829 for sodium and 0.843 for urea, indicating comparable diagnostic performance of both markers in predicting low myocardial sodium content.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePrincipal component analysis (PCA)\u003c/h2\u003e\u003cp\u003eTo reduce dimensionality and address multicollinearity among plasma osmolarity fractions (sodium, urea, glucose, potassium) in relation to myocardial sodium content, we performed principal component analysis (PCA). This method transformed correlated variables into independent components explaining the majority of variance, and provided a visual separation of patients according to salt intake levels.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAs shown in Figure Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the first two components explained 76.5% of the variance (PC1, 51.3%; PC2, 25.2%). The sodium- and urea-derived fractions of plasma osmolarity contributed most strongly to PC1 and PC2, respectively. Myocardial sodium (M_Na) was aligned with the urea vector, consistent with the positive association between myocardial sodium accumulation and plasma urea fraction. The 68% confidence ellipses illustrate clear group separation according to dietary salt intake.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe principal finding of this study is that patients with decompensated chronic heart failure (CHF) demonstrate significantly greater myocardial sodium accumulation compared with healthy controls. Key predictors of this process were features of metabolic aestivation (reduced sodium contribution and increased urea fraction in plasma osmolarity) as well as absolute monocyte count. These findings are consistent with earlier reports in healthy volunteers showing that dietary sodium intake modulates mononuclear phagocyte networks [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Monocytes, as precursors of macrophages and dendritic cells, play an important role in regulating chronic inflammation, which may underlie the observed association between immune activation, tissue sodium storage, and CHF progression.\u003c/p\u003e\u003cp\u003eOur results further support the concept of osmotically neutral sodium storage in interstitial depots, originally described by Titze and colleagues [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In contrast to the classical \u0026ldquo;volume\u0026ndash;sodium\u0026rdquo; model, which links sodium excess to water retention and intravascular volume expansion, our data suggest that sodium can accumulate in tissues independently of plasma sodium levels. This aligns with evidence that negatively charged glycosaminoglycans (GAGs) in the extracellular matrix can bind sodium ions and create osmotically inactive depots [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe positive association between myocardial sodium content and changes in the urea and sodium fractions of plasma osmolarity is consistent with the concept of metabolic aestivation, which describes osmolyte redistribution under chronic sodium overload [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. To our knowledge, these findings provide the first evidence that biochemical markers of plasma osmolarity may reflect tissue sodium storage, opening potential avenues for early diagnosis and prognostic stratification in CHF. The additional link with monocyte counts suggests a contribution of inflammatory mechanisms. This interpretation is in line with contemporary evidence showing that inflammatory activation and extracellular matrix remodeling may enhance tissue sodium-binding capacity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePrevious experimental work from our group demonstrated that myocardial Na⁺ accumulates in the extracellular matrix by binding to GAG structures [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Using high-resolution X-ray fluorescence spectroscopy, we showed that chronic high sodium intake markedly increases interstitial sodium content in animal models. We have also demonstrated in patients that dietary sodium intake is associated with features of metabolic aestivation [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Clinically, the present study is the first to link myocardial sodium accumulation assessed by dual-energy CT with biochemical signatures of metabolic aestivation. This approach may serve as a promising tool to study tissue sodium deposition, particularly in the myocardium of CHF patients, and as an accessible surrogate marker of pathological sodium storage. Such insights open perspectives for individualized diuretic and nutritional therapy.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThe main limitations of this study are the relatively small sample size and baseline imbalances in age and sex between the CHF and control groups. Another important factor is the influence of ongoing diuretic therapy, which may modify water\u0026ndash;electrolyte balance and complicate interpretation of urinary sodium excretion.\u003c/p\u003e\u003cp\u003eFuture directions include validation in larger cohorts across different CHF phenotypes (HFrEF, HFmrEF, HFpEF), longitudinal assessment of myocardial sodium dynamics during therapy, and detailed investigation of inflammatory and immune mechanisms regulating sodium storage. Development of prognostic models integrating imaging and laboratory data, along with exploration of novel therapeutic strategies to mitigate osmotically neutral sodium accumulation, represents a crucial next step.\u003c/p\u003e\u003c/div\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy design\u003c/h2\u003e\n \u003cp\u003e\u003cstrong\u003eDesign and participants.\u003c/strong\u003e This was a prospective two-center observational study conducted at N.I. Pirogov City Clinical Hospital No. 1 and City Clinical Hospital No. 4, Moscow Department of Health, from July 2024 to August 2025. At screening, 130 patients hospitalized with clinical manifestations of decompensated chronic heart failure (CHF) were evaluated at Pirogov Hospital No. 1. A total of 15 patients were included in the final analysis (study group). Upon admission, all patients underwent computed tomography (CT) for quantitative assessment of myocardial sodium content during decompensation.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eControl group.\u003c/strong\u003e Additionally, 30 healthy volunteers without chronic cardiovascular or systemic diseases were screened; 5 individuals were included in the final analysis. All controls adhered to a low-salt diet (\u0026lt;\u0026thinsp;6 g/day), confirmed by questionnaire, dietary interview, and urinary sodium concentration.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eParticipant flow.\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eOf the 130 hospitalized patients, exclusions at screening included: significant comorbidities (e.g., history of cancer, active inflammation, end-stage chronic kidney disease, impaired liver function, prior stroke); inability to undergo CT (n\u0026thinsp;=\u0026thinsp;51); thiazide diuretic use (n\u0026thinsp;=\u0026thinsp;43); absence of standard quadruple therapy (n\u0026thinsp;=\u0026thinsp;31). Fifteen patients were ultimately included.\u003c/p\u003e\n \u003cp\u003eOf 30 volunteers, exclusions were: refusal/contraindication to CT (n\u0026thinsp;=\u0026thinsp;17); nonadherence to a low-salt diet (n\u0026thinsp;=\u0026thinsp;8). Five volunteers were included in the final analysis.\u003c/p\u003e\n \u003cp\u003e(The CONSORT flow diagram is presented in Figure Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e.)\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003ch3\u003eFunding\u003c/h3\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation and conduct of this study.\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;The study was conducted at City Clinical Hospital No. 1 and City Clinical Hospital No. 4 of the Moscow Healthcare Department. Ethical approval was obtained from the Local Ethics Committee of City Clinical Hospital No. 4 (protocol No. 273, December 2023), which served as the primary approving committee for all participating centers. Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Written informed consent was obtained from all patients and healthy volunteers prior to enrollment in the study and the performance of all study procedures, including dual-energy CT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection.\u003c/strong\u003e All participants completed standardized clinical questionnaires, laboratory testing, and imaging assessments. In the CHF group, concurrent pharmacotherapy during decompensation (diuretics, ACE inhibitors/ARBs, \u0026beta;-blockers, mineralocorticoid receptor antagonists, etc.) was additionally documented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparative analysis.\u003c/strong\u003e The primary comparison between groups was myocardial sodium accumulation (primary endpoint), while secondary endpoints included clinical and laboratory indices reflecting cardiovascular function.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics.\u003c/strong\u003e The study was conducted in accordance with the Declaration of Helsinki, approved by the local ethics committee, and written informed consent was obtained from all participants.\u003c/p\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria (CHF group):\u003c/strong\u003e - Age \u0026ge;18 years.\u003cbr\u003e\u0026nbsp;- Hospitalization due to clinical manifestations of decompensated CHF.\u003cbr\u003e\u0026nbsp;- Confirmed diagnosis of CHF (per clinical guidelines).\u003cbr\u003e\u0026nbsp;- Stable background therapy (ACE inhibitors/ARBs, \u0026beta;-blockers) for \u0026ge;3 weeks prior to admission.\u003cbr\u003e\u0026nbsp;- Signed informed consent for participation and CT examination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria (Control group):\u003c/strong\u003e - Age \u0026ge;18 years.\u003cbr\u003e\u0026nbsp;- No chronic cardiovascular or systemic disease.\u003cbr\u003e\u0026nbsp;- Adherence to a low-salt diet (\u0026lt;6 g/day), confirmed by questionnaire, dietary interview, and urinary sodium concentration.\u003cbr\u003e\u0026nbsp;- Signed informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria (Both groups):\u003c/strong\u003e - Refusal to participate or contraindications to CT.\u003cbr\u003e\u0026nbsp;- Inability to undergo CT for technical reasons.\u003cbr\u003e\u0026nbsp;- Low adherence, inability to cooperate, or incapacity.\u003cbr\u003e\u0026nbsp;- Any severe decompensated somatic disease affecting prognosis (e.g., severe anemia, autoimmune or endocrine disorders).\u003cbr\u003e\u0026nbsp;- Alcohol, drug, or medication abuse.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria (CHF group only):\u003c/strong\u003e - Significant comorbidities: history of cancer, active inflammation, end-stage CKD, impaired liver function, or prior stroke.\u003cbr\u003e\u0026nbsp;- Thiazide diuretic use.\u003cbr\u003e\u0026nbsp;- Absence of standard quadruple therapy (ACE inhibitors/ARBs, \u0026beta;-blockers, mineralocorticoid receptor antagonists, loop diuretics).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria (Control group only):\u003c/strong\u003e - Nonadherence to a low-salt diet (\u0026lt;6 g/day).\u003c/p\u003e\n\u003ch3\u003eCalculation of plasma osmolarity\u003c/h3\u003e\n\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\u003cp\u003ePlasma osmolarity was calculated according to Equation 1. Subsequently, the proportion of each osmolyte relative to the estimated plasma osmolarity was determined, yielding the following ratios: Prop\u003csub\u003eNa/eOSM\u003c/sub\u003e, Prop\u003csub\u003eK/eOSM\u003c/sub\u003e, Prop\u003csub\u003eUrea/eOSM\u003c/sub\u003e, and Prop\u003csub\u003eGlucose/eOSM\u003c/sub\u003e.\u003c/p\u003e\n\u003ch3\u003eAssessment of salt intake\u003c/h3\u003e\n\u003cp\u003eSalt intake was assessed using a dietary questionnaire in which patients recorded their diet for one week, including any two weekdays and one weekend day prior to hospitalization. The electronic questionnaire was hosted at http://www.saltquest.ru/Sodium_project/. The questionnaire incorporated a precompiled database of food products manufactured in the Russian Federation with known sodium content per 100 g of product or dish. Individual items and recipes were grouped into similar product types (e.g., popcorn, potato chips, crackers) and subsequently aggregated into broader categories (e.g., snacks) that formed the basis of the dietary diary. For each diary entry, meal type (breakfast, lunch, dinner), portion size, and additional salting were recorded. The amount of added salt was estimated as 0.1 g per additional salting [21].\u003c/p\u003e\n\u003cp\u003eOnly patients with stable sodium intake were included. Weekly fluctuations of up to \u0026plusmn;2 g/day were permitted, provided they did not exceed the following intake categories: (1) \u0026lt;6 g/day, (2) 6\u0026ndash;10 g/day, or (3) \u0026gt;10 g/day of salt.\u003c/p\u003e\n\u003ch3\u003eDual-energy CT protocol\u003c/h3\u003e\n\u003cp\u003eQuantification of myocardial sodium and NaCl was performed using dual-energy computed tomography (DECT). Scanning was conducted on a Revolution GSI scanner (GE Healthcare). The technology employs rapid kV switching between 80 and 140 kV with a 0.25 ms interval, enabling near-simultaneous acquisition at two energy levels. Data collection was performed with a GSI detector, ensuring high measurement accuracy within the short switching interval.\u003c/p\u003e\n\u003cp\u003eData processing was performed on an AW 4.7 workstation (GE Healthcare) using GSI Viewer software. Material decomposition maps were constructed: sodium with water subtraction (H₂O|Na) and NaCl with water subtraction (H₂O|NaCl). From these maps, mean myocardial sodium and NaCl content were determined. Additionally, myocardial attenuation (HU) was measured.\u003c/p\u003e\n\u003ch3\u003eUrinary sodium assessment\u003c/h3\u003e\n\u003cp\u003eIn the CHF group, quantitative assessment of sodium excretion in 24-hour urine was \u003cstrong\u003enot performed\u003c/strong\u003e, as all patients were on diuretic therapy at the time of enrollment, making the results unreliable and not reflective of true dietary sodium intake.\u003c/p\u003e\n\u003cp\u003eIn the control group (healthy volunteers), 24-hour urinary sodium excretion was measured using standard urine collection followed by ionometry with an ion-selective electrode (ISE). To verify completeness of collection, creatinine concentration was additionally assessed.\u003c/p\u003e\n\u003cp\u003eResults were expressed as daily sodium excretion (mmol/day) and sodium excretion normalized to creatinine (mmol/mmol Cr).\u003c/p\u003e\n\u003ch3\u003eDefinition of heart failure\u003c/h3\u003e\n\u003cp\u003eCHF diagnosis was established in accordance with the National Clinical Guidelines for the Diagnosis and Treatment of Chronic Heart Failure [22]. CHF stage and functional class were determined by two independent experienced cardiologists; in cases of disagreement, the final decision was made by consensus. Left ventricular ejection fraction (LVEF) was assessed by Simpson\u0026rsquo;s method in apical four- and two-chamber views, and the mean LVEF was reported.\u003c/p\u003e\n\u003ch3\u003eKidney function and CKD verification\u003c/h3\u003e\n\u003cp\u003eEstimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2011 equation [23]. Albuminuria was assessed using dipstick testing, and the albumin-to-creatinine ratio was measured in a morning urine sample. CKD diagnosis was verified in accordance with national recommendations [24], based on the following criteria:\u003c/p\u003e\n\u003cul class=\"decimal_type\"\u003e\n \u003cli\u003epresence of any clinical markers of kidney damage confirmed twice (\u0026ge;3 months apart);\u003cbr\u003e\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ereduction in eGFR (\u0026lt;60 mL/min/1.73 m\u0026sup2;), albuminuria, or other markers of renal injury confirmed for \u0026ge;3 months;\u003cbr\u003e\u0026nbsp;\u003c/li\u003e\n \u003cli\u003esustained eGFR \u0026lt;60 mL/min/1.73 m\u0026sup2; regardless of other markers;\u003cbr\u003e\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eirreversible structural abnormalities of the kidney confirmed by biopsy or imaging.\u003c/li\u003e\n\u003c/ul\u003e\n\u003ch3\u003eSample size calculation\u003c/h3\u003e\n\u003cp\u003eTo ensure adequate statistical power, an a priori sample size calculation was performed. The assumed effect size was large (Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e = 0.8), with a significance level of \u0026alpha; = 0.05 and a required power of at least 80%. Based on these parameters, the minimum required sample size for a two-sample Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test was approximately 16 participants per group, allowing detection of clinically meaningful differences in the primary endpoint with high probability.\u003c/p\u003e\n\u003cp\u003eThe observed effect size was 1.42 (Cohen\u0026rsquo;s\u0026nbsp;\u003cem\u003ed\u003c/em\u003e), consistent with a large effect.\u003cbr\u003e\u0026nbsp;The mean difference between groups was 46.75 units, with a pooled standard deviation of 32.84.\u003cbr\u003eAccording to the two-sample Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e-test assuming equal variances, the result was \u003cem\u003et\u003c/em\u003e(13) = 2.6,\u0026nbsp;\u003cem\u003ep\u003c/em\u003e = 0.022.\u003cbr\u003e\u0026nbsp;The 95% confidence interval for the mean difference ranged from 7.89 to 85.61 units.\u003cbr\u003e\u0026nbsp;Given the actual group sizes (10 and 5 participants, respectively) and \u0026alpha; = 0.05, the achieved study power was approximately 67.1%.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBozkurt, B. \u003cem\u003eet al.\u003c/em\u003eHeart Failure Epidemiology and Outcomes Statistics: A Report of the Heart Failure Society of America. \u003cem\u003eJournal of Cardiac Failure\u003c/em\u003e\u003cstrong\u003e29,\u003c/strong\u003e 1412\u0026ndash;1451 (2023).\u003c/li\u003e\n\u003cli\u003eMcDonagh, T. A. \u003cem\u003eet al.\u003c/em\u003e2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. \u003cem\u003eEuropean Heart Journal\u003c/em\u003e\u003cstrong\u003e44,\u003c/strong\u003e 3627\u0026ndash;3639 (2023).\u003c/li\u003e\n\u003cli\u003eBagordo, D., Rossi, G. P., Delles, C., Wiig, H. \u0026amp; Rossitto, G. Tangram of Sodium and Fluid Balance. \u003cem\u003eHypertension (Dallas, Tex.: 1979)\u003c/em\u003e\u003cstrong\u003e81,\u003c/strong\u003e 490\u0026ndash;500 (2024).\u003c/li\u003e\n\u003cli\u003eTitze, J. A different view on sodium balance. \u003cem\u003eCurrent Opinion in Nephrology and Hypertension\u003c/em\u003e\u003cstrong\u003e24,\u003c/strong\u003e 14\u0026ndash;20 (2015).\u003c/li\u003e\n\u003cli\u003eTitze, J. \u003cem\u003eet al.\u003c/em\u003eLong-term sodium balance in humans in a terrestrial space station simulation study. \u003cem\u003eAmerican Journal of Kidney Diseases\u003c/em\u003e\u003cstrong\u003e40,\u003c/strong\u003e 508\u0026ndash;516 (2002).\u003c/li\u003e\n\u003cli\u003eMutengo, K. H., Ngalamika, O., Kirabo, A. \u0026amp; Masenga, S. K. Salt sensitivity and myocardial fibrosis: Unraveling the silent cardiovascular remodeling. \u003cem\u003eFrontiers in Pharmacology\u003c/em\u003e\u003cstrong\u003e16,\u003c/strong\u003e (2025).\u003c/li\u003e\n\u003cli\u003ePatel, Y. \u0026amp; Joseph, J. Sodium Intake and Heart Failure. \u003cem\u003eInternational Journal of Molecular Sciences\u003c/em\u003e\u003cstrong\u003e21,\u003c/strong\u003e 9474 (2020).\u003c/li\u003e\n\u003cli\u003eDietary Sodium and Cardiovascular Disease Risk. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e\u003cstrong\u003e375,\u003c/strong\u003e 2404\u0026ndash;2408 (2016).\u003c/li\u003e\n\u003cli\u003eChrysohoou, C., Konstantinou, K. \u0026amp; Tsioufis, K. The Role of NT-proBNP Levels in the Diagnosis and Treatment of Heart Failure with Preserved Ejection FractionIt Is Not Always a Hide-and-Seek Game. \u003cem\u003eJournal of Cardiovascular Development and Disease\u003c/em\u003e\u003cstrong\u003e11,\u003c/strong\u003e 225 (2024).\u003c/li\u003e\n\u003cli\u003eDragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. \u0026amp; Arutyunov, G. P. The impact of high-salt diet and diuretics on the development of the aestival phenomenon in patients with chronic heart failure. \u003cem\u003eFrontiers in Nutrition\u003c/em\u003e\u003cstrong\u003e12,\u003c/strong\u003e 1\u0026ndash;14 (2025).\u003c/li\u003e\n\u003cli\u003eYi, B. \u003cem\u003eet al.\u003c/em\u003eEffects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: a longitudinal study. \u003cem\u003eTranslational Research: The Journal of Laboratory and Clinical Medicine\u003c/em\u003e\u003cstrong\u003e166,\u003c/strong\u003e 103\u0026ndash;110 (2015).\u003c/li\u003e\n\u003cli\u003eDragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. \u0026amp; Arutyunov, G. P. Impact of salt intake on inflammation markers in cardiovascular disease: a retrospective observational case-control study. \u003cem\u003eKuban Scientific Medical Bulletin\u003c/em\u003e\u003cstrong\u003e28,\u003c/strong\u003e (2021).\u003c/li\u003e\n\u003cli\u003eTitze, J. \u003cem\u003eet al.\u003c/em\u003eReduced osmotically inactive na storage capacity and hypertension in the dahl model. \u003cem\u003eAmerican Journal of Physiology-Renal Physiology\u003c/em\u003e\u003cstrong\u003e283,\u003c/strong\u003e F134\u0026ndash;F141 (2002).\u003c/li\u003e\n\u003cli\u003eTitze, J. Sodium balance is not just a renal affair. \u003cem\u003eCurrent opinion in nephrology and hypertension\u003c/em\u003e\u003cstrong\u003e23,\u003c/strong\u003e 101\u0026ndash;105 (2014).\u003c/li\u003e\n\u003cli\u003eTitze, J. \u003cem\u003eet al.\u003c/em\u003eGlycosaminoglycan polymerization may enable osmotically inactive na+ storage in the skin. \u003cem\u003eAmerican Journal of Physiology-Heart and Circulatory Physiology\u003c/em\u003e\u003cstrong\u003e287,\u003c/strong\u003e H203\u0026ndash;H208 (2004).\u003c/li\u003e\n\u003cli\u003eKovarik, J. J. \u003cem\u003eet al.\u003c/em\u003eAdaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. \u003cem\u003eActa Physiologica (Oxford, England)\u003c/em\u003e\u003cstrong\u003e232,\u003c/strong\u003e e13629 (2021).\u003c/li\u003e\n\u003cli\u003eWild, J. \u003cem\u003eet al.\u003c/em\u003eAestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. \u003cem\u003eActa Physiologica\u003c/em\u003e\u003cstrong\u003e232,\u003c/strong\u003e e13628 (2021).\u003c/li\u003e\n\u003cli\u003eSchatz, V. \u003cem\u003eet al.\u003c/em\u003eElementary immunology: Na+ as a regulator of immunity. \u003cem\u003ePediatric Nephrology\u003c/em\u003e\u003cstrong\u003e32,\u003c/strong\u003e 201\u0026ndash;210 (2017).\u003c/li\u003e\n\u003cli\u003eArtyukov, I. \u003cem\u003eet al.\u003c/em\u003eThe first observation of osmotically neutral sodium accumulation in the myocardial interstitium. \u003cem\u003eScientific Reports\u003c/em\u003e\u003cstrong\u003e11,\u003c/strong\u003e (2021).\u003c/li\u003e\n\u003cli\u003eDragunov, D. O., Sokolova, A. V., Mitrokhin, V. M. \u0026amp; Arutyunov, G. P. The impact of high-salt diet and diuretics on the development of the aestival phenomenon in patients with chronic heart failure. \u003cem\u003eFrontiers in Nutrition\u003c/em\u003e\u003cstrong\u003e12,\u003c/strong\u003e 1\u0026ndash;14 (2025).\u003c/li\u003e\n\u003cli\u003eDragunov, D. O., Sokolova, A. V. \u0026amp; Arutjunov, G. P. Development and Validation of a Questionnaire to Assess the Level of Salt Intake in the Adult Population of the Russian Federation Using Machine Learning Methods. \u003cem\u003eThe Russian Archives of Internal Medicine\u003c/em\u003e\u003cstrong\u003e14,\u003c/strong\u003e 284\u0026ndash;297 (2024).\u003c/li\u003e\n\u003cli\u003eRussian Society of Cardiology (RSC), (RSC). 2020 clinical practice guidelines for chronic heart failure. \u003cem\u003eRussian Journal of Cardiology\u003c/em\u003e\u003cstrong\u003e25,\u003c/strong\u003e 4083 (2020).\u003c/li\u003e\n\u003cli\u003eLevey, A. S. \u003cem\u003eet al.\u003c/em\u003eA New Equation to Estimate Glomerular Filtration Rate. \u003cem\u003eAnnals of Internal Medicine\u003c/em\u003e\u003cstrong\u003e150,\u003c/strong\u003e 604 (2009).\u003c/li\u003e\n\u003cli\u003eRussian Association of Nephrologists. Clinical recommendations. Chronic kidney disease (CKD).\u003cem\u003eNephrology (Saint-Petersburg)\u003c/em\u003e\u003cstrong\u003e25,\u003c/strong\u003e 10\u0026ndash;82 (2021).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7759682/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7759682/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo identify clinical, laboratory, and imaging predictors of myocardial sodium accumulation in patients with chronic heart failure (CHF).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis was a prospective two-center observational study including 15 patients with decompensated CHF on a high-salt diet and 5 healthy volunteers on a low-salt diet. All participants underwent dual-energy computed tomography (DECT) with generation of material decomposition maps (H₂O|Na, H₂O|NaCl) for quantitative assessment of myocardial sodium and NaCl. Estimated plasma osmolarity (eOSM) was calculated as 2[Na⁺]\u0026thinsp;+\u0026thinsp;2[K⁺] + [Urea] + [Glucose], followed by calculation of osmolyte fractions (PropNa/eOSM, PropUrea/eOSM, etc.). Between-group comparisons, correlation analysis, ROC analysis, and regression modeling (univariate and multivariate models with FDR correction; internal bootstrap validation of the multivariate model) were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eCompared with healthy controls, CHF patients had higher myocardial relative density (HU: 51.69\u0026thinsp;\u0026plusmn;\u0026thinsp;5.67 vs. 38.65\u0026thinsp;\u0026plusmn;\u0026thinsp;4.72; p\u0026thinsp;=\u0026thinsp;0.004) and sodium concentration (72.24\u0026thinsp;\u0026plusmn;\u0026thinsp;26.38 vs. 25.49\u0026thinsp;\u0026plusmn;\u0026thinsp;44.04 mmol/kg; p\u0026thinsp;=\u0026thinsp;0.025). Myocardial sodium concentration correlated inversely with the sodium fraction of eOSM (R=\u0026ndash;0.63; p\u0026thinsp;=\u0026thinsp;0.0027) and positively with the urea fraction (R\u0026thinsp;=\u0026thinsp;0.66; p\u0026thinsp;=\u0026thinsp;0.0014). Similar associations were observed for NaCl (R=\u0026ndash;0.54; p\u0026thinsp;=\u0026thinsp;0.015 and R\u0026thinsp;=\u0026thinsp;0.66; p\u0026thinsp;=\u0026thinsp;0.0015, respectively). In ROC analysis, sodium and urea fractions of eOSM demonstrated comparable discrimination for low myocardial sodium (AUC\u0026thinsp;=\u0026thinsp;0.829 and 0.843; Youden thresholds 45.6% and 2.25%, respectively). In a multivariate linear model, myocardial sodium accumulation was associated with reduced sodium (β=\u0026ndash;54; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and glucose fractions of eOSM (β=\u0026ndash;27; p\u0026thinsp;=\u0026thinsp;0.014), as well as increased absolute monocyte count (β\u0026thinsp;=\u0026thinsp;21; p\u0026thinsp;=\u0026thinsp;0.047). Internal validation confirmed acceptable calibration of the model.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePatients with decompensated CHF demonstrate increased myocardial sodium content and higher HU on DECT. The plasma osmometric profile\u0026mdash;particularly sodium and urea fractions of eOSM\u0026mdash;together with inflammatory markers, are associated with myocardial sodium accumulation and may serve as predictors for risk stratification and personalized therapy.\u003c/p\u003e","manuscriptTitle":"Predictors of Myocardial Sodium Accumulation in Chronic Heart Failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-31 13:00:46","doi":"10.21203/rs.3.rs-7759682/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e275b1bd-9960-46ba-9bbb-6df3fd968bc1","owner":[],"postedDate":"October 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56629718,"name":"Health sciences/Cardiology"},{"id":56629719,"name":"Health sciences/Diseases"},{"id":56629720,"name":"Health sciences/Medical research"},{"id":56629721,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2025-11-25T08:54:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-31 13:00:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7759682","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7759682","identity":"rs-7759682","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}