Chronotype of Lung Fluid Levels in Patients with Chronic Heart Failure

Background: The variation in lung fluid levels dependent on chronotype in patients with chronic heart failure is unclear. Remote dielectric sensing (ReDSTM) is a novel non-invasive system to quantify the lung fluids, which may correlate to intracardiac filling pressures. We aimed to understand the variation in ReDS measurements by chronotype in patients with chronic heart failure. Methods: The patients who were hospitalized for heart failure exacerbations between November 2021 and March 2022 were prospectively included. ReDS values were measured at clinically stable conditions at the following three time points during the day: 5:00 (morning), 12:00 (noon), and 21:00 (night) (manufacture-recommended reference of ReDS value: between 25% and 35%). Results: Twelve patients were included. The median age was 84 (75, 90) years and four patients (33%) were men. The median plasma B-type natriuretic peptide was 235 (178, 450) pg/mL. The median ReDS value was 38% (23%, 41%) in the morning. The ReDS value decreased significantly at the noon measurement, down to 28% (23%, 29%) (p = 0.005) and again increased significantly at the night measurement, up to 31% (27%, 42%) (p = 0.002). The patients were clinically stabilized during the observational period. Conclusions: the lung fluid level varied considerably in patients with chronic heart failure following clinical stabilization.


Introduction
Variations in human physiology, as exhibited in changes in blood pressure, heart rate, and metabolism, occur over the course of sleep-wake cycles with specific regulation by circadian sleep-wake cycles [1]. Patients with heart failure have unique chronotypes, which may also contribute to changes in day-night vital signs to intracardiac filling pressures, although rigorous data evaluating this question is lacking [2]. For example, the timing of onset of cardiovascular disease, including heart failure, stroke, and acute coronary syndrome, seems to have specific unique trends during the day.
Pulmonary congestion may worsen later in the day, as the effect of neurohormonal agents wane for those who take medical therapy in the morning, whereas pulmonary congestion may be at a nadir mid-day, following the true effect of medical therapy and drops in morning cortisol levels. Of note, changes in lung fluid levels, which often correlate with intracardiac filling pressures and degree of pulmonary congestion [3], by chronotype remains uncertain in patients with chronic heart failure. Thus, we hypothesized that there may be a unique chronotype that explains these potential differences between day and night. Considerable day-night variation data in these important clinical parameters may better inform the clinician on appropriate therapeutic interventions.
The remote dielectric sensing (ReDS TM , Sensible Medical Innovations Ltd., Netanya, Israel) system is a novel electromagnetic-based method to quantify lung fluid levels with robust inter-rater and intra-rater reliability ( Figure 1) [4][5][6]. According to the previous studies, ReDS values had an acceptable correlation with pulmonary capillary wedge 2 of 5 pressure, measured by right heart catheterization and lung fluid amounts, calculated by high-resolution computed tomography in patients with chronic heart failure [7,8].
n. Med. 2022, 11, x FOR PEER REVIEW 2 o studies, ReDS values had an acceptable correlation with pulmonary capillary wedge pre sure, measured by right heart catheterization and lung fluid amounts, calculated by hig resolution computed tomography in patients with chronic heart failure [7,8]. In this prospective study, we measured ReDS values successively during the day patients with chronic heart failure as a primary concern, to better understand the chron type of lung fluid levels.

Participant Selection
The patients who were hospitalized to treat decompensated heart failure were co sidered for inclusion in this prospective study, following clinical stabilization by the i patient treatment team. Following comprehensive informed consents, ReDS values we measured at the following three times during the day: 5:00 (morning), 12:00 (noon), an 21:00 (night). In the morning, the ReDS value was measured under fasting conditions b fore taking any medications, including diuretics.

ReDS System
ReDS values were measured at sitting position, according to the manufacture-recom mended methodology [4]. ReDS employs low-power electromagnetic signals emitted b tween two sensors embedded on the wearable devices ( Figure 1). The manufacture-re ommended reference range is between 25% and 35%.

Statistical Procedures
All continuous data are presented as median with interquartile range. Categoric data are presented as numbers and percentages. The trends of the ReDS values were an lyzed using the Friedman test and post-hoc Wilcoxon signed-rank test. Statistics we performed using SPSS Statistics 23.0 software (IBM Corp, Armonk, NY, USA). Two-sid p values less than 0.05 were considered significant. In this prospective study, we measured ReDS values successively during the day in patients with chronic heart failure as a primary concern, to better understand the chronotype of lung fluid levels.

Participant Selection
The patients who were hospitalized to treat decompensated heart failure were considered for inclusion in this prospective study, following clinical stabilization by the inpatient treatment team. Following comprehensive informed consents, ReDS values were measured at the following three times during the day: 5:00 (morning), 12:00 (noon), and 21:00 (night). In the morning, the ReDS value was measured under fasting conditions before taking any medications, including diuretics.

ReDS System
ReDS values were measured at sitting position, according to the manufacture-recommended methodology [4]. ReDS employs low-power electromagnetic signals emitted between two sensors embedded on the wearable devices ( Figure 1). The manufacture-recommended reference range is between 25% and 35%.

Statistical Procedures
All continuous data are presented as median with interquartile range. Categorical data are presented as numbers and percentages. The trends of the ReDS values were analyzed using the Friedman test and post-hoc Wilcoxon signed-rank test. Statistics were performed using SPSS Statistics 23.0 software (IBM Corp, Armonk, NY, USA). Two-sided p values less than 0.05 were considered significant.

Baseline Characteristics
A total of 12 patients who were hospitalized for decompensated heart failure were included ( Table 1). The median age was 84 (75, 90) years and four patients (33%) were men. Half of the patients had a history of previous heart failure hospitalization; no patient had a history of chronic obstructive pulmonary disease. The median plasma B-type natriuretic peptide was 235 (178, 450) pg/mL and left ventricular ejection fraction was 59% (56%, 62%). Half of the included patients were on diuretics prior to admission.
Seven patients had a ReDS value of >35% in the early morning, which had no significant association with the baseline characteristics (p > 0.05 for all).

Discussion
In this preliminary proof-of-concept prospective study, we observed a unique notype of lung fluid levels, as quantified by the ReDS system. Overall, lung fluid were highest in the morning, with subsequent decreases during the day and an up at night.

Chronotype of Cardiovascular Parameters
In patients with chronic heart failure, sympathetic tone can be abnormally ele at night, as observed with incremental changes in blood pressure and heart rate [9 ditionally, endothelial dysfunction in patients with chronic heart failure may furth crease peripheral vascular constriction. The activation of plasma arginine vasopressi renin-angiotensin systems may be exaggerated during the night hours, which m crease stressed blood volume [10]. These mechanisms may explain the potential in in pulmonary congestion, which in turn triggers heart failure exacerbation [2]. Our ings support this theory, as we observed higher ReDS values in both the night and morning measurements. Consistently, using another modality impedance cardiogr nocturnal whole thoracic volume overload, instead of pulmonary congestion, w cently observed [11].

Other Factors Associated with Chronotype of Lung Fluid Levels
Another trigger of acute heart failure during the night measurement is body po The supine position increases venous return and worsens pulmonary congestion

Discussion
In this preliminary proof-of-concept prospective study, we observed a unique chronotype of lung fluid levels, as quantified by the ReDS system. Overall, lung fluid levels were highest in the morning, with subsequent decreases during the day and an uptrend at night.

Chronotype of Cardiovascular Parameters
In patients with chronic heart failure, sympathetic tone can be abnormally elevated at night, as observed with incremental changes in blood pressure and heart rate [9]. Additionally, endothelial dysfunction in patients with chronic heart failure may further increase peripheral vascular constriction. The activation of plasma arginine vasopressin and reninangiotensin systems may be exaggerated during the night hours, which may increase stressed blood volume [10]. These mechanisms may explain the potential increase in pulmonary congestion, which in turn triggers heart failure exacerbation [2]. Our findings support this theory, as we observed higher ReDS values in both the night and early morning measurements. Consistently, using another modality impedance cardiography, nocturnal whole thoracic volume overload, instead of pulmonary congestion, was recently observed [11].

Other Factors Associated with Chronotype of Lung Fluid Levels
Another trigger of acute heart failure during the night measurement is body position. The supine position increases venous return and worsens pulmonary congestion in patients with chronic heart failure, as we also demonstrated with the ReDS system measurements [12]. Of note, ReDS values were measured in this study at sitting position, instead of spine position. The patients also received their medications, including diuretics, following the ReDS measurements in the morning. This would be another reason for lower ReDS values during the day time.

Study Limitations
This is a preliminary proof-of-concept study and has several limitations. This study consists of a small sample size. We included patients with chronic heart failure following clinical stabilization and most of the ReDS values were within the manufacture-suggested normal range. The findings in this study are not applicable to patients with acute heart failure requiring ongoing medical optimization. Furthermore, the ReDS values were measured in a sitting position while patients were awake, and not recorded during periods of sleep.

Conclusions
The ReDS system is a novel and promising device to quantify the amount of lung fluid with a reference between 25% and 35%. We observed clinically significant variations in the values between 28% (noon) and 38% (morning) during the observed measurement period. These unique time-varying differences may inform the clinician as to when therapies may be dosed to ensure longer periods of clinical stability.  Institutional Review Board Statement: Data acquisition and analysis was performed in compliance with the protocol approved by the Ethical Committee of the University of Toyama (ethical approval number MTK2020007). Written informed consent was obtained from all participants prior to study.