Journal of Cardiovascular Translational Research

https://doi.org/10.1007/s12265-020-10032-5

ORIGINAL ARTICLE

Technology Applications of Capnography Waveform

Analytics for Evaluation of Heart Failure Severity
Takashi Koyama 1 & Masanori Kobayashi 1 & Tomohide Ichikawa 1 & Yasushi Wakabayashi 1 & Hidetoshi Abe 1

Received: 14 November 2019 / Accepted: 13 May 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
This study aimed to elucidate the influential parameter, acquired from the analyses of nasal capnography waveforms,
for the elevated plasma brain natriuretic peptide (BNP) levels in patients (n = 34) with heart failure (HF). The
capnography waveforms were analyzed to evaluate changes in end-tidal CO2 (ETCO2) values and expiratory and
inspiratory durations. The relationship between these parameters, estimated from capnography analyses and plasma
BNP, was then evaluated. Mean ETCO2 values and BNP levels showed a strong negative correlation (R2 = 0.6355,
p < 0.0001) in HF patients with chronic kidney disease (CKD) (R2 = 0.6355, p < 0.0001). The ETCO2 value was
the most influential parameter that indicated elevated BNP levels in HF patients with CKD (β = − 0.577; p =
0.031). The mean ETCO2 level could be a potentially influential parameter reflecting elevated BNP levels in HF
patients, especially in HF patients with CKD. Respiratory parameters, acquired from detailed nasal capnography
analyses, might be reasonable for evaluating the severity of HF.

Keywords Capnography . Heart failure . ETCO2 . Unstable respiration

Introduction measurement of CO2 could be a reasonable methodolog-

Heart failure (HF) could lead to excessively systemic
fluid accumulation and pulmonary congestion due to
the increase in capillary hydrostatic pressure. Fluid ac-
cumulation in the alveoli prevents the exhalation of car-
bon dioxide. Then, carbon dioxide (CO2) reacts with
water to form carbonic acid that eventually dissociates
into bicarbonate and hydrogen ions. The excessive ac-
cumulation of hydrogen ions in the blood increases che-
moreceptors sensitivity in the medulla oblongata that
causes unstable respirations. Therefore, rapid and shal-
low breathing is a common symptom in HF patients [1].
In addition, the circulation delay caused by HF induces
variations in the respiratory rhythm [1]. Therefore, the
Associate Editor Craig M. Stolen oversaw the review of this article
* Takashi Koyama
takashixkoyama@icloud.com
1
Department of Cardiovascular Medicine, Matsumoto Kyoritsu
Hospital, Habaue 9-26, Matsumoto 390-0185, Japan
ical ap proach to evalua te th e seve rity of H F.
Capnography is used to timely monitor ventilation for
a safely delivered anesthesia [2]. Other diseases and
abnormalities related to breathing and circulation can
be quickly diagnosed by analyzing capnography wave-
forms [3]. End-tidal CO2 (ETCO2) monitoring is a non-
invasive technique and extensively used to determine
appropriate ventilation during operation [4]. Previous
studies indicated that the measurement of resting
ETCO 2 levels was closely associated with prognosis
and cardiac output reserve in patients with HF [5–8].
By detailed analyses of capnography waveforms, other vari-
ous parameters related to respiratory functions can be deter-
mined [4]. However, it has not been assessed yet whether
these parameters can reflect the severity of HF or not.
Plasma BNP levels are dramatically increased in a direct pro-
portion to disease severity in patients with HF [9], and it is
currently an established biomarker for HF worldwide [10, 11].
Therefore, this study aimed to elucidate the influential param-
eters, acquired from the detailed analyses of capnography
waveforms, for the plasma BNP levels, which could reflect
the severity of HF.

Materials and Methods
Subjects and Study Design
This study included 34 consecutive patients with stable HF
and plasma brain natriuretic peptide (BNP) level of more than
100 pg/ml, who underwent treatment at our hospital from
August 2019 to October 2019. We excluded patients with
respiratory diseases, such as chronic obstructive pulmonary
disease and interstitial pneumonia, and cerebrovascular dis-
eases. In addition, patients who were undergoing dialysis were
also excluded. We analyzed the capnography waveforms of
the enrolled patients and acquired various parameters related
to respiratory functions. Firstly, the correlation between respi-
ratory parameters and plasma BNP levels was evaluated in all
patients. Secondly, because a previous study showed that day-
time periodic breathing during short-time laboratory recording
was closely associated with central sleep apnea in HF patients,
the relationship between respiratory parameters acquired from
capnography waveform analyses and apnea-hypopnea index
(AHI) was investigated. Furthermore, patients with chronic
kidney disease (CKD) underwent the same previous analyses.
Twelve, out of the thirty-four enrolled patients with HF, were
examined twice to record the capnography 1 month later, so
the changes in the capnography parameters could be analyzed
and evaluated. The dose of drugs and the setting of cardiac
implantable electric devices were not changed during the
follow-up period.
Capnography Waveform Analyses
Figure 1 shows the procedures of analyzing capnography
waveforms for calculating various parameters. Figure 1a
shows the waveforms obtained during measuring CO2.
ETCO2 is defined as the partial pressure of CO2 at the end
of an exhaled breath, which is expressed as mmHg of CO2.
Generally, expiratory phase is from the point when the
capnography starts increasing to the point that is defined as
ETCO2, while the inspiratory phase lasts from the point that is
defined as ETCO2 to the start of the expiratory phase. The
distance between adjacent ETCO2 points was defined as the
respiratory interval. To identify frequency components of
capnography waveforms which comprises various periodic
waveforms, the Discrete Fourier Transform (DFT) analyzed
the raw signals of CO 2 in each patient (Fig. 1b) [12].
Additionally, kurtosis and skewness were used, as statistical
indicators, to evaluate deviation from normal distribution [
12]. Kurtosis was used to examine the sharpness of the fre-
quency distribution, and skewness was used to evaluate the
degree of distortion of the frequency distribution (Fig. 1b).
Finally, the differential CO2 waveforms were constructed,
and the maximum and minimum values were calculated,
where the respiratory intervals and expiratory and inspiratory
J. of Cardiovasc. Trans. Res.
duration could be easily identified and calculated (Fig. 1c).
The maximum/minimum values were defined as the
maximum/minimum rate of increase/decrease in the partial
pressure of CO2 per second. Generally, the maximum value
is observed in the expiratory phase, while the minimum value
is observed in the inspiratory phase. These parameters could
therefore clarify the velocity of expiration and inspiration in
patients with HF. These analyses of capnography waveforms
can calculate the inspiratory/expiratory ratio (I/E ratio) in each
respiration (Fig. 1c).
Data Acquisition and Analyses
After each patient rested in the supine position in a quiet
examination room, a continuous recording of CO2 (using a
nasal expiratory CO2 gas monitor, TG-980, Nihon Kohden
Co. Ltd, Japan) was started. The CO2 data was recorded with
a gas monitor (OLG-3800™; Nihon Kohden Co. Ltd, Japan).
The collected data from the expiratory gas monitor were trans-
ferred to a biological signal recorder (PowerLab 26 T™; AD
Instruments, Colorado Springs, CO, USA), which consisted of
an analogue-digital (A/D) computer and another computer
installed with a signal acquisition/analysis software (Chart
Pro 5™; AD Instruments) [13]. The sampling rate was set at
1 kHz and recorded as matrix data. To identify temporal
changes in ETCO2, local ETCO2 peaks of CO2 waveforms
were identified. To eliminate noise, the frequency between
peaks was set to ≤ 0.16 Hz. Moreover, peaks greater than
0.5 Hz were excluded. Only the peak data were collected,
and mean ETCO2 values and standard deviation (SD) of the
ETCO2 were calculated. The differential coefficient per
0.001 s was calculated from the matrix data obtained from
the biological signal recording device and a graph of the dif-
ferential coefficient was constructed by arranging it in a chro-
nological order (Fig. 1c: magenta lines). The differential co-
efficient curve was constructed at 500–800 points of central
moving averages, which smoothened the data. In addition, the
mean of the maximum value and its standard deviation were
calculated. The differential coefficient was then defined as the
expiratory time (from the point, where differential coefficients
changed from negative to positive, to the point, where they
changed from positive to negative). The minimum value (Fig.
1c: magenta lines), and its mean and standard deviation were
calculated. Similarly, the time for the differential coefficient to
turn from negative to positive was set as the inspiratory time.
Further, the sum of the expiratory and inspiratory durations
was defined as the respiratory interval. Signal processing was
performed using MATLAB™ (2017a, Mathworks, Inc.
Natick, MA, USA) software. Blood samples were collected
from the peripheral vessels of the 34 enrolled patients before
they underwent capnography recordings. The main routes of
eliminating hydrogen ions are kidney, respiratory system, and
skin in the human body. We hypothesized that respiratory
J. of Cardiovasc. Trans. Res.
a b
Fig. 1 Summary of calculation methods for obtaining parameters
obtained from capnography waveforms. a The analyses of raw
waveforms of CO2 signal. Sampling frequency is 1000/s, and recording
duration is 300 s. The distance between adjacent ETCO2 points is defined
as the respiratory interval. Moreover, mean ETCO2, standard deviation
ETCO2, and mean respiratory interval were calculated. CO2 = carbon
dioxide, ETCO2 = end-tidal CO2. b The representative frequency distribu-
tions, which were acquired by ETCO2 waveforms using Discrete Fourier
compensation might increase in HF patients with reduced re-
nal functions due to reduced acid buffering functions.
Consequently, this results in significant changes in the respi-
ratory parameters acquired from capnography waveform anal-
yses. According to this hypothesis, we examined plasma BNP
levels and renal functions in the enrolled patients with HF.
Because the rates of change become statistically stable by
the linear approximation using logarithmic conversion, we
used logarithmic transformation of plasma BNP levels.
Renal function was measured based on the estimated glomer-
ular filtration rate (eGFR). Two-dimensional, M-mode, and
Doppler methods of echocardiography (iE33; Philips
Medical Systems, Andover, MA, USA) were performed to
evaluate various parameters of heart functions in the patients
[14]. The left ventricular ejection fraction (EF) was deter-
mined from an apical 4-chamber view using the Simpson
method to classify two different phenotypes (HF with reduced
EF (HFrEF) and HF with preserved EF (HFpEF)). The sever-
ity of HF was evaluated by using plasma BNP levels so that it
was not affected by cardiac systolic function. To avoid the
effects of HF treatment, the dose of drugs and the setting of
cardiac implantable electric devices were not changed during
Transform. The kurtosis and skewness of the frequency distributions were
statistically calculated in each HF patients. DFT = Discrete Fourier
Transform, HF = heart failure. c Representative capnography waveforms
(blue lines) and their differential CO2 curves (magenta lines) obtained from
an enrolled HF patient in this study. The differential CO2 curve was con-
structed, and the local maximum and minimum values were calculated
where the expiratory, inspiratory durations, and expiratory/inspiratory ratio
could be easily identified and calculated.
the follow-up period. Informed consent, regarding the
capnography monitoring and the use of data, was provided
by all patients. The design, protocol, and handling of patient
data were reviewed and approved by the Matsumoto Kyoritsu
Hospital Ethics Committee (Approval No. 2019-005).
Polysomnography Analyses
Twenty out of the 34 HF patients underwent a complete over-
night polysomnography (PSG) using the ProFusion PSG®
Sleep Diagnostic system (Compumedics, Victoria,
Australia), which continuously monitored the electroenceph-
alogram, electro-oculogram (used in sleep staging), oxygen
saturation (SaO2), airflow, snoring, and thoracoabdominal
motion. Apnea was defined as an absence of breathing with-
out any ribcage or abdominal motion for ≥ 10 s; hypopnea was
defined as a ≥ 30% reduction in monitored airflow accompa-
nied by a ≥ 4% decrease in the SaO2. Arousal responses were
defined according to the recommendations of the American
Sleep Disorders Association. The AHI was defined as the
number of apnea and hypopnea episodes per hour of sleep.
Patients with an AHI score of < 5/h were diagnosed as non-
 J. of Cardiovasc. Trans. Res.

sleep apnea patients, while those with an AHI score of ≥ 5/h
were defined as having sleep apnea syndrome. A diagnosis of
central sleep apnea was assigned for an AHI of ≥ 5/h, with ≥
50% of the events labeled as central rather than obstructive.
Statistical Analyses
All data were represented as means ± standard deviation or
percentage. When comparing the 2 groups, normally distrib-
uted parameters were analyzed using the t test, and parameters
without a normal distribution were analyzed using the
Wilcoxon test. A linear analysis was used to examine the
correlation between the 2 parameters and was represented
with a coefficient, of determination, a regression equation
and a p value. The kurtosis and skewness were used for ana-
lyzing the sharpness and distortion of the frequency distribu-
tion, which was made by DFT. A multivariate analysis was
performed on parameters with a significance probability < 0.1,
which were analyzed by univariate analysis. All statistical
analyses were performed using the SPSS 19.0 J software for
Windows. The significance level was set at < 0.05.
Results
Table 1 presents the background of the subjects included in
this study. Briefly, the mean age of the enrolled HF patients
was 77.4 ± 7.5 years (HF patients with CKD; 80.4 ± 5.5
years), and the percentage of the patients with HF with re-
duced ejection fraction was 29.4% (HF patients with CKD;
40.0%). Twenty out of the 34 HF patients underwent
polysomnography analyses in this study. Thirteen out of those
20 HF patients had sleep apnea with > 50% of the events
labeled as the central type of apnea rather than the obstructive
type. The mean AHI score in 13 HF patients with predominant
central apnea was 36.0 ± 25.3 /h.
Figure 2 presents the representative data of frequency dis-
tribution of capnography waveforms, which was acquired
from DFT analyses. Figure 2 a shows data on the HF patient
with reduced ejection fraction and CKD, while Fig. 2b is on
only one HF patient whose ejection fraction and renal function
were preserved. The patient’s data shown in Fig. 2b had an
extremely sharp frequency spectrum at around 0.3 Hz,
resulting in high kurtosis (3.4323). In contrast, patients’ data
in Fig. 2a have wide frequency distribution without sharp
spectrum. These characteristics of frequency distribution
show low kurtosis (2.7196).
Figure 3 shows the correlation between log-transformed
(Ln) BNP levels and various parameters obtained from
capnography in HF patients with and without CKD (n = 34).
The mean ETCO2 levels were negatively correlated with Ln
BNP levels (R2 = 0.2452; p = 0.0034; Fig. 3a), and the stan-
dard deviation of ETCO2 levels was negatively correlated
with the Ln BNP levels (R2 = 0.1974; p = 0.0125; Fig. 3b).
A significant negative correlation was observed between the
mean ETCO2 values and standard deviation of ETCO2 levels
(R2 = 0.3790; p = 0.0001; Fig. 3c).
Figure 3d and e show the correlation between the AHI
score and mean ETCO2 levels and between the AHI score
and the standard deviation of ETCO2 levels acquired from
capnography waveforms in HF patients with and without
CKD (n = 13). The mean ETCO2 levels were negatively

Table 1 Baseline characteristics

of enrolled HF patients Variable All HF patients (n = 34) HF patients with CKD (n = 20)

Age, years 77.4 ± 7.5 80.4 ± 5.5

Male sex, n (%) 13 (38.2) 10 (50.0)
BMI, kg/m2 24.3 ± 5.2 23.6 ± 5.4
Underlying heart disease
Atrial fibrillation, n (%) 28 (82.4) 17 (85.0)
Ischemic heart disease, n (%) 8 (23.5) 6 (30.0)
Valvular heart disease, n (%) 10 (29.4) 5 (20.0)
Cardiomyopathy, n (%) 4 (11.8) 3 (15.0)
Echocardiography data
LA diameter (mm) 43.4 ± 7.8 43.3 ± 8.6
Ejection fraction (%) 56.7 ± 14.9 53.7 ± 15.7
HFrEF, n (%) 10 (29.4) 8 (40.0)
Laboratory data
eGFR (ml/min/kg) 48.7 ± 17.6 37.9 ± 12.9
Ln BNP (pg/ml) 5.7 ± 0.6 5.8 ± 0.7

The values are reported as the mean ± standard deviation

HF heart failure, CKD chronic kidney disease, BMI body mass index, LA left atrium, HFrEF heart failure with
reduced ejection fraction, eGFR estimated gromerular filtration rate, BNP brain natriuretic peptide
J. of Cardiovasc. Trans. Res.

a b Kurtosis = 3.4323
Kurtosis = 2.7196
Skewness = -0.0815
Skewness = -0.0774
BNP = 132.0 pg/ml
BNP = 851.0 pg/ml
eGFR = 67.0 ml/min/1.73m2
eGFR = 44.0 ml/min/1.73m2
the sum of all power (%)

the sum of all power (%)

Ratio of each power to

Rao of each power to

LVEF = 80.2 %
LVEF = 44.4 %

Frequency (Hz) Frequency (Hz)

Fig. 2 Representative results of frequency distributions of capnography waveforms in HF patients whose plasma BNP levels were high (a) and relatively
low (b). BNP = brain natriuretic peptide; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction

correlated with the AHI score (R2 = 0.4252; p = 0.0157; Fig. 4c) and between Ln BNP and I/E ratio (R2 = 0.2600; p value =
3d). A significant negative correlation was shown between the 0.0216). A significant negative correlation was found between
standard deviation of ETCO2 values and the AHI score (R2 = the values of Ln BNP and respiratory intervals (R2 = 0.3038; p
0.6668; p = 0.0007; Fig. 3e). = 0.0118; Fig. 4g).
Figure 4 presents the plots of the HF patients with CKD In these patients, multivariate analyses, including the mean
with the Ln BNP set on the horizontal axis and various pa- ETCO2 value, standard deviation of ETCO2 levels, mean
rameters, acquired from capnography waveform analyses on maximum values, mean minimum values, the kurtosis of fre-
the longitudinal axis. In the abovementioned patients, the quency distribution, I/E ratio, and respiratory duration showed
mean ETCO2 values and Ln BNP showed a strong positive that the decreased mean ETCO2 value was the most influential
correlation (R2 = 0.6355; p < 0.0001; Fig. 4a). Furthermore, parameter on the elevated BNP levels (Table 2).
the standard deviation of ETCO2 was positively correlated Table 3 shows the differences of respiratory parameters
with the Ln BNP levels (R2 = 0.3561; p = 0.0055; Fig. 4d). between the patients with HFrEF (n = 11) and HFpEF (n =
A significant correlation was found between the values of Ln 23). The mean ETCO2 value was lower (29.6 ± 3.9 vs. 33.3 ±
BNP and means of the maximum values (R2 = 0.2160; p = 3.0) and the standard deviation of ETCO2 value higher (4.9 ±
0.0389; Fig. 4b) and minimum values (R2 = 0.4236; p = 2.0 vs. 3.4 ± 1.1) in the patients with HFrEF, when compared
0.0019; Fig. 4e). A linear correlation was observed between with the patients with HFpEF. Other respiratory parameters
the kurtosis and Ln BNP levels (R2 = 0.2299; p = 0.0324; Fig. were not different between the two groups.

a b c
Standard Deviation of ETCO2 (mmHg)

Y = -3.002*X + 49.22 Y = 1.091*X + 2.332

40 10 40 Y = 1.450*X + 37.88
R2 = 0.2452 R2 = 0.1974
R2 = 0.3790
p = 0.0034 p = 0.0125
Mean ETCO2 (mmHg)
Mean ETCO2 (mmHg)

35 8 35 p = 0.0001

30 6 30

25 4 25
2
20 20
0 0 0
0 4 5 6 7 8 0 4 5 6 7 8 0 2 4 6 8 10
Ln BNP Ln BNP Standard Deviation of ETCO2 (mmHg)

Fig. 3 The correlation between Ln brain natriuretic peptide (BNP) and with and without chronic kidney disease. The correlation between mean
mean end-tidal CO2 (ETCO2) levels (a), and between Ln BNP and stan- ETCO2 levels and apnea-hypopnea index (AHI) score (d), and between
dard deviation of ETCO2 levels (b) in heart failure patients with and standard deviation of ETCO2 levels and AHI score (e) in heart failure
without chronic kidney disease. The correlation between mean ETCO2 patients with and without chronic kidney disease
levels and standard deviation of ETCO2 levels (c) in heart failure patients
 J. of Cardiovasc. Trans. Res.

a b c

Mean Maximum Values (mmHg/sec)

Y = -5.018*X + 61.23 Y = -9.686*X + 172.5 Y = -0.2044*X + 4.470

Kurtosis of Frequency Distribution

40 R2 = 0.6355 160 R2 = 0.2160 4.0 R2 = 0.2299
Mean ETCO2 (mmHg) p < 0.0001 p = 0.0389 p = 0.0324
35 140
3.5
30 120
3.0
25 100

20 80 2.5
0 0 0
0 4 5 6 7 8 0 4 5 6 7 8 0 4 5 6 7 8
LnBNP Ln BNP Ln BNP

d e f

Mean of Minimum Values (mmHg/sec)

Standard Deviation of ETCO2 (sec)

10 Y = 1.645*X – 5.392 250 Y = -30.08*X + 355.2 1.4 Y = -0.07836*X + 1.529

R2 = 0.3561 R2 = 0.4236 R2 = 0.2600
8 p = 0.0055 p = 0.0019 p = 0.0216
200 1.2
6

I/E ratio
4 150 1.0

2
100 0.8
0 0 0.0
0 4 5 6 7 8 0 4 5 6 7 8 0 4 5 6 7 8
Ln BNP Ln BNP LnBNP

g Y = -0.3688*X + 5.627
4.5 R2 = 0.3038
Respiratory Interval (sec)

p = 0.0118
4.0

3.5

3.0

2.5
0
0 4 5 6 7 8
Ln BNP

Fig. 4 The correlation between various parameters acquired from frequency distribution of the ETCO2 waveforms; d between Ln BNP and
capnography analyses and Ln brain natriuretic peptide (BNP) levels in standard deviation of ETCO2 levels; e between Ln BNP and mean min-
heart failure patients with chronic kidney disease. a Between Ln BNP imum values; f between Ln BNP and inspiratory/expiratory ratio; g be-
values and mean end-tidal CO2 (ETCO2) levels; b between Ln BNP tween Ln BNP and respiratory intervals
values and mean maximum values; c between Ln BNP and kurtosis of

Figure 5 shows the relationship between the changes in Ln in ETCO2 levels (Fig. 5a; R2 = 0.5322; p value = 0.0031),
BNP levels and the changes in various parameters acquired mean maximum values (Fig. 5b; R2 = 0.5607; p value =
from the analyses of capnography waveforms. All the changes 0.0051), mean minimum values (Fig. 5d; R2 = 0.3911; p

Table 2 Uni- and multivariate

analyses of influential parameters Variable Univariate analysis Multivariate analysis
on plasma BNP levels
β 95% CI p value β 95% CI p value

Mean ETCO2 value − 0.797 − 0.174, − 0.079 < 0.0001 − 0.577 − 0.200, − 0.011 0.0310
SD of ETCO2 value 0.597 0.072, 0.361 0.0055
Mean maximum value − 0.465 − 0.043, − 0.001 0.0389
Mean minimum value − 0.655 − 0.022, − 0.006 0.0020
Kurtosis − 0.480 − 2.144, − 0.105 0.0324
I/E ratio − 0.510 − 6.090, − 0.546 0.0216
Respiratory interval − 0.551 − 1.441, − 0.206 0.0118

The upper data are adjusted by age and gender

β partial correlation coefficient, CI confidence interval, ETCO2 end-tidal CO2, SD standard deviation, I/E ratio
inspiratory/expiratory ratio
J. of Cardiovasc. Trans. Res.

Table 3 Respiratory parameters

in patients with HFrEF and Variable HFrEF (n = 11) HFpEF (n = 23) p value
HFpEF
Age, years 74.8 ± 7.2 78.5 ± 7.4 0.192
Male sex, n (%) 9 (81.8) 12 (52.1) 0.140
BMI, kg/m2 25.4 ± 6.0 23.2 ± 4.9 0.289
Medication
Diuretics, n (%) 11 (100.0) 18 (78.2) 0.150
ACEI/ARB, n (%) 11 (100.0) 21 (91.3) 0.819
β blocker, n (%) 11 (100.0) 20 (87.0) 0.242
CIED, n (%) 6 (54.5) 6 (26.1) 0.138
Underlying heart disease
Atrial fibrillation, n (%) 10 (91.0) 19 (82.6) 0.507
Ischemic heart disease, n (%) 4 (36.4) 4 (17.4) 0.232
Valvular heart disease, n (%) 3 (27.2) 7 (30.4) 0.849
Cardiomyopathy, n (%) 2 (18.2) 2 (8.7) 0.580
Respiratory parameters
Mean ETCO2 (mmHg) 29.6 ± 3.9 33.3 ± 3.0 0.006
SD of ETCO2 (mmHg) 4.9 ± 2.0 3.4 ± 1.1 0.008
Mean maximum value (mmHg/s) 111.5 ± 10.3 119.6 ± 17.2 0.179
Mean minimum value (mmHg/s) 169.6 ± 28.7 182.5 ± 31.8 0.275
Kurtosis of frequency distribution 3.2 ± 0.4 3.4 ± 0.6 0.407
I/E ratio 1.1 ± 0.3 1.1 ± 0.1 0.986
Respiratory interval 3.7 ± 1.0 3.8 ± 1.1 0.823

The values are reported as the mean ± standard deviation

HF heart failure, CKD chronic kidney disease, BMI body mass index, ACEI angiotensin converting enzyme
inhibitor, ARB angiotensin receptor blocker, CIED cardiac implantable electric device, SD standard deviation,
ETCO2 end-tidal CO2, I/E ratio inspiratory/expiratory ratio

value = 0.0297), and kurtosis in frequency distribution (R2 =
0.4478; p value = 0.0173) were negatively correlated with the
changes in Ln BNP levels.
Discussion
Our results indicated a significant negative correlation be-
tween values of Ln BNP and mean ETCO2 value. However,
a significant positive correlation was found between values of
Ln BNP and standard deviation of ETCO2 values in HF pa-
tients with and without CKD. In addition, in HF patients with
CKD, the mean maximum and minimum values of CO2 par-
tial pressure were negatively correlated with the levels of Ln
BNP. Both the kurtosis of the frequency distribution of
capnography waveforms and the I/E ratio were also negatively
correlated with the Ln BNP values in HF patients with CKD.
In addition, the ETCO2 value was mostly influential on the
fluctuation of the plasma BNP levels in HF patients with
CKD. Furthermore, regarding the changes in ETCO2, the kur-
tosis of frequency distribution, and mean maximum and min-
imum values were negatively correlated with the changes in
Ln BNP values.
There are potential mechanisms that cause irregular rapid
and shallow breathing in HF patients. Firstly, the emission of
blood CO2 is inhibited by pulmonary congestion and fluid
accumulation in HF patients’ alveoli, leading to an increase
in blood CO2 levels. Secondly, the signal transduction of CO2
concentration, from peripheral to central chemoreceptors, is
delayed due to the deterioration of cardiac functions [15].
Thirdly, pulmonary C-fibers endings are stimulated by pulmo-
nary congestion and interstitial edema [1]. These events could
enhance central chemoreceptor sensitivity and destabilize the
CO2 dependent negative feedback system [16]. Hence, rapid
and shallow breathing and irregular respiration in terms of
space could occur in unstable HF patients [16]. These respi-
ratory responses induce the shortness of breath and decrease in
exercise tolerance [17]. Therefore, noninvasive and simple
monitoring of the CO2 concentration in patients with HF
could be a very important methodological approach to manage
HF therapy. Capnography is used to continuously monitor
ventilation to ensure a safely delivered anesthesia [2].
ETCO2 monitoring is a noninvasive technique and extensive-
ly used to evaluate appropriate ventilation during operations
[3]. Furthermore, a previous study showed that ETCO2 levels
were significantly correlated with the cardiac output in an
 J. of Cardiovasc. Trans. Res.

Fig. 5 The correlation between

the changes in Ln brain natriuretic a Y = -5.785*X - 1.067 b Y = -11.64*X + 3.812

Mean Maximum Values (mmHg/sec)

peptide (BNP) and mean end-tidal R2 = 0.5322 R2 = 0.5607
15
p = 0.0031 60 p = 0.0051

Changes of ETCO2 (mmHg)

CO2 (ETCO2) (a), between the
changes in Ln BNP and mean 10
maximum values (b), between the 40

Changes of
changes in Ln BNP and kurtosis 5
of frequency distribution (c), and
between the changes in BNP and 20
0
mean minimum values (d)
-5 0

-10 -20
-3 -2 -1 0 1 -3 -2 -1 0 1
Changes of Ln BNP
Changes of Ln BNP

Mean Minimum Values (mmHg/sec)

c Y = -0.5269*X + 0.07261
100
Y = -19.28*X + 14.01
3 R2 = 0.4478 R2 = 0.3911
of Frequency Distribution

p = 0.0173 p = 0.0297
Changes of Kurtosis

2
50

Changes of
1
0
0

-1 -50
-3 -2 -1 0 1 -3 -2 -1 0 1
Changes of Ln BNP Changes of Ln BNP

animal model [18]. Accordingly, capnography monitoring
could be useful for evaluating circulatory- and respiratory-
related fluctuations in patients with HF.
Accelerated respiration is frequently observed in HF pa-
tients to excrete CO2, leading to a decrease in blood CO2
concentrations [17]. Capnography analyses are effective diag-
nostic approaches to investigate blood CO2 concentrations
noninvasively. This study showed that the mean ETCO2
levels, acquired from the capnography analyses, were nega-
tively correlated to the plasma BNP levels (Fig. 3a), indicating
that these analyses could predict HF severity. A previous
study showed that respiratory irregularities in terms of time
and space, such as central sleep apnea, were frequently ob-
served in HF patients [19]. Our study also showed that the
standard deviation of ETCO2 values positively correlated with
the plasma BNP levels (Fig. 3b), indicating that respiratory
movement became unstable in patients with severe HF.
Hence, the evaluation of variations of ETCO2 values could
be predictive markers of the HF severity. A previous study
revealed that diurnal periodic breathing during short-time lab-
oratory recording was closely associated with central sleep
apnea in HF patients. This implies that diurnal periodic breath-
ing and nocturnal abnormal breathing have the same underly-
ing mechanism [20], where HF destabilizes the CO2-depen-
dent negative feedback system. The significant negative
correlations between mean ETCO2 levels and the AHI score
and positive correlations between the standard deviation of
ETCO2 levels and the AHI score were observed in the en-
rolled HF patients. These results could clarify that those respi-
ratory parameters could reflect central sleep apnea related to
HF severity. Interestingly, the correlations between ETCO2
and Ln BNP levels and between SD of ETCO2 and Ln BNP
levels became stronger in HF patients with CKD compared
with those in all enrolled HF patients (Fig. 4). The possible
mechanism is the strong compensation of respiration due to
impaired renal functions, leading to a decrease in discharge
capacity of hydrogen ions.
The differential coefficients of CO2 waveforms could be
examined to evaluate airflow velocities in expiratory and in-
spiratory phases. The differential coefficients of these CO2
flow waveforms can clarify various abnormalities in respira-
tory functions. This study showed that both expiratory and
inspiratory flow velocities were negatively correlated with
Ln BNP levels (Fig. 4b, e). The underlying mechanism may
be due to fluid accumulation in the pulmonary alveoli or re-
spiratory bronchiole, where these expansion and contraction
compliances might be decreased in HF patients with CKD.
Thus, the calculation and evaluation of the differential coeffi-
cient could be an effective methodological approach to the
respiratory function in HF patients with CKD. To our
J. of Cardiovasc. Trans. Res.
knowledge, this is the first report to show that the analyses of
differential coefficients are effective for evaluating flow ve-
locities in HF patients through the capnography waveforms.
The kurtosis calculations of frequency distribution of
ETCO2 waveforms could moreover show the characteristics
of frequency distribution in each HF patient. The higher levels
of kurtosis the sharper frequency distribution is, where the
respiratory interval is constant (Fig. 2b) [21]. The previous
study showed that irregular rapid and shallow breathing was
frequently observed in HF patients [22]. Because irregular
breathings have various frequency patterns, the frequency dis-
tribution could tend to be flat. As a result, the kurtosis of the
frequency distribution was low (Fig. 2a). This study showed
that the kurtosis of frequency distribution is negatively corre-
lated with the levels of Ln BNP in HF patients who have CKD
(Fig. 4c), indicating that this statistical indicator could be a
predictive parameter for evaluating HF severity. However, if
decompensated HF patients have rapid and shallow breathing
without irregular breathing, the kurtosis of frequency distribu-
tion of ETCO2 waveforms could be a high value. The frequen-
cy, which makes the peak of distributions and other parame-
ters, should be simultaneously analyzed in HF patients who
have regular rapid and shallow breathing.
Also, the I/E ratio could be an important monitoring pa-
rameter to determine appropriate ventilation during operations
[23]. Normal I/E ratio at rest and while asleep is 1:2 or less,
and the I/E ratio generally becomes 1:1 on exertion.
Inspiration is normally an active process (requiring work),
while expiration is passive and requires longer time for exha-
lation. According to these facts, in decompensated HF patients
who have increased ventilation rate, the I/E ratio could be-
come decreased. Furthermore, the I/E ratio was negatively
correlated with the Ln BNP levels in the present study (Fig.
4f), showing that the discharge of CO2 depends on the venti-
lation rate. However, the discharge of CO2 could be secured
by the enough expiratory duration in stable HF patients,
resulting in a greater I/E ratio. Therefore, the I/E ratio could
be an effective predictive parameter for evaluating HF
severity.
One important role of circulatory and respiratory functions
is to discharge hydrogen ions and prevent acidosis in the hu-
man body. Therefore, the measurement of partial pressure of
CO2 levels, which affect circulatory proton ions, gives us im-
portant information on patients with HF by using the
capnography analyses. The decreased mean ETCO2 value
was mostly an influential parameter for elevated plasma
BNP levels (Table 2), indicating that accelerated ventilation
was closely associated with impaired heart function [24]. As
shown in this study, various parameters could be acquired
from the capnography waveform analyses. Although the
ETCO2 value is the strongest influential parameter on the
plasma BNP levels in HF patients, it is important to make
use of the other many capnography parameters to determine
the respiratory characteristics in patients with HF and evaluate
the effects of treatment of HF.
Some previous studies showed that cardiovascular death,
HF death, and HF admission were significantly higher in
HFrEF than in HFpEF patients [25–27]. The results of our
study, showing unstable respiration in the HFrEF patients
(Table 3), could indicate respiratory parameters that possibly
could reflect the severity of HF.
As shown in the Fig. 5, changes in capnography pa-
rameters were correlated with the changes in plasma BNP
levels, indicating that capnography analyses could be ef-
fective in determining changes in the severity of HF.
Interestingly, as plasma BNP levels decreased, hyperven-
tilation might be improved (a), expiratory capacity in-
creased (b), the variability of respiratory intervals de-
creased (c), and inspiratory capacity increased (d). These
results might indicate that the severity of HF is reflected
in the “ease of breathing.”
However, there are limitations to this study: (i) this was not
a randomized study; (ii) the number of subjects was relatively
small, and the study was a single-centered; and (iii) this study
speculated that some parameters obtained from novel
capnography analyses correlated with plasma BNP levels,
which may reflect the severity of HF. (iv) capnography pa-
rameters might be surrogate markers of sleep disordered
breathing in HF patient. Because the number of HF patients
who underwent PSG analysis was insufficient, we could not
perform statistical analyses, including parameters regarding
sleep disordered breathing in this study. Hence, large-scale
and in-depth further studies are required to establish the effi-
cacy of the capnography analyses in HF patients. In conclu-
sion, capnography waveform analyses might show the rela-
tionships between the severity of HF and respiratory condi-
tions noninvasively. These programmed methods can easily
be equipped with capnography devices. If these methodolog-
ical approaches are realized, it will be possible to noninvasive-
ly evaluate the severity of HF at home.
Acknowledgments We would like to thank the outpatients’ department
staff of the Matsumoto Kyoritsu Hospital for their help in this study.
Additionally, we would like to thank Editage (www.editage.com) for
English language editing.
Clinical Relevance This study focused and demonstrated that
capnography waveform analyses could be simple and effective diagnostic
tool for evaluating the severity of HF.
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical Approval The present study conducted according to the
Declaration of Helsinki. The design, protocol, and handling of patient
data were reviewed and approved by the Matsumoto Kyoritsu Hospital

Ethics Committee (Approval No. 2019-005). No animal studies were
carried out by the authors for this study.
Informed Consent All patients provided informed consent.
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