Minimally Invasive Detection of a Sleep Apnoea and Effects of nCPAP Therapy : a Proof-of-concept Study
Conditions: Sleep Disorder; Breathing-Related, Cardiovascular Diseases, Cardiovascular Risk Factor, Cardiovascular Complication
Sponsor: Erasme University Hospital

 
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                                                                            COVER PAGE 
 
Title: Minimally invasive detection of sleep apnoea and 
effects of nCPAP therapy: a proof-of-concept study. 
 
NCT: not available 
 
Date of the document (most recent update): October 22, 
2018.  
 
 
 
 
 

 
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CLINICAL PROJECT 
FOND ERASME 2018-19 
Minimally invasive detection of sleep apnoea 
and effects of nCPAP therapy:  
a proof-of-concept study 
Department of Cardiology 
and  
Sleep Laboratory 
Hôpital Erasme 
Bruxelles 
Belgium 
 
 
 
 
 
 
 

 
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1. Background  
 Basic concepts: from anatomic architecture to ventricular function 
According with the model of a helical myocardium, described for the first time by Turrent and Guasp in the 
1954 (1), cardiomyocytes are functionally divided in an upper-basal loop, where they are disposed 
circumferentially, and in an apical-loop where they are arranged in a right-handed and left-handed helices to 
form a vortex at the apex. This figure-8 configuration, along with interactions between cardiomyocytes, is 
responsible for the complex beat-to-beat mechanical motion of the heart: a global counter-clockwise twist 
during the pre-ejection phase, a vigorous counter-clockwise apical twist during ejection and a clockwise 
apical untwist during the isovolumic phase (2), in order to boost the blood mass into the main vasculature 
with a helical mouvement. Changes in LV pre-load, after-load (3) and contractility (3-5) affect LV twist 
mechanics.  
Recording the beat-to-beat blood velocity and heart-induced chest wall motions: ballistocardiography 
and seismocardiography 
In the late 1887, Gordon assumed that the body moves with each heart beat (6). Nowadays, we can confirm 
Gordon’s hypothesis and state that the micro-movements of the body are due to the blood ejection velocity 
into the ascending aorta (7, 8). These “cardiogenic body movements” can be measured by the mean of 
ballistocardiography (BCG), which measures the displacement, velocity and acceleration of the body in 
response to the displacements of the heart and blood in the main vasculature (9); and the seismocardiography 
(SCG) which assesses the micro-vibrations produced by the heart contraction and blood ejection into the 
vascular tree which are transmitted to wall chest, where they are recorded (10).   
Because of the advent of more performant imaging technologies, such as bi-dimensional and tri-dimensional 
echocardiography and cardiac resonance, BCG and SCG are not used anymore nowadays (11).  
Experimental application of BCG and SCG 
A large body of studies exists on the potential applicability of BCG and SCG in clinical practice. For 
instance, SCG records changes in the ventricular wall motion and compliance after an ischaemic event to a 
similar extent than an ECG (12), and when combined with an ECG, the accuracy of detecting physiologically 
significant coronary artery disease is greater than with an ECG recording alone (13). BCG was successfully 
used in automatic detection of atrial fibrillation (14), and to predict adverse clinical outcome in patients with 
heart failure (15).  
Apart from the clinical setting, BCG and SCG have been used to analyse cardiac function in a microgravity 
environment. The first 3D-BCG recordings were made during the 4th expedition on the Saluyt-6 orbital 
station by the Soviets (16), as well as during the Spacelab mission in 1993 (17). 3D- BCG was also used to 
assess cardiac function (pre-ejection period (PEP)) and left ventricular ejection time (LVET)) on 5 healthy 
volunteers during the European Space Agency parabolic flight campaigns (18). 
SCG and BCG signals: from parameters recording to biological interpretation  
The SCG records the base-to-apex rotational movements transferred to the chest wall in the form of micro-
vibrations. Several parameters of biological interest can be derived from SCG signals, especially the 
amplitude and temporal signals. The amplitude signals are related to left ventricular pressure (19), stroke 
volume and aortic blood pressure (20). Temporal signals provide information about ventricular function: 
namely a) PEP, a marker of cardiac contractility, b) LVET, c) the PEP/LVET ratio, a heart rate independent 
parameter and d) the isovolumic relaxation time (IVRT), which reflects the cardiac performance during the 
diastolic phase of the cardiac cycle (21). The BCG records also several waveforms, three of which are likely 

 
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of main importance for sleep apnoea monitoring: namely the “I”, “J” and “K” waves (7, 8).  These waves are 
elicited by the ventricular contraction which occurs after the QRS complex on the ECG. They represent the 
body movements in response to the cardiac blood ejection (22). Should the thoracic aorta be simplified into 
an ascending and a descending tube, on whom blood pressure and volume flow rate forces act in opposite 
directions, then the BCG waveforms represents the sum of those forces (8). Various cardiovascular 
parameters can be estimated from the BCG signal, and are shortly presented below. The J wave of the BCG 
represents the point of highest amplitude in the BCG waveform; heart rate can be determined by the time 
interval between consecutive J peaks, the J-J intervals (23). Various algorithms can assess heart rate from 
BCG signals (24-28). Also, heart rate variability, a non-invasive tool to assess cardiac sympathetic and 
parasympathetic modulation (29), can be calculated from BCG peak intervals, without the need of RR 
interval calculations obtained from ECG recordings. Changes in BCG waveforms amplitude are related to 
stroke volume (SV) and cardiac output (CO) modifications in healthy subjects (30, 31). Finally, similarly to 
SCG, BCG measurements provide an estimation of the PEP (32, 33), and the LVET which indicates the 
percentage of the cardiac cycle devoted to ejection as compared to ventricular filling (34, 35).  
Sleep disordered breathing and their cardiovascular impact: why detect them? 
Sleep apnoea syndrome is a common chronic respiratory disease characterised by cyclic airflow cessations 
during sleep. Clinically, they are classified in three entities: obstructive, where the airflow cessation is due to 
upper airways collapse; central, where the airflow cessation arise from a central lack in driving to the 
breathing muscles with no compensatory respiratory efforts; mixed, characterised by an initial central event 
followed by an obstructive one.  Nowadays, up to 24% of men and to 9% of women aged 30 to 60 years 
disclose already an asymptomatic and underdiagnosed sleep disorder breathing (SDB) (36). Its current high 
prevalence will supposedly increase in the future years, as a result of the obesity pandemic in an ageing 
population. SDB is a potential cardiovascular risk factor (37). A patent causal relationship between SDB and 
cardiovascular disease has not been clearly established until now, but several chronic patho-physiological 
mechanisms could make sense in supporting such a link. Intermittent hypoxaemia, due to cycled upper 
airway collapse, is responsible for abnormal sympathetic activation (38), endothelial dysfunction (39), 
oxidative stress (40) and inflammation (41), all of which  are related to cardiovascular illnesses, especially 
hypertension (42), atherosclerosis (43), cardiac arrhythmias (44), heart failure (45), and coronary artery 
disease (46). SDB is, likewise, positively correlated with an increased morbidity and mortality in the 
cardiovascular population (47, 48) and seems to be an independent predictive factor in cardiovascular 
mortality after an acute coronary syndrome (49).  
Moreover, the classical profile of patients at risk of having SDB (obese subjects, Pickwickian syndrome) has 
changed in the past year, so that there are new categories of patients who should be evaluated for sleep 
apnoea, above all those with cardiovascular co-morbidities (50).  
Sleep disordered breathing and kino-cardiography: a new and promising tool for 
unobstrusive recording of SDB and its impact on the cardiovascular system. 
Complete laboratory polysomnography (PSG) is the gold standard to diagnose SDB (50, 51). However, it is 
an expensive, time-consuming and uncomfortable tool, limiting its wide-spread use despite the high 
frequency of SDB in the general population. However, considering the high prevalence of SDB in the 
general population and the change in the profile of patients at risk of SDB and then, who should be evaluated 
for, there is growing interest in the research of alternative strategies to reach the most of patients at possible. 
A number of home sleep testing devices has been proposed over years to screen patient at risk of SDB, but 
according to the guidelines, they are NOT recommended for patients with cardiovascular comorbidities (50). 
Moreover, the devices available nowadays do not provide any information on the direct impact of the apnoea 
on the cardiovascular system.  
Nevertheless, taking into account the high prevalence of SDB and the limited accessibility of expensive sleep 
testing on one side and, on the other side, the marked recent technological advances in SCG and BCG 
technologies as well as the peculiar hemodynamic characteristics of sleep apnoea episodes, we wish to test 

 
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the hypothesis that modern SCG and BCG recordings can provide an highly accurate assessment of sleep 
apnoea, and evaluate the effects of nCPAP therapy.  
There are several reasons to believe that the implementation of recent improvements in SCG-BCG will allow 
a precise quantification of such sleep-related events: 
1) The cyclic pharynx collapses during sleep are associated to brain arousal, intrathoracic pressure 
swings (the so called ‘Mueller – manoeuvres’), and intermittent episodes of hypoxaemia and re-
oxygenation (45). When respiration resumes, the cardiac output faces a markedly increased 
peripheral sympathetic activity, leading to sudden rises in systemic blood pressure, and reflex 
reductions in heart rate, while the opposite occurs during the periods of respiratory collapse. As 
explained above, these changes are likely to induce marked modifications in the amplitude and 
temporal recording assessed by SCG recordings, as well as in the “I”, “J” and “K” waves obtained 
from the BCG. 
2) Previous studies which tested if BCG can detect sleep disturbances are encouraging, despite using 
remote techniques: Da Woon et al. used an unobtrusive polyvinylidene fluoride film sensor on a bed 
mattress to record BCG signals in a selected group of 10 OSA patients and 10 controls (52, 53). 
They calculated heart rate (HR) and heart rate variability (HRV) from J-J BCG interval and detected 
awakening periods in OSA patients with an accuracy of 97%. The authors could however not 
determine why sleep was fragmented with this technique. Zaho et al. also used a micro-movement 
sensitive bed mattress in subjects with a BMI < 35 kg/m² and no other concomitant cardiorespiratory 
disease (54). HRV was also retrieved from J-J BCG interval. However, only selected periods of sleep 
were analysed for sleep-breathing events, a surrogate marker for obstructive, but not central 
apnoea. Detection of these events was nevertheless achieved with a sensitivity of 98%, a specificity 
of 94%, and an accuracy of 98% (55). Last, Dehkordi et al. showed that it was possible to distinguish 
between central and obstructive events by recording acceleration from the suprasternal notch, the 
thorax and the abdomen (56). The subjects investigated were however only normal volunteers who 
performed several voluntary breaths hold in the presence of an oral nasal flow detector. 
3) The unique expertise of our research team is that we are capable to record SCG and BCG signals in 3 
dimensions (57, 58), both linearly and rotationally (16-18). While the above mentioned studies (52-
56) assessed BCG changes only in a horizontal plane (x and y axis), which is not representative of 
the complex cardiac mechanic, we are capable to record these changes in a third anteroposterior 
dimensions (z axis). This is important because of the anterior-posterior direction of the aortic arch. In 
addition, as emphasized in the introduction of this research proposal, an important component of the 
body reaction to the heart movements is rotational, which we are capable to record in 3 dimensions. 
Overall the combined SCG and BCG 3D-linear and 3D-rotational signals represent 6 degrees of 
freedom (DOF) while past BCG had only 2-DOF. For simplicity, this 6 DOF signal combination will 
be designated as Kino-cardiography (KCG) recordings in this research proposal. We anticipate that 
the unique KCG properties will considerably increase our detection capability of obstructive and 
central apnoea, as compared to previous studies.  
2. Aims and hypothesis tested  
 
The main hypothesis tested in our study is that KCG provides sensitive and accurate measures of obstructive 
and central apnoea as compared to state-of-the-art polysomnography. Our secondary hypotheses are related 
to modifications in the SCG and BCG parameters during the apnoea and the effects of nCPAP therapy: we 
believe that the KCG signals are profoundly affected by the apnoea and they are reversed to the normal 
baseline with the CPAP. These hypotheses will be tested through a series of studies in normal volunteers and 
patients. 
1-MAIN HYPOTHESES: 

 
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Group A. After a fine tuning period of the KCG signal post processing to maximise the sensitivity and 
specificity of voluntary apnoea detection in health subjects, we will start the first validation study. In 46 
healthy volunteers, a computer program will generate random instructions of periods of normal breathing, 
voluntary end-expiratory breathing cessations periods (as surrogate of central apnoea) and Muller’s 
manœuvre (as surrogate of obstructive apnoea). Meanwhile, the KCG will record the above-mentioned 
parameters. The number and duration of voluntary central and obstructive apnoea will be assessed in the 
KCG recordings, not knowing how many were actually generated by the computer program. We will also 
record the ECG, heart rate, beat to beat non-invasive blood pressure (Finometer), humeral blood pressure 
(Dinamap), ventilation, end-tidal CO2 (AD instruments), O2 saturation (Nellcor), cardiac output (CO) 
(Philips).  
Group B. In patients suspected of sleep apnoea and admitted to the sleep unit of the Erasme hospital to 
perform sleep test as required by their medical condition, we will simultaneously record KCG and PSG and 
qualitatively compare the data. Bland-Altman plots will analyse the agreement between the sleep recordings 
obtained with the two methods. Peculiar attention will be paid to the accuracy of the detection of obstructive 
versus central versus mixed apnoea, of awakenings, and of the time spend in bed. In this second phase of the 
study, we plan to record these parameters only in selected patients, who will not disclose marked 
abnormalities which could hamper the reliability of the KCG recordings, namely moderate or severe valvular 
disease, permanent atrial fibrillation or frequent premature contractions, atrio-ventricular conduction 
disturbances, medications which reduce heart rate and heart rate variability (beta blockers, anti-arrhythmic 
drugs, calcium blockers, …), cardiac rhythm driven by a pace maker, heart failure of any origin, neurological 
diseases responsible for abnormal movements (restless leg syndrome, Parkinson disease, ataxia …).  
Group C. In patients with a diagnosis of OSA, we will determine if KCG is capable to reliably assess the 
efficacy of the nCPAP therapy in comparison to simultaneous PSG recording. Ongoing adjustment in CPAP 
therapy pressure during the night, and its effect on cardiovascular haemodynamic assessed by the KCG, will 
be taken into account as well. The capability of the technique to detect changes in sleep quality will be tested 
both within subjects (before vs. after nCPAP therapy in the same patient) as well among the subjects 
investigated. The same restriction in the recruitment of the subjects of group B will be applied for the present 
group.  
Group D. After validation of the three previous steps, we plan to extend the recordings on 100 unselected 
consecutive patients who will undergo PSG recordings because of complains of sleep apnoea. This will 
validate the clinical usefulness of KCG recording for the detection of sleep apnoea even in patients with 
multiples co-morbidities.  
2-SECONDARY HYPOTHESES 
We will test the hypothesis that the apnoeic events profoundly affected the KCG signals (PEP, LVET and 
PEP/LVET ratios). These parameters are affected by changes in cardiac pre- and after- load and sympathetic 
activity on myocardial contractility. Similarly, we plan to test the hypothesis that the isovolumic relaxation 
time (IVRT), an index of diastolic performance during the cardiac cycle, will be altered during the 
obstructive apneas, because marked variation in intrathoracic pressure result in large increases in LV 
transmural gradient and thereby reduce LV compliance. CPAP therapy should markedly reduce the nighttime 
variability in these parameters.  
We will also asses the R-J interval which is related to blood pressure and determine if this parameter rises 
during the apneas and arousals when sympathetic activity is increased. Determination of the J-J intervals and 
the corresponding HRV, which is under strong autonomic control, should also present distinct changes in 
OSA patients, as compared to subjects receiving efficacious nCPAP therapy.  
Last, breathing effort variations will be assessed. This refers to the mechanical interaction between 
respiration and KCG signals when sleep apnea occurs, independently from an autonomic nervous modulation 
of heart rate variability: when the obstructive apneic event occurs, the airflow decreases, which result in a 

 
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breathing effort thereafter. We will test the hypothesis that theses respiratory abnormalities are readily 
detectable by the KCG.  
3. Methods  
Study design and recruitment, expertise of the research group   
Study A is an interventional pre-study on voluntary breath holding on healthy subjects. The parameter taken 
into consideration for sample size calculation in this group is the total (linear and rotational) systolic kinetic 
energy of the SCG (S_sys_kin) and the rolling ratio between the mean value and the standard deviation of 
this parameter: H = Mean(S_sys_kin) / Std(S_sys_kin). H discriminated voluntary obstructive apneas from 
episodes of normal respiration in a healthy volunteer (H = 1.1627 and 0.2308, respectively). The sample size 
is determined according to: 2·(Zalpha + Z1-beta)2·sigma2 / Delta2, where  alpha = 5% is the accepted error, 
leading to Zalpha = 1.96 (2-sided); beta = 95% is the power of the study, leading to Z1-beta = 1.64; sigma is 
the estimated standard deviation of H;  delta is the estimated effect of obstructive sleep apnea on H in 
patients. Sigma (Hbaseline) = 0.1247 was obtained by H determinations on a group of healthy subjects who 
were breathing regularly. The difference in H during regular breathing and voluntary obstructive apnea, 
divided by 10 (because voluntary apneas may have induced larger changes than those experienced by 
patients) is Delta = (1.1627 - 0.2308) / 10 = 0.09319. Thus, the estimated sample size for study A is 46. 
Studies B and C are observational investigations on subjects referred for PSG as required by their medical 
condition and which fulfill the inclusion/exclusion criteria described previously. The number of subjects will 
be calculated accordingly to the results of the pre-study (group A). 
Study D is an observational prospective investigation conducted on unselected consecutive patients without 
recruitment restrictions, in order to validate the KCG on the real population. Since we do not know how 
many patients will be necessary for the validation of our screening device, we speculate a size simple of 100 
subjects. 
Because the KCG device is not intrusive, we do not anticipate difficulties in the recruitment. Our study will 
not affect in any manner the regular medical care of the patients admitted to the sleep laboratory. The present 
research proposal is in line with my promotor’s expertise, P. van de Borne, P-F. Migeotte and G. Loas, in the 
study of sleep physiology (59-63), and sleep apnea (60, 61): 
4. Perspectives  
As explained above, SDB is a widespread disease with detrimental health effects and its prevalence is 
supposed to increase in the future years, as the result of the obesity pandemic in an ageing population. PSG is 
the gold standard for the diagnosis of sleep related disorders but it is an expensive, uncomfortable and time-
consuming tool, limiting its use in the daily clinical practice, despite the high prevalence of SDB. Several 
home sleep tests have been proposed to screen patients suspected for SDB, but they disclose several 
limitations and are not recommended for patients with cardiovascular, respiratory, metabolic or neurologic 
co-morbidities (50). We strongly believe that the less cumbersome (57-60) KCG will screen patients for 
SDB accurately. One of its unique features (57-60) is also that it can directly identify the consequences of 
SDB and nCPAP therapy on the cardiovascular system, and in especially the presence of frequently 
associated cardiac arrhythmias (44). With a more efficient pre-screening, those who are most likely to be 
eligible for nCPAP therapy will have a better access to the currently existing sleep laboratory facilities. To 
summarize, we aim 1) to propose a new screening tool for patients at risk of SDB, 2) to stratify patients with 
SDB for adverse cardiovascular events, and 3) to highlight new physio-pathological aspect of sleep apnoea. 
The present research project has thus the potential of improving sleep apnoea patients care and health, at no 
additional societal costs. 

 
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