Exercise in Patients With a Total Coronary Occlusion
Phase: NA
Conditions: Coronary Occlusion
Sponsor: University of Hull

 
 
 
 
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Exercise in patients with a total Coronary Occlusion – EChO - 247135 
(Version 9 – 14/11/2018) 
 
Research Team 
Dr Angela Hoye (Clinical Lead / Principal Investigator / Chief Investigator) 
Dr Simon Nichols (Investigator) 
Prof Lee Ingle (Investigator) 
Thomas Nickolay BSc (Hons) (Investigator)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Contents 
 
 
Glossary………………………………………………………………………………………3 
Background and Rationale ......................................................................................... 4 
Summary of Proposed Research ............................................................................... 5 
Physiological Principles  ............................................................................................. 6 
Objectives:  ................................................................................................................ 7 
Hypotheses: ............................................................................................................... 8 
Study Design .............................................................................................................. 8 
Inclusion criteria  ...................................................................................................... 10 
Exclusion criteria  ..................................................................................................... 10 
Sample Size ............................................................................................................. 11 
Study procedures  .................................................................................................... 12 
Symptom Limited Maximal Cardiopulmonary Exercise Testing (Cycle) ................... 12 
Determination of O2/HR and ΔO2/ΔWR inflection ................................................... 12 
Fixed Workload Cardiopulmonary Exercise Testing (Cycle) .................................... 12 
Venepuncture ........................................................................................................... 13 
Resting Echocardiogram .......................................................................................... 13 
Safety and Feasibility ............................................................................................... 13 
Statistical Analysis.................................................................................................... 14 
Study flow chart ........................................................................................................ 15 
References ............................................................................................................... 17 
 
 
 
 
 
 
 

 
 
 
 
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Glossary 
 
CTO – Chronic total Occlusion  
O2 – Oxygen 
CO2 – Carbon Dioxide  
VO2 – Oxygen Uptake  
VCO2 – Carbon Dioxide Output  
CHD – Coronary Heart Disease  
PCI – Percutaneous Coronary Intervention  
HRR – Heart Rate Reserve  
CV – Cardiovascular  
O2/HR – Oxygen pulse 
ΔVO2/ΔWR – The change in oxygen uptake versus the change in work rate 
CPET – Cardiopulmonary exercise test  
SV – Stroke volume  
Q – Cardiac output  
a-vO2 – Arteriovenous oxygen difference  
ATP – Adenosine triphosphate  
HR – Heart rate 
ECG – Electrocardiograph  
VAT – Ventilatory anaerobic threshold  
 
 
  
 

 
 
 
 
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Background and Rationale 
 
Coronary heart disease (CHD) is the biggest cause of death in the United Kingdom 
(UK) accounting for approximately 69,000 deaths each year. The annual incidence of 
CHD is estimated to be 490,000 (Miller 2008, Townsend et al. 2014). Exercise training 
is indicated in patients with coronary heart disease (CHD), including those with 
exercise-induced myocardial ischaemia. Benefits include the attenuation of disease 
progression, symptom improvement, increased exercise tolerance (Hambrecht et al. 
2004, Niebauer et al. 1997) and, improved quality of life (Belardinelli et al. 2001). 
However, there is a paucity of data on the effects of exercise training in patients with 
a total chronic occlusion (CTO) of a major coronary artery.  
A CTO is identified in up to 50% of patients found to have significant coronary artery 
disease on coronary angiography (Christofferson et al. 2005). The presence of a CTO 
has an impact on the subsequent treatment of the patient with the majority either 
managed medically or referred for bypass graft surgery. The reasoning for this relates 
to the challenge of performing percutaneous coronary intervention (PCI). Recent data 
from the UK National database indicates that of 14,439 procedures, the success rate 
of CTO PCI was only 70.6% - considerably lower than if the vessel is not chronically 
occluded (George et al. 2014). 
It is important to appreciate that the vessel distal to the occluded segment is filled 
either antegradely or retrogradely via collaterals. However, these collaterals are not 
sufficient to prevent ischemia to the myocardium (Werner et al. 2006). During activity, 
patients may experience symptomatic or asymptomatic exercise-induced myocardial 
dysfunction, reduced exercise tolerance and limited functional independence.  
The perceived inability of patients to safely and effectively sustain a programme of 
physical activity may lead to a further decline in quality of life and accelerated disease 
progression. This is likely to incur further primary and secondary care costs. However, 
exercise therapy could potentially help the development of the collateral blood supply 
(Möbius-Winkler et al. 2016). This may not only increase the ischemic threshold, but 
might also help to facilitate an increase in the success rate of PCI either antegradely 
(via micro-channels) or retrogradely whereby the collaterals may be traversed to 

 
 
 
 
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facilitate recanalisation. Specialist exercise prescription techniques in this population 
may therefore aid the management of this condition.  
 
Summary of Proposed Research 
 
A CTO is defined as a full coronary artery occlusion with a thrombolysis in myocardial 
infarction (TIMI) flow of zero, for more than three months (Di Mario et al. 2007). Despite 
exercise training forming the ‘corner stone’ of any long-term treatment of patients with 
CHD, there is no specific training advice for patients with a CTO. Current exercise 
training guidance offered by the ACPICR (2015) recommends training intensities of 
40-70% heart rate reserve (HRR), or intensities below the ischaemic threshold for 
those with known myocardial ischaemia. However, not only do patients with a CTO 
often suffer silent ischaemia making the latter training guideline inadequate, sustained 
cardiovascular (CV) exercise below an ischaemic threshold may still lead to patients 
becoming symptomatic owing to VO2 drift, subsequent heart rate (HR compensation) 
and, increased myocardial workload (Mezzani et al. 2013, Ellestad 1996, Zafrir et al. 
1999). Given current cardiac rehabilitation guidelines indicate that increasing total CV 
exercise time should be a key objective, CTO patients may be receiving suboptimal 
training prescriptions.  
Although the safety of exercise training during periods of ST-segments depression (1 
to 3mm) over periods of 12 to 50 minutes has been reported (Noël et al. 2007), 
prolonged periods of myocardial ischaemia may increase the risk of arrhythmias 
(Kléber and Rudy 2004). Moreover, frequent episodes of angina are likely to evoke 
patient anxiety (Arnold et al. 2009). A method of reliably avoiding angina or arrhythmia 
during exercise training would be advantageous. 
Inflections in the oxygen pulse [O2/HR]) or, inflections to the ‘normal’ linear increase 
in VO2 with work rates (ΔVO2/ΔWR) observed during maximal cardiopulmonary 
exercise testing (CPET) indicate the onset of myocardial ischaemia (Belardinelli et al., 
2003). These changes (on ramp-based exercise testing protocols) are reported prior 
to the development of angina symptoms or, ST-segment depression (265 ± 33 
seconds). Exercise intensities corresponding to this work rate may be a safe and 

 
 
 
 
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effective threshold to base exercise training in patients with a CTO. However, no 
investigation has reported the variability in the occurrence of the O2/HR and, ΔO2/ΔWR 
inflection, nor has any visual verification that exercise-induced myocardial ischaemia 
occurs at this point has been provided. In addition, no study has investigated whether 
sustained exercise prescribed at intensities based on these phenomena is feasible in 
this cohort. The purpose of this investigation is therefore to determine the variability in 
the onset of the O2/HR and, ΔO2/ΔWR inflection and, to determine the feasibility and 
safety of exercise prescribed at intensities corresponding to O2/HR and ΔO2/ΔWR 
inflection points.  
 
Physiological Principles  
 
O2/HR is an indirect measure of stroke volume (SV) calculated from a modification of 
the Fick equation. The principle component of VO2 is cardiac output (Q), hence an 
estimation of SV may be made by dividing VO2 by HR (unit: ml O2 per beat). O2/HR 
therefore, is the product of SV and a-vO2 difference (Whipp, Higgenbotham and Cobb 
1996). Because myocardial ischaemia has a profound deleterious effect on SV during 
exercise, changes in the O2/HR can be used to diagnose suspected exercise-induced 
myocardial ischaemia and flow limiting CHD (Belardinelli et al. 2003, Chaudhry et al. 
2009, Wasserman et al. 2011).  
In healthy populations, incremental CPET elicits a linear O2/HR response, however, in 
CHD a spontaneous inflection of this response may be observed. Coronary stenosis 
may inhibit myocardial O2 supply to the point where ATP re-synthesis is impaired and 
myocardial contractions become dyssynchronous. Subsequent myocardial wall 
motion abnormalities cause a reduction in SV causing a compensatory HR increase 
to sustain Q. HR compensation is unlikely to fully normalise VO2. The result of 
increased HR is the compounding of an already inadequate O2 supply by increasing 
myocardial work and, reducing diastolic and coronary artery filling times (Ellestad 
1996, Chaudhry et al. 2009, Zafrir et al. 1999). The point at which a HR increase 
coincides with a spontaneous, premature flattening or inflection of O2/HR (Figure 1A) 
is thought to be indicative of exercise-induced myocardial ischaemia (Belardinelli et 

 
 
 
 
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al., 2003). During ramp-based exercise testing, identification of an ischaemic threshold 
may also be observed to greater effect by combining O2/HR with the VO2 versus work 
rate slope (ΔVO2/ΔWR). In healthy individuals, a linear increase in ΔVO2/ΔWR of ~10 
ml·min-1·watt-1 is maintained until peak exercise where normal limitation to exercise 
performance may cause a plateau. A uniform flattening of this relationship (<10 
ml·min-1·watt-1) is considered indicative of global reduction in CV efficiency and is often 
seen in patients with chronic heart failure (Wasserman et al., 2011). In CHD however, 
the 10 ml·min-1·watt-1 relationship may be maintained until the onset of myocardial 
ischaemia which causes an abrupt decline in the rate of VO2 increase (Figure 1B). 
This may manifest as an objective break-point in the ΔVO2/ΔWR slope.  
Myocardial wall-motion abnormalities and a subsequent reduction in SV are likely to 
occur prior to ECG changes and symptoms of angina (Nesto and Kowalchuk, 1987). 
Therefore inflections in the ΔVO2/ΔWR slope and O2/HR relationship may be regarded 
as more sensitive markers of ischaemia. Indeed, (Belardinelli et al. 2003) reported on 
average, that this inflection occurred 265 ± 33 seconds prior to a 2mm ST segment 
depression. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 – Reproduced from Belardinelli et al. (2003). Panel A and B show the oxygen pulse (O2/HR) and ΔVO2/ ΔWR of a 
healthy patient (closed circles) and a patient with exercise-induced myocardial ischaemia (open circles). Under normal 
circumstances the O2/HR and ΔVO2/ ΔWR increase until peak exercise where a brief plateau occurs reflecting natural 
limitation to VO2. In patients with exercise-induced myocardial ischaemia, O2/HR and ΔVO2/ ΔWR inflect at the point where 
left ventricular function is compromised. 

 
 
 
 
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Objectives:  
  
 To assess the intra-patient variability in the occurrence of the O2/HR and, 
ΔO2/ΔWR inflection in patients with a CTO during an individualised maximal 
CPET.  
  
 To verify that the O2/HR and, ΔO2/ΔWR inflection indicates the onset 
of exercise induced myocardial dysfunction by visual confirmation of its 
occurrence using stress-echocardiography  
 
 To examine the safety and feasibility of sustained exercise prescribed at an 
intensity equal to the O2/HR and, ΔO2/ΔWR inflection in patients with a CTO 
 
 
Hypotheses: 
 
 Primary: The variability in the onset of O2/HR and, ΔO2/ΔWR inflection will be 
low (Intra-class correlation >0.75) when defined as ‘Wattage at inflection 
occurrence’. 
 Secondary: Sustained exercise at the O2/HR and/or, ΔO2/ΔWR inflection will 
elicit clinically-significant myocardial wall motion abnormalities observed using 
echocardiography but will not result in ST-segment depression > 2mm, or other 
ECG changes and symptoms indicative of angina.  
 
 Secondary: Sustained exercise at an intensity equal to the O2/HR and, 
ΔO2/ΔWR inflection will not result in serious adverse event requiring medical 
intervention.    
 
 

 
 
 
 
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Study Design 
 
Figure 2 outlines the study protocol. The study is a single centre, pilot study recruiting 
patients with single vessel disease with a complete chronic occlusion. Consecutive 
patients will either be identified at the time of diagnostic coronary angiography, or 
retrospectively from the dedicated departmental database which contains information 
on every patient who undergoes angiography / angioplasty by their usual clinical care 
team. Patients may be included if they are either 1) awaiting attempted angioplasty or 
2) are being managed with medical therapy. The department performs approximately 
35-40 CTO procedures per year in patients with single vessel disease who would be 
potentially suitable for inclusion into the study. Approximately 5-10 patients per year 
have single vessel disease and a CTO, and have an unsuccessful PCI procedure. 
These patients are maintained on medical therapy and can be identified from the 
departmental database. All patients will have good resting left ventricular function as 
evidenced by either echocardiography or left ventriculography. Patients with multi-
vessel disease will be excluded. Wherever possible, patients will be stabilised on 
optimal medical therapy so that adjustments to this therapy can be avoided during the 
study period. 
Twelve consecutive patients fitting the inclusion criteria will be approached at the time 
of coronary angiography or will receive a telephone call from a member of their usual 
clinical care team inviting them to take part in the study. A patient information leaflet 
(PIL) will be provided or sent through the post if the patient is interested in participating. 
Approximately one week later, after the patient has had time to consider their 
involvement (>24 hours later) they will be followed up by their usual clinical care team 
to ask if they would like to proceed with study participation, and if they consent to be 
contacted by the research team. Once agreed, a patient will be contacted by the 
research team to answer any questions they may have about the protocol and be 
invited for a baseline assessment (visit 1) where informed consent will be obtained. 
Investigations at visit 1 will include; a brief medical assessment involving the collection 
of resting pulse rate, blood pressure, height, weight, resting 12 lead ECG, resting 
echocardiogram, and resting blood sample (full blood count and biochemical profile, 

 
 
 
 
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glucose and troponin T). Following these measures, the patient will complete a 
symptom limited maximal CPET, followed by a repeat blood test for troponin T.  
Patients will then attend a second visit (visit 2) after a minimum of 72 hours up to a 
maximum of two weeks later. This will include all measures from visit 1, minus the pre 
and post exercise blood samples and resting echocardiogram. The repeated maximal 
CPET will follow the same protocol as visit 1. Data from the maximal CPET at visit 1 
and 2 will be analysed to determine the work rate at the onset of O2/HR and/or, 
ΔO2/ΔWR inflection. If an inflection cannot be identified, patients will be withdrawn 
from the study. This will be recorded in any subsequent publications.  
A third visit (visit 3) will take place a minimum of 72 hours up to a maximum of 2 weeks 
following visit 2. Patients will receive; a brief medical assessment involving the 
collection of resting pulse rate, blood pressure, height, weight, resting 12 lead ECG, 
resting echocardiogram, and resting blood sample. A sub-maximal CPET at an 
intensity corresponding to the O2/HR and/or, ΔO2/ΔWR inflection [minus two thirds of 
the CPET ramp rate] (Whipp et al. 1981) lasting 20 minutes will  then be conducted. If 
there is disagreement between the work rate that O2/HR and ΔO2/ΔWR inflection 
occurs, a workload corresponding to the difference between the two will be prescribed. 
During the final 5 minutes of the CPET the cycle ergometer will be placed in the supine 
position and a cardiac sonographer will complete a stress echocardiograph to ensure 
continuous exercise at this work rate does not elicit adverse events. After the CPET is 
complete and the patient has rested for 6 minutes on the bike, a final blood sample 
will be taken for comparison.    
Belardinelli et al (2003) indicate that the patients who exhibit O2/HR and/or, ΔO2/ΔWR 
inflections are most likely to do so below the ventilatory anaerobic threshold (VAT). 
Because work rates below the VAT produce predictable changes in VO2, the influence 
of VO2 drift is unlikely to lead to an internal work rate higher than that documented 
during maximal CPET (Mezzani et al. 2013).   
Following the final blood sample patients will be offered light refreshments. 
 
 
 

 
 
 
 
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Inclusion criteria  
 
 Single vessel disease with a chronic total occlusion of the right coronary artery, 
left anterior descending artery, or left circumflex artery, as identified on 
coronary angiography performed within the preceding 24 months. 
 Willingness to undertake maximal cardiopulmonary exercise test 
 Resting systolic blood pressure <180mmHg 
 Resting Diastolic blood pressure <100mmHg 
 Aged >18yrs  
 Normal resting left ventricular function 
 Able to provide written informed consent 
 
 
Exclusion criteria  
 
 Significant proximal left main stem stenosis. 
 Multi-vessel disease (defined as a diameter stenosis of >50% in another major 
epicardial coronary vessel) 
 Absence of exercise-induced ischaemia evidenced by O2/HR or, ΔVO2/ ΔWR 
inflection at visit 1 and 2 
 O2/HR inflection or, ΔVO2/ ΔWR inflection at a respiratory exchange ratio >1.05 
 Change in cardiac medications within previous two weeks 
 Unstable angina  
 Myocardial infarction within the preceding 6 weeks 
 Canadian classification system for angina class IV 
 Chronic heart failure 
 Significant valvular pathology 
 Resting ejection fraction <40%  
 Severe orthopaedic limitations 
 Past history of Complex arrhythmias 
 Atrial fibrillation 
 Severe COPD 

 
 
 
 
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 Symptoms of intermittent claudication 
 Unable to provide written informed consent 
 Previous permanent pacemaker implant  
 Use of short-term GTN within 30 minutes of exercise testing  
 
 
Sample Size 
 
The aim of this study is to investigate the feasibility and safety of prescribing exercise 
at work rates corresponding to the O2/HR and/or, ΔO2/ΔWR inflection in patients with 
a CTO. There is currently no published literature detailing the use of this technique 
and therefore, this investigation should be considered a pilot study. Julious (2005) 
states that the minimum number of participants for a clinical pilot study is n=12. We 
will therefore recruit n=12 participants into this cohort study. Because the focus of this 
study is on determining agreement rather than determining statistical significance, a 
small sample size will not limit our ability to investigate our primary outcome. 
 
 
Study procedures  
 
Symptom Limited Maximal Cardiopulmonary Exercise Testing (Cycle) 
 
 Breath-by-breath gas analysis 
 Continuous ECG monitoring 
 Three minute unloaded cycling phase at 40-60 rpm 
 Personalised ramp protocol using cycle ergometer (60rpm) 
 Follows (American Thoracic Society/American College of Chest Physicians 
2003) guidelines 
 Rating of perceived exertion (Borg 1982) 
 
 
 

 
 
 
 
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Determination of O2/HR and ΔO2/ΔWR inflection 
 
Following symptom limited maximal CPET, breath-by-breath data will be exported for 
offline analysis (15 second average). The instantaneous ration of oxygen uptake to 
heart rate (O2/HR) will be plotted against work rate (WR).  A plateau or reduction in 
the (O2/HR) despite increasing work rate will be considered indicative of myocardial 
ischaemia. ΔVO2/ΔWR slope will also be calculated as peak VO2-unloaded VO2/T-
0.75×S, where peak VO2 is VO2 at peak exercise, T is the time of incremental exercise, 
S is the slope of work rate increment in watts per minute. A ΔVO2/ΔWR slope will be 
deemed abnormal if an inflection in VO2 is observed with respect to WR despite 
evidence of a normal slope (~10 ml.min-1.watt-1) from the onset of exercise start to the 
inflection point, and a flattened slope. An inflection in the O2/HR or ΔVO2/ΔWR slope 
will not be deemed abnormal if it occurs during the last 30 seconds of exercise as this 
can result from normal physiological limitations to exercise (VO2 plateau). This 
protocol reflects the seminal work by (Belardinelli et al. 2003). 
 
 
Fixed Workload Cardiopulmonary Exercise Testing (Cycle) 
 
 Breath-by-breath gas analysis 
 Three minute unloaded cycling phase at 40-60 rpm 
 20 minutes of exercise at work load corresponding to O2/HR and/or, ΔO2/ΔWR 
inflection 
 Continuous ECG monitoring 
 Rating of perceived exertion (Borg 1982) 
 Stress-echo follows BSE guidelines 
 Termination of exercise upon symptoms or ECG changes indicative of 
myocardial ischaemia 
  
 
 
 

 
 
 
 
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Venepuncture 
 
 Taken from the anti-cubital vein or other routine venous access point 
 Bloods collected in EDTA, SST tubes 
 Centrifugation  
 
 
 
Resting Echocardiogram 
 
 Resting ejection fraction, myocardial dimensions and, end-systolic and diastolic 
volumes 
 Exclude significant valvular pathology 
 Follows BSE guidelines 
 
 
Safety and Feasibility 
 
In addition to data on agreement, symptoms of angina, development of ECG changes 
indicative of myocardial ischaemia will be recorded. Any patients unable or unwilling 
to complete the protocol will also be recorded.  
In the event that any participant complains of chest pains either before or during the 
test that test will be ceased. 
 
Whilst cardiopulmonary exercise testing does bring with it an increased chance of 
adverse events the likelihood of this happening is still relatively low. Indeed previous 
research has suggested these events occur in less than 0.16% of tests (Skalski et al., 
2012). 
Whilst there is no research to date that directly assesses the safety of CPET in CTO 
patients, the afore mentioned study by Skalski et al (2012) did recruit a cohort 
comprising 5060 high-risk cardiac patients. As per the clinical diagnosis pathway most 
of the patients recruited to the study will have already performed exercise stress 
testing, therefore in the clinical opinion of the principle investigator (Dr Angela Hoye) 

 
 
 
 
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there are no clinical concerns (e.g. risk of participation) associated with the protocol. 
To mitigate the chances of adverse events during this study all exercise sessions will 
be conducted at the cardiology research department of Castle Hill Hospital. 
Participants will be encouraged to exercise to the limit of their capacity in an 
environment where they are closely monitored and immediate medical care is on hand. 
This could provide participants intimidated by or reluctant to exercise with the chance 
to test their physical capabilities in a safe and secure manner, thus alleviating some 
of the stress and anxiety caused by their condition. 
 
 
Statistical Analysis 
 
If statistical assumptions are not violated, data analysis will be conducted using intra-
class correlations, coefficient of variation and, Bland-Altman plots detailing mean bias 
and limits of agreement. Because this study is a pilot study, utilisation of p-values will 
be minimal. Number of dropouts, ECG abnormalities and any adverse events will be 
reported descriptively.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Study flow chart 
 
 
Figure 2 – Study flow chart. 
Patients identified at the time 
of angiogram by a member of 
their usual clinical care team  
Patient identified 
retrospectively from a 
departmental database by 
their usual clinical care team  
Patients contacted via phone 
by a member of their usual 
clinical care team to discuss 
the study and ask if they 
would like to receive a copy 
of the PIS 
Ineligible patients 
excluded 
Uninterested patients 
thanked for their time 
Interested patients receive a 
PIS through the post 
After the patient has had sufficient time to read through the PIS a 
member of their usual clinical care will ask for their verbal consent to 
allow members of the research team to make contact, and answer any 
questions they might have about the study    
Interested patients will be invited to attend Castle Hill 
Hospital for Visit 1 
Visit 1 
Comprehensive 
physiological 
assessment, 12 lead 
ECG, resting 
echocardiography, pre 
and post exercise blood 
samples and symptom 
limited CPET 
Visit 2 
Brief physiological 
assessment, 12 lead ECG 
and symptom limited 
CPET 
Visit 3 
Brief physiological 
assessment, 12 lead 
ECG, pre and post 
exercise blood test, 20 
minute sub-maximal 
CPET at an intensity 
corresponding to the 
O2/HR and/or 
∆VO2/∆WR inflection 
(minus 2/3 of the CPET 
ramp rate), and stress 
echo in the final 5 
minutes of the test 
Patients without 
identifiable O2/HR 
and ∆VO2/∆WR 
inflection excluded  

 
 
 
 
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