Properties of Myocardial Microcirculation in Patients With Different Pathomorphological Substrates, Before and After Recanalization of Coronary Artery Chronic Total Occlusion
Phase: NA
Conditions: Chronic Total Occlusion of Coronary Artery
Sponsor: University of Belgrade

Properties of myocardial microcirculation in patients with different 
pathomorphological substrates, before and after recanalization of 
coronary artery chronic total occlusion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
March 28 th, 2017. 
 
 

BACKGROUND 
Chronic total occlusion (CTO) is defined as a complete occlusion of the coronary artery without 
blood flow (TIMI 0) in the occluded segment, which lasts longer than 3 months (1). In various 
published series, the prevalence of CTO lesions in patients with coronary artery disease is 
between 20-30% (2-4). In a large Canadian registry with over 16,000 subjects, the prevalence of 
CTO lesions on diagnostic coronary angiography was 18.4% of all angiographically significant 
coronary stenoses (5). 
This coronary lesion group is especially recognized as technically most complex coronary lesion 
subset for percutaneous revascularization. The success of percutaneous revascularization of 
these lesions has been only 60-70% until recently, which is significantly lower than the 
revascularization of non-occlusive lesions, which is successful in as many as 98% of cases (5,6). 
Over the past decade, significant advances have been made in the technology, equipment, and 
techniques of percutaneous revascularization procedures for the treatment of CTOs, which, with 
increasing operator experience, have resulted in procedural success rates of about 90% (7-9). 
The particular functional characteristics of CTO lesions are the existence of collateral blood 
vessels, and smaller or larger amount of viable myocardium in the area of its vascularization. The 
complex interplay of these two factors depends on the overall coronary physiology and influence 
the clinical manifestations in the patient. 
Collaterals are interarterial connections that allow blood flow from the donor artery to the 
vascular territory that belongs to the occluded epicardial artery. In this manner, the integrity of 
the myocardium supplied by the occluded coronary artery can be preserved partially or even 
completely (10). However, although at rest collateral blood flow can provide preservation of the 
viability and even contractile capacity of the myocardium, it is considered that collateral flow 
during exertion is not sufficient in up to 90% of cases (11). 
Collaterals develop in the process of arteriogenesis through the "recruitment" of preformed and 
preexisting interarterial connections, in a process that depends largely on the hemodynamic 
shear stress along the pressure gradient (between the unoccluded and occluded artery) that 
occurs in the case of coronary artery occlusion, and the presence of a viable myocardium is not 
necessary for the development of collaterals (10,12). 
Numerous studies have been published to date that examined the functional parameters of 
occluded (and recanalized) coronary artery microcirculation (10,11,13–18), while data on the 
potential effects of CTO recanalization on collateral flow and collateral donor physiology are 
scarce. In the presence of CTO, if the myocardium in the area of the occluded artery is perfused 
with significant blood flow through the collateral bloodstream, the CTO recanalization and the 
establishment of normal antegrade flow results in a rapid decrease or termination of the 
collateral flow, and decrease flow in the donor artery, which may alter circulatory parameters of 
donor artery itself (e.g. fractional coronary flow reserve - FFR, coronary flow reserve - CFR, etc.). 
Werner and co-workers have elegantly demonstrated that collateral flow provides about 50% of 

the antegrade flow that is established after CTO recanalization (17). The collateral function 
decreases rapidly after opening the CTO, and practically after a little more than 30 minutes after 
the establishment of antegrade flow reaches the lowest level that is maintained even after 24 
hours from the intervention (17,19). It is not yet clear enough and there is insufficient published 
data on the contribution of collateral flow to coronary artery donor physiology. Thus, Werner et 
al showed that the FFR in the artery donating collateral for CTO was 0.82 ± 0.11 in 18 patients 
who did not have angiographically significant stenosis on the donor artery (15). In this way, they 
showed that small angiographic irregularities or mild diffuse coronary disease in the case of large 
coronary flow (caused by developed collateral blood flow) can give a significant drop in pressure 
in the arterial tree near the border defined for the existence of ischemic lesions. Furthermore, 
several cases have been reported in the literature in which there were significant changes in the 
FFR value in the donor artery after successful CTO recanalization, which in some cases led to a 
change in the indication for revascularization by moving from a FFR value <0.80 to values ≥0.80 
(20-24). It is unclear to what extent these cases represent the broader population of CTO patients 
and whether they can be generalized. "Publication bias" where relatively rare occurrences that 
show major changes in the expected direction are more likely to be published than smaller ones 
or changes in the unexpected direction (25, 26). To our knowledge, only two studies to date have 
been published on a large number of patients examining the impact of CTO reanalysis on FFR in 
the non-occluded arteries. In a study of 14 subjects who had a CTO recanalized, 6 of 9 patients 
with initial ischemic FFR in the donor artery experienced a change in FFR to the non-ischemic 
range (FFR before PCI 0.76 ± 0.04 and after PCI 0.86 ± 0.03) (27). Recently, the largest and most 
important study was published with 34 patients examining the impact of CTO recanalization on 
the functional parameters of non-occluded vessels (28). This study confirmed that after 
successful CTO recanalization, there is a modest increase in FFR (0.810 versus 0.782) in the 
collateral donor artery, as well as a reduction in coronary flow therein (28). Recently, a group of 
Japanese authors also proposed an in vitro model to test the effect of collateral flow on the 
circulation of the donor artery and the recipient of the collateral flow, with a complex 
mathematical model and formulas describing the effect of the collateral recipient's blood vessel 
revascularization on the function of the collateral donor blood vessel (29). Non-invasive 
measurement of coronary flow reserve before and after CTO reanalysis has been reported in only 
one study so far, which in a series of 24 patients showed that after successful recanalization of 
the CTO of the right coronary artery, there was an increase in coronary flow reserve (CFR) after 
3 months of intervention ( 2.3 ± 0.3 vs 1.8 ± 0.3; p <0.001), whereas in the immediate 
postprocedural period (within 24h of PCI), the CFR value through the LAD artery did not increase 
(1.8 ± 0.3 vs 1.8 ± 0.2, p = 0.89). 
Previous studies have not sufficiently examined the relationship between collateral flow changes 
after PCI for CTO and changes in functional parameters of the donor artery with the amount of 
viable myocardium and segmental function of the left ventricle after revascularization. Also, the 
association of the phenomenon of coronary theft with the viability and occurrence of inducible 
myocardial ischemia has not been sufficiently investigated. 

 
WORKING HYPOTHESIS 
 
1. Following successful recanalization of chronic total coronary artery occlusion, the 
hemodynamic microcirculatory parameters (CFR, FFR, HMR) in the non-occluded 
(collateral donor) coronary artery will change as compared to the values before the 
procedure. 
2. The magnitude of change in these parameters depends on the size of the collateral 
blood flow to the territory of the occluded coronary artery and the amount of viable 
myocardium in the vascularization zone of the occluded artery. 
 
 
OBJECTIVES OF THE RESEARCH 
 
1. The primary goal of the study is to determine the magnitude and direction of change in 
the functional parameters of microcirculation in collateral donor coronary artery after the 
successful opening of the chronic total occlusion. 
2. The secondary goals of the study are: 
a) determination of the factors on which the change in hemodynamic parameters of the non-
occluded arteries depend, 
b) determining the factors that influence the improvement of segmental kinetics of the left 
ventricle after six months from the recanalization of the occluded artery, 
c) determination of correlation of functional parameters of microcirculation with ischemia, 
viability and segmental kinetics of the left ventricle, 
d) determining the correlation (change) of microcirculatory functional parameters with the 
quality of life determined by the Seattle Angina Questionnaire. 
 
 
STUDY PROTOCOL  
 
A. Data collection before intervention 
In all patients, the following tests will be performed in the period before the intervention: 
- Electrocardiogram, 
- Echocardiographic examination, 
- Stressechocardiographic test, 
- Measurement of coronary flow reserve for collateral donor artery (RCA or LAD) by non-
invasive transthoracic Doppler echocardiography, 
- Scintigraphy (SPECT) for detection of viable myocardium in the CTO area, 
- Seattle Angina Questionnaire 
 
B. Data collection during PCI for CTO 
At the beginning of the procedure, after administration of nitroglycerin intracoronary (200 µg), 
angiography will be performed with optimal visualization of epicardial coronary circulation and 
collateral blood flow to the area vascularized by the occluded artery. Angiographic quantification 
of collateral and collateral flow will be performed according to Rentrop and CC classifications 

(16,30). Quantitative coronary angiography (QCA) will be used to quantify all coronary stenoses 
except CTO, which by definition is 100% stenosis. 
Before the CTO recanalization, after adequate heparinization of the patient (by administration of 
100 IU / kg heparin intravenously), the following functional parameters will be measured in each 
of the two non-occluded coronary arteries using a coronary wire with pressure and flow sensor 
(Combowire; Volcano Corp, San Diego, CA): 
- Basal blood flow velocity 
- Hyperemic blood flow velocity 
- Coronary flow reserve (CFR) 
- Mean blood pressure in the aorta (Pa) and at the sensor position (Pd) 
- Fractional flow reserve (FFR) 
- Hyperemic microvascular resistance (HMR) 
Hyperemia will be caused by the administration of an intravenous infusion of adenosine (140µg / 
kg / min). 
Following this, the CTO will be opened, using standard contemporary strategies and materials. 
After passage of the occlusion with the antegrade wire, a coronary wire with pressure and flow 
sensor will be introduced distally to the occlusion, and hyperemia will be induced by 
administering adenosine intravenously. After measuring the above functional parameters at this 
location, CTO dilatation and stent implantation will be initiated. Successful percutaneous 
coronary intervention (procedural success) is defined as the establishment of TIMI 3 flow with a 
residual stenosis of less than 30% after stent implantation or balloon dilatation. In the case of 
procedural success, the previously described functional parameters will be measured in the 
recovered coronary artery using the coronary wire with pressure and flow sensors when 
administered adenosine intravenously. 
Finally, to evaluate the effect of CTO opening on the physiological parameters of the non-
occluded arteries, all the functional measurements mentioned above will be repeated with the 
same (or closest possible) sensor positions in both non-occluded arteries, as described in detail 
above. 
 
C. Data collection in the procedure 
The following examinations will be performed in all patients who have achieved procedural 
success: 
- Within the first 24 hours of intervention: measurement of coronary flow reserve for LAD and 
RCA artery by non-invasive Doppler echocardiography, 
- 6 months after the intervention: 
- Electrocardiogram 
- Echocardiographic examination 
- Measurement of coronary flow reserve for LAD and RCA artery by non-invasive Doppler 
echocardiography 
- Seattle Angina Questionnaire 
- Information on possible adverse cardiovascular events from intervention to follow-up (MACE) 
- Catheterization of the heart if clinically indicated 
 
 
MEASUREMENT AND DEFINITION 
 

- The procedural success of recanalizing chronic total occlusion.  
Successful percutaneous coronary intervention (procedural success) is defined as the 
establishment of TIMI 3 flow with residual stenosis of less than 30% after stent implantation or 
balloon dilatation. 
- TIMI flow is a scale that semi-quantifies antegrade flow through the coronary artery as follows: 
TIMI 0 - no antegrade flow behind occlusion; TIMI 1 - there is a flow behind the occlusion site 
with incomplete filling of the distal coronary artery; TIMI 2 - slow antegrade flow that 
completely fills the distal artery; TIMI 3 - Normal coronary flow with complete filling of distal 
artery (31). 
- Rentrop classification of collateral flow (30) is a widely used angiographic system that does not 
describe the characteristics of collateral blood vessels themselves, but their effect on filling the 
occluded artery distal to the site of occlusion. There are 4 grades of collateral flow according to 
this classification: Rentrop 0 - no filling of the occluded vessel via collateral blood flow, Rentrop 
1 - filling only the lateral branches of the occluded vessel without filling the main epicardial 
blood vessel, Rentrop 2 - partial filling of the main epicardial blood vessel, and Rentrop 3 - 
completely filling the major epicardial blood vessel. 
- Semi-quantitative classification of collateral vessels (collateral connections) (16): CC0 - no 
continuous connections, CC1 - continuous collateral threadlike connections, CC2 - lateral 
branches (diameter ≥0.4mm). CC3 - Direct connections ≥1mm in diameter. 
- The Seattle Angina Questionnaire is a modern and validated instrument for assessing the 
quality of life in patients with coronary disease (32). This questionnaire is based on five different 
domains that are assessed in patients: physical limitation, anginal stability, anginal frequency, 
treatment satisfaction and disease perception. 
- Myocardial scintigraphy - All patients will have a 740 MBq 99mTc-MIBI myocardial 
scintigraphy given intravenously 10-15 minutes after sublingual administration of 0.5mg 
nitroglycerin (33) before attempting to recanalize the occlusion. The recording will take place 
45-60 minutes after the administration of the radiopharmaceuticals, in a supine position, with a 
single gamma camera equipped with a high-resolution low energy collimator. 64 projections will 
be taken in the 180-degree range (starting from 45 degrees from the right front oblique to 45 
degrees from the left rear position). After the reconstruction of the image, semi-quantification of 
myocardial perfusion and function will be done software. The size and severity of the perfusion 
defect will be calculated based on a 17-segment radiopharmaceutical uptake model and based on 
a guide from the European Nuclear Medicine Association and the European Association of 
Cardiologists for radionuclide imaging of cardiac function (34). The total download score of 
MIBI radiopharmaceuticals (SRS) will be calculated. The size and severity of the perfusion 
defect will also be indicated according to each of the three major vascular territories: anterior 
descendant, circumflex, and right coronary artery. Assessment of regional left ventricular wall 
thickness will be assessed by visual inspection in the Chinese mode of SPECT perfusion images 
(34). The presence of viable myocardium in the infarct zone will be considered as the absorption 
of radiopharmaceuticals ≥55% of normal perfusion, with left-wall wall thickness gain (35–37). 
Also, the left ventricular ejection fraction, end-diastolic volume, and end-systolic volume will be 
evaluated using an automated algorithm (38). 
- Echocardiography - Transthoracic echocardiographic examination will be performed in all 
subjects. All standard echocardiographic sections will be made. Measurements from orthogonal 
apical sections ("two and four cavities") will be used to estimate the global function of the left 
ventricle, with the simulation fraction calculated using the Simpson method. A 17-segment 

model will be used to calculate the wall motion score index of the left ventricular segment, while 
segmental kinetics will be constructed as follows: 1-normal segment kinetics, 2-hypokinesia, 3-
akinesia, and 4- dyskinesia. This score will be calculated by dividing the sum of the mobility 
levels of the individual segments by the total number of visualized segments (39). 
 
Stressechocardiographic test - a submaximal, symptom-limited stress-echocardiographic test on a 
Bruce protocol will be performed in all subjects. Before the test, at the end of each load step, and 
after the test is completed, arterial blood pressure and SF will be measured. The criteria for 
discontinuation of the test are: onset of anginal problems, fatigue, reaching submaximal 
frequency, the onset of ST depression greater than 1 mm, and the onset of hypertensive reaction 
(blood pressure greater than 240/130 mmHg). According to the protocol of the 
stressechocardiographic test, an echocardiographic examination in the left decubital position will 
be done to everyone before and immediately after the test. The test was defined as positive for 
the presence of inducible myocardial ischemia if there was a deterioration of left ventricular 
segmental kinetics at the EHO after the test. 
- Measurement of coronary flow reserve for LAD artery - Transthoracic Doppler 
echocardiographic examination will record blood flow velocities in the LAD artery, at rest and 
after induction of hyperemia by administering adenosine intravenously (0.14 mg/kg/ min). 
Coronary flow reserve will be calculated as the ratio of maximum hyperemic and maximum 
basal flow rate (40). 
- The following invasive functional parameters will be determined for all subjects where 
technically feasible: 
- Basal blood flow velocity 
- Hyperemic blood flow velocity 
- Mean blood pressure in the aorta (Pa) and at the sensor position (Pd) 
- Coronary flow reserve (CFR) 
- Fractional flow reserve (FFR) 
- Hyperemic microvascular resistance (HMR) 
- Procedural complications - All patients will be monitored for the occurrence of periprocedural 
complications, including myocardial infarction, coronary perforation, cardiac tamponade, 
emergency cardiac surgery, complications at the site of vascular access. 
- Adverse cardiovascular events during the follow-up period - All patients will be monitored for 
adverse cardiovascular events during the follow-up period: cardiovascular death, non-fatal 
myocardial infarction, and any recurrent myocardial revascularisation. 
 
 
SAMPLE SIZE 
 
Based on the primary goal of the study, the required number of subjects was calculated according 
to the appropriate formula for Student's t-test for related samples using the following 
assumptions and data from previous published research: statistical power (1-β) = 0.80; statistical 
significance (α) = 0.05; expected change (increase) of coronary flow reserve (CFR) in the donor 
artery after opening of chronic total occlusion of 0.5 (41-43), expected standard deviation for 
invasive Doppler CFR in the reference artery of 0.85 (44). 
𝑛=
(𝑍1−𝛼
2 + 𝑍1−𝛽)2 ∙𝜎2
𝛿2
= (1,960 + 0,842)2 ∙0.852
0,52
= 22,7 ≈23 

The sample size we calculated to be 23 patients, based on the above assumptions. Taking into 
account that the success of the procedure of opening a chronic total occlusion at the Cardiology 
Clinic of the Clinical Center of Serbia is 90% and that 15% of the respondents will be 
unavailable for a six-month follow-up, a total of 30 patients should be included. 
 
STATYSTICAL ANALYSIS 
 
- The following statistical methods will be used for data description: 
Mean, median, standard deviation, interquartile range 
- The following methods of analytical statistics will be used: 
chi-square test, Student's t-test for independent and related samples, correlation, linear 
regression, logistic regression, The ROC curve and C-statistics will be used to determine the cut-
off values. All tests will be realized as two-way. A p-value of <0.05 will be considered 
statistically significant. Data analysis will be done in the SPSS statistical software package 
(version 19 or above). 
 
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