Each patient will have a peripheral catheter placed, blood will be drawn, followed by
dynamic SPECT on a two-day rest/stress protocol, and then standard gated myocardial
perfusion scintigraphy will be performed (the resting study will be followed by a study
with dobutamine administration at doses of 5 and 10 µg/kg/min). The protocols will be
described in detail in the Interventions section. Based on the results of dynamic SPECT,
patients will be divided into 2 groups depending on the state of myocardial blood flow
reserve. All nuclear examinations will be performed using a hybrid specialized SPECT/CT
Discovery NM/CT570C.
Determination of myocardial blood flow and reserve. Myocardial blood flow and
reserve will be assessed using specialized software (GE Alcyone: Dynamic Analysis
Tool), two series of images will be formed from the array of primary data: 1)
reflecting the passage of the radiopharmaceutical bolus through the LV cavity and
myocardium from 1 to 120 seconds of the study; 2) a group of 8 dynamic
tomoscintigrams (frame duration 30 s) a series of static tomoscintigrams showing the
accumulation of the radiopharmaceutical in the LV walls. The next stage of data
processing (bi means of of specialized software (4DM CFR) will include the analysis
of static and dynamic images, with the establish of "activity-time" graphs based on
areas of interest corresponding to the cavity, walls (anterior, posterior, lateral ,
septum and apex) and 17 segments of the polar map of the left ventricle. On the
basis of the obtained graphs, indices of myocardial blood flow at rest and stress
will be determined (in ml per 1 gram of tissue per minute) on the basis of which the
indices of the reserve of myocardial blood flow will be determined, reflecting the
MBF stress/rest ratio. These indices will be estimated for all walls, vascular
regions and segments of the polar map of the left ventricle.
Evaluation of myocardial perfusion. To evaluate the results of myocardial perfusion,
a specialized software package Corridor 4DM (University of Michigan, Ann Arbor, MI,
USA) will be used with the construction of sections along the short and long axes of
the heart, as well as a 17-segment polar map of the left ventricle normalized to
100%. Semi-quantitative calculation of local disorders of LV perfusion will be
performed in points as follows: 0 - accumulation of radiopharmaceuticals in the
myocardial segment ≥70% of the maximum; 1 - a mild decrease in accumulation
(50-69%), 2 - a moderately reduced accumulation (30-49%), 3 - a pronounced decrease
in accumulation (10-29%) and 4 - a severe decrease of radiopharmaceuticals
accumulation (<10%). The calculation of the total violation of LV perfusion will be
made as follows: a decrease <4 points will be regarded as the norm; 4-8 - as easy;
9-13 - as moderate; >13 - as a severe deterioration of myocardial perfusion. Thus,
the total perfusion impairment on exercise (SSS - Summed Stress Score), at rest (SRS
- Summed Rest Score), as well as SDS - Summed Difference Score - will be calculated.
In addition, the indicator called transient ischemic dilatation (TID) will be
determined in a specialized Quantitative Perfusion SPECT software package (QPS
software, version 2013, Cedars-Sinai).
Evaluation of inotropic function and mechanical dyssynchrony
To assess contractile dysfunction, we will analyze the results of gMPI obtained
during dynamic acquisition with ATP (early post-exercise images), after 60 minutes
after the introduction of radiopharmaceuticals, obtained with dobutamine gMPI, as
well as during the study at rest. The assessment of stress-induced changes will be
estimated as the difference between the score during the stress test and at rest (Δ
= [value at stress] - [value at rest]). To get early post-exercise images from the
array of primary data obtained during dynamic SPECT, list data from 4 to 8 will be
reconstructed. The resulting images will be processed in Corridor 4DM SPECT (INVIA,
Ann Arbor, MI, USA), Emory Cardiac Toolbox (Emory University/ Syntermed, Atlanta,
GA), and QGS/QPS (Cedars-Sinai Medical Center, CA, USA). After construction the
activity-time curve, the following parameters of the LV contractile function will be
automatically estimated:
End-systolic volume (ESV, ml); End-diastolic volume (EDV, ml); Ejection fraction
(EF, %); Peak ejection rate (PER, EDV/s); Peak filling rate (PFR, EDV/s).
After the construction of the phase histogram according to the algorithm "time to
the maximum contraction", the following MD indices will be estimated automatically:
Phase standard deviation (PSD) - standard deviation of the phase histogram;
Histogram bandwidth (HBW) - phase diagram width;
CT coronary angiography CT coronary angiography, based on which patients will be
included in the study, will be performed at the stage according to indications. The
study will be conducted to assess the condition of the coronary bed on a 64-slice GE
Discovery NM/CT 570C (GE Healthcare, Milwaukee, WI, USA). Unenhanced heart scans
with prospective ECG synchronization and subsequent reconstruction in the 75% phase
of the R-R interval will be performed to determine the coronary calcium index. The
study will be conducted from the level of the tracheal bifurcation to the diaphragm.
Scanning parameters will include a tube voltage of 120 kV, current of 435 mA, tube
rotation time of 0.4 s, slice thickness of 2.5 mm, and an interslice interval of 2.5
mm. The coronary artery calcification index will be calculated using a dedicated
Advanced Workstation (GE Healthcare) with SmartScore 4.0 software. The coronary
calcium index will be determined according to the Agatston method for the trunk of
the left coronary artery, the left anterior descending artery, the circumflex
artery, the right coronary artery, the posterior interventricular branch, and also
in total. Before starting CT coronary angiography, each patient's heart rate and
blood pressure will be measured. Patients whose heart rate exceeds 65 beats per
minute at the start of the study will receive an intravenous injection of 1 mg
metoprolol (Betaloc, AstraZeneca). CT coronary angiography will be performed from
the level of the tracheal bifurcation to the diaphragm during breath-holding (6-8 s)
in prospective (for HR≤55) or retrospective (for HR>55) ECG-synchronized mode. To
contrast coronary arteries, an intravenous infusion of 85-90 ml (at a rate of 5
ml/s) of an iodine-containing (370 mg iodine/ml) radiopaque substance will be used.
The scan will start when a density of 200 HU is reached in the ascending aorta. CT
angiography recording will be performed with the following parameters: current
strength of 120 kV, voltage of 300-600 mA with ECG modulation, tube rotation speed
of 0.4 s, and pitch: 0.18-0.22 (depending on heart rate). During the study, the
radiation exposure will range from 1.5-3 mSv (with prospective ECG synchronization)
to 15-20 mSv (with retrospective ECG synchronization). Image reconstruction will
occur at the 75% phase of the cardiac cycle with a slice thickness of 0.625 mm and
an interslice interval of 0.625 mm. In the presence of rhythm artifacts, images
acquired with retrospective synchronization will be additionally reconstructed in
the diastolic phase of the cardiac cycle (70% and 80% of the RR interval duration)
and in the early diastole phase (40%, 45%, and 50% of the RR interval duration).
Images with the best visualization quality of the coronary arteries will be used for
further analysis. All data will be analyzed using multiplanar and curvilinear
reconstructions. After the CT reconstruction, the images will be transferred and
processed on a specialized workstation (AdvantageWorkstation 4.3; GE Healthcare).
Segments of the coronary bed will be analyzed for the presence of atherosclerotic
plaques. The quality of MSCT coronary angiograms will be assessed on a 4-point
scale: 1 - excellent quality (no motion and rhythm artifacts, no significant
artifacts from calcified plaques, clear identification of artery contours); 2 - good
quality (minimum artifacts, minimal blurring of vessel contours); 3 - adequate
quality (moderate artifacts, moderate blurring of vessels without interrupting their
contours); 4 - poor quality (non-interpretable image, doubling or discontinuity of
the vessel contour, lack of clear visualization of a part of the vessel). Only
images with quality 1-3 will be used in the analysis. According to the American
Heart Association criteria, the coronary tree will be divided into 16 segments. The
degree of coronary artery stenosis will be calculated in each segment as the
percentage ratio of the minimum arterial diameter at the level of the constriction
to the diameter of the normal artery immediately proximal to the plaque. Stenoses
≥50% of the arterial lumen will be considered significant.
Epicardial adipose tissue (EAT) analysis will be performed on unenhanced images
using a dedicated Advantage Workstation 4.3 (GE Healthcare). The EAT volume will be
calculated in cubic millimeters automatically after manual marking of the
pericardial contour in the density range from -30 to -190 HU. Also, the maximum
thickness of the EJC will be measured manually on axial sections at two points:
above the apex of the heart and in the right atrioventricular sulcus.