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3. Determining the limit value of the coronary blood flow velocity and its
accuracy in determining the significant stenosis of the left main coronary artery
for the selection of patients for coronary angiography.
4. Evaluating the predictive value of ultrasound parameters of coronary blood
flow for the occurrence of adverse events.
5. Determining the role of myocardial revascularization in the change of
prognosis of patients with altered coronary blood flow upon the transthoracic
ultrasound data.
Scientific Novelty of the Research
1. Determined the proportion of patients with pathological changes in heart artery
blood flow in the cohort of patients referred for routine echocardiography.
2. Found a correlation between the coronary blood flow at rest and changes in
myocardial contractility during stress echocardiography with exercise.
3. Calculated the limit value velocities for non-invasive ultrasound corresponding
to the narrowing of the heart arteries of more than 50% according to coronary
angiography data in an “unselected” cohort of patients with suspected or
diagnosed coronary artery disease.
4. Proved a high risk of immediate adverse outcomes, including death, myocardial
infarction, in patients with high coronary blood flow velocities (>70 cm/s) in the
proximal segments of the left coronary artery.
5. For the first time, showed the positive effect of myocardial revascularization on
the prognosis of patients with high coronary blood flow velocities in the
proximal segments of the left coronary artery.
Theoretical and Practical Significance
Substantiated and proposed quantitative criteria of pathologically altered
coronary blood flow during routine echocardiography.
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Based on the results of the study, determined the indications for coronary
angiography in patients with blood flow velocities in the proximal segments of the
left coronary artery exceeding 70 cm/s.
Using thresholds of non-invasively determined blood flow velocities, it is
possible to predict stenosis of more than 50% of a particular coronary artery
segment.
As a result of the study, we proved the need for revascularization of patients
with high blood flow velocities in the proximal segment of the left coronary artery
as soon as possible, optimally less than 3 months from the date of the examination.
This paper provides the limit value blood flow velocities in the coronary
arteries, indicating a 10% probability of death/myocardial infarction in the
following 10 months.
Research Methodology and Methods
This paper is a clinical single-center prospective study that solves the problem
of timely surgical myocardial revascularization in patients with coronary artery
disease by selecting patients based on the diagnostic and prognostic significance of
ultrasound parameters of coronary blood flow obtained by a new method of
non-invasive examination of the heart arteries.
Object of the research: patients over 18 years old, referred for routine
echocardiography, who have not previously undergone сoronary artery bypass
surgery.
Subject of the research: the results of surgical myocardial revascularization in
patients with altered coronary blood flow detected by transthoracic ultrasound and
the further prognosis of these patients.
Hypothesis of the research: surgical myocardial revascularization in patients with
high coronary blood flow velocities according to ultrasound data will lead to an
improved prognosis compared to patients without revascularization. High coronary
blood flow velocities in certain areas of different coronary arteries will correlate
with the data of stress echocardiography and coronary angiography. Patients with
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high coronary blood flow velocities will have a higher likelihood of adverse
outcomes in the near follow-up term.
The work involved several stages:
1. Determining the frequency of detecting altered coronary blood flow in the
general unselected population of patients referred for echocardiography. From
May 2014 to August 2016, sequential screening of patients was made.
2. Comparing the coronary blood flow parameters with the results of stress
echocardiographic test with exercise, 150 people included.
3. Comparing the data of ultrasound parameters of coronary blood flow with the
data of selective coronary angiography. Involved a group of 100 patients.
4. Assessing the prognostic value of ultrasound parameters of coronary blood flow
for the occurrence of acute coronary events in patients with suspected or proven
coronary artery disease. Involved a group of 361 people with altered blood flow.
5. Determining the role of myocardial revascularization in the change of prognosis
of patients with altered coronary blood flow upon the transthoracic ultrasound
data. Involved a group of 361 people with altered blood flow.
Provisions for Defense
1. Transthoracic ultrasound of the heart arteries at rest can be used to screen for
pathological changes in coronary blood flow in the diagnosis of coronary artery
disease in most patients referred for echocardiography.
2. Blood flow velocities in the left coronary artery correlate with the end-diastolic
volume of the left ventricle at rest, positive stress echocardiographic test, and
ejection fraction at peak load.
3. High velocity of coronary blood flow in the left main coronary artery, according
to ultrasound, may be an indication for coronary angiography.
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4. Non-invasive recording of high velocity of the coronary blood flow in the left
coronary artery basin is a predictor of the risk of adverse cardiovascular events
in the short term.
5. Myocardial revascularization in patients with altered coronary blood flow
according to ultrasound examination has a favorable prognostic effect.
Testing the Research Results
The thesis results were presented at the international congress "ESC, 2016",
Rome, Italy (2016); as a presentation at the international congress
EuroEcho-Imaging 2016, Leipzig, Germany (2016); as a presentation at the
international congress EuroEcho-Imaging 2017, Lisbon, Portugal (2017); as an
oral report at the XXIII Annual Session of A.N. Bakulev National Medical
Research Center of Cardiovascular Surgery (2019); as an oral presentation at the
international conference "2nd International Conference on Cardiovascular
Diseases and Therapeutics" Amsterdam, Netherlands (2019); oral presentation at
the international conference "WCCD-2019 Cardiology and Cardiovascular
Diseases Conference", Barcelona, Spain (2019); oral presentation at the
international conference "World Heart and Cardiothoracic Surgery", Singapore
(2019).
Publications
The main provisions of the scientific paper are provided in 10 published printed
papers, of which 3 were published in peer-reviewed scientific journals
recommended by the Higher Attestation Commission of Russia.
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Degree of Reliability and Validity of the Research Results
Reliability of the results is ensured by a sufficient representative sample,
prospective design of all research stages, the use of modern survey methods and
statistical processing methods corresponding to the objectives. Conclusions and
practical recommendations are entirely based on the results obtained in the paper.
Contribution of the Author
The author independently formulated the goal and objectives, developed the
research design. The author took part in the selection of patients for inclusion in
the research. The author analyzed coronary angiograms. The author independently
performed revascularization of selected patients.The author independently
performed statistical processing and analysis of the resulting data, independently
wrote and co-authored scientific papers based on the research results,
independently wrote the thesis text.
Structure and Volume of the Thesis
The thesis is stated on 124 pages of typewritten text, contains 9 tables and 42
figures. The reference list includes 143 literature sources, including 140 foreign
sources.
The thesis was written at the Federal State Budgetary Educational Institution
of Higher Education "Saint-Petersburg State University".
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Chapter 1. Literature Review
1.1 Statistics and drug treatment of coronary artery disease.
For many decades, coronary artery disease and other cardiovascular diseases are in
the first lines of the annual statistics of morbidity and mortality both in developed
countries of Europe and America, as well as in Russia. According to the American
Heart Association (AHA), in 2016, about 841,000 people died from this disease in
the country [93], and the expected number of acute coronary events was 1,055,000,
including 720.000 new cases. In general, the country has noted a decrease in the
mortality rate from coronary artery disease by 31% over the period 2006-2016,
however, even such successes in the fight against the disease are not a reason to
talk about a victory over it and mortality is still very high, ranking first among
other diseases. The European Heart Association reports that the incidence of
coronary artery disease in Europe averages 4,530 cases per 100.000 population,
ranging from less than 1,600 cases in Switzerland, Israel and France to more than
10.000 cases in Greece and Ukraine. Coronary artery disease is the cause of 38%
of deaths from cardiovascular diseases in women and 44% in men and remains the
most common cause of death in the European Union [96, 123]. Russia, according
to the Rosinfostat.ru portal
1
, for the period from 2000 to 2018, also shows a
decrease in mortality from all cardiovascular diseases by 31%, but the numbers are
still very high and approximately three times higher than mortality from
neoplasms – the second one among the main problems of morbidity in our country.
According to the portal, 28.4% of all deaths in 2017 were caused by coronary
artery disease, which is about 1,200 people per 100.000 population. The number of
newly diagnosed cases of this disease, including acute coronary events is
1,028,000 in 2016. Thus, the rates of morbidity and mortality from coronary artery
disease among the population around the world confirm the high degree of
relevance of studying the problems of combating this disease both in cardiology
and cardiac surgery and in the field of early outpatient diagnosis – a valuable
method for detecting coronary artery disease.
https://rosinfostat.ru/smertnost/#i-7
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Reducing mortality in the treatment of coronary artery disease is the main task
cardiac surgery and conservative methods solve. Conservative treatment proved to
be effective in reducing cardiovascular mortality. In cardiology, many new
treatments for coronary artery disease were developed over the past decades.
Among them, one can especially note the invention of such a group of drugs as
statins, the emergence of new types of disaggregants and oral anticoagulants, new
data on the positive effect of ACE inhibitors on the course of hypertensive heart
disease, coronary artery disease with a reduced ejection fraction.
The history of the relation of hypercholesterolemia with the risk of coronary artery
disease and the search for a drug to mitigate it began about 80 years ago. In 1939,
Müller described the relation of hypercholesterolemia with cardiac angina. In 1949,
Gofman found a correlation between human plasma lipoprotein levels and the risk
of coronary artery disease. In 1976, Endo discovered the first effective statin drug.
1994 marks the beginning of the satin era after the completion of the first
large-scale, randomized, double-blind study (4S), which showed that aggressive
therapy with simvastatin reduces mortality from both coronary artery disease and
from all other causes. In 2010, a team of scientists from Oxford, UK, made a
meta-analysis of 26 randomized studies involving a total of more than 170.000
patients. As a result: Compared to less intense regimens, more intense regimens
resulted in a significant 15% (95% CI 11-18; p<0.0001) reduction in acute vascular
events, for coronary death or nonfatal myocardial infarction 13% (95% CI 7-19;
p<0.0001), with coronary revascularization 19% (95% CI 15-24; p<0.0001) and
with ischemic stroke 16% (95% CI 5-26; p = 0.005). Thus, the emergence of
statins as a drug in the fight against coronary artery disease can be considered a
high merit of science and medicine, because scientists suggest that a decrease in
LDL levels by 2-3 mmol/l can lead to a 40-50% decrease in mortality from
coronary artery disease. [10]
Another group of drugs that have proven their role in reducing the incidence of
death from coronary artery disease are disaggregants. In 2002, a team of scientists
made a meta-analysis of 287 randomized studies involving 212,000 patients.
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Scientists managed to draw the following conclusions: In each of these high-risk
patient groups, the beneficial effects significantly outweighed the risks of major
extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with
doses of 75-150 mg per day as effective as higher daily doses. Clopidogrel reduced
serious vascular events by 10% (4%) compared with aspirin, its analogue
(clopidine) – by 12% (7%). Therefore, aspirin (or another oral anti-thrombocytic
drug) is protective for most types of patients at increased risk of acute vascular
events, including those with acute myocardial infarction or ischemic stroke,
unstable or stable cardiac angina. [9]
ACE inhibitors are also important drugs for reducing cardiovascular mortality.
[121, 105]
Despite the advances in cardiology in recent years, not all patients respond to
conservative treatment. Mortality from this disease is still highest in adults. Thus,
existing treatments are insufficient. Development of other types is required,
including surgical treatment.
1.2 Percutaneous and surgical treatment of coronary artery disease.
1986 saw another landmark event in the surgical treatment of coronary arteries.
The first stenting of the coronary artery was made. Since then, endovascular
techniques strengthened their position as a method of surgical myocardial ischemia
treatment. The minimally invasive technique of stenting of the coronary vessels
was quickly introduced into the practice of cardiologists and cardiac surgeons.
The efficacy of percutaneous coronary intervention and optimal drug therapy was
compared in several meta-analyzes [55, 60, 16, 62, 115, 125] and a large
randomized clinical study [14]. Bucher et al. In 2001, they published their
meta-analysis where 953 patients underwent coronary angioplasty and 951
underwent optimal drug treatment. Patients in the angioplasty group versus the
drug-treated group had risk scores of 0.70 (95% CI 0.50 to 0.98; heterogeneity P
<0.001) for cardiac angina; 1.42 (0.90 to 2.25) for death and nonfatal myocardial
infarction, 1.32 (0.65 to 2.70) for death, 1.59 (1.09 to 2.32) for coronary artery
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bypass surgery and 1.29 (0.71 to 3.36; heterogeneity P <0.001) for repeated
angioplasty. Therefore, the researchers concluded that percutaneous transluminal
coronary angioplasty may lead to a greater reduction in cardiac angina in patients
with coronary artery disease than drug treatment [16].
One meta-analysis [115] revealed an increase in the survival rate of patients
undergoing PCI compared with ODT. Another meta-analysis revealed a decrease
in mortality after PCI compared with ODT even after excluding patients with
myocardial infarction [60]. However, this benefit was not proven in the
COURAGE study [14]. A group of 2,287 patients with significant coronary
atherosclerosis and objective signs of myocardial ischemia were randomized, who
underwent only ODT or PCI on the ODT background. The median follow-up was
4.6 years. The proportion of patients without cardiac angina after 1 year was 12%
higher in the PCI group. After 5 years, primary or repeated revascularization was
made in 21% of patients in the PCI group and in 33% of patients undergoing ODT
(p <0.001), but there were no advantages in survival rate, adverse cardiovascular
events in invasive methods of treatment compared only with optimal drug therapy
[133].
Surgical myocardial revascularization, as a method of treating coronary
artery disease, has been used since the sixties of the last century. During this time,
the surgical technique has been constantly improved, but the essence of the
intervention remains the same – to form new pathways of blood supply to the
myocardium bypassing areas of the coronary artery stenotic with atherosclerotic
plaque. The adverse effects of documented myocardial ischemia on the risk of
clinical outcomes (death, myocardial infarction, acute coronary syndrome, cardiac
angina) have been well known for two decades [29, 50].
Revascularization improves the prognosis in asymptomatic patients with advanced
myocardial ischemia [29, 50. The advantage of coronary artery bypass surgery
over drug therapy in certain subgroups of CAD patients was found in a
meta-analysis of randomized clinical studies [137] held before 2000. For example,
researchers at the National Heart, Lung, and Blood Institute, Bethesda, Maryland,
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made a systematic review using patient data from seven randomized studies
comparing primary coronary artery bypass surgery strategy with one of the basic
drug therapy strategies to assess the effect on prognosis in patients with stable
coronary artery disease. From 1972 to 1984, 1,324 patients were referred to
coronary artery bypass surgery and 1,325 – to drug therapy. The proportion of
patients in the drug treatment group who underwent coronary artery bypass surgery
was 25% after 5 years, 33% after 7 years and 41% after 10 years: 93.7% of patients
referred to the group of surgical vascularization underwent CABG (coronary artery
bypass grafting). The surgical revascularization group had significantly lower
mortality than the drug treatment group after 5 years (10.2 versus 15.8%; OR 0.61
[95% CI 0.48–0.77], p = 0.0001), 7 years (15.8 versus 21.7%; 0.68 [0.56–0.83], p
<0.001) and 10 years (26.4 versus 30.5%; 0.83 [0.70–0.98]; p = 0.03). Therefore,
the group of analysts concluded that the strategy of surgical revascularization is
associated with lower mortality than with medical treatment with delayed surgery,
especially in high and medium-risk patients with stable coronary artery disease. [
137].
With the improvement of the surgery technique, the introduction of new techniques
and the analysis of the results, the data on the surgical myocardial revascularization
effectiveness became increasingly evident. In 1986, Loop FD, Lytle BW, Cosgrove
DM, et al. compared patients in whom coronary artery bypass grafting was
supplemented with mammary coronary artery bypass grafting of the anterior
descending artery (n = 2,306) with patients in whom only autovenous grafts were
used (n = 3,625). The 10-year actuarial survival rate in the group using the internal
mammary artery versus the group using only venous bypass grafting (excluding
inpatient deaths) was 93.4% versus 88.0% (p = 0.05) for patients with single-vessel
lesion, 90.0% versus 79.5% (P less than 0.0001) for people with two-vessel disease;
and 82.6 percent versus 71.0 percent (P less than 0.0001) for patients with
three-vessel disease. After adjusting for demographic and clinical differences using
multivariate Cox analysis, they found that patients who had only venous grafts had
a 1.61 times higher risk of death within 10 years compared with those who had
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