JSC «Astana Medical University» PhD THESIS ANNOTATION. Specialty: 6D «MEDICINE»

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1 JSC «Astana Medical University» PhD THESIS ANNOTATION Specialty: 6D «MEDICINE» Title: «Prognostic efficiency of sudden cardiac death s predictors in preserved and moderately reduced left ventricle ejection fraction due to ischemic origin» UDC: : Thesis supervisor: doctor of medical science Zhussupova Gyulnar Thesis consultant: doctor of medical science Abdrakhmanov Ayan Foreign thesis consultant: Josef Kautzner, MD, PhD, Czech Republic Researcher: Rib Yelena Astana 2018

2 Relevance of the research: according to the European Society of Cardiology 2015 updated Guidelines sudden cardiac death (SCD) it is non-traumatic, unexpected fatal event due to cardiac disease occurring within 1 hour of the onset of symptoms. If death is not witnessed, the definition applies when the victim was in good health 24 hours before the event (Priori S.G. et al, 2015). This term takes into account only cases of SCD due to cardiovascular diseases, and a one hour time restriction presupposes the maximum probability of an arrhythmic mechanism of sudden circulatory arrest. As it is well known that with the duration of terminal conditions up to one hour, arrhythmic death is recorded in 88-93% of cases (Albert C.M. et al., 2003). The phenomenon of SCD is global and depends on the leading position of diseases in the structure of mortality of the population. Despite the worldwide trend in reducing cardiovascular mortality, about 17 million people die each year and about 25% of them due to SCD (Mendis S.P., Norrving B., 2011). According to epidemiological data, every year in the USA thousand people are documented by the sudden circulatory arrest, which in 95% cases end with SCD (Myerburg R.J., Castellanos A., 2001). In Western European countries about 2500 people die suddenly a day, and only 2-5% of deaths occur in hospitals (Kuck K.H. et al., 1996). Unfortunately, in the territory of most countries of the Eurasian Commonwealth there are no reliable statistics of SCD cases. The amount of the population dying suddenly for the Russian Federation, for example, was calculated mathematically, based on the share of mortality from diseases of the cardiovascular system. According to this information, the annual frequency of SCD in Russia can vary from 450 to 600 thousand cases a year (Bokeria L., Revishvili A., 2013). The estimated annual number of SCD cases is about 3 million, with the possibility of survival no more than 1.0% (Myerburg, R.J., 2003). Even considering the high level of the emergency care system in Western Europe, the probability of successful resuscitation of the is not higher than 5%. The majority of cases occurs without witnesses and resuscitation within the "gold" 6-8 minutes is technically impossible. Up to 40% of SCD cases are not witnessed or occur during sleeping and 80% of SCD occur at home (de Vreede- Swagemakers J.J. et al., 1997). The first place in the structure of the causes of SCD is ischemic heart disease (IHD) 80-85%. In 65% of SCD cases, the arrhythmic mechanism is realized due to an acute disorder of the coronary circulatory. Rhythm disorders this is the main realizing mechanism of the sudden circulatory arrest. About 90% circulatory arrest consist ventricular tachyarrhythmias and 10% - pulseless electrical activity and bradyarrhythmias, which significantly reduce the chance of survival in comparison with tachyarrhythmias (Bayes de Luna A. et al., 1989, Myerburg R.J., 2001). The world cardiological community agreed on the opinion that it is much more effective to develop measures SCD risks assessment and prevention. And this remains an extremely difficult task at the present time. Up to date, we do not have precise methods for predicting SCD.

3 According to A.Revishvili (2016), nowadays we know 40% of SCD risk factors, but the remaining 60% of risk factors we does not detect with any known diagnostic methods. At present, there are genetic markers for the development of life-threatening arrhythmias, neurohumoral factors, indices of the systemic inflammatory process, electrophysiological and cardiohemodynamic predictors of SCD are known. Also predictors include the same risk factors of IHD and chronic heart failure, as the leading nosological prerequisites of SCD (sex, age, smoking, obesity, lipid profile, diabetes, arterial hypertension etc.) (Bokeria L., Revishvili A., 2013). The most applicable in practice are several potential predictors: the presence of a disease associated with high risk of SCD, severe systolic dysfunction of the left ventricle (LV) and the presence of ventricular ectopy (Bokeria L., Bokeria O., Bazarsardaeva T., 2009). Most current prospective studies consider the low LV ejection fraction as the main predictor of SCD. Nevertheless for an objective assessment of the threat of SCD, only severe LV dysfunction is not enough. Thus in the Oregon Sudden Unexpected Death Study, it was found that a severe decreasing LV contractility was a predictor of SCD, but only in a third of cases of SCD in the population, while 65% of victims of sudden death did not show significant LV dysfunction and, accordingly, they had not indications for implantation of a cardioverter-defibrillator. In half of the SCD cases, LV ejection fraction was normal, and in 20% it was moderately reduced (LV ejection fraction was 35-50%) (Reddy P.R. et al., 2009). Similar results were obtained after the completion of the Maastricht Circulatory Arrest Registry Study: 51% of SCD cases were documented in patients with a LV ejection fraction above 40% (Gorgels A.P. et al., 2003). Mäkikallio T.H. et al. (2005) presented a meta-analysis of 2,130 patients after a myocardial infarction: more than 60% of the SCD episodes occurred in patients with LVEF more than 35%. Nearly 50% of patients with I-II functional class of heart failure according die due to sudden arrhythmic death without a significant increase of cardiac decompensation (Gurevich M., 2005). Therefore, using the severe systolic LV dysfunction as the traditional predominant predictor of death, we have a great risk of missing most of the patients threatened by SCD. Although reduced LV ejection fraction remains one of the major predictors of SCD, a number of studies confirm the necessity to look for other risk factors or their combinations that can be used in addition to the myocardial contractility index. Thereby a significant group of IHD patients, who have moderate LV dysfunction, attracts attention (Roberto M.L. et al., 2015). Purpose of the study evaluate the possibilities and effectiveness of combination of predictors for predicting SCD in patients with stable IHD with a preserved and moderately reduced LV ejection fraction.

4 Object of study: patients older than 18 years with a chronic stable IHD with a moderately reduced LV systolic function (LV ejection fraction 40-49%) and preserved LV contractility (LV ejection fraction 50%). Subject of study: clinical predictors of SCD, non-invasive predictors of electrical instability of the myocardium, documented life-threatening ventricular arrhythmias, cases of SCD. The research tasks: 1.studying the structure and prevalence of indices of myocardium electrical instability, clinical risk factors of SCD and life-threatening ventricular arrhythmias in patients with stable IHD with a preserved and moderately reduced LV ejection fraction; 2. analyzing the relationship between indicators of non-invasive tests and lifethreatening ventricular arrhythmias in patients with stable IHD; 3. studying the survival data of patients with stable coronary artery disease, depending on the combination of potential predictors of SCD and myocardial contractility; 4. making a prognostic model of SCD risk in patients with stable IHD with moderately reduced and preserved LV ejection fraction. Research methods Type of study: prospective single-center cohort. Research technique: transthoracic echocardiography; anthropometric measurements; complex assessment of a patient with chronic heart failure with the Scale of Clinical Condition Assessment, a six-minute walk test; resting 12-lead ECG; 24-hour Holter ECG monitoring; cardiorhythmography with basic autonomic tests; treadmill test. After 3, 6 and 12 months, patients were invited to follow-up visits with a clinical examination and 24-hour Holter ECG monitoring. Research surrogate endpoints were documented in the study - the presence of life-threatening ventricular arrhythmias; secondary endpoints - acute myocardial infarction, emergency revascularization procedures, cases of cardiovascular death; primary endpoints - SCD cases. Novelty and scientific originality: 1. Determination of the role of noninvasive predictors and treadmill chronotropic parameters of arrhythmogenesis in patients with stable IHD with moderately reduced and preserved LV ejection fraction. 2. Evaluation of the predictive capabilities of the SCD predictors combination. Making a logistic regression model and creating on its basis a calculator for likelihood unfavorable outcome forecasting. Applied value of the research: 1. We propose to take into account the following factor when assessing the individual risk of SCD, the selection of patients for electrophysiological investigation and, possibly, the primary implantation of a cardioverter-defibrillator: the presence of a moderately reduced or preserved LV ejection fraction among

5 patients with stable IHD should not place restrictions on their classification as high-risk groups of sudden circulatory arrest/scd. 2. The combination of non-invasive potential predictors of myocardial electrical instability along with an assessment of a patient's functional status and features of a coronary lesion can predetermine the risk of an unfavorable prognosis irrespective of the LV ejection fraction. 3. The risks of SCD due to arrhythmic events did not differ in the groups of patients with normal and moderately reduced LV ejection fraction. The indicator of systolic dysfunction did not include into the prognostic model as a significant predictor of the unfavorable outcome. Essential provisions for thesis defense: 1.In patients with stable IHD with a preserved and moderately reduced LV ejection fraction there is no difference in the frequency of the main electrophysiological noninvasive predictors of electrical instability of the myocardium. 2. Life-threatening ventricular arrhythmias are detected more often in patients with LV ejection fraction 40-49%. The most reliable correlation with the development of life-threatening ventricular arrhythmias had the indicators of Duke treadmill score, six-minute walk test, the sum of points on the Scale of Clinical Condition Assessment, the number of stenotic coronary vessels. 3. There were no significant statistical differences in the incidence of SCD among patients with a preserved and moderately reduced LV ejection fraction. 4. An unfavorable survival function was defined in patients with stable IHD, LV ejection fraction 40% and the following combination of predictors: Duke treadmill score less than 5 points, the sum of the Clinical Condition Assessment Scale score 4 or more, the overcome distance of the six-minute walk test less than 380 m and the documented life-threatening ventricular arrhythmias in the anamnesis. 5. Using a combination of life-threatening ventricular arrhythmias criteria, a distance of a six-minute walk test, a Duke treadmill score, a score on the Clinical Condition Assessment Scale, the heart rate at rest, the LV end-diastolic diameter, the stenotic lesion of the left anterior descending in the resulting logit-equation helps to determine the risk of SCD among patients with stable IHD and LV ejection fraction 40% with a probability of a true prediction of 81.5%. Approbation of the thesis The main results of the thesis were reported and discussed at: - The 3 rd International Congress "Health for All People. Equality, solidarity and social justice - modern challenges to primary healthcare "(Almaty 2014); - The 57th, 58th, 59th scientific and practical conferences of young scientists and students with international participation (Astana ); - Meeting of the Therapeutic Society of JSC "Medical University Astana" (December 2015); - XII International Congress "Cardiostim" (Russia, St. Petersburg 2016); - International Scientific and Practical Conference AsiaPCR Single Live 2016 (Singapore 2016);

6 - 2 nd International Scientific and Practical Conference of Students and Young Scientists "Health Sciences Conference", (Lithuania, Klaipeda 2016); - IV Republican Scientific and Practical Conference "Essential issues of emergency cardiology" (Astana, April 2017); - Meeting of the Internal Disease Department No. 2, JSC "Astana Medical University" (April 24, 2017); - Meeting of the Scientific Seminar of therapeutic and related specialties of JSC "Astana Medical University" (June 5, 2017). Publications There were 15 scientific works published on the subject of this thesis, including 4 publications in the periodical journals of Kazakhstan; 1 original article in the journal indexed in the Scopus and PubMed databases; 9 publications in the materials of international and republican conferences (Singapore, Lithuania, Russia, Kazakhstan); two acts of implementation (2017); guidelines for practicing doctors (2016), the author was in Working group of the Clinical Protocol of Diagnosis and Treatment "Ventricular arrhythmias and prevention of sudden cardiac death" (approved by the Ministry of Health of the Republic of Kazakhstan, June 23, 2016). Thesis scope and structure The thesis is presented on 137 pages of computer typed text, consists of introduction, review of literature, research results, conclusions, practical recommendations and a list of references. The work is illustrated by 22 tables and 35 drawings, supplemented by 9 applications. The bibliography includes 242 sources, 183 of them are in foreign language.