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I. ДИАГНОСТИКА И ЛЕЧЕНИЕ
мрнти 76.29.30 MODERN DIAGNOSTICS AND TREATMENT OF
HYPERTROPHIC CARDIOMYOPATHY
ABOUT THE АUTHORS
Sagatov I.Y. - Head of the managment department of SR, JSC "NSCS n. a. A.N.
Syzganov"
Shabelyanov S.O. - resident majoring in "Radiation Diagnostics" NSCS n. a. A.N. Syzganov
Yerseit A.B. - resident majoring in "Radiation Diagnostics" NSCS n. a. A.N. Syzganov
Keywords
hypertrophic cardiomyopathy, echocardiography, MRI, mutation, myectomy
Sagatov I.Y., Shabelyanov S.O., Yerseit A.B.
JSC NSCS named after A.N. Syzganov, Almaty, Kazakhstan
Abstract
Introduction. Hypertrophic cardiomyopathy (HC) is a structural and functional pathology characterized by a significantly thickened ventricular myocardial wall. The prevalence of HC is 1:500. Up to 60% of cases in adults is an autosomal dominant disease in which there are mutations in the genes encoding sarcomere protein. Medical history and clinical picture. Manifestation of the disease is diverse and depends on the penetrance of the genes involved in this pathology. Most patients have no complaints. The most common symptoms are shortness of breath, fatigue, swelling in the ankles, feet, abdomen, and neck veins. Often accompanied by obstruction of the left ventricle and is manifested by symptoms such as shortness of breath, chest pain and loss of consciousness. Diagnostics. An important role in the diagnosis of HC is played by ECG, echocardiography, MRI and CT. In adults, hypertrophic cardiomyopathy is diagnosed with an increase in the wall of the left ventricle over 15 mm in one or more segments of the left ventricle, which are established using any conventional diagnostic method. Treatment. In the medical treatment of HC the main role is played by B-blockers and calcium channel blockers. With the ineffectiveness of drug therapy, surgical tactics are used. There are two main invasive treatments for HC: myectomy and alcohol ablation. Myectomy has been used since the early 1960s and is an open operation, which is accompanied by more frequent complications. At the moment, myectomy is the"gold standard" which gives relatively better instrumental and symptomatic indicators compared to alcohol ablation. Conclusion. The fundamental method in the diagnosis of HC is echocardiography. For differential diagnosis and stratification of patient risk, MRI is better suited.It is currently reported that there is no randomized clinical trial to compare myectomy and alcohol ablation, but several meta-analyzes have shown that both methods reduce symptoms and have the same mortality.The choice of treatment tactics should be decided by a multidisciplinary team.
Заманауи гипертрофиялык кардиомиопатияньщ диагностикасы жэне eMi
АВТОРЛАР ТУРАЛЫ
Оагатов I.E. - А.Н. Cbi3FaH0B arbiHMaFbi YFXÜ-ц F3X менеджментi бeлiмiнiц басшысыб м.Ед.
Шабельянов С.О. - А.Н. Cbi3FaH0B атындаFы YFXÜ-ц «Сэулелiдиагностика» мамандь/Fbi бойынша резидент
ЕрсейтА.Б. - А.Н. Cbi3FaH0B атындаFы YFXÜ-ц «Сэулелiдиагностика» мамандь^ы бойынша резидент
Туйш сездер
гипертрофиялык кардиомиопатия, ЭХО-КГ, МРТ, мутация, миоэктомия
Саратов I.E., Шабельянов С.О., Ерсейт А.Б.
Сызганов А.Н. атында?ы YFXO АК,, Алматы к,., Казахстан
Ацдатпа
Kipicne. Гипертрофияльщ кардиомиопатия - карыншалык миокард кабырасыныц едэуiр калындауымен си-патталатын курылымдыкжэне функционалдык патология.ГК таралуы 1:500 курайды.Ересектердеп жагдайлардыц 60% -ы - бул аутосомдык доминантты ауру, онда саркомер акуызын кодтайтын гендерде мутация болады. Ауру тарихы жэне клиникалык KepiHici. Клиникалык кврЫа алуан тYрлi жэне осы патологияра катысатын гендердщ енуiне байланысты.Пациенттердiц квпшiлiгiнде шарымдар жок.Ен жиi кездеселн симптомдар - тыныс алу, ентiгу, шаршау жэне блек, аяк, ¡шжэне мойын веналарында iсiну.Квбiнесе сол жак карыншаныц бiтелуiмен б'рге жYредi жэне дем алу, кеуде ауыруы жэне сананыц жоталуы сиякты белплермен кврiнедi. Диагностикасы. ГКдиагностикасында мацызды рвлдi ЭКГ,ЭХО-КГ, МРТ жэне МСКТ аткдрады.Ересектерде гипертрофиялык кардиомиопатия диагнозысол карыншаныц бiр немесе бiрнеше сегменттерiнде сол карыншаныц кабыррасы 15 мм-ден асакандакойылады. EMi. ГКемдеуде басты рвлдi В-блокаторлары жэне кальций каналдарыныц блока-торлары алады. Дэрiлiк терапияныц тиiмсiздiгiнен хирургиялык ем колданылады. ГК Yшiн ею непзп хирургиялык емдеу эдiсi бар: миоэктомия жэне алкогольдi абляция.Миоэктомия 1960 жылдардыц басынан бастап колданылып келедiжэне жи аскынулармен б'рге журетШ ашык операция болып табылады.Kазiрп уакытта миоэктомия - «алтын стандарт» болып табылады жэне алкогольдi абляциямен салыстыртанда анагурлым жаксы инструменталды жэне симптоматикалык кврсеткiштердi беред'т Цорытынды. ГКдиагностикасындагы непзп эдс - ЭХО-КГ.Дифферен-циалды диагностика жэне наукастыц кдутн стратификациялау Yшiн МРТжаксырак. K,азiрп уакытта миэктомия мен алкогольдi абляцияны салыстыратын рандомизацияламан клиникалык зерттеулер жок, бiрак бiрнеше мета-тал-даулар eKi эдюте симптомдарды азайтып, влiм кврсеткiшi брдей еке^н кврсет. Емдеу тактикасын тандауды кеп салалы топ шeшуi керек.
Современная диагностика и лечение гипертрофической кардиомиопатии
Сагатов И.Е., Шабельянов С.О., Ерсейт А.Б.
АО ННЦХ им. А.Н. Сызганова, Алматы, Казахстан
Аннотация
Введение. Гипертрофическая кардиомиопатия-структурнаяи функциональнаяпатологияхарактеризующа-ясязначительно утолщённой стенкой миокарда желудочков.Распространённость ГК 1на500. До 60% случаев у взрослых является аутосомно-доминантнымзаболеванием при котором имеется мутации в генах кодирующих белок саркомер. История болезни и клиническая картина. Клиническая картина разнообразна и зависит от пенетрантности генов вовлечённых в данную патологию. Большинство пациенты не предъявляют никаких жалоб. Самыми частымисимптомами являются одышка, затрудненное дыхание, утомляемость, припухлость в области лодыжек, ступней, живота и вен шеи. Часто сопровождается обструкцией левого желудочка и проявляется такими симптомами как одышка, загрудинные боли и потеря сознания. Диагностика. В диагностике ГК важную роль играют ЭКГ, ЭХО-КГ, МРТ и МСКТ. У взрослых гипертрофическая кардиомиопатия диагностируется при увеличении стенки левого желудочка больше 15 мм в одном или нескольких сегментах левого желудочка, которые устанавливаются при помощи любого общепринятого метода диагностики. Лечение. В медикаментозном лечении ГК основную роль занимают Б-блокаторы и блокаторы кальциевых каналов.При неэффективности медикаментозной терапии применяют хирургическую тактику. Существуют два основных инвазивных метода лечения ГК: миоэкто-мия и алкогольная абляция. Миоэктомия применяется с начала 1960-х годов и является открытой операцией, что сопровождается более частыми осложнениями.На данный момент миоэктомия является «золотым стандартом» которая даёт сравнительно лучшие инструментальные и симптоматические показатели в сравнении с алкогольной абляцией. Заключение. Основополагающим методом в диагностике ГК является ЭХО-КГ. Для дифференциальной диагностики и стратификации риска пациента лучше подходит МРТ.В настоящее времяне существует рандомизированного клинического исследования для сравнения миоэктомии и алкогольной абляции, но несколько мета-анализов показали, что оба метода уменьшают симптомы и имеют одинаковую смертность. Выбор тактики лечения должна решать многопрофильная команда.
ОБ АВТОРАХ
Cагатов И.Е. - руководитель отдела менеджмента НИР ННЦХ им. А.Н. Сызганова, д.м.н.
Шабельянов С.О. - резидент по специальности «Лучевая диагностика» ННЦХ им. А.Н. Сызганова
Ерсейт А.Б. - резидент по специальности «Лучевая диагностика» ННЦХ им. А.Н. Сызганова
Ключевые слова
гипертрофическая кардиомиопатия, ЭХО-КГ, МРТ, мутация, миоэктомия
Introduction
Hypertrophic cardiomyopathy is a structural and functional pathology which characterized by a significantly thickened ventricular myocardial wall [1]. It is subdivided into a genetic and non-genetic form, also into a primary pathology, in which only the heartis involved and the secondary, where it is a manifestation of systemic diseases. Most cases have a genetic etiology [18].
The prevalence of hypertrophic cardiomyopathy is 1: 500. Multiple studies have also been conducted in various regions of the world where approximately the same prevalence of 0.02-0.23% was detected [19-28].HC is the most common car-diomyopathy and the most common cause of sudden cardiac death in professional athletes [2,4,8]. A correlation was also observed with age, with a much smaller number of patients under 25 years old [25]. In the pediatric population, prevalence is unknown, but some studies report from 0.3 to 0.5 cases per 100,000 [29-30]. Many studies report a lower prevalence in men compared with women [19-28].
Up to 60% of cases in adults is an autosomal dominant disease in which there are mutations in the genes encoding sarcomere protein [31]. Most mutations have been identified in the genes en-
coding the heavy chains of beta-myosin protein (MYH) and myosin-binding protein C (MYBPC3). The genes responsible for troponin I and tropo-nin T (TNNI3, ETTE2), tropomyosin alpha-1 chain (TPM1) and myosin light chain 3 (MYL3) are less involved. In most cases, in patients with mutations in the sarcomere protein, clinical symptoms appear earlier and harder [32]. Hypertrophic cardiomyopathy is also associated with metabolic pathologies (Anderson-Fabry disease, Danone disease) [33,34], mitochondrial diseases (mutations in the genes responsible for the respiratory cycle) [35], neuromuscular diseases (Friedrich's ataxia) [36], malformation syndromes ( Noonan syndrome [37], LEOPARD syndrome [38]), systemic inflammatory diseases (cardiac amyloidosis, primary amyloido-sis, transthyretin-associated amyloidosis, senile amyloidosis) [39], endocrine diseases (Sugar diabetes type 2 [53], pheochromocytoma [54], acromegaly [55]), the use of drugs (anabolic steroids, tacrolimus, hydroxychloroquine [56]).
History and manifestation
The manifestation of the disease is diverse and depends on the penetrance of the genes involved in this pathology. Most patients have no complaints. The most common symptoms are
shortness of breath, fatigue, swelling in the ankles, feet, abdomen, and neck veins [3]. Often accompanied by obstruction of the left ventricle and is manifested by symptoms such as shortness of breath, chest pain and loss of consciousness [5]. In auscultation of the heart, in most cases, pathological murmurs are also not detected. Only with obstruction of the left ventricle, typical symptoms are revealed, such as an increase in arterial pulse and systolic murmur in the region of the left sternal margin radiating to the upper right sternal angle and apex. The noise is amplified by provocative maneuvers that reduce ventricular preload or afterload, such as the Valsalva test and a sharp change of position from sitting to standing. Most patients with left ventricular obstruction show symptoms of mitral regurgitation. Age is one of the most important criteria in identifying the cause of hypertrophic cardiomyopathy. For example, congenital metabolic diseases and dysmorphic symptoms are much more common in newborns and infants than in adults and the elderly people, while amyloidosis associated with transthyretin is much more common in people over 65 years of age. The study of the family tree helps in the diagnosis and identification of other family members with an increased risk of developing this pathology. Genetics consultation is recommended for all patients with hypertrophic cardiomyopathy in whom a hereditary factor is suspected to determine whether screening of family members is necessary (Evidence Class I, Level B)[3]. Genetic counseling by a professional must be performed by a trained doctor for this specific task (Evidence Class IIA, Level C)[3]. By studying the family tree, you can identify the form of the disease. The most common type of inheritance is autosomal dominant. Making a family tree up to the third or fourth generation helps determine the type of inheritance and identify family members with an increased risk of developing this disease. There are special features that you should pay attention to when examining the patient's relatives. These include sudden cardiac death syndrome, unexplained heart failure, heart transplant, presence of pacemakers and defibrillators, systemic diseases at an early age. As mentioned above, the most common type of heredity is autosomal dominant, which is manifested by the presence of a defective gene in each generation, with transmission from parents with the same frequency to children of different sexes and a 50% risk to offspring. There is also X-linked inheritance in which only men are affected, or only the male half shows a severe form of the disease. The autosomal recessive type of heredity is the least encountered. When parents are not affected, but are close relatives. In cases where only women trans-
mit the disease to children of both sexes, mutations in mitochondrial DNA should be considered. Genetic testing is recommended in certified laboratories competent in determining mutations associated with cardiomyopathies (Evidence Class I, Level C)[3]. Genetic testing is indicated for patients with appropriate symptoms only when all relatives are examined (Evidence Class I, Level B) [3]. In case of doubtful symptoms of hypertrophic cardiomyopathy, genetic testing is recommended only after consulting a team of specialists (Evidence Class IIA, Level C)[3].
Diagnostics
An important role in the diagnosis of HC is played by ECG, echocardiography, MRI and MSCT. In adults, hypertrophic cardiomyopathy is diagnosed with an increase in the wall of the left ventricle over 15 mm in one or more segments of the left ventricle, which are established using any conventional diagnostic method. Genetic and non-genetic forms of hypertrophic cardiomyopathy can have a smaller thickness of the left ventricle, which requires an additional examination method, such as a medical history, symptoms, instrumental studies, laboratory indicators and various radiological diagnostic methods. Difficult diagnostic cases are: physiological hypertrophy in athletes, patients with concomitant diseases, isolated septal hypertrophy in the elderly, patients in advanced stages with hypokinetic left ventricle and a decrease in the left ventricular wall [41]. In children, the diagnosis is made when the thickness of the left ventricle is more than two standard deviations than the expected average value [42].
ECG
A standard ECG examination is recommended for all patients with hypertrophic cardiomyopathy to make a diagnosis and establish a cause (Evidence Class I, Level B)[3]. In most patients, suspicion of HC occurs after an ECG study. In 6% of patients with hypertrophic cardiomyopathy, an ECG test is normal. But more often it shows signs of left ventricular hypertrophy, altered by ST segments and abnormal T, Q waves. A 48-hour outpatient ECG study is recommended for patients to determine atrial and ventricular arrhythmias (Evidence class I, level B)[3]. The frequency of arrhythmias is associated with age. In particular, HC is accompanied by ECG signs such as ventricular tachycardia in 25% of cases, paroxysmal supraventricular arrhythmia in 38% of cases. An ECG is recommended for all patients as an initial screening method for assessing the risk of sudden cardiac death. Thus, the ECG has a very high sensitivity, but low specificity for this pathology [43].
Echocardiography
The most frequent, simple and relatively cheap method that is used to screen for HC is echocardiography. Echocardiographyis a fundamental method for the diagnosis and monitoring of patients with hypertrophic cardiomyopathy. In most patients, interventricular septal hypertrophy is localized at the base of the left ventricle, and can also spread to the lateral wall, posterior wall, and apex of the left ventricle. As the enlargement of the walls of the left ventricle progresses, hypertrophy can affect any section, including the right ventricle. Hypertrophy of the walls of the ventricles should be documented using standard projections. The correct position of the transducer and the direction of the waves helps minimize the percentage of measurement errors. Measurement of the thickness of the left ventricle should be performed at the end of the diastole [44]. There are many indirect echocardiography signs with which you can suspect a diagnosis, but for the diagnostic purpose the most valuable is the maximum thickness of the left ventricle at any level. In patients with suspected hypertrophic cardiomyopa-thy, left ventricular segments should be examined from the base to the apex, especially carefully in the area of the mitral valve, the middle of the left ventricle and the apex (Evidence Class I, Level C) [3]. Difficult cases when there is an increase in one or two segments, in particular the anterolateral wall or the apex of the left ventricle. In such cases, additional diagnostic sections in different projections are needed to avoid the influence of artifacts. In case of doubt, it is necessary to use echocardiog-raphywith contrast or MRI [45]. Approximately one third of patients at rest have an anterior systolic mitral valve leaf motion that leads to left ventricular obstruction, another third has this symptom during maneuvers that provoke left ventricular load and contractility [46]. Other morphological features that contribute to obstruction of the left ventricle include pathologies of the papillary muscles (hypertrophy, anterior and internal displacement, direct attachment to the cusps of the mitral valve) and pathology of the cusps of the mitral valve such as lengthening or additional tissue [47]. Left ventricular obstruction also occurs in diseases such as calcification of the posterior mitral valve ring, arterial hypertension, hypovolemia, and conditions characterized by increased contractility of the heart. Left ventricular obstruction is diagnosed with a peak Doppler gradient of the outflow of the left ventricle of more than 30 mm Hg. Gradient greater than 50 mm Hg is the threshold at which obstruction has hemodynamic significance. Identifying left ventricular obstruction is important in the treatment and risk assessment of sudden cardiac death. In all patients with hypertrophic cardiomyopathy at the initial stage, 2D and
Doppler echocardiographyare recommended at rest and during the Valsalva maneuver. In a sitting and semi recumbent position. With a gradient above 50 mm Hg it is recommended to begin treatment for left ventricular outlet tract obstruction. With a pressure gradient of less than 50 mmHg in asymptomatic patients, it is recommended to repeat echo-cardiographyevery year. In asymptomatic patients, stress echocardiographyis usually not used. Stress echocardiographyis recommended for patients with symptoms if their lying position does not raise pressure in the output section of the left ventricle above 50 mm Hg. With an increase in the border, obstruction is treated; at normal values, it is necessary to carry out therapy according to the protocol (Evidence class - I, level - B)[3].
An increase in the left atrium has an important prognostic role [48]. The reason for the enlargement of the left ventricle is multifactorial, but the most important mechanism is the anterosystolic movement of the cusp of the mitral valve and an increase in filling pressure in the left ventricle. Patients with hypertrophic cardiomyopathy often have diastolic dysfunction, but echocardiographydoes not have any specific parameter for determining this pathology [49]. Therefore, to determine diastolic dysfunction, it is necessary to evaluate indirect parameters, such as Doppler assessment of the mitral valve inflow, blood flow velocity in the mitral ring tissue, blood flow velocity in the pulmonary vein region, pulmonary arterial systolic pressure, assessment of the size and volume of the left ventricle [49] (Evidence class - I , level - C)[3]. Radial contractile function is usually normal or increased. However, estimating the ejection fraction is a poor prognostic indicator for hypertrophy. Longitudinal myocardial deformation is usually reduced at the site of hypertrophy [50]. There are also certain symptoms in which specific diseases associated with hypertro-phic cardiomyopathy can be suspected [51].
Echo-CG with an intravenous contrast medium is indicated for poor visualization of apex hypertrophy and lateral wall of the left ventricle, suspicion of aneurysm of the left ventricle to improve endocardial contours. This technique may be an alternative to magnetic resonance imaging of the heart [52]. (Class of evidence - IIA, level - C)[3].
For all patients with alcohol ablation, intracoro-narycontrast echocardiography is indicated to accurately determine the location of the surgical intervention. (The evidence class is IA, level B)[3].
Preoperative transesophagealechocardiogra-phyis recommended for patients who are preparing for septal myectomy to confirm the mechanism of left ventricular outflow tract obstruction, to determine surgical tactics, evaluate postoperative complications and to determine the residual left
ventricular outflow tract obstruction. (The evidence class is IA, level B)[3]. The disadvantages of trans-esophagealare operator dependence, poor visualization of the left ventricular wall and an inaccurate assessment of LV mass [6, 7]. These shortcomings make it difficult to make an accurate diagnosis and lead to incorrect treatment tactics [6, 7].
MRI
MRI is better for differential diagnosis, stratification of the patient's risk, in cases where the transesophageal echocardiographydiagnosis is controversial, incomplete or a false negative result is suspected. The main advantage of MRI over echocardiography, it is operator independent method, the best visualization of the LV wall, more accurate determination of the mass, volume, thickness of the LV and its function. The implementation and interpretation of MRI results is recommended by an experienced team of specialists specializing in this area. (Evidence class - IA, level - C)[3]. In the absence of contraindications, it is recommended to perform heart MRI with contrast to confirm the diagnosis in patients with limited ultrasound imaging. (The evidence class is IA, level B)[3]. Heart MRI with contrast also helps to complement diagnostic criteria, to evaluate the anatomy of the heart, ventricular function, the presence and prevalence of fibrosis. (Class of evidence - IIA, level - B)[3]. MRI contrast is indicated for patients with suspected apical hypertrophy, aneurysm, amyloidosis. (Class of evidence - IIA, level - C)[3]. MRI contrast is useful before myectomy or alcohol ablation to assess the spread of hypertrophy and fibrosis (Evidence class IIB, grade C)[3].
Nuclear imaging and CT
Bone scintigraphy is recommended for those patients who suspect hypertrophic cardiomyopa-thy caused by transthyretin-associated amyloi-dosis. (Class of evidence - IIA, level - B)[3]. The main advantage of MSCT is high-quality visualization in all planes, the ability to create 3D images, the exclusion of IHD and the use in patients who have contraindication for MRI [8] (Evidence class - IIA, level - C)[3]. The drawbacks of MSCT are radiation exposure, risks when using contrast, a less perfect assessment of the characteristics of the heart.
Treatment
Drug therapy
In the medical treatment of HC, the main role is played by B-blockers and calcium channel blockers [12]. Non-vasodilating B-blockers with the maximum tolerated dose are recommended as drugs of choice for patients with left ventricular outlet
obstruction [57] (Evidence class - I, level - B)[3]. Verapamil with the maximum tolerated dose is recommended as a drug for the selection of patients with outlet obstruction of the left ventricle in patients who have intolerance or contraindications to taking B-blockers [57] (Evidence class - I, level - B) [3]. Disopyramide in the maximum tolerated dose is recommended in supplemented to B-blockers (if there are contraindications to Verapamil) (Evidence class - I, level - B)[3].
Surgical treatment
With the ineffectiveness of drug therapy, surgical tactics are used. There are two main invasive treatments for HC: myectomy and alcohol ablation. Myectomy has been used since the beginning of the 1960s and is an open operation, which is accompanied by more frequent complications [16, 17]. At the moment, myectomy gives relatively better instrumental and symptomatic indicators compared to alcohol ablation [^.Recommended performance of septal reduction therapy by an experienced team of surgeons(Evidence class - I, level - B)[3].Myectomy is recommended for those patients who have other associated pathologies(Evidence class - I, level - B)[3].It is currently reported that there is no randomized clinical trial to compare myectomy and alcohol ablation, but several meta-analyzes have shown that both methods reduce symptoms and have the same mortality.Alcohol ablation also reduces mortality from sudden cardiac death and increases survival, but this method often has complications such as complete heart block and arrhythmia [14]. Alcohol ablation is a less invasive method and is therefore better suited for patients with comorbid conditions who have contraindications for open surgery. However, the question about the treat-mentchoice for a particular patient is debatable [15]. In comparison of these two methods, it was noted that myectomy produces a more stable result [10].
Conclusion
The fundamental method for the diagnosis and monitoring of patients with hypertrophic cardio-myopathy is echocardiography[44]. But when the diagnosis of echocardiographyis controversial, incomplete, or a false-negative result is suspected, MRI is better suited for differential diagnosis and stratification of patient risk[3]. It is currently reported that there is no randomized clinical trial to compare myectomy and alcohol ablation, but several meta-analyzes have shown that both methods reduce symptoms and have the same mortality.The choice of treatment tactics should be decided by a multidisciplinary team[3].
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