Radionuclide imaging methods in the diagnosis of microvascular dysfunction in non-obstructive coronary artery disease

Non-obstructive coronary artery disease is generally considered as a favorable type of pathology, however, a number of studies indicate that in non-obstructive atherosclerosis, the risk of such cardiovascular events as myocardial infarction, ischemic stroke, sudden cardiac death and decompensated heart failure cannot be completely ruled out. This may be due to microvascular dysfunction. However, due to the small diameter of vessels, none of the imaging techniques used in clinical practice makes it possible to assess microvascular morphology. To date, the most well-established methods for assessing myocardial perfusion are single-photon emission computed tomography (SPECT) and positron emission tomography (PET). The ability to quantify myocardial blood flow and coronary flow reserve allows SPECT and PET to be the methods of choice for non-invasive diagnosis of microvascular dysfunction. This review is devoted to current data on the clinical significance of radionuclide diagnosis of microvascular dysfunction in patients with non-obstructive coronary artery disease

Влияние терапии β-адреноблокаторами на уровень растворимой формы белка ST2 в сыворотке крови пациентов с сердечной недостаточностью с сохраненной и умеренно сниженной фракцией выброса

Aim. To study the prognostic value of high serum concentration of soluble ST2 protein (sST2) in the development of cardiovascular events after endovascular myocardial revascularization and the possibility of using this biomarker as a target for β-blocker therapy in patients with chronic heart failure (CHF) with preserved (HFpEF) and mildly reduced (HFmrEF) left ventricular ejection fraction.Materials and methods. The study included 72 patients (aged 57–69 years, 81.94% were men) with class I–III CHF of ischemic etiology with HFpEF and HFmrEF. The patients were admitted to the cardiology department for endovascular myocardial revascularization. Before myocardial revascularization, serum concentrations of sST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) in all patients were analyzed by enzyme-linked immunosorbent assay (ELISA). Doses of β-blockers used in all patients were recalculated into a total daily dose equivalent to metoprolol succinate. Patients were divided into 2 groups depending on the median equivalent dose of metoprolol succinate (“high” ≥ 100 mg / day and “low” < 100 mg / day).Results. In patients of group 1, the serum concentration of sST2 was 30.7% higher (p < 0.001) than in patients of group 2 (40.26 [34.39; 48.92] ng /ml and 27.9 [23.05; 35.27] ng / ml, respectively), the serum NT-proBNP level in group 1 was 22.8% higher (p = 0.049) than in group 2 (167 [129; 330] ng / ml vs. 129 [125; 147] ng / ml, respectively). In patients receiving an equivalent dose of metoprolol succinate < 100 mg / day, the incidence of cardiovascular events was 34% higher (p = 0.002) than in patients receiving an equivalent dose of metoprolol succinate ≥ 100 mg/day. The ROC analysis showed that serum sST2 level ≥ 34.18 ng / ml (sensitivity 78.0%, specificity 90.0%, area under the curve (AUC) 0.906; p < 0.0001) predicts a high risk of cardiovascular events within one year. However, the serum NT-proBNP level was not an informative predictor of cardiovascular events. Conclusion. It was confirmed that increased sST2 serum concentration has high prognostic value in the development of cardiovascular events within a year after endovascular myocardial revascularization. The possibility of using this biomarker as a target for β-blocker therapy in patients with HFpHF and HFmrEF was substantiated. Aggressive use of β-blockers in the group of patients with HFpEF and HFmrEF and sST2 overexpression is preferable in order to reduce the incidence of cardiovascular events.Цель – изучение прогностического значения высокой концентрации в сыворотке крови растворимой формы белка ST2 (sST2) в развитии сердечно-сосудистых событий после эндоваскулярной реваскуляризации миокарда и возможности использования этого биомаркера в качестве мишени для терапии β-блокаторами у пациентов с хронической сердечной недостаточностью (ХСН) с сохраненной (СНсФВ) и умеренно сниженной (СНусФВ) фракцией выброса левого желудочка.Материалы и методы. В исследование включены 72 пациента (в возрасте 57–69 лет, 81,94% мужчин) с ХСН I–III функционального класса ишемической этиологии с СНсФВ и СНусФВ, госпитализированных в кардиологическую клинику для выполнения эндоваскулярной реваскуляризации ишемизированного миокарда. У всех пациентов перед реваскуляризацией миокарда анализировали концентрацию в сыворотке крови sST2 и N-терминального промозгового натрийуретического пептида (NT-proBNP) с помощью иммуноферментного анализа (ELISA). Дозы применяемых у всех пациентов β-блокаторов были пересчитаны в общую суточную дозу, эквивалентную метопрололу сукцинату. Больные были разделены на две группы в зависимости от медианы эквивалентной дозы β-блокатора метопролола сукцината («высокая» ≥100 мг/сут и «низкая» <100 мг/сут).Результаты. У пациентов первой группы сывороточная концентрация sST2 была на 30,7% (p < 0,001) больше, чем у больных, вошедших во вторую группу (40,26 [34,39; 48,92] нг/мл и 27,9 [23,05; 35,27] нг/мл соответственно), уровень NT-proBNP в сыворотке крови больных первой группы также был выше (на 22,8%; p = 0,049), чем у пациентов второй группы (167 [129; 330] нг/мл против 129 [125; 147] нг/мл соответственно). У пациентов, получавших эквивалентную дозу метопролола сукцината <100 мг/сут, частота сердечно-сосудистых событий была выше на 34% (p = 0,002), чем у пациентов, получавших эквивалентную дозу метопролола сукцината ≥ 100 мг/сут. По данным ROC-анализа установлено, что сывороточный уровень sST2 ≥ 34,18 нг/мл (чувствительность 78,0%, специфичность 90,0%, AUC 0,906; p < 0,0001) позволяет прогнозировать высокий риск развития сердечно-сосудистых событий в течение ближайшего года. Уровень NT-proBNP в сыворотке крови при этом не являлся информативным предиктором сердечно-сосудистых событий.Заключение. Подтверждено высокое прогностическое значение повышения концентрации в сыворотке крови sST2 в развитии сердечно-сосудистых событий в течение года после эндоваскулярной реваскуляризации миокарда и обоснована возможность использования этого биомаркера в качестве мишени для терапии β-блокаторами у пациентов с СНсФВ и СНусФВ. Агрессивное применение β-блокаторов в группе пациентов с СНсФВ и СНусФВ и гиперэкспрессий sST2 предпочтительнее с целью снижения частоты сердечно-сосудистых событий

Role of humoral markers in the pathogenesis of heart failure with preserved ejection fraction in patients with non-obstructive coronary artery disease

Aim. To study the role of molecular biomarkers potentially influencing the formation and progression of heart failure (HF) with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease (CAD).Material and methods. We examined 48 patients with newly diagnosed HFpEF against the background of non-obstructive CAD. Group 1 (n=31) included patients with class I-II HF and group 2 (n=17) included patients with class III HF; the control group consisted of patients without heart failure (n=17). The content of NT-proBNP and sST2, diastolic dysfunction and coronary flow reserve parameters were assessed.Results. The content of NT-proBNP in patients of group 1 was 45% higher than in group 2 (p<0,001). The mean levels of sST2 did not exceed the reference values and significantly exceeded the control group (p<0,001). Coronary flow reserve (CFR) decreased (p<0,001) depending on the severity of HF. Negative associations of sST2 levels with LVEF, septal e’ and CFR were revealed, as well as NT-proBNP with CFR.Conclusion. HFpEF in non-obstructive CAD is triggered due to progressive impairment of endothelial function, which affects the decrease in coronary and myocardial flow reserves, diastolic function, hyperproduction of humoral factors that initiate perivascular fibrosis and apoptosis of cardiomyocytes

Cardiology Research Institute, Tomsk National Research Medical Center

Aim. To assess the prognostic role of cardiac biomarkers (galectin-3, soluble ST2 (sST2), and N-terminal pro-brain natriuretic peptide (NT-proBNP)) in risk stratification of adverse cardiovascular events (CVEs) in patients with heart failure (HF) after implantation of an automatic implantable cardioverter-defibrillator (AICD) within 12-month follow-up period.Material and methods. The study included 57 patients (men, 41; mean age, 65 (59; 68) years) with coronary artery disease and NYHA class II-III HF with left ventricular ejection fraction of 34 [26; 40]%. All patients were implanted with AICD. Serum levels of NT-proBNP, sST2, and galectin-3 were determined by enzyme immunoassay prior to AICD implantation.Results. It has been established that in order to stratify the risk of unfavorable HF in patients after AICD implantation for 12-month follow-up, all three studied biomarkers can be considered as prognostic factors. Thus, an increase in the level of NT-proBNP ≥1046,6 pg/ml (AUC=0,68; p=0,009), sST2 ≥34,43 ng/ml (AUC=0,78; p<0,0001) and galectin-3 ≥11,6 ng/l (AUC=0,72; p=0,0014) predicts a high risk of adverse CVEs. The combination of sST2 and galectin-3 increased the predictive value of the analysis (AUC=0,84; p<0,0001), while the addition of NTproBNP did not increase the accuracy of risk stratification.Conclusion. The determination of the combination of galectin-3 and sST2 can potentially help identify a group of patients with HF after AICD implantation with a high risk of adverse CVEs for intensification and optimization of treatment

НОВЫЕ МАРКЕРЫ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТИ: ЗНАЧЕНИЕ ДЛЯ ДИАГНОСТИКИ И ПРОГНОЗИРОВАНИЯ NT-proBNP И ИНТЕРЛЕЙКИНОВЫХ РЕЦЕПТОРОВ – ЧЛЕНОВ СЕМЕЙСТВА ST2

The article discusses the use of new biomarkers for assessing the severity of the clinical course and the prognosis of chronic heart failure. In recent decades, prospective possibilities for using biomarkers as the part of early personalized diagnosis of cardiovascular disease have been actively studied to optimize the diagnosis process, patients’ prognosis and increase the effectiveness of therapy for chronic heart failure. New biomarkers are highly sensitive mediators for evaluation of pathogenetic mechanisms of the development and progression of chronic heart failure. Plasma levels of a new biomarker expressed by cardiomyocytes, fibroblasts and endothelial cells, a member of the IL-1 family of soluble isoform ST2 (sST2), which ligand is IL-33 cytokine, is of particular interest. Risk personification using NT-proBNP and ST2 biomarkers allows identifying themostvulnerablepatients for further monitoringand intensification of therapeutic interventions.Статья посвящена перспективе использования новых биомаркеров для оценки тяжести течения и прогноза хронической сердечной недостаточности (ХСН). В последние десятилетия для оптимизации диагностики, прогнозирования и повышения эффективности терапии ХСН активно изучаются перспективные возможности применения биомаркерной стратегии ранней персонифицированной диагностики кардиоваскулярной патологии. Современные биомаркеры являются высокочувствительными медиаторами для оценки патогенетических механизмов развития и прогрессирования ХСН. Особый интерес представляют данные по плазменной концентрации нового биомаркера, экспрессируемого кардиомиоцитами, фибробластами и эндотелиальными клетками, члена семейства рецепторов интерлейкина-1 (IL1) – растворимой изоформы ST2 (sST2), лигандом которого является цитокин IL-33. Персонификация риска с помощью определения биомаркеров NT-proBNP и ST2 позволит выявить наиболее уязвимых пациентов, в отношении которых наиболее оправдана тактика мониторинга и интенсификации терапевтических вмешательств

Coronary flow reserve in patients with heart failure with preserved ejection fraction

Aim. To study the parameters of myocardial blood flow (MBF) and coronary flow reserve (CFR) in patients with heart failure (HF) with preserved ejection fraction and evaluate their relationship with the severity of HF.Material and methods. The study included 47 patients (men, 68,7%) aged 65,0 (58,0; 72,0) years with left ventricular ejection fraction of 62 (56; 67)% and coronary artery stenosis <50%. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were assessed by enzyme immunoassay. MBF and CFR values were assessed using cardiac single photon emission computed tomography.Results. Depending on NT-proBNP levels, the patients were divided into 2 groups (p<0,001): the 1st group included (n=15) patients with NT-proBNP <125 pg/ml (58,2 [41,6; 70,7] pg/ml), while in the 2nd group (n=32) — with NT-proBNP ≥125 pg/ml (511,4 [249,8; 1578,1] pg/ml). The group of patients with high NTproBNP levels was characterized by higher values (by 33,8%, p=0,0001) of resting MBF and reduced CFR (by 14,7%, p=0,001) compared with patients with normal NT-proBNP level: resting MBF — 0,65 (0,44; 0,79) vs 0,43 (0,30; 0,58) ml/min/g; CFR — 2,21 (1,52; 2,83) vs 2,59 (2,47; 3,05), respectively. At the same time, MBF at stress did not differ between the groups. The relationship of NTproBNP levels with global CFR (p=0,012; r=-0,339) and MBF at rest (p=0,012; r=0,322) was established. A stepwise decrease in global CFR was revealed depending on the NYHA class as follows (p<0,001): 2,79 (2,52; 2,93); 1,8 (1,55; 2,08); 1,31 (1,23; 1,49) — for class I, II, and III, respectively.Conclusion. A decrease in CFR in patients with HF with preserved ejection fraction indicates impaired myocardial blood supply, which, in this group of patients, is associated with microcirculatory changes. At the same time, the severity of MBF alterations is closely related to HF severity

Association of impaired myocardial flow reserve with risk factors for cardiovascular diseases in patients with nonobstructive coronary artery disease

Aim. To reveal the association between disorders of myocardial blood flow and reserve, according to dynamic single photon emission computed tomography (SPECT), with risk factors for cardiovascular diseases (CVD) in patients with nonobstructive coronary artery disease (CAD).Material and methods. The study included patients with suspected stable nonobstructive (<50%) CAD. Based on the survey data, anamnesis, out- and in-patient medical records, we analyzed main CVD risk factors. All patients underwent dynamic myocardial SPECT and analysis of blood lipid profile in vitro. Depending on myocardial flow reserve (MFR), two groups were formed: 1. With reduced MFR <2,0 (rMFR); 2. With normal MFR ≥2,0 (nMFR).Results. The study included 47 patients divided into 2 following groups: the rMFR group consisted of 24 patients (15 men, age 56,3±9,1 years), the nMFR group — 23 patients (13 men, age 58,4±10,7 years). There was no significant difference in prevalence of CVD risk factors in groups. However, dyslipidemia was detected more often in rMFR patients (p=0,053): 58% vs 30%, respectively. In patients with rMFR, there were significantly higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Correlation analysis revealed significant negative inverse relationships between MFR values with TC (ρ=-0,36, p=0,01) and LDL-C (ρ=-0,38, p=0,009). According to univariate logistic regression, significant predictors of reduced MFR were TC (odds ratio (OR), 2,32; 95% confidence interval (CI), 1,17-4,59; p=0,01) and LDL-C (OR, 2,16; 95% CI, 1,04-4,51; p=0,04). According to a stepwise multivariate logistic regression analysis, only TC was an independent predictor of a decrease in MFR (OR, 2,32; 95% CI, 1,17-4,59; p=0,02).Conclusion. MFR, determined by dynamic SPECT, is associated with TC and LDL-C levels. TC level is an independent predictor of a decrease in MFR

Предикторы неблагоприятного течения сердечной недостаточности с сохраненной фракцией выброса левого желудочка у больных с синдромом обструктивного апноэ во сне

 Aim. To study the relationship of obstructive respiratory disorders during sleep with subclinical development of right ventricular dysfunction and pulmonary hypertension, as well as with the risk of an adverse course of chronic heart failure (CHF) with preserved left ventricular ejection fraction (LVEF).Materials and methods. The study included 86 men with moderate and severe forms of obstructive sleep apnea syndrome (OSAS) (with an apnea/hypopnea index (AHI) > 15 per hour). All patients had abdominal obesity and hypertension. Upon inclusion in the study, all patients underwent polysomnography and echocardiography according to the  standard protocol with an additional assessment of the fractional area  change in the right ventricular myocardium (ΔSRV) and the right ventricular  stroke work index (RVSWI). Also, the content of the N-terminal brain natriuretic peptide precursor (NT-proBNP) in the blood serum was  determined by enzyme immunoassay analysis. A six-minute walk test (6MWT) was performed after inclusion in the study and after 12 months of  follow-up. Depending on the course of CHF during the follow-up,  retrospectively, the patients were divided into 2 groups: with an unfavorable (n = 33) and favorable (n = 53) prognosis.Results. A significant relationship between AHI and ΔSRV, RVSWI, NT-proBNP, and 6MWT was revealed. Based on the results of one-way correlation analysis, it was found that ΔSRV (odds ratio (OR) 2.51; 95%  confidence interval (CI) 2.42–3.24; p = 0.0009), NT-proBNP (OR 1.92; 95% CI  1.32–2.78; p = 0.003), and AHI (OR 3.93; 95% CI 2.87–4.11; p = 0.018) were predictors of an adverse course of CHF. In a multivariate analysis, it was found that AHI was an independent predictor of an adverse course of CHF (OR 3.49; 95% CI 2.17–11.73; p = 0.0008), while the addition of NT-proBNP improved risk stratification of an adverse course of CHF (OR 4.66; 95% CI 3.87–13.11; p < 0.0001).Conclusion. The fractional area change in the right ventricular myocardium (ΔSRV) can be considered as a non-invasive marker for determining the  emerging right ventricular dysfunction and predicting adverse cardiovascular events in patients with preserved LVEF and OSAS. Moreover, the combined use of echocardiographic (ΔSRV) and laboratory (NT-proBNP) markers can improve risk stratification of CHF progression.   Цель. Изучить взаимосвязь обструктивных нарушений дыхания во сне с развитием дисфункции правого желудочка (ПЖ) и легочной гипертензии, а также с риском  неблагоприятного течения хронической сердечной  недостаточности (ХСН) с сохраненной фракцией выброса  левого желудочка (ФВ ЛЖ). Материалы и методы. В исследование включены 86  мужчин со среднетяжелой и тяжелой формами синдрома  обструктивного апноэ во сне (СОАС) (с индексом апноэ/ гипопноэ (ИАГ) более 15 в час). Все пациенты имели  абдоминальное ожирение и артериальную гипертензию.  При включении в исследование всем больным выполнено полисомнографическое исследование, а также  эхокардиография по стандартному протоколу с  дополнительной оценкой фракционного изменения  площади и индекса работы миокарда правого желудочка (ΔSПЖ и ИРМПЖ), определено содержание  предшественника мозгового натрийуретического пептида (NT-proBNP) в сыворотке крови методом  иммуноферментного анализа. Тест 6-минутной ходьбы (ТШХ) выполняли после включения в исследование и через  12 мес наблюдения. В зависимости от характера течения  ХСН за период наблюдения, ретроспективно, пациенты  были разделены на две группы: с неблагоприятным (n = 33) и благоприятным (n = 53) прогнозом.Результаты. Выявлена значимая взаимосвязь между ИАГ и  ΔSПЖ, ИРМПЖ, ТШХ, уровнем NT-proBNP. На основании результатов однофакторного корреляционного анализа  установлено, что ΔSПЖ (отношение шансов (ОШ) 2,51; 95%-й доверительный интервал (ДИ) 2,42–3,24; p = 0,0009), NT- proBNP 1,92; 95%-й ДИ 1,32–2,78; p = 0,003), ИАГ (ОШ 3,93; 95%-й ДИ 2,87–4,11; p = 0,018) были предикторами  неблагоприятного течения ХСН. При проведении  многофакторного анализа установлено, что независимым  предиктором неблагоприятного течения ХСН являлся ИАГ (ОШ 3,49; 95%-й ДИ 2,17–11,73; р = 0,0008), при этом  добавление NT-proBNP улучшало стратификацию риска  неблагоприятного течения ХСН (ОШ 4,66; 95%-й ДИ 3,87–13,11; р < 0,0001).Заключение. Фракционное изменение площади ПЖ ΔSПЖ  можно рассматривать в качестве неинвазивного маркера  для определения формирующейся правожелудочковой  дисфункции и прогнозирования неблагоприятных  сердечно-сосудистых событий у больных с сохраненной ФВ  ЛЖ и СОАС. При этом комбинированное использование  эхокардиографического (ΔSПЖ) и лабораторного (NT- proBNP) маркеров позволяет улучшить стратификацию риска прогрессирования ХСН.