The myocardial flow reserve in patients with heart failure with preserved ejection fraction.

To evaluate the myocardial flow reserve (MFR) and myocardial blood flow (MBF) parameters in patients with heart failure with preserved ejection fraction (HFpEF) and to assess their relationship with the severity of HF and the levels of soluble ST2 (sST2). A total of 59 consecutive patients (median age of 65.0 (58.0; 69.0) years) with non-obstructive coronary artery disease (CAD) and preserved EF were enrolled. Serum levels biomarkers were measured by enzyme immunoassay. MBF and MFR parameters were evaluated by dynamic CZT-SPECT. All patients were divided into two groups: group 1 comprised patients (n = 41) with HFpEF, and group 2 comprised those (n = 18) without HFpEF. In group 1 global MFR (gMFR) values were lower by 27.8% (p = 0.003) than in group 2. The values of gMFR correlated with NT-proBNP (r = - 0.290) and sST2 (r = -0.331) levels. Based on ROC-analysis, gMFR ≤ 2.27 (AUC = 0.746; p < 0.001) were associated with the presence of HFpEF. In patients with HFpEF (n = 41) the values of gMFR were related to NYHA classes (p < 0.001) and the parameters of diastolic dysfunction (p < 0.001). The values of gMFR ≤ 2.27 may be used for the evaluation of microvascular changes in patients with HFpEF and non-obstructive CAD.

Tetranectin as a potential novel prognostic biomarker in anthracycline-related cardiac dysfunction.

To assess the association of serum tetranectin levels with cardiac remodeling parameters and to evaluate its prognostic role in women with anthracycline-related cardiac dysfunction (ARCD) and without previous cardiovascular diseases (CVD) during 24-month follow-up period. A total of 362 women with primary diagnosed breast cancer who were planned to be treated with anthracyclines were examined. At 12 months after chemotherapy completion, all women were examined and ARCD was diagnosed in 114 patients. After 24 months of follow-up, all patients with ARCD were divided into 2 groups: group 1 comprised women with the adverse course of ARCD (n = 54), group 2 comprised those without it (n = 60). In group 1, the levels of tetranectin were lower than group 2 by 27.6% (p < 0.001) and the patients without ARCD by 33.7% (p < 0.001). In group 1, the levels of tetranectin decreased (p < 0.001) from 11.8 (7.1; 14.3) to 9.02 (5.3; 14.6) pg/mL at 24 months. Moreover, in group 2 (p = 0.871) and in patients without ARCD (p = 0.716), they did not change. The tetranectin values were the independent predictor (odds ratio 7.08; p < 0.001) and its levels ≤ 15/9 ng/mL (AUC = 0.764; p < 0.001) were identified as the predictors for the adverse course of ARCD. NT-proBNP levels did not show the prognostic role, but the addition of NT-proBNP improved prognostic value of analysis (AUC = 0.954; p = 0.002). The cut-off values of tetranectin were established as predictor for adverse course of ARCD, when NT-proBNP was not. The combined use of tetranectin and NT-proBNP demonstrated higher diagnostic value for prediction of adverse outcomes.

Anthracycline-Induced Cardiotoxicity: The Role of Endothelial Dysfunction.

Cardiovascular disease remains the leading cause of mortality accounting up to 40% of all deaths, but, currently, cancer is prominent cause of death globally. Anthracyclines are the cornerstone of chemotherapy in women with breast cancer. However, its clinical use is limited by their cardiotoxic effects that can trigger heart failure development. Vascular toxicity of chemotherapy may be linked with endothelial dysfunction because anthracycline damage of endothelial cells can lead to the development and progression of cardiomyopathy by decreasing the release and activity of endothelial factors and, ultimately, endothelial cell death. These processes suppress anti-inflammatory and vascular reparative functions and initiate the development of future cardiovascular events. Recent studies have shown that chemotherapy may induce toxicity in the vascular endothelium and is accompanied by systemic endothelial dysfunction in patients with diagnosed cardiovascular diseases. Because the initial endothelial cell insult is likely asymptomatic, there is often a long delay between the termination of doxorubicin therapy and the onset of vascular disorders. In this case, genetic susceptibility factor will help to identify susceptible patients in the future. The objectives of this study were to evaluate prognostic role of molecular (endothelin-1) and genetic factors (gene polymorphisms of endothelial nitric oxide (NO) synthase (NOS3, rs1799983), endothelin-1 receptor type A (EDNRA, C+70G, rs5335) and NADPH oxidase (C242T, rs4673) in development of endothelial dysfunction and anthracycline-induced cardiotoxicity in women without cardiovascular diseases.

Interdisciplinary approach to compensation of hypoglycemia in diabetic patients with chronic heart failure.

Diabetes mellitus is a chronic disease requiring lifelong control with hypoglycemic agents that must demonstrate excellent efficacy and safety profiles. In patients taking glucose-lowering drugs, hypoglycemia is a common cause of death associated with arrhythmias, increased thrombus formation, and specific effects of catecholamines due to sympathoadrenal activation. Focus is now shifting from merely glycemic control to multifactorial approach. In the context of individual drugs and classes, this article reviews interdisciplinary strategies evaluating metabolic effects of drugs for treatment of chronic heart failure (CHF) which can mask characteristic hypoglycemia symptoms. Hypoglycemia unawareness and cardiac autonomic neuropathy are discussed. Data suggesting that hypoglycemia modulates immune response are reviewed. The potential role of gut microbiota in improving health of patients with diabetes and CHF is emphasized. Reports stating that nondiabetic CHF patients can have life-threatening hypoglycemia associated with imbalance of thyroid hormones are discussed. Regular glycemic control based on HbA1c measurements and adequate pharmacotherapy remain the priorities in diabetes management. New antihyperglycemic drugs with safer profiles should be preferred in vulnerable CHF patients. Multidrug interactions must be considered. Emerging therapies with reduced hypoglycemia risk, telemedicine, sensor technologies, and genetic testing predicting hypoglycemia risk may help solving the challenges of hypoglycemia in CHF patients with diabetes. Interdisciplinary work may involve cardiologists, diabetologists/endocrinologists, immunologists, gastroenterologists, microbiologists, nutritionists, imaging specialists, geneticists, telemedicine experts, and other relevant specialists. This review emphasizes that systematic knowledge on pathophysiology of hypoglycemia in diabetic patients with CHF is largely lacking and the gaps in our understanding require further discoveries.

The Influence of Kinetic Models and Attenuation Correction on Cadmium-Zinc-Telluride Single-Photon Emission Computed Tomography (CZT SPECT)-Derived Myocardial Blood Flow and Reserve: Correlation with Invasive Angiography Data.

(1) Background: The objective of this study was to determine the optimal post-processing model for dynamic cadmium-zinc-telluride single-photon emission computed tomography (CZT-SPECT). (2) Methods: A total of 235 patients who underwent diagnostic invasive coronary angiography within three months of the SPECT and those who had coronary computed tomography angiography (CCTA) before SPECT (within 3 months) were enrolled in this study. Each SPECT study was processed to obtain global and regional stress myocardial blood flow (sMBF), rest-MBF (rMBF), myocardial flow reserve (MFR) and flow difference (FD) estimates obtained with 1-tissue-compartment (1TCM) and net retention (NR) modes, both with and without attenuation correction. (3) Results: The use of AC led to significantly higher sMBF, rMBF and DF values obtained by 1TCM compared those values derived by 1TCM with NAC; the lowest values of stress MBF and rest MBF were obtained by 1TCM_NAC. The resting flow, MFR and DF were significantly (p < 0.005) higher in the AC model than in NAC. All quantitative variables were significantly (p < 0.05) higher in NR_NAC than in the 1TC_NAC model. Finally, sMBF, rMBF and FD showed significantly (p < 0.05) higher values by using 1TMC_AC compared to NR_AC. (4) Conclusions: We suggested that 1-compartment and net retention models correctly reflect coronary microcirculation and can be used for clinical practice for evaluating quantitative myocardial perfusion by dynamic SPECT. Attenuation correction is an important step in post-processing dynamic SPECT data, which increases the consistency and diagnostic accuracy of models.

Coronary Microvascular Dysfunction: Features and Prognostic Value.

(1) Background: The results of the international studies support the assumption that coronary microvascular dysfunction (CMD) occurs significantly more often than previously identified and is associated with adverse outcomes. However, there is a lack of the accurate comprehension of its pathophysiology. The objectives of this study were to evaluate the clinical and instrumental features of CMD and to assess its prognostic value during 12 months of follow-up period. (2) Methods: A total of 118 patients with non-obstructive coronary artery disease (CAD) and preserved LV ejection fraction (62 [59; 64]%) were enrolled in the study. Serum levels of biomarkers were analyzed by enzyme-linked immunoassay. CMD was defined as the reduced myocardial flow reserve (MFR) ≤ 2 obtained by dynamic CZT-SPECT. Two-dimensional transthoracic echocardiography with evaluation of LV diastolic dysfunction was performed baseline. (3) Results: Patients were divided into groups depending on the presence of CMD: CMD+ group (MFR ≤ 2; n = 45), and CMD- group (MFR > 2; n = 73). In CMD+ group, the severity of diastolic dysfunction, the levels of biomarkers of fibrosis and inflammation were higher than in CMD- group. Multivariate regression analysis showed that the presence of diastolic dysfunction (OR 3.27; 95% CI 2.26-5.64; p < 0.001), the hyperexpression of NT-proBNP ≥ 760.5 pg/mL (OR 1.67; 95% CI 1.12-4.15; p = 0.021) and soluble ST2 ≥ 31.4 ng/mL (OR 1.37; 95% 1.08-2.98; p = 0.015) were independent factors associated with CMD. Kaplan-Meier analysis showed that a rate of the adverse outcomes was significantly (p < 0.001) higher in patients with CMD (45.2%, n = 19) than in patients without it (8.6%, n = 6). (4) Conclusions: Our data suggest that the presence of CMD was associated with the severe diastolic dysfunction and hyperexpression of the biomarkers of fibrosis and inflammation. Patients with CMD had higher rate of the adverse outcomes than those without it.

Serum Cytokines as Biomarkers in Heart Failure with Preserved Ejection Fraction and Sleep Apnea: A Prospective Cohort Study.

Heart failure with preserved ejection fraction (HFpEF) and obstructive sleep apnea (OSA) frequently co-occur and this comorbidity represents a separate phenotype of HFpEF. While many research attempts are focused on biomarkers of HFpEF, currently, there is a lack of validated biomarkers of HFpEF and OSA. In this study, we aimed to evaluate prognostic significance of several serum cytokines in patients with HFpEF and OSA. The patients with HFpEF and OSA were recruited from the Sleep Apnea Center of Novosibirsk, Russian Federation and followed up for 12 months. The main analyzed outcomes were five-point major adverse cardiovascular events (MACE) and the 6-min walk test (6MWT). The analyzed cytokines were circulating IL-6, IL-10, and VEGF measured at baseline. We recruited 77 male patients with HFpEF and OSA, the data of 71 patients were available for analyses. Patients who developed MACE had four-fold elevated concentrations of serum IL-10. There was no association between baseline cytokine levels and longitudinal changes in 6MWT. Circulating IL-10 levels are positively associated with MACE in men with HFpEF and OSA and thus may be a potential prognostic biomarker in this subgroup of patients. These results should be confirmed in larger studies encompassing both males and females.

Prognostic Role of Dynamic CZT Imaging in Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: The objective of the study was to evaluate the prognostic role of myocardial flow reserve (MFR) and myocardial blood flow (MBF) estimates obtained with dynamic cadmium-zinc-telluride (CZT) imaging in the development and progression of heart failure with preserved ejection fraction (HFpEF) in patients with nonobstructive coronary artery disease (CAD) during a 12-month follow-up period. PATIENTS AND METHODS: A total of 112 patients (70 men; median age of 62.5 [57.0; 69.0] years) with nonobstructive coronary artery disease were enrolled in the study. Dynamic CZT-SPECT, echocardiography, and coronary CT angiography studies were performed baseline. RESULTS: Distribution of patients was performed by adverse events: group 1 comprised patients with adverse outcomes (n = 25), and group 2 comprised those without it (n = 87). Based on receiver operating characteristic analysis, the levels of MFR ≤1.62 (area under the curve [AUС], 0.884; Р < 0.001), stress-MBF ≤1.35 mL/min per gram (AUС, 0.750; Р < 0.001), and NT-proBNP ≥760.5 pg/mL (AUС, 0.764; Р = 0.001) were identified as cutoff values to predict adverse outcomes. Univariate analysis revealed that type 2 diabetes mellitus ( P = 0.044), the levels of MFR ≤1.62 ( P = 0.014), stress-MBF ≤1.35 mL/min per gram ( P = 0.012), NT-proBNP ≥760.5 pg/mL ( P = 0.018), and diastolic dysfunction ( P = 0.009) were potential risk factors for the development and progression of HFpEF. Multivariate analysis demonstrated that the values of NT-proBNP ≥760.5 pg/mL (odds ratio, 1.87; 95% confidence interval, 1.17-3.62; P = 0.027) and MFR ≤1.62 (odds ratio, 2.801; 95% confidence interval, 1.19-6.55; P = 0.018) were independent predictors of adverse outcomes. CONCLUSIONS: Our data suggest that reduced MFR ≤1.62 obtained with dynamic CZT imaging and overexpression of NT-proBNP ≥760.5 pg/mL can individuate patients at high risk of development and progression of HFpEF during a 12-month follow-up period, independently of baseline clinical parameters and imaging variables.

Extracellular matrix remodeling in anthracycline-induced cardiotoxicity: What place on the pedestal?

OBJECTIVE: To evaluate the role of matrix metalloproteinases (MMP)-2 and 9 and the gene polymorphisms of MMP-2 (rs243865) and MMP-9 (rs3918242) in the course of anthracycline-induced cardiotoxicity (AIC) in women without previous cardiovascular diseases (CVD) during 24-months. METHODS: A total of 114 women (47.0 [44.0; 52.0] years old) with AIC of NYHA class I-III who received doxorubicin for breast cancer were enrolled. RESULTS: After 24 months patients had breast cancer remission and were divided into 2 groups: group 1 comprised women with adverse course of AIC (n = 54), group 2 comprised those without it (n = 60). Serum levels of MMP-2 were higher by 8% (p = 0.017) MMP9 by 18.4% (p < 0.001) in group 1 than in group 2. In group 1 the levels of MMP-2 increased (p < 0.001) from 376.8 (329.5; 426.7) to 481.4 (389.8; 518.7) pg/mL, and MMP-9 increased (p < 0.001) from 23.6 (21.4; 24.6) to 26.0 (23.3; 27.0) pg/mL at 24 months. In group 2 the both MMP-2 and MMP-9 level decreased at 24 months. Based on ROC-analysis, the levels of MMP2 ≥ 388.2 pg/mL (AUС = 0.64; р = 0.013) and MMP-9 ≥ 21.25 pg/mL (AUС = 0.9; р < 0.001) were identified as predictors for adverse course of AIHF. The presence of C/C genotype of MMP2 (OR = 4.76; p = 0.029) and C/C genotype of MMP-9 (OR = 15.2; p < 0.0001) were related with adverse course of AIHF and higher levels of MMP-2 and MMP-9. CONCLUSION: Gene polymorphisms of MMP-2 (rs243865) and MMP-9 (rs3918242) and serum levels of MMP-2 and MMP-9 levels in women without previous CVD were associated with adverse course of AIC during 24 months.

Anthracycline-induced cardiotoxicity in women without cardiovascular diseases: molecular and genetic predictors.

OBJECTIVE: To evaluate role of molecular (endothelin-1, soluble Fas-L, NT-proBNP, TNF-α, interleukin-1ß,) and genetic factors (NOS3 (rs1799983), EDNRA (C + 70G, rs5335), NADPH oxidase (C242T, rs4673), p53 protein (polymorphic marker-Arg72Pro exon 4, rs1042522), NOS3 (Glu298Asp, rs1799983), Caspase 8 (CASP8, rs3834129 and rs1045485), interleukin-1ß gene (Il-1ß, rs1143634), TNF-α gene (rs1800629), SOD2 (rs4880), GPX1 (rs1050450) in development of anthracycline-induced cardiotoxicity (AIC) in women without cardiovascular diseases. METHODS: A total of 176 women with breast cancer and without cardiovascular diseases who received anthracyclines were enrolled in the study. After the 12 months of chemotherapy (CT), all patients were divided into two groups: group 1 (n = 52) comprised patients with AIC, group 2 (n = 124) comprised those without it. RESULTS: Based on ROC-analysis, levels of endothelin-1 of ≥9.0 pg/mL (AUC of 0.699), sFas-L of ≥98.3 ng/mL (AUC of 0.990), and NT-proBNP of ≥71.5 pg/mL (AUC of 0.994;) were identified as a cut-off values predicting AIC during 12 months after CT. Whereas, NT-proBNP and sFas-L were more significant predictors than endothelin-1 (p < 0.001). The development of AIC was significantly related to Arg/Arg of p53 protein gene (OR = 2.972; p = 0.001), T/T of NOS3 gene (OR = 3.059, p = 0.018), T/T of NADPH oxidase gene (OR = 2.753, p = 0.008), and C/C of GPX1 (OR = 2.345; p = 0.007). CONCLUSION: Evaluation of polymorphisms genes of p53 (rs1042522), NOS3 (rs1799983), GPX1 (rs1050450), and NADPH oxidase (rs4673) can be recommended before CT for the risk assessment of AIC development. The serum levels of NT-proBNP and soluble Fas-L after CT may be considered as non-invasive biomarkers for prediction of AIC development during the 12 months.

Chemically Modified Biomimetic Carbon-Coated Iron Nanoparticles for Stent Coatings: In Vitro Cytocompatibility and In Vivo Structural Changes in Human Atherosclerotic Plaques.

Atherosclerosis, a systematic degenerative disease related to the buildup of plaques in human vessels, remains the major cause of morbidity in the field of cardiovascular health problems, which are the number one cause of death globally. Novel atheroprotective HDL-mimicking chemically modified carbon-coated iron nanoparticles (Fe@C NPs) were produced by gas-phase synthesis and modified with organic functional groups of a lipophilic nature. Modified and non-modified Fe@C NPs, immobilized with polycaprolactone on stainless steel, showed high cytocompatibility in human endothelial cell culture. Furthermore, after ex vivo treatment of native atherosclerotic plaques obtained during open carotid endarterectomy surgery, Fe@C NPs penetrated the inner structures and caused structural changes of atherosclerotic plaques, depending on the period of implantation in Wistar rats, serving as a natural bioreactor. The high biocompatibility of the Fe@C NPs shows great potential in the treatment of atherosclerosis disease as an active substance of stent coatings to prevent restenosis and the formation of atherosclerotic plaques.