Progression Of Cardiovascular Complications Research Articles

#1585 Ten years’ practice with calcimimetics and paricalcitol for the treatment of secondary hyperparathyroidism. Experience of one dialysis center

Abstract Background and Aims Secondary hyperparathyroidism (SHPT) remains one of the main problems in patients with chronic kidney disease (CKD), associated with deterioration in quality of life, progression of cardiovascular complications and mortality. Method Patients on HD (n = 2517) were treated from 2012 to 2023 years in our dialysis center with secondary SHPT were included in this study. All patients were divided into 2 groups: 1 gr. included −1536 (61%) patients whose PTH levels remained in the target range from 300 to 600 pg/ml, without therapy or with low doses of alfacalcidol (0.75-5 μg/week ); 2 gr. included - 981 (39%) patients with PTH levels >600 pg/ml were treated with calcimimetics (doses of cinacalcet used from 30 mg to 90 mg/day, doses of etelcalcetide used from 5 to 15 mg/week) as monotherapy or in combination with paricalcitol (5–15 μg/week). Phosphorus levels were controlled by an adequate dose of dialysis and administration of phosphate binders (sevelamer and sucrose iron oxyhydroxide). Results The average PTH level in 2 gr. of patients at the time of treatment initiation was 916.7 ± 879.9 pg/ml (601-2500 pg/ml). During the treatment the level of PTH decreased to target values and amounted 523.4 ± 216.7 pg/ml (63-594 pg/ml) in 73% of patients. Monotherapy with calcimimetics was effective in 41%; the remaining of patients (59%) were required the addition of paricalcitol to therapy to achieve target PTH values. Therapy of SHPT was also carried out in 15 (0.6%) patients with identified parathyroid adenomas (volume more than 1 cm3) and PTH levels >1000 pg/ml; the effect was achieved in 9 patients (60%), 6 patients underwent parathyroidectomy. During the previous years of observation, parathyroidectomy was required in all patients with SHPT with similar changes in the parathyroid glands. Conclusion In the overwhelming majority of patients with CKD5D and SHPT, the administration of calcimimetics as monotherapy or in combination with paricalcitol during the progression of SHPT allowed us to achieve target PTH values and maintain it for a long time (from 1 to 10 years), as well as reduce the number of surgical interventions for parathyroid glands, compared to the previous period.

Prognostic value of echocardiographic parameters of cardiac remodeling in patients with hypertension and obstructive sleep apnea

Objective. To study the prognostic value of echocardiographic parameters of early cardiac remodeling in patients with hypertension (HTN) and obstructive sleep apnea (OSA). Design and methods. The study included 59 men with HTN and OSA (with an apnea/hypopnea index > 15 per hour). At baseline, all patients underwent polysomnography and echocardiography with an additional assessment of the global longitudinal strain (GLS). At baseline and at 12-month follow-up, a 6-minute walk test was performed. After 12 months, the clinical course of the disease was assessed. The criteria for an unfavorable course were episodes of hospitalization, the development of acute coronary syndrome, cerebral stroke, paroxysmal atrial fibrillation, worsening of chronic heart failure with a transition to a higher NYHA functional class. Results. In groups with favorable and unfavorable clinical course, some baseline echocardiographic parameters differed significantly: interventricular septal thickness (p = 0,037), left ventricular myocardial mass index (LVMI) (p = 0,003), tricuspid annular plane systolic excursion (TAPSE) (p < 0.001), GLS (p = 0,019), peak tricuspid regurgitation (p = 0,027), left atrial volume index (p = 0,048). Regression analysis showed that baseline TAPSE and LVMI had predictive value for an unfavorable clinical course. Conclusions. Our results confirm that certain echocardiographic parameters, in particular, LVMI and TAPSE, are predictors of the development and progression of cardiovascular complications in OSA patients.

Bach1 modulates AKT3 transcription to participate in hyperglycaemia-mediated EndMT in vascular endothelial cells.

Hyperglycaemia-mediated endothelial-to-mesenchymal transition (EndMT) is involved in the occurrence and progression of cardiovascular complications in diabetic patients. Previous studies reported that AKT serine/threonine kinase 3 (AKT3) and Bric-a-brac/Tramtrack/Broad (BTB) and cap'n'collar (CNC) homology 1 (bach1) participates in endothelial injury and epithelial-to-mesenchymal transition. In the present study, we proposed that bach1 regulates AKT3 transcription, thus involved in hyperglycaemia-mediated EndMT in vascular endothelium. Our results indicated that hyperglycaemia/high glucose increased AKT3 expression and induced EndMT in aorta of diabetic rats and hyperglycaemic human umbilical vein endothelial cells (HUVECs). Moreover, inhibition of AKT3 expression reversed high glucose-mediated EndMT in HUVECs. Further, hyperglycaemia/high glucose augmented bach1 expression in aorta of diabetic rats and hyperglycaemic HUVECs. Furthermore, si-bach1 countered high glucose-induced AKT3 expression and EndMT in HUVECs. In addition, the effect of bach1 overexpression is similar to that of high glucose treatment, which was reversed by si-AKT3. ChIP assays found bach1 enriched in the promoter region of AKT3. Bach1 overexpression augmented AKT3 promoter activity, which lost after specific binding site mutation. Bach1 was involved in hyperglycaemia-induced EndMT via modulation of AKT3 transcription.

Circadian rhythm of plasminogen activator inhibitor-1 and cardiovascular complications in type 2 diabetes.

Cardiovascular complications are a common death cause in type 2 diabetes patients, as they are often combined. Plasminogen-activator Inhibitor 1 (PAI-1) participates in the development and progression of cardiovascular complications in diabetes. Insulin resistance increases PAI-1 production, and high PAI-1 levels lead to an environment conducive to thrombosis and earlier and more severe vascular disease. Current evidence also suggests that PAI-1 has a rhythmic profile of circadian fluctuations and acrophase in the morning within a single day, which might explain the high morning incidence of cardiovascular events. Thus, PAI-1 is a possible drug target. Although several PAI-1 inhibitors have been developed, none have yet been allowed for clinical use. Research on rhythm has also led to the concept of "chronotherapy", a rhythm-based drug regimen expected to improve the treatment of cardiovascular complications in diabetic patients. Herein, we searched several databases and reviewed relevant articles to describe the circadian rhythm characteristics and endogenous molecular mechanisms of PAI-1, its relationship with insulin resistance, the causes of cardiovascular complications caused by PAI-1, and the current development of PAI-1 inhibitors. We also summarized the possibility of using the circadian rhythm of PAI-1 to treat cardiovascular complications in diabetic patients.

Basic principles of dietary therapy in type 2 diabetes mellitus: focus on antioxidant protection and endothelial dysfunction

Oxidative stress and endothelial dysfunction have been identified as the most important pathogenetic pathways for the development and progression of vascular complications in type 2 diabetes (T2DM). Objective. To evaluate the effect of individual dietary components on oxidative stress and endothelial dysfunction in patients with T2DM. Material and methods. The search and analysis of publications was carried out using the PubMed, MEDLINE, Web of Science databases, mainly for the last 10 years, using the keywords "type 2 diabetes mellitus", "endothelial dysfunction", "polyphenols", "antioxidants", "diet". Results. It has been shown that despite the progress in the development of drugs for the correction of clinical and metabolic disorders in T2DM, diet therapy is an important therapeutic factor influencing the main mechanisms of development and progression of cardiovascular complications in T2DM, including hyperglycemia, dyslipidemia, arterial hypertension, subclinical inflammation, endothelial dysfunction. Properly organized and built on modern scientific principles, clinical nutrition improves glycemic control, correction of arterial hypertension, dyslipidemia and overweight/obesity. Influencing the mechanisms of development of oxidative stress, therapeutic nutrition can serve as a preventive approach to protect against the occurrence of endothelial dysfunction and subsequent complications, primarily atherosclerotic origin. Conclusion. The review presents current data on the effect of diet therapy on the main clinical and metabolic parameters in T2DM, endothelial function and oxidative stress, as the most significant factors in the development of systemic vascular complications.

Ремоделювання міокарда в пацієнтів із цукровим діабетом 2-го типу в поєднанні з неалкогольною жировою хворобою печінки

З метою вивчення особливостей ранніх кардіоваскулярних ускладнень у хворих на цукровий діабет (ЦД) 2-го типу в поєднанні з неалкогольною жировою хворобою печінки (НАЖХП) проведено вивчення частоти серцево-судинних захворювань і зіставлення клініко-метаболічних параметрів із даними ехокардіографічного і допплерівського дослідження сонних артерій.Було обстежено 70 хворих на ЦД 2-го типу, із них 27 пацієнтів без НАЖХП, 24 — із ЦД 2-го типу та НАЖХП із нормальною діастолічною функцією і 19 — із ЦД 2-го типу та НАЖХП з порушеною діастолічною функцією.Установлено роль запалення вісцеральної жирової тканини в генезі кардіоваскулярних ускладнень у всіх хворих на ЦД 2-го типу та вплив мезенхімального запалення в печінці на ризик виникнення даних ускладнень у пацієнтів із ЦД 2-го типу та НАЖХП за даними рівня трансаміназ. Виявлено збільшення частоти гіпертрофії міокарда лівого шлуночка у хворих на ЦД 2-го типу в поєднанні з НАЖХП більше ніж утричі порівняно з хворими без НАЖХП. До того ж збільшення частоти гіпертрофії міокарда лівого шлуночка було прямо пропорційно наростанню маси тіла (45–88 %) у хворих із поєднаною патологією і порушеною діастолічною функцією. У хворих на ЦД 2-го типу в поєднанні з НАЖХП зареєстровано ремоделювання міокарда лівого шлуночка за типом гіпертрофії і порушення діастолічної функції, що свідчить про більш виражений атеросклеротичний процес у даної категорії хворих порівняно з пацієнтами без НАЖХП.Також установлено збільшення фактора некрозу пухлини α у хворих на ЦД 2-го типу в поєднанні з НАЖХП порівняно з хворими без НАЖХП.Виявлено виражені атеросклеротичні зміни в міокарді і сонних артеріях при використанні високочутливих інструментальних методів, а саме: гіпертрофія міокарда лівого шлуночка реєструвалася в 60 % хворих на ЦД 2-го типу, у 83 % — із ЦД 2-го типу в поєднанні з НАЖХП, при цьому 44 % із них мали порушену діастолічну функцію міокарда та потовщення комплексу інтима-медіа зі звуженням і вже наявністю атеросклеротичних бляшок в області гирла і біфуркації сонних артерій.Отримані результати свідчать про необхідність включення до переліку обов’язкових діагностичних досліджень у хворих на ЦД 2-го типу протягом перших двох років із моменту встановлення діагнозу ехокардіографії серця і допплерографії сонних артерій, а також встановлення рівня фактора некрозу пухлини α, що відіграє важливу роль у прогресуванні серцево-судинних ускладнень у хворих на поєднану патологію.

Update on the Classification and Pathophysiological Mechanisms of Pediatric Cardiorenal Syndromes.

Cardiorenal syndrome (CRS) is defined as a disorder resulting from the abnormal interaction between the heart and kidney, in which acute or chronic dysfunction of one organ may lead to acute and/or chronic dysfunction of the other. The functional interplay between the heart and kidney is characterized by a complex bidirectional symbiotic interaction, regulated by a wide array of both genetic and environmental mechanisms. There are at least five known subtypes of CRS, based on the severity of clinical features and the degree of heart/renal failure. The fourth subtype (cardiorenal syndrome type 4 (CRS4)) is characterized by a primary chronic kidney disease (CKD), which in turn leads to a decreased cardiac function. Impairment of renal function is among the most important pathophysiological factors contributing to heart failure (HF) in the pediatric age group, and cardiovascular complications could be one of the most important causes of mortality in pediatric patients with advanced CKD. In this context, a loss of glomerular filtration rate directly correlates with both the progression of cardiovascular complications in CRS and the risk of HF. This review describes the interaction pathways between the heart and kidney and the recently identified pathophysiological mechanisms underlying pediatric CRS, with a special focus on CRS4, which encompasses both primary CKD and cardiovascular disease (CVD).

Intermittent hypoxia changes the interaction of the kinin-VEGF system and impairs myocardial angiogenesis in the hypertrophic heart.

Intermittent hypoxia (IH) is a feature of obstructive sleep apnea (OSA), a condition highly associated with hypertension‐related cardiovascular diseases. Repeated episodes of IH contribute to imbalance of angiogenic growth factors in the hypertrophic heart, which is key in the progression of cardiovascular complications. In particular, the interaction between vascular endothelial growth factor (VEGF) and the kallikrein‐kinin system (KKS) is essential for promoting angiogenesis. However, researchers have yet to investigate experimental models of IH that reproduce OSA, myocardial angiogenesis, and expression of KKS components. We examined temporal changes in cardiac angiogenesis in a mouse IH model. Adult male C57BI/6 J mice were implanted with Matrigel plugs and subjected to IH for 1–5 weeks with subsequent weekly histological evaluation of vascularization. Expression of VEGF and KKS components was also evaluated. After 3 weeks, in vivo myocardial angiogenesis and capillary density were decreased, accompanied by a late increase of VEGF and its type 2 receptor. Furthermore, IH increased left ventricular myocardium expression of the B2 bradykinin receptor, while reducing mRNA levels of B1 receptor. These results suggest that in IH, an unexpected response of the VEGF and KKS systems could explain the reduced capillary density and impaired angiogenesis in the hypoxic heart, with potential implications in hypertrophic heart malfunction.

CARDIOVASCULAR COMPLICATIONS FROM COVID-19 MAY BE PREDICTED BY THE INCREASED LEVEL OF C-REACTIVE PROTEIN: A META-ANALYSIS

Objective: Current evidence suggests that the most common cardiovascular complications in the COVID-19 patients include acute myocardial injury, congestive heart failure (CHF), coronary artery disease (CAD), cardiac arrhythmias and thromboembolic events. Considering that the mechanism for myocardial injury is reported to result mainly from the direct viral involvement of cardiomyocytes and the effects of systemic inflammation, our scope is to evaluate the relation of the increased level of C-Reactive Protein (CRP) and the cardiovascular complications due to COVID-19. Design and method: We conducted a systematic literature search on various databases such as PubMed, Web of Science and Scopus to identify the relevant articles. We included studies published until September 2020. The receiver operating characteristic (ROC) curve was utilized to analyze the prognostic ability of CRP in the cardio-vascular complications from COVID-19. Subgroup and sensitivity analyses were performed. Heterogeneity was assessed using Cochran's Q test and I2 test. The presence of publication bias was evaluated by visual inspection of the symmetry in funnel plots Results: Nineteen studies met the inclusion criteria with more than 10,630 participants. Subgroup analysis of the clinical classification included acute myocardial injury, CHF, CAD and thromboembolic events. The ROC curve shows that AUC (CHF)=85% (95% CI of 0.598 to 1); AUC (CAD)=81% (95% CI of 05.44 to 1); AUC (Thromboembolic events)=100% (95% CI of 1 to 1). The Kaplan-Meier curve and the log-rank test were applied to further assess the potential risk factors associated with the progression of cardiovascular complications from COVID-19. The Youden index was implemented to set cutoff values. Data analysis was conducted using SPSS 23.0 software. Conclusions: This meta-analysis implies that CRP could be a valuable marker to anticipate the cardiovascular complications from COVID-19. Further evidence based research is mandated for the evaluation of the prognostic role of CRP in these patients.

Cardiovascular Features of Chronic Inflammation and Endothelial Dysfunction in Patients with Diabetic Nephropathy on Programmed Hemodialysis

Introduction and purpose: It is important today to determine the factors that form a very high cardiovascular risk in patients with type 2 diabetes mellitus (DM) with kidney damage on programmed hemodialysis (HD). The aim of the study has been to determine the cardiovascular features of chronic inflammation and endothelial dysfunction (ED) in HD patients with diabetic nephropathy (DN). Material and methods: The study has included 136 patients treated with HD (men, 78; age, 53.9±1.0 year, duration of HD, 47.6±4.2 months). Depending on the presence/absence of type 2 diabetes, they have been divided into two groups: the first – without DN (n=88); the second – with DN (n=48). The intensity of inflammation has been assessed by the serum content of tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), fibrinogen (FG) and albumin. Vasomotor function of the brachial artery (BA) has been determined using a test with reactive hyperemia (endothelium-dependent vasodilation, (EDVD)). The content of nitrite anions (NO2-) and the number of circulating endothelial cells (CECs) in blood plasma have been measured. Results: In patients with DN, TNF-α (p=0.002), CRP (p<0.001) and FG (p=0.008) significantly exceeded those in non-diabetics. The average value of EDVD BA (p=0.001), NO2- (p=0.008) in patients of the second group has been lower, and the number of CECs – higher (p<0.001) compared with the first group. Vasoconstriction (EDVD<0%) and undilatation (EDVD=0%) reactions in the case of DN have been registered more often (52.1 vs. 19.1%, p<0.001). In patients with DN for the first time have been established correlations between CECs and TNF-α (Rs=0.73, p<0.001), CRP (Rs=0.53, p<0.001), FG (Rs=0.53, p<0.001), albumin (Rs=-0.43, p=0.002). Conclusions: Chronic inflammation in the constellation with endothelial damage in patients with DN in the case of HD is obviously an important factor in cardiovascular remodeling, a predictor of progression of cardiovascular complications.

Chicoric acid attenuates hyperglycemia-induced endothelial dysfunction through AMPK-dependent inhibition of oxidative/nitrative stresses

Background Endothelial dysfunction is a driving force during the development and progression of cardiovascular complications in diabetes. Targeting endothelial injury may be an attractive avenue for the management of diabetic vascular disorders. Chicoric acid is reported to confer antioxidant and anti-inflammatory properties in various diseases including diabetes. However, the role and mechanism of chicoric acid in hyperglycemia-induced endothelial damage are not well understood. Methods In the present study, human umbilical vein endothelial cells (HUVECs) were incubated with high glucose/high fat (HG + HF) to induce endothelial cell injury. Results We found that exposure of HUVECs to HG + HF medium promoted the release of cytochrome c (cytc) from mitochondrion into the cytoplasm, stimulated the cleavage of caspase-3 and poly ADP-ribose-polymerase (PARP), then inducing cell apoptosis, the effects that were prevented by administration of chicoric acid. Besides, we found that chicoric acid diminished HG + HF-induced phosphorylation and degradation of IκBα, and subsequent p65 NFκB nuclear translocation, thereby contributing to its anti-inflammatory effects in HUVECs. We also confirmed that chicoric acid mitigated oxidative/nitrative stresses under HG + HF conditions. Studies aimed at exploring the underlying mechanisms found that chicoric acid activated the AMP-activated protein kinase (AMPK) signaling pathway to attenuate HG + HF-triggered injury in HUVECs as AMPK inhibitor Compound C or silencing of AMPKα1 abolished the beneficial effects of chicoric acid in HUVECs. Conclusion Collectively, chicoric acid is likely protected against diabetes-induced endothelial dysfunction by activation of the AMPK signaling pathway. Chicoric acid could be a novel candidate for the treatment of the diabetes-associated vascular endothelial injury.

1056-P: Effect of Dulaglutide on Glycemic Variability: Post Hoc Analysis of the AWARD Studies

Glycemic variability (GV) may contribute to the development and progression of cardiovascular complications. This post-hoc analysis assessed GV in people with type 2 diabetes, treated with once-weekly dulaglutide (DU), and not receiving any concomitant insulin treatment. Analysis included pooled data from 5 randomized, parallel-arm, phase 3 studies (AWARD 1,2,3,6 and 8). The participants (N=1114, 48% male) received DU 1.5 mg without any concomitant insulin for 26 weeks and with evaluable GV measurements at baseline and study endpoint (week 26). The measurements included within-day and between-day GV calculated by standard deviation (SD) and coefficient of variation (CV) from self-monitored plasma glucose (SMPG), and between-day fasting self-monitored plasma glucose (FSMPG) values. At baseline, the mean (SD) age was 55.9 (9.7) years, BMI 32.7 (5.2) kg/m2, HbA1c 8.0 (0.9) % and fasting plasma glucose 166.5 (47.8) mg/dL. At 26 weeks, DU significantly reduced within-day and between-day GV from SMPG values (SD values, p<0.001, Figure) and between-day GV from FSMPG (p<0.001). SMPG GV changes were significant and consistent across studies. Analysis by CV gave consistent results (Figure). Overall, the analysis suggests that treatment with once-weekly DU 1.5 mg reduces within-day and between-day GV from SMPG and between-day GV from FSMPG. Disclosure E. Jodar: Other Relationship; Self; Elli Lilly & Co, Novo Nordisk, MSD, Lilly, Janssen, Pfizer, AstraZeneca, Sanofi, UCB, Amgen, FAES, Shire, Mundipharma, Novartis. Q. Wang: Employee; Self; Eli Lilly and Company. I. Romera: Employee; Self; Eli Lilly and Company. E. Caveda: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L. Garcia: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Funding Eli Lilly and Company

P1027THE DIFFERENCES EFFECTS OF GLUCAGON LIKE PEPTIDE-1(GLP-1) ANALOGUES AND SODIUM-COTRANSPORTER 2 (SGLT-2) INHIBITORS ON TYPE 2 DIABETES PATIENTS WITH RENAL IMPAIRMENT

Abstract Background and Aims Diabetes mellitus (DM) is a progressive multifactorial disease associated with cardiovascular complications. To prevent the progression of cardiovascular complications in DM patients, glycemic control is important. In this study, we examined impact on cardiac function between glucagon like peptide-1(GLP-1) analogue and sodium-glucose cotransporter-2 (SGLT-2) inhibitors to treat type 2 diabetes patients with renal impairment. Method A total of 125 type 2 DM patients with renal impairment were recruited for this study. All patients were divided into two groups according to the anti-diabetic agents at baseline: Group G; 0.9mg/day liraglutide, n=53, Group S; n=72; 5mg/day dapagliflozin, n=32, empagliflozin n=14, 20mg/day tofogliflozin n=19, or 50mg/day ipragliflozin n=16. Blood glucose levels, glycosylated hemoglobin (HbA1c), serum creatinine, and albuminuria were obtained 12 months before and every 3 months for 36 months. Echocardiography, ankle brachial pressure index(ABI) and cardio-ankle vascular index(CAVI) were obtained every 12 months for 36 months. Results At baseline, the mean age was 68.5±6.0 years, DM vintage was 12.0±6.0 years, and mean total oral pill counts was 12.0±6.0. Compared with baseline, mean total pill counts were reduced at 12 months after initiation of new anti-diabetic agents (ADA) and remained afterward (Group G; 12.3±5.3 at baseline, 8.9±4.0 at 12 months (p<0.05), Group S; 11.8±4.2 at baseline, 8.6±3.4 at 12 months (p<0.05)). The counts of ADAs were also decreased (Group G; 3.85±2.61 at baseline, 1.41±2.01 at 12 months (p<0.01), Group S; 3.48±2.43 at baseline, 2.41±1.44 at 12 months (p<0.05)). HbA1c and systolic blood pressure were significantly decreased after initiation of GLP-1 analogue or SGLT-2 inhibitor in both groups. Nevertheless, eGFRs were gradually decreased in both groups. Albuminuria indicated by urinary albumin creatinine ratio were decreased significantly after initiation of anti-diabetic agents. Left ventricular mass index (LVMI) (Group G; 135.8 at baseline, 110.2 at 12 months,114.5 at 24 months, 107.2 g/m2 at 36 months, Group S; 130.0 at baseline, 113.2 at 12 months,106.4 at 24 months, 115.9 g/m2 at 36 months) and left atrial volume index (LAVi) (Group G; 25.6 at baseline, 22.3 at 12 months, 21.4 at 24 months, 20.8 mL/m2 at 36 months, Group S; 24.0 at baseline, 21.8 at 12 months,21.7 at 24 months, 22.7 mL/m2 at 36 months) were significantly decreased in both groups. Cardiac systolic function indicated by ejection fraction (EF) and diastolic function indicated by E/e’ (Group G; 12.9 at baseline, 10.4 at 12 months, 9.4 at 24 months, 9.5 at 36 months, Group S; 12.4 at baseline, 10.6 at 12 months, 12.5 at 24 months, 12.9 at 36 months) or left atrial dimension were remained or improved only in group G. Moreover, arterial stiffness indicated by cardio-ankle vascular index (CAVI) was improved in group G (Group G; 10.2 at baseline, 9.9 at 12 months, 9.9 at 24 months, 9.9 at 36 months, Group S; 10.3 at baseline, 10.5 at 12 months, 10.6 at 24 months, 10.6 at 36 months) (Table1). With respect to admission due to cardiovascular events, cerebrovascular infarction were occurred higher in group S (3.8% vs 1.3% / yea; p<0.05), congestive heart failure were higher in group G (1.9%. vs 0.5% / year; p<0.05). Conclusion These findings suggest that liraglutide and SGLT-2 inhibitor for type 2 DM patients with renal impairment have similar effects on renal function including eGFR and albuminuria and left ventricular and atrial volume. However, liraglutide could provide more benefit for arterial stiffness than SGLT-2 inhibitors.

3,4-Dihydroxybenzalacetone (DBL) Prevents Aging-Induced Myocardial Changes in Senescence-Accelerated Mouse-Prone 8 (SAMP8) Mice.

Aging is a predominant risk factor for the development and progression of cardiovascular complications. Physiologically and anatomically, the heart undergoes numerous changes that result in poor cardiac function in the elderly population. Recently, several studies have provided promising results, confirming the ability of the senescence-accelerated mouse-prone 8 (SAMP8) model to accurately model age-related cardiovascular alterations. In this study, using a murine model of senescence, SAMP8, we aimed to investigate the effect of 3,4-dihydroxybenzalacetone (DBL), a catechol-containing phenylpropanoid derivative isolated from Inonotus obliquus (Chaga), on cardiac aging. DBL was administered at the doses of 10 mg/kg and 20 mg/kg by oral gavage to SAMP8 mice to examine aging-mediated cardiac changes, such as oxidative DNA damage, oxygen radical antioxidant capacity (ORAC) value, fibrosis, inflammation, and apoptosis. The treatment with DBL at both doses significantly reduced aging-mediated oxidative DNA damage, and simultaneously increased the ORAC value in the SAMP8 assay. Cardiac fibrosis was assessed with Azan-Mallory staining, and the number of cardiac remodeling markers was found to be significantly reduced after the treatment with DBL. We also observed a decrease in cardiomyocyte apoptosis as measured by the terminal transferase-mediated dUTP nick end labeling (TUNEL) staining method and the caspase-3 levels in SAMP8 mice compared with senescence-resistant control (SAMR1) mice. The findings from this study suggest that DBL has a potentially beneficial effect on aging-mediated myocardial alterations. Further studies are warranted to confirm the promising potential of this catechol compound against aging-associated myocardial dysfunction.

Organoprotective effects of glucagon-like peptide-1 receptor agonists with regard to findings of evidencebased cardiovascular safety studies

The article discusses the potential opportunities for impact of antidiabetic drugs from the group of glucagon-like peptide-1 (GLP- 1) receptor agonists on the risks of development and progression of cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) and their possible role in increasing the patients’ expectancy and quality of life. The existing differences between the drugs of this class should be taken into account in using personalized approach to therapy, developing and introducing new guidelines for specialized medical care for patients with type 2 diabetes into clinical practice. The article presented data on the efficacy and safety of the use of GLP-1 receptor agonists and discusses data on the possible mechanisms of non-glycemic effects underlying their cardio and nephroprotection. The features of pharmacological characteristics affecting the clinical efficacy and development of side effects are considered. The article also provides data from randomized clinical trials of various GLP-1 receptor agonists that demonstrate the positive effect of drugs of this class on cardiovascular and nephrological outcomes in patients with type 2 diabetes.

Cardiovascular complications in hemodialysis patients: current approaches to prolong and improve quality of patients’ life

Cardiovascular complications are a leading cause of morbidity and mortality in dialysis patients. Cardiovascular mortality is more than 40% of the total mortality in this cohort of patients. Recently, there has been an increase in publications on the role of uremic toxins, including “middle molecules”, in the development and progression of cardiovascular complications in dialysis patients.
 Conventional low-flux (LF) hemodialysis well removes small molecular weight uremic toxins not bound with protein. Evidence for the role of "middle molecules" in the development of many complications, including cardiovascular complications, has contributed to the emergence and development of such dialysis therapy methods as high-flux (HF) hemodialysis, hemofiltration (HF) and hemodiafiltration (HDF).
 Further evolution of membrane technology has led to the development of protein-leaking membranes or super-flux or high cutoff (HCO) membranes. These membranes are capable of removing molecules in excess of the molecular weight of albumin. The use of these membranes is limited because of the risk of hypoalbuminemia.
 Today, the closest approximation to the natural glomerular membrane is the so-called Middle Cut-Off (MCO) membrane. The use of MSO membranes is implemented in a new method of dialysis therapy - expanded hemodialysis (HDx). The method is defined as a treatment where diffusion and convection are conveniently combined inside a hollow-fibre dialyser equipped with an MCO membrane. A standard hemodialysis machine is used for the HDx. Increased removal of large medium molecules in HDx may lead to an improvement of clinical outcomes, including a decrease of the cardiovascular events incidence, an all-cause and cardiovascular mortality reduction in dialysis patients.

In Vivo Targeting of the Endothelium to Improve Vascular Function in a Rodent Model of Type 2 Diabetes

Endothelial dysfunction has been identified as an early event in the progression of cardiovascular complications (e.g. hypertension, cardiomyopathy, stroke) commonly observed in patients with Type 2 Diabetes (T2D). Importantly, reduction/reversal of endothelial dysfunction is expected to mitigate the cardiovascular deficits associated with T2D. Small‐ and intermediate‐conductance, Ca2+‐activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacologic activators of these channels (e.g. SKA‐31) induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of KCa activators such as SKA‐31 have not been examined to date. In our current study, we have hypothesized that daily administration of SKA‐31 (10 and 30 mg/kg, I.P. injection) to male, Type 2 Diabetic Goto‐Kakizaki rats (T2D GK, 14 weeks of age) for 12 weeks would ameliorate diabetes‐related cardiovascular deficits. In isolated mesenteric resistance arteries examined by pressure myography, we observed that SKA‐31 treatment significantly improved endothelium‐dependent vasodilation in response to 0.3 μM acetylcholine (ACh) (percent of maximal dilation = 37.7 ± 7.3% and 33.6 ± 6.2% for 10 and 30 mg/kg treatments) compared with vehicle‐treated animals (20.7 ± 3.1%) (means ± S.D., n = 6 animals/group). Similar effects were observed for 0.3 μM bradykinin (BK) (evoked vasodilation = 54.1 ±7.8% and 47.9 ± 6.6% for 10 and 30 mg/kg SKA‐31, respectively) compared with vehicle (33.6 ±6.1%). SKA‐31 administration also reduced alpha1‐adrenergic (phenylephrine, 1 μM) stimulated constriction in 10 and 30 mg/kg treated T2D GK rats (percent of maximal contraction = 37.1 ± 5.0% and 36.1 ± 3.7%, respectively) compared with vehicle treated animals (46.6 ± 4.5%, n = 6 per group). Western blot analyses further revealed that SKA‐31 administration increased the expression of mesenteric KCa2.3 and KCa3.1 channels and associated cell‐signaling components (i.e. type 1 IP3 receptor and the SERCA2 Ca2+‐ATPase) that contribute to endothelium‐dependent, agonist‐evoked vasodilation. In contrast, SKA‐31 treatment did not augment ACh and BK evoked vasodilation in myogenically active, cremaster skeletal muscle resistance arteries from the same animals, compared with the vehicle treated group. Collectively, these data demonstrate that in vivo administration of an endothelial KCa channel activator can selectively improve vascular function in the setting of T2D.Support or Funding InformationThis study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP‐142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116), and to HW from the National Institutes of Health (R21 NS101876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prolonged Administration of the KCa Channel Activator SKA‐31 Improves Cardiac Function and Blood Pressure in Type 2 Diabetic Goto‐Kakizaki Rats

Endothelial dysfunction represents an independent risk factor contributing to the onset and progression of cardiovascular complications (e.g. hypertension, cardiomyopathy, stroke) in patients with Type 2 Diabetes (T2D). It is further predicted that reduction/reversal of endothelial dysfunction will mitigate T2D‐associated cardiovascular deficits. Small‐ and intermediate‐conductance, Ca2+‐activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacologic activators of these channels (e.g. SKA‐31) induce robust vasodilation upon acute application to isolated resistance arteries and intact animals. However, the effects of prolonged, in vivo administration of a KCa activator on the cardiovascular system have not been examined to date. In our current study, we have hypothesized that daily administration of SKA‐31 (10 and 30 mg/kg, I.P. injection) to male, non‐obese Type 2 Diabetic Goto‐Kakizaki rats (T2D GK, 14 weeks of age) for 12 weeks would oppose the development of diabetes‐related cardiac dysfunction. Echocardiographic analyses revealed that left ventricular (LV) ejection fraction, stroke volume and fractional shortening all significantly declined over time in vehicle‐treated rats, but remained at pre‐trial levels in animals administered either 10 or 30 mg/kg SKA‐31 for 12 weeks (n = 5–6/group). Chronic blood pressure measurements over the same period via radiotelemetry further revealed that SKA‐31 treatment lowered mean arterial pressure, compared with vehicle treated animals, with effects observed on both systolic and diastolic pressures (n = 5–6/group). To determine if the observed improvements in cardiac performance may be due to direct changes in the responsiveness of the coronary vasculature, isolated hearts from vehicle and SKA‐31 treated T2D GK rats were mounted in a Langendorff perfusion system under constant pressure (n ≥ 3/group). We observed that endothelium‐dependent, agonist‐evoked increases in coronary flow were similar in hearts from vehicle and SKA‐31 treated animals, as was baseline LV developed pressure. Histological staining of isolated hearts revealed differing levels of LV collagen content in the 3 treatment groups. In summary, these results indicate that prolonged SKA‐31 administration in T2D GK rats can improve cardiac function, which likely occur via both direct and indirect effects.Support or Funding InformationThis study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP‐142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116), and to HW from the National Institutes of Health (R21 NS101876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The relationship of vitamin D level with markers of cardiorenal syndrome in patients with chronic obstructive pulmonary disease

The aim of the study was to examine the relationship of vitamin D levels with markers of cardiorenal syndrome in patients with COPD depending on the severity of bronchial obstruction.198 patients with COPD were divided into 2 groups depending on the severity of bronchial obstruction. A deficiency of vitamin D was significantly more prevalent in COPD patients with GFRcys <60 ml/min/1,73 m2 compared to patients with preserved renal function. A medium positive correlation of vitamin D levels with the severity of bronchial obstruction (r=0,419, p=0,001), medium negative correlation of vitamin D levels with exacerbation frequency (r=0,421, p=0,01) and CRP (r=0,301, p=0,02) were observed. Significant negative correlation of vitamin D levels with the magnitude of albuminuria (r=0,345, p=0,02) was also discovered. Significant lower relative frequency of hyperphosphatemia in patients with COPD 3, 4 severity (63,16 vs 78,69%, χ2=6,627, p<0,05), there was a positive correlation between the phosphorus level of the blood serum level of 25(ОН)D (r=+0,475, p=0,025).The level of vitamin D in some clinical situations can be considered as a promising biomarker of current cardiorenal continuum in patients with COPD, and its correction, as a possible way of slowing the progression of cardiovascular complications in such patients.

Astragaloside IV inhibits Angiotensin II-stimulated proliferation of rat vascular smooth muscle cells via the regulation of CDK2 activity

AimsAstragaloside IV (AS-IV) is the central active component extracted from Radix astragali, an herbal remedy widely used in traditional Chinese medicine for the treatment of cardiovascular diseases. Aberrant proliferation of vascular smooth muscle cells (VSMCs) is closely involved in the initiation and progression of cardiovascular complications, such as atherosclerosis. Here we investigated whether AS-IV inhibited agonist-induced vascular smooth muscle cells (VSMCs) proliferation and the underlying mechanism. Main methodsQuiescent cultured A10 cells (adult rat VSMCs) were treated with Angiotensin II (AngII) or AngII plus AS-IV for 48 h. The growth rate of A10 cells was analyzed by CCK8 assay. RT-PCR analysis was carried out to examine the expression of α-smooth muscle actin (α-SMA), an important phenotypic modulation marker. In addition, whether the interference of AS-IV on AngII-mediated growth of VSMCs via regulation of cell cycle was evaluated by flow cytometry. In order to explore the role of cell cycle machinery, we measured kinase activity of CDK2 by Kinase assay and the protein level of Cdc25 by western blot, respectively. Key findingsThese data suggested that AS-IV exerted beneficial effects on AngII -induced abnormal growth in rat VSMCs through disturbing cell cycle, especially block G1/S transition by attenuating CDK2 activity, which may hinder the process of pathological vascular remodeling during atherosclerosis.