Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Get to the heart of pediatric kidney transplant recipients: Evaluation of left- and right ventricular mechanics by three-dimensional echocardiography.

Background: Kidney transplantation (KTX) markedly improves prognosis in pediatric patients with end-stage kidney failure. Still, these patients have an increased risk of developing cardiovascular disease due to multiple risk factors. Three-dimensional (3D) echocardiography allows detailed assessment of the heart and may unveil distinct functional and morphological changes in this patient population that would be undetectable by conventional methods. Accordingly, our aim was to examine left- (LV) and right ventricular (RV) morphology and mechanics in pediatric KTX patients using 3D echocardiography. Materials and methods: Pediatric KTX recipients (n = 74) with median age 20 (14-26) years at study enrollment (43% female), were compared to 74 age and gender-matched controls. Detailed patient history was obtained. After conventional echocardiographic protocol, 3D loops were acquired and measured using commercially available software and the ReVISION Method. We measured LV and RV end-diastolic volumes indexed to body surface area (EDVi), ejection fraction (EF), and 3D LV and RV global longitudinal (GLS) and circumferential strains (GCS). Results: Both LVEDVi (67 ± 17 vs. 61 ± 9 ml/m2; p < 0.01) and RVEDVi (68 ± 18 vs. 61 ± 11 ml/m2; p < 0.01) were significantly higher in KTX patients. LVEF was comparable between the two groups (60 ± 6 vs. 61 ± 4%; p = NS), however, LVGLS was significantly lower (-20.5 ± 3.0 vs. -22.0 ± 1.7%; p < 0.001), while LVGCS did not differ (-29.7 ± 4.3 vs. -28.6 ± 10.0%; p = NS). RVEF (59 ± 6 vs. 61 ± 4%; p < 0.05) and RVGLS (-22.8 ± 3.7 vs. -24.1 ± 3.3%; p < 0.05) were significantly lower, however, RVGCS was comparable between the two groups (-23.7 ± 4.5 vs. -24.8 ± 4.4%; p = NS). In patients requiring dialysis prior to KTX (n = 64, 86%) RVGCS showed correlation with the length of dialysis (r = 0.32, p < 0.05). Conclusion: Pediatric KTX patients demonstrate changes in both LV and RV morphology and mechanics. Moreover, the length of dialysis correlated with the contraction pattern of the right ventricle.

SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes.

INTRODUCTION: Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. METHODS: Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.). RESULTS: DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. CONCLUSIONS: These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

Subclinical cardiac dysfunction in pediatric kidney transplant recipients identified by speckle-tracking echocardiography.

BACKGROUND: Kidney transplantation (KTx) improves prognosis in children with kidney failure; still, these patients are prone to cardiovascular damage due to multiple risk factors. Our aim was to assess myocardial structure and function in pediatric KTx by conventional and speckle-tracking echocardiography (STE) in association with established cardiovascular risk factors. METHODS: Forty-two KTx and 39 healthy age- and gender-matched children were evaluated. KTx recipients were further categorized according to the control of hypertension assessed by 24-h ambulatory blood pressure monitoring (ABPM). Subjects underwent pulse wave velocity (PWV) measurement, conventional echocardiography, and 2-dimensional STE. Left and right ventricular (LV, RV) global longitudinal strain (GLS), and LV circumferential strain (GCS) were measured. Glomerular filtration rate (eGFR) was calculated according to the Schwartz formula. RESULTS: KTx patients had increased blood pressure and arterial stiffness. LV ejection fraction (EF) was preserved along with elevated LV mass index (LVMi) while LVGLS was significantly lower, whereas LVGCS and RVGLS were increased in KTx. Uncontrolled hypertensives had lower LVGLS compared to those with controlled hypertension. Using multiple forward stepwise regression analysis, 24-h SBP and relative wall thickness (RWT) were independent determinants of LVMi, whereas antihypertensive therapy, eGFR, and HOMA-IR were independent determinants of LVGLS. CONCLUSIONS: Cardiac morphology and function show distinct changes after KTx. Along with comparable ventricular volumes, LV hypertrophy and subclinical myocardial dysfunction are present. Control of hypertension and kidney graft function are major factors of LV performance. STE may be useful to reveal early myocardial dysfunction in pediatric KTx. A higher resolution version of the Graphical abstract is available as Supplementary information.

Follow-Up of Blood Pressure, Arterial Stiffness, and GFR in Pediatric Kidney Transplant Recipients.

Pediatric renal transplant recipients (RTx) were studied for longitudinal changes in blood pressure (BP), arterial stiffness by pulse wave velocity (PWV), and graft function. Patients and Methods: 52 RTx patients (22 males) were included; office BP (OBP) and 24 h BP monitoring (ABPM) as well as PWV were assessed together with glycemic and lipid parameters and glomerular filtration rate (GFR) at 2.4[1.0-4.7] (T1) and 9.3[6.3-11.8] years (T2) after transplantation (median [range]). Results: Hypertension was present in 67 and 75% of patients at T1 and T2, respectively. Controlled hypertension was documented in 37 and 44% by OBP and 40 and 43% by ABPM. Nocturnal hypertension was present in 35 and 30% at T1 and T2; 24 and 32% of the patients had masked hypertension, while white coat hypertension was present in 16 and 21% at T1 and T2, respectively. Blood pressure by ABPM correlated significantly with GFR and PWV at T2, while PWV also correlated significantly with T2 cholesterol levels. Patients with uncontrolled hypertension by ABPM had a significant decrease in GFR, although not significant with OBP. Anemia and increased HOMAi were present in ~20% of patients at T1 and T2. Conclusion: Pediatric RTx patients harbor risk factors that may affect their cardiovascular health. While we were unable to predict the evolution of renal function based on PWV and ABPM at T1, these risk factors correlated closely with GFR at follow-up suggesting that control of hypertension may have an impact on the evolution of GFR.

Distance measurement for pulse wave velocity estimation in pediatric age: Comparison with intra-arterial path length.

BACKGROUND AND AIMS: Central pulse wave velocity (PWV) is a marker of arterial stiffness and is calculated by dividing the pulse wave travel distance by the transit time. However, there is no consensus as to the ideal distance measurement in children. The aim of our study was to identify the more reliable method to assess the distance measurement in the pediatric age. METHODS: Carotid-femoral PWV was measured by applanation tonometry in 988 healthy children aged 6.5-19.9 years. Two different surface distances were assessed: the subtraction method, representing the distance from the suprasternal notch to the femoral artery minus the distance from the carotid artery to the suprasternal notch, and the direct method, consisting of 80% of the distance from the carotid artery to the femoral artery. Both these methods were compared with the actual path length determined by magnetic resonance imaging (MRI) in 31 children. RESULTS: Subtraction and direct methods were significantly correlated in patients aged <14 years and the corresponding PWV values showed a good agreement. In children aged ≥14 years, a significant difference between the two methods was found: subtraction - direct distance = -45 ± 28 mm, with a significant difference in the resulting PWV values = -0.57 ± 0.35 m/s (p < 0.0001). This result was confirmed by MRI, showing a 10% overestimation in distance measurement by the direct method in subjects aged ≥14 years, resulting in a significantly higher PWV. CONCLUSIONS: These data suggest a greater reliability of the subtractive method of distance measurement compared to the direct method in children.

Novel therapeutic potential of angiotensin receptor 1 blockade in a rat model of diabetes-associated depression parallels altered BDNF signalling.

AIMS/HYPOTHESIS: Diabetes is a worldwide epidemic linked with diverse diseases of the nervous system, including depression. A few studies suggested a connection between renin-angiotensin-aldosterone system blockers and reduced depressive symptoms, although underlying mechanisms are unclear. Here we investigated the antidepressant effect and the mechanisms of action of the angiotensin receptor 1 blocker (ARB) losartan in an experiential model of diabetes-associated depression. METHODS: Experimental diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated for 2 weeks with a non-pressor oral dose of losartan (20 mg/kg). In protocol 1, cerebrovascular perfusion and glial activation were evaluated by single-photon emission computed tomography-MRI and immunohistochemistry. In protocol 2, behaviour studies were performed (forced swim test and open field test). Hippocampal proinflammatory response and brain-derived neurotrophic factor (BDNF) signalling were also assessed. RESULTS: Here, we show that diabetic rats exhibit depression-like behaviour, which can be therapeutically reversed by losartan. This action of losartan occurs via changes in diabetes-induced neuroinflammatory responses rather than altered cerebral perfusion. We also show that as a part of its protective effect losartan restores BDNF production in astrocytes and facilitates BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signalling in the diabetic brain. CONCLUSIONS/INTERPRETATION: We identified a novel effect of losartan in the nervous system that may be implemented to alleviate symptoms of diabetes-associated depression. These findings explore a new therapeutic horizon for ARBs as possible antidepressants and suggest that BDNF could be a target of future drug development in diabetes-induced complications.

Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients.

OBJECTIVES: Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children. METHODS: A total of 42 LT recipients (21 men, age 9.93 ±â€Š3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed. RESULTS: Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m, whereas PWV values were above the 95th percentile in 12%. CONCLUSIONS: Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long-term follow-up is needed to evaluate their impact on CV health and survival.