Pathophysiology of Vascular Calcification and Bone Loss: Linked Disorders of Ageing?

Vascular Calcification (VC), low bone mass and fragility fractures are frequently observed in ageing subjects. Although this clinical observation could be the mere coincidence of frequent age-dependent disorders, clinical and experimental data suggest that VC and bone loss could share pathophysiological mechanisms. Indeed, VC is an active process of calcium and phosphate precipitation that involves the transition of the vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Among the molecules involved in this process, parathyroid hormone (PTH) plays a key role acting through several mechanisms which includes the regulation of the RANK/RANKL/OPG system and the Wnt/ß-catenin pathway, the main pathways for bone resorption and bone formation, respectively. Furthermore, some microRNAs have been implicated as common regulators of bone metabolism, VC, left ventricle hypertrophy and myocardial fibrosis. Elucidating the common mechanisms between ageing; VC and bone loss could help to better understand the potential effects of osteoporosis drugs on the CV system.

Multi-species transcriptomic data analysis reveal three candidate genes, responsible for the transition from compensated left ventricle hypertrophy to heart failure

Introduction Heart failure (HF) is the common final event for a wide spectrum of compensated left ventricle hypertrophy (LVH), including hypertrophic cardiomyopathy, hypertension, aortic stenosis and aortic coarctation. Despite its importance, the transition from hypertrophy to HF in humans is poorly understood. In this study, we aimed to find a molecular signature for the transition from compensated hypertrophy to decompensated HF conserved within species and disease induction methods. Methods Four datasets, containing gene expression data of hypertrophy and heart failure samples, were selected from GEO data repository. The selected datasets include three different species: Rattus norvegicus (GSE4286 and GSE47495), Canis lupus familiaris (GSE5247) and Cavia porcellus (GSE78077); with different models of left ventricle hypertrophy (pressure-overload, genetic, and both). The CEL files containing the expression data were analyzed using the Transcriptome Analysis Console 4.0 (TAC 4.0.2.15, Applied Biosystems). To identify differentially expressed genes a p-value cutoff of 0.05 was applied. Results The lists of DEGs obtained in the comparison hypertrophy versus HF, in each dataset, were uniformized to human identifiers and merged, resulting in a list containing 8307 genes. Most of the genes were differentially expressed in only one dataset (6252, 75.3%). DEGs present in two datasets were 1850 (22.3%), in three datasets 202 (2.4%), and finally, present in all datasets were only 3 genes. The first gene identified was CDKS1B, which belongs to a family of proteases related to the cell cycle. CKS1B upregulation activates the STAT3 and MEK/ERK pathways and promotes cell proliferation. Indeed, negative regulation of the MEK/ERK reduces cardiac hypertrophy induced by pressure overload. Secondly, type 2 phosphatidylinositol-5-phosphate 4-kinase (PI5P4K) converts phosphatidylinositol-5-phosphate to phosphatidylinositol-4,5-bisphosphate, and plays an important role in inflammatory response and autophagy. However, its role in the heart remains unknow. Lastly, the adipokine MEDAG was also differentially expressed in HF. Its role in myocyte metabolism is not defined but may parallel nutrient uptake role seen in adipose and reflect reliance on lipid oxidation. Conclusions We identified three genes that are differentially expressed in HF compared to compensated hypertrophy, involved in cell proliferation, autophagy, inflammation and lipid metabolism. This data requires confirmation in human studies. Such advance would be an important step toward identifying those risk factors, especially genetic variation, that predispose individuals to develop HF. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FCT Portugal

Ubiquinol ameliorates endothelial dysfunction and increases expression of miRNA-34a in a rat model of pulmonary hypertension

Introduction: In this research, we evaluate the effect of intravenously administrated solubilized ubiquinol on 4-week monocrotalin-induced pulmonary hypertension (PH) in rats. Materials and methods: To reproduce the model, some male Wistar rats were subcutaneously injected with alcohol solution of monocrotaline 60 mg/kg and the rest – with alcohol solution (Control). Those with monocrotaline (MCT) were divided into 3 groups. They underwent intravenous administration of 1% ubiquinol solution 30 mg/kg (MCT-Ubiquinol), the vehicle (MCT-Vehicle) and saline (MCT-saline) three times on days 7, 14 and 21, depending on the group. The hemodynamic parameters were measured in anesthetized rats on day 29. Right ventricle hypertrophy, pulmonary arteries reactivity and expression of miRNA-21 and miRNA-34a were estimated after euthanasia. Results and discussion: All MCT-groups demonstrated an increase in right ventricle systolic pressure and hypertrophy in comparison with the control group. An increase in lung weight was shown in MCT-Vehicle and MCT-Saline; however, the MCT-Ubiquinol indicators did not differ from those of the Control. There was an increased vasodilatation response to acetylcholine at concentrations of 1*10-6M and 1*10-5M in MCT-Ubiquinol in contrast to the other two MCT-groups. A significantly lower level of expression of miRNA-34a was observed in MCT-Ubiquinol. Conclusion: Our findings suggest that a triple ubiquinol injection influences pulmonary changes and endothelium-depended vasodilatation, which contributes to pulmonary vascular tone and reactivity. A decrease in miRNA-34a expression in MCT-Ubiquinol group demonstrates the ubiquinol anti-inflammatory properties.

Inhibition of HDAC1 alleviates monocrotaline-induced pulmonary arterial remodeling through up-regulation of miR-34a

Background It has been found that up-regulation of histone deacetylases 1 (HDAC1) is involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether inhibition of HDAC1 suppresses the development of PAH via restoring miR-34a level in monocrotaline (MCT)-induced PAH rats. Methods PAH rat models were induced by intraperitoneal injection of MCT. HDAC1 was suppressed by intraperitoneal injection of the class I HDAC inhibitor MS-275, and miR-34a was over-expressed via tail vein injection of miR-34a agomiR. Results HDAC1 protein was significantly increased in MCT-induced PAH rats; this was accompanied with down-regulation of miR-34a and subsequent up-regulation of matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) and MMP-2/TIMP-2. Administration of PAH rats with MS-275 or miR-34a agomiR dramatically abolished MCT-induced reduction of miR-34a and subsequent up-regulation of MMP-9/TIMP-1 and MMP-2/TIMP-2, finally reduced extracellular matrix (ECM) accumulation, pulmonary arterial remodeling, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) in PAH rats. Conclusions HDAC1 contributes to the development of MCT-induced rat PAH by suppressing miR-34a level and subsequently up-regulating the ratio of MMP-9/TIMP-1 and MMP-2/TIMP-2. Inhibition of HDAC1 alleviates pulmonary arterial remodeling and PAH through up-regulation of miR-34a level and subsequent reduction of MMP-9/TIMP-1 and MMP-2/TIMP-2, suggesting that inhibition of HDAC1 might have potential value in the management of PAH.

Etiologic-sociodemographic assessment and comparison of dialysis modalities in pediatric Syrian migrants with chronic kidney disease

Background: Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are among the important causes of mortality and morbidity in childhood. Early diagnosis and treatment of the underlying primary disease may prevent most of CKD patients from progressing to ESRD. There is no study examining chronic kidney diseases and dialysis modalities in Syrian immigrant children. We aimed to retrospectively research the etiologic, sociodemographic, and clinical factors in CKD among Syrian refugee children, and at the same time, to compare the clinical characteristics of patients with ESRD on peritoneal dialysis and hemodialysis. Methods: Our study included a total of 79 pediatric Syrian patients aged from 2-16 years monitored at Hatay State Hospital pediatric nephrology clinic with diagnosis of various stages of CKD and with ESRD. Physical-demographic features and clinical-laboratory information were retrospectively screened. Results: The most common cause of CKD was congenital anomalies of the kidneys and urinary tracts (CAKUT) (37.9%). Other causes were urolitiasis (15.1%), nephrotic syndrome (10.1%), spina bifida (8.8%), hemolytic uremic syndrome (7.5%), and glomerulonephritis (7.5%). Twenty-five patients used hemodialysis due to bad living conditions. Only 2 of the patients with peritoneal dialysis were using automatic peritoneal dialysis (APD), with 5 using continuous ambulatory peritoneal dialysis (CAPD). Long-term complications like left ventricle hypertrophy and retinopathy were significantly higher among hemodialysis patients. There was no difference identified between the groups in terms of hypertension and sex. Conclusion: Progression to ESRD due to preventable reasons is very frequent among CKD patients. For more effective use of peritoneal dialysis in pediatric patients, the responsibility of states must be improved.

The interobserver agreement of ECG abnormalities using Minnesota codes in people with type 2 diabetes

Objectives To assess the interobserver agreement in categories of electrocardiogram (ECG) abnormalities using the Minnesota Code criteria. Methods We used a random sample of 180 ECGs from people with type 2 diabetes. ECG abnormalities were classified and coded using the Minnesota ECG Classification. Each ECG was independently rated on several abnormalities by an experienced rater (rater 1) and by two cardiologists (raters 2 and 3) trained to apply the Minnesota codes on four Minnesota codes; 1-codes as an indication for myocardial infarction, 4 en 5-codes as an indication for ischemic abnormalities, 3-codes as an indication for left ventricle hypertrophy, 7-1-codes as an indication for ventricular conduction abnormalities, and 8-3-codes as an indication for atrial fibrillation / atrial flutter. After all pairwise tables were summed, the overall agreement, the specific positive and negative agreement were calculated with a 95% confidence interval (CI) for each abnormality. Also, Kappa’s with a 95% CI were calculated. Results The overall agreement (with 95% CI) were for myocardial infarction, ischemic abnormalities, left ventricle hypertrophy, conduction abnormalities and atrial fibrillation/atrial flutter respectively: 0.87 (0.84–0.91), 0.79 (0.74–0.84), 0.81 (0.76–0.85), 0.93 (0.90–0.95), 0.96 (0.93–0.97). Conclusion This study shows that the overall agreement of the Minnesota code is good to excellent.

Nitric Oxide–cGMP Pathway Modulation in an Experimental Model of Hypoxic Pulmonary Hypertension

Manipulation of nitric oxide (NO) may enable control of progression and treatment of pulmonary hypertension (PH). Several approaches may modulate the NO-cGMP pathway in vivo. Here, we investigate the effectiveness of 3 modulatory sites: (i) the amount of l-arginine; (ii) the size of plasma NO stores that stimulate soluble guanylate cyclase; (iii) the conversion of cGMP into inactive 5′-GMP, with respect to hypoxia, to test the effectiveness of the treatments with respect to hypoxia-induced PH. Male rats (n = 80; 10/group) maintained in normoxic (21% O2) or hypoxic chambers (10% O2) for 14 days were subdivided in 4 sub-groups: placebo, l-arginine (20 mg/ml), the NO donor molsidomine (15 mg/kg in drinking water), and phoshodiesterase-5 inhibitor sildenafil (1.4 mg/kg in 0.3 ml saline, i.p.). Hypoxia depressed homeostasis and increased erythropoiesis, heart and right ventricle hypertrophy, myocardial fibrosis and apoptosis inducing pulmonary remodeling. Stimulating anyone of the 3 mechanisms that enhance the NO-cGMP pathway helped rescuing the functional and morphological changes in the cardiopulmonary system leading to improvement, sometimes normalization, of the pressures. None of the treatments affected the observed parameters in normoxia. Thus, the 3 modulatory sites are essentially similar in enhancing the NO-cGMP pathway, thereby attenuating the hypoxia-related effects that lead to pulmonary hypertension.

MO367USEFULNESS OF ECHOCARDIOGRAPHIC PARAMETERS IN LONG - TERM CARDIOVASCULAR EVENTS AFTER AN ACUTE KIDNEY INJURY EPISODE

Background and Aims Acute kidney injury (AKI), a frequent condition during hospitalizations, leads to an increase morbidity and mortality. Cardiovascular events are one of the most post-AKI studied complications, but the role of the baseline functional and structural cardiac alterations on prognosis has not been widely studied. The aim of the present study is to evaluate the prognostic value of echocardiographic parameters in the incidence of cardiovascular events (CVE) after a hospitalization-acquire AKI. Method In this is retrospective observational cohort study 1255 patients who presented AKI from 2013 to 2014 at our center were included. Baseline epidemiological data, comorbidities and echocardiographic parameters were collected. After discharge, patients were followed (mean 49±28 months) and post-AKI CVE were registered. In addition, new performed echocardiograms after discharge were collected. Associated factors to CVE and the predictive role of echocardiographic parameters were analyzed. Results Among the 1255 included patients, 676 (54%) had a registered echocardiogram in the six months before the AKI episode. Of them, 231 patients (38%) had left ventricle hypertrophy (LVH), 178 (30%) pulmonary hypertension (PHT), 178 (30%) diastolic dysfunction and 138 (21%) systolic dysfunction. After discharge (and prior to post-AKI CVE), 248 (20%) patients had a new echocardiogram that revealed LVH in 108 patients (45%), diastolic dysfunction in 96 (42%), PHT in 68 (32%) and systolic dysfunction in 47 (19%). During follow-up, 484 (39%) patients had CVE. The presence of diastolic dysfunction, systolic dysfunction, PHT and LVH in any moment were associated factors to the incidence of CVE. An adjusted multivariate model showed that systolic dysfunction (hazard ratio [HR] 1.44, 95% confidence interval [95%CI] 1.073-1.943, p=0.015), age (HR 1.018, 95%CI 1.003-1.030, p=0.02), diabetes mellitus (HR 1.373, 95%CI 1.041-1.811, p=0.025), atrial fibrillation (HR 1.397, 95%CI 1.055-1.851, p=0.020) and diuretic intake (HR 1.580, 95%CI 1.171-2.131, p=0.003) were independent predictors of post-AKI CVE. Conclusion The evaluation of cardiac structure and functionality valued by echocardiographic parameters can be a useful tool for stratifying CVE risk after an AKI. Systolic dysfunction is an independent predictor of post-AKI CVE.

Pulmonary hypertension is attenuated and ventilation-perfusion matching is maintained during chronic hypoxia in deer mice native to high altitude

Hypoxia at high altitude can constrain metabolism and performance, and can elicit physiological adjustments that are deleterious to health and fitness. Hypoxic pulmonary hypertension is a particularly serious and maladaptive response to chronic hypoxia, which results from vasoconstriction and pathological remodeling of pulmonary arteries, and can lead to pulmonary edema and right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia, and whether evolved changes or hypoxia-induced plasticity in pulmonary vasculature might impact ventilation-perfusion (V-Q) matching in chronic hypoxia. Deer mouse populations from both high and low altitudes were born and raised to adulthood in captivity at sea level, and various aspects of lung function were measured before and after exposure to chronic hypoxia (12 kPa O2, simulating the O2 pressure at 4300 m) for 6-8 weeks. In lowlanders, chronic hypoxia increased right ventricle systolic pressure (RVSP) from 14 to 19 mmHg (P = 0.001), in association with thickening of smooth muscle in pulmonary arteries and right ventricle hypertrophy. Chronic hypoxia also impaired V-Q matching in lowlanders (measured at rest using SPECT-CT imaging), as reflected by increased log SD of the perfusion distribution (log SDQ) from 0.55 to 0.86 (P = 0.031). In highlanders, chronic hypoxia had attenuated effects on RVSP and no effects on smooth muscle thickness, right ventricle mass, or V-Q matching. Therefore, evolved changes in lung function help attenuate maladaptive plasticity and contribute to hypoxia tolerance in high-altitude deer mice.

Diagnosis dan Tatalaksana Terkini Penyakit Jantung Hipertensi

Hypertensive heart disease is a response to a prolonged increase in blood pressure that causes various changes in the myocardial structure. This study was aimed to obtain the recent diagnosis and management of hypertensive heart disease. This was a literature review study using 4 databases, as follows: Pubmed, Clinical Key, Science Direct, and Google Scholar. The keywords used were Hypertensive Heart Disease diagnosis of Hypertensive heart disease OR Screening of hypertensive heart disease OR imaging of hypertensive heart disease AND therapy OR treatment OR management of hypertensive heart disease. The results showed that there were 10 literatures that fulfilled the criteria, consisting of 6 randomized controlled trials and 4 article reviews. Among patients with hypertensive heart disease, left ventricle hypertrophy, left ventricular dilation, and diastolic and systolic disfunction were the most commonly found in ECG, echocardiography, chest X-ray, and CMR. Therapy of hypertensive heart disease was according to ACC/AHA guidelines with non-pharmacological therapy by adopting the DASH diet and pharmacological therapy of choice was ACE-I or ARB. In conclusion, in hypertensive heart disease, the most common structural changes were left ventricle hypertrophy, left ventricular dilation, diastolic and systolic disfunction found in ECG, echocardiography, chest X-ray, and CMR. Therapy of hypertensive heart disease was according to ACC/AHA guidelines.Keywords: hypertensive heart disease Abstrak: Penyakit jantung hipertensi merupakan respon terhadap peningkatan tekanan darah berkepanjangan yang menyebabkan berbagai perubahan pada struktur miokard. Penelitian ini bertujuan untuk mendapatkan diagnosis dan tatalaksana terkini mengenai penyakit jantung hipertensi. Jenis penelitian ialah literature review menggunakan 4 database, yaitu Pubmed, Clinical Key, Science Direct, dan Google Scholar. Kata kunci yang digunakan ialah Hypertensive Heart Disease diagnosis of Hypertensive heart disease OR Screening of hypertensive heart disease OR imaging of hypertensive heart disease AND therapy OR treatment OR management of hypertensive heart disease. Hasil penelitian mendapatkan 10 literatur yang memenuhi kriteria penelitian, terdiri dari 6 randomized controlled trial dan 4 review article. Pada penyakit jantung hipertensi kelainan struktural yang sering ditemukan ialah hipertrofi ventrikel kiri (konsentrik maupun eksentrik), dilatasi ventrikel kiri, disfungsi diastolik dan sistolik, yang dapat dideteksi lewat pemeriksaan EKG, ekokardiografi, rontgen toraks, dan CMR. Terapi penyakit jantung hipertensi menurut pedoman ACC/AHA yakni nonfarmakologi seperti pola diet DASH dan terapi farmakologi pilihan yaitu ACE-I atau ARB. Simpulan penelitian ini ialah pada penyakit jantung hipertensi terdapat hipertrofi ventrikel kiri, dilatasi ventirkel kiri, disfungsi diastolik maupun sistolik, dideteksi menggunakan EKG, ekokardiografi, rontgen toraks dan CMR. Terapi penyakit jantung hipertensi sesuai dengan pedoman penatalaksanaan ACC/AHA.Kata kunci: penyakit jantung hipertensi