Vascular calcification: the role of microRNAs

AbstractVascular calcification represents the deposition of calcium phosphate salts in the tunica media of the vascular wall. It occurs during aging but is accelerated and pronounced in patients with diabetes mellitus, chronic kidney disease (CKD) and established cardiovascular disease. Due to the loss of elasticity of the vessel wall, vascular calcification might result in left ventricular hypertrophy and compromise coronary perfusion. Accordingly, several studies showed that vascular calcification is associated with increased risk for cardiovascular morbidity and mortality. Accumulating data suggest that microRNAs (miRs) play an important role in vascular calcification. A variety of miRs have been implicated in the development of vascular calcification, whereas others appear to play a protective role. Accordingly, miRs might represent promising targets for the prevention of vascular calcification and its adverse cardiovascular sequelae. However, given the complexity of regulation of this process and the multitude of miRs involved, more research is needed to identify the optimal candidate miRs for targeting.

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Cardio-oncology: what you need to know now for clinical practice and echocardiography

Echo Research and Practice ◽

10.1530/erp-17-0013 ◽

2017 ◽

Vol 4 (1) ◽

pp. R33-R41 ◽

Cited By ~ 17

Author(s):

Carolyn M Larsen ◽

Sharon L Mulvagh

Keyword(s):

Left Ventricular Systolic Dysfunction ◽

Systolic Dysfunction ◽

Chemotherapeutic Agents ◽

Left Ventricular ◽

Baseline Assessment ◽

Oncology Patients ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk

Cardio-oncology is a rapidly growing field aimed at minimizing the effects of cardiovascular morbidity and mortality in cancer survivors. To meet this aim, patients are assessed at baseline to define their risk of cardiotoxicity and then followed closely during and after chemotherapy to assess for early signs or symptoms of cardiovascular disease. Cardiac imaging, and in particular, transthoracic echocardiography, plays an essential role in the baseline assessment and serial follow-up of cardio-oncology patients. The objectives of this paper are to review the mechanisms of cardiotoxicity of several common chemotherapeutic agents associated with an increased risk for left ventricular systolic dysfunction and to outline recommendations regarding the baseline assessment and serial follow-up of cardio-oncology patients with a focus on the role of echocardiography.

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Myocardial Noncompaction

Revista de Chimie ◽

10.37358/rc.18.8.6500 ◽

2018 ◽

Vol 69 (8) ◽

pp. 2209-2212

Author(s):

Alexandru Radu Mihailovici ◽

Vlad Padureanu ◽

Carmen Valeria Albu ◽

Venera Cristina Dinescu ◽

Mihai Cristian Pirlog ◽

...

Keyword(s):

Ventricular Arrhythmias ◽

Specific Treatment ◽

Left Ventricular ◽

Left Ventricular Noncompaction ◽

Ventricular Noncompaction ◽

Genetic Transmission ◽

Asymptomatic Patients ◽

Increased Risk ◽

Patients With Heart Failure

Left ventricular noncompaction is a primary cardiomyopathy with genetic transmission in the vast majority of autosomal dominant cases. It is characterized by the presence of excessive myocardial trabecularities that generally affect the left ventricle. In diagnosing this condition, echocardiography is the gold standard, although this method involves an increased risk of overdiagnosis and underdiagnosis. There are also uncertain cases where echocardiography is inconclusive, a multimodal approach is needed, correlating echocardiographic results with those obtained by magnetic resonance imaging. The clinical picture may range from asymptomatic patients to patients with heart failure, supraventricular or ventricular arrhythmias, thromboembolic events and even sudden cardiac death. There is no specific treatment of left ventricular noncompaction, but the treatment is aimed at preventing and treating the complications of the disease. We will present the case of a young patient with left ventricular noncompactioncardiomyopathy and highlight the essential role of transthoracic echocardiography in diagnosing this rare heart disease.

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Role of depressive symptoms in cardiometabolic diseases and subsequent transitions to all-cause mortality: an application of multistate models in a prospective cohort study

Stroke and Vascular Neurology ◽

10.1136/svn-2020-000693 ◽

2021 ◽

pp. svn-2020-000693

Author(s):

Yanan Qiao ◽

Siyuan Liu ◽

Guochen Li ◽

Yanqiang Lu ◽

Ying Wu ◽

...

Keyword(s):

Heart Disease ◽

Depressive Symptoms ◽

Depression Scale ◽

European Population ◽

Multistate Models ◽

Cardiometabolic Diseases ◽

Increased Risk ◽

All Cause Mortality ◽

Patients With Diabetes

Background and purposeThe role of depression in the development and outcome of cardiometabolic diseases remains to be clarified. We aimed to examine the extent to which depressive symptoms affect the transitions from healthy to diabetes, stroke, heart disease and subsequent all-cause mortality in a middle-aged and elderly European population.MethodsA total of 78 212 individuals aged ≥50 years from the Survey of Health Ageing and Retirement in Europe were included. Participants with any baseline cardiometabolic diseases including diabetes, stroke and heart disease were excluded. Depressive symptoms were measured by the Euro-Depression scale at baseline. Participants were followed up to determine the occurrence of cardiometabolic diseases and all-cause mortality. We used multistate models to estimate the transition-specific HRs and 95% CIs after adjustment of confounders.ResultsDuring 500 711 person-years of follow-up, 4742 participants developed diabetes, 2173 had stroke, 5487 developed heart disease and 7182 died. Depressive symptoms were significantly associated with transitions from healthy to diabetes (HR: 1.12, 95% CI: 1.05 to 1.20), stroke (HR: 1.31, 95% CI: 1.18 to 1.44), heart disease (HR: 1.26, 95% CI: 1.18 to 1.34) and all-cause mortality (HR: 1.41, 95% CI: 1.34 to 1.49). After cardiometabolic diseases, depressive symptoms were associated with the increased risk of all-cause mortality in patients with diabetes (HR: 1.54, 95% CI: 1.25 to 1.89), patients who had stroke (HR: 1.29, 95% CI: 1.03 to 1.61) and patients with heart disease (HR: 1.21, 95% CI: 1.02 to 1.44).ConclusionsDepressive symptoms increase the risk of diabetes, stroke and heart disease, and affect the risk of mortality after the onset of these cardiometabolic conditions. Screening and treatment of depressive symptoms may have profound implications for the prevention and prognosis of cardiometabolic diseases.

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Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01142.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. H153-H162 ◽

Cited By ~ 114

Author(s):

Sabrina Serpillon ◽

Beverly C. Floyd ◽

Rakhee S. Gupte ◽

Shimran George ◽

Mark Kozicky ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Rat Heart ◽

Mitochondrial Respiratory Chain ◽

Posterior Wall ◽

Left Ventricular ◽

Posterior Wall Thickness ◽

Patients With Diabetes ◽

Protein Kinase C Inhibitor ◽

Glucose 6 Phosphate Dehydrogenase

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O2−)] and the mechanisms underlying O2− production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O2− and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O2− generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9–11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased ( P < 0.05). O2− levels were elevated (70–90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91ds-tat (50 μM) or by the mitochondrial respiratory chain inhibitors antimycin (10 μM) and rotenone (50 μM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 μM) also reduced ( P < 0.05) O2− production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole ( P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O2− generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O2− production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.

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Abstract 3269: Association of Aortic Regurgitation with Cardiovascular Morbidity and Mortality in Hypertensive Patients with Left Ventricle Hypertrophy: The LIFE study

Circulation ◽

10.1161/circ.116.suppl_16.ii_735-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Zhibin Li ◽

Kristian Wachtell ◽

Sverre E. Kjeldsen ◽

Stevo Julius ◽

Michael H. Olsen ◽

...

Keyword(s):

Aortic Regurgitation ◽

Cox Regression ◽

Left Ventricular ◽

Morbidity And Mortality ◽

Hypertensive Patients ◽

Life Study ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Lv Mass ◽

Ventricle Hypertrophy

Background : Whether aortic regurgitation (AI) is associated with higher cardiovascular (CV) morbidity and mortality in hypertension with electrocardiographic (ECG) left ventricular hypertrophy (LVH) is unknown. Methods : Hypertensive patients with ECG-LVH were randomized to losartan- or atenolol-based treatment and followed for 4.8 years in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. In the LIFE echo substudy, echocardiograms were used to detect AI. Baseline clinical, echocardiographic variables and cardiovascular endpoints data were used in current analyses. Results: The presence of AI was detected in 132 participants (68 women; 68.4 ± 7.3 years). AI was associated with older age (p < 0.001) but not gender. After adjustment for age, AI was associated with significantly increased LV mass indexed by body surface area (BSA) and height 2.7 (both p < 0.005), echocardiographic eccentric LVH (p < 0.05) but not concentric left ventricular (LV) geometry (p < 0.05). After adjusting for significant confounders including history of CV disease, Framingham risk score, randomized antihypertensive therapy, LV eccentric geometry, LV mass indexed by BSA and height 2.7 , multivariate Cox regression analyses showed that AI was independently associated with 2.83-fold more CV death (95% confidence interval [CI] 1.12 to 7.13), 2.24-fold more all-cause mortality (95% CI 1.17 to 4.28) (both p < 0.05). Conclusion : In hypertensive patients with ECG-LVH, AI independently identifies patients at increased risk of CV and all-course mortality.

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Abstract 187: Electrocardiographic Heart Rate-corrected Qt Interval And Risk Of Stroke In The REasons For Geographic And Racial Differences In Stroke (REGARDS) Study

Stroke ◽

10.1161/str.43.suppl_1.a187 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Elsayed Z Soliman ◽

George Howard ◽

Mary Cushman ◽

Brett Kissela ◽

...

Keyword(s):

Heart Rate ◽

Racial Differences ◽

Qt Interval ◽

Proportional Hazards ◽

Left Ventricular ◽

Cox Proportional Hazards ◽

Corrected Qt Interval ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Regards Study

Background: Prolongation of heart rate-corrected QT interval (QTc) is a well established predictor of cardiovascular morbidity and mortality. Little is known, however, about the relationship between this simple electrocardiographic (ECG) marker and risk of stroke. Methods: A total of 27,411 participants aged > 45 years without prior stroke from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study were included in this analysis. QTc was calculated using Framingham formula (QTcFram). Stroke cases were identified and adjudicated during an up to 7 years of follow-up (median 2.7 years). Cox proportional hazards analysis was used to estimate the hazard ratios for incident stroke associated with prolonged QTcFram interval (vs. normal) and per 1 standard deviation (SD) increase, separately, in a series of incremental models. Results: The risk of incident stroke in the study participants with baseline prolonged QTcFram was almost 3 times the risk in those with normal QTcFram [HR (95% CI): 2.88 (2.12, 3.92), p<0.0001]. After adjustment for age, race, sex, antihypertensive medication use, systolic blood pressure, current smoking, diabetes, left ventricular hypertrophy, atrial fibrillation, prior cardiovascular disease, QRS duration, warfarin use, and QT-prolonging drugs (full model), the risk of stroke remained significantly high [HR (95% CI): 1.67 (1.16, 2.41), p=0.0060)], and was consistent across several subgroups of REGARDS participants. When the risk of stroke was estimated per 1 SD increase in QTcFram, a 24% increased risk was observed [HR (95% CI): 1.24 (1.16, 1.33), p<0.0001)]. This risk remained significant in the fully adjusted model [HR (95% CI): 1.12 (1.03, 1.21), p=0.0055]. Similar results were obtained when other QTc correction formulas including Hodge’s, Bazett’s and Fridericia’s were used. Conclusions: QTc prolongation is associated with a significantly increased risk of incident stroke independently from known stroke risk factors. In light of our results, examining the risk of stroke associated with QT-prolonging drugs may be warranted.

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Abstract 1680: Notch Signaling Directly Targets Msx2: Possible Role of Notch Signaling in Osteogenic Conversion of Vascular Smooth Muscle Cells and Vascular Calcification

Circulation ◽

10.1161/circ.118.suppl_18.s_368-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Takehisa Shimizu ◽

Toru Tanaka ◽

Tatsuya Iso ◽

Masahiko Kurabayashi

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Notch Signaling ◽

Vascular Calcification ◽

Transcriptional Activity ◽

Muscle Cells ◽

Matrix Mineralization ◽

Cardiovascular Morbidity And Mortality ◽

Notch Ligands

Vascular calcification is a prominent feature of atherosclerosis and closely correlated with cardiovascular morbidity and mortality. In this study, we hypothesize that Notch signaling plays an important role in osteogenic conversion of smooth muscle cells (SMCs) and vascular calcification. <Methods and Results> Either Notch ligand-expressing cells or overexpression of Notch intracellular domains (NICDs) induced expression of Msx2, a key regulator of osteogenic conversion, in human aortic SMCs (HASMCs). In addition, overexpression of Notch1 intracellular domain (N1-ICD) markedly upregulated alkaline phosphatase (ALP) activity and matrix mineralization of HASMCs. A knockdown experiment with a small interfering RNA confirmed that Msx2, but not Runx2/Cbfa1, another key osteogenic transcription factor, is responsible for Notch1-induced osteogenic conversion of HASMCs. Furthermore, this Notch1-Msx2 pathway was independent of bone morphogenetic protein-2 (BMP-2), an osteogenic morphogen upstream of Msx2. The transcriptional activity of the Msx2 promoter was significantly enhanced by Notch ligands stimulation, whereas it was abrogated by a specific Notch signaling inhibitor. The RBP-Jk binding element within the Msx2 promoter was critical to Notch1-induced Msx2 gene expression, and correspondingly, neither N1-ICD overexpression nor Notch ligands stimulation increase the Msx2 expression or transcriptional activity of the Msx2 promoter, respectively, in RBP-Jk-deficient fibroblasts. Immunohistochemistry of human artery specimens revealed colocalization of Notch1 and Msx2 within atherosclerotic plaques, indicating a role of Notch1-Msx2 pathway in vascular calcification in vivo. These results suggest that Notch signaling directly targets Msx2, thus accelerating osteogenic conversion of HASMCs and, as a result, a formation of vascular calcification.

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Ligustrazine activate the PPAR-γ pathway and play a protective role in vascular calcification

Vascular ◽

10.1177/17085381211051477 ◽

2021 ◽

pp. 170853812110514

Author(s):

Hui Li ◽

Min Yang

Keyword(s):

Vascular Calcification ◽

Chondrogenic Differentiation ◽

Calcium Content ◽

Protective Role ◽

Peroxisome Proliferation ◽

Rt Pcr ◽

Alizarin Red ◽

Ppar Γ ◽

Related Proteins

Objective The purpose of this study was to explore the role of ligustrazine in vascular calcification. Methods After β-GP stimulation, vascular smooth muscle cells (VSMCs) were detected by Alizarin Red Staing staining. Calcium content and alkaline phosphatase (ALP) activity were detected by intracellular calcium assay kit and ALP assay kit, respectively. The expression of peroxisome proliferation-activated receptor (PPAR-γ) pathway–related proteins was detected by Western blot. PPAR-γ, MSX2, osteopontin (OPN), sclerostin, and BGP were detected by RT-PCR. Results β-GP induced the decreased activity and expression of PPAR-γ and ALP in VSMCs, while ligustrazine activated the expression of PPAR-γ. Through activation of PPAR-γ, ligustrazine decreased β-GP–induced VSMC calcification, decreased the expression of markers of osteogenesis and chondrogenic differentiation, and increased the expression of VSMC markers. Conclusion Ligustrazine activates the PPAR-γ pathway and plays a protective role in vascular calcification.

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Inflammation and thrombosis in diabetes

Thrombosis and Haemostasis ◽

10.1160/ths10-11-0739 ◽

2011 ◽

Vol 105 (S 06) ◽

pp. S43-S54 ◽

Cited By ~ 70

Author(s):

Katharina Hess ◽

Peter Grant

Keyword(s):

Plaque Rupture ◽

Thrombus Formation ◽

Atherosclerotic Lesion ◽

Coagulation Factors ◽

Fibrin Clot ◽

Thrombotic Risk ◽

Cardiovascular Morbidity And Mortality ◽

Increased Risk ◽

Patients With Diabetes ◽

Inflammatory State

SummaryPatients with diabetes mellitus are at increased risk of cardiovascular morbidity and mortality. Atherothrombosis, defined as atherosclerotic lesion disruption with superimposed thrombus formation, is the most common cause of death among these patients. Following plaque rupture, adherence of platelets is followed by local activation of coagulation, the formation of a cross-linked fibrin clot and the development of an occlusive platelet rich fibrin mesh. Patients with diabetes exhibit a thrombotic risk clustering which is composed of hyper-reactive platelets, up regulation of pro-thrombotic markers and suppression of fibrinolysis. These changes are mainly mediated by the presence of insulin resistance and dysglycaemia and an increased inflammatory state which directly affects platelet function, coagulation factors and clot structure. This prothrombotic state is related to increased cardiovascular risk and may account for the reduced response to antithrombotic therapeutic approaches, underpinning the need for adequate antithrombotic therapy in patients with diabetes to reduce their cardiovascular mortality.

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Losartan Increases No Production from the Bovine Aortic Wall That is Stimulated by Angiotensin II

European Journal of Inflammation ◽

10.1177/1721727x0300100304 ◽

2003 ◽

Vol 1 (3) ◽

pp. 113-117 ◽

Cited By ~ 1

Author(s):

M. Myronidou ◽

B. Kokkas ◽

A. Kouyoumtzis ◽

N. Gregoriadis ◽

A. Lourbopoulos ◽

...

Keyword(s):

Nitric Oxide ◽

Angiotensin Ii ◽

Aortic Wall ◽

Vascular Wall ◽

Protective Role ◽

Normal Function ◽

No Production ◽

Chemical Inactivation

In these studies we investigated if losartan, an AT1- receptor blocker has any beneficial effect on NO production from the bovine aortic preparations in vitro while under stimulation from angiotensin II. Experiments were performed on intact specimens of bovine thoracic aorta, incubated in Dulbeco's MOD medium in a metabolic shaker for 24 hours under 95 % O2 and 5 % CO2 at a temperature of 37°C. We found that angiotensin II 1nM−10 μM does not exert any statistically significant action on NO production. On the contrary, angiotensin II 10nM increases the production of NO by 58.14 % (from 12.16 + 2.9 μm/l to 19.23 + 4.2 μm/l in the presence of losartan 1nM (P<0.05). Nitric oxide levels depend on both rate production and rate catabolism or chemical inactivation. Such an equilibrium is vital for the normal function of many systems including the cardiovascular one. The above results demonstrate that the blockade of AT1-receptors favors the biosynthesis of NO and indicate the protective role of losartan on the vascular wall.

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