scholarly journals Transcriptomic analysis of the cardiac left ventricle in a rodent model of diabetic cardiomyopathy: molecular snapshot of a severe myocardial disease

2007 ◽  
Vol 28 (3) ◽  
pp. 284-293 ◽  
Author(s):  
Sarah Glyn-Jones ◽  
Sarah Song ◽  
Michael A. Black ◽  
Anthony R. J. Phillips ◽  
Soon Y. Choong ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Molecular Basis ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Myocardial Disease ◽  
Chronic Hyperglycemia ◽  
Expression Of Genes ◽  
Streptozotocin Induced Diabetes ◽  
Quantitative Verification ◽  
Disproportionate Number

Heart disease is the major cause of death in diabetes, a disorder characterized by chronic hyperglycemia and cardiovascular complications. Diabetic cardiomyopathy (DCM) is increasingly recognized as a major contributor to diastolic dysfunction and heart failure in diabetes, but its molecular basis has remained obscure, in part because of its multifactorial origins. Here we employed comparative transcriptomic methods with quantitative verification of selected transcripts by reverse transcriptase quantitative PCR to characterize the molecular basis of DCM in rats with streptozotocin-induced diabetes of 16-wk duration. Diabetes caused left ventricular disease that was accompanied by significant changes in the expression of 1,614 genes, 749 of which had functions assignable by Gene Ontology classification. Genes corresponding to proteins expressed in mitochondria accounted for a disproportionate number of those whose expression was significantly modified in DCM, consistent with the idea that the mitochondrion is a key target of the pathogenic processes that cause myocardial disease in diabetes. Diabetes also induced global perturbations in the expression of genes regulating cardiac fatty acid metabolism, whose dysfunction is likely to play a key role in the promotion of oxidative stress, thereby contributing to the pathogenesis of diabetic myocardial disease. In particular, these data point to impaired regulation of mitochondrial β-oxidation as central in the mechanisms that generate DCM pathogenesis. This study provides a comprehensive molecular snapshot of the processes leading to myocardial disease in diabetes.

scholarly journals Genes Encoding ACE2, TMPRSS2 and Related Proteins Mediating SARS-CoV-2 Viral Entry are Upregulated with Age in Human Cardiomyocytes

2020 ◽  
Author(s):  
Emma L. Robinson ◽  
Kanar Alkass ◽  
Olaf Bergmann ◽  
Janet J. Maguire ◽  
H. Llewelyn Roderick ◽  
...  
Keyword(s):  
Viral Entry ◽  
Enzyme Inhibitors ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Older Individuals ◽  
Human Cardiomyocytes ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Approved Drugs ◽  
Related Proteins

AbstractAge is an independent risk factor for adverse outcome in patients following COVID-19 infection. We hypothesised that differential expression of genes encoding proteins proposed to be required for entry of SARS-Cov-2 in aged compared to younger cardiomyocytes might contribute to the susceptibility of older individuals to COVID-19-associated cardiovascular complications.We generated strand-specific RNA-sequencing libraries from RNA isolated from flow-sorted cardiomyocyte nuclei from left ventricular tissue. RNASeq data were compared between five young (19-25yr) and five older (63-78yr) Caucasian males who had not been on medication or exhibited evidence of cardiovascular disease post-mortem.Expression of relevant genes encoding ACE2, TMPRSS2, TMPRS11D, TMPRS11E, FURIN, CTSL, CTSB and B0AT1/SLC6A19 were upregulated in aged cardiomyocytes and the combined relative cardiomyocyte expression of these genes correlated positively with age. Genes encoding proteins in the RAAS and interferon/interleukin pathways were also upregulated such as ACE, AGTR1, MAS1 and IL6R.Our results highlight SARS-CoV-2 related genes that have higher expression in aged compared with young adult cardiomyocytes. These data may inform studies using selective enzyme inhibitors/antagonists, available as experimental compounds or clinically approved drugs e.g. remdesivir that has recently been rapidly accepted for compassionate use, to further understand the contribution of these pathways in human cardiomyocytes to disease outcome in COVID-19 patients.

Abstract 15: Glucose-Mediated Remodeling of Cardiac DNA Methylation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Mark E Pepin ◽  
David K Crossman ◽  
Joseph P Barchue ◽  
Salpy V Pamboukian ◽  
Steven M Pogwizd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Dna Methylation ◽  
Diabetic Cardiomyopathy ◽  
Left Ventricular ◽  
Epigenetic Mark ◽  
Gene Transcript ◽  
Transcript Levels ◽  
Glycemic Memory

To identify the role of glucose in the development of diabetic cardiomyopathy, we had directly assessed glucose delivery to the intact heart on alterations of DNA methylation and gene expression using both an inducible heart-specific transgene (glucose transporter 4; mG4H) and streptozotocin-induced diabetes (STZ) mouse models. We aimed to determine whether long-lasting diabetic complications arise from prior transient exposure to hyperglycemia via a process termed “glycemic memory.” We had identified DNA methylation changes associated with significant gene expression regulation. Comparing our results from STZ, mG4H, and the modifications which persist following transgene silencing, we now provide evidence for cardiac DNA methylation as a persistent epigenetic mark contributing to glycemic memory. To begin to determine which changes contribute to human heart failure, we measured both RNA transcript levels and whole-genome DNA methylation in heart failure biopsy samples (n = 12) from male patients collected at left ventricular assist device placement using RNA-sequencing and Methylation450 assay, respectively. We hypothesized that epigenetic changes such as DNA methylation distinguish between heart failure etiologies. Our findings demonstrated that type 2 diabetic heart failure patients (n = 6) had an overall signature of hypomethylation, whereas patients listed as ischemic (n = 5) had a distinct hypermethylation signature for regulated transcripts. The focus of this initial analysis was on promoter-associated CpG islands with inverse changes in gene transcript levels, from which diabetes (14 genes; e.g. IGFBP4) and ischemic (12 genes; e.g. PFKFB3) specific targets emerged with significant regulation of both measures. By combining our mouse and human molecular analyses, we provide evidence that diabetes mellitus governs direct regulation of cellular function by DNA methylation and the corresponding gene expression in diabetic mouse and human hearts. Importantly, many of the changes seen in either mouse type 1 diabetes or human type 2 diabetes were similar supporting a consistent mechanism of regulation. These studies are some of the first steps at defining mechanisms of epigenetic regulation in diabetic cardiomyopathy.

Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Rebecca H Ritchie ◽  
Nga Cao ◽  
Yung George Wong ◽  
Sarah Rosli ◽  
Helen Kiriazis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Ex Vivo ◽  
Systolic Function ◽  
Left Ventricular ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Diastolic Dysfunction ◽  
The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

Abstract 4239: Speckle Tracking Imaging Detects Sub-Clinical Myocardial Dysfunction in Asymptomatic Patients with Type 2 Diabetes Mellitus

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Laura Ernande ◽  
Cyrille Bergerot ◽  
Ernst R Rietzschel ◽  
Marc L De Buyzere ◽  
Nico Van de Veire ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Cardiomyopathy ◽  
Speckle Tracking ◽  
Myocardial Dysfunction ◽  
Univariate Analysis ◽  
Radial Strain ◽  
Left Ventricular ◽  
Male Gender ◽  
Type Ii ◽  
Speckle Tracking Imaging

Diabetic cardiomyopathy, a major complication of diabetes mellitus (DM), is preceded by a silent phase of progressive left ventricular (LV) remodeling. Our aim was to evaluate whether speckle tracking imaging (STI) was able to detect early, sub-clinical myocardial dysfunction in a population of asymptomatic type II DM patients with no signs or history of heart disease and a normal conventional echo . 114 patients with type II DM (52 ± 4 years, 45 females, HbA1c 7.7 ± 1.4%) and 88 age-matched healthy volunteers (HV) without any cardiovascular risk factor (52 ± 3 years, 58 females) underwent a conventional and STI echocardiography (Vivid 7, GE). Mean longitudinal strain (S L ) was assessed from the basal, mid and apical segments of the myocardial walls in apical 2- and 4-chamber views. Mean radial strain (S R ) was calculated from the short-axis view at the midventricular level. Univariate and multivariate regression analyses were used to identify the parameters contributing to the difference in S L and S R between the 2 groups. Variables used for analysis were as follows: DM, gender, BMI, systolic (sBP) and diastolic blood pressure (dBP), heart rate, IVSd and PWd thickeness, LV end-diastolic (LVEDD) and end-systolic diameters (LVESD). Clinical, conventional echo and STI parameters in the 2 groups are summurized in the table . On univariate analysis, factors associated with a significant lower strain in type II DM patients were: DM, male gender, BMI, sBP and dBP for S L and DM, sex and LVESD for S R (p<0.05 for all). On multiple regression analysis, the only factors accociated with a significant decrease in strain in the DM group were DM (p = 0.005) and male gender (p = 0.008) for S L and DM (p = 0.01) for S R . STI is able to early detect subclinical myocardial dysfunction in a population with Type II DM. This decrease in S L and S R might be considered as a preclinical marker of diabetic cardiomyopathy.

The Effect of Gypenosides on Cardiac Function and Expression of Cytoskeletal Genes of Myocardium in Diabetic Cardiomyopathy Rats

2009 ◽  
Vol 37 (06) ◽  
pp. 1059-1068 ◽  
Author(s):  
Min Ge ◽  
Shanfeng Ma ◽  
Liang Tao ◽  
Sudong Guan
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Diastolic Pressure ◽  
Pure Water ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Sprague Dawley ◽  
Gene Expressions ◽  
Ventricular Systolic Pressure

The relationship between changes of cardiac function and the gene expressions of two major myocardial skeleton proteins, titin and nebulin, and the effect of gypenosides on these gene expressions in diabetic cardiomyopathy rat were explored in the present study. Forty Sprague-Dawley rats were randomly divided into three groups: control group, diabetic cardiomyopathy group and gypenosides-treated diabetic cardiomyopathy group. The diabetic cardiomyopathy was induced in rats by injecting streptozotocin (STZ, 55 mg/kg) intraperitoneally. Seven weeks after the rats suffered from diabetes, the rats were treated with gypenosides 100 mg/kg per day orally for six weeks in gypenosides-treated group. In the meanwhile, the pure water was given to diabetic cardiomyopathy and the control groups. Subsequently, the cardiac functions, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), ± dP/dtmax and t–dP/dmaxt, as well as the mRNA content and proteins of titin and nebulin in myocardium were determined. The results indicated that (1) the diabetic cardiomyopathy rats had decreased LVSP and ± dP/dtmax, increased LVEDP, and prolonged t–dP/dtmax than normal rats; (2) LVSP and ± dP/dtmax in diabetic cardiomyopathy rats treated with gypenosides were significantly higher and LVEDP and t–dP/dtmax were significantly lower than those without giving gypenosides; (3) the mRNA contents and proteins of titin and nebulin in diabetic cardiomyopathy rats were remarkably lower than those in the control rats and gypenosides had no effect on mRNA and protein expression levels of titin and nebulin in diabetic cardiomyopathy rats. We conclude that (1) the cardiac function as well as the mRNA expressions of titin and nebulin decreased in diabetic cardiomyopathy rats; (2) gypenosides secure cardiac muscles and their function from diabetic impairment and these beneficial effects of gypenosides are not by changing the expressions of titin and nebulin.

scholarly journals Anthracycline-Induced Cardiotoxicity in Young Cancer Patients: The Role of Carnitine

2016 ◽  
Vol 68 (Suppl. 3) ◽  
pp. 10-14 ◽  
Author(s):  
Saro H. Armenian
Keyword(s):  
Cancer Survivors ◽  
Childhood Cancer ◽  
Cancer Patients ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Childhood Cancer Survivors ◽  
Chronic Health Condition ◽  
Cardiovascular Complications ◽  
Left Ventricular

While the increased rates of survival in childhood cancers have increased progressively in recent decades, many childhood cancer survivors will have at least one chronic health condition within 40 years of age. In this regard, cardiovascular complications have emerged as a leading cause of long-term morbidity and mortality in long-term survivors of childhood cancer, likely due to exposure to anthracycline chemotherapy, and outcomes in patients with anthracycline-related cardiomyopathy remain poor. Some progress has been made in understanding the mechanisms at the basis of anthracycline-related cardiomyopathy, which appear to involve generation of reactive oxygen species, leading to mitochondrial dysfunction, followed by myocyte apoptosis and maladaptive left ventricular remodeling. Even if several guidelines currently exist for monitoring cancer patients treated with cardiotoxic therapies who are at high risk for heart failure, much work remains to be done in finding reliable markers for screening for cardiac dysfunction. Studies from our group have identified alterations in L-carnitine in cancer survivors. While additional investigations are needed, preliminary studies suggest a role for carnitine in primary prevention (during treatment) and secondary prevention (to improve function after treatment).

scholarly journals Familial Myocardial Disease with and without Obstruction to Left Ventricular Outflow

Circulation ◽  
1967 ◽  
Vol 35 (4) ◽  
pp. 638-652 ◽  
Author(s):  
W. K. NASSER ◽  
J. F. WILLIAMS ◽  
M. E. MISHKIN ◽  
R. H. CHILDRESS ◽  
C. HELMEN ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Myocardial Disease ◽  
Left Ventricular Outflow

scholarly journals Mst1 Knockout Alleviates Mitochondrial Fission and Mitigates Left Ventricular Remodeling in the Development of Diabetic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Xinyu Feng ◽  
Shanjie Wang ◽  
Xingjun Yang ◽  
Jie Lin ◽  
Wanrong Man ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Ventricular Remodeling ◽  
Mitochondrial Dynamics ◽  
Left Ventricular Remodeling ◽  
Mitochondrial Fission ◽  
Left Ventricular ◽  
Neonatal Cardiomyocytes ◽  
Primary Neonatal Cardiomyocytes ◽  
Hemodynamic Measurements ◽  
Medium Culture

The disruption of mitochondrial dynamics is responsible for the development of diabetic cardiomyopathy (DCM). However, the mechanisms that regulate the balance of mitochondrial fission and fusion are not well-understood. Wild-type, Mst1 transgenic and Mst1 knockout mice were induced with experimental diabetes by streptozotocin injection. In addition, primary neonatal cardiomyocytes were isolated and cultured to simulate diabetes to explore the mechanisms. Echocardiograms and hemodynamic measurements revealed that Mst1 knockout alleviated left ventricular remodeling and cardiac dysfunction in diabetic mice. Mst1 knockdown significantly decreased the number of TUNEL-positive cardiomyocytes subjected to high-glucose (HG) medium culture. Immunofluorescence study indicated that Mst1 overexpression enhanced, while Mst1 knockdown mitigated mitochondrial fission in DCM. Mst1 participated in the regulation of mitochondrial fission by upregulating the expression of Drp1, activating Drp1S616 phosphorylation and Drp1S637 dephosphorylation, as well as promoting Drp1 recruitment to the mitochondria. Furthermore, Drp1 knockdown abolished the effects of Mst1 on mitochondrial fission, mitochondrial membrane potential and mitochondrial dysfunction in cardiomyocytes subjected to HG treatment. These results indicated that Mst1 knockout inhibits mitochondrial fission and alleviates left ventricular remodeling thus prevents the development of DCM.

scholarly journals Cardiovascular morbidity and mortality in patients treated with hemodialysis: Epidemiological analysis

2008 ◽  
Vol 65 (12) ◽  
pp. 893-900 ◽  
Author(s):  
Dejan Petrovic ◽  
Biljana Stojimirovic
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Mortality Rate ◽  
Cardiovascular Mortality ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Cardiovascular Morbidity ◽  
Morbidity And Mortality ◽  
Cardiovascular Morbidity And Mortality ◽  
Lv Mass

Background/Aim. Cardiovascular diseases are the leading cause of death in patients treated with hemodialysis (HD). The annual cardiovascular mortality rate in these patients is 9%. Left ventricular (LV) hypertrophy, ischemic heart disease and heart failure are the most prevalent cardiovascular causes of death. The aim of this study was to assess the prevalence of traditional and nontraditional risk factors for cardiovascular complications, to assess the prevalence of cardiovascular complications and overall and cardiovascular mortality rate in patients on HD. Methods. We investigated a total of 115 patients undergoing HD for at least 6 months. First, a cross-sectional study was performed, followed by a two-year follow-up study. Beside standard biochemical parameters, we also determined cardiac troponins and echocardiographic parameters of LV morphology and function (LV mass index, LV fractional shortening, LV ejection fraction). The results were analyzed using the Student's t test and Mann-Whitney U test. Results. The patients with adverse outcome had significantly lower serum albumin (p < 0.01) and higher serum homocystein, troponin I and T, and LV mass index (p < 0.01). Hyperhomocysteinemia, anemia, hypertriglyceridemia and uncontrolled hypertension had the highest prevalence (86.09%, 76.52%, 43.48% and 36.52%, respectively) among all investigated cardiovascular risk factors. Hypertrophy of the LV was presented in 71.31% of the patients and congestive heart failure in 8.70%. Heart valve calcification was found in 48.70% of the patients, pericardial effusion in 25.22% and disrrhythmia in 20.87% of the investigated patients. The average annual overall mortality rate was 13.74%, while average cardiovascular mortality rate was 8.51%. Conclusion. Patients on HD have high risk for cardiovascular morbidity and mortality.

scholarly journals Quantitative Assessment of Myocardial Ischemia in Multi-Vessel Coronary Artery Disease by Multimodal Stress Echocardiography with Semi-Supine Bicycle Ergometry

2020 ◽  
Vol 15 (6) ◽  
pp. 813-819
Author(s):  
S. N. Koretskiy ◽  
O. M. Drapkina ◽  
F. B. Shukurov ◽  
D. K. Vasiliev
Keyword(s):  
Stress Echocardiography ◽  
Peak Load ◽  
Three Dimensional ◽  
Ventricular Myocardium ◽  
Cardiovascular Complications ◽  
Artery Occlusion ◽  
Left Ventricular ◽  
Myocardial Imaging ◽  
Left Ventricular Myocardium ◽  
Bicycle Ergometry

Stress echocardiography is a modern widely used method of noninvasive diagnosis of coronary heart disease and stratification of the risk of cardiovascular complications. In addition, exercise echocardiography is an important tool to clarify the localization of ischemia and establish a symptomassociated artery for management of patient with known coronary angiography data. This is especially important in multivessel lesions, the presence of an occluded artery or borderline stenosis. Currently, various stress agents are used for stress echocardiography in clinical practice: pharmacological drugs (dobutamine or adenosine), transesophageal or endocardial pacing, treadmill, semi-supine bicycle. To detect signs of ischemia usually used only visual estimation of local contractility in the two-dimensional gray-scale mode. Modern modes of myocardial imaging, such as speckletracking echocardiography or three-dimensional visualization, are practically not used. In the presented clinical case, the possibility of combining standard and modern imaging modes to clarify the localization and quantification of ischemia in multivessel coronary lesions, including chronic artery occlusion, is shown. As a stress agent, a semi-supine bicycle was chosen, the use of which allowed to obtain a qualitative image of the left ventricular myocardium at rest and at peak load, suitable for assessing deformation and threedimensional visualization. Evaluation of left ventricular myocardial deformation by speckle-tracking echocardiography was more accurate than standard diagnosis in detecting signs of ischemia in a patient with multivessel lesions. Three-dimensional imaging was inferior in sensitivity to speckletracking stress echocardiography and, at present, seems to have more research value.

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