scholarly journals Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hongfei Ge ◽  
Gongxin Liu ◽  
Tracy M. Yamawaki ◽  
Caroline Tao ◽  
Shawn T. Alexander ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Arrhythmias ◽  
Cardiac Fibrosis ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cardiac Injury ◽  
Pathophysiological Mechanism ◽  
Premature Ventricular Contractions ◽  
Impaired Cardiac Function

AbstractHeart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.

scholarly journals Phytosterol Accumulation Results in Ventricular Arrhythmia, Impaired Cardiac Function and Death

2021 ◽  
Author(s):  
Hongfei Ge ◽  
Gongxin Liu ◽  
Tracy M. Yamawaki ◽  
Caroline Tao ◽  
Shawn T. Alexander ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Arrhythmias ◽  
Cardiac Fibrosis ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Pathophysiological Mechanism ◽  
Premature Ventricular Contractions ◽  
Increased Risk ◽  
Impaired Cardiac Function

Abstract Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.

Abstract 269: Miofibroblast Tgf-beta Signaling in a Proteotoxic Mouse Model

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Bidur Bhandary ◽  
Qinghang Meng ◽  
Hanna Osinska ◽  
Kritton Shay-Winkler ◽  
James Gulick ◽  
...  
Keyword(s):  
Heart Disease ◽  
Mouse Model ◽  
Cardiac Function ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Prolonged Survival ◽  
Tgfβ Signaling ◽  
Specific Expression ◽  
Western Blots

Introduction: Transforming Growth Factor Beta (TGFβ) is an important cytokine in mediating the fibrogenic response and, in particular, cardiac fibrosis. Extensive fibrosis accompanies the cardiac remodeling that occurs during development of the protein conformation-based disease caused by cardiomyocyte-specific expression of a mutant, small, heat shock-like protein and chaperone, aB crystallin (CryABR120G). During the onset of fibrosis, fibroblasts are activated to the so-called “myofibroblast” state and TGFβ binding is thought to mediate an essential signaling pathway underlying this process. Our central hypothesis is that TGFβ signaling processes that result in significant cardiac fibrosis in a mouse model of proteotoxic heart disease are mediated by cardiac fibroblasts, rather than cardiomyocytes. Here, we have partially ablated TGFβ signaling only in cardiac myofibroblasts to observe if cardiac fibrosis is reduced. Aims and Methods: The objective of this study was to understand the contributions of fibroblast-derived TGFβ signaling to the development of cardiac fibrosis in a proteotoxic mouse model that results in significant cardiac fibrosis. To test the hypothesis we partially deleted the myofibroblast specific canonical and non-canonical signaling by crossing CryAB R120G mice with Tgfbr1 or Tgfbr2 floxed mice. The double transgene containing mice were further crossed with activated myofibroblast specific Cre mice in which Cre expression was driven off the periostin promoter. Echocardiography, Masson’s Trichome staining, PCR arrays, IHC and western blots were performed to characterize the fibrotic progression in CryAB R120G transgenic mice. Results: We observed that myofibroblast-targeted partial knockdown of Tgf βr1 signaling prolonged survival, modestly reducing fibrosis and improving cardiac function . Similarly, Tgf βr2 partial knockdown prolonged survival, modestly reducing fibrosis without improving cardiac function during fibrosis development in CryAB R120G mice. Conclusion: These findings suggest that, in a model of proteotoxic heart disease, myofibroblast based TGFβ signaling in the heart may contribute to cardiac hypertrophy/dysfunction but cannot account entirely for the fibrotic response.

scholarly journals Human trophoblast-derived exosomes attenuate doxorubicin-induced cardiac injury by regulating miR-200b and downstream Zeb1

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Jie Ni ◽  
Yihai Liu ◽  
Lina Kang ◽  
Lian Wang ◽  
Zhonglin Han ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Cardiomyocyte Apoptosis ◽  
Luciferase Reporter ◽  
Human Trophoblast ◽  
Trophoblast Stem

AbstractHuman trophoblast stem cells (TSCs) have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell-derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox)-induced injury remains unclear. In the present study, TSC-Exos were isolated from the supernatants of human trophoblasts using the ultracentrifugation method and characterized by transmission electron microscopy and western blotting. In vitro, primary cardiomyocytes were subjected to Dox and treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cellular apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then, different groups of mice were administered either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exos via tail vein injection. Then, the cardiac function, cardiac fibrosis and cardiomyocyte apoptosis in each group were evaluated, and the downstream molecular mechanism was explored. TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocyte apoptosis. Similarly, mice receiving TSC-Exos and AAV-miR-200b inhibitor exhibited improved cardiac function, accompanied by reduced apoptosis and inflammation. The bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b and had an antiapoptotic effect. TSC-Exos attenuated doxorubicin-induced cardiac injury by playing antiapoptotic and anti-inflammatory roles. The underlying mechanism could be an increase in Zeb1 expression by the inhibition of miR-200b expression. In summary, this study sheds new light on the application of TSC-Exos as a potential therapeutic tool for heart failure.

scholarly journals SHBG-C57BL/ksJ-db/db: A New Mouse Model to Study SHBG Expression and Regulation During Obesity Development

Endocrinology ◽  
2015 ◽  
Vol 156 (12) ◽  
pp. 4571-4581 ◽  
Author(s):  
Cristina Saéz-López ◽  
Marta Rivera-Giménez ◽  
Cristina Hernández ◽  
Rafael Simó ◽  
David M. Selva
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
The Body ◽  
Sex Hormone Binding Globulin ◽  
In Vivo Models ◽  
The Metabolic Syndrome

Low plasma sex hormone-binding globulin (SHBG) levels in overweight individuals are a biomarker for the metabolic syndrome and are predictive of type 2 diabetes and cardiovascular disease risk. There are no in vivo models to study SHBG expression and regulation during obesity development. The main reason for this is that the obesity-prone rodent models cannot be used to study this issue, because rodents, unlike humans, do not express the SHBG gene in their livers. We have developed a unique mouse model that expresses the human SHBG, and it develops obesity, by crossing the human SHBG transgenic mice with the C57BL/ksJ-db/db mice. The results obtained with the SHBG-C57BL/ksJ-db/db mouse model have allowed us to determine that the SHBG overexpression in the C57BL/ksJ-db/db reduced the body weight gain but did not change the metabolic profile of these mice. Moreover, we elucidated the molecular mechanisms and transcription factors causing the SHBG down-regulation during obesity development, which involved changes in liver hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor-γ mRNA and protein levels. Furthermore, these results were confirmed using human liver biopsies. Importantly, we also showed that this model resembles what occurs in human obese subjects, because plasma SHBG and total testosterone levels where reduced in obese mice when compared with lean mice. Future research using this unique mouse model will determine the role of SHBG in the development and progression of obesity, type 2 diabetes, or fatty liver disease.

scholarly journals Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury

2014 ◽  
Vol 592 (8) ◽  
pp. 1771-1783 ◽  
Author(s):  
Christopher R. West ◽  
Mark A. Crawford ◽  
Malihe-Sadat Poormasjedi-Meibod ◽  
Katharine D. Currie ◽  
Andre Fallavollita ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cardiac Function ◽  
Hind Limb ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Experimental Spinal Cord Injury ◽  
Cord Injury

scholarly journals Association of antecedent cardiovascular risk factor levels and trajectories with cardiovascular magnetic resonance-derived cardiac function and structure

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Roberto Lorbeer ◽  
Susanne Rospleszcz ◽  
Christopher L. Schlett ◽  
Sophia D. Rado ◽  
Barbara Thorand ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Cardiac Function ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Individual Risk ◽  
The Individual ◽  
And Function ◽  
Individual Risk Factors

Abstract Background The association of longitudinal trajectories of cardiovascular risk factors with cardiovascular magnetic resonance (CMR)-measures of cardiac structure and function in the community is not well known. Therefore we aimed to relate risk factor levels from different examination cycles to CMR-measures of the left ventricle (LV) and right ventricle in a population-based cohort. Methods We assessed conventional cardiovascular disease risk factors in 349 participants (143 women; aged 25–59 years) at three examination cycles (Exam 1 [baseline], at Exam 2 [7-years follow-up] and at Exam 3 [14-years follow-up]) of the KORA S4 cohort and related single-point measurements of individual risk factors and longitudinal trajectories of these risk factors to various CMR-measures obtained at Exam 3. Results High levels of diastolic blood pressure, waist circumference, and LDL-cholesterol at the individual exams were associated with worse cardiac function and structure. Trajectory clusters representing higher levels of the individual risk factors were associated with worse cardiac function and structure compared to low risk trajectory clusters of individual risk factors. Multivariable (combining different risk factors) trajectory clusters were associated with different cardiac parameters in a graded fashion (e.g. decrease of LV stroke volume for middle risk cluster β = − 4.91 ml/m2, 95% CI − 7.89; − 1.94, p < 0.01 and high risk cluster β = − 7.00 ml/m2, 95% CI − 10.73; − 3.28, p < 0.001 compared to the low risk cluster). The multivariable longitudinal trajectory clusters added significantly to explain variation in CMR traits beyond the multivariable risk profile obtained at Exam 3. Conclusions Cardiovascular disease risk factor levels, measured over a time period of 14 years, were associated with CMR-derived measures of cardiac structure and function. Longitudinal multivariable trajectory clusters explained a greater proportion of the inter-individual variation in cardiac traits than multiple risk factor assessed contemporaneous with the CMR exam.

Black Bean Extract Inhibits Cardiac Fibrosis and Restores Cardiac Function in an Acute Non-Ischemic Cardiomyopathy Mouse Model

2009 ◽  
Vol 15 (6) ◽  
pp. S19
Author(s):  
Keith A. Youker ◽  
Ahmad Khalil ◽  
Carlos Orrego ◽  
Jose Flores-Arredondo ◽  
Sergio Serrano ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cardiac Function ◽  
Ischemic Cardiomyopathy ◽  
Cardiac Fibrosis ◽  
Black Bean

scholarly journals Human Trophoblasts-derived Exosomes Attenuate Doxorubicin Induced Cardiac Injury via Regulating Mir-200b and Downstream Zeb1

2020 ◽  
Author(s):  
Jie Ni ◽  
Yihai Liu ◽  
Kun Wang ◽  
Wenfeng Zhang ◽  
Zhonglin Han ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Cardiac Injury ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Human Trophoblast ◽  
Downstream Target ◽  
Trophoblast Stem

Abstract Purpose:Human trophoblast stem cells (TSC)have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox) induced injury remains unclear. Methods:In the present study, TSC-Exos were isolated from the supernatant of Human Trophoblasts using the ultracentrifugation method and characterized by transmission electron microscope and western blotting.In vitro, primary cardiomyocytes subjected to Dox were treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cell apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then they received a tail injection of either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exosfor different groups. Then cardiac function, cardiac fibrosis and cardiomyocyte apoptosis among groups were evaluated and downstream molecular mechanism was explored. Results: TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocytes apoptosis. Similarly, mice receivingTSC-Exos andAAV-miR-200b-inhibitor have improved cardiac function, accompanied by reduced apoptosis and inflammation. Bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b, which had an antiapoptotic effect. Conclusion:TSC-ExosattenuatedDoxorubicin induced cardiac injury by playing an antiapoptosis and antiinflammation role. The underlying mechanism could be increased expression of Zeb1 by inhibiting miR-200b expression, due to the TSC-Exos treatment. This study sheds newlight on the application of MSC-Exo as a potential therapeutic tool for heart failure.

Hypoglycaemia and Cardiovascular Disease Risk in Patients with Diabetes

2020 ◽  
Vol 26 (43) ◽  
pp. 5637-5649
Author(s):  
Niki Katsiki ◽  
Kalliopi Kotsa ◽  
Anca P. Stoian ◽  
Dimitri P. Mikhailidis
Keyword(s):  
Cardiac Arrhythmias ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Patient Characteristics ◽  
The Elderly ◽  
Carotid Disease ◽  
Patients With Diabetes ◽  
Artery Disease ◽  
Cv Disease ◽  
The Impact

Hypoglycaemia represents an important side effect of insulin therapy and insulin secretagogues. It can occur in both type 1 and type 2 diabetes mellitus patients. Also, some associations between hypoglycaemia and cardiovascular (CV) risk have been reported. Several mechanisms may be involved, including the sympathoadrenal system, hypokalaemia, endothelial dysfunction, coagulation, platelets, inflammation, atherothrombosis and impaired autonomic cardiac reflexes. This narrative review discusses the associations of hypoglycaemia with CV diseases, including coronary heart disease (CHD), cardiac arrhythmias, stroke, carotid disease and peripheral artery disease (PAD), as well as with dementia. Severe hypoglycaemia has been related to CHD, CV and all-cause mortality. Furthermore, there is evidence supporting an association between hypoglycaemia and cardiac arrhythmias, potentially predisposing to sudden death. The data linking hypoglycaemia with stroke, carotid disease and PAD is limited. Several factors may affect the hypoglycaemia-CV relationships, such as the definition of hypoglycaemia, patient characteristics, co-morbidities (including chronic kidney disease) and antidiabetic drug therapy. However, the association between hypoglycaemia and dementia is bilateral. Both the disorders are more common in the elderly; thus, glycaemic goals should be carefully selected in older patients. Further research is needed to elucidate the impact of hypoglycaemia on CV disease.

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