MRI-based in vivo detection of coronary microvascular dysfunction before alterations in cardiac function induced by short-term high-fat diet in mice

AbstractEndothelial dysfunction is one of the hallmarks of vascular abnormalities in metabolic diseases and has been repeatedly demonstrated in coronary and peripheral circulation in mice fed high-fat diet (HFD), particularly after long-term HFD. However, the temporal relationship between development of coronary microvascular endothelial dysfunction and deterioration in diastolic and systolic cardiac function after short-term feeding with HFD has not yet been studied. This study aimed to correlate the changes in coronary microvascular endothelial function and global cardiac performance indices in vivo after short-term feeding with HFD in mice. Short-term feeding with a HFD (60% fat + 1% cholesterol) resulted in severely impaired coronary microvascular function, as evidenced by the diminished effect of nitric oxide synthase inhibition (by L-NAME) assessed using T1 mapping via in vivo MRI. Deterioration of coronary microvascular function was detected as early as after 7 days of HFD and further declined after 8 weeks on a HFD. HFD-induced coronary microvascular dysfunction was not associated with impaired myocardial capillary density and was present before systemic insulin resistance assessed by a glucose tolerance test. Basal coronary flow and coronary reserve, as assessed using the A2A adenosine receptor agonist regadenoson, were also not altered in HFD-fed mice. Histological analysis did not reveal cardiomyocyte hypertrophy or fibrosis. Increased lipid accumulation in cardiomyocytes was detected as early as after 7 days of HFD and remained at a similar level at 8 weeks on a HFD. Multiparametric cardiac MRI revealed a reduction in systolic heart function, including decreased ejection rate, increased end-systolic volume and decreased myocardial strain in diastole with impaired ejection fraction, but not until 4 weeks of HFD. Short-term feeding with HFD resulted in early endothelial dysfunction in coronary microcirculation that preceded alteration in cardiac function and systemic insulin resistance.

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Author Correction: MRI-based in vivo detection of coronary microvascular dysfunction before alterations in cardiac function induced by short-term high-fat diet in mice

Scientific Reports ◽

10.1038/s41598-021-99611-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Grzegorz Kwiatkowski ◽

Anna Bar ◽

Agnieszka Jasztal ◽

Stefan Chłopicki

Keyword(s):

Cardiac Function ◽

High Fat Diet ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

High Fat ◽

Short Term ◽

In Vivo Detection

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In Vivo Magnetic Resonance Imaging‐Based Detection of Heterogeneous Endothelial Response in Thoracic and Abdominal Aorta to Short‐Term High‐Fat Diet Ascribed to Differences in Perivascular Adipose Tissue in Mice

Journal of the American Heart Association ◽

10.1161/jaha.120.016929 ◽

2020 ◽

Vol 9 (21) ◽

Author(s):

Anna Bar ◽

Anna Kieronska‐Rudek ◽

Bartosz Proniewski ◽

Joanna Suraj‐Prażmowska ◽

Krzysztof Czamara ◽

...

Keyword(s):

Adipose Tissue ◽

Endothelial Dysfunction ◽

High Fat Diet ◽

Soluble Form ◽

Induced Response ◽

Resonance Imaging ◽

High Fat ◽

Short Term ◽

Perivascular Adipose Tissue

Background Long‐term feeding with a high‐fat diet (HFD) induces endothelial dysfunction in mice, but early HFD‐induced effects on endothelium have not been well characterized. Methods and Results Using an magnetic resonance imaging‐based methodology that allows characterization of endothelial function in vivo, we demonstrated that short‐term (2 weeks) feeding with a HFD to C57BL/6 mice or to E3L.CETP mice resulted in the impairment of acetylcholine‐induced response in the abdominal aorta (AA), whereas, in the thoracic aorta (TA), the acetylcholine‐induced response was largely preserved. Similarly, HFD resulted in arterial stiffness in the AA, but not in the TA. The difference in HFD‐induced response was ascribed to distinct characteristics of perivascular adipose tissue in the TA and AA, related to brown‐ and white‐like adipose tissue, respectively, as assessed by histology, immunohistochemistry, and Raman spectroscopy. In contrast, short‐term HFD‐induced endothelial dysfunction could not be linked to systemic insulin resistance, changes in plasma concentration of nitrite, or concentration of biomarkers of glycocalyx disruption (syndecan‐1 and endocan), endothelial inflammation (soluble form of vascular cell adhesion molecule 1, soluble form of intercellular adhesion molecule 1 and soluble form of E‐selectin), endothelial permeability (soluble form of fms‐like tyrosine kinase 1 and angiopoietin 2), and hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). Conclusions Short‐term feeding with a HFD induces endothelial dysfunction in the AA but not in the TA, which could be ascribed to a differential response of perivascular adipose tissue to a HFD in the AA versus TA. Importantly, early endothelial dysfunction in the AA is not linked to elevation of classical systemic biomarkers of endothelial dysfunction.

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Imaging of microvascular disease

The ESC Textbook of Cardiovascular Imaging ◽

10.1093/med/9780198849353.003.0033 ◽

2021 ◽

pp. 481-494

Author(s):

Paolo G. Camici ◽

Ornella Rimoldi

Keyword(s):

Myocardial Ischaemia ◽

Imaging Techniques ◽

Microvascular Disease ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Maximal Increase ◽

Asymptomatic Subjects ◽

Coronary Microvascular Function

Beside obstructive disease of the epicardial coronary arteries dysfunction of the coronary microvasculature has emerged in the past 20 years as an additional mechanism of myocardial ischaemia. The coronary microvasculature cannot be directly visualized in vivo, therefore, both invasive and non-invasive techniques, have been developed to assess parameters that depend directly on coronary microvascular function. Studies at the microcirculatory level entail the use of vasodilators to obtain near-maximal vasodilation. The ratio of the maximal increase of blood flow above its resting value the coronary flow reserve (CFR) allows to gain an insight into the integrated circulatory function. The diagnostic accuracy of imaging techniques can be exploited to detect impairments of myocardial perfusion in asymptomatic subjects with cardiovascular risk factors. The assessment of the coronary microvascular function has provided novel details on the pathophysiological role of coronary microvascular dysfunction in the development of myocardial ischaemia bearing also important prognostic implications.

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The role of 5-HT7 receptors on isoproterenol-induced myocardial infarction in rats with high-fat diet exacerbated coronary endothelial dysfunction

Human & Experimental Toxicology ◽

10.1177/0960327120916821 ◽

2020 ◽

Vol 39 (8) ◽

pp. 1005-1018 ◽

Cited By ~ 1

Author(s):

I Cinar ◽

Z Halici ◽

B Dincer ◽

B Sirin ◽

E Cadirci

Keyword(s):

Myocardial Infarction ◽

Endothelial Dysfunction ◽

High Fat Diet ◽

Density Lipoprotein ◽

Heart Tissue ◽

High Fat ◽

Inflammatory Status

The presence of 5-HT7r’s in both human and rat cardiovascular and immune tissues and their contribution to inflammatory conditions prompted us to hypothesize that these receptors contribute in acute myocardial infarction (MI) with underlying chronic endothelial dysfunction. We investigated the role of 5-HT7 receptors on heart tissue that damaged by isoproterenol (ISO)-induced MI in rats with high-fat diet (HFD). In vitro and in vivo effects of 5-HT7r agonist (LP44) and antagonist (SB269970) have been investigated on the H9C2 cell line and rats, respectively. For in vivo analyses, rats were fed with HFD for 8 weeks and after this period ISO-induced MI model has been applied to rat. To investigate the role of 5-HT7r’s, two different doses of LP44 and SB269970 were evaluated and compared with standard hypolipidemic agent, atorvastatin. In vitro studies showed that LP44 has protective and proliferative effects on rat cardiomyocytes. Also in in vivo studies stimulating 5-HT7r’s by LP44 improved blood lipid profile (decreased total cholesterol, low-density lipoprotein-C, and triglyceride, increased high-density lipoprotein), decreased cardiac damage markers (creatine kinase and troponin-I), and corrected inflammatory status (tumor necrosis factor-α, interleukin-6). Our results showed significant improvement in LP44 administered rats in terms of histopathologic analyses. In damaged tissues, 5-HT7 mRNA expression increased and agonist administration decreased this elevation significantly. We determined for the first time that 5-HT7r’s are overexpressed in ISO-induced MI of rats with underlying HFD-induced endothelial dysfunction. Restoration of this overexpression by LP44, a 5-HT7r agonist, ameliorated heart tissue in physiopathologic, enzymatic, and molecular level, showing the cardiac role of these receptors and suggesting them as future potential therapeutic targets.

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Kupffer cell activation is a causal factor for hepatic insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. G107-G116 ◽

Cited By ~ 138

Author(s):

Nicolas Lanthier ◽

Olivier Molendi-Coste ◽

Yves Horsmans ◽

Nico van Rooijen ◽

Patrice D. Cani ◽

...

Keyword(s):

Insulin Resistance ◽

Kupffer Cell ◽

High Fat Diet ◽

Cell Activation ◽

Hepatic Insulin Resistance ◽

High Fat ◽

Short Term ◽

Adipose Tissue Macrophages ◽

Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

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PAF attenuates endothelium-dependent coronary arteriolar vasodilation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.6.h2094 ◽

1996 ◽

Vol 270 (6) ◽

pp. H2094-H2099 ◽

Cited By ~ 1

Author(s):

D. V. DeFily ◽

L. Kuo ◽

W. M. Chilian

Keyword(s):

Endothelial Dysfunction ◽

Platelet Activating Factor ◽

Microvascular Dysfunction ◽

Coronary Microvascular Dysfunction ◽

Canine Heart ◽

Activated Neutrophils ◽

Significant Attenuation ◽

Arteriolar Diameter

Platelet-activating factor (PAF) has been reported to play a role in neutrophil activation, microvascular permeability, and endothelial dysfunction in a variety of vascular preparations. Although a majority of the effects of PAF are thought to be mediated by the activation of neutrophils, it is unclear the extent to which the deleterious effects of PAF extend to coronary resistance vessels. Therefore, the purpose of this study was to determine whether PAF causes coronary arteriolar endothelial dysfunction in vivo and whether this dysfunction is independent of activated neutrophils. To test these hypotheses, we measured changes in coronary arteriolar diameter to endothelium-dependent and -independent dilators in vivo by measuring coronary microvascular diameters in a beating canine heart using intravital videomicroscopy following intracoronary infusion of PAF (20 ng.kg-1.min-1). Changes in coronary arteriolar diameter following incubation with PAF were also measured in isolated coronary arterioles. In vivo, incubation with PAF resulted in a significant attenuation of endothelium-dependent dilation to intracoronary acetylcholine (0.1 microgram.kg-1.min-1, 39 +/- 7 vs. 20 +/- 3% dilation) and serotonin (1 microgram.kg-1.min-1, 29 +/- 6 vs. 2 +/- 2% dilation). Papaverine-induced relaxation, however, was unchanged. Likewise, in vitro relaxation to serotonin (10 nM) was significantly reduced (38 +/- 4 vs. 3 +/- 5%) following treatment with PAF, whereas nitroprusside (10 nM)-induced relaxation was unchanged. Because PAF impaired endothelium-dependent arteriolar dilation both in vivo and in vitro, we conclude that the presence of activated neutrophils is not required for PAF-induced coronary microvascular dysfunction.

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Abstract P278: Coronary Microvascular Dysfunction Is Associated With Augumented Autophagy-lysosomal Signaling In Mice With Hypercholesterolemic Diet

Hypertension ◽

10.1161/hyp.78.suppl_1.p278 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Yun-Ting Wang ◽

Wei Zhao ◽

Ashton A Huckaby ◽

Xiang Li ◽

Yang Zhang

Keyword(s):

Cardiac Function ◽

Signaling Pathway ◽

Microvascular Dysfunction ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction ◽

Chow Diet ◽

Flow Reserve ◽

Hypercholesterolemic Diet ◽

Early Effects ◽

Coronary Microvascular Function

Accumulating evidence indicates coronary microvascular dysfunction (CMD) contributes to myocardial ischemia with or without epicardial coronary atherosclerosis. However, it remains unknown which molecular pathway is associated with compromised coronary microvascular function preceding the development of myocardial ischemic injury. Recent studies suggest that autophagy-lysosomal signaling pathway is involved in the regulation of endothelial homeostasis under various metabolic stresses such as hypercholesterolemia. In this study, the early effects of hypercholesterolemia on the function and integrity of coronary microcirculation were studied in mice and the expressions of various molecular markers of autophagy-lysosome pathway were also determined in the coronary circulation. Mice were fed a hypercholesterolemic paigen diet (PD) for 8 weeks and coronary microvascular function was determined by measuring coronary flow reserve (CFR) under baseline and hyperemic conditions. The effects of PD on cardiac function or remodeling were also assessed by echocardiograph or immunohistochemistry studies. In PD-fed hypercholesterolemic mice, hyperemia-induced increase in CFR was significantly abrogated compared to that in normal chow diet-fed (ND) control mice (PD: 1.583±0.4193 vs. ND: 3.087±0.586) (n=7-8). The diet-induced hypercholesterolemia did not lead to cardiac dysfunction (EF%, PD: 59.870±7.549 vs ND: 64.040±9.088) or hypertrophic remodeling (LV mass (mg), PD: 92.240±14.410 vs ND: 96.030±25.07). PD increased mild cardiac inflammation and fibrosis but did not resulted in rarefaction in the myocardium. In small coronary arterial wall, PD induced endothelial inflammasome activation and inflammation, which was accompanied by upregulation of autophagy and lysosome signaling pathway. In conclusion, hypercholesterolemic diet induces CMD without alterations in cardiac function or remodeling. These alterations in coronary microvascular function represent the early effects of diet-induced hypercholesterolemia, which may be ameliorated with activation of autophagy and lysosome signaling pathways.

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Abstract 117: Ponatinib Mediated Cardiotoxicity Is Driven By Pro-inflammatory S100A8/A9-NLRP3-IL-1β Signaling Circuit

Circulation Research ◽

10.1161/res.129.suppl_1.117 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Anand P Singh ◽

Sultan Tousif ◽

Prachi Umbarkar ◽

Cristi L Galindo ◽

Nicholas Wheeler ◽

...

Keyword(s):

Cardiac Function ◽

High Fat Diet ◽

Kinase Inhibitor ◽

Clinical Investigation ◽

Pressure Overload ◽

Immunosuppressive Agent ◽

Myelogenous Leukemia ◽

High Fat

Background: Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) for chronic myelogenous leukemia (CML) treatment. Of note, ponatinib is the only treatment option for CML patients with T315I (gatekeeper) mutation. Unexpected clinical cardiotoxicity, including fatal myocardial infarction and congestive heart failure, has hampered its clinical use. Herein, we aimed to investigate the cardiotoxic mechanism of ponatinib and strategies to prevent the cardiotoxic manifestations. Methods: We employed wild-type C57BL/6, cardiovascular (CV) comorbidity models e.g., transverse aortic constriction (TAC)-pressure overload (cardiac comorbidity) and high-fat diet fed ApoE -/- (vascular comorbidity), to investigate the cardiotoxic mechanism of ponatinib. Echocardiography was performed to assess cardiac function. Comprehensive immune profiling was performed to identify ponatinib-induced immune dynamics using flow cytometry analysis. Results: Echocardiographic assessment of ponatinib treated high-fat diet fed ApoE -/- and pressure overload (PO) murine model showed significant decline in cardiac function, suggesting the key role of CV-comorbidities in ponatinib-induced cardiomyopathy. An unbiased RNA-Seq analysis identified the enrichment of dysregulated inflammatory genes, including a multi-fold upregulation of alarmins S100A8/A9 as a top hit in ponatinib-treated hearts. A combination of in vitro and in vivo mechanistic analysis, identified that ponatinib activates the S100A8/9-TLR4-NLRP3-IL-1β signaling pathway in cardiac and systemic myeloid cells (monocytes and neutrophils), thereby leading to excessive myocardial and systemic inflammation. Finally, we demonstrate that ponatinib-induced excessive inflammation is central to the cardiac pathology because a broad immunosuppressive agent dexamethasone abolished the adverse cardiac remodeling and dysfunction of ponatinib treated hearts. Conclusions: These findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. Our results provide critical preclinical data and rationale for clinical investigation into immunosuppressive interventions to mitigate ponatinib-induced cardiotoxicity.

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Diet-induced obese mice are resistant to improvements in cardiac function resulting from short-term adropin treatment

10.1101/2021.10.15.464576 ◽

2021 ◽

Author(s):

Dharendra Thapa ◽

Bingxian Xie ◽

Bellina AS Mushala ◽

Manling Zhang ◽

Janet R Manning ◽

...

Keyword(s):

Cardiac Function ◽

High Fat Diet ◽

Contractile Function ◽

Ex Vivo ◽

Obese Mice ◽

High Fat ◽

Short Term ◽

Neonatal Cardiomyocytes ◽

Low Fat Diet ◽

Short Term Exposure

Previous studies have shown that treatment with recombinant adropin, a circulating peptide secreted by the liver and brain, restores glucose utilization in the hearts of diet-induced obese mice. This restoration of fuel substrate flexibility, which is lost in obese and diabetic animals, has the potential to improve contractile function in the diabetic heart. Using an ex vivo approach, we examined whether short-term adropin treatment could enhance cardiac function in a mouse model of diet-induced obesity. Our study showed that acute adropin treatment reduces inhibitory phosphorylation of pyruvate dehydrogenase in primary neonatal cardiomyocytes, and leads to moderate improvements in ex vivo cardiac function in mice fed a low fat diet. Conversely, short-term exposure to adropin led to a small decrease in cardiac function in mice fed a long-term high fat diet. Insulin treatment did not significantly alter cardiac function in adropin treated hearts from either low or high fat diet mice, however acute adropin treatment did moderately restore downstream insulin signaling in high fat diet fed mice. Overall, these data suggest that in an ex vivo setting, acute adropin treatment alone is not sufficient to promote improved cardiac function in obese animals.

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