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1.
Theranostics ; 11(16): 7879-7895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335970

RESUMO

Rationale: Previous studies have shown that human embryonic stem cell-derived cardiomyocytes improved myocardial recovery when administered to infarcted pig and non-human primate hearts. However, the engraftment of intramyocardially delivered cells is poor and the effectiveness of clinically relevant doses of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in large animal models of myocardial injury remains unknown. Here, we determined whether thymosin ß4 (Tb4) could improve the engraftment and reparative potency of transplanted hiPSC-CMs in a porcine model of myocardial infarction (MI). Methods: Tb4 was delivered from injected gelatin microspheres, which extended the duration of Tb4 administration for up to two weeks in vitro. After MI induction, pigs were randomly distributed into 4 treatment groups: the MI Group was injected with basal medium; the Tb4 Group received gelatin microspheres carrying Tb4; the CM Group was treated with 1.2 × 108 hiPSC-CMs; and the Tb4+CM Group received both the Tb4 microspheres and hiPSC-CMs. Myocardial recovery was assessed by cardiac magnetic resonance imaging (MRI), arrhythmogenesis was monitored with implanted loop recorders, and tumorigenesis was evaluated via whole-body MRI. Results: In vitro, 600 ng/mL of Tb4 protected cultured hiPSC-CMs from hypoxic damage by upregulating AKT activity and BcL-XL and promoted hiPSC-CM and hiPSC-EC proliferation. In infarcted pig hearts, hiPSC-CM transplantation alone had a minimal effect on myocardial recovery, but co-treatment with Tb4 significantly enhanced hiPSC-CM engraftment, induced vasculogenesis and the proliferation of cardiomyocytes and endothelial cells, improved left ventricular systolic function, and reduced infarct size. hiPSC-CM implantation did not increase incidence of ventricular arrhythmia and did not induce tumorigenesis in the immunosuppressed pigs. Conclusions: Co-treatment with Tb4-microspheres and hiPSC-CMs was safe and enhanced the reparative potency of hiPSC-CMs for myocardial repair in a large-animal model of MI.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/metabolismo , Timosina/farmacologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , China , Modelos Animais de Doenças , Células Endoteliais/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/patologia , Regeneração , Transplante de Células-Tronco/métodos , Suínos , Timosina/metabolismo , Timosina/fisiologia
2.
J Mol Cell Cardiol ; 144: 15-23, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32387242

RESUMO

AIMS: Recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after postnatal day 3. However, it is unknown if corticosteroid, a broad anti-inflammatory agent, will abrogate the regenerative capacity in the hearts of neonatal pigs. The aim of the current study is to evaluate the effect Dexamethasone (Dex), a broad anti-inflammatory agent, on heart regeneration, structure, and function of the neonatal pigs' post-myocardial infarction (MI). METHODS AND RESULTS: Dex (0.2 mg/kg/day) was injected intramuscularly into the neonatal pig (age: 2 days postnatal) during the first week post-MI. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine (BrdU) pulse-chase labeling, histology, immunohistochemistry, and flow cytometry were performed to determine inflammatory cell infiltration, CM cytokinesis, and myocardial fibrosis. Dex injection during the first-week suppressed acute inflammation post-MI in the pig hearts. It inhibited BrdU incorporation to pig CMs and CM cytokinesis via inhibiting aurora-B protein expression which was associated with mature scar formation and thinned walls at the infarct site. CMR imaging showed Dex caused left ventricular aneurysm and poor ejection fraction. CONCLUSIONS: Dex inhibited CM cytokinesis and functional recovery and caused ventricular aneurysm in the hearts of 2-day old pigs post-MI.

3.
ESC Heart Fail ; 7(1): 92-102, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31851785

RESUMO

AIMS: A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. METHODS AND RESULTS: Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P < 0.001, and two-fold increase in mass compared to sham control, P < 0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P < 0.05-P < 0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. CONCLUSIONS: Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies.


Assuntos
Insuficiência Cardíaca , Imageamento por Ressonância Magnética , Animais , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Volume Sistólico , Suínos
4.
Sci Rep ; 9(1): 5532, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940842

RESUMO

Emerging studies have recently shown the potential importance of ketone bodies in cardio-metabolic health. However, techniques to determine myocardial ketone body utilization in vivo are lacking. In this work, we developed a novel method to assess myocardial ketone body utilization in vivo using hyperpolarized [3-13C]acetoacetate and investigated the alterations in myocardial ketone body metabolism in diabetic rats. Within a minute upon injection of [3-13C]acetoacetate, the production of [5-13C]glutamate and [1-13C] acetylcarnitine can be observed real time in vivo. In diabetic rats, the production of [5-13C]glutamate was elevated compared to controls, while [1-13C]acetylcarnitine was not different. This suggests an increase in ketone body utilization in the diabetic heart, with the produced acetyl-CoA channelled into the tricarboxylic acid cycle. This observation was corroborated by an increase activity of succinyl-CoA:3-ketoacid-CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone body utilization, in the diabetic heart. The increased ketone body oxidation in the diabetic hearts correlated with cardiac hypertrophy and dysfunction, suggesting a potential coupling between ketone body metabolism and cardiac function. Hyperpolarized [3-13C]acetoacetate is a new probe with potential for non-invasive and real time monitoring of myocardial ketone body oxidation in vivo, which offers a powerful tool to follow disease progression or therapeutic interventions.


Assuntos
Acetoacetatos/análise , Cardiomegalia/diagnóstico por imagem , Diabetes Mellitus Experimental/fisiopatologia , Cetonas/química , Miocárdio/química , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cardiomegalia/metabolismo , Diabetes Mellitus Experimental/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Masculino , Oxirredução , Ratos , Volume Sistólico
5.
Diabetes Obes Metab ; 21(2): 357-365, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30225964

RESUMO

AIM: To investigate the effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on myocardial ketone body utilization in diabetic, obese rats with spontaneously hypertensive heart failure (SHHF), after 6 months of treatment. MATERIALS AND METHODS: Myocardial ketone body utilization was measured in vivo real time using a novel ketone probe (hyperpolarized [3-13 C]acetoacetate) and magnetic resonance spectroscopy (MRS). Myocardial glucose utilization and cardiac function were also determined in vivo using hyperpolarized [1-13 C]pyruvate MRS and magnetic resonance imaging (MRI), respectively. Myocardial fatty acid uptake and liver ketogenesis were assessed via protein expression. RESULTS: At baseline, myocardial ketone and glucose utilization were both higher in SHHF compared with control rats. Six months of empagliflozin treatment in SHHF rats was associated with less obesity, lower blood pressure, reduced blood glucose and insulin levels, and increased fasting blood ß-hydroxybutyrate levels, as expected. Contrary to the hypothesis, myocardial ketone body utilization was lower in empagliflozin-treated SHHF rats, while glucose utilization and cardiac function were unaltered and hepatic congestion was reduced, compared with vehicle-treated SHHF rats. CONCLUSIONS: In diabetic hypertensive heart disease, empagliflozin reduces afterload without altering myocardial function and glucose utilization in the face of falling blood glucose levels, but does not enhance myocardial ketone utilization despite increased circulating levels.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Diabetes Mellitus Experimental , Angiopatias Diabéticas/diagnóstico , Glucose/metabolismo , Glucosídeos/uso terapêutico , Cetonas/metabolismo , Miocárdio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/métodos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/prevenção & controle , Coração/diagnóstico por imagem , Masculino , Miocárdio/química , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Ganho de Peso/efeitos dos fármacos
6.
Diabetes Obes Metab ; 21(4): 949-960, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30536560

RESUMO

AIM: To investigate the effects of long-term low-carbohydrate low-protein ketogenic diet (KD) on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats. MATERIALS AND METHODS: Diabetic GK rats were fed with KD for 62 weeks. Cardiac function and metabolism were assessed using magnetic resonance imaging and 13 C magnetic resonance spectroscopy (13 C-MRS), at rest and under dobutamine stress. 13 C-MRS was performed following injection of hyperpolarized [3-13 C]acetoacetate, [1-13 C]butyrate or [1-13 C]pyruvate to assess ketone body, short-chain fatty acid or glucose utilization, respectively. Protein expression and cardiomyocyte structure were determined via Western blotting and histology, respectively. RESULTS: KD lowered blood glucose, triglyceride and insulin levels while increasing blood ketone body levels. In KD-fed diabetic rats, myocardial ketone body and glucose oxidation were lower than in chow-fed diabetic rats, while myocardial glycolysis and short-chain fatty acid oxidation were unaltered. Dobutamine stress revealed an increased cardiac preload and reduced cardiac compliance in KD-fed diabetic rats. Dobutamine-induced stimulation of myocardial glycolysis was more enhanced in KD-fed diabetic rats than in chow-fed diabetic rats, which was potentially facilitated via an upregulation in basal expression of proteins involved in glucose transport and glycolysis in the hearts of KD-fed rats. The metabolic profile induced by KD was accompanied by cardiac hypertrophy, a trend for increased myocardial lipid and collagen content, and an increased marker of oxidative stress. CONCLUSION: KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity.


Assuntos
Diabetes Mellitus/metabolismo , Dieta Cetogênica , Dieta com Restrição de Proteínas , Glucose/metabolismo , Corpos Cetônicos/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Acetoacetatos , Animais , Glicemia/metabolismo , Butiratos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cardiotônicos , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Dieta com Restrição de Carboidratos , Dobutamina , Ácidos Graxos Voláteis/metabolismo , Glicólise , Insulina/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/patologia , Ácido Pirúvico , Ratos , Triglicerídeos/metabolismo
8.
Circulation ; 138(24): 2798-2808, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30030417

RESUMO

BACKGROUND: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate. METHODS: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. RESULTS: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. CONCLUSIONS: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.


Assuntos
Coração/fisiologia , Infarto do Miocárdio/patologia , Animais , Animais Recém-Nascidos , Citocinese/genética , Ecocardiografia , Fibrose , Imagem Cinética por Ressonância Magnética , Infarto do Miocárdio/diagnóstico por imagem , Miocárdio/patologia , Miócitos Cardíacos/fisiologia , Regeneração , Suínos , Troponina I/análise , Função Ventricular Esquerda
9.
Physiol Rep ; 6(7): e13591, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29611320

RESUMO

The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (-13% and -19%, respectively) as was the decay of cytosolic calcium during diastole (-15% and -21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α-MHC/ß-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.


Assuntos
Cálcio/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Miócitos Cardíacos/metabolismo , Insuficiência Renal Crônica/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Nefrectomia , Insuficiência Renal Crônica/complicações
10.
Cardiovasc Res ; 114(10): 1324-1334, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635338

RESUMO

Aims: Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism. Methods and results: We generated and characterized a knock in mouse model expressing the CPT1BE3A mutant enzyme, which has reduced sensitivity to malonyl-CoA. In isolated perfused hearts, FAO was 1.9-fold higher in Cpt1bE3A/E3A hearts compared with Cpt1bWT/WT hearts. Metabolomic, proteomic and transcriptomic analysis showed increased levels of malonylcarnitine, decreased concentration of CPT1B protein and a small but coordinated downregulation of the mRNA expression of genes involved in FAO in Cpt1bE3A/E3A hearts, all of which aim to limit FAO. In vivo assessment of cardiac function revealed only minor changes, cardiac hypertrophy was absent and histological analysis did not reveal fibrosis. Conclusions: Malonyl-CoA-dependent inhibition of CPT1B plays a crucial role in regulating FAO rate in the heart. Chronic elevation of FAO has a relatively subtle impact on cardiac function at least under baseline conditions.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Metabolismo Energético , Ácidos Graxos/metabolismo , Malonil Coenzima A/metabolismo , Mitocôndrias Cardíacas/enzimologia , Miocárdio/enzimologia , Animais , Carnitina O-Palmitoiltransferase/genética , Genótipo , Glucose/metabolismo , Glicólise , Preparação de Coração Isolado , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Oxirredução , Fenótipo , Função Ventricular Esquerda
11.
Biochim Biophys Acta Mol Basis Dis ; 1864(5 Pt B): 1939-1948, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29175056

RESUMO

Alterations in myocardial energy metabolism have been implicated in the pathophysiology of cardiac diseases such as heart failure and diabetic cardiomyopathy. 31P magnetic resonance spectroscopy (MRS) is a powerful tool to investigate cardiac energetics non-invasively in vivo, by detecting phosphorus (31P)-containing metabolites involved in energy supply and buffering. In this article, we review the historical development of cardiac 31P MRS, the readouts used to assess cardiac energetics from 31P MRS, and how 31P MRS studies have contributed to the understanding of cardiac energy metabolism in heart failure and diabetes. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Metabolismo Energético , Insuficiência Cardíaca/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Isótopos de Fósforo , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores/metabolismo , Creatina Quinase/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Isquemia Miocárdica/fisiopatologia , Fosfocreatina/metabolismo
12.
Cardiovasc Res ; 113(10): 1148-1160, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28549111

RESUMO

Aims: Heart failure is associated with altered myocardial substrate metabolism and impaired cardiac energetics. Comorbidities like diabetes may influence the metabolic adaptations during heart failure development. We quantified to what extent changes in substrate preference, lipid accumulation, and energy status predict the longitudinal development of hypertrophy and failure in the non-diabetic and the diabetic heart. Methods and results: Transverse aortic constriction (TAC) was performed in non-diabetic (db/+) and diabetic (db/db) mice to induce pressure overload. Magnetic resonance imaging, 31P magnetic resonance spectroscopy (MRS), 1H MRS, and 18F-fluorodeoxyglucose-positron emission tomography (PET) were applied to measure cardiac function, energy status, lipid content, and glucose uptake, respectively. In vivo measurements were complemented with ex vivo techniques of high-resolution respirometry, proteomics, and western blotting to elucidate the underlying molecular pathways. In non-diabetic mice, TAC induced progressive cardiac hypertrophy and dysfunction, which correlated with increased protein kinase D-1 (PKD1) phosphorylation and increased glucose uptake. These changes in glucose utilization preceded a reduction in cardiac energy status. At baseline, compared with non-diabetic mice, diabetic mice showed normal cardiac function, higher lipid content and mitochondrial capacity for fatty acid oxidation, and lower PKD1 phosphorylation, glucose uptake, and energetics. Interestingly, TAC affected cardiac function only mildly in diabetic mice, which was accompanied by normalization of phosphorylated PKD1, glucose uptake, and cardiac energy status. Conclusion: The cardiac metabolic adaptations in diabetic mice seem to prevent the heart from failing upon pressure overload, suggesting that restoring the balance between glucose and fatty acid utilization is beneficial for cardiac function.


Assuntos
Aorta/cirurgia , Glicemia/metabolismo , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus/sangue , Metabolismo Energético , Insuficiência Cardíaca/prevenção & controle , Imageamento por Ressonância Magnética , Miocárdio/metabolismo , Tomografia por Emissão de Pósitrons , Espectroscopia de Prótons por Ressonância Magnética , Adaptação Fisiológica , Animais , Aorta/fisiopatologia , Pressão Arterial , Constrição , Complicações do Diabetes/diagnóstico por imagem , Complicações do Diabetes/metabolismo , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/fisiopatologia , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fluordesoxiglucose F18/administração & dosagem , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Valor Preditivo dos Testes , Proteína Quinase C/metabolismo , Compostos Radiofarmacêuticos/administração & dosagem , Fatores de Tempo , Função Ventricular Esquerda , Remodelação Ventricular
13.
NMR Biomed ; 28(10): 1218-27, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26269430

RESUMO

(31)P MRS provides a unique non-invasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but the application of (31)P MRS in the in vivo mouse heart has been limited. The small-sized, fast-beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of three-dimensional image-selected in vivo spectroscopy (3D ISIS) for localized (31)P MRS of the in vivo mouse heart at 9.4 T. Cardiac (31)P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory-gated, cardiac-triggered 3D ISIS. Localization and potential signal contamination were assessed with (31)P MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gases. The myocardial energy status, assessed via the phosphocreatine (PCr) to adenosine 5'-triphosphate (ATP) ratio, was approximately 25% lower in TAC mice compared with controls (0.76 ± 0.13 versus 1.00 ± 0.15; P < 0.01). Localization with one-dimensional (1D) ISIS resulted in two-fold higher PCr/ATP ratios than measured with 3D ISIS, because of the high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 ± 0.24; n = 8) confirmed the in vivo observations in control mice. Heart rate (497 ± 76 beats/min), mean arterial pressure (90 ± 3.3 mmHg) and blood oxygen saturation (96.2 ± 0.6%) during the experimental conditions of in vivo (31)P MRS were within the normal physiological range. Our results show that respiratory-gated, cardiac-triggered 3D ISIS allows for non-invasive assessments of in vivo mouse myocardial energy homeostasis with (31)P MRS under physiological conditions.


Assuntos
Trifosfato de Adenosina/análise , Imageamento Tridimensional/métodos , Espectroscopia de Ressonância Magnética/métodos , Miocárdio/química , Fosfocreatina/análise , Anestesia por Inalação , Anestésicos Inalatórios , Animais , Aorta , Metabolismo Energético , Hemodinâmica , Homeostase , Isoflurano , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Oxigênio/sangue , Isótopos de Fósforo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
14.
Prog Nucl Magn Reson Spectrosc ; 88-89: 1-47, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26282195

RESUMO

The use of MR imaging and spectroscopy for studying cardiovascular disease processes in small animals has increased tremendously over the past decade. This is the result of the remarkable advances in MR technologies and the increased availability of genetically modified mice. MR techniques provide a window on the entire timeline of cardiovascular disease development, ranging from subtle early changes in myocardial metabolism that often mark disease onset to severe myocardial dysfunction associated with end-stage heart failure. MR imaging and spectroscopy techniques play an important role in basic cardiovascular research and in cardiovascular disease diagnosis and therapy follow-up. This is due to the broad range of functional, structural and metabolic parameters that can be quantified by MR under in vivo conditions non-invasively. This review describes the spectrum of MR techniques that are employed in small animal cardiovascular disease research and how the technological challenges resulting from the small dimensions of heart and blood vessels as well as high heart and respiratory rates, particularly in mice, are tackled.


Assuntos
Doenças Cardiovasculares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Animais , Doenças Cardiovasculares/fisiopatologia , Coração/anatomia & histologia , Coração/diagnóstico por imagem , Coração/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Radiografia
15.
Cardiovasc Res ; 106(2): 194-205, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25765936

RESUMO

The shift in substrate preference away from fatty acid oxidation (FAO) towards increased glucose utilization in heart failure has long been interpreted as an oxygen-sparing mechanism. Inhibition of FAO has therefore evolved as an accepted approach to treat heart failure. However, recent data indicate that increased reliance on glucose might be detrimental rather than beneficial for the failing heart. This review discusses new insights into metabolic adaptations in heart failure. A particular focus lies on data obtained from mouse models with modulations of cardiac FA metabolism at different levels of the FA metabolic pathway and how these differently affect cardiac function. Based on studies in which these mouse models were exposed to ischaemic and non-ischaemic heart failure, we discuss whether and when modulations in FA metabolism are protective against heart failure.


Assuntos
Modelos Animais de Doenças , Metabolismo Energético/fisiologia , Insuficiência Cardíaca/metabolismo , Metabolismo dos Lipídeos/fisiologia , Camundongos , Miocárdio/metabolismo , Animais , Ácidos Graxos/metabolismo , Humanos
16.
Magn Reson Med ; 73(6): 2069-74, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24962369

RESUMO

PURPOSE: Proton magnetic resonance spectroscopy ((1) H-MRS) for quantitative in vivo assessment of mouse myocardial metabolism requires accurate acquisition timing to minimize motion artifacts and corrections for T1 -dependent partial saturation effects. In this study, mouse myocardial water and metabolite T1 relaxation time constants were quantified. METHODS: Cardiac-triggered and respiratory-gated PRESS-localized (1) H-MRS was employed at 9.4 T to acquire signal from a 4-µL voxel in the septum of healthy mice (n = 10) while maintaining a steady state of magnetization using dummy scans during respiratory gates. Signal stability was assessed via standard deviations (SD) of zero-order phases and amplitudes of water spectra. Saturation-recovery experiments were performed to determine T1 values. RESULTS: Phase SD did not vary for different repetition times (TR), and was 13.1° ± 4.5°. Maximal amplitude SD was 14.2% ± 5.1% at TR = 500 ms. Myocardial T1 values (mean ± SD) were quantified for water (1.71 ± 0.25 s), taurine (2.18 ± 0.62 s), trimethylamine from choline-containing compounds and carnitine (1.67 ± 0.25 s), creatine-methyl (1.34 ± 0.19 s), triglyceride-methylene (0.60 ± 0.15 s), and triglyceride-methyl (0.90 ± 0.17 s) protons. CONCLUSION: This work provides in vivo quantifications of proton T1 values for mouse myocardial water and metabolites at 9.4 T.


Assuntos
Miocárdio/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Animais , Técnicas de Imagem de Sincronização Cardíaca , Eletrocardiografia , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Imagem de Sincronização Respiratória
17.
MAGMA ; 28(4): 315-27, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25381179

RESUMO

OBJECTIVES: In this study, we established and validated a time-resolved three-dimensional phase-contrast magnetic resonance imaging method (4D PC MRI) on a 9.4 T small-animal MRI system. Herein we present the feasibility of 4D PC MRI in terms of qualitative and quantitative flow pattern analysis in mice with transverse aortic constriction (TAC). MATERIALS AND METHODS: 4D PC FLASH images of a flow phantom and mouse heart were acquired at 9.4 T using a four-point phase-encoding scheme. The method was compared with slice-selective PC FLASH and ultrasound using Bland-Altman analysis. Advanced 3D streamlines were visualized utilizing Voreen volume-rendering software. RESULTS: In vitro, 4D PC MRI flow profiles showed the transition between laminar and turbulent flow with increasing velocities. In vivo, 4D PC MRI data of the ascending aorta and the pulmonary artery were confirmed by ultrasound, resulting in linear regressions of R (2) > 0.93. Magnitude- and direction-encoded streamlines differed substantially pre- and post-TAC surgery. CONCLUSIONS: 4D PC MRI is a feasible tool for in vivo velocity measurements on high-field small-animal scanners. Similar to clinical measurement, this method provides a complete spatially and temporally resolved dataset of the murine cardiovascular blood flow and allows for three-dimensional flow pattern analysis.


Assuntos
Estenose da Valva Aórtica/fisiopatologia , Velocidade do Fluxo Sanguíneo/fisiologia , Insuficiência Cardíaca/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Animais , Aorta , Estenose da Valva Aórtica/diagnóstico por imagem , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Aumento da Imagem/métodos , Imageamento Tridimensional , Imageamento por Ressonância Magnética/instrumentação , Camundongos , Camundongos Endogâmicos C57BL , Imagens de Fantasmas , Ultrassonografia
18.
Biochim Biophys Acta ; 1842(10): 1525-37, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25086219

RESUMO

Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac (31)P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo (1)H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.

19.
Magn Reson Med ; 69(3): 648-56, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22517471

RESUMO

To assess left ventricular (LV) diastolic function in mice with Cine MRI, a high frame rate (>60 frames per cardiac cycle) is required. For conventional electrocardiography-triggered Cine MRI, the frame rate is inversely proportional to the pulse repetition time (TR). However, TR cannot be lowered at will to increase the frame rate because of gradient hardware, spatial resolution, and signal-to-noise limitations. To overcome these limitations associated with electrocardiography-triggered Cine MRI, in this paper, we introduce a retrospectively triggered Cine MRI protocol capable of producing high-resolution high frame rate Cine MRI of the mouse heart for addressing left ventricular diastolic function. Simulations were performed to investigate the influence of MRI sequence parameters and the k-space filling trajectory in relation to the desired number of frames per cardiac cycle. An optimized protocol was applied in vivo and compared with electrocardiography-triggered Cine for which a high-frame rate could only be achieved by several interleaved acquisitions. Retrospective high frame rate Cine MRI proved superior to the interleaved electrocardiography-triggered protocols. High spatial-resolution Cine movies with frames rates up to 80 frames per cardiac cycle were obtained in 25 min. Analysis of left ventricular filling rate curves allowed accurate determination of early and late filling rates and revealed subtle impairments in left ventricular diastolic function of diabetic mice in comparison with nondiabetic mice.


Assuntos
Algoritmos , Técnicas de Imagem de Sincronização Cardíaca/métodos , Cardiomiopatias Diabéticas/diagnóstico , Interpretação de Imagem Assistida por Computador/métodos , Imagem Cinética por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/diagnóstico , Animais , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/fisiopatologia , Aumento da Imagem/métodos , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
20.
NMR Biomed ; 26(4): 451-7, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23109290

RESUMO

We introduce a new protocol to obtain very high-frame-rate cinematographic (Cine) MRI movies of the beating mouse heart within a reasonable measurement time. The method is based on a self-gated accelerated fast low-angle shot (FLASH) acquisition and compressed sensing reconstruction. Key to our approach is that we exploit the stochastic nature of the retrospective triggering acquisition scheme to produce an undersampled and random k-t space filling that allows for compressed sensing reconstruction and acceleration. As a standard, a self-gated FLASH sequence with a total acquisition time of 10 min was used to produce single-slice Cine movies of seven mouse hearts with 90 frames per cardiac cycle. Two times (2×) and three times (3×) k-t space undersampled Cine movies were produced from 2.5- and 1.5-min data acquisitions, respectively. The accelerated 90-frame Cine movies of mouse hearts were successfully reconstructed with a compressed sensing algorithm. The movies had high image quality and the undersampling artifacts were effectively removed. Left ventricular functional parameters, i.e. end-systolic and end-diastolic lumen surface areas and early-to-late filling rate ratio as a parameter to evaluate diastolic function, derived from the standard and accelerated Cine movies, were nearly identical.


Assuntos
Aceleração , Coração/fisiologia , Processamento de Imagem Assistida por Computador , Imagem Cinética por Ressonância Magnética/métodos , Animais , Ventrículos do Coração , Camundongos Endogâmicos C57BL
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