Lipidomics Reveals Myocardial Lipid Composition in a Murine Model of Insulin Resistance Induced by a High-Fat Diet.

Ectopic fat accumulation in non-adipose tissues is closely related to diabetes-related myocardial dysfunction. Nevertheless, the complete picture of the lipid metabolites involved in the metabolic-related myocardial alterations is not fully characterized. The aim of this study was to characterize the specific lipid profile in hearts in an animal model of obesity/insulin resistance induced by a high-fat diet (HFD). The cardiac lipidome profiles were assessed via liquid chromatography-mass spectrometry (LC-MS)/MS-MS and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging in hearts from C57BL/6J mice fed with an HFD or standard-diet (STD) for 12 weeks. Targeted lipidome analysis identified a total of 63 lipids (i.e., 48 triacylglycerols (TG), 5 diacylglycerols (DG), 1 sphingomyelin (SM), 3 phosphatidylcholines (PC), 1 DihydroPC, and 5 carnitines) modified in hearts from HFD-fed mice compared to animals fed with STD. Whereas most of the TG were up-regulated in hearts from animals fed with an HFD, most of the carnitines were down-regulated, thereby suggesting a reduction in the mitochondrial ß-oxidation. Roughly 30% of the identified metabolites were oxidated, pointing to an increase in lipid peroxidation. Cardiac lipidome was associated with a specific biochemical profile and a specific liver TG pattern. Overall, our study reveals a specific cardiac lipid fingerprint associated with metabolic alterations induced by HFD.

Differentiating the Prognostic Determinants of Myocardial Steatosis for Heart Failure With Preserved Ejection Fraction by Cardiac Magnetic Resonance Imaging.

Background Myocardial steatosis and fibrosis may play a role in the pathophysiology of heart failure with preserved ejection fraction. We therefore investigated the prognostic significance of epicardial fat (epicardial adipose tissue [EAT]) and myocardial diffuse fibrosis. Methods and Results Myocardial fibrosis, estimated as extracellular volume (ECV), and EAT were measured using cardiac magnetic resonance imaging in 163 subjects with heart failure with preserved ejection fraction. We also evaluated cardiac structure and diastolic and systolic function by echocardiography and cardiac magnetic resonance imaging. After 24 months' follow-up, 39 (24%) subjects had experienced cardiovascular events, including hospitalization for heart failure, acute coronary syndrome, and cardiovascular death. Median EAT and mean ECV were significantly higher in subjects with cardiovascular events than survivors (EAT, 35 [25-45] versus 31 [21-38], P=0.006 and ECV, 28.9±3.16% versus 27.2±3.56%, P=0.04). Subjects with high EAT (≥42 g) had increased risk of cardiovascular events (hazard ratio [HR], 2.528 [95% CI, 1.704-4.981]; P=0.032). High ECV (>29%) was also significantly associated with poorer outcomes (HR, 1.647 [95% CI, 1.263-2.548]; P=0.013). With respect to secondary end points, high EAT and high ECV were associated with increased risk of the incident acute coronary syndrome (HR, 1.982 [95% CI, 1.008-4.123]; P=0.049) and hospitalization for heart failure (HR, 1.789 [95% CI, 1.102-6.987]; P=0.033), respectively. Conclusions Our study suggested that increased epicardial fat and ECV detected by cardiac magnetic resonance imaging have an impact on cardiovascular prognosis, in particular acute coronary syndrome and hospitalization for heart failure, respectively.

Longitudinal effect of myocardial fat deposition on left ventricular diastolic function: a retrospective cohort study.

There is a known correlation between myocardial steatosis and heart function, but it is unclear how left ventricular diastolic function worsens over time in the myocardial steatosis setting. We sought to investigate whether intramyocardial fat deposition affects diastolic function over time. This was a retrospective analysis of patients who had undergone 1-3 echocardiography assessments between April 2011 and April 2017. Patients were divided into two groups: those with the presence of myocardial fat deposition in the left ventricular myocardium (assessed by having tissue within any 10-mm2 region with computed tomography values between - 190 and - 30 Hounsfield units; + MF), and those with absence of deposition not meeting the threshold (- MF). The rates of change of the standard early diastolic mitral annulus velocity (e') and the transmitral early peak velocity (E)/e' ratio at the second and third echocardiograph assessments were calculated relative to baseline. In total, 125 patients were eligible (+ MF, n = 39; - MF, n = 86) for inclusion. Compared with the - MF group, e' was significantly lower and E/e' was significantly higher in the + MF group at each scan timepoint, even when adjusted for body mass index and sex. A significant average decrease in e' and increase in E/e' was also observed in the + MF group across all scans compared with the - MF group. Myocardial steatosis was associated with an acceleration of decreased left ventricular diastolic function over time.

Pediatric Right Ventricular Cardiac Steatosis following Immunosuppressive Treatment.

Background Right ventricular myocardial fatty infiltration has been observed in pediatric cardiac allografts with an associated decrease in graft life expectancy. A possible explanation included an immunosuppressant drug effect which prompted us to examine common factors between non-cardiac transplanted immunosuppressed patients and postmortem hearts of pediatric patients who died of non-cardiac causes.Materials and Methods Sixty-one of 1,030 pediatric autopsies were from immunosuppressed children who were treated with corticosteroids for malignant tumors, non-cardiac transplantations, or other chronic clinical conditions. 62 children who died for non-medical reasons served as controls. Cardiac H&E autopsy slides were examined for right ventricular fatty infiltration.Results There was a significant increase in right ventricular fatty infiltration in patients that were non-cardiac transplanted and immunosuppressed compared to controls. None of the index patients had other features of arrhythmogenic right ventricular dysplasia.Conclusions Immunosuppression may lead to right ventricular fatty infiltration in childhood.

Myocardial Steatosis Among Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus Participating in the REPRIEVE Trial.

BACKGROUND: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants. METHODS: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content. RESULTS: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively). CONCLUSIONS: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group. CLINICAL TRIALS REGISTRATION: NCT02344290; NCT03238755.

Metabolic syndrome and myocardium steatosis in subclinical type 2 diabetes mellitus: a 1H-magnetic resonance spectroscopy study.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that collectively cause an increased risk of type 2 diabetes mellitus (T2DM) and nonatherosclerotic cardiovascular disease. This study aimed to evaluate the role of myocardial steatosis in T2DM patients with or without MetS, as well as the relationship between subclinical left ventricular (LV) myocardial dysfunction and myocardial steatosis. METHODS AND MATERIALS: We recruited 53 T2DM patients and 20 healthy controls underwent cardiac magnetic resonance examination. All T2DM patients were subdivide into two group: MetS group and non-MetS. LV deformation, perfusion parameters and myocardial triglyceride (TG) content were measured and compared among these three groups. Pearson's and Spearman analysis were performed to investigate the correlation between LV cardiac parameters and myocardial steatosis. The receiver operating characteristic curve (ROC) was performed to illustrate the relationship between myocardial steatosis and LV subclinical myocardial dysfunction. RESULTS: An increase in myocardial TG content was found in the MetS group compared with that in the other groups (MetS vs. non-MetS: 1.54 ± 0.63% vs. 1.16 ± 0.45%; MetS vs. normal: 1.54 ± 0.63% vs. 0.61 ± 0.22%; all p < 0.001). Furthermore, reduced LV deformation [reduced longitudinal and radial peak strain (PS); all p < 0.017] and microvascular dysfunction [increased time to maximum signal intensity (TTM) and reduced Upslope; all p < 0.017)] was found in the MetS group. Myocardial TG content was positively associated with MetS (r = 0.314, p < 0.001), and it was independently associated with TTM (ß = 0.441, p < 0.001) and LV longitudinal PS (ß = 0.323, p = 0.021). ROC analysis exhibited that myocardial TG content might predict the risk of decreased LV longitudinal myocardial deformation (AUC = 0.74) and perfusion function (AUC = 0.71). CONCLUSION: Myocardial TG content increased in T2DM patients with concurrent MetS. Myocardial steatosis was positively associated with decreased myocardial deformation and perfusion dysfunction, which may be an indicator for predicting diabetic cardiomyopathy.

Myocardial adipose deposition and the development of heart failure with preserved ejection fraction.

AIMS: It has been proposed that an increase of myocardial adiposity is related to left ventricular (LV) diastolic dysfunction. The specific roles of myocardial steatosis including epicardial fat and intramyocardial fat for diastolic function are unknown in those patients suffering heart failure (HF) with reduced (HFrEF) or preserved ejection fraction (HFpEF). This study aims to determine the complex relationship between myocardial adiposity in patients with HFrEF or HFpEF. METHODS AND RESULTS: Using cardiac magnetic resonance imaging (CMRI), myocardial steatosis was measured in 305 subjects (34 patients with HFrEF, 163 with HFpEF, and 108 non-HF controls). We also evaluated cardiac structure and diastolic and systolic function by echocardiography and CMRI. Patients with HFpEF had significantly more intramyocardial fat than HFrEF patients or non-HF controls [intramyocardial fat content (%), 1.56 (1.26, 1.89) vs. 0.75 (0.50, 0.87) and 1.0 (0.79, 1.15), P < 0.05]. Intramyocardial fat amount (%) was higher in HFpEF women than in men [1.91% (1.17%, 2.32%) vs. 1.22 (0.87%, 2.02%), P = 0.01]. When estimated by CMRI (left ventricular peak filling rate), echocardiographic E/e' level, or left atrial volume index, intramyocardial fat correlated with LV diastolic dysfunction parameters in HFpEF patients, and this was independent of age, co-morbidities, body mass index, gender, and myocardial fibrosis (standardized coefficient: ß = -0.34, P = 0.03; ß = 0.29, P = 0.025; and ß = 0.25, P = 0.02, respectively). CONCLUSIONS: Patients with HFpEF had significantly more intramyocardial fat than HFrEF patients or non-HF controls. Independent of risk factors or gender, intramyocardial fat correlated with LV diastolic dysfunction parameters in HFpEF patients.

Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation.

AIMS/HYPOTHESIS: The aim of this work was to assess the effect of liraglutide on ectopic fat accumulation in individuals with type 2 diabetes mellitus. METHODS: This study is a pre-specified subanalysis of the MAGNetic resonance Assessment of VICTOza efficacy in the Regression of cardiovascular dysfunction In type 2 diAbetes mellitus (MAGNA VICTORIA) study, with primary endpoints being the effects of liraglutide on left ventricular diastolic and systolic function. The MAGNA VICTORIA study was a single-centre, parallel-group trial in 50 individuals with type 2 diabetes mellitus (BMI >25 kg/m2) who were randomly assigned (1:1, stratified for sex and insulin use) to receive liraglutide 1.8 mg once daily or placebo for 26 weeks, added to standard care. Participants, study personnel and outcome assessors were blinded to treatment allocation. The secondary endpoints of visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT) and epicardial fat were measured with MRI. Hepatic triacylglycerol content (HTGC) and myocardial triacylglycerol content (MTGC) were quantified with proton MR spectroscopy. Between-group differences (change from baseline) were tested for significance using ANCOVA. Mean differences with 95% CIs were reported. RESULTS: The trial was completed in 2016. Twenty-four participants were randomised to receive liraglutide and 26 to receive placebo. One patient in the liraglutide group withdrew consent before having received the study drug and was not included in the intention-to-treat analysis. Liraglutide (n = 23) vs placebo (n = 26) significantly reduced body weight (liraglutide 98.4 ± 13.8 kg to 94.3 ± 14.9 kg; placebo 94.5 ± 13.1 kg to 93.9 ± 13.2 kg; estimated treatment effect -4.5 [95% CI -6.4, -2.6] kg). HbA1c declined in both groups without a significant treatment effect of liraglutide vs placebo (liraglutide 66.7 ± 11.5 mmol/mol to 55.0 ± 13.2 mmol/mol [8.4 ± 1.1% to 7.3 ± 1.2%]; placebo 64.7 ± 10.2 mmol/mol to 56.9 ± 6.9 mmol/mol [8.2 ± 1.0% to 7.5 ± 0.7%]; estimated treatment effect -2.9 [95% CI -8.1, 2.3] mmol/mol or -0.3 [95% CI -0.8, 0.2]%). VAT did not change significantly between groups (liraglutide 207 ± 87 cm2 to 203 ± 88 cm2; placebo 204 ± 63 cm2 to 200 ± 55 cm2; estimated treatment effect -7 [95% CI -24, 10] cm2), while SAT was reduced by a significantly greater extent with liraglutide than with placebo (liraglutide 361 ± 142 cm2 to 339 ± 131 cm2; placebo 329 ± 107 cm2 to 333 ± 125 cm2; estimated treatment effect -29 [95% CI -51, -8] cm2). Epicardial fat did not change significantly between groups (liraglutide 8.9 ± 4.3 cm2 to 9.1 ± 4.7 cm2; placebo 9.6 ± 4.1 cm2 to 9.6 ± 4.6 cm2; estimated treatment effect 0.2 [95% CI -1.5, 1.8] cm2). Change in HTGC was not different between groups (liraglutide 18.1 ± 11.2% to 12.0 ± 7.7%; placebo 18.4 ± 9.4% to 14.7 ± 10.0%; estimated treatment effect -2.1 [95% CI -5.3, 1.0]%). MTGC was not different after treatment with liraglutide (1.5 ± 0.6% to 1.2 ± 0.6%) vs placebo (1.3 ± 0.5% to 1.2 ± 0.6%), with an estimated treatment effect of -0.1 (95% CI -0.4, 0.2)%. There were no adjudicated serious adverse events. CONCLUSIONS/INTERPRETATION: Compared with placebo, liraglutide-treated participants lost significantly more body weight. Liraglutide primarily reduced subcutaneous fat but not visceral, hepatic, myocardial or epicardial fat. Future larger studies are needed to confirm the results of this secondary endpoint study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01761318. FUNDING: This study was funded by Novo Nordisk A/S (Bagsvaerd, Denmark).

Diabetic cardiomyopathy: Pathophysiology, theories and evidence to date.

The prevalence of type 2 diabetes (T2D) has increased worldwide and doubled over the last two decades. It features among the top 10 causes of mortality and morbidity in the world. Cardiovascular disease is the leading cause of complications in diabetes and within this, heart failure has been shown to be the leading cause of emergency admissions in the United Kingdom. There are many hypotheses and well-evidenced mechanisms by which diabetic cardiomyopathy as an entity develops. This review aims to give an overview of these mechanisms, with particular emphasis on metabolic inflexibility. T2D is associated with inefficient substrate utilisation, an inability to increase glucose metabolism and dependence on fatty acid oxidation within the diabetic heart resulting in mitochondrial uncoupling, glucotoxicity, lipotoxicity and initially subclinical cardiac dysfunction and finally in overt heart failure. The review also gives a concise update on developments within clinical imaging, specifically cardiac magnetic resonance studies to characterise and phenotype early cardiac dysfunction in T2D. A better understanding of the pathophysiology involved provides a platform for targeted therapy in diabetes to prevent the development of early heart failure with preserved ejection fraction.

Phenotyping diabetic cardiomyopathy in Europeans and South Asians.

BACKGROUND: The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans. METHODS: T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy (1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model. RESULTS: A total of 131 individuals were included (54 South Asians [50.1 ± 8.7 years, 33% men, 33 patients vs. 21 controls) and 77 Europeans (58.8 ± 7.0 years, 56% men, 48 patients vs. 29 controls)]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [- 0.20 (- 0.36; - 0.03), P = 0.021] and Europeans [- 0.20 (- 0.36; - 0.04), P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass [+ 22 g (15; 30), P < 0.001] (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction [- 1.9% (- 3.4; - 0.4), P = 0.013] (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content [+ 0.59% (0.35; 0.84), P = 0.001] (P for interaction = 0.002) than their control group. CONCLUSIONS: Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required.

Obesity-induced activation of JunD promotes myocardial lipid accumulation and metabolic cardiomyopathy.

AIMS: Metabolic cardiomyopathy (MC)-characterized by intra-myocardial triglyceride (TG) accumulation and lipotoxic damage-is an emerging cause of heart failure in obese patients. Yet, its mechanisms remain poorly understood. The Activator Protein 1 (AP-1) member JunD was recently identified as a key modulator of hepatic lipid metabolism in obese mice. The present study investigates the role of JunD in obesity-induced MC. METHODS AND RESULTS: JunD transcriptional activity was increased in hearts from diet-induced obese (DIO) mice and was associated with myocardial TG accumulation and left ventricular (LV) dysfunction. Obese mice lacking JunD were protected against MC. In DIO hearts, JunD directly binds PPARγ promoter thus enabling transcription of genes involved in TG synthesis, uptake, hydrolysis, and storage (i.e. Fas, Cd36, Lpl, Plin5). Cardiac-specific overexpression of JunD in lean mice led to PPARγ activation, cardiac steatosis, and dysfunction, thereby mimicking the MC phenotype. In DIO hearts as well as in neonatal rat ventricular myocytes exposed to palmitic acid, Ago2 immunoprecipitation, and luciferase assays revealed JunD as a direct target of miR-494-3p. Indeed, miR-494-3p was down-regulated in hearts from obese mice, while its overexpression prevented lipotoxic damage by suppressing JunD/PPARγ signalling. JunD and miR-494-3p were also dysregulated in myocardial specimens from obese patients as compared with non-obese controls, and correlated with myocardial TG content, expression of PPARγ-dependent genes, and echocardiographic indices of LV dysfunction. CONCLUSION: miR-494-3p/JunD is a novel molecular axis involved in obesity-related MC. These results pave the way for approaches to prevent or treat LV dysfunction in obese patients.

Late effects of pediatric hematopoietic stem cell transplantation on left ventricular function, aortic stiffness and myocardial tissue characteristics.

BACKGROUND: Pediatric hematopoietic stem cell transplantation (HSCT) recipients are at increased risk of cardiovascular disease later in life. As HSCT survival has significantly improved, with a growing number of HSCT indications, tailored screening strategies for HSCT-related late effects are warranted. Little is known regarding the value of cardiovascular magnetic resonance (CMR) for early identification of high-risk patients after HSCT, before symptomatic cardiovascular disease manifests. This study aimed to assess CMR-derived left ventricular (LV) systolic and diastolic function, aortic stiffness and myocardial tissue characteristics in young adults who received HSCT during childhood. METHODS: Sixteen patients (22.1 ± 1.5 years) treated with HSCT during childhood and 16 healthy controls (22.1 ± 1.8 years) underwent 3 T CMR. LV systolic and diastolic function were measured as LV ejection fraction (LVEF), the ratio of transmitral early and late peak filling rate (E/A), the estimated LV filling pressure (E/Ea) and global longitudinal and circumferential systolic strain and diastolic strain rates, using balanced steady-state free precession cine CMR and 2D velocity-encoded CMR over the mitral valve. Aortic stiffness, myocardial fibrosis and steatosis were assessed with 2D velocity-encoded CMR, native T1 mapping and proton CMR spectroscopy (1H-CMRS), respectively. RESULTS: In the patient compared to the control group, E/Ea (9.92 ± 3.42 vs. 7.24 ± 2.29, P = 0.004) was higher, LVEF (54 ± 6% vs. 58 ± 5%, P = 0.055) and global longitudinal strain (GLS) ( -20.7 ± 3.5% vs. -22.9 ± 3.0%, P = 0.063) tended to be lower, while aortic pulse wave velocity (4.40 ± 0.26 vs. 4.29 ± 0.29 m/s, P = 0.29), native T1 (1211 ± 36 vs. 1227 ± 28 ms, P = 0.16) and myocardial triglyceride content (0.47 ± 0.18 vs. 0.50 ± 0.13%, P = 0.202) were comparable. There were no differences between patients and controls in E/A (2.76 ± 0.92 vs. 2.97 ± 0.91, P = 0.60) and diastolic strain rates. CONCLUSION: In young adults who received HSCT during childhood, LV diastolic function was decreased (higher estimated LV filling pressure) and LV systolic function (LVEF and GLS) tended to be reduced as compared to healthy controls, whereas no concomitant differences were found in aortic stiffness and myocardial tissue characteristics. When using CMR, assessment of LV diastolic function in particular is important for early detection of patients at risk of HSCT-related cardiovascular disease, which may warrant closer surveillance.

Subclinical myocardial disease by cardiac magnetic resonance imaging and spectroscopy in healthy HIV/Hepatitis C virus-coinfected persons.

Objective The contribution of hepatitis C virus (HCV) infection to the risk of heart failure in human immunodeficiency virus (HIV)-coinfected persons is unknown. The objective was to characterize cardiac function and morphology in HIV-treated coinfected persons. Methods In a cross-sectional study, HIV-infected patients virologically suppressed on antiretroviral therapy without known cardiovascular disease or diabetes mellitus underwent cardiac magnetic resonance imaging and spectroscopy for measures of cardiac function, myocardial fibrosis, and steatosis. Results The study included 18 male patients with a median age of 44 years. Of these, 10 had untreated HCV coinfection and eight had HIV monoinfection. Global systolic and diastolic function in the cohort were normal, and median myocardial fat content was 0.48% (interquartile range 0.35-1.54). Left ventricular (LV) mass index and LV mass/volume ratio were significantly greater in the HIV/HCV-coinfected group compared with the HIV-monoinfected group. In the HIV-monoinfected group, there was more myocardial fibrosis as measured by extracellular volume fraction. Conclusions There were differences between HIV/HCV-coinfected and HIV-monoinfected patients in cardiac structure and morphology. Larger studies are needed to examine whether HIV and HCV independently contribute to mechanisms of heart failure.

Myocardial steatosis as a possible mechanistic link between diastolic dysfunction and coronary microvascular dysfunction in women.

Women with coronary microvascular dysfunction (CMD) and no obstructive coronary artery disease (CAD) have increased rates of heart failure with preserved ejection fraction (HFpEF). The mechanisms of HFpEF are not well understood. Ectopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in other metabolic diseases. We investigated the prevalence of myocardial steatosis and diastolic dysfunction in women with CMD and subclinical HFpEF. In 13 women, including eight reference controls and five women with CMD and evidence of subclinical HFpEF (left ventricular end-diastolic pressure >12 mmHg), we measured myocardial triglyceride content (TG) and diastolic function, by proton magnetic resonance spectroscopy and magnetic resonance tissue tagging, respectively. When compared with reference controls, women with CMD had higher myocardial TG content (0.83 ± 0.12% vs. 0.43 ± 0.06%; P = 0.025) and lower diastolic circumferential strain rate (168 ± 12 vs. 217 ± 15%/s; P = 0.012), with myocardial TG content correlating inversely with diastolic circumferential strain rate (r = -0.779; P = 0.002). This study provides proof-of-concept that myocardial steatosis may play an important mechanistic role in the development of diastolic dysfunction in women with CMD and no obstructive CAD. Detailed longitudinal studies are warranted to explore specific treatment strategies targeting myocardial steatosis and its effect on diastolic function.

Myocardial steatosis and necrosis in atria and ventricles of rats given pyruvate dehydrogenase kinase inhibitors.

Pharmaceutical therapies for non-insulin-dependent diabetes mellitus (NIDDM) include plasma glucose lowering by enhancing glucose utilization. The mitochondrial pyruvate dehydrogenase (PDH) complex is important in controlling the balance between glucose and fatty acid substrate oxidation. Administration of pyruvate dehydrogenase kinase inhibitors (PDHKIs) to rats effectively lowers plasma glucose but results in myocardial steatosis that in some instances is associated primarily with atrial and to a lesser degree with ventricular pathology. Induction of myocardial steatosis is not dose-dependent, varies from minimal to moderate severity, and is either of multifocal or diffuse distribution. Ventricular histopathology was restricted to few myocardial degenerative fibers, while that in the atrium/atria was of either acute or chronic appearance with the former showing myocardial degeneration/necrosis, acute myocarditis, edema, endothelial activation (rounding up), endocarditis, and thrombosis associated with moderate myocardial steatosis and the latter with myocardial loss, replacement fibrosis, and no apparent or minimal association with steatosis. The evidence from these evaluations indicate that excessive intramyocardial accumulation of lipid may be either primarily adverse or represents an indicator of other adversely affected cellular processes.

Myocardial steatosis and left ventricular contractile dysfunction in patients with severe aortic stenosis.

BACKGROUND: Aortic stenosis (AS) leads to left ventricular (LV) hypertrophy and dysfunction. We hypothesized that cardiac steatosis is involved in the pathophysiology and also assessed whether it is reversible after aortic valve replacement. METHODS AND RESULTS: Thirty-nine patients with severe AS (symptomatic=25, asymptomatic=14) with normal LV ejection fraction and no significant coronary artery disease and 20 age- and sex-matched healthy controls underwent cardiac 1H-magnetic resonance spectroscopy and imaging for the determination of steatosis (myocardial triglyceride content) and cardiac function, including circumferential strain (measured by magnetic resonance tagging). Strain was lower in both symptomatic and asymptomatic AS (-16.4 ± 2.5% and -18.1 ± 2.9%, respectively, versus controls -20.7 ± 2.0%, both P<0.05). Myocardial steatosis was found in both symptomatic and asymptomatic patients with AS (0.89 ± 0.42% in symptomatic AS; 0.75 ± 0.36% in asymptomatic AS versus controls 0.45 ± 0.17, both P<0.05). Importantly, multivariable analysis indicated that steatosis was an independent correlate of impaired LV strain. Spectroscopic measurements of myocardial triglyceride content correlated significantly with histological analysis of biopsies obtained during aortic valve replacement. At 8.0 ± 2.1 months after aortic valve replacement, steatosis and strain had recovered toward normal. CONCLUSIONS: Pronounced myocardial steatosis is present in severe AS, regardless of symptoms, and is independently associated with the degree of LV strain impairment. Myocardial triglyceride content measured by magnetic resonance spectroscopy correlates with histological quantification. Steatosis and strain impairment are reversible after aortic valve replacement. Our findings suggest a novel pathophysiological mechanism in AS, myocardial steatosis, which may be amenable to treatment, thus potentially delaying onset of LV dysfunction.

Downregulation of adipose triglyceride lipase in the heart aggravates diabetic cardiomyopathy in db/db mice.

Adipose triglyceride lipase (ATGL) was recently identified as a rate-limiting triglyceride (TG) lipase and its activity is stimulated by comparative gene identification-58 (CGI-58). Mutations in the ATGL or CGI-58 genes are associated with neutral lipid storage diseases characterized by the accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, is characterized by TG accumulation in coronary atherosclerotic lesions and in the myocardium. Recent reports showed that myocardial TG accumulation is significantly higher in patients with diabetes and is associated with impaired left ventricular diastolic function. Therefore, we investigated the roles of ATGL and CGI-58 in the development of myocardial steatosis in the diabetic state. Histological examination with oil red O staining showed marked lipid deposition in the hearts of diabetic fatty db/db mice. Cardiac triglyceride and diglyceride contents were greater in db/db mice than in db/+ control mice. Next, we determined the expression of genes and proteins that affect lipid metabolism, and found that ATGL and CGI-58 expression levels were decreased in the hearts of db/db mice. We also found increased expression of genes regulating triglyceride synthesis (sterol regulatory element-binding protein 1c, monoacylglycerol acyltransferases, and diacylglycerol acyltransferases) in db/db mice. Regarding key modulators of apoptosis, PKC activity, and oxidative stress, we found that Bcl-2 levels were lower and that phosphorylated PKC and 8-hydroxy-2'-deoxyguanosine levels were higher in db/db hearts. These results suggest that reduced ATGL and CGI-58 expression and increased TG synthesis may exacerbate myocardial steatosis and oxidative stress, thereby promoting cardiac apoptosis in diabetic mice.