Myocardial Lipid Content Research Articles

Effect of exogenous ketone supplementation on cardiac energetics, function, and perfusion in type 2 diabetes, heart failure, and healthy participants- A single center, open labelled clinical study

Abstract Background Type 2 diabetes (T2D) confers loss of cardiac metabolic flexibility in fuel selection and impaired mitochondrial function. Enhanced ketone metabolism observed in T2D may represent a compensatory adaptive mechanism as ketones are a more energy efficient resource than carbohydrates or fatty acids. Favorable energetic properties of ketones may potentially mitigate the energy starved state in T2D and heart failure (HF). Purpose To test whether exogenous oral ketone supplementation would reverse cardiac energetic deficit, as well as improve cardiac function and perfusion in patients with T2D, with HF with reduced ejection fraction (HFrEF), and healthy volunteers (HV). Methods Three groups of patients were recruited: patients with T2D (n=33); patients with HFrEF (n=29, 14 with T2D); and HVs(n=25). Participants underwent cardiovascular magnetic resonance and spectroscopy to assess left ventricular (LV) function, rest and dobutamine stress perfusion and energetics (phosphocreatine/adenosine triphosphate ratio[PCr/ATP]). After the initial visit, participants had an identical second visit following 2 weeks of oral ketone supplementation (30g daily). Results Participants were matched in age and sex distribution. There were no significant differences in LV ejection fraction (LVEF) between T2D and HV groups with significantly lower LVEF in HFrEF group. Both the T2D group and the HFrEF group showed significant reductions in PCr/ATP ratio and the rest and stress GLS compared to the HV. The resting and dobutamine-stress myocardial blood flow (MBF) were only significantly reduced in patients with HFrEF compared to T2D and HV groups. Subgroup analyses of HFrEF group with and without T2D showed no significant differences in energetics, perfusion, or functional assessments. Significant increase in PCr/ATP ratio was seen only in T2D group from baseline after 2 weeks of ketone supplementation (Visit-1:1.6[1.5,1.8] vs Visit-2:1.9[1.7,2.1]; P=0.01). This significant increment was not observed in HFrEF or HV groups. Two weeks of ketone supplementation was not associated with any significant changes in LVEF, GLS, rest or dobutamine-stress myocardial blood flow, or in myocardial lipid content (Table-1). Conclusions Short-term ketone supplementation is associated with isolated significant improvements in resting cardiac energetics in patients with T2D and preserved LVEF, without changes cardiac function or perfusion. In contrast to patients with T2D and preserved LVEF, short-term ketone supplementation does not lead to any significant improvements in energetics in patients with HFrEF suggesting loss of mitochondrial plasticity with transition to HFrEF. Moreover, healthy volunteers experience no further increments of myocardial energetics from the normal range values at baseline with ketone supplementation.

Reduction of myocardial lipid content assessed by H1 magnetic resonance spectroscopy in dyslipidemic patients after statins

BackgroundDyslipidemia is one of the main modifiable risk factors for cardiovascular diseases, which accounts for one third of total deaths worldwide. Statin is considered the cornerstone therapy for treating dyslipidemic patients. H1 Cardiac magnetic resonance spectroscopy (MRS) is a special non-invasive, non-irradiating method for assessing myocardial lipid content in vivo in both health and disease.AimTo compare dyslipidemic patients and healthy individuals, and to detect the efficacy of statin on the myocardial lipid content in dyslipidemic patients to detect if there will be changes 6 months after starting statin therapy.MethodsLaboratory lipid profile and myocardial lipid content had been measured by H1 MRS in thirty dyslipidemic patients and fifteen healthy matched age and sex individuals as a control group, then dyslipidemic patients were followed up 6 months after statin therapy at Cardiovascular Medicine and Radiology departments; Mansoura University Hospitals, Dakahlia Governorate, Egypt, during the period from January 2020 to October 2022.ResultsA total of thirty dyslipidemic patients were screened for lipid profile, myocardial lipid content by H1 MRS; 56.67% were male, with a mean age of 49 ± 9.19 years, and compared with fifteen healthy matched age and sex individuals as a control group. Laboratory lipid profile, and triglyceride lipid concentration by MRS were significantly higher in dyslipidemic group before initiating statin therapy compared to control group (p value, 0.001, 0.019 respectively). Median LDL levels were 161.10 ± 30.28 mg/dl before the start of statin therapy and were 114.27 ± 48.33 mg/dl after statin therapy (p < 0.001). There was a statistically significant reduction in triglyceride lipid concentration in dyslipidemic patients after 6 months of statin therapy: from 0.011 (0.001–0.55 (mmol/l), to 0.0025 (0.001–0.04 mmol/l) with a p value < 0.001.ConclusionsIncreased myocardial lipid content as measured by magnetic resonance spectroscopy was demonstrated in dyslipidemic patients in our study that decreased after 6 months of statin therapy.

Role of Cardiac Energetics in Aortic Stenosis Disease Progression: Identifying the High-risk Metabolic Phenotype.

Severe aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and cardiac metabolic alterations with evidence of steatosis and impaired myocardial energetics. Despite this common phenotype, there is an unexplained and wide individual heterogeneity in the degree of hypertrophy and progression to myocardial fibrosis and heart failure. We sought to determine whether the cardiac metabolic state may underpin this variability. We recruited 74 asymptomatic participants with AS and 13 healthy volunteers. Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to adenosine triphosphate ratio. Myocardial lipid content was determined using proton spectroscopy. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging. Phosphocreatine/adenosine triphosphate was reduced early and significantly across the LV wall thickness quartiles (Q2, 1.50 [1.21-1.71] versus Q1, 1.64 [1.53-1.94]) with a progressive decline with increasing disease severity (Q4, 1.48 [1.18-1.70]; P=0.02). Myocardial triglyceride content levels were overall higher in all the quartiles with a significant increase seen across the AV pressure gradient quartiles (Q2, 1.36 [0.86-1.98] versus Q1, 1.03 [0.81-1.56]; P=0.034). While all AS groups had evidence of subclinical LV dysfunction with impaired strain parameters, impaired systolic longitudinal strain was related to the degree of energetic impairment (r=0.219; P=0.03). Phosphocreatine/adenosine triphosphate was not only an independent predictor of LV wall thickness (r=-0.20; P=0.04) but also strongly associated with myocardial fibrosis (r=-0.24; P=0.03), suggesting that metabolic changes play a role in disease progression. The metabolic and functional parameters showed comparable results when graded by clinical severity of AS. A gradient of myocardial energetic deficit and steatosis exists across the spectrum of hypertrophied AS hearts, and these metabolic changes precede irreversible LV remodeling and subclinical dysfunction. As such, cardiac metabolism may play an important and potentially causal role in disease progression.

Angiotensin II type 1a receptor knockout ameliorates high-fat diet-induced cardiac dysfunction by regulating glucose and lipid metabolism.

Obesity-related cardiovascular diseases are associated with overactivation of the renin-angiotensin system (RAS). However, the underlying mechanisms remain elusive. In this study, we investigate the role of angiotensin II (Ang II) in high-fat diet (HFD)-induced cardiac dysfunction by focusing on cardiac glucose and lipid metabolism and energy supply. Ang II plays a role in cardiovascular regulation mainly by stimulating angiotensin II type 1 receptor (AT1R), among which AT1aR is the most important subtype in regulating the function of the cardiovascular system. AT1aR gene knockout (AT1aR ‒/‒) rats and wild-type (WT) rats are randomly divided into four groups and fed with either a normal diet (ND) or a HFD for 12 weeks. The myocardial lipid content, Ang II level and cardiac function are then evaluated. The expressions of a number of genes involved in glucose and fatty acid oxidation and mitochondrial dynamics are measured by quantitative polymerase chain reaction and western blot analysis. Our results demonstrate that AT1aR knockout improves HFD-induced insulin resistance and dyslipidemia as well as lipid deposition and left ventricular dysfunction compared with WT rats fed a HFD. In addition, after feeding with HFD, AT1aR ‒/‒ rats not only show further improvement in glucose and fatty acid oxidation but also have a reverse effect on increased mitochondrial fission proteins. In conclusion, AT1aR deficiency ameliorates HFD-induced cardiac dysfunction by enhancing glucose and fatty acid oxidation, regulating mitochondrial dynamics-related protein changes, and further promoting cardiac energy supply.

Abstract 13652: A Randomised Double-Blind Placebo-Controlled Study of Fenofibrate as a Metabolic Modulator to Augment Cardiac Physiology in Moderate-Severe Aortic Stenosis

Background: Pressure overload in aortic stenosis (AS) is associated with reduced cardiac fatty acid oxidation (FAO) and evidence of myocardial steatosis and impaired myocardial energetics. Here, we investigated whether modulating myocardial metabolism to increase FAO with a PPARα agonist, Fenofibrate in moderate-severe AS had effects on cardiac metabolism and physiology. Methods: 67 participants with asymptomatic moderate-severe AS were prospectively randomised (double-blinded) to receive either Fenofibrate 200mg once daily (N= 54) or placebo (N=13) for 6 months (180 ± 7 days duration). Follow-up data is available in 42 patients. Primary endpoint was reduction in myocardial triglyceride content (MTG) measured using proton magnetic resonance spectroscopy (MRS). Secondary endpoints included cardiac PCr/ATP measured by 31P-MRS and LV strain assessed using MR tagging. Results: There was significant reduction in MTG content (-0.40%, CI -0.74 to -0.06, p= 0.022), with a no significant reduction seen in placebo. (-0.46%, CI -1.1 to 0.17, p= 0.13). A significant increase in venous butyrate levels was seen in the fibrate group (+0.09 mmol/l, CI 0.006 to 0.17, p= 0.036) in line with increased fatty acid oxidation. No change in cardiac energetics was seen in either group. No change in cardiac function was seen in either group, global longitudinal strain (-0.07%, p 0.89 Fibrate vs -0.31%, p 0.67 Placebo), circumferential strain ( -0.15 %, p 0.80 Fibrate vs 1.71%, p 0.07 Placebo). Conclusions: Fenofibrate can potentially upregulate fatty acid oxidation in hypertrophied AS hearts reducing myocardial lipid content, but this did not have any measurable beneficial physiological effect in moderate-severe AS.

Protective Effects of Huangqi Shengmai Yin on Type 1 Diabetes-Induced Cardiomyopathy by Improving Myocardial Lipid Metabolism.

Diabetic cardiomyopathy (DCM) is one of the many complications of diabetes. DCM leads to cardiac insufficiency and myocardial remodeling and is the main cause of death in diabetic patients. Abnormal lipid metabolism plays an important role in the occurrence and development of DCM. Huangqi Shengmai Yin (HSY) has previously been shown to alleviate signs of heart disease. Here, we investigated whether HSY could improve cardiomyopathy caused by type 1 diabetes mellitus (T1DM) and improve abnormal lipid metabolism in the diabetic heart. Streptozotocin (STZ) was used to establish the T1DM mouse model, and T1DM mice were subsequently treated with HSY for eight weeks. The changes in the cardiac conduction system, histopathology, blood myocardial injury indices, and lipid content and expression of proteins related to lipid metabolism were evaluated. Our results showed that HSY could improve electrocardiogram; decrease the serum levels of CK-MB, LDH, and BNP; alleviate histopathological changes in cardiac tissue; and decrease myocardial lipid content in T1DM mice. These results indicate that HSY has a protective effect against T1DM-induced myocardial injury in mice and that this effect may be related to the improvement in myocardial lipid metabolism.

Marathon running transiently depletes the myocardial lipid pool.

Lipids, stored as intracellular triacylglycerol droplets within the myocardium, serve as an important source of energy, particularly in times of prolonged increased energy expenditure. In only a few studies, the acute effects of exercise on such ectopic myocardial lipid storage were investigated. We studied the dynamic behavior of the myocardial lipid pool in response to completing the 2017 Amsterdam Marathon using proton magnetic resonance (MR) spectroscopy (1H‐MRS). We hypothesized that the prolonged increased myocardial energy demand of running a marathon could shift the balance of myocardial triacylglycerol turnover from triacylglycerol synthesis toward lipolysis and mitochondrial fatty acid β‐oxidation, and decrease the myocardial lipid pool.We employed two 3 Tesla MR systems in parallel to noninvasively examine endurance‐trained healthy men (n = 8; age 50.7 [50.1–52.7] y) at 1 week prior (baseline), <6 hr after finishing the marathon (post‐marathon), and 2 weeks thereafter (recovery). Exercise intensity was 89 ± 6% of the age‐predicted maximal heart rate, with a finish time of 3:56 [3:37–4:42] h:min. Myocardial lipid content was 0.66 [0.58–0.87]% of the total myocardial water signal at baseline, was lower post‐marathon (0.47 [0.41–0.63]% of the total myocardial water signal), and had restored to 0.55 [0.49–0.83]% of the total myocardial water signal at recovery, representing a transient marathon running‐induced depletion of 29 ± 24% (p = .04). The magnitude of this myocardial lipid pool depletion did not correlate with exercise intensity (r = −0.39; p = .39), nor with marathon finishing time (ρ = 0.57; p = .15).Our data show that prolonged high‐intensity exercise can induce a transient depletion of the myocardial lipid pool, reinforcing the dynamic nature of ectopic triacylglycerol storage under real‐life conditions of extreme endurance exercise.

Subclinical effects of long-chain fatty acid β-oxidation deficiency on the adult heart: A case-control magnetic resonance study.

Cardiomyopathy can be a severe complication in patients with long‐chain fatty acid β‐oxidation disorders (LCFAOD), particularly during episodes of metabolic derangement. It is unknown whether latent cardiac abnormalities exist in adult patients. To investigate cardiac involvement in LCFAOD, we used proton magnetic resonance imaging (MRI) and spectroscopy (1H‐MRS) to quantify heart function, myocardial tissue characteristics, and myocardial lipid content in 14 adult patients (two with long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD); four with carnitine palmitoyltransferase II deficiency (CPT2D); and eight with very long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD)) and 14 gender‐, age‐, and BMI‐matched control subjects. Examinations included cine MRI, MR tagging, native myocardial T1 and T2 mapping, and localized 1H‐MRS at 3 Tesla. Left ventricular (LV) myocardial mass (P = .011) and the LV myocardial mass‐to‐volume ratio (P = .008) were higher in patients, while ejection fraction (EF) was normal (P = .397). LV torsion was higher in patients (P = .026), whereas circumferential shortening was similar compared with controls (P = .875). LV hypertrophy was accompanied by high myocardial T1 values (indicative of diffuse fibrosis) in two patients, and additionally a low EF in one case. Myocardial lipid content was similar in patients and controls. We identified subclinical morphological and functional differences between the hearts of LCFAOD patients and matched control subjects using state‐of‐the‐art MR methods. Our results suggest a chronic cardiac disease phenotype and hypertrophic LV remodeling of the heart in LCFAOD, potentially triggered by a mild, but chronic, energy deficiency, rather than by lipotoxic effects of accumulating lipid metabolites.

SUN-048 Cardiometabolic Effects of Cross-Sex Hormone Therapy in Transgender Patients

Background: Sex hormones are believed to play an important role in development and progression of cardiovascular disease. However, the gender gap in onset and mortality is not yet completely understood. Transsexuals undergoing hormone therapy are a promising collective for analysing the effects of sex hormones on cardiometabolic disease. Methods: Aim of this study is to identify gender specific cardiovascular changes attributed to high-dose cross-sex hormone therapy (HT) in male-to-female (MtF) and female to male (FtM) transgender patients by performing an oral glucose tolerance test (OGTT) and 3 Tesla magnet resonance spectroscopy for hepatic (HCL) and myocardial (MYCL) lipid content analysis. The control group (CON) is conducted by age, sex and BMI matched healthy individuals. Results: Until now we included 26 MtF,14 FtM patients and 12 age and BMI matched healthy controls. The mean age was comparable in all 3 groups (MtF 30.12±2.31, FtM 29.72±1,91, CON 30,23±1.22 as well as BMI (22.59±3.81, 21.62±2.53, 21.33±1.20 kg/m2, p=ns, respectively). The mean hormone therapy duration was similar in both groups (MtF 4.58±1.20 vs FtM 2.35±0,95, p=0,29). HOMA Index did not significantly differ between the groups (MtF 1,78±0,92 vs FtM 1,96±1.22 vs CON 1,8±1.01, p=0,3 vs 0,4 vs 0,3 respectively). HCL was significantly higher in MtF than FtM (1,50±0,41 % vs 0.54±0,33 %, p=0,022, respectively). We also found a significant correlation between ejection fraction (EF) and Testosterone levels (Spearmans Rho 0,80, p=0.002). Conclusio: These preliminary data could indicate a positive effect of Testosterone therapy on heart function. Contradictory to current data we found a higher HCL in MtF than FtM suggesting a not so protective estrogen effect when looking at the liver. Long-term studies are warranted to assess whether cross-sex HT results in different outcomes regarding cardiovascular disease.

Noninvasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI.

The recent development of hyperpolarized 13C magnetic resonance spectroscopy has made it possible to measure cellular metabolism in vivo, in real time. By comparing participants with and without type 2 diabetes mellitus (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. Thirteen people with T2DM (glycated hemoglobin, 6.9±1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-magnetic resonance spectroscopy), and lipid content (1H-magnetic resonance spectroscopy) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate magnetic resonance spectra were also acquired and in 5 of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75 g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via PDH (pyruvate dehydrogenase, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate), and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with T2DM (Fasted: 0.0084±0.0067 [Control] versus 0.0016±0.0014 [T2DM], Fed: 0.0184±0.0109 versus 0.0053±0.0041; P=0.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (P<0.001). As is characteristic of diabetes mellitus, impaired myocardial energetics, myocardial lipid content, and diastolic function were also demonstrated in the wider study cohort. This work represents the first demonstration of the ability of hyperpolarized 13C magnetic resonance spectroscopy to noninvasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.

Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects

Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue. Ten healthy subjects (age: 28±19 y; BMI: 22.2±0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4±3.95 y; BMI: 28.4±1.25) were characterized as "positive controls." Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T. High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured [Δhepatocellular lipid (HCL)_healthy_baseline: -15.9±10.7 compared with ± ΔHCL_healthy_follow-up: -6.9±4.6; P=0.17] and hepatic glycogen (Δglycogen_baseline: 64.4±14.1 compared with Δglycogen_follow-up: 51.1±9.8; P=0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD. Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.

Fatty acid binding protein 4 (FABP4) as a potential biomarker reflecting myocardial lipid storage in type 2 diabetes

ObjectiveFatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone involved in the crosstalk between adipose and peripheral tissues, and it contributes to widespread insulin resistance in cells, including cardiac cells. However, the role of this adipokine in regulating cardiac metabolism and myocardial neutral lipid content in patients with type 2 diabetes has not been elucidated. MethodsThe impact of circulating FABP4 on the cardiac neutral lipid content was measured by proton magnetic resonance spectroscopy (1H-MRS) in patients with type 2 diabetes. Additionally, circulating FABP4 and the cardiac triglyceride content were analysed in high-fat diet (HFD)-fed mice, and the impact of the exogenous FABP4 was explored in HL-1 cardiac cells. ResultsSerum FABP4 levels were higher in type 2 diabetic patients compared to healthy individuals. Circulating FABP4 levels were associated with myocardial neutral lipid content in type 2 diabetic patients. In HFD-fed mice, both serum FABP4 and myocardial triglyceride content were increased. In FABP4-challenged HL-1 cells, extracellular FABP4 increased intracellular lipid accumulation, which led to impairment of the insulin-signalling pathway and reduced insulin-stimulated glucose uptake. However, these effects were partially reversed by FABP4 inhibition with BMS309403, which attenuated the intracellular lipid content and improved insulin signalling and insulin-stimulated glucose uptake. ConclusionsTaken together, our results identify FABP4 as a molecule involved in diabetic/lipid-induced cardiomyopathy and indicate that this molecule may be an emerging biomarker for diabetic cardiomyopathy-related disturbances, such as myocardial neutral lipid accumulation. Additionally, FABP4 inhibition may be a potential therapeutic target for metabolic-related cardiac dysfunctions.

Cardiac metabolic modulation upon low-carbohydrate low-protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13 C pyruvate, butyrate and acetoacetate probes.

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. 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. 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. KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity.

A high‐fat diet impairs mitochondrial biogenesis, mitochondrial dynamics, and the respiratory chain complex in rat myocardial tissues

A high‐fat diet (HFD) has been associated with heart failure and arrhythmias; however, the molecular mechanisms underlying these associations are poorly understood. The mitochondria play an essential role in optimal heart performance, most of the energy for which is obtained from the oxidation of fatty acids. As such, chronic exposure to excess fatty acids may cause mitochondrial dysfunction and heart failure. To investigate the effects of a HFD on the mitochondrial function in the myocardium, 40 male rats were randomly divided into two groups and fed with either a normal diet or a HFD for 28 weeks. The myocardial lipid content, cardiac parameters and function, and mitochondrial morphology and function were evaluated. The expression of a number of genes involved in mitochondrial dynamics was measured using quantitative polymerase chain reaction and Western blot analyses. Proteomic analysis was also performed to identify the proteins affected by HFD treatment. Significant fat deposition in the myocardia, cardiac hypertrophy, and cardiac dysfunction were all observed in HFD‐treated rats. Electron microscopy showed abnormal mitochondrial density and morphology. In addition, abnormal expression of genes involved in mitochondrial dynamics, decreased mitochondrial DNA copy numbers, reduced complex I‐III and citrate synthase activities, and decreased mitochondrial respiration were observed in HFD‐treated rats. High performance liquid chromatography showed downregulated adenosine triphosphate (ATP) and adenosine diphosphate levels and an increased adenosine monophosphate (AMP)/ATP ratio. Proteomic analysis confirmed the alteration of mitochondrial function and impaired expression of proteins involved in mitochondrial dynamics in HFD‐treated rats. Mitochondrial dysfunction and impaired mitochondrial dynamics play an important role in heart dysfunction induced by a HFD, thus presenting a potential therapeutic target for the treatment of heart disease.

Myocardial lipid content in Fabry disease: a combined 1H-MR spectroscopy and MR imaging study at 3 Tesla.

BackgroundFabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by 1H magnetic resonance spectroscopy (MRS) at 3 Tesla.MethodsMyocardial lipid content was quantified in vivo by 1H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined 1H-MRS with cardiac cine imaging and LGE MRI in a single examination.ResultsMyocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076).ConclusionsThis study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by 1H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; 1H-MRS; T1 mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.

Perilipin 5 is protective in the ischemic heart

BackgroundMyocardial ischemia is associated with alterations in cardiac metabolism, resulting in decreased fatty acid oxidation and increased lipid accumulation. Here we investigate how myocardial lipid content and dynamics affect the function of the ischemic heart, and focus on the role of the lipid droplet protein perilipin 5 (Plin5) in the pathophysiology of myocardial ischemia. Methods and resultsWe generated Plin5−/− mice and found that Plin5 deficiency dramatically reduced the triglyceride content in the heart. Under normal conditions, Plin5−/− mice maintained a close to normal heart function by decreasing fatty acid uptake and increasing glucose uptake, thus preserving the energy balance. However, during stress or myocardial ischemia, Plin5 deficiency resulted in myocardial reduced substrate availability, severely reduced heart function and increased mortality. Importantly, analysis of a human cohort with suspected coronary artery disease showed that a common noncoding polymorphism, rs884164, decreases the cardiac expression of PLIN5 and is associated with reduced heart function following myocardial ischemia, indicating a role for Plin5 in cardiac dysfunction. ConclusionOur findings indicate that Plin5 deficiency alters cardiac lipid metabolism and associates with reduced survival following myocardial ischemia, suggesting that Plin5 plays a beneficial role in the heart following ischemia.

Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure.

The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se. We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate. These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.

Influence of breathing on the measurement of lipids in the myocardium by ¹H MR spectroscopy.

The myocardium examination by MR spectroscopy is very challenging due to movements caused by the cardiac rhythm and breathing. The aim of the study was to investigate the influence of breathing on the quantitative measurement of lipid/water ratios in different groups of volunteers and different measuring protocols. We examined the lipid content of myocardium at 3T using the proton single voxel spectroscopy. Three protocols (free breathing, breath hold and the use of respiratory navigator) controlled by ECG were used for the examination of 42 adult volunteers including 14 free divers. Spectra were evaluated using jMRUI software. An average content of lipids in the healthy interventricular septum, gained by all protocols was equal to 0.6 %, which is in agreement with other published data. Based on the quality of examinations and the highest technical success, the best protocol seems to be the one containing a respiratory navigator since it is more acceptable by patients. Based on our results and the literature data we can conclude that MR spectroscopy is able to distinguish patients from controls only if their myocardial lipid content is higher than 1.6 % (mean value of lipids plus two standard deviations).

Suppression of plasma free fatty acid concentrations similarly reduces myocardial lipid content and left ventricular systolic function in type 2 diabetic patients and healthy controls

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

INCREASED PERICARDIAL FAT ACCUMULATION IS ASSOCIATED WITH INCREASED INTRAMYOCARDIAL LIPID CONTENT AND DURATION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY EXPOSURE IN PATIENTS INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS

Our aim was to examine whether the use of highly active antiretroviral therapy (HAART) in patients with HIV is associated with changes in pericardial fat and myocardial lipid content measured from cardiac magnetic resonance imaging (CMR). We prospectively compared 27 HIV seropositive (+) male