Myocardial steatosis across the spectrum of human health and disease.

Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using 1 H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research.

Myocardial steatosis impairs left ventricular diastolic-systolic coupling in healthy humans.

Mounting evidence suggests that myocardial steatosis contributes to left ventricular diastolic dysfunction, but definitive evidence in humans is lacking due to confounding comorbidities. As such, we utilized a 48-h food restriction model to acutely increase myocardial triglyceride (mTG) content - measured by 1 H magnetic resonance spectroscopy - in 27 young healthy volunteers (13 men/14 women). Forty-eight hours of fasting caused a more than 3-fold increase in mTG content (P < 0.001). Diastolic function - defined as early diastolic circumferential strain rate (CSRd) - was unchanged following the 48-h fasting intervention, but systolic circumferential strain rate was elevated (P < 0.001), indicative of systolic-diastolic uncoupling. Indeed, in a separate control experiment in 10 individuals, administration of low-dose dobutamine (2 µg/kg/min) caused a similar change in systolic circumferential strain rate as was found during 48 h of food restriction, along with a proportionate increase in CSRd, such that the two metrics remained coupled. Taken together, these data indicate that myocardial steatosis contributes to diastolic dysfunction by impairing diastolic-systolic coupling in healthy adults, and suggest that steatosis may contribute to the progression of heart disease. KEY POINTS: Preclinical evidence strongly suggests that myocardial lipid accumulation (termed steatosis) is an important mechanism driving heart disease. Definitive evidence in humans is limited due to the confounding influence of multiple underlying comorbidities. Using a 48-h food restriction model to acutely increase myocardial triglyceride content in young healthy volunteers, we demonstrate an association between myocardial steatosis and left ventricular diastolic dysfunction. These data advance the hypothesis that myocardial steatosis may contribute to diastolic dysfunction and suggest myocardial steatosis as a putative therapeutic target.

Plasma osteopontin relates to myocardial fibrosis and steatosis and to immune activation among women with HIV.

OBJECTIVE: Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk. DESIGN: Prospective, cross-sectional. METHODS: We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH). RESULTS: Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters. CONCLUSION: Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH. CLINICALTRIALSGOV REGISTRATION: NCT02874703.

Reduced myocardial perfusion is common among subjects with ischemia and no obstructive coronary artery disease and heart failure with preserved ejection fraction: a report from the WISE-CVD continuation study.

Aim: Women with evidence of ischemia and no obstructive coronary artery disease (INOCA) have an increased risk of major adverse cardiac events, including heart failure with preserved ejection fraction (HFpEF). To investigate potential links between INOCA and HFpEF, we examined pathophysiological findings present in both INOCA and HFpEF. Methods: We performed adenosine stress cardiac magnetic resonance imaging (CMRI) in 56 participants, including 35 women with suspected INOCA, 13 women with HFpEF, and 8 reference control women. Myocardial perfusion imaging was performed at rest and with vasodilator stress with intravenous adenosine. Myocardial perfusion reserve index was quantified as the ratio of the upslope of increase in myocardial contrast at stress vs. rest. All CMRI measures were quantified using CVI42 software (Circle Cardiovascular Imaging Inc). Statistical analysis was performed using linear regression models, Fisher's exact tests, ANOVA, or Kruskal-Wallis tests. Results: Age (P = 0.007), Body surface area (0.05) were higher in the HFpEF group. Left ventricular ejection fraction (P = 0.02) was lower among the INOCA and HFpEF groups than reference controls after age adjustment. In addition, there was a graded reduction in myocardial perfusion reserve index in HFpEF vs. INOCA vs. reference controls (1.5 ± 0.3, 1.8 ± 0.3, 1.9 ± 0.3, P = 0.02), which was attenuated with age-adjustment. Conclusion: Reduced myocardial perfusion reserve appears to be a common pathophysiologic feature in INOCA and HFpEF patients.

1 Year HIIT and Omega-3 Fatty Acids to Improve Cardiometabolic Risk in Stage-A Heart Failure.

OBJECTIVES: This study aims to determine whether 1 year of high-intensity interval training (HIIT) and omega-3 fatty acid (n-3 FA) supplementation would improve fitness, cardiovascular structure/function, and body composition in obese middle-aged adults at high-risk of heart failure (HF) (stage A). BACKGROUND: It is unclear if intensive lifestyle interventions begun in stage A HF can improve key cardiovascular and metabolic risk factors. METHODS: High-risk obese adults (n = 80; age 40 to 55 years; N-terminal pro-B-type natriuretic peptide >40 pg/mL or high-sensitivity cardiac troponin T >0.6 pg/mL; visceral fat >2 kg) were randomized to 1 year of HIIT exercise or attention control, with n-3 FA (1.6 g/daily omega-3-acid ethyl esters) or placebo supplementation (olive oil 1.6 g daily). Outcome variables were exercise capacity quantified as peak oxygen uptake (V.O2), left ventricular (LV) mass, LV volume, myocardial triglyceride content (magnetic resonance spectroscopy), arterial stiffness/function (central pulsed-wave velocity; augmentation index), and body composition (dual x-ray absorptiometry scan). RESULTS: Fifty-six volunteers completed the intervention. There was no detectible effect of HIIT on visceral fat or myocardial triglyceride content despite a reduction in total adiposity (Δ: -2.63 kg, 95% CI: -4.08 to -0.46, P = 0.018). HIIT improved exercise capacity by ∼24% (ΔV.O2: 4.46 mL/kg per minute, 95% CI: 3.18 to 5.56; P < 0.0001), increased LV mass (Δ: 9.40 g, 95% CI: 4.36 to 14.44; P < 0.001), and volume (Δ: 12.33 mL, 95 % CI: 5.61 to 19.05; P < 0.001) and reduced augmentation index (Δ: -4.81%, 95% CI: -8.63 to -0.98; P = 0.009). There was no independent or interaction effect of n-3 FA on any outcome. CONCLUSIONS: One-year HIIT improved exercise capacity, cardiovascular structure/function, and adiposity in stage A HF with no independent or additive effect of n-3 FA administration. (Improving Metabolic Health in Patients With Diastolic Dysfunction [MTG]; NCT03448185).

Hot Flashes and Cardiovascular Disease Risk Indices Among Women With HIV.

Women with HIV (WWH) transitioning through menopause have heightened cardiovascular disease (CVD) risk. In the general population, hot flash burden relates to CVD risk indices. We found higher hot flash burden among women with vs without HIV. Further, among WWH, hot flash burden related to select CVD risk indices. CLINICALTRIALSGOV REGISTRATION: NCT02874703.

Proton magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations.

1 H-MR spectroscopy of skeletal muscle provides insight into metabolism that is not available noninvasively by other methods. The recommendations given in this article are intended to guide those who have basic experience in general MRS to the special application of 1 H-MRS in skeletal muscle. The highly organized structure of skeletal muscle leads to effects that change spectral features far beyond simple peak heights, depending on the type and orientation of the muscle. Specific recommendations are given for the acquisition of three particular metabolites (intramyocellular lipids, carnosine and acetylcarnitine) and for preconditioning of experiments and instructions to study volunteers.

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.

Brief Report: Vascular Dysfunction and Monocyte Activation Among Women With HIV.

OBJECTIVE: Women with HIV (WHIV) on antiretroviral therapy (ART) face an increased risk of cardiovascular disease (CVD) in the context of heightened systemic immune activation. Aortic stiffness, a measure of vascular dysfunction and a robust predictor of CVD outcomes, is highly influenced by immune activation. We compared aortic stiffness among women with and without HIV and examined interrelationships between aortic stiffness and key indices of systemic immune activation. METHODS: Twenty WHIV on ART and 14 women without HIV group-matched on age and body mass index (BMI) were prospectively recruited and underwent cardiovascular magnetic resonance imaging, as well as metabolic and immune phenotyping. RESULTS: Age and BMI did not differ significantly across groups (age: 52 ± 4 vs. 53 ± 6 years; BMI: 32 ± 7 vs. 32 ± 7 kg/m). Aortic pulse wave velocity (aPWV) was higher among WHIV (8.6 ± 1.3 vs. 6.5 ± 1.3 m/s, P < 0.0001), reflecting increased aortic stiffness. Among the whole group and among WHIV, aPWV related to sCD163 levels (whole group: R = 0.65, P < 0.0001; WHIV: R = 0.73, P = 0.0003) and to myocardial fibrosis (extracellular volume; whole group: R = 0.54, P = 0.001; WHIV: R = 0.47, P = 0.04). Both HIV status and sCD163 levels independently predicted aPWV, controlling for age, BMI, cigarette smoking status, and systolic blood pressure (HIV status: ß-estimate = 0.69, 95% CI [0.1 to 1.3], P = 0.02; sCD163: ß-estimate = 0.002, 95% CI [0.0006 to 0.004], P = 0.01). Among WHIV, sCD163 levels independently predicted aPWV, controlling for duration of HIV, CD4 count, and HIV viral load (sCD163: ß-estimate = 0.004, 95% CI [0.002 to 0.005], P = 0.0005). CONCLUSIONS: Asymptomatic WHIV on ART have increased aortic stiffness as compared to matched control subjects. Among WHIV, aPWV related to heightened monocyte activation (sCD163) and to downstream CVD pathology (myocardial fibrosis). CLINICALTRIALS. GOV REGISTRATION: NCT02874703.

Immune Correlates of Diffuse Myocardial Fibrosis and Diastolic Dysfunction Among Aging Women With Human Immunodeficiency Virus.

Human immunodeficiency virus (HIV) imparts increased heart failure risk to women. Among women with HIV (WHIV), immune pathways relating to heart failure precursors may intimate targets for heart failure prevention strategies. Twenty asymptomatic, antiretroviral-treated WHIV and 14 non-HIV-infected women matched on age and body mass index underwent cardiac magnetic resonance imaging and immune phenotyping. WHIV (vs non-HIV-infected women) exhibited increased myocardial fibrosis (extracellular volume fraction, 0.34 ± 0.06 vs 0.29 ± 0.04; P = .002), reduced diastolic function (diastolic strain rate, 1.10 ± 0.23 s-1 vs 1.39 ± 0.27 s-1; P = .003), and heightened systemic monocyte activation. Among WHIV, soluble CD163 levels correlated with myocardial fibrosis (r = 0.53; P = .02), while circulating inflammatory CD14+CD16+ monocyte CCR2 expression related directly to myocardial fibrosis (r = 0.48; P = .04) and inversely to diastolic function (r = -0.49; P = .03). Clinical Trials Registration. NCT02874703.

Intramyocardial Triglycerides Among Women With vs Without HIV: Hormonal Correlates and Functional Consequences.

CONTEXT: Women with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure. OBJECTIVE: We investigated metabolic/hormonal/immune parameters relating to diastolic dysfunction-a precursor to heart failure-among WHIV without known cardiovascular disease (CVD). DESIGN AND OUTCOME MEASURES: Nineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures [cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI]. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed. RESULTS: Among WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher [1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01], and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = -0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02). CONCLUSIONS: For asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women's reproductive aging are noted.

Insulin access to skeletal muscle is impaired during the early stages of diet-induced obesity.

OBJECTIVE: Insulin must move from the blood to the interstitium to initiate signaling, yet access to the interstitium may be impaired in cases of insulin resistance, such as obesity. This study investigated whether consuming a short- and long-term high-fat diet (HFD) impairs insulin access to skeletal muscle, the major site of insulin-mediated glucose uptake. METHODS: Male mongrel dogs were divided into three groups consisting of control diet (n = 16), short-term (n = 8), and long-term HFD (n = 8). Insulin sensitivity was measured with intravenous glucose tolerance tests. A hyperinsulinemic euglycemic clamp was performed in each animal at the conclusion of the study. During the clamp, lymph fluid was measured as a representation of the interstitial space to assess insulin access to muscle. RESULTS: Short- and long-term HFD induced obesity and reduced insulin sensitivity. Lymph insulin concentrations were approximately 50% of plasma insulin concentrations under control conditions. Long-term HFD caused fasting plasma hyperinsulinemia; however, interstitial insulin concentrations were not increased, suggesting impaired insulin access to muscle. CONCLUSIONS: A HFD rapidly induces insulin resistance at the muscle and impairs insulin access under basal insulin concentrations. Hyperinsulinemia induced by a long-term HFD may be a compensatory mechanism necessary to maintain healthy insulin levels in muscle interstitium.

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.

Rapid development of cardiac dysfunction in a canine model of insulin resistance and moderate obesity.

AIMS/HYPOTHESIS: The worldwide incidence of obesity and diabetes continues to rise at an alarming rate. A major cause of the morbidity and mortality associated with obesity and diabetes is heart disease, yet the mechanisms that lead to cardiovascular complications remain unclear. METHODS: We performed cardiac MRI to assess left ventricular morphology and function during the development of moderate obesity and insulin resistance in a well-established canine model (n = 26). To assess the influence of dietary fat composition, we randomised animals to a traditional lard diet (rich in saturated and monounsaturated fat; n = 12), a salmon oil diet (rich in polyunsaturated fat; n = 8) or a control diet (n = 6). RESULTS: High-fat feeding with lard increased body weight and fasting insulin and markedly reduced insulin sensitivity. Lard feeding also significantly reduced left ventricular function, evidenced by a worsening of circumferential strain and impairment in left ventricular torsion. High-fat feeding with salmon oil increased body weight; however, salmon oil feeding did not impair insulin sensitivity or cardiac function. CONCLUSIONS/INTERPRETATION: These data emphasise the importance of dietary fat composition on both metabolic and cardiac function, and have important implications for the relationship between diet and health.

Transwomen and the Metabolic Syndrome: Is Orchiectomy Protective?

Background: Male-to-female transsexual women or transwomen who undergo cross-sex hormone treatments experience increased health-related risks (e.g., increased rates of cardiovascular disease and premature death). Yet, the exact mechanism by which altering biochemistry leads to metabolic impairment remains unclear. While much attention has been paid to cross-sex hormone therapy, little is known about the metabolic risk associated with orchiectomy. Methods: To address the above limitation, we prospectively enrolled 12 transwomen: 4 who had undergone bi-lateral orchiectomy and 8 who had not. Both groups were using cross-sex hormones. Glucose tolerance was assessed using a standard 75g oral glucose tolerance test. Hepatic steatosis was assessed by 1H magnetic resonance spectroscopy. The amount of subcutaneous and visceral abdominal fat was determined from a single abdominal axial image at the level between the vertebral L2 and L3 bodies. Baseline venous fasting blood sampling was performed for measurement of hemoglobin A1c, glucose, insulin, sex hormones, and sex hormone binding globulin. Results: The major novel findings were: (1) orchiectomy and cross-sex hormone therapy is associated with less hepatic steatosis and insulin resistance; (2) orchiectomy may be metabolically protective, and (3) circulating concentrations of sex hormones may be a major determinant of metabolic health in transwomen. Conclusions: To our knowledge, this is the first study to suggest an independent and protective role of orchiectomy on the metabolic health of transwomen.

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: a 3T cardiovascular magnetic resonance feasibility study.

BACKGROUND: The aim of the current study 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 by cardiovascular magnetic resonance (CMR). METHODS: In this prospective case-control study, we compared 27 HIV seropositive (+) male subjects receiving HAART to 22 control male subjects without HIV matched for age, ethnicity and body mass index. All participants underwent CMR imaging for determination of pericardial fat [as volume at the level of the origin of the left main coronary artery (LM) and at the right ventricular free wall] and magnetic resonance spectroscopy (MRS) for evaluation of intramyocardial lipid content (% of fat to water in a single voxel at the interventricular septum). All measurements were made by two experienced readers blinded to the clinical history of the study participants. Two-sample t-test, Spearman's correlation coefficient or Pearson's correlation coefficient and multivariable logistic regression were used for statistical analysis. RESULTS: Pericardial fat volume at the level of LM origin was higher in HIV (+) subjects (33.4 cm(3) vs. 27.4 cm(3), p = 0.03). On multivariable analysis adjusted for age, Framingham risk score (FRS) and waist/hip ratio, pericardial fat remained significantly associated to HIV-status (OR 1.09, p = 0.047). For both HIV (+) and HIV (-) subjects, pericardial fat volume showed strong correlation with intramyocardial lipid content (r = 0.58, p < 0.0001) and FRS (r = 0.53, p = 0.0002). Among HIV (+) subjects, pericardial fat was significantly higher in patients with lipo-accumulation (37 cm(3) vs. 27.1 cm(3), p = 0.03) and showed significant correlation with duration of both HIV infection (r = 0.5, p = 0.01) and HAART (r = 0.46, p = 0.02). CONCLUSIONS: Pericardial fat content is increased in HIV (+) subjects on chronic HAART (>5 years), who demonstrate HAART-related lipo-accumulation and prolonged HIV duration of infection. Further investigation is warranted to determine whether increased pericardial fat is associated with higher cardiovascular risk leading to premature cardiovascular events in this patient population.

Elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation during diet-induced insulin resistance in dogs.

AIMS/HYPOTHESIS: A normal consequence of increased energy intake and insulin resistance is compensatory hyperinsulinaemia through increased insulin secretion and/or reduced insulin clearance. Failure of compensatory mechanisms plays a central role in the pathogenesis of type 2 diabetes mellitus; consequently, it is critical to identify in vivo signal(s) involved in hyperinsulinaemic compensation. We have previously reported that high-fat feeding leads to an increase in nocturnal NEFA concentration. We therefore designed this study to test the hypothesis that elevated nocturnal NEFA are an early signal for hyperinsulinaemic compensation for insulin resistance. METHODS: Blood sampling was conducted in male dogs to determine 24 h profiles of NEFA at baseline and during high-fat feeding with and without acute nocturnal NEFA suppression using a partial A1 adenosine receptor agonist. RESULTS: High-fat feeding increased nocturnal NEFA and reduced insulin sensitivity, effects countered by an increase in acute insulin response to glucose (AIR(g)). Pharmacological NEFA inhibition after 8 weeks of high-fat feeding lowered NEFA to baseline levels and reduced AIR(g) with no effect on insulin sensitivity. A significant relationship emerged between nocturnal NEFA levels and AIR(g). This relationship indicates that the hyperinsulinaemic compensation induced in response to high-fat feeding was prevented when the nocturnal NEFA pattern was returned to baseline. CONCLUSIONS/INTERPRETATION: Elevated nocturnal NEFA are an important signal for hyperinsulinaemic compensation during diet-induced insulin resistance.

Increase in visceral fat per se does not induce insulin resistance in the canine model.

OBJECTIVES: To determine whether a selective increase of visceral adipose tissue content will result in insulin resistance. METHODS: Sympathetic denervation of the omental fat was performed under general inhalant anesthesia by injecting 6-hydroxydopamine in the omental fat of lean mongrel dogs (n = 11). In the conscious animal, whole-body insulin sensitivity was assessed by the minimal model (SI ) and the euglycemic hyperinsulinemic clamp (SICLAMP ). Changes in abdominal fat were monitored by magnetic resonance. All assessments were determined before (Wk0) and 2 weeks (Wk2) after denervation. Data are medians (upper and lower interquartile). RESULTS: Denervation of omental fat resulted in increased percentage (and content) of visceral fat [Wk0: 10.2% (8.5-11.4); Wk2: 12.4% (10.4-13.6); P < 0.01]. Abdominal subcutaneous fat remained unchanged. However, no changes were found in SI [Wk0: 4.7 (mU/l)(-1) min(-1) (3.1-8.8); Wk2: 5.3 (mU/l)(-1) min(-1) (4.5-7.2); P = 0.59] or SICLAMP [Wk0: 42.0 × 10(-4) dl kg(-1) min(-1) (mU/l)(-1) (41.0-51.0); Wk2: 40.0 × 10(-4) dl kg(-1) min(-1) (mU/l) (-1) (34.0-52.0); P = 0.67]. CONCLUSIONS: Despite a selective increase in visceral adiposity in dogs, insulin sensitivity in vivo did not change, which argues against the concept that accumulation of visceral adipose tissue contributes to insulin resistance.

Is cardiorespiratory fitness a determinant of cardiomyopathy in the setting of type 2 diabetes?

OBJECTIVE: The aim of this study was to determine whether high fitness attenuates the defects in left ventricular (LV) structure, function and triglyceride (TG) content in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Patients (n = 74) with T2DM and ≥1 additional cardiac risk factor were recruited to participate in this cross-sectional study. Outcome measures of interest were LV structure and function by magnetic resonance imaging (MRI) and myocardial TG content by (1)H-magnetic resonance spectroscopy (MRS). The primary exposure variable was cardiorespiratory fitness defined by peak oxygen consumption scaled to fat-free mass (FFM; VO2peak-FFM). RESULTS: Mean age was 53.5 years; 42.9% were women and mean glycosylated haemoglobin (HbA1c) was 8.0% with the mean duration of T2DM 8.2 years. VO2peak-FFM was crudely associated with both LV end systolic (r = 0.35, p = 0.002) and diastolic volumes (r = 0.32, p = 0.004), but not with ejection fraction (r = -0.15, p = 0.206), myocardial TG (r = -0.04, p = 0.734) or early diastolic peak filling rate (PFR; r = -0.01, p = 0.887). In multiple linear regression analyses, among measures of LV structure/function, VO2peak-FFM was independently associated only with LV end-diastolic volume (EDV) (ß = 1.037, p = 0.038). CONCLUSION: In individuals with T2DM at increased cardiovascular (CV) risk, cardiorespiratory fitness is not associated with LV morphology, function or myocardial TG content.