The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models—the diacylglycerol (DAG) model and the ceramide model—have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD ⁺ /NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

The prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine β-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a “beige” phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications.

The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. Plasma TMAO increased in mice on ‘unhealthy’ high-choline diets and notably also on ‘healthy’ high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE^−/− and Ldlr^−/− mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. Dietary-induced changes in the microbiome, of both ‘healthy’ and ‘unhealthy’ diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.

Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 106 MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI. Stem Cells 2015;33:2726–2737

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.