Obesity is characterized by a low-grade chronic inflammation phenotype with an excessive amount of body fat leading to heart disease, diabetes, and high blood pressure. More than 34.9%, almost 78.6 million of US adults are obese (7). Obese and overweight individuals are prone to insulin resistance and diabetes, accompanied frequently by LV eccentric or concentric hypertrophy (8). Obesity is characterized on the basis of body mass index (BMI) and has been proved to be associated with ventricular hypertrophy (9, 10). The association of obesity with systolic dysfunction and with the prevalence of diabetes makes obesity a confounding factor of DCM. The predicted body weight along with the excess fat mass accounts for a rise in LV stroke volume and stroke works due to accelerated heart rate. The Framingham study suggested that a BMI >30 kg/m² is positively correlated with increased LV wall thickness, LV internal dimension in diastole, and LV mass (11). A number of studies have shown that visceral adipose tissue has higher levels of pro-inflammatory cytokines when associated with LV diastolic dysfunction (12). Studies performed on the isolated hearts of genetic animal models of obesity, such as Zucker fatty (ZF) rats or leptin-deficient obese mice, showed a depression in cardiac function (13, 14). However, a few studies also reported the normal function of the heart in obese rodent models (15, 16). As type of fat, duration, and dose consumed impacts LV structure, function, and healing in the myocardial infarction (MI)-induced model, the translational prospects of fat intake and intervention studies should be used with caution. This is exemplified by studies from Brainard and colleagues suggesting that a high-fat diet in the form of lard or milk before and after MI is insufficient to induce cardiac dysfunction, despite adiposity and impaired glucose disposal (17). The study showed that the signs of cardiac dysfunction are not visible in commonly used mouse model [type 2 diabetic Lepr-deficient (db/db) mice or streptozotocin (STZ)-treated wild-type mice] when subjected to pressure overload. But the db/db model showed depressed cardiac function when subjected to ischemia–reperfusion injury in comparison with non-diabetic mice (17). By contrast, when the obesity is superimposed on aging that is the trigger to develop non-resolving inflammation post-MI. Recent study by Lopez et al. highlighted that supplementation of n-6 FAs in aged mice resulted in higher levels of 12-S-hydroxyeicosatetraenoic acids (HETE) leading to an acute inflammatory response, further delaying healing in MI (18). These results are similar to the findings that showed higher levels of 12-HETE in individuals with stable angina (19). Studies of aging coupled with obesity have shown that the n-6 enriched fat diet creates lipid metabolites that are pro-inflammatory in nature (Figure 1). Aging mice fed a diet enriched in linoleic acid showed increased neutrophils in the gut and development of dysbiosis (20). Thus, these metabolites and their action in disease pathology such as pressure overload, post-MI healing, and overall cardiac remodeling will provide novel tools for drug discovery and target identification.

Type 2 diabetes is defined as a metabolic syndrome with a combination of insulin resistance and defective insulin secretion by pancreatic β-cells. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study was important in showing the role of hyperglycemia in micro- and macro-vascular diabetes-mediated complications (21, 22). Impaired insulin sensitivity results from obesity and physical inactivity or genetic susceptibility (23, 24). Currently, 39 million Americans are diabetic, predisposing them to cardiovascular risk. Clinical data have demonstrated that diabetes is an independent risk factor for cardiovascular complications. In both men and women, diabetes has been observed to be one of the primary causes of DCM and subsequent heart failure over the last three decades (5, 25). The development of diabetes with LV dysfunction was clinically evident 20 years earlier (26). Many clinical studies have shown that more than 60% of diabetic patients compared with well controlled subjects are diagnosed with early and mild ventricular diastolic dysfunction (27, 28). Studies have confirmed that DCM is not an unusual condition but caused by low-grade non-resolving inflammation, uncontrolled hyperglycemia (glucotoxicity), or hyperlipidemia (lipotoxicity). These factors mainly contribute to metabolic syndrome, leading to cardiac dysfunction and increasing the risk of MI or recurrent MI (29). Glucotoxicity refers to uncontrolled hyperglycemia and subsequent metabolic changes triggered by excess sugar or carbohydrate (30). Lipotoxicity is more complex and diverse because of the essential nature of FAs, but excessive intake in aging may lead to bone marrow adiposity and non-resolving inflammation post-MI (31–35). The consequences of glucotoxicity or lipotoxicity considering the metabolic health and physical inactivity of a diverse human population are key challenges in the prevention and treatment of DCM (36). The Framingham Heart Study showed that the frequency of heart failure is doubled in diabetic men and quintupled in diabetic women in comparison with age-matched control subjects. Clinical studies have shown that diabetic subjects have a high risk of cardiac failure accompanied with systolic dysfunction and LV hypertrophy (37, 38). Number of surveys and studies have shown a higher prevalence of diastolic dysfunction in diabetic patients (39, 40). Rodent and clinical studies in diabetes setting have shown functional and structural alterations in myocardium tissue. Studies performed in type 1 diabetic model, i.e., STZ-induced diabetic mouse, and rodents with type 2 diabetes, i.e., ZF rats or db/db mice, have shown diastolic dysfunction (Table 2) (13, 41). In fat and fructose-feeding studies, serum uric acid levels led to an increase in cardiac tissue xanthine oxidase activity, which was temporally related to an increase in body weight, fat mass, and insulin resistance without changes in blood pressure, when these mice were subjected to excess fat (46%) and fructose (17.5%) for 16 weeks. The high-fat and fructose diet led to cardiomyocyte hypertrophy, oxidative stress, interstitial fibrosis with impaired diastolic relaxation, and macrophage polarization toward a pro-inflammatory phenotype (42). Recent studies in many models have shown increases in levels of the 12/15-lipoxygenase (LOX) pro-inflammatory intermediate metabolite 12-HETE (43, 44). Insulin resistance is the prime risk factor to initiate the defects in insulin signaling pathways and glucose transport to cells. The resistance of the body toward insulin results in increased production of insulin in the pancreas leading to hyperinsulinemia (45). An association between insulin resistance and heart failure was noted a century ago and later traced to metabolic alteration (46).

Studies have shown that insulin resistance is a common factor in patients with non-ischemic cardiomyopathy compared with control populations, which exclude pre-existing diabetes patients (47). A study of 1,187 Swedish people showed that heart failure could be anticipated in the patients with insulin resistance without any prior heart failure history, excluding all other factors (48). Lack of insulin response can lead to inactivation of cellular pathways such as AKT inactivation, reduced nitric oxide production, and increased apoptosis with alterations in myocardial structure (49–51). Insulin resistance is now considered to be a cardiometabolic disorder predisposing people to both CVD and diabetes. Metabolic risk factors in patients with insulin resistance are atherogenic dyslipidemia, hypertension, glucose intolerance, and a prothrombotic state (52). Further, McGavock et al., by using proton magnetic resonance spectroscopy, have shown that triglyceride accumulation occurs in human myocardium in association with diabetes mellitus and insulin resistance, much earlier than the symptoms of heart failure develop (53). Thus, the accumulation of fat and abundance of FAs is associated with an impaired cardiac efficiency and lipotoxicity.

Elevated blood pressure exerted on the vessel wall is commonly referred to as hypertension. Hypertension is a well-known risk factor for dilated hypertrophy, heart failure, and stroke. About 50% of ischemic strokes are caused by hypertension with a high-risk factor for hemorrhagic stroke. The risk ratio of MI doubles when the diastolic pressure is 94 mm Hg and systolic pressure is 140 mm Hg (54). Untreated hypertension is an add-on factor for DCM, as it leads to the rapid advancement of mild subclinical DCM to the clinically visible diastolic dysfunction and then later systolic dysfunction (55). Studies have shown that the hypertensive-diabetic rats have greatest relative cardiac hypertrophy and increased interstitial fibrosis compared with only diabetic or hypertensive animals. The combination of hypertension and diabetes mellitus led to myocardial degeneration similar as observed in human patients (56). Increased blood pressure is linked with sodium intake, hyperlipidemia, insulin resistance, impaired glucose tolerance, obesity, pre-diabetes, and diabetes and can lead to pulmonary edema and heart attack. The progression of DCM leads to activation of the renin-angiotensin system, which leads to an increase in oxidative damage with cell apoptosis and necrosis in the heart thereby increasing interstitial fibrosis (57). The potent vasoconstrictor endothelin-1 (ET-1) isolated from endothelial cells has inotropic, chemotactic, and mitogenic properties, activating the renin-angiotensin-aldosterone system to increase blood pressure. Many in vitro studies have highlighted that high glucose activates ET-1, which mediates cardiomyocyte hypertrophy via mitogen-activated protein kinase (MAPK) activation (58). Genetic deletion or pharmacological inhibition of ET-1 results in salt-sensitive hypertension (59). Depending upon its presence in either medulla or cortex, the renal ET-1 has different effects on blood pressure. The upregulation of cortical ET-1 expression has been well demonstrated in various hypertensive models via an increase in renal vascular resistance and a reduction in glomerular filtration rate (60, 61). Further, activation of the glomerular ETA receptor leads to hypertension by enhancing production of monocyte chemoattractant protein-1 and other pro-inflammatory factors, sequestering macrophages and lymphocytes, thereby increasing sodium reabsorption (62). Clinically, it has been observed that mortality of patients suffering from MI is greater in hypertensive patients, as showed in the PROCAM study (63). Hypertension, when it coexists with diabetes, doubles the risk of cardiac failure. Other trials, 4S, CARE, and LIPID, which included patients with MI and angina pectoris, showed a 23–45% incidence of hypertension (64, 65, 166). Recent studies suggest the involvement of 12/15-LOX in the murine models of experimental hypertension by altering macrophage functions (66). Patients with essential hypertension were observed to have higher levels of 12-HETE and 12/15-LOX protein compared with control subjects (67). A randomized, double-blinded, and controlled clinical trial with patients having peripheral arterial disease (75% hypertensive) showed that patients who consumed a diet including 30 g of milled flaxseed (n-3-fatty acid-α-linolenic acid) for 6 months displayed significant reductions in systolic (−10 mm Hg) and diastolic (−7 mm Hg) blood pressure (68). The plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) patients exhibited significant decreases in 5,6-, 8,9-, 11,12-, and 14,15-dihydroxyeicosatrienoic acid and 9,10- and 12,13-dihydroxyoctadecenoic acid versus controls. The study showed that inhibition of soluble epoxide hydrolase contributed to the antihypertensive effects and could be one of the pharmacological targets (68).

Inflammation is an essential biological process to restore normal tissue homeostasis after injury. The state of inflammation is mediated by upregulation of multiple signaling pathways, such as NF-κB, c-Jun NH2-terminal kinase, or p38-MAPK associated with insulin resistance, which have profound roles in diabetic complications (69, 70). Thus, overactive inflammation is unifying component of many chronic diseases eventually leading to heart failure. Since in early 1950s, several reports validates that chronic inflammation is key hallmark signature in congestive heart failure pathology. Levine et al., in 1990, documented a positive correlation between TNF-α and chronic heart failure (71). Direct correlation between many chemokines/cytokines and heart failure suggests large oxidative products, which are key regulators of the inflammatory process, exerting both pro- and anti-inflammatory effects (72, 73). The lipid-metabolizing enzymes, including different members of the LOX family, are major players in the pathogenesis of heart failure. LOXs are enzymes that metabolize polyunsaturated FAs (74). The differential prostaglandins are produced by the cyclooxygenase pathway and leukotrienes through the LOX pathway, with availability of arachidonic acid substrate leading to overactive inflammation during the healing process in heart failure pathology. Arachidonic acid serves as the substrate for LOX pathway that facilitates interaction with 5-, 12-, and 15-LOX. Within the family of LOXs, 12- and 15-LOX (referred as together 12/15-LOX) forms a subgroup of phylogenetically closely related enzymes that are highly, but not exclusively, expressed in distinct monocyte-derived cells (74). 12/15-LOX is often referred to as “leukocyte-type” 12-LOX, and has orthologs in other species such as human 15-LOX and rabbit 15-LOX-1 (75). Murine and human 12/15-LOX differ in their enzymatic activity and in their position during arachidonic acid oxygenation resulting in the predominant generation of 12-(S)-HETE by murine 12/15-LOX and 15-HETE by human 12/15-LOX (15-LOX-1), respectively (76). The pro-inflammatory role of 12/15-LOX has been evidenced in failing hearts (44, 77). Wen and colleagues demonstrated that 12/15-LOX products, i.e., 12(S)-HpETE (12(S)-hydroperoxyeicosatetraenoic acid) and 12(S)-HETE, are pro-inflammatory in nature and stimulate TNF-α and IL-6 expression in macrophages as a particular effect of the 12/15-LOX products. A recent report by Suzuki et al. demonstrated that the TNF-α and collagen markers were elevated with increases in 12/15-LOX expression in the STZ-induced diabetic heart (44). By contrast, 12/15-LOX knockout mice showed suppressed levels of TNF-α and collagen markers with improved cardiac function. These authors also demonstrated that administration of a 12/15-LOX inhibitor (CDC) suppressed the TNF-α levels associated with high blood glucose levels in vitro (44).

The beta-oxidation of FAs is the primary mechanism for the heart to produce energy. Under resting conditions, FAs cover more than 70% of the cardiac energy needs by meeting this demand through the tricarboxylic acid cycle and electron transport chain. The excess of FAs is stored in adipose tissue. During obesity and diabetes, the adipose tissue increases in size that overspills free FAs leading to imbalance between energy demand and supply (78). An imbalance of FA oxidation or glucose oxidation leads to changes in cardiac mitochondrial metabolic energy that leads to ventricular dysfunction and to a decrease in cardiac performance. The impaired FA oxidation or increase in FA uptake in diabetes leads to an intramyocardial lipid overload (79). Myocardial abundance triggers defects in insulin signaling and activation of peroxisome proliferator-activated receptor-α (PPAR-α)/PGC-1 (80). The changes in FA oxidation lead to lipotoxicity and ceramide accumulation in cardiac tissue. Wu et al. have demonstrated that the deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT) in the liver/pancreas leads to a diabetic phenotype with twofold increase in FA oxidation. The deletion of ARNT leads to an increase in the expression of PPAR-α and its target genes (81). FA oxidation is a major contributor of carbon substrates to ATP generation in the adult heart. However, the heart has a unique ability of metabolic flexibility and utilizes glucose, lactate, ketones, and amino acids (82). The heart has the capacity to selectively use substrate based on availability and pathophysiological state. It is well documented that glucose and lactate are preferred by the fetal heart; however, lipids are the predominant fuel in the adult heart. Animal models of cardiac hypertrophy are observed to switch their substrate metabolism, recapitulating the “fetal metabolic profile” utilizing carbohydrates as primary energy sources (83, 84). Cardiac hypertrophy models show the consistent appearance of fetal gene expression, which is considered prime trigger in the pathological remodeling of the heart.

Altered FA utilization and intramyocardial lipid accumulation are key major factors in the pathogenesis of DCM. The metabolic preference of the diabetic heart toward glucose leads to an increase in FAs, which leads to lipid accumulation resulting in lipotoxicity. Clinical studies suggest that congenital lipodystrophy, a rare disease causing accumulation of lipids in non-adipose tissue, is one of the causes of premature cardiomyopathy (85). In diabetic and obese animal models, accumulation of triglycerides in cardiomyocytes is often associated with impaired contractile function (86). Further, rat models of obesity have shown that defects in the leptin receptor result in an excess of fat overload in non-adipose tissues resulting in lipotoxicity (87). A study in obese Zucker rats have shown that PPAR-α-regulated genes play a crucial role in FA oxidation but become impaired in the failing heart, suggesting that metabolic dysregulation due to triglyceride overload and gene expression alteration leads to contractile dysfunction. It has also been reported that intake of unsaturated FAs increases low-density lipoprotein (LDL), triacylglycerols, and Lp(a) lipoprotein, and decreases high-density lipoprotein with a reduction in LDL cholesterol particle size, which leads to alteration in serum lipid profiles, thereby doubling the risk of CVD (88). Further, the consumption of FAs increases inflammation altering the prostaglandin balance. This impairment in the activity of desaturase (the enzyme converting linoleic acid to arachidonic acid and other n-6 polyunsaturated FAs) confers a high-risk of CVD (89–91).

Dysregulation of myocardium FAs use for energy source results into glucotoxicity in hyperglycemia setting developing progressive myocardial fibrosis due to glycosylation, cross-linking, and accumulation of extracellular matrix proteins (92). There is a reduction in glucose transporter expression, which inhibits glucose translocation from plasma membrane to the cell in DCM. During ischemia, PPAR’s inhibits insulin’s action that reduces the rates of glycolysis and pyruvate oxidation resulting in shutdown of glucose metabolism to the hexosamine biosynthesis pathway (93–95). The inappropriate hexosamine biosynthesis metabolism leads to the production of reactive oxygen species (ROS) and the increased formation of intracellular advanced glycosylation end-products (AGEs). AGEs and hexosamine biosynthesis impacts the sarco-endoplasmic reticulum Ca²⁺-ATPase and the Ca²⁺ release channel, ryanodine receptor 2, leading to abnormal cardiac relaxation and contractility (96, 97). Wang et al. showed a novel role of active heparanase in modulating cardiac metabolism via cross talk between endothelial cell and cardiomyocyte to increase lipoprotein lipase secretion after hyperglycemia (98). The study showed that high glucose is a common stimulus for latent heparanase secretion from the endothelial cells and promotes its uptake into the cardiomyocyte (99). Presence of latent form of heparanase in the cardiomyocyte leads to the significant shift in the expression of apoptosis-targeted genes, providing an acute cardioprotective effect indicating diversified roles of heparanase in DCM and heart failure pathology (99).