The thickest layer of the heart wall is the myocardium, composed of cardiac muscle cells, thus, the knowledge provided by skeletal muscle cell physiology helps explain the cardiac metabolic function [135]. The mammalian heart must contract incessantly; which means the energy requirement for an optimal function is immense and this is an interesting phenomenon because there is no ATP reserve in heart muscle. Instead, energy is stored in cardiac muscle cells in three forms:

1. The first is Phosphocreatine (PCr), which can rapidly donate its high-energy phosphates to produce ATP from ADP [136]. The energy available from PCr is relatively modest, used only during very rapid bursts of exercise [137]. 2. The second is glycogen, which forms the endogenous form of energy in the cell. The muscle’s storage capacity for glycogen is limited. However, its advantage is that it consumes much less oxygen compared to fatty acids and is readily available for use as fuel in muscle [138]. 3. The third form is triglycerides and FFA. Their oxidation is less efficient compared to glycogen, though it has greater energy input.

It is widely accepted that FFAs are the predominant substrates used in the adult myocardium for ATP production in the mitochondrion [139]. Thus, between 60 and 70% of the energy needed to maintain cardiac work comes from the β-oxidation of FFAs [140]. The levels of circulating FFAs determines largely FFA uptake in the heart [141]. Once the FFA is absorbed, its metabolism is regulated predominantly at the transcriptional level by a family of ligand-activated transcriptional factors namely peroxisome proliferator activator receptor α (PPAR-α) [142].

Depending on their availability or energy requirement (feeding, fasting, and intense exercise), the cardiac metabolic network is highly flexible in using other substrates [143]. The cardiomyocytes are capable of using glucose and lactate that accounts between 25 and 30% and a lesser proportion of amino acids, and ketone bodies [140, 144]. However, glycogen-derived glucose may contribute ≤ 40% of glucose-mediated ATP production, demonstrated in rat heart [145].

Glucose uptake is mediated via glucose transporters. There are two different types of transporters, the Na2+-coupled carrier system and the facilitative glucose transporters (GLUT). GLUT1 and GLUT4 are the major players for glucose transport in the heart. GLUT4 represents the major mechanism that regulates glucose entry in the beating heart, with GLUT1 playing a lesser role as it is primarily localized on plasma membranes and is responsible for basal cardiac glucose uptake. GLUT4 is mostly present in the intracellular vesicles at resting stages and is translocated to the plasma membrane upon insulin stimulation [143]. After uptake, free glucose is rapidly phosphorylated to glucose 6-phosphate (G6P), which subsequently enters many metabolic pathways [13]. Glycolysis represents the major pathway in glucose and yields pyruvate for subsequent oxidation. Beside glycolysis, G6P also may be channeled into glycogen synthesis or the pentose phosphate pathway (PPP). The PPP is an important source of NADPH, which plays a critical role in regulating cellular oxidative stress and is required for lipid synthesis [146].

In response to an increased energy demand, heart muscle cells initially rely on carbohydrate oxidation. For example, under stress such as exercise, ischemia and pathological hypertrophy, the substrate preference of glucose can be changed [147]. Under stress, a rapid increase in GLUT4 expression is an early adaptive response that suggests the physiological role of this adaptation is to enhance the replenishment of muscle glycogen stores. When glycogen content is high, the heart preferentially uses glycogen as a source, but when glycogen stores are low, it changes to fatty acid oxidation. This induction can be prevented by a high carbohydrate diet during recovery. The control of metabolism in recovery by glycogen levels underlines its importance as the metabolic muscles reserve [147].

In insulin resistance, the heart is embedded in a rich fatty acid and glucose environment [148,149,150]. An excess of insulin promotes increased uptake of FFA in the heart due to up regulation of the cluster differentiation protein 36 (CD36) [151], which is a potent FFA transporter; this increases intracellular fatty acids levels and PPAR-α expression. The latter, increases the gene expression in the three stages of fatty acid oxidation by increasing the synthesis of (1) FFA transporters in the cell, (2) proteins that imports FFA to the mitochondrium, and (3) enzymes in the fatty acid oxidation [152]. On the other hand, due to the inhibition of glucose utilization, a glycolytic intermediate accumulates in the cardiomyocytes, which induces glucotoxicity.

Furthermore, when diabetes progresses or when additional stresses are posed on the heart; metabolic mal-adaptation can occur and there is a great loss of metabolic flexibility [153]. The heart decreases its ability to use fatty acids, increasing FFA delivery, and leading to intramyocardial lipid accumulation (ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines) [154]. This lipid accumulation may contribute to apoptosis, impairing mitochondrial function, cardiac hypertrophy, and contractile dysfunction [155, 156] (Fig. 2). For example, diacylglycerol and fatty acyl-coenzyme (CoA) induce activation of atypical PKC, which results in impaired insulin signal transduction [139]. Ceramides act as key components of lipotoxic signaling pathways linking lipid-induced inflammation with insulin signaling inhibition [157]. On other hand, high lipid contents can induce contractile dysfunction independently of insulin resistance [158]. Therefore, the resultant defect in myocardial energy production impairs myocyte contraction and diastolic function [93, 159] (Fig. 2). These alterations produce functional changes that lead to cardiomyopathy and heart failure [160,161,162,163].

In uncontrolled diabetes, the body goes from the fed to the fasted state and the liver switches from carbohydrate or lipid utilization to ketone production in response to low insulin levels and high levels of counter-regulatory hormones [164].

The ketone bodies generated in the liver enter in the blood stream and are used by other organs, such as the brain, kidneys, skeletal muscle, and heart. Disruptions in myocardial fuel metabolism and bioenergetics contribute to cardiovascular disease as the adult heart requires high energy for contractile function [165].

In cardiovascular disease, the capacity of the heart to utilize fatty acids, the heart’s primary fuel, is diminished. In this situation, the heart uses alternative pathways such as ketone bodies as fuel for oxidative ATP production [166]. However, there is still controversy around whether this fuel shift is adaptive or maladaptive. In this sense, recently it has been shown that cyclic ketone bodies preserve “young cardiac phenotype” in old mice [167]. On the other hand, it has been reported that isocaloric ketogenic diet (very low in carbohydrates and high in fats and/or proteins) increases lifespan [168]. The ketogenic diet effect can be mediated by suppressing longevity-related insulin signaling and mTOR pathway, and activation of peroxisome proliferator activated receptor α (PPARα), the master regulator that switches on genes involved in ketogenesis [169].

Several reports suggest that ketogenic diet may be associated with a decreased incidence of risk factors of cardiovascular disease such obesity, diabetes, arterial blood pressure and cholesterol levels, but these effects are usually limited in time [170]. However other reports indicated that cardiac risk factor reductions corresponded with weight loss regardless of a type of diet used [171].