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Cardiac Metabolism in Perspective

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ABSTRACT

The heart is a biological pump that converts chemical to mechanical energy. This process of energy conversion is highly regulated to the extent that energy substrate metabolism matches energy use for contraction on a beat‐to‐beat basis. The biochemistry of cardiac metabolism includes the biochemistry of energy transfer, metabolic regulation, and transcriptional, translational as well as posttranslational control of enzymatic activities. Pathways of energy substrate metabolism in the heart are complex and dynamic, but all of them conform to the First Law of Thermodynamics. The perspectives expand on the overall idea that cardiac metabolism is inextricably linked to both physiology and molecular biology of the heart. The article ends with an outlook on emerging concepts of cardiac metabolism based on new molecular models and new analytical tools. © 2016 American Physiological Society. Compr Physiol 6:1675‐1699, 2016.

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Figure 1. Figure 1. Perfusion apparatus for beating frog heart used by Yeo (1885). Using electrical stimulation as a mean to increase cardiac work and using reduction of oxyhemoglobin as a mean to estimate oxygen consumption, Yeo (1885) was the first to demonstrate correlation between work and oxygen consumption in heart muscle. This advance was the result of a new perfusion technique depicted here. Reproduced, with permission, from J. Physiol, vol. 6y, pg. 97, 1885 ().
Figure 2. Figure 2. Perfusion apparatus for the beating mammalian heart introduced by Langendorff (1895). Langendorff constructed this apparatus for the perfusion of the “surviving mammalian heart” to demonstrate that the heart receives its nutrients from the coronary circulation (and not from the ventricular cavities, as it was hitherto believed). Modifications of the Langendorff perfusion system have made important contributions to the study of cardiac metabolism and are still used in many biochemical and pharmacological laboratories. Reproduced, with permission, from B.D. Ross: Perfusion Techniques in Biochemistry, 1974. Oxford University Press, p. 267 ().
Figure 3. Figure 3. Perfusion apparatus for the working frog heart by Frank (1895). The principle of the “working” heart preparation was first elaborated by Otto Frank in Munich. In his now classical studies on the factors, affecting cardiac work Frank used the preparation depicted in this figure. Both the filling pressure of the left atrium as well as the resistance of the aorta could be controlled. Frank showed that the greater the passive tension before contraction, the greater was the developed tension during contraction. Reproduced, with permission, from Zeitschrift für Biologie, vol. 32, p. 375, 1895 ().
Figure 4. Figure 4. Comparison between Langendorff's technique and the working heart. The principal difference between the retrograde perfusion by Langendorff's technique (i) and the “working heart” technique (ii) is that in the latter the heart pumps fluid against a pressure head and cardiac work can be measured. Approximate values of aortic flow and coronary flow are given. A rat heart (wet wt—approx. 1 g) is able to generate a pressure, which is sufficient to overcome an aortic pressure head of 140 cm H2O). This is illustrated in Figure 3. The size of the heart and the height of the aortic fluid column are drawn to scale (vertical bar—50 cm).
Figure 5. Figure 5. The heart is a “metabolic omnivore”: The heart can process a variety of energy providing substrates to fuel ATP production that support the contractile process.
Figure 6. Figure 6. The heart as a biological pump. The heart transforms chemical energy–in the form of substrates and oxygen—into mechanical energy—contraction and cardiac output—on a beat‐to‐beat basis throughout the lifespan of an individual.
Figure 7. Figure 7. Metabolic cycles improve the efficiency of energy transfer. From the circulation of the blood to the crossbridges of the sarcomeres energy transfer makes use of a series of moiety conserved cycles. The metabolic cycles are located in the mitochondria (red). Ca2+ is considered the main regulator of both contraction and Krebs cycle flux. Panel A depicts a model of normal energy transfer (arrow on top of each panel). Panel B depicts a model of increased energy transfer in the adaptive response to an increase in workload of the heart. Panel C depicts a model of decreased energy transfer in the maladaptive state of heart failure. ADP, adenosine diphosphate; ATP, adenosine triphosphate; FAD, flavine adenine dinucleotide; FADH, reduced flavine adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide dinucleotide. Reproduced, with permission, from Taegtmeyer and Lubrano, 2014 ().
Figure 8. Figure 8. The metabolism of energy providing substrates is organized into four stages. All of these stages are regulated: delivery and uptake (I), acetyl‐coA formation (II), oxidation of smaller carbon units in the Krebs cycle providing reducing equivalents for the respiratory chain (III), and ATP production (IV). ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ac‐CoA: acetyl coenzyme A; CP: Phosphocreatine; OAA: Oxaloacetate. Modified, with permission, from Olson et al., 1959 ().
Figure 9. Figure 9. Differential substrate metabolism during acute increase of heart workload. In the isolated working heart, an acute increase in workload results in an acute increase of oxygen consumption (A) and oxidation of carbohydrates (B). Note the instant, but transient, increase in glycogen oxidation, and the sustained increase in glucose and lactate oxidation. All three substrates support the increase in cardiac work. Reproduced, with permission, from Goodwin et al., 1998 ().
Figure 10. Figure 10. Glucose 6‐phosphate (G6P) has four possible metabolic fates. G6P can be converted to ribose‐5‐phosphate through the pentose phosphate pathway, glycogen through glycogen synthesis, UDP‐GlcNAc through HBP, and pyruvate through glycolysis.
Figure 11. Figure 11. Pyruvate as a branching point in metabolism. Pyruvate has multiple metabolic fates and can be converted into the Krebs cycle intermediates malate and oxaloacetate, fermented to produce lactate in the absence of oxygen, transaminated to alanine, or decarboxylated to produce acetyl‐coA.
Figure 12. Figure 12. Fatty acid oxidation in the muscle. The main fuels for respiration in heart muscle uptake and oxidation of glucose and of long‐chain fatty acids are tightly regulated to meet the energy needs for contraction of the heart. Acetyl‐CoA, acetyl coenzyme A; Acyl‐CoA, acyl‐coenzyme A; ADP, adenosine diphosphate; ATP adenosine triphosphate; CPT, carnitine‐palmitoyl transferase; FAD, flavine adenine dinucleotide; FADH2, flavine adenine dinucleotide, reduced form; FFA, free fatty acid; G‐6‐P, glucose‐6‐phosphate; MHC, myosin heavy chain; NAD+, nicotinamide adenine dinucleotide, reduced form; Pi, inorganic phosphate; SERCA, sarcoendoplasmic reticulum ATPase. Reproduced, with permission, from Willerson et al., 3rd edition. Springer, 2007 ().
Figure 13. Figure 13. Schematic drawing showing substrate metabolism as source of energy provision and modulator of cellular functions. Products of metabolism can provide energy (red), building blocks of complex molecules (yellow) and lipid bilayers (blue), substrates for protein posttranslational modifications (PTMs) (purple), for epigenetic modifications (green), and metabolic signals (orange) such as glucose 6‐phosphate (G6P), AMP/ATP ratio, acyl‐, acetyl‐, and methyl‐ groups that can serve as substrates for epigenetic changes and PTMs. AMP, adenosine monophosphate; ATP, adenosine triphosphate; G6P: Glucose 6‐phosphate. Reproduced, with permission, from Davogustto G, Taegtmeyer H., 2015 ().
Figure 14. Figure 14. Number of Pubmed publications per year containing the Mesh terms “Metabolism” and “Cardiovascular diseases” in different biological systems. Since 1945, the number of publications per year of metabolism and cardiovascular diseases has increased in humans (blue line) and animal models (orange line). This growth is closely correlated and likely the consequence of landmark discoveries in science (purple arrows in text). The surge has been more pronounced in the last 20 years, especially after the introduction of metabolomics () PCR, polymerase chain reaction; HGP, human genome project.


Figure 1. Perfusion apparatus for beating frog heart used by Yeo (1885). Using electrical stimulation as a mean to increase cardiac work and using reduction of oxyhemoglobin as a mean to estimate oxygen consumption, Yeo (1885) was the first to demonstrate correlation between work and oxygen consumption in heart muscle. This advance was the result of a new perfusion technique depicted here. Reproduced, with permission, from J. Physiol, vol. 6y, pg. 97, 1885 ().


Figure 2. Perfusion apparatus for the beating mammalian heart introduced by Langendorff (1895). Langendorff constructed this apparatus for the perfusion of the “surviving mammalian heart” to demonstrate that the heart receives its nutrients from the coronary circulation (and not from the ventricular cavities, as it was hitherto believed). Modifications of the Langendorff perfusion system have made important contributions to the study of cardiac metabolism and are still used in many biochemical and pharmacological laboratories. Reproduced, with permission, from B.D. Ross: Perfusion Techniques in Biochemistry, 1974. Oxford University Press, p. 267 ().


Figure 3. Perfusion apparatus for the working frog heart by Frank (1895). The principle of the “working” heart preparation was first elaborated by Otto Frank in Munich. In his now classical studies on the factors, affecting cardiac work Frank used the preparation depicted in this figure. Both the filling pressure of the left atrium as well as the resistance of the aorta could be controlled. Frank showed that the greater the passive tension before contraction, the greater was the developed tension during contraction. Reproduced, with permission, from Zeitschrift für Biologie, vol. 32, p. 375, 1895 ().


Figure 4. Comparison between Langendorff's technique and the working heart. The principal difference between the retrograde perfusion by Langendorff's technique (i) and the “working heart” technique (ii) is that in the latter the heart pumps fluid against a pressure head and cardiac work can be measured. Approximate values of aortic flow and coronary flow are given. A rat heart (wet wt—approx. 1 g) is able to generate a pressure, which is sufficient to overcome an aortic pressure head of 140 cm H2O). This is illustrated in Figure 3. The size of the heart and the height of the aortic fluid column are drawn to scale (vertical bar—50 cm).


Figure 5. The heart is a “metabolic omnivore”: The heart can process a variety of energy providing substrates to fuel ATP production that support the contractile process.


Figure 6. The heart as a biological pump. The heart transforms chemical energy–in the form of substrates and oxygen—into mechanical energy—contraction and cardiac output—on a beat‐to‐beat basis throughout the lifespan of an individual.


Figure 7. Metabolic cycles improve the efficiency of energy transfer. From the circulation of the blood to the crossbridges of the sarcomeres energy transfer makes use of a series of moiety conserved cycles. The metabolic cycles are located in the mitochondria (red). Ca2+ is considered the main regulator of both contraction and Krebs cycle flux. Panel A depicts a model of normal energy transfer (arrow on top of each panel). Panel B depicts a model of increased energy transfer in the adaptive response to an increase in workload of the heart. Panel C depicts a model of decreased energy transfer in the maladaptive state of heart failure. ADP, adenosine diphosphate; ATP, adenosine triphosphate; FAD, flavine adenine dinucleotide; FADH, reduced flavine adenine dinucleotide; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide dinucleotide. Reproduced, with permission, from Taegtmeyer and Lubrano, 2014 ().


Figure 8. The metabolism of energy providing substrates is organized into four stages. All of these stages are regulated: delivery and uptake (I), acetyl‐coA formation (II), oxidation of smaller carbon units in the Krebs cycle providing reducing equivalents for the respiratory chain (III), and ATP production (IV). ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ac‐CoA: acetyl coenzyme A; CP: Phosphocreatine; OAA: Oxaloacetate. Modified, with permission, from Olson et al., 1959 ().


Figure 9. Differential substrate metabolism during acute increase of heart workload. In the isolated working heart, an acute increase in workload results in an acute increase of oxygen consumption (A) and oxidation of carbohydrates (B). Note the instant, but transient, increase in glycogen oxidation, and the sustained increase in glucose and lactate oxidation. All three substrates support the increase in cardiac work. Reproduced, with permission, from Goodwin et al., 1998 ().


Figure 10. Glucose 6‐phosphate (G6P) has four possible metabolic fates. G6P can be converted to ribose‐5‐phosphate through the pentose phosphate pathway, glycogen through glycogen synthesis, UDP‐GlcNAc through HBP, and pyruvate through glycolysis.


Figure 11. Pyruvate as a branching point in metabolism. Pyruvate has multiple metabolic fates and can be converted into the Krebs cycle intermediates malate and oxaloacetate, fermented to produce lactate in the absence of oxygen, transaminated to alanine, or decarboxylated to produce acetyl‐coA.


Figure 12. Fatty acid oxidation in the muscle. The main fuels for respiration in heart muscle uptake and oxidation of glucose and of long‐chain fatty acids are tightly regulated to meet the energy needs for contraction of the heart. Acetyl‐CoA, acetyl coenzyme A; Acyl‐CoA, acyl‐coenzyme A; ADP, adenosine diphosphate; ATP adenosine triphosphate; CPT, carnitine‐palmitoyl transferase; FAD, flavine adenine dinucleotide; FADH2, flavine adenine dinucleotide, reduced form; FFA, free fatty acid; G‐6‐P, glucose‐6‐phosphate; MHC, myosin heavy chain; NAD+, nicotinamide adenine dinucleotide, reduced form; Pi, inorganic phosphate; SERCA, sarcoendoplasmic reticulum ATPase. Reproduced, with permission, from Willerson et al., 3rd edition. Springer, 2007 ().


Figure 13. Schematic drawing showing substrate metabolism as source of energy provision and modulator of cellular functions. Products of metabolism can provide energy (red), building blocks of complex molecules (yellow) and lipid bilayers (blue), substrates for protein posttranslational modifications (PTMs) (purple), for epigenetic modifications (green), and metabolic signals (orange) such as glucose 6‐phosphate (G6P), AMP/ATP ratio, acyl‐, acetyl‐, and methyl‐ groups that can serve as substrates for epigenetic changes and PTMs. AMP, adenosine monophosphate; ATP, adenosine triphosphate; G6P: Glucose 6‐phosphate. Reproduced, with permission, from Davogustto G, Taegtmeyer H., 2015 ().


Figure 14. Number of Pubmed publications per year containing the Mesh terms “Metabolism” and “Cardiovascular diseases” in different biological systems. Since 1945, the number of publications per year of metabolism and cardiovascular diseases has increased in humans (blue line) and animal models (orange line). This growth is closely correlated and likely the consequence of landmark discoveries in science (purple arrows in text). The surge has been more pronounced in the last 20 years, especially after the introduction of metabolomics () PCR, polymerase chain reaction; HGP, human genome project.
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Heinrich Taegtmeyer, Truong Lam, Giovanni Davogustto. Cardiac Metabolism in Perspective. Compr Physiol 2016, 6: 1675-1699. doi: 10.1002/cphy.c150056