Background-Previous studies suggest that the failing heart reactivates fetal genes and reverts to a fetal pattern of energy substrate metabolism. We tested this hypothesis by examining metabolic gene expression profiles in the fetal, nonfailing, and failing human heart. Methods and Results-Human left ventricular tissue (apex) was obtained from 9 fetal, 10 nonfailing, and 10 failing adult hearts. Using quantitative reverse transcription-polymerase chain reaction, we measured transcript levels of atrial natriuretic factor, myosin heavy chain-␣ and -␤, and 13 key regulators of energy substrate metabolism, of which 3 are considered "adult" isoforms (GLUT4, mGS, mCPT-I) and 3 are considered "fetal" isoforms (GLUT1, lGS, and lCPT-I), primarily through previous studies in rodent models. Compared with the nonfailing adult heart, steady-state mRNA levels of atrial natriuretic factor were increased in both the fetal and the failing heart. The 2 myosin heavy chain isoforms showed the highest expression level in the nonfailing heart. Transcript levels of most of the metabolic genes were higher in the nonfailing heart than the fetal heart. Adult isogenes predominated in all groups and always showed a greater induction than the fetal isogenes in the nonfailing heart compared with the fetal heart. In the failing heart, the expression of metabolic genes decreased to the same levels as in the fetal heart. Conclusions-In the human heart, metabolic genes exist as constitutive and inducible forms. The failing adult heart reverts to a fetal metabolic gene profile by downregulating adult gene transcripts rather than by upregulating fetal genes.

A common feature of the hemodynamically or metabolically stressed heart is the return to a pattern of fetal metabolism. A hallmark of fetal metabolism is the predominance of carbohydrates as substrates for energy provision in a relatively hypoxic environment. When the normal heart is exposed to an oxygen rich environment after birth, energy substrate metabolism is rapidly switched to oxidation of fatty acids. This switch goes along with the expression of "adult" isoforms of metabolic enzymes and other proteins. However, the heart retains the ability to return to the "fetal" gene program. Specifically, the fetal gene program is predominant in a variety of pathophysiologic conditions including hypoxia, ischemia, hypertrophy, and atrophy. A common feature of all of these conditions is extensive remodeling, a decrease in the rate of aerobic metabolism in the cardiomyocyte, and an increase in cardiac efficiency. The adaptation is associated with a whole program of cell survival under stress. The adaptive mechanisms are prominently developed in hibernating myocardium, but they are also a feature of the failing heart muscle. We propose that in failing heart muscle at a certain point the fetal gene program is no longer sufficient to support cardiac structure and function. The exact mechanisms underlying the transition from adaptation to cardiomyocyte dysfunction are still not completely understood.

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulinlike growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth.Cardiac hypertrophy occurs during normal physiological growth of the organism and as an adaptive response to pressure or volume stress, mutations in cardiac proteins, or metabolic perturbations (1). Hypertrophy is characterized by an increase in cell size, enhanced protein synthesis and, in some cases, reorganization of the sarcomere. In pathological hypertrophy, the increase in cardiac myocyte size is thought to be a compensatory mechanism to diminish wall stresses that result from hypertension, valvular heart disease, or myocardial infarction. Ventricular hypertrophy is associated with a significantly increased risk of heart failure and malignant arrhythmias (2).Multiple signaling pathways contribute to the hypertrophic phenotype (3, 4). A number of studies have shown that the serine-threonine kinase Akt (protein kinase B) is an important regulator of myocyte growth (5) and survival (6). Many stimuli activate Akt including the growth factors insulin and IGF 1 (7), angiotensin II (8), and mechanical stress (9). Constitutive overexpression of Akt in transgenic mice can lead to enhanced contractility (10), cytoprotection (11), and pathological cardiac hypertrophy (12, 13). Akt signaling is also an important determinant of physiological heart growth and coordinates heart size with body size as the nutritional status of the organism varies (7). The growth factor/Akt signaling pathway up-regulates protein expression through mechanisms involving the activation of the mammalian target of rapamycin (13), eukaryotic initiation factor 4E-binding proteins (14), p70S6k (7), and the inhibition of GSK3␤ (15).Relatively little is known about the mechanisms that negatively regulate the hypertrophic phenotype. Hearts undergo a reduction in size in response to a...

We investigated whether decreased responsiveness of the heart to physiological increases in fatty acid availability results in lipid accumulation and lipotoxic heart disease. Lean and obese Zucker rats were either fed ad libitum or fasted overnight. Fasting increased plasma nonesterified fatty acid levels in both lean and obese rats, although levels were greatest in obese rats regardless of nutritional status. Despite increased fatty acid availability, the mRNA transcript levels of peroxisome proliferator-activated receptor (PPAR)-␣-regulated genes were similar in fed lean and fed obese rat hearts. Fasting increased expression of all PPAR-␣-regulated genes in lean Zucker rat hearts, whereas, in obese Zucker rat hearts, muscle carnitine palmitoyltransferase and medium-chain acyl-CoA dehydrogenase were unaltered with fasting. Rates of oleate oxidation were similar for hearts from fed rats. However, fasting increased rates of oleate oxidation only in hearts from lean rats. Dramatic lipid deposition occurred within cardiomyocytes of obese, but not lean, Zucker rats upon fasting. Cardiac output was significantly depressed in hearts isolated from obese rats compared with lean rats, regardless of nutritional status. Fasting increased cardiac output in hearts of lean rats only. Thus, the heart's inability to increase fatty acid oxidation in proportion to increased fatty acid availability is associated with lipid accumulation and contractile dysfunction of the obese Zucker rat.

Metabolism transfers energy from substrates to ATP. As a "metabolic omnivore," the normal heart adapts to changes in the environment by switching from one substrate to another. We propose that this flexibility is lost in the maladapted, diseased heart. Both adaptation and maladaptation are the results of metabolic signals that regulate transcription of key cardiac regulatory genes. We propose that metabolic remodeling precedes, initiates, and sustains functional and structural remodeling. The process of metabolic remodeling then becomes a target for pharmacological intervention restoring metabolic flexibility and normal contractile function of the heart.

Abstract-Diurnal variation of cardiac function in vivo has been attributed primarily to changes in factors such as sympathetic activity. No study has investigated previously the intrinsic properties of the heart throughout the day. We therefore investigated diurnal variations in metabolic flux and contractile function of the isolated working rat heart and how this related to circadian expression of metabolic genes. Contractile performance, carbohydrate oxidation, and oxygen consumption were greatest in the middle of the night, with little variation in fatty acid oxidation. The expression of all metabolic genes investigated (including regulators of carbohydrate utilization, fatty acid oxidation, and mitochondrial function) showed diurnal variation, with a general peak in the night. In contrast, pressure overloadinduced cardiac hypertrophy completely abolished this diurnal variation of metabolic gene expression. Thus, over the course of the day, the normal heart anticipates, responds, and adapts to physiological alterations within its environment, a trait that is lost by the hypertrophied heart. We speculate that loss of plasticity of the hypertrophied heart may play a role in the subsequent development of contractile dysfunction. Key Words: function Ⅲ gene expression Ⅲ metabolism Ⅲ perfusions Ⅲ rat C ells are able to anticipate, respond, and adapt to fluctuations in their environment. Anticipation is achieved through self-sustained intracellular clocks, providing advantageous priming of the cell in preparation to a given stimulus. 1 The response of any cell is dictated by the level of the stimulus, as well as the sensitivity to that stimulus. The latter is affected by both intracellular (genotype, circadian clocks) and extracellular (eg, neuronal and humoral factors) influences. The resultant adaptation can be either immediate (alterations in preexisting proteins) or prolonged (changes in gene and protein expression) depending on the length of exposure to the stimulus.The heart, not unlike other organs, possesses both internal clocks and the ability to respond to external stimuli, both of which could potentially influence gene expression, metabolism, and function. [2][3][4] It is well known that the onset of heart failure, myocardial infarction, and sudden death is greatest in the early hours of the morning. 5-7 For this reason, several studies have investigated diurnal variation in cardiac function in vivo, in both rodents and humans, and have correlated findings with fluctuations in neurohumoral influences. 5,8 -11 However, to date, no study has either postulated or investigated whether the intrinsic properties of the heart fluctuate during the day, or whether loss of synchronization between the presence of a stimulus (eg, sympathetic activity) and responsiveness of the heart plays a role in the development of contractile dysfunction.We set out to characterize the diurnal variation in contractile function and metabolic flux of the heart in the absence of confounding extracardiac influences by using the isolat...

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