Author + information
- Published online December 3, 2018.
- Heinrich Taegtmeyer, MD, DPhil∗ ()
- Department of Internal Medicine, Division of Cardiology, McGovern Medical School at the University of Texas Health Science Center at Houston, Houston, Texas
- ↵∗Address for correspondence:
Dr. Heinrich Taegtmeyer, Department of Internal Medicine, Division of Cardiology, McGovern Medical School at The University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 1.246, Houston, Texas 77030.
- cardiac triglycerides
- developmental programming
- glucose metabolism
- positron emission tomography
In the heart, as in every other living organ, metabolism is both the source for ATP and the source for the building block of the organ’s cells. At a time when cellular regeneration of the heart is receiving a great deal of attention from the cardiovascular community, the intracellular dynamics of metabolism need to be examined in a new light. Even more importantly, cardiac metabolism can no longer be examined in isolation.
A fitting example in this issue of iJACC is the study by Guzzardi et al. (1). The authors set out to investigate the consequences of maternal overweight for cardiac development in infants and in minipigs (a standard large-animal model in cardiovascular research). The authors found that neonatal changes in the structure of the heart were related to third-trimester body mass index, possibly the result of the heart’s overexposure to glucose. Long-term effects in minipigs were associated with a hyperdynamic left ventricular systolic function, myocardial insulin resistance, and alterations in enzyme activities.
The findings are important for the following reasons. First, the prevalence of cardiovascular disease is now more global than ever, and in the West, we observe a shift from atherothrombotic manifestations toward disease triggered by metabolic stress (2). This means that systemic metabolic dysregulation affects both structure and function of the heart. In other words, metabolism cannot be viewed in isolation.
Second, the prevalence of gestational obesity is high, and being overweight is a risk factor for insulin resistance, high birth weight, and a metabolic form of cardiomyopathy in the offspring. The reasons for this cardiomyopathy of metabolic overload are complex, but they expose several new roles of cardiac metabolism. Conventionally ascribed to cardiac metabolism is the provision of energy for contraction (3). The metabolism of the main energy providing substrates, fatty acids, glucose, and amino acids can be assessed and imaged noninvasively by labeled positronic tracers or tracer analogs, using positron emission tomography (4). However, this is not the goal of the present study. Instead, the investigators provide compelling evidence for crosstalk between metabolic dysregulation in the mother and structural as well as functional abnormalities of the heart in the offspring.
Third, in experimental physiology, parabiosis describes a class of techniques in which 2 living organisms are joined together and develop a single, shared physiological entity (5). Parabiosis is a common strategy in the discovery of hormone action and metabolic regulation, including the discovery of cardiac secreted factors such as metabolic regulators (6). Unlike symbiosis, which is defined as unlike organisms living together to their mutual advantage, parabiosis is a profitable tool in any problem which involves hormones or metabolites. In this respect, the maternal-fetal interaction can be defined as a parabiotic interaction, as the work described here has shown.
Fourth, the results support the concept of long-term regulation of gene expression in a model of maternal-fetal parabiosis. In other words, the offspring’s heart carries a “metabolic memory,” reflecting the metabolic, structural, and functional rewiring of the fetal heart through post-transcriptional modifications of processes and/or transcriptional modifications of DNA and RNA (7), in other words, the interactions of genes with their environment from the molecular basis for profound structural and functional changes of the heart. The concept of epigenetic regulation has received recent attention in the developing and failing heart (8). This is, however, not a new concept. Writing about genetics assimilation, Waddington proposed as early as 1942 that if selection was practiced for the readiness of a strain of organisms to respond to an environmental stimulus in a particular manner, genotypes might eventually be produced which would develop into the favored phenotype, even in the absence of the environmental stimulus. What was initially acquired has become genetically assimilated (9). Today, epigenetics has evolved from a collection of phenomena to a defined molecular entity (10). We recognize 4 forms of epigenetic mechanisms, all of which are related to the intermediary metabolism of energy-providing substrates. These mechanisms include DNA methylation, covalent histone modifications (e.g., acetylation, trimethylation), noncoding RNA-mediated pathways, and ATP-dependent chromatin remodeling (10). In addition, post-translational modifications of proteins other than histones are increasingly recognized as key mediators of many cardiovascular pathophysiological processes (11,12).
In summary, the work by Guzzardi et al. (1) reveals that maternal-fetal parabiosis combined with maternal metabolic stress results in structural and functional remodeling of the fetal heart. This remodeling continues and is sustained post-partum. Collectively, these observations expose unexpected and still incompletely understood mechanisms of cardiac growth and metabolism. This study also highlights the power of contemporary cardiac imaging and molecular techniques as tools with which to generate new and exciting hypotheses.
The author thanks Dolly Fernandez, MA, for expert editorial assistance and Ramesha Papanna, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern Medical School at UTHealth Houston, for helpful discussions.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of iJACC or the American College of Cardiology.
Dr. Taegtmeyer is supported by U.S. National Institutes of Health/National Heart, Lung, and Blood Institute grant R01-HL-61483-14.
- 2018 American College of Cardiology Foundation
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