Coordinated Metabolic Responses Facilitate Cardiac Growth in Pregnancy and Exercise

Current Heart Failure Reports https://doi.org/10.1007/s11897-023-00622-0 Coordinated Metabolic Responses Facilitate Cardiac Growth in Pregnancy and Exercise Emily B. Schulman‑Geltzer1 · Helen E. Collins1 · Bradford G. Hill1 · Kyle L. Fulghum1,2 Accepted: 19 July 2023 © The Author(s) 2023 Abstract Purpose of Review Pregnancy and exercise are systemic stressors that promote physiological growth of the heart in response to repetitive volume overload and maintenance of cardiac output. This type of remodeling is distinct from pathological hypertrophy and involves different metabolic mechanisms that facilitate growth; however, it remains unclear how metabolic changes in the heart facilitate growth and if these processes are similar in both pregnancy- and exercise-induced cardiac growth. Recent Findings The ability of the heart to metabolize a myriad of substrates balances cardiac demands for energy provision and anabolism. During pregnancy, coordination of hormonal status with cardiac reductions in glucose oxidation appears important for physiological growth. During exercise, a reduction in cardiac glucose oxidation also appears important for physiological growth, which could facilitate shuttling of glucose-derived carbons into biosynthetic pathways for growth. Understanding the metabolic underpinnings of physiological cardiac growth could provide insight to optimize cardiovascular health and prevent deleterious remodeling, such as that which occurs from postpartum cardiomyopathy and heart failure. Summary This short review highlights the metabolic mechanisms known to facilitate pregnancy-induced and exerciseinduced cardiac growth, both of which require changes in cardiac glucose metabolism for the promotion of growth. In addition, we mention important similarities and differences of physiological cardiac growth in these models as well as discuss current limitations in our understanding of metabolic changes that facilitate growth. Keywords Physiological cardiac growth · Pregnancy · Exercise · Metabolism · Heart Introduction Repetitive or sustained increases in cardiac workload promote hypertrophy of the adult heart, which begins as a compensatory growth process to reduce overall ventricular wall stress and maintain cardiac output. Interestingly, cardiac hypertrophy occurs in response to both pathological (e.g., hypertension) and physiological (e.g., pregnancy, exercise) stressors, with notable distinctions between the cellular and metabolic processes underlying the response to each type of stressor. Although there has been remarkable progress in the understanding of pathological cardiac hypertrophy and * Kyle L. Fulghum 1 2 Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA the stimuli which lead to harmful remodeling of the heart, much less is known regarding the mechanisms leading to physiological growth of the heart. Both pregnancy and exercise training increase cardiac workload and drive physiological growth of the heart, which is a reversible phenomenon after parturition or prolonged cessation from exercise, respectively [1, 2]. We understand that these physiological stressors present differently in the heart than pathological stress, but recent studies support that not all physiological growth relies upon the same metabolic mechanisms for growth. By understanding the metabolic mechanisms underlying pregnancy- and exercise-induced cardiac growth, strategies can be developed to optimize cardiovascular health in response to these events and prevent adverse remodeling. In this review, we address the following questions: 1. What is physiological cardiac growth? 2. What are the metabolic determinants of pregnancyinduced cardiac growth? 13 Vol.:(0123456789) Current Heart Failure Reports 3. What are the metabolic determinants of exercise-induced cardiac growth? 4. What causes adverse cardiac events associated with pregnancy and exercise? What Is Physiological Cardiac Growth? Cardiac growth is simply defined as increased mass of the heart, and this typically occurs in response to elevated functional demand. Physiological growth is distinct from pathological hypertrophy in that physiological growth is associated with normal or enhanced cardiac function, increased capillary density, and no induction of the fetal gene program [1, 3]. Additionally, there are distinct metabolic events that distinguish physiological cardiac growth from pathological hypertrophy. One important distinction is that physiological cardiac growth results from intermittent or transient stress and is known to be reversible [2]. The heart is comprised of many cell types. While cardiomyocytes account for about one-third of the cells in the heart, they contribute to at least 70% of cardiac mass [4, 5]. In response to repetitive stimuli, cardiomyocyte growth is facilitated by the addition of sarcomeres, the contractile units of the heart, which form myofibrils and increase the length or width of cardiomyocytes. Parallel addition of sarcomeres increases cardiomyocyte width and leads to concentric cardiac growth—this form of growth is often associated with pressure overload from pathological stimuli such as sustained hypertension or from physiological stimuli such as weightlifting exercises. Serial addition of sarcomeres increases cardiomyocyte length and leads to eccentric cardiac growth—this form of growth is often associated with volume overload from pathological stimuli such as valvular disease or physiological stimuli such as pregnancy or aerobic exercise (reviewed in [6–8]). The focus of this review is on the metabolic mechanisms contributing to eccentric cardiac growth in response to pregnancy and aerobic exercise. Several molecular events initiate and facilitate cardiac growth. Some studies have shown the requirement of signaling cascades mediated by insulin-like growth factor 1 (IGF1) [9] and protein kinase B (AKT1) [10], while others imply the necessity of increased expression of genes such as Cbp/ P300 interacting transactivator with GluAsp rich carboxyterminal domain 4 (CITED4) [11] or microRNAs such as miR-222 [12] for physiological cardiac growth. Moreover, recent work highlights the contributions of long noncoding RNAs [13], calcium signaling [14], and lymphangiogenesis [15] in the progression of physiological cardiac growth. There are also mechano-sensing mechanisms and stretchsensitive ion channels that are thought to coordinate overload of the heart with increased synthesis of proteins [16, 17] and could also be associated with synthesis of membrane 13 components or nucleotides that are important for growing cells. Consistent with the requirement of increased macromolecule synthesis for growth, there are important changes in cardiac metabolism that are unique to physiological cardiac gr (...truncated)