Reply to Skalidis et al.

Letter to the EditorIntegrative Cardiovascular Physiology and PathophysiologyReply to Skalidis et al.Jussara M. do Carmo, Ana C. M. Omoto, John E. Hall, Xuemei Dai, Emily C. Ladnier, Marilia C. Mouro, Odecio E. S. Tosta, Zhen Wang, Xuan Li, and Alexandre A. da SilvaJussara M. do CarmoDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, Ana C. M. OmotoDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, John E. HallDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, Xuemei DaiDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, Emily C. LadnierDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, Marilia C. MouroCentro Universitário Barão de Mauá, Ribeirão Preto, Brazil, Odecio E. S. TostaCentro Universitário Barão de Mauá, Ribeirão Preto, Brazil, Zhen WangDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, Xuan LiDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United States, and Alexandre A. da SilvaDepartment of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, Mississippi, United StatesPublished Online:02 Oct 2025https://doi.org/10.1152/ajpheart.00425.2025MoreSections PDF (276 KB) ToolsExport citationAdd to favoritesTrack citations ShareShare onFacebookXLinkedInWeChat reply: We are grateful to Dr. Skalidis et al. (1) for their thoughtful and insightful comments regarding our recent paper on the impact of parental obesity on post-myocardial infarction (MI) outcomes in nonobese offspring (2). They highlight three important areas where there are still gaps in our understanding that deserve further investigation. We agree with their comments and are currently addressing some of these gaps with additional studies.CONNEXIN 43 AND SEX-SPECIFIC POST-MI REMODELING We agree that the selective reduction in connexin 43 (Cx43) expression in male offspring at baseline is an intriguing observation. Although our study did not directly assess arrhythmias, the potential link between reduced Cx43 and increased susceptibility to post-MI arrhythmogenesis, particularly in a sex-specific manner, is plausible. Future studies using telemetry and programmed electrical stimulation may help clarify whether altered gap junction protein expression contributes to the increased mortality we observed in nonobese offspring of obese parents (HFD-Offs), particularly in males.MITOCHONDRIAL DYSFUNCTION AND CARDIAC METABOLIC FLEXIBILITY Dr. Skalidis et al.'s (1) point regarding mitochondrial metabolic flexibility is well-taken. Our findings of impaired carbohydrate-supported oxidative phosphorylation and increased reactive oxygen species (ROS) production in both sexes suggest a preexisting metabolic vulnerability. Investigating whether targeted interventions, such as exercise training (3), pharmacological agents (4), or dietary modifications (5), may improve mitochondrial efficiency and thereby attenuate susceptibility to MI-induced injury is a promising avenue that we are actively exploring in ongoing studies.PREEXISTING DIASTOLIC DYSFUNCTION AND LONG-TERM REMODELING We appreciate the interest in our finding of early diastolic dysfunction in HFD-Offs (6) and agree that chronic follow-up models could provide valuable insights into the progression of cardiac remodeling. Although pulmonary congestion markers were not elevated at the time points evaluated, more severe maladaptive cardiac remodeling may occur over longer periods of time. Future longitudinal studies incorporating pressure-volume loop analyses and serial imaging may help to address this question. We thank the authors for their kind remarks. Their questions highlight broader implications of our findings and underscore the need for continued exploration of the mechanisms underlying developmental programming of cardiovascular disease.GRANTS The authors were supported by grants from the National Institute of General Medical Sciences (P20 GM104357, P30 GM149404, and U54 GM115428), National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK121411), and the National Heart, Lung, and Blood Institute (R01 HL163076).DISCLAIMERS The content and any opinions expressed in this article are those of the authors and do not necessarily represent the views of the American Physiological Society.DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONS J.M.d.C. drafted manuscript; J.E.H., Z.W., X.L., and A.A.d.S. edited and revised manuscript; X.D., E.C.L., M.C.M., O.E.S.T., Z.W., X.L., and A.A.d.S. approved final version of manuscript.REFERENCES1. Skalidis I, Ktenopoulos N, Vlachakis PK, Antiochos P. Exploring the influence of parental obesity on myocardial infarction outcomes in offspring. Am J Physiol Heart Circ Physiol 329: H311, 2025. doi:10.1152/ajpheart.00386.2025. Link | Web of Science | Google Scholar2. do Carmo JM, Omoto ACM, Hall JE, Dai X, Ladnier EC, Mouro MC, Tosta OES, Wang Z, Li X, da Silva AA. Parental obesity predisposes male and female offspring to exacerbated cardiac dysfunction and increased mortality after myocardial infarction. Am J Physiol Heart Circ Physiol 328: H1039–H1050, 2025. doi:10.1152/ajpheart.00827.2024. Link | Web of Science | Google Scholar3. Kristiansen J, Sjúrðarson T, Grove EL, Rasmussen J, Kristensen SD, Hvas AM, Mohr M. Feasibility and impact of whole-body high-intensity interval training in patients with stable coronary artery disease: a randomised controlled trial. Sci Rep 12: 17295, 2022. doi:10.1038/s41598-022-21655-w. Crossref | PubMed | Web of Science | Google Scholar4. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation 136: 1643–1658, 2017. doi:10.1161/CIRCULATIONAHA.117.030012. Crossref | PubMed | Web of Science | Google Scholar5. Jaca A, Durão S, Harbron J. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. S Afr Med J 110: 1158–1159, 2020. doi:10.7196/SAMJ.2020.v110i12.14730. Crossref | PubMed | Web of Science | Google Scholar6. do Carmo JM, Omoto ACM, Dai X, Moak SP, Mega GS, Li X, Wang Z, Mouton AJ, Hall JE, da Silva AA. Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency, and diastolic function early in life. Am J Physiol Heart Circ Physiol 321: H485–H495, 2021. doi:10.1152/ajpheart.00176.2021. Link | Web of Science | Google ScholarAUTHOR NOTESCorrespondence: J. M. do Carmo (jdocarmo@umc.edu). Previous Back to Top Download PDF FiguresReferencesRelatedInformation More from this issue > Volume 329Issue 4October 2025Pages H989-H990 Crossmark Copyright & PermissionsCopyright © 2025 The Authors.Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society.https://doi.org/10.1152/ajpheart.00425.2025PubMed41036821History Received 13 June 2025 Accepted 17 June 2025 Published online 2 October 2025 Published in print 1 October 2025 Keywordsconnexin 43mitochondrial functionmortality ratemyocardial infarctionparental obesity Metrics