The mechanisms responsible for elevated exercise systolic blood pressure (SBP) in young adults remain unclear but may be influenced by cardiorespiratory fitness. The present study examined the contributions of cardiac ou...The mechanisms responsible for elevated exercise systolic blood pressure (SBP) in young adults remain unclear but may be influenced by cardiorespiratory fitness. The present study examined the contributions of cardiac output (Q̇) and total peripheral resistance (TPR) to peak SBP and peak SBP normalized per metabolic equivalent (ΔSBP/MET). Fifty-one normotensive adults (28 females) underwent a graded maximal cycling test with brachial blood pressure measured using automated auscultation (Tango M2 Monitor). Q̇ was measured using the nitrous oxide rebreathe technique (Innocor; COSMED). Participants were analyzed across the whole cohort and compared between those with and without an exaggerated SBP (males ≥ 210 mmHg; females ≥ 190 mmHg) or ΔSBP/MET (≥9 mmHg/MET). Higher peak SBP was related to higher peak exercise Q̇ ( = 0.53, < 0.001) but not TPR ( = -0.15, = 0.29). In contrast, higher SBP/MET tended to be related to higher peak exercise TPR ( = 0.26, = 0.067), but not Q̇ ( = 0.07, = 0.65). Participants with an exaggerated peak SBP ( = 20) had larger increases in Q̇ during exercise (Δ+12.7 vs. Δ+10.2 L/min, = 0.002) and greater relative peak oxygen uptake (V̇o) ( = 0.03), whereas the reduction in TPR did not differ (Δ-8.62 vs. Δ-8.85 mmHg/L/min = 0.23). Participants with an exaggerated ΔSBP/MET ( = 13) had an attenuated reduction in TPR during exercise (Δ-6.47 vs. Δ-9.24 mmHg/L/min, = 0.03), whereas the rise in Q̇ did not differ (Δ+10.4 vs. Δ+11.6 L/min, = 0.16). In normotensive young adults, a higher peak SBP during cycling exercise is associated with a larger Q̇, likely linked to higher aerobic fitness, whereas a higher ΔSBP/MET is related to attenuated vasodilation during exercise and reduced aerobic fitness. Whether interindividual differences in exercise blood pressure (BP) are mediated by changes in cardiac output or total peripheral resistance remain unclear. We demonstrate in healthy normotensive adults that higher peak exercise systolic BP during cycling is related to a larger cardiac output, whereas the rise in systolic BP per metabolic equivalent is related to a diminished fall in total peripheral resistance. Sex also appears to modulate this relation in those with an exaggerated exercise BP.
Protein kinase C (PKC) targeted thin filament cardiac troponin I (cTnI) Ser43/45 phosphorylation (p-S43/45) increases during heart failure (HF). Chronic cTnI p-S43/45 causes contractile dysfunction in cardiac myocytes, b...Protein kinase C (PKC) targeted thin filament cardiac troponin I (cTnI) Ser43/45 phosphorylation (p-S43/45) increases during heart failure (HF). Chronic cTnI p-S43/45 causes contractile dysfunction in cardiac myocytes, but the in vivo impact is less clear. To investigate the in vivo impact of this cluster, three lines of transgenic mice were generated with high (HE-), moderate (ME-), and low (LE-) phosphomimetic cTnIS43/45D (SD) replacement of endogenous cTnI within sarcomere thin filament. Each mouse line developed chronic in vivo and/or cellular contractile dysfunction, which initiated structural remodeling and a progressive deterioration in cardiac function. Higher cTnISD replacement levels accelerated the rate of deterioration and progression to end-stage heart failure. In further work, cTnISD initiated sarcomere communication to produce early alterations in mitochondria before the progressive deterioration in cardiac performance. Specifically, early reductions developed in mitochondrial/nuclear DNA, mitochondrial master regulator gene expression, electron transport proteins, and antioxidants along with increased mitochondria-related oxidative stress before extensive remodeling in cTnISD mice. In addition, cTnISD mice developed early differences in mitochondrial ultrastructure and evidence favoring fusion over fission compared with nontransgenic (Ntg) littermates. A second-generation peptide derived from elamipretide improved survival and slowed the progression of remodeling and contractile dysfunction. Overall, the results demonstrate that chronic cTnISD causes cardiac dysfunction and initiates early mitochondrial responses that serve as important drivers of progressive deterioration in cardiac performance to end-stage HF. Elevated cardiac troponin I (cTnI) Ser43/45 phosphorylation accompanies human heart failure. A mouse model with phosphomimetic substitutions shows that chronic sarcomere replacement with cTnI Ser43/45Asp causes cardiac dysfunction and initiates early downstream changes in mitochondria before the onset of progressive remodeling and progressive deterioration in cardiac performance. These early alterations include differences in mitochondrial architecture and function and oxidative stress. Early mitochondrial targeting improves survival and cardiac function.
Am J Physiol Heart Circ Physiol
· 2026 Apr · PMID 41705944
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Heart failure is a major cause of cardiac mortality in the United States and globally. It occurs when the heart cannot pump enough blood to meet the body's needs, often due to stiffness of the heart muscle or dysfunction...Heart failure is a major cause of cardiac mortality in the United States and globally. It occurs when the heart cannot pump enough blood to meet the body's needs, often due to stiffness of the heart muscle or dysfunction in its ability to contract. Cardiac remodeling in heart failure is an adaptive response to this impaired function. Among the pathways involved in this adaptation, the sympathetic nervous system, specifically, β-adrenergic receptors (β-ARs), plays a central role. Stimulation of β-ARs enhances cardiac contractility by activating protein kinase A (PKA), a key mediator in downstream signaling that regulates excitation-contraction coupling (ECC) through ECC-related proteins. A-kinase-anchoring proteins (AKAPs) act as scaffolds for PKA, organizing compartmentalized signaling events. Recent studies have highlighted the role of AKAP12 in recruiting phosphodiesterase 8 (PDE8) following β-ARs activation. PDE8 is a cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase that hydrolyzes cAMP, thereby limiting the inotropic responses mediated by β-ARs. Although other PDE isoforms (PDE3, PDE4, and PDE5) have been extensively studied and targeted for therapy in heart failure, PDE8 has received relatively little attention. This review discusses the emerging roles of PDE8 across various physiological systems, with a particular focus on the cardiovascular system and its potential as a therapeutic target.
Periostin (Postn) is a matricellular protein that plays a crucial role in cardiac fibrosis following myocardial infarction (MI). However, the role of Postn in infarct healing to date has been derived from experiments con...Periostin (Postn) is a matricellular protein that plays a crucial role in cardiac fibrosis following myocardial infarction (MI). However, the role of Postn in infarct healing to date has been derived from experiments conducted exclusively on male animals, leaving its sex-specific functions unaddressed. Thus, we investigated the sex-specific role of Postn in acute wound healing and extracellular matrix (ECM) remodeling post-MI using a Postn knockout (KO) mouse model. Survival analysis revealed increased mortality in male Postn KO mice compared with that of females post-MI. qPCR analysis of the infarct scar showed that Postn was required for the increased expression of structural collagen ( and ), collagen fibrillogenesis (), collagen stabilization (), collagen synthesis (), and alpha-smooth muscle actin () genes in males, whereas in females, the regulation of these genes occurred independently of Postn post-MI. We note that fibromodulin protein levels were higher in female Postn KO mice than in males, suggesting a putative protective role. Transcriptomic analysis revealed distinct gene expression patterns between sexes and phenotypes, with male Postn KO infarct scars showing the greatest dysregulation of genes, characterized by increased expression of ECM-related genes and suppressed mitochondrial-related gene expression, whereas female Postn KO infarct scars exhibited increased mitochondrial-related gene expression and reduced expression of fibrosis-associated genes. These findings emphasize sex as a biological variable in Postn actions in heart and highlight distinct molecular mechanisms underlying male and female infarct healing. We determined that cardiac wound healing following MI is periostin (Postn) dependent in male mice but Postn independent in female mice. To date, previous Postn knockout (KO) studies have exclusively used male animals. The current experimental design includes both sexes and reveals that the underlying mechanism of action to be sex dependent. Specifically, changes in the expression of collagen synthesis and cross-linking genes in the infarct scar are dependent on Postn expression in males only.
Dempster T, Corker A, Vu K
… +8 more, Troncoso M, Bradley N, Hazzard A, Milligan K, Macaulay B, Dasgupta S, Li M, DeLeon-Pennell KY
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41693664
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Vericiguat (Merck, marketed as Verquvo) is a soluble guanylate cyclase stimulator that is Food and Drug Administration-approved for use in heart failure patients with reduced or mildly reduced ejection fraction (HFrEF an...Vericiguat (Merck, marketed as Verquvo) is a soluble guanylate cyclase stimulator that is Food and Drug Administration-approved for use in heart failure patients with reduced or mildly reduced ejection fraction (HFrEF and HFmrEF) to decrease heart failure hospitalization and cardiovascular mortality. We hypothesized that earlier administration of vericiguat post-myocardial infarction (MI) would reduce the workload of the viable cardiomyocytes, leading to an earlier switch toward anti-inflammatory macrophages and reduced adverse remodeling. Male and female C57BL/6J mice ( = 6/sex/group) underwent permanent occlusion of the left anterior descending coronary artery, followed by implantation of a subcutaneous osmotic minipump (vericiguat or saline) 24 h later. Echocardiography and histological assessment were performed for cardiomyocyte size (wheat germ agglutinin), vascularity ( lectin I), and collagen area fraction (Picrosirius red). Macrophages were isolated from the infarct at post-MI and conditioned media was collected. Although cardiomyocyte size did not significantly differ between treatment groups, female drug-treated mice trended toward smaller cardiomyocytes in the border zone compared with males. Macrophage numbers were not affected, however, proteomic analysis demonstrated a proangiogenic phenotype with vericiguat. In vitro stimulation of endothelial cells with the macrophage-conditioned media from female drug-treated mice demonstrated a more organized and robust tubule network. Drug-treated females trended toward greater collagen in the infarct at post-MI, whereas drug-treated males had decreased vessel density in the remote area compared with controls. Despite the molecular changes observed, no significant differences in cardiac function were observed at post-MI. Our data demonstrate that acute administration of vericiguat post-MI stimulates macrophages toward a proangiogenic phenotype that was more exaggerated in females. Acute administration of Vericiguat after myocardial infarction alters macrophage phenotype but not cell numbers. Macrophages from Vericiguat-treated mice led to more robust endothelial cell tubule formation. Acute administration of Vericiguat stimulates macrophages toward a proangiogenic phenotype that was more exaggerated in females.
Dzierlega K, Soliman AM, Chen H
… +13 more, Vu J, Parker D, Roberts B, Wagner M, Akter A, Hassane M, Kilic T, Wong J, Akbari M, Elhenawy W, Oudit GY, Tsai S, Clemente-Casares X
Doxorubicin (DOX), an effective chemotherapy, exhibits a narrow therapeutic index and detrimental adverse effects involving muscle atrophy and dysfunction. The precise mechanisms underlying DOX-mediated myopathy are not...Doxorubicin (DOX), an effective chemotherapy, exhibits a narrow therapeutic index and detrimental adverse effects involving muscle atrophy and dysfunction. The precise mechanisms underlying DOX-mediated myopathy are not fully understood. Although the contribution of inflammation is well appreciated, the mechanisms by which inflammatory cells mediate muscular pathologies remain to be identified. In this study, we characterized the dynamics of neutrophil responses during DOX treatment. DOX administration induced expansion of neutrophils in the heart, spleen, and muscle of mice. Depletion of these cells with anti-Ly6G antibodies ameliorated DOX-mediated cardioskeletal atrophy and dysfunction, including ejection fraction, stroke volume, and cardiac output. DOX-expanded neutrophils demonstrated constitutive production of reactive oxygen species (ROS), and elimination of the ROS-producing enzyme NOX2, but not myeloperoxidase, prevented DOX-induced cardioskeletal myopathy. Our findings underscore the pivotal role of neutrophil-derived ROS in driving DOX-induced cardiotoxicity and skeletal myopathy. DOX is a commonly used cancer treatment, but its severe side effects, limit its clinical use. This research highlights neutrophil-derived reactive oxygen species (ROS) production through the NOX2 complex as a key contributor to this myopathy, offering a potential therapeutic to protect against cardiotoxicity without compromising DOX's anticancer benefits. These insights open new avenues for safer, more effective cancer treatments.
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41661147
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In patients with aortic valve stenosis (AS), the pathophysiological abnormalities involved in the transition to heart failure are unclear. As chronic heart failure progresses, the ratio between myocardial stroke work and...In patients with aortic valve stenosis (AS), the pathophysiological abnormalities involved in the transition to heart failure are unclear. As chronic heart failure progresses, the ratio between myocardial stroke work and oxygen consumption, that is, myocardial external efficiency (MEE), steadily deteriorates. However, in patients with AS, it is unknown whether changes in MEE are involved in disease progression. We investigated changes in MEE and whether MEE was associated with long-term prognosis in patients with AS. Ten healthy controls and 38 patients with moderate-to-severe AS and preserved left ventricular ejection fraction ≥ 50% were included in the study. To evaluate MEE, we used serial C-acetate positron emission tomography, cardiovascular magnetic resonance imaging, and echocardiography, with a median follow-up period of 2.8 yr. Furthermore, we conducted a long-term follow-up for a median of 5.2 yr to detect cardiac events and relate them to MEE. In patients with AS, MEE increased during follow-up from 25.2% [95% confidence interval (CI): 24.0-26.5%] to 29.5% (95% CI: 27.3-31.8%; = 0.001) and was higher than healthy volunteers, 19.9% (18.1-21.8; < 0.001). Patients who experienced a cardiac event during long-term follow-up ( = 24, 63%) had higher baseline MEE, 26.5% (95% CI: 24.6-28.4%), than event-free patients, 23.3% (95% CI: 22.2-24.3%; = 0.004). In asymptomatic patients with AS, MEE increased over time and high baseline MEE predicted a poor prognosis. Thus, the myocardium displayed an inherent capacity to improve the coupling between oxidative metabolism and contractile function in response to pressure overload. Patients with aortic valve stenosis can improve myocardial efficiency-delaying heart failure.
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41651448
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Electronic cigarette adoption has transformed nicotine delivery patterns globally, with 15% prevalence among youth aged 13-15 years. The cardiovascular implications of combined electronic cigarette and combustible tobacc...Electronic cigarette adoption has transformed nicotine delivery patterns globally, with 15% prevalence among youth aged 13-15 years. The cardiovascular implications of combined electronic cigarette and combustible tobacco use remain incompletely characterized. We examined the associations of combined smoking and/or vaping vs. no nicotine exposure with elevated blood pressure (BP) and hypertension prevalence using nationally representative United States data from 2021 to 2023. Data from the US National Health and Nutrition Examination Survey (NHANES) 2021-2023 cycle, which included 6,262 individuals aged ≥12 years old with complete smoking/vaping status: any smoking and/or vaping ( = 1,190) vs. no smoking or vaping ( = 5,072), were used. Elevated BP was classified as ≥120/70 mmHg and hypertension as ≥140/90 mmHg, and a history of smoking and/or vaping was collected with a questionnaire. Multivariable logistic regression and mediation path analysis were conducted. Among 6,262 participants (mean age 42.2 years [SD 21], 63.3% female), smokers/vapers had significantly higher prevalence of elevated BP compared with nonsmokers/nonvapers (54.4% vs. 39.2%, < 0.001) and hypertension (15.4% vs. 11.8%, < 0.001). In fully adjusted models, smoking/vaping was associated with increased odds of elevated BP [adjusted odds ratio (aOR): 1.34, 95% CI: 1.12-1.60, = 0.001] and hypertension (aOR: 1.46, 95% CI: 1.06-1.99, < 0.001). Smoking/vaping was associated with a 1.05 mmHg higher diastolic BP ( < 0.001) but had no association with systolic BP. Mediation analysis revealed that higher total cholesterol partly mediated (6.7% mediation effect) the relationship between smoking/vaping and diastolic BP. Combined smoking and/or vaping exposure was associated with higher odds of elevated BP and hypertension compared to no nicotine use. The selective diastolic BP elevation suggests an increased peripheral vascular resistance as the primary mechanism; however, longitudinal studies examining these direct vascular mechanisms are warranted. In this cross-sectional analysis of 6,262 multiracial US participants with diverse age groups, tobacco smoking and vaping were significantly associated with elevated blood pressure and hypertension. Smoking and vaping were predominantly associated with diastolic blood pressure, an association that was partly mediated by higher cholesterol levels.
There are numerous differences in arrhythmia propensity and cardiac electrophysiology between women and men. One proposed reason is differences in the autonomic nervous system (ANS) influence. We therefore compared the s...There are numerous differences in arrhythmia propensity and cardiac electrophysiology between women and men. One proposed reason is differences in the autonomic nervous system (ANS) influence. We therefore compared the sympathetic and parasympathetic influence (sympathovagal balance) on the sinoatrial node (SAN) at rest in healthy young women ( = 15) and men ( = 15) with a mean age of 24 yr. Pharmacological blockade of the ANS influence on the SAN was induced by sequential bolus injections of atropine (0.04 mg/kg body wt) and propranolol (0.2 mg/kg body wt) during continuous electrocardiographic recordings. The heart rate (HR) at baseline, after atropine, and the intrinsic heart rate (IHR) after adding propranolol were used to calculate the accelerator "," which is ≥1.00, and decelerator "," which is ≤1.00 according to the Rosenblueth and Simeone concept and equation: HR = × × IHR. On the group level, IHR was median [interquartile range (IQR)] 93.3 (88.4-98.8) beats/min, was 1.16 (1.13-1.22), was 0.58 (0.55-0.64), and the sympathovagal balance × was 0.70 (0.65-0.76), confirming dominant parasympathetic influence at rest. There were no significant differences between women and men in any of these measures, and thus no fundamental difference in the ANS influence on the main impulse generator of the heart at rest. This result contrasts with the significant differences in electrophysiological measures at rest and their responses to stress tests, as well as to the differences in arrhythmia propensity between women and men on both the atrial and ventricular level of the heart. Differences in the autonomic nervous system (ANS) activity is one potential explanation for differences in cardiac electrophysiology between women and men. We therefore compared the ANS influence on the sinoatrial node (SAN; main cardiac impulse generator), between women and men at rest. Atropine and propranolol were used to sequentially block the two ANS limbs. There were no statistically significant differences between women and men in the ANS influence on the SAN at rest.
Rees J, Winkler A, Huettemeister J
… +17 more, Stengel L, Spangler P, Ramesh G, Kamp J, Funk-Hilsdorf TC, Michalick L, Herm AL, Deissler PM, Melnikov A, Höpfner M, Hohendanner F, Crocini C, Zgierski-Johnston C, Pabel S, Nitzsche B, Grune J, Hegemann N
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41643643
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Cardiac glycosides (CGs) such as ouabain exert positive inotropic effects by inhibiting the Na-K-ATPase. CGs' wide spread use is limited by CGs' narrow therapeutic window. Mis- or overdosing with CGs may cause cardiac ar...Cardiac glycosides (CGs) such as ouabain exert positive inotropic effects by inhibiting the Na-K-ATPase. CGs' wide spread use is limited by CGs' narrow therapeutic window. Mis- or overdosing with CGs may cause cardiac arrhythmias, resulting from electrolyte disturbances. To study the ethically challenging topic of CG overdosing, we here optimized the in ovo platform to test whether treatment with the selective ouabain antagonist rostafuroxin prevents CG-mediated electrophysiological derangements and arrhythmia by restoring electrolyte homeostasis. We used incubated chicken eggs (iCEs), a 3 R-compliant model, for which we established electrocardiograms (ECGs). ECGs were recorded under ) baseline conditions, ) after treatment with ouabain, and ) after cotreatment with rostafuroxin. Underlying mechanisms of ouabain and rostafuroxin effects were studied using blood gas analysis and fluorescence microscopy. Isolated murine and human cardiomyocytes served as an independent model to confirm in ovo results. Ouabain treatment resulted in increased heart rate variability (HRV), transient sinus arrest, and atrio-ventricular dyssynchrony, accompanied by plasma hyperkalemia and cardiomyocyte Na overload. Cotreatment of ouabain and rostafuroxin led to reduced HRV and ameliorated the frequency and duration of transient sinus arrest, whereas plasma K levels remained unchanged. In isolated cardiomyocytes, ouabain treatment induced intracellular Na overload, which was abolished by additional rostafuroxin treatment. Our work demonstrates the in ovo platform and corresponding readouts as a suitable tool to study cardiac electrophysiology in a 3 R-compliant manner. We found that rostafuroxin treatment ameliorated ouabain-induced electrophysiological disturbances, suggesting rostafuroxin as a potential therapeutic intervention for ouabain mis- or overdosing. This study evaluates rostafuroxin, a selective ouabain inhibitor, for its potential to antagonize electrophysiological derangements in ouabain overdosing. Methodologically, the study uses the iCE model, previously introduced as a suitable 3 R-compliant cardiovascular research platform. We developed and validated a comprehensive electrophysiological workflow in iCEs to perform our investigations. Ouabain increased heart rate variability, induced arrhythmia and electrolyte imbalances in iCEs, whereas rostafuroxin largely protected them from these effects.
Eickelmann C, Gedik N, Lieder HR
… +5 more, Kollipara L, Sickmann A, Sturek M, Heusch G, Kleinbongard P
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41638602
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Ossabaw minipigs differ from other (mini)pig strains by their genetic predisposition to develop full metabolic syndrome and their nonresponsiveness to cardioprotective interventions, even before developing the diseased p...Ossabaw minipigs differ from other (mini)pig strains by their genetic predisposition to develop full metabolic syndrome and their nonresponsiveness to cardioprotective interventions, even before developing the diseased phenotype. Previous DNA sequencing data revealed differences in a cluster of mitochondrial protein-coding genes between Ossabaw and Göttingen minipigs-a large animal model without such a genetic predisposition and a responsiveness to cardioprotection. Alterations in mitochondrial protein composition affect mitochondrial function, and mitochondria play a crucial role in the development of metabolic syndrome and for cardioprotection. Therefore, we aimed to compare the cardiac mitochondrial proteome between lean Ossabaw minipigs with a healthy phenotype and Göttingen minipigs to gain initial insights into potential differences in mitochondrial protein composition and function. Cardiac mitochondria (left ventricular tissue) of both minipig strains (male/female pigs) were isolated, and the proteome was analyzed by liquid chromatography-tandem mass spectrometry. An unbiased, nonhypothesis-driven proteome analysis identified 97% overlap in the proteome. Among the 3% of differentially expressed proteins, 19 were related to mitochondrial metabolism, 8 to transcription and translation, 3 to small molecule transport, 2 to oxidative phosphorylation, and 1 to dynamics and surveillance. These small differences in protein composition were associated with an altered mitochondrial energy turnover-ATP production was reduced by 49% in Ossabaw compared with Göttingen minipig mitochondria. This proteome analysis provides a broader basis to understand how genetic alterations result in changes of the mitochondrial proteome and function, which might be relevant for the development and progression of metabolic syndrome and/or the primordial nonresponsiveness to cardioprotection in Ossabaw minipigs. Our comprehensive cardiac mitochondrial proteome of Ossabaw and Göttingen minipigs is a valuable resource for cardiac biomedical research. Moreover, our proteome analysis provides a broader basis for understanding how genetic alterations result in changes of the mitochondrial proteome and support a mechanistic link between subtle, strain-specific mitochondrial proteomic signatures and altered mitochondrial energy turnover. These changes may be relevant for the development and progression of metabolic syndrome and/or primordial nonresponsiveness to cardioprotection in Ossabaw minipigs.
Costa PCTD, Magnani M, Martins VJB
… +10 more, Moraes RCS, Silva-Luis CC, Rodrigues JMA, Cabral L, Noronha MF, Vitalis O, Chikh K, Godet M, Vidal H, de Brito Alves JL
Am J Physiol Heart Circ Physiol
· 2026 Feb · PMID 41638193
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Childhood obesity is associated with gut microbiome dysbiosis, inflammation, and early cardiac autonomic dysfunction. Lifestyle interventions integrating physical activity and dietary modification represent a primary str...Childhood obesity is associated with gut microbiome dysbiosis, inflammation, and early cardiac autonomic dysfunction. Lifestyle interventions integrating physical activity and dietary modification represent a primary strategy to mitigate cardiometabolic risk during childhood. This longitudinal intervention study investigated cardiovascular, autonomic, inflammatory, metabolic, and gut microbiome-related outcomes before and after a 4-month program combining structured physical exercise with food and nutrition education in 51 children with obesity aged 7 to 10 years. The intervention promoted favorable dietary changes, including reduced intake of saturated fatty acids (SFA), sodium, and total energy. These modifications were accompanied by a reduction in body fat percentage and systemic inflammation, evidenced by lower circulating interleukin-17A (IL-17A) and tumor necrosis factor-alpha (TNF-α) levels. Improvements in biochemical profiles were observed, including increased albumin and high-density lipoprotein cholesterol (HDL-c), and reduced serum triglyceride and urea levels. Metabolomic analyses revealed beneficial shifts in circulating phosphatidylethanolamines, phosphatidylglycerols, choline, and branched-chain amino acids (BCAA). Cardiovascular assessments demonstrated significant reductions in systolic and diastolic blood pressure and improvements in heart rate variability, indicating enhanced cardiac autonomic modulation. Gut microbiota analyses showed no differences in alpha or beta diversity; however, Bray-Curtis volatility analyses identified significant within-subject compositional shifts. Exploratory multivariate analyses suggested potential associations between specific gut taxa (e.g., ), circulating metabolites, and cardiovascular autonomic indices, supporting the existence of microbiota-metabolite-heart interactions. In summary, a 4-month multicomponent lifestyle intervention improved cardiovascular autonomic function, inflammatory status, and cardiometabolic profiles in children with obesity. These findings highlight the cardiovascular benefits of early lifestyle modification and support integrative approaches targeting autonomic and metabolic pathways in pediatric obesity.
Xu L, Aghagolzadeh P, Morandi C
… +5 more, Wagner J, Lépine LM, Segers VFM, de Keulenaer GW, Brink M
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41632968
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Neuregulin-1β (NRG1) improves cardiac output in heart failure patients, yet concerns remain that erythroblastic oncogene B (ErbB) activation may promote maladaptive hypertrophy, particularly during hemodynamic stress. We...Neuregulin-1β (NRG1) improves cardiac output in heart failure patients, yet concerns remain that erythroblastic oncogene B (ErbB) activation may promote maladaptive hypertrophy, particularly during hemodynamic stress. We investigated how NRG1 influences structural, functional, and molecular remodeling during pressure overload. Male and female C57BL/6NRj mice underwent transverse aortic constriction (TAC) or sham surgery and received saline or recombinant NRG1 via osmotic minipumps or daily injection. In male mice, NRG1 increased ejection fraction at 1 and 4 wk after TAC. NRG1 accentuated TAC-induced concentric remodeling without increasing left ventricular weight or cardiomyocyte cross-sectional area. It markedly reduced fibrosis and macrophage infiltration and prevented progression toward early cardiac decompensation. NRG1 amplified TAC-induced and expression and also shifted toward their fetal profile. Transcriptomic analysis identified two novel NRG1-regulated genes: NRG1 reversed TAC-induced upregulation of the skeletal muscle gene myosin binding protein C () and induced the expression of Popeye domain-containing protein 2 (). Furthermore, NRG1 increased expression of and localization of connexin 43 at the intercalated disc, consistent with enhanced electrical coupling. In female mice, NRG1 increased systolic function and regulated similar molecular targets yet did not reduce the modest increase in fibrosis that was observed. In conclusion, our findings show that NRG1 promotes adaptive molecular and structural remodeling under pressure overload and enhances contractile performance without exacerbating hypertrophy. The identification of NRG1-responsive genes linked to contraction and conduction highlights potential mechanisms and supports further exploration of NRG1-based strategies for cardiac disease. Our study demonstrates that neuregulin-1β (NRG1) enhances systolic function during pressure overload while promoting adaptive remodeling without exacerbating hypertrophy. NRG1 regulates fetal gene programs in both sexes and reduces fibrosis in male mice. The identification of myosin binding protein C () and Popeye domain-containing protein 2 () as novel NRG1-responsive genes reveals previously unrecognized mechanisms underlying its cardioprotective effects. These findings support further investigation of NRG1-based therapeutic strategies and highlight potential sex-specific responses.