American Journal Of Physiology. Heart And Circulatory Physiology[JOURNAL]
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200 papers
Cerebral vascular diameter and flow irregularities due to ischemic stroke after middle cerebral artery occlusion.
Khokhar MR, Bloemen P, van Bavel E … +1 more , Mulder IA
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42228947 · Publisher ↗
Acute ischemic stroke is a major cause of death and disability. Although reperfusion therapies are effective, early and lasting alterations in the microvasculature can limit recovery. Research has largely focused on micr...
Acute ischemic stroke is a major cause of death and disability. Although reperfusion therapies are effective, early and lasting alterations in the microvasculature can limit recovery. Research has largely focused on microvascular impairment, whereas the pial arterial network remains relatively underexplored. Using the middle cerebral artery occlusion model and in vivo microscopy in mice, we assessed pial vessel dynamics during occlusion, recanalization, and the first 24 h of reperfusion. We analyzed vessel diameter, irregularity, resistance, blood flow, and microthrombus formation. Results revealed marked vasoconstriction throughout the pial network during occlusion, which persisted after recanalization, with vessel diameters reduced to 72 ± 27% (SD) of baseline at 24 h. Smaller pial vessels (<30 µm) reacted differently over time compared with larger vessels. Vessel irregularity and resistance increased and peaked at 24 h. A considerable proportion of vessels had impaired flow and microthrombi at all time points. Thrombosis risk in daughter vessels rose when a mother vessel contained a thrombus. In conclusion, recanalization is insufficient to avert early and persistent vascular dysfunction in this model. Our findings underscore the role of pial artery impairment in disturbed reperfusion and point to the need for complementary strategies to restore adequate blood flow and improve outcomes. This study investigated vasoconstriction in the larger pial arteries, a network relatively underexplored in vascular stroke research, during and after ischemic stroke. By measuring vessel diameters along the entire vessel length, we uncovered effects of local constriction on vessel irregularity and resistance not reported before in vascular literature. By imaging during occlusion and hyperacutely after reperfusion, this study investigated thrombi formation and flow impairments at critical time points, providing insight lacking in prior research.
Skeletal muscle mitochondrial function and muscle oxygenation measured by near-infrared spectroscopy during brachial artery occlusion.
Jeskanen T, Ylinen VP, Valtonen RIP … +7 more , Stenbäck V, Mäkelä KA, Kerkelä R, Pöllänen N, Pirinen E, Herzig KH, Tulppo MP
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42227998 · Publisher ↗
Near-infrared spectroscopy (NIRS) is a widely used technique allowing the noninvasive measurement of skeletal muscle microvascular and mitochondrial function. However, the association between NIRS technology measurements...
Near-infrared spectroscopy (NIRS) is a widely used technique allowing the noninvasive measurement of skeletal muscle microvascular and mitochondrial function. However, the association between NIRS technology measurements and mitochondrial function analyzed from muscle biopsy by high-resolution respirometry is not clear. Healthy adults ( = 20; 10 females; age 25.3 ± 4.6 yr) participated in the study. A NIRS device was used to measure muscle oxygenation during a 5-min brachial occlusion. Muscle oxygen consumption (mV̇o) and the change in tissue saturation index (TSI) from baseline to the end of occlusion (ΔTSI Base-Min) were calculated. Muscle biopsy from the vastus lateralis was collected on a separate day to assess complex I-mediated mitochondrial respiration. mV̇o (from 0.021 to 0.070 mLO/min/100 g), ΔTSI Base-Min (from 25.2% to 50.2%), and complex I-mediated mitochondrial respiration (from 9.7 to 57.3 pmol·mg·s) showed wide interindividual variation. Complex I-mediated mitochondrial respiration was correlated negatively with mV̇o ( = -0.64, = 0.002) and ΔTSI Base-Min ( = -0.80, = 0.0003). In multivariate linear regression analysis (Enter method), complex I-mediated respiration was the only variable significantly associated with mV̇o and ΔTSI Base-Min when sex, body fat percentage, and peak oxygen uptake (V̇o) during cycle ergometer test were included in the analysis as confounding factors (standardized coefficients β = -0.431, = 0.017 and β = -0.691, = 0.0006, respectively). Our findings suggest that during 5-min occlusion, higher mitochondrial respiratory capacity is associated with lower mV̇o utilization. Lower oxygen utilization during occlusion may indicate a more efficient use of oxygen by mitochondria and better preserved energy metabolism. This study evaluated the relationship between near-infrared spectroscopy (NIRS)-derived measures of muscle oxygenation and mitochondrial respiration from biopsy in healthy adults. During arterial occlusion, higher complex I-mediated mitochondrial respiration was independently associated with lower muscle oxygen consumption and smaller declines in tissue oxygenation. These findings suggest that greater mitochondrial capacity is linked to more efficient oxygen utilization, supporting the physiological relevance of NIRS-derived indices as indirect markers of mitochondrial function.
Genetic deletion of cytoglobin exacerbates cardiac hypertrophy and inhibits cardiac fibroblast activation independent of changes in blood pressure.
Pham LGC, Gilliard K, Jourd'heuil F … +4 more , Mistretta S, Schwarz JJ, Singer HA, Jourd'heuil D
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42223197 · Publisher ↗
Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressur...
Hypertension-mediated left ventricular hypertrophy and cardiac fibrosis often precede heart failure. Recent studies indicate that cytoglobin (Cygb), a globin expressed in the vasculature, increases systemic blood pressure. The present work aims to determine the role of Cygb in angiotensin II (Ang II)-induced cardiac hypertrophy and fibrosis in the mouse. Males and females global Cygb knockout ), and wild-type () mice were treated with Ang II (1.5 µg/kg/day) for 2 wk via subcutaneous osmotic minipumps. Cardiac function was assessed through echocardiography, and hearts were analyzed for changes in hypertrophy, fibrosis, and gene expression. Functional studies were also performed in isolated cardiac fibroblasts. mice from both sexes showed an increase in cardiac hypertrophy over mice. Cardiac functions were also depressed in males with no changes in females. Importantly, genetic deletion of Cygb did not affect systemic blood pressure in mice, at baseline or after Ang II treatment. We established that Cygb was expressed in fibroblasts and pericytes in human and mice hearts. Finally, we found that cardiac fibroblast did not upregulate the expression of genes associated with myofibroblasts following treatment with Ang II. This was reversed following the expression of human cytoglobin. Our findings indicate that Cygb plays a protective role in the mouse heart during Ang II-induced cardiac stress. This is the first study detailing the function of Cygb in the heart as a regulator of cardiac hypertrophy. This study also reveals a role for Cygb in regulating cardiac fibroblast activation by Ang II. We identified cytoglobin as an important globin in cardiac pathophysiology. Genetic deletion of cytoglobin led to exacerbation of angiotensin II-mediated cardiac hypertrophy in the absence of any effect on systemic blood pressure. Cytoglobin is expressed in cardiac fibroblasts and pericytes and is required for cardiac fibroblast activation. The present study reveals for the first time a role for cytoglobin in regulating angiotensin II signaling.
Disrupting the heart-brain axis: the combined impact of parental obesity and Alzheimer disease.
Speretta GF
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42223193 · Publisher ↗
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Loss of SIRT2 in cardiomyocytes reduces glycolytic flux via increased acetylation of glycolytic enzymes.
Ketema EB, Han R, Ahsan M … +6 more , Fairuz F, Persad KL, Sun Q, Zhang L, Dyck JRB, Lopaschuk GD
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42223184 · Publisher ↗
Cardiac glycolytic rates are altered under many pathological conditions, although the mechanism(s) responsible for these changes in glycolysis is not completely clear. Since cardiac hyperacetylation also occurs under man...
Cardiac glycolytic rates are altered under many pathological conditions, although the mechanism(s) responsible for these changes in glycolysis is not completely clear. Since cardiac hyperacetylation also occurs under many pathological conditions, we determined whether glycolytic enzyme lysine acetylation can regulate cardiac glycolysis rates. The effects of modifying cardiac acetylation on glycolysis were examined in isolated working rat hearts and H9c2 cardiomyocytes using sirtuin 2 (SIRT2) inhibition (AGK2 or siRNA knockdown), SIRT1 inhibition (EX-527), pan-sirtuin inhibition (NAM), or acetyltransferase inhibition (C646). Glycolysis rates were directly measured in hearts or cardiomyocytes perfused with 5 mM glucose and 0.8 mM palmitate, using radiolabeled [5-H] glucose. SIRT2 inhibition significantly decreased glycolysis rates in isolated working rat hearts compared with controls (1,844 ± 153 vs. 2,753 ± 236 nmol·g dry wt·min, < 0.05) with no significant effect on glucose oxidation rates. In H9c2 cardiomyocytes, both SIRT2 inhibition and knockdown reduced glycolysis rates compared with controls (524 ± 108 vs. 2,631 ± 372 and 745 ± 31 vs. 1,659 ± 168 nmol·mg protein·h, < 0.05, respectively). This decrease in glycolysis was accompanied by increased acetylation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoglycerate mutase (PGAM), without changes in global acetylation patterns. SIRT2 inhibition or knockdown did not affect the phosphorylation status of insulin signaling proteins. However, SIRT2 inhibition did attenuate the phenylephrine-mediated hypertrophic response in H9c2 cells. We conclude that SIRT2 inhibition increases the acetylation of cardiac glycolytic enzymes and decreases glycolysis rates, suggesting that posttranslational acetylation is an important pathway regulating cardiac glycolysis. Protein lysine acetylation differentially regulates cardiac fatty acid and glucose oxidation. However, its role in controlling glycolysis remains poorly defined. Using pharmacological inhibition and siRNA-mediated knockdown of sirtuin 2 (SIRT2), we demonstrate that loss of SIRT2 increases acetylation of glycolytic enzymes and reduces cardiac glycolytic flux in isolated working hearts and cardiomyocytes, independent of insulin signaling. Our findings reveal an important role of SIRT2-dependent deacetylation in regulating cardiac glycolytic flux.
Chemerin knockout reveals sex difference in the role of chemerin in blood pressure and vascular remodeling.
Wabel E, Garver H, Krieger-Burke T … +5 more , Xie F, Zeng L, Mullick A, Fink GD, Watts SW
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42223180 · Publisher ↗
The adipokine chemerin contributes to vascular function, blood pressure regulation, and adiposity-associated hypertension. Mechanistic chemerin research has used three key tools: an antisense oligonucleotide (ASO) agains...
The adipokine chemerin contributes to vascular function, blood pressure regulation, and adiposity-associated hypertension. Mechanistic chemerin research has used three key tools: an antisense oligonucleotide (ASO) against chemerin, the Chemerin1 receptor inhibitor CCX832, and a knockout (KO) in Dahl SS rats. We administered the ASO to the KO rat to test that the ASO against chemerin reduced blood pressure by preventing chemerin production only. However, the ASO against chemerin lowered blood pressure both in wild-type (WT) and KO rats, indicating the ASO has off-target effects. This finding necessitated the use of CCX832 and the chemerin KO rat to understand chemerin's role in cardiovascular health and disease. Here, we test the hypothesis that CCX832 administration or genetic chemerin loss will reveal chemerin's role in driving adiposity-associated hypertension and vascular stiffness. CCX832 reduced blood pressure in high-fat diet (HFD)-induced, but not high-salt diet (HSD)-induced hypertensive males, supporting that chemerin's effects on blood pressure are obesity-related and at least in part Chemerin1-mediated. In addition, genetic chemerin loss blunted development of HFD-induced hypertension in males but, interestingly, exacerbated it in females. Aortic arch stiffening was prevented in the KO male rat on HFD, but no differences were observed in females. KO males on HFD had significantly lower collagen deposition in thoracic aorta than control diet (CD) or HFD-fed male WTs, whereas there were no significant differences among females. Our findings support chemerin as a sex-dependent driver of adiposity-associated hypertension and vascular stiffness and prompt broader investigation into chemerin's role in other vascular or sex-specific diseases. Chemerin contributes to obesity-associated hypertension through the Chemerin1 receptor. Chemerin drives adiposity-associated hypertension in males and protects against it in females. Chemerin plays a potential role in collagen deposition and vascular stiffening in males.
Myeloid-derived immunosuppressive PD-1/PD-L1 signaling is essential to maintain adult heart homeostasis.
Toro Cora A, Bhati AS, Huque A … +9 more , Ansari I, Singh B, Sethi R, Li DY, Zhang Q, Pant A, Devarashetty SP, Lal H, Tousif S
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42223114 · Publisher ↗
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events, including myocarditis. Although T cell involvement in ICI-associa...
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events, including myocarditis. Although T cell involvement in ICI-associated myocarditis is well established, the contribution of myeloid-specific programmed death-ligand 1 (PD-L1) signaling to cardiac immune regulation remains unclear. To investigate the role of myeloid-specific PD-L1 in maintaining cardiac immune homeostasis, we generated a myeloid-specific PD-L1 conditional knockout (KO) mouse model using LysMCre-driven deletion. Cardiac function was assessed by echocardiography. Immune profiling of cardiac and systemic compartments was performed using flow cytometry, quantitative PCR, ELISA, and histological analyses. In vitro coculture assays were conducted to assess macrophage-fibroblast (FB) and macrophage-T cell interactions. Myeloid PD-L1 KO mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, left ventricular fractional shortening, and upregulated heart failure markers. Immune profiling revealed systemic and myocardial inflammation, with increased C-C chemokine receptor type 2 macrophages and activated T cells. Coculture assays confirmed that PD-L1-deficient myeloid cells enhance T cell activation, Th17 polarization, and FB-mediated fibrotic gene expression. Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity. Its deficiency promotes a proinflammatory microenvironment, contributing to cardiac dysfunction and implicating it as a key player in ICI-associated myocarditis. These findings identify myeloid PD-L1 as a potential therapeutic target to mitigate immune-mediated cardiotoxicity. Immune checkpoint inhibitor-associated myocarditis is incompletely understood beyond T cell-driven mechanisms. This study identifies myeloid-specific PD-L1 as a critical regulator of cardiac immune homeostasis. Loss of myeloid PD-L1 triggers early myocardial inflammation, immune cell infiltration, FB activation, and subsequent cardiac dysfunction. These findings uncover a previously unrecognized myeloid checkpoint pathway contributing to immune-mediated cardiotoxicity and highlight myeloid PD-L1 as a potential therapeutic target.
Growth arrest of thoracic aortic aneurysms in aging Marfan mice.
Means CW, Mays G, Yeung N … +5 more , Cavinato C, Manning EP, Lam TT, Humphrey JD, Weiss D
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42222959 · Publisher ↗
There remains a pressing need to identify pathological mechanisms that render a thoracic aortic aneurysm susceptible to continued enlargement, dissection, or rupture, yet additional insight can be gleaned by understandin...
There remains a pressing need to identify pathological mechanisms that render a thoracic aortic aneurysm susceptible to continued enlargement, dissection, or rupture, yet additional insight can be gleaned by understanding compensatory mechanisms that limit disease progression and thereby stabilize a lesion. Our biomechanical data suggest that the ascending aorta within a common mouse model of Marfan syndrome, , exhibits progressive disease from 12 wk to 1 yr of age but near growth arrest from 1 to 2 yr of age. Comparison of the biomechanical phenotype, histological characteristics, and proteomic signature from 12 wk to 1 yr to 2 yr plus the transcriptional profile from 12 wk to 2 yr suggests that multiple differentially expressed genes (including downregulated and ) and associated proteins may contribute to late-term growth arrest. Although there is a need to better understand the interconnected roles of temporal changes in differential gene expression and protein abundance, modulating transforming growth factor-beta (TGF-β) signaling and reducing mTOR signaling appear to merit increased attention in limiting aneurysmal expansion in Marfan syndrome. Aneurysms in a mouse model of Marfan syndrome develop over the first year of life, only to stabilize over the second year of life. Remarkably, this paper is the first to identify, in a genetic condition of thoracic aortopathy, particular strategies that cells have identified to limit lesion growth and thus enhance resiliency.
The unexpected bright side of TNXIP in myocardial biology.
Civati C, Segers VFM
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42222940 · Publisher ↗
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A perinatal approach for unraveling mitochondrial function in preeclampsia and fetal growth restriction: a role for mitochondrial-targeted therapies.
Brink MJ, Terstappen F, Lely AT … +1 more , Nijholt KT
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42222929 · Publisher ↗
Preeclampsia (PE) is a complex hypertensive disorder resulting from placental insufficiency during pregnancy. PE contributes to maternal and fetal morbidity and mortality and often co-occurs with fetal growth restriction...
Preeclampsia (PE) is a complex hypertensive disorder resulting from placental insufficiency during pregnancy. PE contributes to maternal and fetal morbidity and mortality and often co-occurs with fetal growth restriction (FGR); these two are both considered placental insufficiency syndromes. Alterations in mitochondrial function levels due to placental insufficiency play an important role in the pathophysiology of PE and FGR. Changes in these processes can lead to maternal and fetal organ damage with subsequent risk to develop cardiovascular disease. This review therefore investigates the effects of placental insufficiency syndromes, including PE and FGR, on mitochondrial function and its underlying mechanisms, using a perinatal approach including maternal heart and kidney, placenta, and fetal heart and kidney. This review also explores the potential of mitochondrial-targeted therapies in mitigating these effects. We provide an overview of the literature at hand and demonstrate the critical role of mitochondrial function in different organ systems. Subsequently, we also discuss the need for mitochondrial-targeted therapies, in particular, focused on oxidative stress, metabolic pathways, mitochondrial quality control, and mitochondrial calcium handling. This knowledge provides guidance for future studies and potential therapies to improve PE and FGR and their consequences for maternal and fetal outcomes during pregnancy and cardiovascular health later in life.
Modeling sex-dependent cardiovascular responses to lower body negative pressure.
Bergauer A, Urevc J, Halilovič M … +3 more , Batzel J, Pivec V, Goswami N
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42213715 · Publisher ↗
Lower body negative pressure (LBNP) induces controlled central hypovolemia, yet the regional mechanisms of cardiovascular compensation remain difficult to resolve experimentally. This study presents a computational frame...
Lower body negative pressure (LBNP) induces controlled central hypovolemia, yet the regional mechanisms of cardiovascular compensation remain difficult to resolve experimentally. This study presents a computational framework for estimating regional parameter changes consistent with observed hemodynamic responses to progressive LBNP using a refined lumped-parameter model calibrated to experimental data. Hemodynamic responses to graded LBNP (0 to -40 mmHg) and recovery were obtained from a previously published experimental study in 35 healthy adults (17 females, 18 males), including heart rate, cardiac output, arterial pressure, total peripheral resistance, and ultrasound-derived internal jugular and portal venous flow. The model was structurally refined by separating head and arm circulations, enabling explicit modeling of cerebral venous outflow and jugular vein dynamics, and calibrated using a sensitivity- and correlation-guided identification strategy. Baseline calibration revealed distinct vascular architectures, with males exhibiting higher arterial compliance and dominant lower-body resistance, and females showing greater splanchnic and renal tone. During progressive LBNP, the identified splanchnic resistance increased monotonically in both sexes, whereas lower-body resistance rose markedly in males but remained near baseline in females, indicating sex-dependent compensation strategies. The calibrated model quantifies regional vascular resistance changes and venous blood volume redistribution during hypovolemia, providing a model-based interpretation of possible regulatory mechanisms into sex-specific cardiovascular regulation that cannot be directly measured in vivo. We present the first lumped-parameter cardiovascular model calibrated to sex-specific hemodynamic responses during graded lower body negative pressure, integrating internal jugular and portal venous flow as calibration targets. Baseline identification reveals coherent structural sex differences: females exhibit higher splanchnic and renal vascular resistance, and males exhibit higher lower-limb resistance and arterial compliance. Across all LBNP levels, splanchnic vasoconstriction emerges as the dominant compensatory pathway in both sexes, whereas lower-limb resistance diverges markedly between sexes.
Early cardiometabolic dysfunction: subclinical indicators and sex-specific considerations.
Turner CG, Stute NL, Parker DKS … +2 more , Gladden LB, Roberts MD
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42213700 · Publisher ↗
Cardiometabolic disease develops over decades, yet most research emphasizes markers of disease risk in those with established disease or focuses primarily on traditional risk factors (e.g., low-density lipoprotein, faste...
Cardiometabolic disease develops over decades, yet most research emphasizes markers of disease risk in those with established disease or focuses primarily on traditional risk factors (e.g., low-density lipoprotein, fasted blood glucose). Meanwhile, indicators of early cardiometabolic dysfunction in young adults are not well-characterized but are crucial for advancing early detection and prevention efforts. The present review addresses this gap in the literature by providing a synthesis of subclinical indicators of early cardiometabolic dysfunction in young adults, including pathophysiological vascular/endothelial, metabolic, inflammatory, and neuroendocrine indicators, as well as newly emerging targets. Importantly, it is well-established that cardiometabolic risk and disease differ by biological sex. This review also incorporates sex-specific considerations where possible to address this difference. This review summarizes the available literature regarding subclinical indicators of early cardiometabolic dysfunction, aiming to improve the mechanistic understanding of cardiometabolic disease pathogenesis and offer a novel conceptual framework to advance how researchers and clinicians approach early detection and prevention of cardiometabolic dysfunction and disease.
Milieu-dependent small-cavity diabetic HFpEF in the DIO-STZ model.
Zhu H, Zhou Y
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42188109 · Publisher ↗
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Aging and cardiopulmonary interactions: physiologic and pathophysiologic consequences.
Carvalho EB, Barros FCB, Rocha NN … +1 more , Silva PL
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42173513 · Publisher ↗
Monitoring hemodynamics and its response to fluid challenges is important for in-hospital patients to maintain adequate tissue perfusion without leading to organ edema or dysfunction. The physiologic background of bedsid...
Monitoring hemodynamics and its response to fluid challenges is important for in-hospital patients to maintain adequate tissue perfusion without leading to organ edema or dysfunction. The physiologic background of bedside hemodynamic indexes depends on the cardiopulmonary interactions. However, monitoring fluid responsiveness in older adults may be particularly challenging because age-related physiologic changes and prevalent comorbidities can alter cardiopulmonary interactions. Those alterations are often neglected in clinical studies and even in the classic formulas used to estimate basic variables for hemodynamics. This issue becomes even more important because many studies on fluid responsiveness include cohorts composed of older adults, but few directly address the unique physiologic and pathophysiologic features of aging as the central variable of interest. This narrative review aims to highlight the physiologic consequences of aging and the difficulty in assessing fluid responsiveness in an aging population. Conditions such as heart failure with preserved ejection fraction may shift the Frank-Starling relationship, thereby reducing preload dependence in older adults and narrowing the therapeutic window between the beneficial and deleterious effects of intravenous fluid administration. Additional conditions, including aortic stenosis, may further confound the interpretation of dynamic indices used to assess fluid responsiveness. Future experimental and clinical research agendas should adopt a phenotype-oriented approach, investigating the impacts on hemodynamic assessment from age-related physiologic adaptations and the most prevalent cardiopulmonary conditions, such as heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and aortic stenosis. The stratification of older adults and data analysis from clinical studies could be of great value.
Bioactive factors in endometriosis peritoneal fluid remodel human cardiomyocytes.
Simon J, Blickenstaff E, Mitchell B … +2 more , Sinning K, Santanam N
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42172437 · Full text
Endometriosis is associated with increased cardiovascular disease (CVD) risk, yet the cellular basis for this relationship remains unclear. We examined whether peritoneal fluid (PF) from women with endometriosis alters c...
Endometriosis is associated with increased cardiovascular disease (CVD) risk, yet the cellular basis for this relationship remains unclear. We examined whether peritoneal fluid (PF) from women with endometriosis alters cardiomyocyte behavior in vitro. Human-induced pluripotent stem cell-derived cardiomyocytes were exposed for 48 h to standard or hypertrophic media supplemented with peritoneal fluid from endometriosis or control patients. Beating frequency was measured using calcium transient imaging, differential gene expression was assessed with the Human CVD-PCR array, and sarcomere features were quantified using gray-level cooccurrence matrix (GLCM)-based texture analysis. Under standard conditions, PF increased beats per minute compared with media alone (control = 0.0006; endometriosis < 0.0001), and beating frequency was higher with endometriosis PF than with control PF ( = 0.0214). Sarcomere length increased, and organization metrics reduced following PF (endo and ctrl) exposure under baseline conditions ( < 0.0001), suggesting remodeling. CVD array showed that >40% of the genes were altered by Endo-PF vs. <10% by control-PF, compared with media-alone treatment. Network analysis showed enrichment of adrenoceptor and G protein-coupled receptor signaling pathways. An increased expression of (2.49-fold, = 0.016) and reduced (-5.24-fold, = 0.037), along with regulation of and , was seen when Endo-PF was compared with Ctrl-PF. In hypertrophic media, PF treatment produced significant differences in sarcomere organization. Outcomes were condition-dependent rather than uniformly significant. Endometriosis-associated PF shifts in cardiomyocyte function, gene expression, and sarcomere structure. This supports a cell-intrinsic link between endometriosis and altered cardiac signaling states and carries implications concerning long-term cardiovascular morbidity and mortality in women with endometriosis. Endometriosis is linked to cardiovascular disease, but its direct effects on the heart are not well understood, reflecting broader mechanistic gaps in the disease. This study shows that exposure to peritoneal fluid (PF) from women with endometriosis is sufficient to change human cardiomyocyte beating frequency, sarcomere organization, and cardiovascular disease-associated gene expression in vitro. These findings support a cell-intrinsic mechanism through which endometriosis-associated factors may influence cardiac signaling and structure, extending beyond or supporting epidemiologic associations.
Brief repetitive pressure overload in mice induces eccentric remodeling and impaired contractile reserve.
Lang JK, Pon T, Eagler LA … +2 more , Weil BR, Canty JM
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42166637 · Publisher ↗
Repetitive pressure overload (RPO) in swine leads to the rapid development of increased left ventricular (LV) chamber stiffness, a preserved ejection fraction, and the absence of anatomic hypertrophy, which appears to pr...
Repetitive pressure overload (RPO) in swine leads to the rapid development of increased left ventricular (LV) chamber stiffness, a preserved ejection fraction, and the absence of anatomic hypertrophy, which appears to protect the heart from chronic strain-induced injury. Murine hearts are more amenable to mechanistic approaches modifying specific molecular pathways, but whether mice develop similar adaptive responses to RPO remains undefined. We hypothesized that repetitive pressure overload in mice would increase LV chamber stiffness and attenuate strain-induced myocardial injury, recapitulating key features of the swine model. We subjected mice to single (SPO, = 8) or daily repetitive pressure overload (RPO, = 6) using 30-min phenylephrine infusions via a chronically implanted catheter. At baseline, LV end-diastolic pressure was increased after RPO compared with SPO (13 ± 2 mmHg vs. 6 ± 1 mmHg, < 0.05), whereas ejection fraction remained preserved. During phenylephrine infusion, LV end-diastolic volume increased to a greater extent in RPO than in SPO mice (4.0 ± 0.5 µL/g vs. 2.4 ± 0.1 µL/g, < 0.05). In contrast to the increased stiffness that develops in swine subjected to RPO, end-diastolic LV chamber stiffness decreased (end-diastolic pressure-volume relationship slope 5 ± 3 vs. 24 ± 4 mmHg/µL/g after SPO, < 0.05) along with a reduction in contractility (end-systolic pressure-volume relationship 10 ± 2 vs. 33 ± 5 mmHg/µL/g after SPO, < 0.05). Markers of myocardial injury were increased following pressure overload, including cardiomyocyte apoptosis and circulating troponin I levels, with no attenuation following repetitive exposure. Thus, despite a preserved ejection fraction, repetitive pressure overload in mice results in ventricular dilation, reduced chamber stiffness, and persistent myocardial injury. These findings contrast with the adaptive response observed in swine and highlight important species-specific differences in myocardial remodeling in response to transient pressure overload. This study introduces a novel murine model of RPO using serial phenylephrine infusions to mimic chronic episodic hemodynamic stress. Unlike porcine models of RPO that demonstrate increased LV chamber stiffness and protection against strain-induced myocyte injury, mice exhibit reduced LV chamber stiffness and persistent myocyte apoptosis that is accompanied by loss systolic dysfunction with a preserved ejection fraction at rest. These findings indicate important species differences in the response to transient pressure overload.
Remote ischemic preconditioning and exercise-induced cardioprotection via extracellular vesicle-delivered microRNAs.
Self MS, Drasbek KR, Vissing K
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42166636 · Publisher ↗
Ischemic heart disease remains a major global health burden, with ischemia-reperfusion injury representing a critical determinant of myocardial damage. Remote ischemic conditioning (RIC) and differentiated physical exerc...
Ischemic heart disease remains a major global health burden, with ischemia-reperfusion injury representing a critical determinant of myocardial damage. Remote ischemic conditioning (RIC) and differentiated physical exercise regimens have emerged as potential preconditioning strategies enhancing myocardial resilience, and increasing evidence suggests that these cardioprotective effects may, in part, be mediated by targeted delivery of extracellular vesicle (EV)-carried microRNAs (miRNAs). RIC induces rapid alterations in circulating EV cargo, including miRNAs known to promote cell survival, attenuate oxidative stress, and modulate inflammation. This transient yet pronounced miRNA response to RIC indicates a rapid EV-associated molecular change that may be relevant to early signaling events underlying remote organ preconditioning. EV-miRNA content also changes acutely in response to exercise. These changes are associated with vascular remodeling, anti-apoptotic signaling, and metabolic adaptations, suggesting that exercise-induced EVs provide both immediate and sustained cardioprotection, although temporal dynamics remain incompletely defined. Consequently, RIC and exercise elicit distinct yet overlapping EV-miRNA signatures that may affect myocardial preconditioning. Here, we review whether EV-delivered miRNAs elicited by RIC and exercise may contribute to cardioprotection and may be therapeutically exploited in clinical settings such as heart failure and ischemic disease.
Myocardial expression of and is related to regression of left ventricular hypertrophy after aortic valve replacement in a sex-dependent manner.
Halldórsson KB, Karagianni K, Leite-Moreira AF … +3 more , Dafou D, Falcão-Pires I, Kararigas G
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42166614 · Publisher ↗
Aortic stenosis (AS) may lead to left ventricular (LV) hypertrophy (LVH). After aortic valve replacement (AVR), LVH often does not regress fully. This has been associated with a worse prognosis. This study aimed at compa...
Aortic stenosis (AS) may lead to left ventricular (LV) hypertrophy (LVH). After aortic valve replacement (AVR), LVH often does not regress fully. This has been associated with a worse prognosis. This study aimed at comparing LVH regression between male and female patients and to discover cardiac molecular factors associated with it. Myocardial samples were collected from 18 patients (50% female) who underwent surgical AVR. Preoperative and postoperative LV mass indices (LVMi) were compared between male and female patients. Expression of and was quantified by PCR and assessed with relative regression of LVMi. High-depth RNA-sequencing data from LV free-wall tissues of subjects with heart failure were employed for RNA editing analysis. Male patients had significant LVH regression ( < 0.05) after AVR, while female patients did not ( = 0.116). In male patients, a significant relationship was found between the expression of ( < 0.05, = 0.497) and ( < 0.05, = 0.576) and LVMi regression after AVR. This relationship was insignificant for ( = 0.704, = 0.0220) and ( = 0.860, = 0.00477) in female patients. RNA editing analysis revealed significant sex-biased differences in intronic adenosine-to-inosine (A-to-I) editing of , with five positions, particularly within elements, along with sex-biased predicted RBP binding motifs. Recognizing patients at risk of defective LVH regression using molecular factors could lead to more intensive postoperative follow-up and earlier treatment, consequently improving reverse remodeling and prognosis. The present findings warrant further research in a larger study. Regression of left ventricular hypertrophy is associated with better long-term outcome. This study demonstrates a significant relationship between and gene expression in perioperatively collected myocardial tissues and the regression of left ventricular mass postoperatively in male patients with aortic stenosis only. This could contribute to the development of a sex-based tool to predict the extent of postoperative hypertrophy regression.
Sex differences in the peripheral determinants of oxygen transport and utilization in patients with heart failure with preserved ejection fraction.
Hearon CM, Skow RJ, Wakeham DJ … +13 more , Kissell C, Brazile TL, Nelson MD, Bartlett MF, Ren J, Samels M, MacNamara JP, Taherzadeh Z, Lutz K, Levine BD, Fadel PJ, Haykowsky MJ, Sarma S
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42166612 · Publisher ↗
Heart failure with preserved ejection fraction (HFpEF) disproportionately affects females; however, the influence of sex on peripheral contributors to exercise intolerance remains poorly understood. Forty-three patients...
Heart failure with preserved ejection fraction (HFpEF) disproportionately affects females; however, the influence of sex on peripheral contributors to exercise intolerance remains poorly understood. Forty-three patients with HFpEF (71 ± 7 yr, 28 females; 38.3 ± 6.7 kg/m) performed incremental single-leg knee extension (SLKE) exercise to determine peak leg blood flow (BF; duplex Doppler ultrasound), arterial-to-venous oxygen content difference (a-vO) (femoral venous catheter), leg oxygen consumption (V̇o), and muscle oxygen diffusive conductance (DMO). Whole body and thigh adiposity and lean mass (TLM) were determined by DXA, and myosteatosis (TLM/fat ratio) by MRI. After adjusting for differences in TLM, females had ∼30% lower peak exercise leg V̇o/TLM ( < 0.001) and ∼15% lower BF/TLM compared with males ( = 0.024). However, when normalized to V̇o, the leg BF/leg V̇o slope was higher in females (9.5 ± 2.3 vs. 8.1 ± 2.1, = 0.017) and was associated with markedly lower a-vO difference ( < 0.001) and ∼40% lower DMO (3.6 ± 1.6 vs. 6.4 ± 1.7, < 0.0001). Metrics of muscle adiposity were not correlated with peak leg V̇o or its determinants ( > 0.150 for all). Females with HFpEF have lower muscle oxygen diffusive conductance during peak SLKE compared with males. However, peripheral determinants of aerobic capacity were not differentially related to adiposity in males and females with HFpEF. Interventions to improve muscle quality and diffusive capacity are of particular importance for improving peripheral limitations to exercise in females with obesity and HFpEF. This study was registered as a clinical trial on https://www.clinicaltrials.gov (NCT04068844). Females with heart failure with preserved ejection fraction have lower muscle oxygen diffusive conductance during peak exercise compared with males. Interventions to improve muscle quality and diffusive capacity are of particular importance for improving peripheral limitations to exercise in females with HFpEF.
Cerebral arteries in mice with sickle cell disease are exposed to larger areas of low wall shear stress.
Montes AR, Rivera CP, Zhang SX … +3 more , Lee HS, Huo Y, Platt MO
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42160480 · Publisher ↗
Sickle cell anemia (SCA) is the most severe form of sickle cell disease and causes increased stroke risk, even in children. Hemodynamic mechanisms underlying cerebral vasculopathy remain unclear. To test the hypothesis t...
Sickle cell anemia (SCA) is the most severe form of sickle cell disease and causes increased stroke risk, even in children. Hemodynamic mechanisms underlying cerebral vasculopathy remain unclear. To test the hypothesis that SCA causes disturbed flow and increased regions of low wall shear stress (WSS) in cerebral arteries, we combined high-frequency ultrasound, micro-computed tomography, and computational fluid dynamics (CFD) using mice that are homozygous sickle (SS) and heterozygous trait (AS) at 4, 12, and 24 wk of age. At 12 wk, common carotid artery diameters were 12.4%-18.6% larger in SS mice ( < 0.02), but common carotid inflow, blood velocity, and WSS did not differ significantly between genotypes. SS cerebral arteries demonstrated that branch- and age-specific reductions in velocities and volumetric flow were measured in SS cerebral arteries, particularly the middle cerebral artery (MCA), independent of common carotid artery inflow. Time-averaged mean-of-the-maximum velocity (TAMMV) was ∼40%-50% lower in the MCA of SS mice at 4 and 12 wk ( < 0.03), and MCA volumetric flow was lower by 56%-67% ( < 0.05). CFD models revealed more regions of low WSS (<5 dyn/cm) in cerebral arteries of SS mice, even in straight regions of the arteries at 12 and 24 wk. Our findings indicate that SCA reduces blood velocity and volumetric blood flow in the cerebral arteries while increasing endothelial exposure to pathological shear stress, providing a link between altered hemodynamics and arterial wall damage unique to sickle cell disease. Sickle cell disease hemodynamics identifies: ) stenoses and aneurysms along the lengths of carotid and cerebral arteries in sickle cell transgenic mouse model; ) disturbed flow in the straight regions of the carotid and cerebral arteries; and ) reduced blood flow and increased regions of low wall shear stress can predispose cerebral arteries to pathological and accelerated arterial damage and risk of strokes.
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