American Journal Of Physiology. Heart And Circulatory Physiology[JOURNAL]
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200 papers
Cardiovascular expression varies by anatomical site, with selective age- and sex- associated changes in human tissue datasets.
Bax M, Sinha S
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42302735 · Publisher ↗
Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor implicated in atherosclerosis, arterial dissection, and vascular disease, with roles in lipid handling, extracellular matrix turnove...
Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor implicated in atherosclerosis, arterial dissection, and vascular disease, with roles in lipid handling, extracellular matrix turnover, growth factor signaling, and vascular homeostasis. Although tissue-specific roles of LRP1 have been described, whether cardiovascular expression varies by age, sex, and vascular bed remains unclear. Here, we analyzed publicly available human transcriptomic datasets to define the cardiovascular expression landscape of across tissues, demographic strata, and cell populations. GTEx-derived data showed that vascular expression differed significantly between the aorta, coronary artery, and tibial artery, with the highest expression in the aorta, where levels were 30% higher than coronary artery and 50% higher than tibial artery. In the heart, atrial expression was approximately two-fold higher than in the left ventricle. Among these five cardiovascular tissues, only the aorta showed sexual dimorphism, with 7.4% higher expression in females than males. Tibial artery was the only tissue in which LRP1 expression changed significantly with age, doubling over female adulthood (adjusted P=0.0019), and increasing 40% in male adulthood (adjusted P=0.0284). Single-cell analyses of human heart and arterial datasets showed prominent expression in adipocytes, fibroblasts, macrophages, and smooth muscle cells, indicating that tissue-level patterns reflect non-uniform expression across vascular and stromal cell populations. Together, these data indicate that cardiovascular expression is not static, but can vary by anatomical and demographic context. This work establishes a baseline for interpreting LRP1-related mechanisms in vascular and cardiac disease.
Metabolic and Redox Pathway Dysregulation in HIV-Associated Coronary Endothelial Dysfunction.
Keole KS, Bukhari S, Minhas A … +7 more , Cohen CD, Wallace A, Piggott DA, Leucker TM, Sun K, Adamo L, Hays AG
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42302383 · Publisher ↗
People with HIV (PWH) remain at increased risk for cardiovascular disease despite sustained viral suppression on antiretroviral therapy, but the biological mechanisms underlying this risk are incompletely understood. We...
People with HIV (PWH) remain at increased risk for cardiovascular disease despite sustained viral suppression on antiretroviral therapy, but the biological mechanisms underlying this risk are incompletely understood. We hypothesized that coronary endothelial dysfunction in virally suppressed PWH is associated with specific circulating proteomic signatures reflecting metabolic and redox pathway dysregulation. We conducted a prospective observational study integrating in vivo stress cardiovascular magnetic resonance imaging with high-throughput serum proteomics to investigate mechanisms of coronary endothelial dysfunction in treated HIV. Forty-five virally suppressed PWH and twenty-nine age- and sex-matched healthy controls underwent coronary magnetic resonance imaging during isometric handgrip exercise to quantify coronary endothelial function, defined as the percent change in coronary cross-sectional area from rest to stress, with an increase <2% indicating endothelial dysfunction. Parallel serum proteomic profiling was performed using the SomaScan 7K platform, and differential protein expression was analyzed using linear modeling. Coronary endothelial dysfunction was significantly more prevalent among PWH than controls (67% vs 10%, p<0.001). Pathway enrichment analysis of differentially expressed proteins between participants with and without endothelial dysfunction identified significant dysregulation of glutathione-dependent detoxification, oxidative metabolism, and fatty acid β-oxidation pathways (adjusted p<0.05). However, despite the higher prevalence of coronary endothelial dysfunction among PWH compared with controls without HIV, we did not identify a distinct baseline clinical or proteomic profile that fully explained this difference. These findings demonstrate that coronary endothelial dysfunction in virally suppressed PWH is associated with metabolic and redox imbalance, identifying glutathione and fatty acid oxidation pathways as potential therapeutic targets to mitigate residual cardiovascular risk in this population.
Combined androgen excess polycystic ovary syndrome and obesity are associated with elevated beat-to-beat blood pressure variability in adult women.
Young BE, Colburn A, Oldham ZR … +5 more , Berbrier D, Usselman CW, Stone T, Fadel PJ, Stachenfeld NS
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42294856 · Publisher ↗
Androgen excess polycystic ovary syndrome (AE-PCOS) is associated with elevated risk for hypertension and cardiovascular disease. Greater beat-to-beat blood pressure variability (BPV) has emerged as a novel marker of car...
Androgen excess polycystic ovary syndrome (AE-PCOS) is associated with elevated risk for hypertension and cardiovascular disease. Greater beat-to-beat blood pressure variability (BPV) has emerged as a novel marker of cardiovascular risk. Little is known about beat-to-beat BPV in AE-PCOS, but prior studies suggest blunted baroreflex sensitivity (BRS), a major contributor to beat-to-beat BP regulation. Both obesity and androgen excess are implicated as driving factors of cardiovascular risk in AE-PCOS. We hypothesized that 1) beat-to-beat BPV would be greater in AE-PCOS compared to both women with overweight/obesity (OW/OB) and lean controls; 2) beat-to-beat BPV would be augmented in OW/OB compared to lean controls. We measured beat-to-beat BP (finger photoplethysmography) during ~5-10 minutes of supine rest in 18 lean controls, 14 OW/OB controls, and 14 women with AE-PCOS. Serum testosterone was measured and spontaneous cardiovagal BRS was assessed via sequence technique. In AE-PCOS, resting BP was greater than lean controls (P<0.05) and serum testosterone greater than both control groups (P<0.001). Diastolic BP standard deviation was greater in AE-PCOS (3.9 ± 1.0 mmHg) compared to both control groups (lean: 3.0 ± 1.5; OW/OB: 2.9 ± 1.2 mmHg; P=0.007). Cardiovagal BRS was not different between groups (P=0.196). Neither cardiovagal BRS nor serum testosterone were related to beat-to-beat BPV in AE-PCOS. Collectively, these data suggest greater beat-to-beat BPV in AE-PCOS which cannot be accounted for by obesity alone and is not associated with cardiovagal BRS or circulating androgens.
Deep Learning-Driven 3D Histopathology Method: A Pipeline for Cellular-Resolution Myocarditis Analysis.
Nieth A, Karmaker P, Martinez Naya N … +3 more , Saad AG, Condor Capcha J, Shehadeh LA
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42294766 · Publisher ↗
Infiltrative cardiovascular diseases are characterized by complex spatial distributions of abnormal tissue that hinder accurate diagnosis and therapeutic monitoring. Conventional 2D histopathological analysis often fails...
Infiltrative cardiovascular diseases are characterized by complex spatial distributions of abnormal tissue that hinder accurate diagnosis and therapeutic monitoring. Conventional 2D histopathological analysis often fails to capture their full extent, limiting quantitative assessment of disease burden and treatment response. We present a Linux-optimized, Cellular-resolution Organ Digital Analysis (CODA) pipeline, for quantitative 3D reconstruction of whole murine hearts at cellular resolution. Our adaptations ensure compatibility with Linux environments, incorporate visualization tools for integration with external software, and integrate myocarditis-specific training data to improve segmentation accuracy, along with STL format export for visualization in 3D Slicer. Applied to a COVID-19-induced myocarditis model (n=6), the modified pipeline achieved >90% accuracy in segmenting affected tissue, revealing significantly greater volumes of inflammatory and necrotic foci compared to controls. This open-source platform provides a scalable, pathologist-AI hybrid workflow for precise 3D tissue analysis across infiltrative cardiac diseases.
Muscle Metaboreflex Dysfunction in Cardiovascular Disease.
de Araújo Alves CC, de Andrade RD, Goulart CDL … +3 more , Alves IM, de Oliveira LVF, Cipriano G
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42294636 · Publisher ↗
Muscle metaboreflex dysfunction has emerged as a key contributor to autonomic imbalance and exercise intolerance across cardiovascular diseases. By amplifying or blunting reflex sympathetic, hemodynamic, and ventilatory...
Muscle metaboreflex dysfunction has emerged as a key contributor to autonomic imbalance and exercise intolerance across cardiovascular diseases. By amplifying or blunting reflex sympathetic, hemodynamic, and ventilatory responses to metabolite accumulation in contracting skeletal muscle, abnormal metaboreflex activity can worsen peripheral perfusion, impair the matching between oxygen delivery and utilization, and increase symptom burden during exertion. This review integrates physiological and clinical evidence linking metaboreflex dysregulation to impaired cardiopulmonary and skeletal muscle responses, summarizes key approaches used to assess this reflex function in humans, and discusses how cardiac rehabilitation and exercise training may recalibrate these pathways, particularly in heart failure. Sex and menopausal status may modify metaboreflex expression and vasoconstrictor transduction; therefore, we synthesize evidence in both sexes and highlight gaps in female representation and sex-stratified reporting. We appraise exercise modalities used in cardiac rehabilitation and highlight how aerobic exercise improves sympathovagal balance, ventilatory control, and metabolic efficiency, while resistance training and inspiratory muscle training provide complementary adaptations in peripheral muscle, vascular function, and respiratory reflex control. In selected stable patients, high-intensity interval training may be incorporated under supervision to potentiate cardiorespiratory gains. This targeted approach to metaboreflex modulation supports individualized, mechanism-driven prescriptions aligned with ventilatory thresholds and clinical status, with expected gains in functional capacity, prognostic markers, and patient-centered outcomes.
Glycolysis and hexosamine biosynthesis regulate inflammatory protein expression and maturation and key steps of monocyte recruitment by human aortic valve cells.
Sánchez-Bayuela T, Peral-Rodrigo M, López J … +9 more , Gómez C, Perez-Riesgo E, Cacace J, López-Andrés N, Fernández N, Víctor VM, San Román JA, Sánchez Crespo M, García-Rodríguez C
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42284201 · Publisher ↗
Inflammation and metabolism reprogramming are hallmarks of calcific aortic valve disease (CAVD). Recent studies link hyperglycolysis, inflammation, and calcification in valve interstitial cells (VICs). The metabolism of...
Inflammation and metabolism reprogramming are hallmarks of calcific aortic valve disease (CAVD). Recent studies link hyperglycolysis, inflammation, and calcification in valve interstitial cells (VICs). The metabolism of valve endothelial cells (VECs) has received less attention despite the fact that both resident valve cells are exposed to alike inflammatory clues involved in the biosynthesis of pathologically relevant glycoproteins at early stages of CAVD. Given this, we investigated the outcomes of glucose metabolism rewiring on glycoprotein maturation and monocyte adhesion in human resident valve cells. Real-time metabolic analysis revealed that basal VECs are more glycolytic than VICs. Also, VECs and VICs exposed to inflammatory stimuli exhibited a distinct rewiring, with VECs shifting to a more energetic metabolism, despite a similar upregulation of glycolytic genes. Blunting glucose metabolism in VICs and VECs inhibited inflammatory routes canonically associated with glycolysis, and the expression of proteins associated to the inflammatory response like interleukin-6 and cyclooxygenase-2. Moreover, the expression and post-translational modifications of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 showed glucose-dependency and sex-related differences. The ensuing process of monocyte-valve cell adhesion was glucose-dependent. Notably, inhibiting the branch route of hexosamine biosynthesis with DON and N-glycosylation by tunicamycin disrupted adhesion molecule maturation. Under shear stress conditions, 2-DG impaired monocyte rolling and adhesion to VECs monolayers, while DON reduced rolling. In conclusion, glycolysis and its side-branch route of hexosamine biosynthesis are necessary for nutrient-driven post-translational modifications of inflammatory proteins in inflamed valve cells and key steps of monocyte recruitment, a crucial process in early-stages of CAVD.
Non-invasive surrogate of main pulmonary artery stiffness is associated with right ventricular function in experimental pulmonary arterial hypertension.
Dauz JD, Mirani B, Santerre JP … +3 more , Bendeck MP, Simmons CA, Friedberg MK
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42275165 · Publisher ↗
Main pulmonary artery (MPA) stiffening increases right ventricular (RV) afterload and is associated with worse outcomes in pulmonary arterial hypertension (PAH). Measures of pulmonary artery compliance (PAC) and vascular...
Main pulmonary artery (MPA) stiffening increases right ventricular (RV) afterload and is associated with worse outcomes in pulmonary arterial hypertension (PAH). Measures of pulmonary artery compliance (PAC) and vascular resistance (PVR) require invasive catheterization, limiting clinical application. Echocardiographic assessment of MPA pulsatility, the relative change in MPA diameter, may be useful but not well validated. We investigated the relationship between MPA pulsatility and passive stiffness, PAC, PVR, RV function, and RV-PA coupling in sugen-hypoxia (SuHx) rats and children with idiopathic PAH (iPAH) and controls. Groups of 3-week and 6-week SuHx rats and controls underwent echocardiography and invasive catheterization to characterize progressive changes in MPA pulsatility, PAC, PVR, and RV function. Harvested MPAs underwent biaxial tensile testing to determine its passive stiffness. RV echo function and MPA pulsatility were retrospectively analyzed in iPAH patients and healthy subjects. PAH rats and iPAH patients had reduced MPA pulsatility (23±7.9% at 3-weeks and 18±5.0% at 6-weeks SuHx; 14.5(7.7) in iPAH) compared to controls (40±7% at 3-weeks and 31±6% at 6-weeks in healthy controls; 30.8(6.9) in healthy subjects). Reduced MPA pulsatility correlated with increased high-strain circumferential passive stiffness (r=-0.88, p<0.0001), reduced PAC (r=0.78, p<0.0001), increasing PVRi (r=0.47, p<0.0001), RV dysfunction and impaired coupling in PAH rats. MPA pulsatility in iPAH and healthy subjects was inversely related to RV size and positively linearly related to RV systolic function. Our results suggest that MPA pulsatility is an accessible measure of MPA stiffness, expanding the assessment of RV afterload and RV-PA coupling in PAH.
Impaired peripheral oxygen diffusion is the primary determinant of exercise intolerance in high-risk older breast cancer survivors.
Haykowsky MJ, Weeldreyer NR, La Gerche A … +2 more , Sarma S, Foulkes SJ
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42275154 · Publisher ↗
Peak oxygen uptake (V̇o) is a strong predictor of survival in breast cancer survivors (BCSs), with values ≤1.09 L/min associated with increased mortality. The relative contributions of convective oxygen delivery (QO) and...
Peak oxygen uptake (V̇o) is a strong predictor of survival in breast cancer survivors (BCSs), with values ≤1.09 L/min associated with increased mortality. The relative contributions of convective oxygen delivery (QO) and muscle oxygen diffusing capacity (DO) to reduced V̇o in BCS remain unclear. In 49 BCS, we measured V̇o from cycle ergometry with gas-exchange analysis, and derived QO and DO using Fick-based calculations and computational modeling. BCS were stratified by mortality risk: high-risk (V̇o ≤1.09 L/min; = 11) and lower-risk ( = 38), and compared using tests, Mann-Whitney tests, and analysis of covariance (ANCOVA). Dominance analysis quantified the relative contributions of QO and DO to V̇o within each group. The high-risk group was older (72 ± 6 vs. 69 ± 5 years), had longer time since treatment (17 ± 5 vs. 13 ± 6 years), and higher cumulative doxorubicin-equivalent doses (291 ± 134 vs. 163 ± 120 mg/m; all ≤ 0.05). After ANCOVA, the high-risk group had lower V̇o (1.0 ± 0.1 vs. 1.4 ± 0.2 L/min), QO (1.8 ± 0.3 vs. 2.5 ± 0.5 L/min), and DO (28.2 ± 4.8 vs. 41.5 ± 9.0 mL/min/mmHg; all ≤ 0.001). Dominance analysis revealed DO as the strongest contributor to V̇o with 81.7% and 66.0% of explained variance in high-risk and lower-risk groups, whereas QO accounted for 14.1% and 30.3%, respectively. In older, long-term BCS with reduced V̇o (≤1.09 L/min), impairments in both QO and DO contribute to reduced exercise tolerance. However, DO emerged as the strongest modeled contributor in the high-risk group. Interventions prioritizing skeletal muscle-vascular function, alongside complementary targeting of QO, may have a greater impact on V̇o improvements and survival in this high-risk population. Exercise intolerance in older breast cancer survivors, particularly those with severely reduced peak oxygen uptake (i.e., ≤1.09 L/min), is predominantly associated with impaired peripheral muscle oxygen transport and utilization, and to a lesser extent by reductions in convective oxygen delivery. These findings support a comprehensive approach where therapeutic strategies primarily targeting skeletal muscle-vascular function, coupled with complementary attention to convective oxygen transport, may result in the greatest improvement in peak oxygen uptake, and potentially, long-term breast cancer survivorship.
Reply to Pal and Sadhu.
Romano GS, McCarthy DG, Millar PJ
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42275139 · Publisher ↗
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Central and peripheral hemodynamic determinants of exercise systolic blood pressure phenotypes in young normotensive adults.
Pal A, Sadhu A
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42275138 · Publisher ↗
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Regional heterogeneity and sex differences along the mouse aorta.
Sveeggen TM, Kosmach A, Mitchell R … +6 more , Brockmann BC, Meisinger TM, Stratman AN, Mack JJ, Cook JR, Bagher P
Am J Physiol Heart Circ Physiol · 2026 Jun · PMID 42267937 · Publisher ↗
The aorta varies in structural and biomechanical properties along its length, however, the influence of these properties on aortic pathology is poorly understood. By understanding vascular reactivity profiles along the a...
The aorta varies in structural and biomechanical properties along its length, however, the influence of these properties on aortic pathology is poorly understood. By understanding vascular reactivity profiles along the aorta, we can target treatment with regional specificity. Here, we characterize vascular function in four distinct segments of the aorta (ascending, proximal thoracic, distal thoracic, and infrarenal) in C57BL/6J mice. Aortic segments were isolated and assessed functionally via wire myography, where segments were treated with exogenous pharmacological agents or electrical field stimulation (EFS) to evaluate changes in isometric force measurement. Overall, we observed distinct functional profiles and length-tension relationships for each aortic segment, including sex differences. With exception of the infrarenal aortic segment, we observed enhanced vasoconstriction in females to the α1-adrenergic receptor agonist, phenylephrine. The infrarenal aorta was uniquely resistant to KCl-mediated vasoconstriction relative to the other segments regardless of sex. Nonspecific adrenergic receptor stimulation by norepinephrine showed regional differences in vasoconstriction, while the sex differences were less apparent compared to phenylephrine. Although regional differences in vasoconstriction were observed during sympathetic nerve stimulation by EFS, sex differences were not seen. Our findings suggest that sex as a variable differs along the aorta when comparing endogenous neurovascular transmission to exogenous pharmacological agents. Interestingly, we found that the magnitude of endothelial-dependent vasodilation varied by aortic region, while smooth muscle-dependent vasodilation was consistent across all segments. These data highlight the importance of sex as a biological variable in understanding vascular reactivity along the aorta and demonstrate that aortic function is region specific.
Continuous blood pressure variability within young, healthy adults: a test-retest study to assess relative and absolute reliability.
Valtadoros LE, Valdez Rendon DA, Newton CA … +3 more , Morgan GB, Bigalke JA, Carter JR
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42262764 · Publisher ↗
Variability in 24-h and visit-to-visit blood pressure (BP) has been reported to be predictive of adverse cardiovascular outcomes. Although recent studies have used beat-to-beat blood pressure variability (BPV) as a predi...
Variability in 24-h and visit-to-visit blood pressure (BP) has been reported to be predictive of adverse cardiovascular outcomes. Although recent studies have used beat-to-beat blood pressure variability (BPV) as a predictor of cardiovascular risk, the reliability of beat-to-beat BPV remains equivocal. The purpose of this study was to examine the intraindividual reliability of BPV and to compare that reliability to more widely documented heart rate variability (HRV) in young healthy adults. Continuous heart rate (HR, electrocardiogram), beat-to-beat blood pressure (BP, finger plethysmography), and respiratory rate (pneumobelt) were recorded during 10 min of rest in 77 participants [38 males and 39 females; age: 23 ± 5 yr; body mass index (BMI): 25 ± 4 kg·m] on two occasions separated by ≥2 days (25 ± 19 days; 2-98 days). Reliabilities of beat-to-beat BPV, HRV (time- and frequency-domain), and additional cardiovascular (heart rate, blood pressure) assessments were quantified as relative and absolute reliability using the intraclass correlation coefficient (ICC) and the coefficient of variation (CoV), respectively. Beat-to-beat BPV demonstrated moderate relative and good absolute reliability (10-min duration: ICC = 0.601-0.684, CoV = 14%-16%). In contrast, relative reliability of time-domain HRV was good-to-excellent, whereas absolute reliability was poor-to-good (10-min duration: ICC = 0.844-0.904, CoV = 13%-34%). Frequency-domain HRV demonstrated moderate to excellent relative reliability and poor absolute reliability (10-min duration: ICC = 0.626-0.903, CoV = 34%-37%). In summary, the rigor and reliability of continuous BPV and HRV are different when parsed out by relative versus absolute reliability, with relative reliability being stronger with HRV and absolute reliability being stronger with BPV. These findings suggest both caution and specificity when using continuous BPV or HRV for cardiovascular disease (CVD) risk-stratification purposes. Beat-to-beat blood pressure variability (BPV) has gained attention as a noninvasive predictor of cardiovascular disease. However, the reliability of BPV has not been adequately characterized. We investigated the intraindividual reliability of beat-to-beat BPV and compared that reliability to more traditional heart rate variability (HRV). BPV demonstrated higher absolute, but lower relative, reliability compared with HRV. These findings suggest a need for caution and specific reporting when using continuous BPV or HRV for cardiovascular risk-stratification purposes.
Near-infrared spectroscopy demonstrates preserved and reproducible resting skeletal muscle oxygenation across anatomical sites in stable heart failure.
Eng-Frost J, Ravikulan R, De Pasquale JA … +5 more , Antonio L, Sibbin C, Bihari S, Bersten A, De Pasquale CG
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42258365 · Publisher ↗
Near-infrared spectroscopy (NIRS) enables noninvasive assessment of regional tissue oxygenation ([Formula: see text]). Although impaired skeletal muscle oxygenation during stress is well documented in heart failure (HF),...
Near-infrared spectroscopy (NIRS) enables noninvasive assessment of regional tissue oxygenation ([Formula: see text]). Although impaired skeletal muscle oxygenation during stress is well documented in heart failure (HF), the reproducibility of resting [Formula: see text] and its potential utility for clinical monitoring remain unclear. Twenty adults (10 healthy; 10 chronic HF) underwent [Formula: see text] assessment using the Medtronic INVOS 7100 system at five sites: pectoralis major, deltoid, biceps, flexor carpi, and rectus femoris. Duplicate measurements were obtained over 1 min with sensor repositioning between recordings. Effects of time and group were evaluated using general linear models. Reproducibility was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman analyses ( < 0.05). Resting [Formula: see text] was similar between healthy participants and those with HF across all anatomical sites (pectoralis major: = 0.73; deltoid: = 0.71; biceps: = 0.12; flexor carpi: = 0.20; rectus femoris: = 0.32). No significant effects of time, group, or group-by-time interactions were observed (all > 0.10), except for a small increase in biceps [Formula: see text] in HF ( = 0.04). Reproducibility remained high following sensor repositioning, with strong ICCs across all sites (all ≥ 0.84; < 0.001) and minimal bias on Bland-Altman analyses. Resting skeletal muscle [Formula: see text] measured by NIRS is preserved and highly reproducible across anatomical sites in stable HF, despite inherent microvascular and oxygen delivery abnormalities. These findings support the feasibility of NIRS for longitudinal [Formula: see text] monitoring. However, resting [Formula: see text] alone does not discriminate HF status, suggesting that NIRS may have greater clinical utility for detecting dynamic changes during physiological stress or acute HF decompensation. Near-infrared spectroscopy (NIRS)-derived skeletal muscle oxygenation ([Formula: see text]) remained preserved across five clinically accessible anatomical sites in stable chronic heart failure (HF) despite established microvascular abnormalities. Measurements were highly reproducible following sensor repositioning, supporting the reliability of NIRS for longitudinal monitoring. The inability of resting [Formula: see text] to discriminate HF status suggests greater diagnostic value during physiological stress or acute HF decompensation.
Does a (cardiac) maelstrom await infants born prematurely?
Phoon CKL, Ketterling JA
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42246448 · Publisher ↗
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Sex-specific molecular signatures of reverse remodeling after aortic valve replacement.
Halade GV
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42246423 · Publisher ↗
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Sleep restriction and cardiovascular disease risk: insights into potential mechanisms and sex differences.
Craighead DH, Fonkoue IT
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42246421 · Publisher ↗
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Progranulin deficiency induces premature vascular senescence and dysfunction.
Luvizotto RAM, Nascimento AF, Pimenta GF … +13 more , de Costa RM, Beling T, Singh S, Alves JV, Awata WMC, Russ A, Haastrup AI, Cuevas RA, Behzadi P, St Hilaire C, Roberts JT, Bruder A, Bruder-Nascimento T
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42233590 · Publisher ↗
Cellular senescence-an age-associated state characterized by irreversible cell cycle arrest and proinflammatory signaling-contributes to vascular dysfunction and cardiovascular disease. However, the molecular mechanisms...
Cellular senescence-an age-associated state characterized by irreversible cell cycle arrest and proinflammatory signaling-contributes to vascular dysfunction and cardiovascular disease. However, the molecular mechanisms linking senescence to vascular impairment remain incompletely defined. Progranulin (PGRN) is a multifunctional protein involved in inflammation, lysosomal function, and cellular homeostasis, but its role in vascular aging is not well understood. We assessed PGRN expression in human and mouse arteries and in senescent vascular smooth muscle cells (VSMCs). Vascular function was examined in PGRN-deficient () mice. Cellular senescence was pharmacologically targeted using the senolytic agents navitoclax (ABT-263) and fisetin, and vascular phenotypes were evaluated in adult (6-mo-old) and aged (18-mo-old) mice. PGRN expression increased with age in human and mouse arteries and strongly correlated with p21 expression. In adult mice, PGRN deficiency induced endothelial dysfunction, enhanced vasoconstriction, and promoted vascular inflammation and remodeling. Transcriptomic profiling of PGRN VSMCs revealed a senescence-associated signature characterized by impaired oxidative phosphorylation, epigenetic dysregulation, and enrichment of collagen-related pathways. Senolytic treatment improved endothelial-dependent relaxation but increased vascular contractility in PGRN mice. In aged mice, PGRN deficiency exacerbated vascular dysfunction, remodeling, and renal injury without further increases in senescence markers, consistent with premature rather than progressive vascular senescence. PGRN deficiency promotes premature vascular dysfunction through coordinated mitochondrial, epigenetic, inflammatory, and structural mechanisms. These findings identify PGRN as a key modulator of vascular homeostasis and suggest that impaired PGRN signaling may predispose to early-onset vascular and cardiorenal dysfunction. This study identifies progranulin (PGRN) as a key regulator of premature vascular dysfunction. Using human and mouse arteries and integrated multi-omics analyses, we show that PGRN deficiency induces early vascular senescence, mitochondrial dysfunction, epigenetic remodeling, and fibrosis. Senolytic treatment uncovers divergent roles of endothelial versus smooth muscle cell senescence in vascular function, highlighting PGRN as an important modulator of vascular homeostasis during aging.
Left ventricular chamber stiffness and strain determines the myocardial transcriptional response to elevated filling pressure.
Graser LA, Weil BR, Miecznikowski JC … +1 more , Canty JM
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42233541 · Publisher ↗
Transient hypertension precedes sustained hypertension and can arise from reduced aortic compliance with aging. We recently demonstrated that daily hypertension transients in swine rapidly lead to irreversible increases...
Transient hypertension precedes sustained hypertension and can arise from reduced aortic compliance with aging. We recently demonstrated that daily hypertension transients in swine rapidly lead to irreversible increases in left ventricular (LV) chamber stiffness without the development of anatomic hypertrophy (LVH). This dissociation was surprising and led us to hypothesize that the transcriptional response to pressure overload was determined by LV diastolic chamber stiffness. Myocardial tissue for RNASeq was obtained 24 h after transient pressure elevation (left ventricular end-diastolic pressure from 12.2 ± 0.8 mmHg to 34.3 ± 2 mmHg and LVSP from 105 ± 3 mmHg to 223 ± 8 mmHg) using phenylephrine. Animals with a single episode [single pressure overload (SPO), = 6] were compared with those with daily repetitive pressure overload (RPO) for 2 wk (RPO, = 8). After RPO, LV diastolic chamber stiffness increased fourfold (0.55 ± 0.08 to 2.38 ± 0.50 mmHg/mL/m after RPO, < 0.01) and fibrosis increased (normal 5.7 ± 0.2% to 12.9 ± 1.8% after RPO, < 0.01) without the development of LVH (128 ± 6.6 g/m vs. 129 ± 3.6 g/m after RPO, p-ns). There was a robust transcriptional response to SPO, with 5,885 of 12,483 genes (47%) differentially expressed (DEGs). These included potential determinants of chamber stiffness (extracellular matrix, fibrosis, and actin-cytoskeleton), hypertrophy, and inflammation. In contrast, after 2 wk of RPO, the transcriptional response to similar elevations in pressure was markedly attenuated with only 841 DEGs (7%). Our data indicate that LV chamber stiffness is a key determinant of the transcriptional response to pressure overload that attenuates hypertrophic gene expression. This may explain the wide variability of LVH among patients with a similar extent of pressure overload. Data indicate that left ventricular (LV) chamber stiffness is the key determinant of the myocardial transcriptional response to transient pressure overload. In contrast to sustained pressure overload, repetitive LV pressure overload stimulates fibrosis, increases LV chamber stiffness in the absence of hypertrophy, and attenuates multiple transcriptional pathways. Alterations in chamber stiffness from blood pressure transients may explain the wide variability of LV hypertrophy seen among patients despite similar pressure overload.
COP9 signalosome deneddylation activity is required for proliferation but not dedifferentiation of vascular smooth muscle cells in neointimal hyperplasia.
Giri S, Wang X
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42233540 · Full text
Neointimal hyperplasia (NH) is a prominent pathological consequence following vascular injury and is driven in part by aberrant vascular smooth muscle cell (VSMC) proliferation. COP9 signalosome (CSN) subunit 5 (CSN5/JAB...
Neointimal hyperplasia (NH) is a prominent pathological consequence following vascular injury and is driven in part by aberrant vascular smooth muscle cell (VSMC) proliferation. COP9 signalosome (CSN) subunit 5 (CSN5/JAB1/COPS5) is the deneddylase component of the CSN holocomplex responsible for deneddylation of cullin-RING ligases. Although CSN5/CSN is well studied in cancer biology, the role of CSN5/CSN in NH and vascular biology remains largely unexplored. Here, we investigated whether selective inhibition of CSN deneddylase activity using CSN5i-3 could mitigate neointimal remodeling following arterial injury. Adult mice were subjected to daily intraperitoneal injections of CSN5i-3 (20 mg/kg/day) or vehicle and left common carotid artery ligation. The left and the right common carotid arteries were then assessed for VSMC phenotypic modulation and neointima formation after 7 days of treatment. CSN5i-3 treatment markedly attenuated the ligation-induced changes in the mRNA level of , , , and , genes associated with extracellular matrix deposition and cell-cycle progression, but did not alter expression changes of canonical smooth muscle differentiation markers (, and ) and in the ligated vessel. Importantly, CSN5i-3 significantly blunted the increases of proliferating cell nuclear antigen (PCNA) expression and Ki67-positive VSMCs and reduced neointimal areas. These findings demonstrate that CSN deneddylase activity is dispensable for the dedifferentiation of contractile VSMCs into the synthetic state but promotes VSMC proliferation, supporting the concept that the dedifferentiation and proliferation of VSMCs in neointimal formation are separately regulated processes and differentially regulated by different CSN actions. This study also indicates that CSN5i-3 is highly promising in preventing neointimal hyperplasia. This study provides compelling in vivo evidence that selective inhibition of COP9 signalosome (CSN) deneddylation activity by CSN5i-3 suppresses neointimal hyperplasia through reducing proliferation of vascular smooth muscle cells without impacting their dedifferentiation. This not only identifies CSN5i-3 as a promising agent in preventing neointimal hyperplasia but also supports the new concept that dedifferentiation and proliferation of vascular smooth muscle cells in neointimal formation are separately regulated processes and differentially regulated by CSN-mediated deneddylation.
In vivo evidence of blood flow slippage: failure of the no-slip boundary condition assumption.
Jarolímová A, Hron J, Tůma K … +3 more , Chabiniok R, Málek J, Rajagopal K
Am J Physiol Heart Circ Physiol · 2026 Jul · PMID 42228951 · Publisher ↗
The assumption that blood adheres to vessel walls with zero tangential velocity component, the so-called "no-slip" boundary condition, is a foundational premise of cardiovascular fluid dynamics. Whether the no-slip condi...
The assumption that blood adheres to vessel walls with zero tangential velocity component, the so-called "no-slip" boundary condition, is a foundational premise of cardiovascular fluid dynamics. Whether the no-slip condition holds in vivo, however, remains unknown. Seven healthy adult volunteers underwent cardiovascular magnetic resonance imaging. With four-dimensional flow magnetic resonance imaging of the descending thoracic aorta and modeling blood as a Navier-Stokes fluid, near-wall blood velocities were quantified, and wall shear stress was calculated based on the measured velocity fields. Within the Navier-Stokes data assimilation framework, tangential wall velocities of ∼30-80% of the mean luminal velocity were consistently obtained. These results provide evidence for effective macroscopic slip behavior at the aortic wall in vivo. Consequently, wall shear stresses were substantially reduced compared with values obtained under the assumption of no-slip. This finding challenges the universal use of the classical no-slip boundary condition in macroscopic cardiovascular flow modeling and directly affects key blood flow characteristics such as pressure drop, vorticity, wall shear stress, and energy dissipation, which play important roles in both normal and disease-state cardiovascular conditions. Using in vivo magnetic resonance imaging data from healthy adult volunteers, we provide evidence for effective macroscopic slip behavior along the endothelial surface in the descending thoracic aorta. Not a single case exhibited zero tangential velocity, which would define the classical no-slip boundary condition. We introduce a robust analysis framework that ensures consistent and reproducible results across manual, AI-based, and uniformly dilated AI-based vascular segmentations.
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