Doxorubicin (DOX) is a potent chemotherapeutic drug used to treat a variety of cancer types, but its usage is limited due to major cardiovascular side effects. According to World Health Organization reports, by 2050, new...Doxorubicin (DOX) is a potent chemotherapeutic drug used to treat a variety of cancer types, but its usage is limited due to major cardiovascular side effects. According to World Health Organization reports, by 2050, new cancer cases are projected to increase to >35 million, implying an enhanced risk of DOX-induced cardiomyopathy (DIC). Despite its cardiotoxic side effects, DOX has remained an effective therapeutic choice for cancer treatment. Current evidence suggests that multiple pathophysiological mechanisms are involved in DIC, including oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, calcium dysregulation, and inflammation, all of which lead to cardiac cell death and disease progression. Recently, several oxidative stress and inflammation-mediated signaling pathways, including MAPK, HMGB1/TLR4, NFκB, NLRP3 inflammasome, JAK-STAT, and TNFα, have been identified as contributing factors to cardiac remodeling in DIC. Although significant progress has been made over the past two decades in understanding the pathophysiological mechanisms of DIC, the exact mechanism leading to DIC remains unclear. Hence, in this review, we discuss various types of immune cells, including neutrophils, monocytes, and macrophages, cellular and molecular pathological mechanisms of inflammation, and various types of cell death in DIC. Further we discussed how understanding the significance of inflammatory mechanisms may enhance therapeutic efficacy and inform future perspectives.
The effects of heat exposure on dynamic cerebral autoregulation (dCA), the capacity of the cerebrovasculature to buffer rapid changes in arterial pressure, and its directional sensitivity, defined as the asymmetric cereb...The effects of heat exposure on dynamic cerebral autoregulation (dCA), the capacity of the cerebrovasculature to buffer rapid changes in arterial pressure, and its directional sensitivity, defined as the asymmetric cerebrovascular response to increases versus decreases in mean arterial pressure (MAP), remain incompletely understood. This uncertainty is largely attributable to concomitant heat-induced reductions in arterial carbon dioxide. We hypothesized that moderate isocapnic hyperthermia would impair dCA, particularly at higher frequencies of MAP oscillations, while preserving directional sensitivity across thermal conditions. Twenty healthy young participants (9 females, age: 24 ± 5 yrs) completed oscillatory lower body negative pressure trials at 0.05 and 0.10 Hz under normothermic and hyperthermic (core temperature +1.0°C) conditions. End-tidal carbon dioxide partial pressure (PCO) was clamped at baseline using a computer-controlled gas delivery system. Middle cerebral artery mean blood velocity (MCAvmean), MAP, PCO, heart rate, and core temperature were continuously recorded. dCA was assessed using transfer function analysis (TFA), and directional sensitivity was quantified using time-adjusted absolute (∆MCAvmean/∆MAP) and relative (RelMCAvmean/RelMAP) metrics. Moderate isocapnic hyperthermia increased TFA coherence at both frequencies and selectively impaired dCA at 0.10 Hz, as evidenced by increased TFA gain and normalized gain. Directional sensitivity was present at 0.05 Hz, indicated by higher ∆MCAvmean/∆MAP and RelMCAvmean/RelMAP during MAP decreases compared with increases, but was absent at 0.10 Hz. These findings demonstrate that isocapnic hyperthermia impairs dCA at higher frequency while preserving directional sensitivity at lower frequency, suggesting that distinct physiological mechanisms govern these components of cerebrovascular regulation beyond the influence of carbon dioxide.
Wingert J, Haase L, Meinhardt E
… +2 more, Frey N, Schlegel P
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42370963
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Echocardiographic evaluation of diastolic function in murine HFpEF models remains challenging due to insufficient temporal resolution of current high frequency doppler probes at heart rates beyond 450 beats per minute (b...Echocardiographic evaluation of diastolic function in murine HFpEF models remains challenging due to insufficient temporal resolution of current high frequency doppler probes at heart rates beyond 450 beats per minute (bpm). Aiming to optimize anesthesia for diastolic assessment in mice, we compared standard isoflurane sedation with a combination of isoflurane and either of the negative chronotropic substances medetomidine or esmolol. Both combined anesthetic regimens preserved doppler measurement accuracy while resulting in lower heart rates, better discernibility of separate doppler velocity waves and shorter examination times. However, the combination of isoflurane and medetomidine showed a superior safety profile, preservation of systolic function as well as higher inter-rater reliability, recommending itself as a refined anesthetic protocol for echo-based HFpEF phenotyping in C57BL6/N mice.
Gonçalves A, Zhelan Chen E, Rastegarpouyani H
… +6 more, Araújo Fernandes A, N Alves I, Sequeira V, Kwon C, Chelko SP, Landim-Vieira M
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42363865
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Pathogenic variants in desmoglein-2 () are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling....Pathogenic variants in desmoglein-2 () are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in -associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous mutant () mouse to define chamber-specific mitochondrial remodeling in -linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
Richard A, Zhou Z, Esparza Pinelo JE
… +6 more, Kwartler CS, Kalyanaraman H, Boss GR, Lu HS, Daugherty A, Milewicz DM
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42363828
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Thoracic aortic aneurysms involving the root and ascending aorta progressively enlarge and can lead to life-threatening acute aortic dissections, collectively termed thoracic aortic disease (TAD). Oxidative stress due to...Thoracic aortic aneurysms involving the root and ascending aorta progressively enlarge and can lead to life-threatening acute aortic dissections, collectively termed thoracic aortic disease (TAD). Oxidative stress due to an excess of reactive oxygen species (ROS), has been implicated in TAD pathogenesis by promoting vascular inflammation, extracellular matrix (ECM) degradation, and smooth muscle cell (SMC) apoptosis. Cobinamide (Cbi), a potent antioxidant and vitamin B12 analog, has been reported to slow aortic aneurysm growth in TAD mouse models. We evaluated its efficacy in mice administered β-aminopropionitrile (BAPN) to induce TAD, a model in which aneurysms progress to dissections. C57BL/6J mice of both sexes were administered either BAPN alone or BAPN plus Cbi in drinking water from postnatal day 21 (P21). Survival analysis showed that 56% of mice in the BAPN group died from aortic rupture by P49, whereas mortality increased to 91% in the BAPN+Cbi group (P=0.049). Necropsy confirmed thoracic aortic rupture as the cause of death. At P35, proximal aortic analyses showed that Cbi significantly reduced ROS abundance in the ascending aorta, based on decreased dihydroethidium staining and lower oxidative stress markers, including protein carbonylation and DNA oxidation by 8-hydroxy-deoxyguanosine staining. Cbi did not affect aortic diameters by echocardiography, or elastic fiber fragmentation. Cbi was associated with reduced oxidative stress in aortic tissue, it did not prevent aortic dissection and was associated with increased rupture-related mortality in the BAPN model. These findings highlight context-dependent roles of ROS in TAD and the importance of carefully evaluating antioxidant strategies in dissection-prone settings.
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42345613
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Atrial fibrillation (AF) is a highly prevalent arrhythmia and a major cause of morbidity and mortality. Although AF is not a primarily immunologic disorder, increasing clinical, translational, and experimental evidence i...Atrial fibrillation (AF) is a highly prevalent arrhythmia and a major cause of morbidity and mortality. Although AF is not a primarily immunologic disorder, increasing clinical, translational, and experimental evidence indicates that leukocytes can modify substrate vulnerability to AF. In this review, we summarize how neutrophils, monocytes, macrophages, B-cells, T-cells, mast cells, and less-studied leukocyte populations contribute to AF initiation, maintenance, and complications. We first outline core electrophysiologic mechanisms of AF, including focal ectopic activity and re-entry. We then discuss how leukocytes may influence these processes through atrial recruitment, immune-mediated electrical remodeling, NET-associated thromboinflammation, and fibrosis. We highlight context-specific differences in the role of leukocytes between postoperative AF, cardiometabolic AF models, and persistent AF, and distinguish leukocyte populations with causal evidence from those supported primarily by associative human data. Finally, we review immune-targeted therapeutic approaches and discuss why clinical translation has been inconsistent, emphasizing timing, patient selection, disease stage, and endpoint heterogeneity.
Nagalingam RS, Beak JY, Lutze RD
… +10 more, Huang W, Akkina D, Kang C, Zhao A, Alcira B, Aghajanian A, Gerrish K, Kang HS, Jetten AM, Jensen BC
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42345523
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AIMS: We recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (RORα)protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The target gen...AIMS: We recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (RORα)protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The target genes for this ligand-activated transcriptional co-regulator have not been defined in the heart. METHODS: We used RNA microarrays to profile the cardiac transcriptomes of "staggerer" (RORα) mice that carry a naturally occurring mutation in the ligand-binding domain of RORα, resulting in a global loss-of-function genetic model. We then used genetic and pharmacologic loss-and-gain of function studies in cultured cardiomyocytes to ascertain whether RORα regulates transcription of Adra1a, the gene that encodes the alpha-1A-adrenergic receptor (α1A-AR). RESULTS: The absence of functional RORα results in broad transcriptomic changes in the heart, suggesting that transcriptional regulation rather than non-canonical effects of RORα likely underlie the RORα cardiac phenotype. and studies confirm that RORα directly regulates transcription. This effect is enhanced by hypoxia. CONCLUSIONS: Collectively these findings suggest that RORα may contribute broadly to regulating the cardiac transcriptome and identify RORα as the first recognized transcriptional regulator of in cardiomyocytes. Future studies will probe the contribution of RORα-mediated transcriptional regulation of to both the response to cardiomyocyte injury and maintenance of circadian biology.
Berry AR, Ruzzene ST, Garcia VP
… +8 more, Wegerson KN, Cardenas HL, Ostrander EI, Fandl HK, Izaias JE, Greiner JJ, Stauffer BL, DeSouza CA
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42318983
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The aim of this study was to determine, in vitro, the effect of endothelial cell-derived extracellular vesicles (EEVs) from older adults on brain microvascular endothelial cell oxidative stress, inflammation, nitric oxid...The aim of this study was to determine, in vitro, the effect of endothelial cell-derived extracellular vesicles (EEVs) from older adults on brain microvascular endothelial cell oxidative stress, inflammation, nitric oxide (NO) and endothelin (ET)-1 production as well as tissue-type plasminogen activator (t-PA) release. Circulating EEVs (CD144+ extracellular vesicles) were enumerated and isolated (flow cytometry) from the plasma of 30 healthy, sedentary, non-obese, adults: 15 young (age: 21-35 yr; 7 M/8 F) and 15 older (55-80 yr; 7 M/8 F). Human cerebral microvascular endothelial cells (hCMECs) were cultured and treated with EEVs from either group. EEVs from older adults induced higher ROS (140±51 vs 99±16 % of control; P=0.02) production and lower expression of catalase (13.7±3.7 vs 23.2±7.4 AU; P<0.01) and SOD-1(147.6±41.1 vs 281.2±78.3; P<0.01) in hCMECs than EEVs from young adults. EEVs from older adults did not induce cellular inflammation. Expression of phosphorylated (p)-eNOS (Ser1177) was significantly lower (61.6±13.0 vs 77.7±17.6 AU), p-eNOS (Thr495) significantly higher (49.9±16.4 vs 38.0±10.9 AU) and NO production (5.9±1.6 vs 7.3±1.3 µmol/L)was significantly lower in hCMECs treated with EEVs from older adults. Big ET-1 (95.3±17.1 vs 69.4±20.6 AU; P<0.001) and ECE (164.8±26.0 vs 128.4±18.5 AU: P<0.001) expression as well as ET-1 production (27.3±9.1 vs 21.2±5.5 pg/mL; P=0.03) were significantly higher in hCMECs treated with EEVs from older adults. t-PA release in response to thrombin was significantly lower (~30%) in hCMECs treated with EEVs from older adults. Circulating EEVs represent a potential mechanistic factor contributing to increased stroke risk with aging.
Heart failure with preserved ejection fraction (HFpEF) is traditionally characterized as a disorder of diastolic dysfunction. However, this framework does not fully explain the dissociation between preserved left ventric...Heart failure with preserved ejection fraction (HFpEF) is traditionally characterized as a disorder of diastolic dysfunction. However, this framework does not fully explain the dissociation between preserved left ventricular ejection fraction (LVEF) and impaired functional capacity. HFpEF may be conceptualized as a syndrome of reduced effective stroke volume despite preserved LVEF. Structural remodeling, increased myocardial stiffness, and impaired diastolic suction contribute to limited ventricular filling, whereas preserved circumferential and radial mechanics may help maintain LVEF in some patients. This can result in a mismatch between forward flow and filling pressures, which may contribute to limited cardiac output reserve and, in a subset of patients, neurohormonal activation and congestion. This perspective is supported by existing physiological and clinical observations. HFpEF may present as a phenotype characterized by impaired systemic perfusion and elevated filling pressures in many patients, although significant heterogeneity exists. This article proposes an integrative physiological framework in which heart failure with preserved ejection fraction (HFpEF) is conceptualized as a syndrome of reduced effective stroke volume despite preserved left ventricular ejection fraction. It highlights the dissociation between preserved ejection fraction and impaired forward flow, integrating ventricular filling abnormalities, myocardial deformation, diastolic suction impairment, and systemic hemodynamic consequences into a unified model. This perspective may improve understanding and management of HFpEF.
Sanches GS, Hakim MA, Brooks SD
… +9 more, Marins TDSB, da Silva Moreira A, Gomes F, Seara FAC, Benoit-Smith R, Daniel-Ribeiro CT, Ponte CG, Ackerman HC, Carvalho LJM
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42315097
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Experimental cerebral malaria (ECM) is associated with abnormalities in cerebral perfusion, yet the mechanisms underlying vascular dysfunction remain incompletely defined. Ex vivo pressure myography of middle cerebral a...Experimental cerebral malaria (ECM) is associated with abnormalities in cerebral perfusion, yet the mechanisms underlying vascular dysfunction remain incompletely defined. Ex vivo pressure myography of middle cerebral arteries (MCAs) was used to assess intrinsic arterial function in control and ECM mice. Mesenteric arteries were used to compare intraluminal perfusion versus abluminal superfusion with healthy plasma or serotonin (5-HT). Wire myography of aortic rings as a biosensor for plasma-derived vasoactive factors was used to investigate circulating modulators of vascular tone. MCAs from ECM animals showed preserved constriction to 5-HT, preserved endothelium-dependent relaxation to methacholine (MCh), and intact responses to nitroprusside. MCh relaxation was inhibited by L-NAME, indicating preserved endothelial NO signaling. In aortic rings, ECM plasma produced concentration-dependent vasoconstriction, enhanced by NOS inhibition. Blockade of 5-HT₂A receptors with ketanserin abolished >80% of this constriction in a sex-independent manner, demonstrating that plasma 5-HT is the predominant circulating vasoconstrictor. Plasma or 5-HT induced robust vasoconstriction when applied abluminally, but not intraluminally. ECM does not cause intrinsic endothelial or smooth muscle dysfunction of the MCA. Vasoconstrictive responses to plasma from ECM or control mice were similar, suggesting no major differences in plasma vasoregulatory molecules. Plasma serotonin exerts a vasoconstrictive effect in the setting of NOS inhibition when plasma contacts the adventitial, but not the luminal, aspect of an artery. Based on these findings, we propose that normal circulating levels of serotonin could potentially have vasoconstrictive effects in disease conditions that compromise vascular barrier integrity.
Fang YJ, Gonzalez K, Konecny F
… +2 more, Chicco AJ, Chung E
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42312966
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Maternal exercise may influence long-term cardiovascular health in offspring, yet its effects on intrinsic myocardial performance and mitochondrial metabolism remain incompletely defined. We investigated whether maternal...Maternal exercise may influence long-term cardiovascular health in offspring, yet its effects on intrinsic myocardial performance and mitochondrial metabolism remain incompletely defined. We investigated whether maternal voluntary wheel running before and during pregnancy is associated with cardiac adaptations in adult offspring. Female C57BL/6J mice were assigned to sedentary (Sed) or exercise (Ex) groups, with running initiated 3 weeks before mating and continued through gestation and lactation. Adult offspring (29-32 weeks) underwent high-fidelity pressure-volume (P-V) loop analysis at baseline and, in females, during β-adrenergic stimulation to assess systolic reserve. Cardiac mitochondria were evaluated by high-resolution respirometry together with measurements of reactive oxygen species emission. Maternal exercise did not alter maternal body weight before delivery or adult offspring body weight, whereas cardiac mass index was significantly lower in A-Ex offspring than in A-Sed offspring. Baseline hemodynamics were largely similar between maternal groups. In females, maternal exercise was associated with lower end-systolic elastance (E) at rest and a greater dobutamine-induced increase in E, consistent with enhanced load-independent systolic reserve. Mitochondrial analyses revealed substrate-dependent adaptations in females: maternal exercise was associated with lower pyruvate/malate-supported LEAK respiration, higher fatty acid-supported LEAK respiration, and reduced fatty acid coupling efficiency compared with sedentary offspring. ROS emission, sarcoplasmic reticulum Ca-handling proteins, fetal gene expression, and collagen-related transcript expression were unaffected. These findings suggest persistent functional and mitochondrial respiratory adaptations in adult offspring following maternal exercise, with the clearest adaptations observed in females.
Khorasani N, Morotti S, Saucerman JJ
… +2 more, Dobrev D, Grandi E
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 42302746
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Atrial fibrillation (AF), the most common sustained arrhythmia, is both cause and consequence of atrial remodeling, with atrial fibrosis playing a key role in AF maintenance, progression, and treatment response. AF preva...Atrial fibrillation (AF), the most common sustained arrhythmia, is both cause and consequence of atrial remodeling, with atrial fibrosis playing a key role in AF maintenance, progression, and treatment response. AF prevalence rises with age, as sex hormone (estrogen, E2, and testosterone, TS) levels decline in both sexes, and aging-associated ECM remodeling parallels these hormonal transitions during menopause and andropause. Furthermore, extensive experimental evidence supports the protective effect of E2 and TS against fibrotic remodeling. However, the mechanistic basis of sex hormone-dependent antifibrotic effects remains unclear. To identify potential underlying mechanisms, we extended our computational model of atrial-enriched fibroblast (Fb) by incorporating E2 and TS pathways. We validated predictions against a broad set of independent experimental data, demonstrated 81% concordance in cardiac Fbs and 100% in atrial Fbs under two AF-relevant profibrotic stimuli, angiotensin-II (AngII) and transforming growth factor-β (TGFβ). E2 and TS significantly attenuated profibrotic remodeling triggered by both AngII and TGFβ. E2 exerted protection by suppressing Smad3 and upstream regulators of Ca signaling, reactive oxygen species (ROS) formation, and JUN N-Terminal Kinase (JNK). TS showed limited protection against TGFβ-induced fibrogenesis, but significantly blunted AngII-induced fibrotic responses mainly through Smad3. These analyses identified hormone-specific regulatory nodes through which E2 and TS mitigate atrial fibrogenesis, offering mechanistic insight into how loss of sex hormone-mediated protection may contribute to age- and sex-dependent atrial remodeling. Our findings provide a quantitative framework for exploring sex hormone-mediated regulation of atrial remodeling and highlight potential therapeutic targets for antifibrotic AF treatment.