Sjöberg P, Frieberg P, Alsafi Z
… +2 more, Liuba P, Arheden H
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41617636
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Ventricular function is vital in patients with single ventricles but repeated surgeries and changes in ventricular volume load may change the relation between longitudinal and radial function. To expand the knowledge of...Ventricular function is vital in patients with single ventricles but repeated surgeries and changes in ventricular volume load may change the relation between longitudinal and radial function. To expand the knowledge of cardiac mechanics in this population, the aim of this study was to assess longitudinal and radial contribution to stroke volume using cardiac magnetic resonance (CMR) imaging in patients before and after Fontan operation. We also aimed to assess whether the atrioventricular coupling was intact in these patients despite multiple pericardiotomies. Twelve children underwent CMR before and after completion of Fontan circulation. Endocardial borders of the atria and the ventricle as well as the epicardial border of the heart were delineated. The percentage of the stroke volume attributed to longitudinal and radial function was calculated and pulmonary venous blood flow during the cardiac cycle was assessed. Longitudinal function correlated strongly with atrial filling ( = 0.90, ICC = 0.92) and its contribution to stroke volume was 40 [38-49] % before and 39 [33-45] % after completion of Fontan circulation ( = 0.092). All patients lacked the late systolic flow peak in the pulmonary veins corresponding to the lack of a normal right ventricle. In conclusion, patients with single ventricles exhibit preserved atrioventricular coupling but the ventricle has lower longitudinal and higher radial contribution to stroke volume as a consequence of the passive pulmonary blood flow relative to healthy hearts. Completion of Fontan circulation does not change this relationship. This study shows that patients with single ventricles exhibit lower longitudinal systolic function than healthy subjects. The longitudinal contribution to stroke volume was about 40% compared with ∼80% in a normal right ventricle and 60% in a normal left ventricle. This difference is likely related to the passive blood flow through the lungs and did not change after Fontan completion. Furthermore, atrioventricular coupling seems to be preserved despite previous pericardiotomies.
Oakland HT, Bellumkonda L, Sugeng L
… +10 more, Joseph P, Kundu P, Izzi D, Zalik F, McCabe S, Raza A, Amendola R, Heerdt PM, Hunter KS, Singh I
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41616802
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Traditional echocardiographic metrics of right ventricular (RV) function, including tricuspid annular plane systolic excursion and two-dimensional (2-D) strain, are limited to the description of longitudinal systolic fun...Traditional echocardiographic metrics of right ventricular (RV) function, including tricuspid annular plane systolic excursion and two-dimensional (2-D) strain, are limited to the description of longitudinal systolic function. These metrics, however, fail to account for the complex, three-dimensional (3-D) deformation of the RV. 3-D echocardiograms (3DE) were obtained simultaneously during clinically indicated right heart catheterization (RHC). We determined the maximum principal surface strain (PS) and angle (ϴ) of RV surface deformation in pulmonary arterial hypertension (PAH) and control patients. We compared 22 control patients to 37 patients with PAH, of whom 11 met hemodynamic criteria for right heart (RH) failure. Compared with 2-D descriptors of RV function, PS was significantly different between controls and patients with PAH and between PAH patients with and without RH failure. ϴ was progressively oriented longitudinally in PAH patients without RH failure compared to PAH patients with RH failure [37.5° (34.3° to 40.8°) vs. 34.3° (32.1° to 36.2°), = 0.042] and in PAH patients with worse New York Heart Association functional class. Thirty-day outcomes were significantly different with an optimal cutoff of PS of -21.4%, with a hazard ratio of 6.8 (95% CI 1.3 to 35.2, = 0.022). PS is a robust marker of RH failure and provides prognostic value in PAH beyond conventional 2-D descriptors of RH function. Progressive longitudinal deformation of ϴ is associated with worse RH function and functional class. Impaired PS is associated with worse RV systolic function and outcomes in PAH when compared with conventional 2-D metrics of RV systolic function, while ϴ is progressively oriented longitudinally in PAH patients with RH failure compared to those without RH failure, potentially reflecting an echocardiographic representation of maladaptive RV myofiber reorientation. PS and ϴ represent a powerful and concise way to describe RV systolic function that may prove useful in the care of PAH patients.
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41616783
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Autonomic dysfunction is a common clinical feature of wild-type transthyretin amyloidosis (wtATTR) that may include disease-related changes in baroreflex function. We tested the hypothesis that central and peripheral hem...Autonomic dysfunction is a common clinical feature of wild-type transthyretin amyloidosis (wtATTR) that may include disease-related changes in baroreflex function. We tested the hypothesis that central and peripheral hemodynamic responses to progressive lower-body negative pressure (LBNP; -10, -20, -30, -40 mmHg; 5 min per stage)-induced hypovolemia would be attenuated in patients with wtATTR ( = 13, 74 ± 6 yr) compared with control subjects with HFpEF of nonamyloid etiology ( = 13, 72 ± 4 yr). Changes in heart rate (HR) and stroke volume (SV) during LBNP assessed central cardiac responsiveness, and changes in forearm blood flow (FBF) and vascular conductance (FVC) evaluated peripheral vascular responsiveness. Lower levels of LBNP (-10 and -20 mmHg) were used to evaluate the cardiopulmonary baroreflex, whereas higher levels of LBNP (-30 and -40 mmHg) assessed integrated (cardiopulmonary + arterial) baroreflex function. There were no group differences in LBNP-induced changes in HR or SV at any stage of LBNP ( > 0.05 for all comparisons). Vasoconstriction, as quantified by changes in FVC, was reduced in wtATTR at -30 mmHg (CON, -0.20 ± 0.20 mL/min/mmHg; wtATTR, -0.04 ± 0.17 mL/min/mmHg; = 0.011) and -40 mmHg (CON, -0.26 ± 0.22 mL/min/mmHg; wtATTR, -0.02 ± 0.20 mL/min/mmHg; < 0.01). MAP was unchanged across all levels of LBNP in controls, but decreased in the wtATTR group at the highest level of LBNP ( = 0.039). These findings provide new evidence for derangements in integrative baroreflex function beyond what is present in HFpEF from nonamyloid etiology that may contribute to blood pressure dysregulation during orthostasis in wtATTR. Wild-type transthyretin amyloidosis (wtATTR) is a unique cause of heart failure typically associated with orthostatic hypotension, likely implicating baroreflex dysfunction; however, this is yet to be investigated. Using the lower-body negative pressure technique to simulate orthostatic stress, we have identified impaired peripheral vascular responsiveness, which occurred in tandem with an inability to arterial blood pressure, suggesting that diminished sympathetic vasomotor responsiveness likely contributes to baroreflex dysfunction and impaired blood pressure regulation in patients with wtATTR.
Wang M, Ghazal R, Srinivas AN
… +18 more, Nguyen TTL, Murthy V, McNamara DM, Skime MK, Batzler A, Jenkins GD, Barlera S, Pileggi S, Mestroni L, Merlo M, Pinet F, Krejčí J, Chaloupka A, de Groote P, Weinshilboum RM, Tschumperlin DJ, Liu D, Pereira NL
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41609618
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A genome-wide association study (GWAS) identified neuron navigator 3 () as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in car...A genome-wide association study (GWAS) identified neuron navigator 3 () as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicate that expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with transforming growth factor β1 (TGF-β1) induced expression in a dose and time-dependent manner. Small-interfering-RNA-mediated knockdown of significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-smooth muscle actin (α-SMA), collagens, and fibronectin. RNA sequencing of -silenced fibroblasts, confirmed by Western blot, revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into 's novel role in cardiac fibrosis, showing that reduced expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM. This study uncovers a previously unrecognized role for in TGF-β1-driven cardiac fibroblast activation. We show that facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.
Evolution of gas exchange during intact cord resuscitation (ICR) remains unexplored. We aimed to investigate changes in placental hemodynamics and gas exchange during ICR in lambs with and without congenital diaphragmati...Evolution of gas exchange during intact cord resuscitation (ICR) remains unexplored. We aimed to investigate changes in placental hemodynamics and gas exchange during ICR in lambs with and without congenital diaphragmatic hernia (CDH). Eight CDH lambs (4.2 kg, 4 females) and nine controls (3.9 kg, 3 females) underwent ICR. At 80 days gestation (term = 142 days), CDH was induced by diaphragmatic incision. After c-section at term, mean arterial pressure (MAP) was monitored via an aortic catheter. Umbilico-placental blood flow (Qup) was assessed with a flow transducer on the umbilical artery. Umbilical venous pressure was recorded, and blood gases from the aorta and umbilical vein were analyzed to evaluate placental oxygen transfer. ICR was performed for 60 min, followed by cord clamping (CC). Qup and umbilical venous Po were similar and stable in both groups up to 50 min. MAP was 20% lower in normal lambs compared with CDH lambs ( < 0.05) but equalized after CC. In CDH lambs, placental oxygen transfer was maintained during ICR (2.7 [2.2-3.3] mL/kg/min). [Formula: see text] was unchanged during ICR (53 [50-58] mmHg) and abruptly increased after CC (83 [60-101] mmHg) ( < 0.05). For control lambs, placental oxygen transfer dropped to 0 [-0.3 to 0.2] mL/kg/min within 20 min of starting resuscitation, coinciding with an significant increase in [Formula: see text] ( = 16 [12; 18] mmHg; = 50 [48-105] mmHg and [50; 110] mmHg after CC). ICR may support oxygenation and carbon dioxide removal in CDH newborns through placental gas exchange. Maternal anesthesia with halogenated gas sustains placental circulation for 1 h postbirth. Intact cord resuscitation supports oxygenation (placental oxygen transfer ∼2.7 mL/kg/min) for 1 h in the congenital diaphragmatic hernia (CDH) lamb model. Maintaining feto-placental circulation during delivery room resuscitation in the context of CDH ensures continuous oxygenation and carbon dioxide clearance for up to 1 h.
Salomon JD, Karl AC, Ahmad R
… +3 more, Bastola D, Singh AB, Mishra PK
Am J Physiol Heart Circ Physiol
· 2026 Apr · PMID 41605465
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Gut dysbiosis is increasingly recognized as a contributor to heart failure; however, its specific role in the development of metabolic syndrome-induced heart failure (MetS-HF) remains poorly defined. A defining feature o...Gut dysbiosis is increasingly recognized as a contributor to heart failure; however, its specific role in the development of metabolic syndrome-induced heart failure (MetS-HF) remains poorly defined. A defining feature of MetS-HF is cardiac steatosis, which drives lipotoxicity, maladaptive remodeling, and progressive cardiac dysfunction. This review integrates mechanistic and translational evidence showing how gut microbiota dysbiosis initiates and exacerbates MetS-HF by disrupting lipid homeostasis, leading to myocardial steatosis, metabolic remodeling, cardiomyocyte death, adverse structural remodeling, and impaired cardiac performance. We also highlight how gut dysbiosis promotes systemic inflammation and hypertension, further aggravating cardiac dysfunction in MetS-HF. Finally, we discuss the potential of artificial intelligence, integrative multiomics, and network-based bioinformatics to elucidate the molecular pathways linking gut dysbiosis to MetS-HF and to identify novel therapeutic targets.
van Doorn ECH, Zhang L, Veen KM
… +4 more, Amesz JH, Kluin J, de Groot NMS, Taverne YJHJ
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41605459
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Atrial dysfunction plays a critical role in cardiac disease, particularly during arrhythmias and in heart failure, where impaired atrial contraction can compromise cardiac output. Yet, models that allow direct assessment...Atrial dysfunction plays a critical role in cardiac disease, particularly during arrhythmias and in heart failure, where impaired atrial contraction can compromise cardiac output. Yet, models that allow direct assessment of human atrial biomechanics remain scarce. Living myocardial slices (LMS) have the potential to revolutionize preclinical cardiac studies by preserving native architecture and performance in near-physiological environments, offering a patient-specific platform to investigate atrial function. To address this gap, we present the first functional analysis of human atrial LMS across diverse disease phenotypes, including healthy tissue, heart failure (HF), rhythm disorders, and atrial dilatation. Using the largest human atrial LMS dataset to date, containing 250 slices from 48 patients, we assessed contractile force, kinetics, force-frequency relationships, and refractoriness during the acute culture phase. Atrial slices exhibited faster contractions than ventricular LMS. HF and dilated atria showed reduced contractile force and prolonged contraction and relaxation, whereas slices from patients with atrial fibrillation displayed preserved or enhanced kinetics with increased variability in refractoriness. Structural analyses confirmed elevated fibrosis in all disease groups, along with disease-specific alterations in cellular morphology and tissue organization. Together, these findings provide a reference framework for human atrial biomechanics, thereby positioning LMS as a promising model for studying atrial pathophysiology in vitro. Human atrial living myocardial slices (LMS) bridge the gap between clinical disease and tissue-level mechanistic insight. Using the largest dataset of human atrial slices to date, this study maps the biomechanical landscape of the atrium and reveals preserved disease-specific signatures in vitro. These findings position LMS as a promising platform for studying atrial pathophysiology and therapeutic development.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give ris...Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-β (TGF-β) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.
Debebe SK, Rahman A, DeYoung T
… +5 more, Cahill LS, Parks WT, Macgowan CK, Kingdom JC, Sled JG
Am J Physiol Heart Circ Physiol
· 2026 Jan · PMID 41592716
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Placental insufficiency associated with impaired uteroplacental blood flow is the leading cause of human fetal growth restriction. While preclinical studies have examined the effects of global reductions in uterine blood...Placental insufficiency associated with impaired uteroplacental blood flow is the leading cause of human fetal growth restriction. While preclinical studies have examined the effects of global reductions in uterine blood flow, the downstream consequences of a focal disruption in flow remains unknown. We investigate how murine maternal canal occlusion(s) impacts placental development and fetal growth. Pregnant CD-1 mice at embryonic (E) day 15.5 underwent abdominal surgery to exteriorize the uterus. Under ultrasound guidance, zero, one or two of the, typically three, placental canals were microinjected with an embolizing agent. Survival at term (E18.5) was 81% for shams, 62% for single embolized, and 24% for the double embolized. Surviving double embolized fetuses weighed significantly less than both internal and external controls. The brain-to-liver volume ratio was significantly elevated in the singles and doubles versus controls (p = 0.00537, p = 0.00861) and shams (p = 0.01207, p = 0.017738). Placental histopathology, and 3D MRI confirmed, a reduction in junctional zone volume and significantly higher whole placenta-to-junctional zone volume ratio in the single embolized cohort (9.66, 95% CI [8.23-11.1]) compared to naïve controls and shams (6.21, 95% CI [4.79-7.63], p = 0.0298; (6.20, 95% CI [4.71-7.70], p = 0.00394, respectively). Canal occlusion resulted in impaired fetal growth and altered placental morphology yet did not cause focal placental infarction typical of impaired uteroplacental blood flow in humans. This placental model of fetal growth restriction may be amenable to testing new intervention strategies aimed at supporting fetal growth when placental function is impaired.
Gumbo CT, Corbin D, Zhang N
… +5 more, Mclaughlin SL, Muthu S, Venkatesh S, Karelina K, Weil ZM
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41592702
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Traumatic brain injury (TBI) is a prevalent neurological condition with long-term consequences that extend beyond the brain. Individuals with a history of TBI are at increased risk for cardiovascular complications, but t...Traumatic brain injury (TBI) is a prevalent neurological condition with long-term consequences that extend beyond the brain. Individuals with a history of TBI are at increased risk for cardiovascular complications, but the mechanisms remain poorly understood. Here, we tested the hypothesis that mild-to-moderate chronic cerebral hypoperfusion, modeled via bilateral carotid artery stenosis (BCAS), exacerbates cardiac dysfunction following TBI. Male and female Swiss Webster mice (8-10 wk old) were randomly assigned to Sham, BCAS, TBI, and BCAS + TBI groups. Cerebral blood flow (CBF) was evaluated at rest and after acetazolamide challenge to evaluate cerebrovascular reserve. Neuroinflammation was assessed in the insular cortex, using ionized calcium-binding adapter molecule 1 (IBA-1) and glial fibrillary acidic protein (GFAP) immunostaining. Cardiac function was evaluated using transthoracic echocardiography, and myocardial morphology was detected by hematoxylin and eosin staining. TBI significantly reduced cardiac function in both sexes, whereas BCAS had no effect by itself. Similar structural changes in cardiomyocytes, such as decreased nuclear density and increased nuclear size, were observed in both TBI and BCAS + TBI mice. BCAS alone robustly elicited gliosis in the insular cortex in the absence of cardiac dysfunction. BCAS + TBI also decreased CBF and cerebrovascular reactivity, along with enhanced glial activation in the insula. These results indicate that TBI-elicited cardiac injury is accompanied by neuroinflammation in central autonomic centers, and preexisting cerebral hypoperfusion does not increase cardiac vulnerability. This study highlights the role of the brain-heart axis as a key driving force in post-TBI morbidity and raises the possibility that cerebrovascular health may serve as a mediator of cardiac outcomes following brain injury. TBI impairs cardiac function and induces glial activation in the insular cortex, a key autonomic region. Although mild-to-moderate chronic cerebral hypoperfusion (BCAS) induces gliosis and reduces cerebrovascular reserve, it does not exacerbate TBI-related cardiac dysfunction. Our findings demonstrate that TBI-driven neuroinflammatory signaling, rather than chronic hypoperfusion, underlies cardiac vulnerability after brain injury, highlighting the brain-heart axis as a key contributor to cardiovascular morbidity.
Yang B, Adekunbi DA, Huber HF
… +12 more, Camones R, Li J, Moody AJ, Riojas AM, Li C, Hall-Ursone S, Frost P, Register TC, Cox LA, Nathanielsz PW, Salmon AB, Clarke GD
Am J Physiol Heart Circ Physiol
· 2026 Apr · PMID 41592575
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Women threatening premature delivery receive synthetic glucocorticoids (sGC) to reduce offspring neonatal respiratory distress. Evidence linking prenatal sGC exposures to adverse cardiovascular outcomes is accumulating....Women threatening premature delivery receive synthetic glucocorticoids (sGC) to reduce offspring neonatal respiratory distress. Evidence linking prenatal sGC exposures to adverse cardiovascular outcomes is accumulating. We studied adult baboons, which had been exposed in utero to sGC equivalent to a human therapeutic dose, and compared with age-matched saline-exposed controls (CTR). Magnetic resonance imaging was performed in middle-aged male offspring (∼10.5 yr) and in both sexes at old age (∼16.5 yr) to assess heart structure, function, and paracardial adipose thickness (PAT). Postmortem left ventricular (LV) tissues were analyzed for mitochondrial electron transport chain complex activities and protein expression. In sGC versus CTR males, LV end-systolic (ESSI) and end-diastolic (EDSI) sphericity indexes increased with age (ESSI: = 0.0001, EDSI: = 0.002) being greater in elderly sGC group (ESSI: = 0.03, EDSI: = 0.0001 2-way ANOVA). In sGC-exposed males, global longitudinal strain (GLS) decreased with age versus CTR ( = 0.03) and PAT was greater ( = 0.03) than CTR males. In elderly sGC-exposed baboons, ejection fraction ( = 0.04), ESSI ( = 0.002), and PAT ( = 0.002) were greater in males than females, whereas global radial strain ( = 0.032) and GLS ( = 0.014) were lower. EDSI was higher in both male and female sGC than in CTR (M: = 0.014, F: = 0.009). Mitochondrial analyses revealed reduced complex I-linked respirations ( < 0.05) with a negative correlation between PAT and MTCO1 mitochondrial protein in males ( = 0.02), but not in females. These results indicate that fetal sGC exposure impairs heart function and metabolism. Enhanced lifelong monitoring could improve understanding of the sex-specific mechanisms impacted by antenatal sGC. Antenatal maternal synthetic glucocorticoids (sGC) treatment effectively prevents neonatal respiratory distress but may predispose offspring to adverse cardiovascular outcomes later in life. Using longitudinal MRI and mitochondrial analysis in a well-characterized nonhuman primate model, we report progressive lipid dysregulation, impaired myocardial function, and left ventricular remodeling specifically in aging male but not female offspring. These findings underscore the need to refine sGC therapy to avert long-term cardiovascular risks in exposed offspring.
Ikonomidis I, Papageorgiou A, Pavlidis G
… +12 more, Georgiopoulos G, Katogiannis K, Maratou E, Thymis J, Pliouta L, Kountouri A, Korakas E, Kostelli G, Parissis J, Nikolaou PE, Andreadou I, Lambadiari V
Am J Physiol Heart Circ Physiol
· 2026 Feb · PMID 41579346
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Carotid intima-media thickness (cIMT), amyloid-β1-40 (Aβ1-40), and oxidative stress are markers of vascular aging and cardiovascular risk. We compared the effects of insulin, glucagon-like peptide-1 receptor agonists (GL...Carotid intima-media thickness (cIMT), amyloid-β1-40 (Aβ1-40), and oxidative stress are markers of vascular aging and cardiovascular risk. We compared the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on the aforementioned markers in type 2 diabetes (T2DM). We prospectively studied 183 metformin-treated T2DM patients, propensity-score-matched to 12-mo treatment with insulin, liraglutide, empagliflozin, or liraglutide plus empagliflozin. Six-segment cIMT and plaque-equivalent lesions (cIMT ≥ 1.5 mm) were assessed at baseline, 6, and 12 mo; plasma Aβ1-40 and malondialdehyde (MDA) were measured. All regimens were associated with reductions in cIMT and Aβ1-40 at 12 mo ( < 0.05). MDA decreased overall with the largest reduction in GLP-1RA-based regimens. Compared with insulin, liraglutide, empagliflozin, and their combination achieved greater reductions in cIMT (-8.2, -5.6, and -10.7% vs. -1.7%, < 0.05) and in Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%, < 0.05). Patients achieving cIMT < 1.5 mm at 12 mo was the highest with combination therapy (75%), followed by liraglutide (67%) and empagliflozin (54%) versus insulin (40%; < 0.05). Patients who regressed <1.5 mm showed greater reduction in Aβ1-40 than those with ≥1.5 mm (-56.2% vs. -25.1%, = 0.028). Liraglutide, empagliflozin, and their combination induced greater reduction of cIMT (-8.2, -5.6, and -10.7% vs. -1.7%) and Aβ1-40 (-52.1, -40.3, and -50.7% vs. -30.7%; < 0.05) compared with insulin. cIMT regression was associated with Aβ1-40 and MDA reductions ( < 0.05). In T2DM patients, GLP-1RA and SGLT-2i-particularly in combination-were associated with improvements in carotid atherosclerotic burden, amyloid-related vascular injury, and oxidative stress. We investigated the effect of insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on carotid intima-media thickness (cIMT) and amyloid-β1-40 (Aβ1-40) in diabetes. Twelve-month treatment with GLP-1RA, SGLT-2i, and their combination confers significant reductions in cIMT and Aβ1-40 compared with insulin. cIMT regression was associated with Aβ1-40 and malondialdehyde reductions. Our findings support that newer antidiabetic agents can favorably modify structural and biochemical markers of atherosclerosis.
Hua Y, Chu Y, Fu S
… +5 more, Verma A, Zhang J, Sethu P, Lee T, Xie M
Am J Physiol Heart Circ Physiol
· 2026 Jan · PMID 41569637
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Mitochondrial DNA (mtDNA) has emerged as a key signaling molecule, extending beyond its primary role in supporting energy production. Its replication, release, and degradation are tightly regulated, and their dysregulati...Mitochondrial DNA (mtDNA) has emerged as a key signaling molecule, extending beyond its primary role in supporting energy production. Its replication, release, and degradation are tightly regulated, and their dysregulation can activate immune pathways, including TLR9, cGAS-STING, and inflammasomes. In this review, we summarize recent advances in understanding mtDNA biology, including mechanisms of replication and release, recognition by pattern recognition receptors, and its impact on disease. We highlight evidence linking mtDNA to cardiovascular disease, as well as the aging-related chronic kidney disease, lung disorders, and neurodegeneration, and discuss the utility of circulating mtDNA copy number as a biomarker. Finally, we outline therapeutic strategies to reduce mtDNA release, block its sensing, and enhance clearance via autophagy/mitophagy. These findings underscore mtDNA as both a driver of pathology and a promising target for diagnosis and therapy across multiple organ systems.
Kim DS, Goo B, Shi H
… +29 more, Dong S, Weintraub DS, Coffey P, Veerapaneni P, Chouhaita R, Guduru M, Cyriac N, Aboud G, Ong V, Cave S, Greenway J, Mundkur R, Ahmadieh S, Harb R, Ogbi M, Fulton DJ, Huo Y, Zhang W, Long X, Guha A, Kim HW, Shi Y, Rice RD, Zhou J, Chiang AWT, Gallo DR, Patel VS, Lee R, Weintraub NL
Am J Physiol Heart Circ Physiol
· 2026 Feb · PMID 41569144
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Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dy...Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of and matrix metalloproteinase 2- and 14-positive () expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease. Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.
Am J Physiol Heart Circ Physiol
· 2026 Mar · PMID 41556835
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Adults with Down syndrome (Ds) demonstrate unique cardiovascular features, including smaller left ventricular volumes and lower blood pressure. Ventricular-arterial coupling (VAC), a key measure of cardiovascular efficie...Adults with Down syndrome (Ds) demonstrate unique cardiovascular features, including smaller left ventricular volumes and lower blood pressure. Ventricular-arterial coupling (VAC), a key measure of cardiovascular efficiency, has not been previously studied in this adult population. Understanding VAC in adults with Ds may reveal compensatory mechanisms that maintain cardiac output despite distinct cardiovascular characteristics. This study used echocardiographic parameters to compare the VAC ratio of adults with and without Ds. Baseline echocardiographic data were collected from 28 adults with Ds and 18 adults without Ds (aged 18-35 yr), all of whom had low physical activity levels. The VAC ratio was calculated using the single-beat method. Adults with Ds had lower VAC ratios and diastolic blood pressure, faster preejection times, shorter normalized systolic durations, and a higher ejection fraction than adults without Ds. Adults with Ds exhibit distinct cardiovascular adaptations, including a lower VAC ratio and a shorter systolic duration, suggesting increased cardiac workload. Higher ejection fraction and faster preejection period indicate potential compensatory mechanisms to maintain cardiac output, whereas lower diastolic blood pressure may reduce coronary perfusion and preload. These findings demonstrate differences in cardiac function and timing in adults with Ds in this study. This study reveals, for the first time, that adults with Down syndrome exhibit significantly lower ventricular-arterial coupling ratios, reflecting distinct cardiac timing and functional adaptations. These findings could indicate a compensatory mechanism to maintain cardiac output despite reduced diastolic pressure and smaller cardiac chambers, providing novel insight into the integrated cardiovascular physiology of adults with Down syndrome and its potential implications for exercise tolerance and long-term cardiovascular health.