Cox JR, Ahmed F, Liao C
… +3 more, Avolio AP, Qasem A, Butlin M
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 41996130
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Arterial stiffness, as measured by carotid-femoral pulse wave velocity (cfPWV), is an independent cardiovascular risk factor. Arterial stiffness measurement requires the acquisition of pulse waveforms at two arterial sit...Arterial stiffness, as measured by carotid-femoral pulse wave velocity (cfPWV), is an independent cardiovascular risk factor. Arterial stiffness measurement requires the acquisition of pulse waveforms at two arterial sites. This technique is often constrained to clinical or laboratory settings. Estimated PWV (ePWV) addresses these limitations by only requiring the measurement of a single pulse, or no pulse at all, providing a wider application for cardiovascular health monitoring. The aim of this systematic literature review is to investigate the various approaches and clinical utility of ePWV as a surrogate measure of arterial stiffness. The literature search followed the PRISMA guidelines and was conducted in the following databases: Embase, MEDLINE, PubMed, and Scopus. The initial search identified 409 papers: Embase ( = 38), MEDLINE ( = 98), PubMed ( = 93), and Scopus ( = 180). After screening and applying the exclusion criteria, 131 eligible papers remained. Peak topic publication occurred in 2024 (30%). Most papers (69%) used regression-based approaches in ePWV while 34% used a pulse wave analysis (PWA)-based approach. Most PWA approaches (57%) used an oscillometric cuff. There were few validation studies (12%). Validation studies presented correlations (r) from 0.35 to 0.92 and standard deviations reaching ±2.54 m/s. The use of ePWV as a surrogate for arterial stiffness is positively observed across the literature. However, validation studies reveal substantial individual differences hidden within acceptable population averages, underscoring the need to refine estimation algorithms for greater precision. This structured literature review provides a collective overview of the various indirect approaches that have been used for noninvasive estimation of pulse wave velocity (PWV), along with the various clinical applications they have been used in. It focuses on the vast use of simple regression-based approaches, the individual differences hidden in the population averages, and how the inclusion of pulse wave analysis (PWA), currently underutilized, may enhance the assessment of arterial stiffness.
Mapelli M, Puttini F, Mattavelli I
… +13 more, Salvioni E, Galotta A, Ferrarini G, Canevari M, Willixhofer R, Caputo R, Costantino S, Biroli M, Lustri C, Grandi D, Teglia A, Valenti M, Agostoni P
Am J Physiol Heart Circ Physiol
· 2026 Jun · PMID 41996086
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Body posture influences cardiovascular and respiratory responses during exercise, yet in a clinical setting, differences in body positions are not considered when comparing different methodologies analyzing physical effo...Body posture influences cardiovascular and respiratory responses during exercise, yet in a clinical setting, differences in body positions are not considered when comparing different methodologies analyzing physical effort, such as cardiopulmonary exercise testing (CPET), stress echo, or invasive hemodynamic. We aimed to investigate how upright (UP), semirecumbent (SR), and supine (SP) positions affect key CPET variables and cardiac output (CO) in healthy adults. Twelve healthy volunteers (30.9 ± 4.4 yr; 50% female) performed three randomized CPETs in UP, SR, and SP positions. Breath-by-breath gas exchange data [oxygen uptake (V̇o) carbon dioxide production (V̇co), minute ventilation (V̇e), tidal volume (TV), respiratory rate (RR)] and hemodynamic parameters [CO by thoracic bioimpedance, stroke volume (SV), heart rate (HR)] were continuously monitored. Data were analyzed at rest, anaerobic threshold, iso-watt stages, and peak exercise. At rest and submaximal workloads, HR decreased, and SV increased with more reclined positions, maintaining CO. V̇e and TV were lower in SR and SP positions, whereas RR and peripheral oxygen saturation ([Formula: see text]) were unchanged. At peak exercise, V̇o, V̇co, workload, and exercise duration declined progressively from UP to SP (V̇o: 2,587 ± 1,009, 2,520 ± 982, 2,269 ± 847 mL/min; < 0.001), with lower V̇e driven by reduced TV. Despite reduced metabolic and ventilatory demands, CO was unchanged via increased SV. Dyspnea perception was lower in reclined postures. Body posture modulates cardiopulmonary responses during exercise. Semirecumbent and supine positions reduce V̇o and V̇e preserving CO. These findings highlight the importance of posture-specific reference values for accurate interpretation in clinical practice. Body position during exercise testing profoundly affects cardiopulmonary responses, even in healthy individuals. Results obtained in different postures are not directly comparable. Upright, semirecumbent, and supine exercise produce systematic changes in oxygen uptake, ventilation, workload, and dyspnea, with lower performance in reclined positions. Despite this, cardiac output is preserved through adjustments in heart rate and stroke volume, indicating that posture-rather than cardiac dysfunction-drives differences. Without posture-specific reference values, disease severity may be misinterpreted.
Horváth C, Jarabicová I, Hrdlička J
… +5 more, Marciníková A, Neckář J, Nekvindová E, Olejníčková V, Adameová A
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41989875
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Sex profoundly influences cardiac adaptation to stressful stimuli; however, sex-specific mechanisms underlying heart failure (HF) due to necrosis-like cell death remain unclear. Using a neonatal rat model of abdominal ao...Sex profoundly influences cardiac adaptation to stressful stimuli; however, sex-specific mechanisms underlying heart failure (HF) due to necrosis-like cell death remain unclear. Using a neonatal rat model of abdominal aortic constriction, which mimics pressure overload-induced HF, we investigated cardiac function and morphology and provided a comprehensive molecular analysis of cell death pathways. Although necroptosis was evident in failing hearts of both sexes, albeit with more excessive remodeling in males, pyroptosis and ferroptosis were not prominent. At the cellular level, macrophages likely underlie this damage via different mechanisms in each sex. In females, the upstream activators of necroptosis indicated a proinflammatory environment, with a role of tumor necrosis factor-mediated canonical pathway involving receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like pseudokinase. Conversely, in males, RIP3 activation was linked to an altered redox status and increased mitochondrial DNA oxidation. These sex-divergent pronecroptotic events underscore the necessity for personalized therapeutic strategies targeting distinct cell-damaging molecular pathways to improve HF outcomes. This study identifies necroptosis as a key pathomechanism in pressure overload-induced heart failure, with sex-dependent, prodeath molecular events. Novel findings indicate distinct pronecroptotic triggers: in males, necroptosis is driven by oxidative stress and mitochondrial DNA damage, whereas in females, a proinflammatory pathway involving tumor necrosis factor and compensatory mitochondrial biogenesis predominates. Pyroptosis and ferroptosis do not appear to be prominent. These sex-specific molecular necrosis-like divergences are important for developing personalized therapeutic strategies for heart failure.
Dokic V, Jayachandran M, Vaughan L
… +6 more, Suvakov S, Hatamova J, Gavrilovici P, Zhang S, Garcia Valencia O, Garovic VD
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41973512
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Compared with men, women with similar coronary artery calcification (CAC) scores face higher cardiovascular disease (CVD) mortality. We posited that circulatory factors, such as blood-borne extracellular vesicles (EVs) a...Compared with men, women with similar coronary artery calcification (CAC) scores face higher cardiovascular disease (CVD) mortality. We posited that circulatory factors, such as blood-borne extracellular vesicles (EVs) and metabolites, may be associated with the development of CAC and subsequent CVD in postmenopausal women. In addition, we hypothesized that a history of preeclampsia (PE), a sex-specific risk factor, might be a contributing factor. Clinical data were obtained from medical records for postmenopausal women (median age 60 yr) free of cardiovascular events with ( = 29) and without ( = 29) CAC. EVs per microliter plasma were quantified by digital flow cytometry, and plasma metabolites were measured using gas chromatography-mass spectrometry. CACs were measured by computer tomography and reported as the Agatston score. Patients with, versus those without, CAC demonstrated ) less favorable cardiovascular and metabolic profiles; ) elevation in six EV populations, including those positive for tissue factor, CD3 (T-cells), SM22α (smooth muscle cells), Pref-1 (adipocytes), fatty acid-binding protein 4 (adipocytes/macrophages), and p16 (senescent cells); ) significantly higher levels of proline, allothreonine (amino acid metabolism), and ribitol (carbohydrate metabolism), and lower levels of lactic acid (carbohydrate metabolism); and ) significantly increased risk of developing CVD and chronic kidney disease (CKD) ( < 0.05 for all). In the CAC-positive group, women with PE versus those with normotensive pregnancy histories demonstrated a four times higher risk of developing cardiovascular events or CKD later in life ( = 0.028). Selected plasma metabolites, EVs, and PE history could serve as biomarkers and potential therapeutic targets for CAC and CVD in postmenopausal women. Circulating extracellular vesicles, proinflammatory/pro-oxidant metabolites, and history of preeclampsia may be used as biomarkers for diagnosis of early CAC in postmenopausal women.
Fernández-Topham J, Guerrero-Hurtado M, Del Álamo JC
… +2 more, Bermejo J, Martinez-Legazpi P
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41956567
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Pressure-volume (PV) loop analysis remains the gold standard for assessing the intrinsic global diastolic properties of the left ventricle (LV). Traditional fitting techniques rely on local, phase-constrained fittings an...Pressure-volume (PV) loop analysis remains the gold standard for assessing the intrinsic global diastolic properties of the left ventricle (LV). Traditional fitting techniques rely on local, phase-constrained fittings and are limited due to their sensitivity to noise, landmark selection, violation of assumptions, and nonconvergence. We aimed to develop and validate DIA-, a physics-informed neural network (PINN) framework capable of calculating intrinsic diastolic properties of the LV from measured instantaneous PV data, combining mechanistic interpretability with machine learning flexibility. Instantaneous LV diastolic pressure was modeled as the sum of ) time-dependent relaxation-related pressure and ) volume-dependent recoil and stiffness-related pressures. DIA-PINN was trained using time, LV pressure, and LV volume as inputs, enforcing data fidelity, model consistency, and physiological plausibility within the loss function. Performance was evaluated in 4,000 Monte Carlo simulations of LV PV-loops, and in clinical data from 59 patients who underwent catheterization (39 with heart failure and normal ejection fraction and 20 controls). DIA-PINN-derived indices were compared with those obtained from a previously validated global optimization method (GOM). On the simulation data, DIA-PINN accurately recovered all constitutive indices (intraclass correlation coefficients near unity) and improved GOM performance. On the clinical data, diastolic indices derived using DIA-PINN strongly correlated with GOM estimates ( > 0.90, < 0.001) but were insensitive to initialization. DIA-PINN performed best under vena cava occlusion, as varying preload improved parameter identifiability. When applied to instantaneous pressure-volume data, a generalizable PINN framework, DIA-PINN, provides an improved method for assessing global intrinsic diastolic properties of cardiac chambers. Our work introduces DIA-PINN, a physics-informed neural network framework to process instantaneous ventricular pressure-volume data, solving a mechanistic model of diastole with machine learning techniques. Compared with current conventional or optimization-based approaches, the PINN provides the most reliable estimates of diastolic stiffness, relaxation, and elastic recoil, insensitive to initialization. By embedding physiological constraints into network training, this approach achieves robust, interpretable, and clinically applicable quantification of gold-standard metrics of intrinsic global diastolic chamber properties.
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41954137
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Blood pressure regulation involves bidirectional brain-heart interactions mediated by both neurochemical signals and mechanosensitive pathways that include recently identified piezo receptors. We review current findings...Blood pressure regulation involves bidirectional brain-heart interactions mediated by both neurochemical signals and mechanosensitive pathways that include recently identified piezo receptors. We review current findings on the dynamic interplay between neural activity and blood pressure, highlighting insights from neuroimaging, systemic electrophysiology, and cellular biology. At a systemic level, blood pressure dynamics is regulated by coordinated oscillatory patterns across brain, cardiac, and respiratory signaling that couple with autonomic outflow and vascular pulsatility. Central autonomic networks, sympathetic-parasympathetic activity, and beat-to-beat blood pressure variability are mainly involved in such bidirectional interactions. At the cellular level, astrocytes, pericytes, endothelial cells, and cardiac and neural glia integrate mechanical pressure signals with metabolic and synaptic activity, forming distributed mechanosensory networks within the neurovascular unit and the cardiac autonomic nervous system. We show that optimal perfusion depends on arterial pressure remaining above a critical threshold to maintain vascular patency, with autoregulatory, metabolic, neurogenic, and glia-mediated mechanisms buffering systemic pressure fluctuations. When perfusion falls, astrocyte- and pericyte-dependent baroreflex mechanisms increase sympathetic drive, whereas pressure surges and altered arterial compliance promote vasoconstriction through coordinated neurovascular and central-autonomic responses. Pathological changes in arterial compliance and pulsatility, including loss of Windkessel function and nonphysiological flow states, distort neural pressure sensing and contribute to cardiovascular, cerebrovascular, and cognitive dysfunction and altered emotional processing. Invasive and noninvasive neuromodulation strategies may offer therapeutic potential by restoring physiological mechanosensory and autonomic control. These insights highlight the importance of mapping systemic central-autonomic networks and cell-specific neuromechanotransduction in health and in neurological, cardiovascular, and psychiatric disorders (1).
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41926628
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The physiological role of the Orai1 channel, a store-operated Ca channel in adult ventricular cardiomyocytes, remains incompletely defined. Here, we report that Orai1 may contribute to excitation-contraction coupling (EC...The physiological role of the Orai1 channel, a store-operated Ca channel in adult ventricular cardiomyocytes, remains incompletely defined. Here, we report that Orai1 may contribute to excitation-contraction coupling (ECC) in a sex-specific manner. Using a mouse model with cardiac-specific expression of a dominant-negative human Orai1 mutant (C-dnO1), we found elevated Ca transients and Ca spark amplitudes in female C-dnO1 mice in comparison with littermate wild-type (WT) controls, but not in male mice. The Orai1 protein expression, cellular distribution, and store-operated Ca entry activity were similar in WT males and females and equally diminished in both sexes with C-dnO1 expression. These findings reveal that chronic functional suppression of Orai1 abrogates sex differences in cardiomyocyte ECC, uncovering a novel mechanistic contribution of Orai1 to sexual dimorphism in cardiac function. This short report reveals a novel mechanistic contribution of the Ca channel Orai1 to sexual dimorphism in cardiac physiology. We demonstrated that the chronic functional suppression of Orai1 abrogates sex differences in cardiomyocyte excitation-contraction coupling.
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41910178
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Although cardiovascular disease is the leading cause of death globally, therapeutic development in this field is slow. Given the high cost of developing new drugs and running clinical trials for cardiovascular disease, r...Although cardiovascular disease is the leading cause of death globally, therapeutic development in this field is slow. Given the high cost of developing new drugs and running clinical trials for cardiovascular disease, repurposing of drugs with approved safety profiles is an attractive strategy for therapeutic development that can significantly reduce the time and cost investment before phase II clinical trials. In the era of "Omics," various new methods and several large databases have been developed to enable the use of transcriptomics data for drug repurposing. This review summarizes the principles and workflow of signature mapping, which forms the foundation of statistical models used for transcriptome-based drug repurposing. We highlight the features of different analysis pipelines and databases that have been developed for signature mapping. These analysis pipelines prioritize genes that are statistically important, an approach that fundamentally differs from the pharmacological approach of identifying disease-driving and therapeutically targetable pathways. Outcomes of signature mapping pipelines are sensitive to the quality of input data, and results are not always reproducible. Moreover, all widely used RNA-seq databases are derived from cancer research and lack high-quality molecular data for cardiovascular disease. These unmet needs call for interdisciplinary collaboration and large networks of cardiovascular research-oriented biobanks to create the databases needed for transcriptomic-based signature mapping for drug repurposing efforts.
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41886287
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Total carotid pulse wave velocity (T-PWV), a measure of arterial stiffness, is caused by structural (S) remodeling and elevated blood pressure exerting a pressure-load on the arterial wall. Isoprostanes are oxidative str...Total carotid pulse wave velocity (T-PWV), a measure of arterial stiffness, is caused by structural (S) remodeling and elevated blood pressure exerting a pressure-load on the arterial wall. Isoprostanes are oxidative stress biomarkers that have been associated with arterial stiffness. We sought to investigate the cross-sectional and longitudinal associations of urinary 8-isoprostane (iPF2α-III) and its metabolite (iPF2α-III-M), measured at a single timepoint at baseline, with carotid T-PWV, S-PWV, and load-dependent (LD)-PWV in a subset ( = 744) of participants enrolled in the Multi-Ethnic Study of Atherosclerosis. We hypothesized that higher iPF2α-III and iPF2α-III-M concentrations would be associated with higher T-PWV, S-PWV, and LD-PWV. These relationships were evaluated using multivariable linear regression models adjusted for potential confounders in the entire analytical sample and in analyses stratified by hypertension medication class and race/ethnicity. In cross-sectional analyses of the entire analytic sample, there were no associations of acute iPF2α-III or iPF2α-III-M with carotid T-PWV, S-PWV, or LD-PWV after adjusting for risk factors. In adults taking angiotensin-II acting antihypertensive medications, higher iPF2α-III was associated with higher S-PWV, whereas higher iPF2α-III-M was associated with higher T-PWV and S-PWV. In the entire analytic sample, baseline isoprostanes were not associated with carotid PWV measured nearly a decade later. However, in analyses stratified by race/ethnicity, higher baseline iPF2α-III was associated with higher S-PWV nearly a decade later among self-identified White participants. These results suggest that single-timepoint measures of urinary 8-isoprostane are not a robust biomarker of arterial stiffness but may be associated with structural remodeling in select populations. We examined cross-sectional and longitudinal associations of urinary isoprostanes with carotid T-PWV, and its associated mechanisms (S-PWV and LD-PWV), in a multiethnic cohort of adults. Higher isoprostanes were cross-sectionally associated with carotid artery stiffness driven by structural remodeling in adults who self-reported taking angiotensin-II acting medications or self-identified as White. No associations were observed with isoprostanes and carotid stiffness a decade later in the entire analytic sample. Oxidative stress may augment the risk of structural remodeling in select populations.
Caligiuri SPB, Ravandi A, Aukema HM
… +1 more, Shah AH
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41886286
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The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation ofte...The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation often develop progressive multisystem dysfunction, the biochemical underpinnings of which remain poorly understood. Oxylipins are bioactive lipid mediators implicated in cardiovascular disease and represent targetable pathways that may contribute to the pathophysiology of the Fontan state. The study aims to quantify plasma oxylipins in individuals with Fontan circulation, compared with matched controls, and assess correlations with hemodynamic function and exercise capacity. A total of 20 adult patients with Fontan circulation and 20 matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. Compared with controls, Fontan participants exhibited significantly increased (34%) total plasma oxylipin concentrations, with a 42% elevation in ω-6 fatty acid-derived oxylipins. Among these, metabolites generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%. In addition, product-to-substrate ratios reflecting putative soluble epoxide hydrolase (sEH) activity for ω-6 fatty acids were nearly threefold higher in the Fontan group. Several oxylipins derived from ω-3 and ω-6 fatty acids, including those generated by 15-LOX and sEH pathways, demonstrated significant correlations with key clinical parameters, including resting and exercise hemodynamics, ventilatory efficiency, and peak oxygen consumption (V̇o). Individuals with Fontan circulation exhibit marked alterations in circulating oxylipins, particularly those involving ω-6 fatty acid metabolism via 15-LOX and sEH. These findings offer mechanistic insights and identify potentially modifiable targets. Fontan patients exhibit a distinct oxylipin signature characterized by markedly elevated total and ω-6-derived oxylipins, including increased 15-LOX activity and higher sEH product-to-substrate ratios, alongside reduced ω-3 species such as 20-hydroxydocosahexanoic acid (20-HDoHE) and 17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated ω-6 oxylipins correlated with poorer exercise capacity, greater frailty, and impaired hemodynamics, whereas ω-3 oxylipins showed the opposite trend. These findings identify oxylipin dysregulation as a central metabolic hallmark and potential therapeutic target in Fontan circulation.
Spencer LW, Flannery MD, Janssens K
… +9 more, Bekhuis Y, Wright L, Howden EJ, Van Puyvelde T, Prior DL, Mitchell AM, Rowe SJ, Foulkes SJ, La Gerche A
Am J Physiol Heart Circ Physiol
· 2026 May · PMID 41886278
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Cardiac filling is constrained by a reduced ejection time and diastolic period as heart rate increases during exercise. We compared cardiac filling dynamics in endurance athletes and controls during exercise to determine...Cardiac filling is constrained by a reduced ejection time and diastolic period as heart rate increases during exercise. We compared cardiac filling dynamics in endurance athletes and controls during exercise to determine how athletic status influences hemodynamic constraints during exercise. Thirty-two participants (21 endurance athletes and 11 controls) underwent exercise echocardiography at 20, 40, and 60% of peak power output. We measured cardiac timing, stroke volume (SV), and flow rates (SV indexed to body surface area and phase duration). Data were analyzed using linear mixed models. Athletes demonstrated resting bradycardia (44 ± 8 vs. 68 ± 14 beats/min, < 0.001), through an extended ejection time (296 ± 38 vs. 247 ± 30 ms, < 0.001) and diastolic filling (811 ± 229 vs. 560 ± 161 ms, = 0.005). Preexercise cardiac outputs were matched ( = 0.969). During exercise, there was a significant group × exercise interaction for left ventricular (LV) ejection time ( < 0.001) and diastolic period ( < 0.001), indicating distinct athletic adaptations. Although the systolic-to-diastolic (S/D) ratio was similar at rest, a significant interaction occurred during exercise ( = 0.013). Athletes also achieved a greater cardiac output response (group × exercise interaction: < 0.001). Indexed stroke volume increased similarly in both groups (interaction: = 0.271) yet remained significantly higher in athletes (group effect: < 0.001). Consequently, athletes maintained superior absolute volumes throughout the protocol, resulting in greater high-intensity stroke volumes. Athletes are able to produce greater reductions in both LV ejection and diastolic filling time and generate higher stroke volumes during exercise, permitting greater cardiac outputs and a greater exercise response. This study reveals that endurance athletes' slow resting heart rates provide additional time for ventricular filling. During intense exercise, athletes compensate for dramatically shortened filling times by achieving remarkably higher flow rates, particularly during systole. These differences allow athletes to maintain larger stroke volumes at both rest and at high heart rates, producing superior cardiac outputs and highlighting a key physiological mechanism underlying endurance performance.