Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency () exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized mice and employed isolated, ventilated, and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in mice compared with WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in mice, whereas SNP-induced responses were similar in wild-type (WT) and mice. Inhibition of NO synthase with (ω)-nitro-l-arginine methyl ester increased agonist-induced PVR in WT but not in mice. Pulmonary arteries isolated from mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, and NO-mediated maintenance of PVR in mice. Our study reveals a novel role for ESAM in contributing to the maintenance of pulmonary vascular resistance under normal physiological conditions. Employing mice with global genetic deficiency of ESAM and using isolated whole lung preparation, we show significant impairments in nitric oxide-mediated pulmonary artery function. In vitro cell culture studies demonstrate impaired fluid shear stress-induced cell alignment in human lung endothelial cells after siRNA-mediated ESAM knockdown.

Lower body negative pressure (LBNP) has been used for decades in humans to model arterial baroreceptor unloading and represents a powerful tool for evaluating cardiovascular responses to orthostatic challenges. However, LBNP studies in animals have been limited to conditions of anesthesia or sedation, where cardiovascular reflexes are altered. Given the consequent uncertainties, the usefulness of LBNP studies in these preclinical models has been severely hampered. Here, we developed an approach using a novel system to study LBNP responses in awake rats instrumented for telemetric blood pressure (BP) measurement. BP responses to progressive levels of LBNP (-3 to -15 mmHg) were first made in awake rats, followed by measurements under various treatments. In awake untreated rats, BP was well maintained up to -15 mmHg LBNP and there was a robust baroreceptor response in heart rate (HR). Under anesthesia with 3% isoflurane, BP was not maintained at LBNP below -3 mmHg and baroreceptor responses in HR were completely blocked, confirming the limited usefulness of this method under anesthesia. Interrogation of the autonomic pathways involved in the response revealed that muscarinic (atropine) and β-adrenergic (atenolol) blockade, separately or together, blocked the HR responses, but BP remained well maintained. α-adrenergic blockade (prazosin) severely blunted the ability to maintain BP in response to LBNP. These data are consistent with findings in human subjects in that the vascular component of the orthostatic reflex predominates in preserving BP. Validation of this novel method provides a valuable tool for investigating orthostatic (in)tolerance in a facile preclinical model. Orthostatic hypotension or intolerance is a common but often underappreciated disorder that is associated with a variety of neurological comorbidities. LBNP studies provide a valuable tool to study these conditions, but heretofore could only be used in human subjects, since animal subjects needed to be anesthetized or sedated, which blunts or eliminates neurocardiovascular reflexes. This novel method allowing LBNP studies in awake rats will provide a valuable preclinical model for studying these disorders.

Although previous work has demonstrated that oral contraceptive pill (OCP) use does not affect resting muscle sympathetic nerve activity (MSNA), growing evidence indicates that it attenuates neurogenic vasoconstriction. Despite these advances, it remains unknown how OCP use affects the ability of MSNA to dynamically control vascular tone and arterial blood pressure (BP) on a beat-by-beat basis. Thus, we tested the hypothesis that, compared with naturally menstruating females (MC), those using OCPs will exhibit attenuated sympathetic vascular transduction at rest. Forty-three females [MC: = 21, 26 (4) yrs; OCP: = 22, 24 (4) yrs; data are presented as means (SD)] completed 10 min of supine rest with continuous measurements of beat-by-beat BP, femoral artery blood flow (26 females; MC: = 13, OCP: = 13), and MSNA. Spike-triggered averaging was used to determine sympathetic transduction into leg vascular conductance (LVC) and BP for 12 cardiac cycles following MSNA bursts. Overall sympathetic-BP transduction ( = 0.293), as well as sympathetic-BP transduction of MSNA burst quartiles ( = 0.741) and burst firing patterns ( = 0.452) were not different between the MC and OCP groups. Conversely, sympathetic vascular transduction per unit MSNA burst amplitude ( = 0.026) and burst firing pattern ( = 0.014) were attenuated among females using OCPs. In addition, females using OCPs demonstrated progressively smaller leg vasoconstrictor responses as a function of MSNA burst firing pattern compared with MC females ( = 0.021). Collectively, these data indicate that, in premenopausal females, OCP use attenuates the leg vasoconstrictor responses to bursts of MSNA, particularly during periods of increased sympathetic neural drive, without affecting the transduction of MSNA bursts into beat-by-beat changes in BP. This study investigated the impact of OCP use on the transduction of MSNA bursts into regional vasoconstriction and blood pressure in premenopausal females. We demonstrated that females using OCPs exhibit attenuated sympathetic transduction into LVC; however, this does not translate to reductions in sympathetic blood pressure transduction. Collectively, these data indicate that OCP use may alter the local vasoconstrictor response to bursts of MSNA; however, compensatory mechanisms may contribute to maintain sympathetic blood pressure transduction.

The endothelin-B receptor (ETR) mediates vasodilation in young women, an effect that is absent in postmenopausal women. We have previously demonstrated that ETR-mediated vasodilation is regulated by estradiol (E) in young women; however, the impact of E on ETR function in postmenopausal women remains unknown. Accordingly, the objective of this study was to test the hypothesis that E exposure restores ETR-mediated dilation in postmenopausal women. Ten healthy postmenopausal women (55 ± 2 years of age, 5 ± 3 years since menopause) completed the study. E was administered by transdermal patch for 7 days (0.1 mg/day, Vivelle-Dot patch). Vasodilation in the cutaneous microcirculation (microvascular endothelial function) was measured via local heating (42°C) using laser Doppler flowmetry combined with intradermal microdialysis perfusions of lactated Ringer's (control) and ETR antagonist (BQ-788, 300 nM) at baseline and after E administration. There was no effect of E on ETR function (hormone*site, F = 0.77, P = 0.40). These data demonstrate that in contrast to findings in premenopausal women, E administration does not restore ETR function in postmenopausal women.

Increased blood pressure upon standing is considered a cardiovascular risk factor. We investigated the reproducibility of changes in aortic blood pressure, heart rate, stroke volume, cardiac output, and systemic vascular resistance during three passive head-up tilts (HUT) in 223 participants without cardiovascular medications (mean age 46 years, BMI 28 kg/m2, 54% male). Median time gap between the first and the second HUT was 9 weeks and the second and the third HUT 4 weeks. We utilized whole-body impedance cardiography and radial artery tonometry as methods. The participants were divided into quartiles of the changes in each hemodynamic variable during the first HUT, and the reproducibility of these changes was tested during successive HUTs. During the first HUT, significant differences were present in all between-quartile comparisons (n=6) of all variables. The differences persisted as follows: reduction of stroke volume in six out of six (6/6) between-quartile comparisons (p<0.001), decrease in cardiac output (p<0.001) and increase in heart rate in 5/6 comparisons (p<0.001), change in systemic vascular resistance in 3/6 comparisons (p<0.001), change in aortic systolic blood pressure in 1/6 comparisons (p=0.043), and change in aortic diastolic blood pressure in none (p=0.266). To conclude, the reproducibility of upright posture-induced changes is high for stroke volume, cardiac output, and heart rate, moderate for systemic vascular resistance, and modest for aortic blood pressure. While an increase in blood pressure during upright posture may be a cardiovascular risk factor, this effect may be attributed to other underlying hemodynamic variables that exhibit more reproducible posture-related changes.

Aortic regurgitation (AR) is more prevalent in male, although cellular and molecular mechanisms underlying the sex differences in prevalence and pathophysiology are unknown. This study evaluates the impact of sex on aortic valve (AV) inflammation and remodeling as well as the cellular differences in valvular interstitial cells (VICs) and valvular endothelial cells (VECs) in patients with AR. A total of 144 patients (27.5% female) with severe chronic AR were included. AVs were analyzed by imaging, histological and molecular biology techniques (ELISA, RT-PCR). VICs and VECs isolated from patients with AR were characterized and further treated with transforming growth factor (TGF)-β. Anatomically, male had smaller index aortic dimensions and greater AV thickness. Proteome profiler analyzes in AVs (n=40/sex) evidenced higher expression of inflammatory markers in male and that was further validated (interleukins, chemokines). Histological composition showed higher expression of inflammatory mediators and collagen thick fibers in AVs from male. Male VICs and VECs secreted higher levels of inflammatory markers than female cells. Interestingly, male VICs produced higher amounts of collagen type I and lower fibronectin and aggrecan, whereas male VECs secreted lower decorin. TGF-β exclusively enhanced inflammation in male VICs, and decorin and aggrecan in female VICs. Compared to male, AVs from female were thinner, less inflamed and fibrotic. VIC seem to be the key cell type responsible for the sex-differences. Valvular inflammation associated with an active remodeling process could be a key pathophysiological process involved in AR.

Lipid phosphate phosphatase 3 (LPP3) is a membrane-bound enzyme that hydrolyzes lipid phosphates including the bioactive lipid, lysophosphatidic acid (LPA). Elevated circulating LPA production and cellular LPA signaling are implicated in obesity-induced metabolic and cardiac dysfunction. Deletion of LPP3 in the cardiomyocyte increases circulating LPA levels and causes heart failure and mitochondrial dysfunction in mice. To examine the influence of LPP3 modulation in the cardiomyocyte on obesity-induced cardiomyopathy, we generated mice with cardiomyocyte-specific LPP3 overexpression (LPP3 mice) driven by the α myosin heavy chain promoter. Female and male control (LPP3) and LPP3 mice were fed low-fat diet (LFD) or high-fat diet (HFD) for up to 22-23 weeks, followed by the analysis of glucose homeostasis, cardiac function, plasma LPA levels, and mitochondrial respiration in cardiac myofibers. On LFD, both female and male LPP3 mice had markedly reduced plasma LPA levels and increased pyruvate-linked respiration when compared to LPP3 mice while body weight and global insulin sensitivity were similar between genotypes. Following HFD feeding, female LPP3 mice were protected from an increase in plasma LPA levels, excess adiposity, systemic insulin resistance, and systolic and diastolic cardiac dysfunction compared to LPP3 mice. Female LPP3 mice also maintained elevated cardiac pyruvate-linked mitochondrial respiration following HFD feeding while mitochondrial respiration was similar between genotypes in HFD-fed male mice. This study suggests that cardiomyocyte-specific LPP3 upregulation protects particularly female mice from HFD-induced metabolic dysfunction and cardiomyopathy.

This study investigated the sexual dimorphism in right ventricle (RV) remodeling in right heart failure susceptible Fischer CDF rats using the pulmonary artery banding (PAB) model. Echocardiography and hemodynamic measurements were performed in adult male and female Fischer CDF rats at 1- or 2-weeks post-PAB. RV systolic pressure and RV hypertrophy were significantly elevated in PAB rats compared to sham control at 1- and 2-weeks post-PAB; however, no differences were observed between male and female rats. Increase in cardiomyocyte cross-sectional area and RV end-diastolic diameter was observed in male rats compared to female rats at 2-weeks post-PAB. Conversely, higher fractional area change and cardiac index were observed in female rats compared to male rats at 2-weeks post-PAB. To explore the mechanisms, a focused PCR array was performed and higher expression of angiogenic genes, including sphingosine kinase-1 (Sphk1), was observed in the RV of female rats compared to male rats. Consistent with the higher angiogenic gene expression, female rats had a higher RV vascular density at 2-weeks post-PAB compared to male rats. Female RV endothelial cells (RVEC) had better angiogenic ability compared to male cells that was potentiated by estradiol. Furthermore, effect of estradiol on RVEC was inhibited by Sphk1 inhibitor (PF-543). Together, female Fischer CDF rats develop adaptive RV remodeling post-PAB compared to mal-adaptive remodeling in male rats. Moreover, the adaptive remodeling in female rats is associated with better RV angiogenic response that may result from better angiogenic ability of female RVEC and proangiogenic effects of estradiol through Sphk1.

Maternal mortality rates in the US have been increasing steadily over the past decade, with rates significantly increased versus the rest of the developed world, despite the vast healthcare infrastructure. The purpose of this paper is to discuss key areas that need to be addressed within basic science, clinical, and community-based settings to help promote increased education, research, and awareness of specific pregnancy-associated changes that can occur during both healthy and complicated pregnancies. Through increased awareness, we can promote healthier pregnancies and not only help to reduce maternal mortality rates but also improve the long-term cardiovascular outcomes in mothers and their children.

Diabetes mellitus (DM) increases the risk of aortic stenosis (AS) and worsens its pathophysiology in a sex-specific manner. Aldosterone/mineralocorticoid receptor (Aldo/MR) pathway participates in early stages of AS and in other diabetic-related cardiovascular complications. We aim to identify new sex-specific Aldo/MR targets in AS complicated with DM. We performed discovery studies using Olink Proteomics® technology in 87 AS patient-derived aortic valves (AVs) (N=28 and N=19 non-diabetic and diabetic men; N=32 and N=8 non-diabetic and diabetic women, respectively) and human cytokine array (N=24 AVs/sex/condition). Both approaches revealed chemerin as a target differentially upregulated in AVs from male diabetic patients, further validated in a cohort of stenotic AVs (N=283, 27.6% DM, 59.4% men). Valvular chemerin levels directly correlated with VIC activation, MR, inflammation, angiogenesis and calcification markers exclusively in diabetic men. , Aldo (10M) treatment exclusively increased chemerin levels in valve interstitial cells (VICs) from male DM patients. Aldo also upregulated inflammatory, angiogenic and osteogenic markers in DM and non-DM donors' VICs, which were prevented by MR antagonism. Increased glucose levels in cell media upregulated chemerin in VICs from male diabetic patients. Overall, -knockdown in male diabetic VICs resulted in downregulation of inflammatory, angiogenic and osteogenic markers and blocked Aldo-induced responses in high glucose conditions. These data suggest the Aldo/MR pathway selectively increases chemerin in VICs from diabetic men, promoting inflammation, angiogenesis and calcification associated to AS progression.

The study was designed to investigate the pattern of intraventricular Hemo-Dynamic Forces (HDF) and myocardial performance during exercise in Elite Cyclists (EC). Transthoracic stress echocardiography was performed on nineteen EC and thirteen age-matched sedentary controls (SC) at three incremental exercise intensities based on Heart Rate Reserve (HRR). Left Ventricular (LV) HDF were computed from echocardiography long-axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base and latero-septal directions. Pressure Volume (PV) loops were non-invasively investigated using the single-beat approach. Differences between groups were investigated using mixed model analysis. At PV loops EC showed a steeper increase in stroke work compared to SC, without acute changes in ventricular capacity (EDVI). Contractility, measured as Ventricular Elastance (Ees), increased during exercise with no difference between groups (P=0.625). At rest, EC had significantly lower heart rates and generated lower HDF than SC. However, during exercise the pressure gradient developed by EC in systole, and therefore systolic HDF, was significantly higher than that developed by SC (P<0.009), also showing greater elastic rebound in late systole compared to SC (P<0.032). Importantly, during early diastolic filling, EC showed lower HDF deceleration than SC (P<0.043), indicating a facilitated relaxation of the left ventricle. Analysis of the HDF pattern during exercise shows the functional changes that occur in EC, characterized by increased HDF generation in systole, and facilitated relaxation in early diastole. This is the first time LV structural and functional remodeling is reported for elite cyclists during exercise.

Cholinesterase (ChE) inhibitors are under consideration to be used in the treatment of cardiovascular pathologies. A prerequisite to advancing ChE inhibitors into the clinic is their thorough characterization in the heart. The aim here was to provide a detailed analysis of cardiac ChE to understand their molecular composition, localization, and physiological functions. A battery of biochemical, microscopic, and physiological experiments was used to analyze two known ChE, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), in hearts of mutant mice lacking different ChE molecular forms. Overall, AChE activity was exceeded by BChE, while it was localized mainly in the atria and the ventricular epicardium of the heart base. AChE was anchored by collagen Q (ColQ) in the basal lamina or by PRiMA at the plasma membrane and co-localized with the neuronal marker TUJ1. In absence of anchored AChE, heart rate was unresponsive to a ChE inhibitor. BChE, the major ChE in heart, was detected predominantly in ventricles, presumably as a precursor (soluble monomers/dimers). Mice lacking BChE were more sensitive to a ChE inhibitor. Nevertheless, the overall impact on heart physiology was subtle, showing mainly a role in cholinergic antagonism to the positive inotropic effect of β-adrenergic stimulation. Our results help to unravel the mechanisms of ChE in cardiovascular pathologies and provide a foundation to facilitate the design of novel, more effective pharmacotherapies, which may reduce morbidity and mortality of patients with various heart diseases.

Heart failure (HF) is a leading cause of death worldwide. We have shown that pressure overload (PO)-induced inflammatory cell recruitment leads to heart failure in IL-10 knockout (KO) mice. However, it's unclear if PO-induced inflammatory cells also target the gut mucosa, causing gut dysbiosis and leakage. We hypothesized that TAC (transverse aortic constriction) exacerbates immune cell homing to the gut (small intestine and colon), promoting dysbiosis and gut leakage in IL-10 KO mice. HF was induced in 8-10 weeks old C57BL/6J wild-type (WT) and B6.129P2-Il10tm1Cgn/J mutant (IL-10 KO) male and female mice by TAC and cardiac function was measured using visual sonics VEVO 3100. Fourteen days post-TAC, levels of monocytes, macrophages, neutrophils, and proinflammatory cytokines were measured in blood and gut. Gut dysbiosis was assessed via 16S rRNA sequencing in feces at 56 days post-TAC. IL-10 KO mice showed worsened cardiac dysfunction post-TAC. TAC worsened monocytes, and neutrophils infiltration in systemic circulation and facilitated their homing to the gut in IL-10 KO mice. Intriguingly, proinflammatory cytokines level was increased in blood, and gut of IL-10 KO mice following TAC. Furthermore, IL-10 expression was reduced in the colon of WT mice post-TAC. Moreover, TAC exacerbated gut dysbiosis in IL-10 KO mice. Finally, an impaired intestinal permeability was noted in IL-10 KO mice post-TAC. In conclusion, TAC-induced systemic inflammation leads to gut dysbiosis and impaired gut permeability in IL-10 KO mice, indicating IL-10's potential role in regulating intestinal integrity and microbiota balance during heart failure.

The contribution of sex hormones to cardiovascular disease, including arterial stiffness, is established; however, the role of sex chromosome interaction with sex hormones, particularly in women, is lagging. Arterial structural stiffness depends on the intrinsic properties and transmural wall geometry that comprise a network of cells and extracellular matrix (ECM) proteins expressed in a sex-dependent manner. In this study, we used four-core genotype (FCG) mice to determine the relative contribution of sex hormones versus sex chromosomes or their interaction with arterial structural stiffness. Gonadal intact FCG mice included females (F) and males (M) with either XX or XY sex chromosomes (n=9-11/group). We isolated the thoracic aorta, and a tissue puller was used to assess structural resistance to changes in shape under control, collagenase, or elastase conditions. We determined histological collagen area fraction and evaluated aortic ECM genes by PCR microarrays followed by RT-qPCR. Stress-strain curves showed higher elastic modulus (P<0.001), denoting decreased extensibility in XXF compared to XYF aortas, which were significantly reversed by collagenase and elastase treatments (P<0.01). Aortic gene expression analysis indicated a significant reduction in Emilin1, Thbs2, and Icam1 in the XXF versus XYF aorta (P<0.05). Uniaxial stretching of XXF aortic vascular smooth muscle cells indicated decreased Thbs2, Ctnna1, and Ecm1 genes. We observed a significant (P<0.05) reduction in Masson's trichrome staining in collagenase but not elastase-treated aortic rings compared to the control. The increased aortic elastic modulus in XXF compared to XYF mice suggests a decrease in aortic extensibility mediated by a reduction in ECM genes.

Regulators of G protein signaling (RGS) proteins finetune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, kidney, heart, and the vasculature. Impaired regulation of G protein signaling by RGS proteins is implicated in the pathogenesis of several human diseases including various forms of cardiomyopathy such as hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Both genetic and non-genetic changes that impinge on G protein signaling in cardiomyocytes are implicated in the etiology of DCM, and there is accumulating evidence that such genetic and non-genetic changes affecting G protein signaling in cell types other than cardiomyocytes could serve as a DCM trigger in humans. This review discusses and highlights mammalian RGS proteins and their roles in cardiac physiology and disease, with specific focus on the current understanding of the etiology of DCM and the pathogenic roles of RGS proteins that are prominently expressed in the cardiovascular system. Growing evidence suggests that defects in G protein regulation by RGS proteins in the cardiovascular system likely contribute to cardiomyocyte structural damage and decreased contractile function that hallmark DCM. Further studies that enhance the understanding of the dynamics of G protein regulation by RGS proteins in several cell types in the myocardium and the vasculature are critical to gaining more insight into the etiology of DCM and heart failure, and to the identification of novel therapeutic targets.

The acute response to therapeutic afterload reduction differs between heart failure with preserved (HFpEF) versus reduced ejection fraction (HFrEF), with larger left ventricular (LV) stroke work augmentation in HFrEF compared to HFpEF. This may (partially) explain the neutral effect of HFrEF-medication in HFpEF. It is unclear whether such differences in hemodynamic response persist and/or differentially trigger reverse remodeling in case of long-term afterload reduction. A systematic search was performed, identifying 21 clinical trials investigating renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers and sodium-glucose cotransport 2 inhibitors that report data on afterload reduction, stroke volume and reverse remodeling in HFpEF and/or HFrEF. In both HFpEF and HFrEF, meta-analyses revealed limited long-term change in systolic/diastolic blood pressure (-5.6/-3.2 and -4.6/-1.4 mmHg, respectively) and LV afterload reduction (arterial elastance: -0.039 and -0.055 mmHg/mL, respectively). Long-term treatment did not result in increase in stroke volume, with the exception of beta-blockers in HFrEF. Indexed LV mass decreased slightly in both HFpEF and HFrEF (-2.8 and -2.3 g/m2, respectively). In HFrEF, treatment reduced LV end-diastolic and end-systolic volume (-8 and -6 ml, respectively), whereas in HFpEF there was no relevant change. Contrary to acute heart failure studies, long-term afterload reduction had little effect on blood pressure and stroke volume augmentation in both HFpEF and HFrEF. On the other hand, reverse remodeling was clearly present in HFrEF, but was essentially absent in HFpEF.

An increasing number of procedures over the past two decades for aortic stenosis (AS) reflects the combination of an aging population and less invasive transcatheter options. As a result, the hemodynamics of the aortic valve (AV) have gained renewed interest to understand its behavior and to optimize patient selection. We studied the hemodynamic relationship between pressure loss (ΔP) and transvalvular flow (Q) of the normal AV as well as the impact of a variable supravalvular stenosis. Our mechanistic study included 11 healthy swine monitored during dobutamine stress and followed by acute aortic banding to simulate AS. Hemodynamics were continuously recorded, and transvalvular ΔP versus Q were analyzed using proportional and linear models. During dobutamine infusion, normal valves exhibited a highly linear relationship between ΔP and Q (median R of 0.93). Progressive aortic banding eventually displayed a highly linear relationship between an increasing ΔP and the decreasing Q, characterized by a constant systemic circulatory resistance (median R of 0.91). Consequently, a normal AV can be described by a single parameter: its resistance, median 0.37 Wood units [WU] in swine. During dobutamine stress and aortic banding, the systemic bed behaves like a constant and stable resistance, median 11.9 WU in swine. These findings carry significant implications for quantifying normal and diseased AV behavior, and potentially might improve patient selection and treatment outcomes.

Positive end-expiratory pressure (PEEP) improves respiratory conditions. However, the complex interaction between PEEP and hemodynamics in heart failure patients makes it challenging to determine appropriate PEEP settings. In this study, we developed a framework for the impact of PEEP on hemodynamics considering cardiac function, by integrating the impact of PEEP in the generalized circulatory equilibrium framework, and validated the framework by assessing its ability to accurately predict PEEP-induced hemodynamics. In eight dogs, PEEP was increased stepwise, and hemodynamic responses were measured under normal, volume-loaded, and myocardial infarction (MI)-induced heart failure conditions. For predicting hemodynamics under PEEP using the proposed framework, the PEEP-intrathoracic pressure (ITP) relationship was empirically established in dogs. Hemodynamic parameters were estimated at each PEEP level based on the hemodynamics recorded without PEEP. The parameters were then used to predict hemodynamics under various heart conditions. The predicted and measured values were compared. Stepwise increase of PEEP decreased arterial pressure (AP) and cardiac output (CO). Left atrial pressure (LAP) decreased in normal hearts but increased in MI hearts. Predicted AP [R, 0.92; root mean squared error (RMSE), 6.3 mmHg], CO (R, 0.96; RMSE, 7.9 ml∙min∙kg) and LAP (R, 0.92; RMSE, 2.3 mmHg) matched measured values with high accuracy, irrespective of volume status or heart condition. In conclusion, we developed a framework for the hemodynamic impact of PEEP considering cardiac function and demonstrated its validity. The results indicate that the effects of PEEP on hemodynamics can be explained primarily by ITP, and are modulated by cardiac function.

Swine are increasingly utilized in cardiovascular research due to their anatomical and physiological similarities to humans, particularly for studying diastolic dysfunction. While MRI offers excellent structural imaging, echocardiography provides superior real-time assessment of diastolic parameters. To address the lack of standardized methods and reduce variability across studies, we present a comprehensive guide for performing echocardiography in Yorkshire pigs, detailing anatomical considerations, equipment requirements, and technical approaches. We describe systematic approaches for obtaining and optimizing right parasternal long and short-axis views, apical four-chamber, and subcostal imaging windows, with specific attention to anatomical variations from human cardiac orientation and standard clinical transducer positioning. These tomographic views enable comprehensive assessment of systolic and diastolic function, including ventricular volumes, wall thicknesses, chamber dimensions, ejection fraction, and Doppler measurements of blood flow and tissue velocities. This standardized methodology for echocardiographic images acquisition enhances data reliability in cardiovascular pig models, improving the interpretation of preclinical study results and strengthening translational research outcomes. The protocol also provides consistency for veterinary applications, making echocardiography a preferred modality for longitudinal studies in this valuable translational model.

Regulation of myocardial mass is key for maintaining cardiovascular health. This review highlights the complex and regulatory relationship between mechanosignaling and myocardial mass, influenced by many internal and external factors including hemodynamic and microgravity, respectively. The heart is a dynamic organ constantly adapting to changes in workload (preload and afterload) and mechanical stress exerted on the myocardium, influencing both physiological adaptations and pathological remodeling. Mechanosignaling pathways such as the mitogen-activated protein kinases (MAPK) and the phosphoinositide 3-kinases and serine/threonine kinase (PI3K/Akt) pathways, mediate downstream effects on gene expression and play key roles in transducing mechanical cues into biochemical signals, thereby modulating cellular processes, including control of myocardial mass. Dysregulation of these processes can lead to pathological cardiac remodeling, such as hypertrophic cardiomyopathy. Furthermore, recent studies have highlighted the importance of protein quality control mechanisms, such as the ubiquitin-proteasome system, in settings of extreme physiological conditions that alter the heart workload such as pregnancy and microgravity. Overall, this review provides a thorough insight into how mechanical signals are converted into chemical signals to regulate myocardial mass in both healthy and diseased conditions.