bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single‐Beat Estimation of Isovolumic Maximum Pressure can Predict Left Ventricular Contractility in Rats
Authors: Tohyama Takeshi , Saku Keita , Nishikawa Takuya , Oga Yasuhiro , Kishi Takuya , Sunagawa Kenji 
Published: November 2023

BackgroundAlthough the end‐systolic elastance (Ees), the slope of the end‐systolic pressure‐volume (PV) relationship, has been used as a load insensitive index of cardiac contractility, technical difficulties in measuring left ventricular (LV) volume under various loading conditions prevent its wide clinical acceptance. In theory, if we can estimate the isovolumic maximum pressure (Pmax) for a given end‐diastolic volume, the slope of the line drawn from the Pmax to the left upper corner of a single PV loop (Fig. 1) gives Ees. Since various clinical approaches allow us to depict PV loops or their surrogates, we can clinically predict Ees once we can estimate Pmax. Thus, in this study, we developed a method to estimate Pmax from a single LVP and predicted Ees in rats under various systolic functions. We assumed that the waveform of ejecting LVP during the isovolumic contraction phase is a scaled version of the isovolumic LVP in time and amplitude.MethodsIn 5 urethane‐anesthetized rats, we inserted a 2F Millar catheter into LV. We attached a flow probe around the ascending aorta. We measured ejecting LVP and isovolumic LVP by cross clamping the ascending aorta under the baseline condition, dobutamine infusion (5 μg/kg/min) or landiolol infusion (100 μg/kg/min). We digitized both LVP and aortic flow at 1000 Hz. We extracted the standard isovolumic LVP from multiple isovolumic contractions (327 waveforms). To eliminate the noise and phase distortion associated with numerical time derivatives of LVP, we approximated LVP by Fourier series expansion and algebraically derived their first and second time derivatives. On the basis of the unique waveform during isovolumic contraction phase, taking the ratio of the first derivative of ejecting LVP to that of the standard LVP at the moment of the maximum second derivative and scaling Pmax of standard LVP by the ratio yields the Pmax estimation. Ees was calculated from the tangential line drawn from the Pmax at end‐diastolic volume to the end‐systolic point of a single PV loop.ResultsThe estimated Pmax matched reasonably well with measured over the wide range of LV contractility (Y = 1.16 × − 9.71, r2=0.918, Fig. 2). Dobutamine significantly increased Ees, while landiolol decreased it (vehicle; 532.5±152.4 mmHg/ml, dobutamine; 728.5±178.7 mmHg/ml, landiolol; 186.1±111.4 mmHg/ml, p<0.05, Fig. 3).ConclusionsOur proposed method accurately estimated Pmax from a single LVP. This is to say that we validated that the waveform of ejecting LVP during the isovolumic contraction phase is indeed a scaled version of the isovolumic LVP in time and amplitude. This approach would broaden the clinical applicability of Ees for assessing systolic function, therapeutic response and eventually managing patients with heart failure.
A Support Vector Machine to Predict Impending Pre‐Syncope from Hemodynamic Derived Signals During Progressive Central Hypovolemia
Authors: van der Ster Jacob P. , Bennis Frank C. , Stok Wim J. , Westerhof Berend E. , Settels Jos J. , Hatib Feras , van Lieshout Johannes J. 
Published: November 2023

BackgroundHypovolemic shock is characterized by a critically reduced central blood volume (CBV). The heart rate and blood pressure responses to a reduced CBV do not predict onset of hypovolemic shock. We hypothesized that a machine learning model detects subtle changes and patterns within hemodynamic signals that predict impending pre‐syncope as an expression of a critically reduced CBV.MethodsIn 33 healthy subjects we provoked pre‐syncope by reducing CBV using continuous lower body negative pressure. We extracted information from the arterial pressure wave and used it as model input. Next to blood pressure and heart rate, we introduced a new set of blood pressure wave features. We trained a support vector machine to predict time remaining till pre‐syncope using leave‐one‐out methods. We expressed the model performance as absolute error and a squared correlation coefficient (r2).ResultsIn 72% of the predictions the model followed the decreasing time remaining towards pre‐syncope. Mean r2 was 0.43 [0.13 – 0.64]. In 13 subjects the model predicted pre‐syncope with an median error of −49 seconds [−312 −27].ConclusionThe model detects a trend towards pre‐syncope conforming to a worsening condition of subjects in a controlled progressive hypovolemia setting, but cannot pinpoint the onset of pre‐syncope exactly. Future research may reveal the most valuable input feature and allow for testing current models during real hemorrhage.Support or Funding InformationEducational grant supplied by Edwards Lifesciences.
Role of leptin in coronary vascular dysfunction and proliferation
Authors: Noblet Jillian Nicole , Goodwill Adam G , Sassoon Daniel J , Kiel Alex M , Tune Johnathan D 
Published: November 2023

The purpose of this investigation was to test the hypothesis that leptin augments vasoconstriction and impairs dilation via a Rho kinase‐dependent pathway and promotes proliferation of coronary smooth muscle. Coronary arteries from domestic swine were cleaned of surrounding tissue and incubated with/without leptin (30 ng/mL) for 30 min. Leptin administration significantly augmented contractile responses to KCl (10 – 60 mM), with active tension development increased by ~1.3 g at doses >40mM, and reduced maximal vasodilation to adenosine (30 μM) ~18% compared to untreated controls. To examine the extent to which longer‐term exposure to leptin influences coronary vascular reactivity, arteries were placed in organ culture for 3 days. Following incubation in serum‐free media, leptin treatment significantly augmented overall active tension development to KCl (10 – 60 mM), with an average increase of ~2.0 g at doses >40 mM, and reduced maximal vasodilation to adenosine (30 μM) ~50% compared to untreated controls. The acute and chronic effects of leptin administration on maximal KCl (60 mM) contractions were essentially abolished in the presence of the Rho kinase inhibitor, fasudil (1 μM). Short‐term leptin exposure significantly increased the level of Rho kinase activity, while no difference in Rho kinase (Rock‐2) protein abundance was detected. In contrast, long‐term leptin administration in cultured arteries significantly increased the abundance of Rock‐2 protein, while no difference in Rho kinase activity level was detected. Global proteomic assessment of arteries cultured (3 days) in the presence or absence of leptin (30 ng/mL) revealed significant alterations in the coronary artery proteome and Ingenuity Pathway Analysis identified associations between leptin treatment and numerous cellular processes, namely cellular growth and proliferation (35 proteins). To assess the effects of leptin on vascular smooth muscle proliferation, additional studies were conducted in which coronary arteries were cultured in serum‐containing media with/without leptin (30 ng/mL) for 2 or 8 days. 5‐Bromo‐2′‐deoxyuridine (BrdU) staining revealed a significantly higher percentage of BrdU‐positive nuclei in leptin treated arteries (~10%) compared to untreated controls at both time points. Taken together, data from this investigation indicate that leptin alters coronary smooth muscle reactivity and potentiates contraction via a Rho kinase‐dependent pathway. Additionally, these findings support the potential for leptin to modulate a key network of pathways that promote vascular smooth muscle proliferation.Support or Funding InformationIndiana University Health, Indiana University School of Medicine Strategic Research Initiative (CECARE); HL117620 (J.D. Tune‐Mather); TL1 TR001107 and UL TR001108 (A. Shekhar).
Osteoprotegerin and Receptor Activator of Nuclear Factor‐κB Ligand Alter Intracellular Ca2+ Handling in Coronary Smooth Muscle Cells in an In Vitro Model of Coronary Artery Calcification
Authors: Badin Jill K. , Sturek Michael 
Published: November 2023

Metabolic syndrome (MetS) increases the risk of adverse cardiovascular events such as arterial calcification and injury. In response to this MetS‐induced injury, smooth muscle cells often dedifferentiate into an osteoblast‐like phenotype that is associated with augmented expression of certain osteogenic factors, including osteoprotegerin (OPG) and receptor activator of nuclear factor‐κB ligand (RANKL). These secreted proteins have autocrine and paracrine effects in the vasculature and several studies indicate that OPG confers protection against and RANKL exacerbates vascular calcification. We investigated the effects of OPG and RANKL on calcium handling in coronary smooth muscle (CSM) in OPG‐conferred protection and RANKL‐induced vascular calcification. Porcine coronary arteries were cultured in DMEM with either OPG (10 ng/mL) or RANKL (3.0 pmol/L) in normal glucose (100 mg/dL) and high glucose (180 mg/dL). After up to ten days in culture, arterial rings were either fixed for histological analysis or CSM cells were dispersed enzymatically for assessment of sarco‐endoplasmic reticulum Ca2+‐ATPase (SERCA) and voltage‐gated Ca2+ channel (VGCC) activity with imaging of fura‐2 fluorescence. Cells from both OPG‐treated and RANKL‐treated arteries demonstrated increased Ca2+ entry following activation of VGCCs with 80 mM K+. Release of the sarcoplasmic reticulum (SR) Ca2+ store with caffeine revealed an elevated SR Ca2+ store in OPG‐treated arteries, while the SR Ca2+ store was decreased with RANKL treatment. Histological analysis revealed a lack of macrocalcification in all samples. Overall, the most profound effects observed were OPG‐induced increase and RANKL‐induced decrease in SR Ca2+ store, which may provide insight into the differential effects of OPG and RANKL on CSM.Support or Funding InformationNIH HL125385, IUSM CECARE
Caveolin‐3 expression is increased in anthracycline‐induced heart failure in rabbits
Authors: Ichikawa Yasuhiro , Zemlic‐Harpf Alice , Hammond Kirk H , McKirnan Dan M , Patel Hemal H , Roth David M 
Published: November 2023

IntroductionAnthracyclines, such as daunorubicin, are widely used anticancer drugs. Anthracyclines are cardiotoxic and induce development of heart failure during chemotherapy. Caveolins are structural proteins in cell membranes that bind, organize and regulate receptors and signaling molecules. Caveolin‐3, a muscle specific subtype of caveolin, is highly expressed in the heart and is involved in protection of the heart from cardiac stress. In previous reports, left ventricular (LV) caveolin protein expression is decreased in failing hearts after myocardial infarction; however, the effect of anthracycline‐induced heart failure on caveolin expression is not known. We tested the hypothesis that daunorubicin modulates caveolin expression in the heart.MethodsNew Zealand rabbits were given daunorubicin (3mg/kg, iv) weekly for 8–11 weeks to induce heart failure. LV systolic function was followed using echocardiography and LV fractional shortening (FS) and ejection fraction (EF) were measured. When the LVFS was under 20% (average; 9.0 weeks) heart tissue was collected and divided into 3 parts (LV, intraventricular septum (IVS), right ventricle (RV)). The heart tissue was homogenized and western blot was performed to measure caveolin protein expression.ResultsDaunorubicin treatment (Dau) resulted in progressive and significant decline of LVFS (Control; 32.4% (n=8) vs Dau; 15.9% (n=6), P<0.001) and EF (Control; 69.1% vs Dau; 38.2%, P<0.001) at the end of study. LV end diastolic dimension in Dau was significantly dilated compared to control group (Control; 16.2 mm vs Dau; 19.2 mm, P<0.05). In control hearts, caveolin‐3 expression in RV was higher than in LV or IVS (2.0 and 1.9 ‐fold vs. LV and IVS, respectively, P<0.01, n=6); however, no significant difference in caveolin‐1 expression was observed in the three regions. In heart failure induced by daunorubicin, caveolin‐3 expression was increased in LV, IVS and RV compared to control tissues (2.8, 2.4 and 2.6‐fold vs. control LV, IVS and RV, P<0.05, n=6, respectively) with no change in caveolin‐1 expression.ConclusionsThese results suggest that in heart failure induced by daunorubicin caveolin‐3 expression is increased in the rabbit heart. The pathophysiological role for caveolin‐3 in daunorubicin‐induced heart failure remains to be determined.
Endothelin‐B Receptor Responses in Young and Postmenopausal Women
Authors: Kuczmarski Andrew , Sebzda Kelly N , Mraz Stephanie N , Wenner Megan M 
Published: November 2023

Cardiovascular disease (CVD) is the leading cause of the death in women, and postmenopausal women (PMW) are at an increased risk for developing CVD. Endothelin‐1 (ET‐1) contributes to age‐related endothelial dysfunction in men via the ETA receptor. However, there are sex differences in ET‐1 regulation of vascular function, and ETB receptors are influenced by fluctuations in ovarian hormones.PURPOSEThe purpose of this study was to test the hypothesis that ETB receptors contribute to impaired microvascular function in PMW.METHODSWe measured skin blood flow (SkBF) in 11 young women (YW; 22±1 years, 22±1 kg/m2) and 10 PMW (58±2 years, 24±1 kg/m2) using laser Doppler flowmetry during microdialysis perfusions of lactated Ringer's (control), an ETB receptor antagonist (BQ‐788, 300nM), and an ETA receptor antagonist (BQ‐123, 500 nM). We utilized local skin heating (42°C) to induce microvascular vasodilation, followed by perfusion of sodium nitroprusside (28mM) to elicit maximal dilation. Mean arterial blood pressure (MAP) was measured throughout. Cutaneous vascular conductance (CVC) was calculated as SkBF/MAP during the plateau established during local heating, and expressed as a percent of maximal dilation. Unpaired t‐tests were used to compare variables between YW and PMW.RESULTSResting MAP was higher in PMW (93±2 mmHg) compared to YW (80±2 mmHg; P<0.05). Vasodilatory responses to local heating (control site) tended to be lower in PMW (YW: 91±2 vs. PMW: 81±5 CVC % max; P=0.12). ETB receptor blockade tended to decrease cutaneous vasodilation in YW (control: 91±2 vs. BQ‐788: 85±3 CVC % max; P=0.08), but tended to enhanced vasodilation in PMW (control: 81±5 vs. BQ‐788: 92±1 CVC % max; P=0.08). ETA receptor blockade had minimal effect in YW (control: 91±2 vs. BQ‐123: 92±2 CVC % max; P=0.35), but tended to increase cutaneous vasodilation in PMW (control: 81±5 vs. BQ‐123: 90±2 CVC % max; P=0.11).CONCLUSIONETB receptors appear to mediate vasodilation in YW. However, microvascular vasodilation is blunted in PMW, possibly due to greater ETB and ETA mediated vasoconstriction.Support or Funding InformationSupported by NIH Grant U54 GM 104941 01A1 and University of Delaware Research Foundation.
Within‐Day Test‐Restest Reliability of the Single Passive Leg Movement Technique: Evidence of Clinical Utility
Authors: Broxterman Ryan M. , Groot H. Jonathan , Rossman Matthew J. , Garten Ryan S. , Venturelli Massimo , Kwon Oh‐Sung , Hydren Jay R. , Gifford Jayson R. , Richardson Russell S. 
Published: November 2023

Passive leg movement (PLM) is emerging as a potentially better assessment of nitric oxide (NO)‐mediated vascular function than brachial artery flow‐mediated dilation, as it elicits a robust NO‐mediated increase in both leg vascular conductance (LVC) and leg blood flow (LBF). Typically, PLM is conducted with continuous movements spanning one to two minutes, with the assessment of alterations in LVC. However, single movement PLM with the assessment of alterations in LBF is more appealing as a clinical technique due to the relative ease of administration and minimal central hemodynamic effects. The reproducibility of the evoked physiological responses from single PLM is important for both clinical and research interpretation, but is currently unknown. Therefore, the current study investigated the within‐day test‐retest reliability of the hemodynamic responses elicited by single PLM. In nine subjects (7 men and 2 women), three single PLM trials were performed within the same visit, while second‐by‐second measurements of the central and peripheral hemodynamic responses were acquired with finger photoplethysmography and Doppler ultrasound, respectively. The peak change in LBF (ΔLBFpeak) was not significantly different across the three trials (Mean ± SD; Trial 1: 702.5 ± 483.3; Trial 2: 685.7 ± 421.9; Trial 3: 626.2 ± 383.0 ml min−1, p = 0.77). The intra‐class correlation coefficient (ICC) for these trials was 0.73 (p < 0.0001), the Cronbach's Alpha 0.88, and the coefficient of variation (CV) 34.3 ± 23.3 %. The ΔLBFpeak was not significantly different when the two most similar trials of the three were analyzed (Trial A: 728.1 ± 458.7; Trial B: 703.7 ± 387.2 ml min−1, p = 0.639). The ICC was 0.95 (p < 0.0001), the Cronbach's Alpha 0.97, and the CV 13.3 ± 14.6 %. The ΔLBFpeak and ΔLVCpeak were significantly correlated across all three trials (r = 0.97, p < 0.0001) and the two most similar trials (r = 0.95, p < 0.0001), as determined by Pearson product‐moment correlation. These findings suggest that single PLM assessment of vascular function is reproducible, with clinical utility. For research purposes, conducting single PLM in triplicate greatly enhances the ability to detect within‐subject differences.Support or Funding InformationThis work was supported by National Institutes of Health Grant P01 HL091830 (to R.S.R.) and Veterans Affairs Rehabilitation Research and Development Service Grants E1697‐R and E6910‐R (to R.S.R.).
Impact of Sodium Nitrate on Measures of Vascular Function and Biomarkers of Inflammation in Patients with Peripheral Artery Disease: A Preliminary Assessment
Authors: Norton Samuel L , Ueda Kenichi , Ganger Charles T , Treichler David P , Casey Darren P 
Published: November 2023

Peripheral artery disease (PAD) is associated with attenuated limb blood flow, reduced nitric oxide (NO) bioavailability, as well as elevated levels of circulating inflammatory and adhesion biomarkers. NO is a critical regulator of vascular tone and possesses several anti‐inflammatory properties. Recent evidence suggests that inorganic nitrate can be reduced to bioavailable NO in blood and various tissues. Thus, the aim of this study was to test the hypothesis that long‐term dietary nitrate supplementation in patients with PAD would 1) improve peak vasodilator capacity in resistance arteries of the arm and leg and 2) decrease plasma markers of inflammation (IL‐6) and cell adhesion (ICAM, VCAM, MCP‐1). 19 older adults with PAD (73 ± 10 yr) were randomly assigned to either 8‐weeks of daily oral sodium nitrate (NaNO3; 1g) or placebo. Peak blood flow was assessed using venous occlusion plethysmography in the forearm and calf following 5 minutes of ischemia (reactive hyperemia). Peak vascular conductance (surrogate for vasodilation) was calculated as blood flow/mean arterial pressure. Plasma levels of inflammatory and cell adhesion molecules were determined utilizing commercially available enzyme‐linked immunosorbent assays (RnD Systems). Preliminary analysis (2 way repeated measures ANOVA) of 12 patients that received NaNO3 and 7 patients that received placebo revealed no significant group × time interactions for any of the outcome measures. However, examination of only the NaNO3 group demonstrated that peak calf blood flow (10.7 ± 1.7 vs. 12.8 ± 1.8 ml/dL of limb volume/min) and vascular conductance (10.1 ± 1.5 vs. 12.7 ± 1.8 ml/dL of limb volume/min/100mmHg) increased post treatment (P < 0.05). Peak blood flow (P = 0.44) and vascular conductance (P= 0.45) in the arm did not change following treatment with NaNO3. Plasma levels of IL‐6 decreased post treatment (3.98 ± 0.64 vs. 3.49 ± 0.56 pg/ml, P < 0.05), however, NaNO3 had no effect on any of the plasma adhesion molecules (P = 0.15 – 0.43). Our preliminary data suggest that oral NaNO3 may provide a therapeutic benefit to vasodilator capacity in the lower extremity (i.e. diseased limb) of patients with severe PAD. Moreover, NaNO3 may promote an anti‐inflammatory effect in this patient population.Support or Funding InformationFunded by the American Heart Association 13GRNT16490002 (DPC). The Undergraduate Summer Research Fellowship program is supported by the American Physiological Society (SLN).
Mapping gender‐specific modifiers of doxorubicin cardiotoxicity in BN and SS rats
Authors: Flister Michael , Plasterer Cody , Paddock Samantha , Jacob Julia , Lemke Angela 
Published: November 2023

As the efficacy of cancer treatment improves, patients are living longer and the management of life‐threating toxicities of many anticancer drugs is being pushed to the forefront. The most insidious toxicities are those affecting the heart (i.e., cardiotoxicity) and anthracyclines, such as doxorubicin (DOX), are among the most cardiotoxic drugs used to treat cancer. Most breast cancer patients receive DOX and many develop cardiotoxicity do to unknown underlying genetic risks, yet no models for mapping DOX cardiotoxicity in females exist. Here, we identified the first rodent model for mapping gender‐specific modifiers of DOX cardiotoxicity in females. Echocardiography was used to assess cardiotoxicity in SS and BN rats treated with DOX (2mg/kg for 8 weeks; n=5–7 rats per group). Compared with controls, male BN and SS rats both developed significantly reduced cardiac output following 8 weeks of DOX treatment, which did not differ between the strains. In comparison, fractional shortening (FS) in female SS rats decreased by 27±3% (P<0.001) following DOX treatment, whereas female BN rats had no changes in FS (2±3%). In total, we compared pathological changes in 59 physiological and cardiovascular traits in DOX‐treated female BN and SS rats, of which 8 (13%) and 21 (36%) changed significantly (P<0.05), respectively. These physiological measurements ranging from serum profiles to cardiac fibrosis, capillary density, and echocardiography, suggest that SS female rats are far more susceptible to DOX cardiotoxicity than BN female rats. Collectively, these data also suggest that the BN and SS rat strains can be used to map female‐specific genetic modifiers of DOX‐mediated cardiotoxicity for the first time.Support or Funding InformationNational Institutes of Health (1R01CA193343‐01)