Paradoxical Reduction Research Articles

Analysis of patient health questionnaire-9 (PHQ-9) based depression prevalence according to a discordance between quantitative urinary cotinine levels and self-report of second-hand smoke exposure among adults: A cross-sectional study

BackgroundSecond-hand smoke (SHS) exposure appears to be more common among individuals with depression. However, self-report of SHS exposure is an inaccurate classification compared to confirming SHS exposure using urinary cotinine (UC). Additionally, the dose-response relationship between depression and UC is controversial. MethodsThe severe stress rate and depression prevalence was estimated among 14530 Korean participants aged ≥19 years using data patient health questionnaire-9 (PHQ-9) and on UC from the Korean National Health and Nutrition Examination Survey. Measured UCs were divided into four categories: UC– (≤0.3 μg/L), UC± (0.4 μg/L–0.9 μg/L), UC+ (1.0 μg/L–11.9 μg/L), and UC++ (≥12.0 μg/L). ResultsAbout 55.0 % participants were female and participants’ mean age was 51.1 years. Non-smokers were 80.3 %. Among non-smokers, non-SHS exposure participants (SR–) and SHS exposure participants (SR+) were 83.0 % and 17.0 %, respectively. When UC– was used as the reference subgroup, the UC++ subgroup showed a higher depression prevalence, whereas the UC ± subgroup showed a lower prevalence. In the same UC categories, the depression prevalence and severe stress rate were higher among females than among males. Furthermore, the SR + subgroup had a higher severe stress rate than the SR– subgroup. ConclusionsOur study showed a paradoxical reduction in the depression prevalence and severe stress rate in the UC ± subgroup compared to the UC– subgroup. Additionally, the dose-response relationship between the SHS exposure biomarker and the depression prevalence was not linear. Our study indicates that an emotional stress-based model may be more appropriate for explaining the relationship between depression and SHS exposure.

Vascular service provision during the COVID-19 pandemic worsened major amputation rates in socially deprived diabetic populations.

The Coronavirus Disease - 2019 (COVID-19) pandemic significantly impacted healthcare service provision and put diabetic patients at increased risk of adverse health outcomes. We aimed to assess the impact of the COVID-19 pandemic on the incidence and demographic shift of major lower-limb amputation in diabetic patients. We performed a retrospective analysis of diabetic patient records undergoing major lower-limb amputation between 01/03/2019 and 01/03/2021 at the Royal Sussex County Hospital, the regional arterial hub for Sussex. Primary outcomes were amputation incidence rates and patient demographics compared between the prepandemic and pandemic cohorts. The incidence rate ratio of major lower-limb amputations shows a drop in amputations during the pandemic compared to pre-pandemic (IRR 0.82; 95% CI 0.57-1.18). Data suggests a shift in the social deprivation background of patients receiving amputations to disproportionately affect those in the more deprived 50% of the population (p=0.038). Younger patients received more amputations during the pandemic compared to prepandemic levels (p=0.001). Results suggest that during the COVID-19 pandemic there was a paradoxical reduction in amputations compared to prepandemic levels. However, changes to the demographic makeup of patient's receiving amputations are alarming as younger, and more deprived patients have been disproportionately affected by the pandemic.

Plasma fibroblast activation protein is decreased in acute heart failure despite cardiac tissue upregulation

BackgroundCardiac fibroblast activation protein (FAP) has an emerging role in heart failure (HF). A paradoxical reduction in its levels in pathological conditions associated with acute processes has been observed. We aimed to identify FAP cardiac tissue expression and its relationship with the main cardiac fibrosis-related signaling pathways, and to compare plasma FAP levels in acute and chronic HF patients.MethodsTranscriptomic changes were assessed via mRNA/ncRNA-seq in left ventricle tissue from HF patients (n = 57) and controls (n = 10). Western blotting and immunohistochemistry were used to explore FAP protein levels and localization in cardiac tissue. ELISA was performed to examine plasma FAP levels in acute HF (n = 48), chronic HF (n = 15) and control samples (n = 7).ResultsFAP overexpression in cardiac tissue is related to the expression of molecules directly involved in cardiac fibrosis, such as POSTN, THBS4, MFAP5, COL1A2 and COL3A1 (P < 0.001), and is directly and inversely related to pro- and antifibrotic microRNAs, respectively. The observed FAP overexpression is not reflected in plasma. Circulating FAP levels were lower in acute HF patients than in controls (P < 0.05), while chronic HF patients did not show significant changes. The clinical variables analyzed, such as functional class or etiology, do not affect plasma FAP concentrations.ConclusionsWe determined that in HF cardiac tissue, FAP is related to the main cardiac fibrosis signaling pathways as well as to pro- and antifibrotic microRNAs. Additionally, an acute phase of HF decreases plasma FAP levels despite the upregulation observed in cardiac tissue and regardless of other clinical conditions.Graphical abstract

Age and Gender Difference among Elderly Stroke Patients in a Rehabilitation Center, Retrospective Study

Aims This study aims to report the patients’ associated factors related to the study cohort. Methods This is a retrospective hospital-based cohort study that recruited 503 elderly patients (>55 years) with stroke from a tertiary rehabilitation center. Data were collected through a pre-designed case report form, and stroke was classified according to Data on Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Results There was a female predominance at a rate of 52.9% and a significant co-morbidity related to diabetes, hyperlipidemia, and hypertension in addition to cardiac disease. The ischemic stroke affected 84.7% of the studied sample. The univariate analysis reported that male gender, diabetes, hypertension, and hyperlipidemia were not associated with an increased risk of non-ischemic stroke, while obesity showed a paradoxical reduction in the risk of stroke. Conclusion Stroke among old patients behaves differently and warrants initiating both primary and secondary prevention programs.

Dosage and organic acid residue of MOG35-55 peptide influences immunopathology and development of BCG induced experimental autoimmune encephalomyelitis (EAE).

Experimental autoimmune encephalomyelitis (EAE) serves as a model for studying multiple sclerosis, with immunization strategies utilizing MOG35-55 peptide, emulsified in adjuvant enriched with mycobacterium tuberculosis (Mtb). This study examined the effects of Bacillus Calmette-Guérin (BCG) as an adjuvant, alongside the impact of MOG35-55 peptide doses and their residual counter ions on EAE development. We found that BCG can be effectively used to induce EAE with similar incidence and severity as heat-killed H37Ra, contingent upon the appropriate MOG35-55 peptide dose. Different immunization doses of MOG35-55 peptide significantly affect EAE development, with higher doses leading to a paradoxical reduction in disease activity, probably due to peripheral tolerance mechanisms. Furthermore, doses of MOG35-55 peptides with acetate showed a more pronounced effect on disease development compared to those containing trifluoroacetic acid (TFA), suggesting the potential influence of residual counter ions on EAE activity. We highlighted the feasibility of applying BCG to the establishment of EAE for the first time. Our findings emphasized the importance of MOG peptide dosage and composition in modulating EAE development, offering insights into the mechanisms of autoimmunity and tolerance. This could have implications for autoimmune disease research and the design of therapeutic strategies.

Noninvasive evaluation of dynamic microvascular dysfunction in ischemia and no obstructive coronary artery disease patients with suspected vasospasm.

In patients with ischemia and no obstructive coronary artery disease (INOCA), a dynamic coronary microvascular dysfunction (CMD) is frequent but difficult to capture by noninvasive means.The aim of our study was to assess dynamic CMD in INOCA patients with stress echocardiography after vasoconstrictive and vasodilator stimuli. In this prospective single-center study, we have enrolled 40 INOCA patients (age 56.3 ± 13 years, 32 women). All participants underwent stress echocardiography with hyperventilation (HYP), followed by supine bicycle exercise (HYP+EXE) and adenosine (ADO). Stress echocardiography included an assessment of regional wall motion abnormality (RWMA) and coronary flow velocity (CFV) in the distal left anterior descending (LAD) coronary artery. HYP induced a 30% increase in rate pressure product (rest = 10 244 ± 2353 vs. HYP = 13 214 ± 3266 mmHg x bpm, P < 0.001) accompanied by a paradoxical reduction in CFV (HYP< rest) in 21 patients (52%). HYP alone was less effective than HYP+EXE in inducing anginal pain (6/40, 15% vs. 10/40, 25%, P = 0.046), ST segment changes (6/40, 15% vs. 24/40, 60%, P < 0.001), and RWMA (6/40, 15% vs. 13/40, 32.5%, P = 0.008). ADO-induced vasodilation was preserved (≥2.0) in all patients. In patients with INOCA, a coronary vasoconstriction after HYP is common, in absence of structural CMD detectable with ADO. HYP+EXE test represents a more powerful ischemia inducer than HYP alone. Stress echocardiography with LAD-CFV may allow the noninvasive assessment of dynamic and structural coronary microcirculation during stress.

Rescuing impaired cortical‐hippocampal interactions during sleep with 40Hz stimulation directed to hippocampus in 3xTg‐AD/PVcre mice

AbstractBackgroundIn preclinical Alzheimer’s disease (AD), spatial learning and memory is impaired (Allison et al., 2016). We reported similar impairments in 6‐month 3xTg‐AD female mice on a virtual spatial‐reorientation‐task (VM) that requires memory for using landmarks to navigate (Cushing et al., 2020). Memory replay during sleep is critical for learning related plasticity (Ego‐Stengel &amp; Wilson, 2009; Jadhav et al, 2012; Maingret et al, 2016), and hippocampal‐cortical dysfunction is a potential mechanism for memory impairments in AD (Gennaro et al, 2017; Khan et al, 2014). Consistent with this hypothesis, we previously found deficits in hippocampal‐parietal cortex (HPC‐PC) coordination during sleep coinciding with impairments on the VM (Cushing et al, 2020). 40Hz stimulation has been shown to clear AD pathology in mice (Iaccarino et al, 2016; Martorell et al, 2019), and improve functional connectivity in preclinical AD patients (He et al, 2021), but see (Soula et al, 2023).MethodThus, we assessed HPC‐PC coordination in 3xTg‐AD/PVcre mice learning the VM. We implanted a 16‐tetrode recording array targeting PC and HPC and an optical fiber targeting HPC. Daily recording sessions of rest‐task‐rest commenced as mice learned the VM, followed by HPC optogenetic stimulation, with either 40Hz or SHAM stimulation. We assessed sleep quality metrics, delta waves (DW) in PC, and HPC markers of memory replay (SWRs) during slow wave sleep (SWS).ResultIn SHAM stimulated mice SWR‐DW cross‐correlations were reduced, similar to 3xTg‐AD mice (Cushing et al, 2020); while in the 40Hz stimulated mice, this phase‐locking was rescued. Furthermore, the 40Hz stimulated mice have restored performance on the VM compared to SHAM mice. However, this rescued HPC‐PC coupling no longer predicted performance as in NonTg animals (Cushing et al, 2020). Instead, DWTs independently predicted performance in 40Hz animals, but not SHAM animals. We also found paradoxical reduction of amyloid beta in contralateral PC and ventral CA1, but no reduction in contralateral dorsal CA1, synaptically closer to where stimulation occurred.ConclusionThus, 40Hz stimulation of HPC rescued learning and memory related functional interactions in the HPC‐PC network during sleep and as a consequence rescued impairments in spatial navigation, despite a decoupling between HPC‐PC coupling and learning and memory.

1468 Lymphatic dysfunction affects both collagen degradation and collagen synthesis, leading to a paradoxical reduction in dermal fibrosis

1468 Lymphatic dysfunction affects both collagen degradation and collagen synthesis, leading to a paradoxical reduction in dermal fibrosis

Paradoxical reduction of plasma lipids and atherosclerosis in mice with adenine-induced chronic kidney disease and hypercholesterolemia.

Atherosclerotic cardiovascular disease is prevalent among patients with chronic kidney disease (CKD). In this study, we initially aimed to test whether vascular calcification associated with CKD can worsen atherosclerosis. However, a paradoxical finding emerged from attempting to test this hypothesis in a mouse model of adenine-induced CKD. We combined adenine-induced CKD and diet-induced atherosclerosis in mice with a mutation in the low-density lipoprotein receptor gene. In the first study, mice were co-treated with 0.2% adenine in a western diet for 8 weeks to induce CKD and atherosclerosis simultaneously. In the second study, mice were pre-treated with adenine in a regular diet for 8 weeks, followed by a western diet for another 8 weeks. Co-treatment with adenine and a western diet resulted in a reduction of plasma triglycerides and cholesterol, liver lipid contents, and atherosclerosis in co-treated mice when compared with the western-only group, despite a fully penetrant CKD phenotype developed in response to adenine. In the two-step model, renal tubulointerstitial damage and polyuria persisted after the discontinuation of adenine in the adenine-pre-treated mice. The mice, however, had similar plasma triglycerides, cholesterol, liver lipid contents, and aortic root atherosclerosis after being fed a western diet, irrespective of adenine pre-treatment. Unexpectedly, adenine pre-treated mice consumed twice the calories from the diet as those not pre-treated without showing an increase in body weight. The adenine-induced CKD model does not recapitulate accelerated atherosclerosis, limiting its use in pre-clinical studies. The results indicate that excessive adenine intake impacts lipid metabolism.

NO CLOT, NO PROBLEM? NOT EXACTLY

NO CLOT, NO PROBLEM? NOT EXACTLY

Community prevalence and dyad disease pattern of multimorbidity in China and India: a systematic review

BackgroundDriven by the increasing life expectancy, China and India, the two most populous countries in the world are experiencing a rising burden of multimorbidity. This study aims to explore community...

The difference in the diaphragmatic physiological measures between inspiratory and expiratory phases in ALS.

We aimed to clarify the differences in static and dynamic diaphragm parameters between the expiratory and inspiratory phases in amyotrophic lateral sclerosis (ALS). Twenty patients with early-stage ALS and 16 healthy controls were enrolled in the study. We measured the amplitudes of compound muscle action potential (phCMAP) by electrical stimulation of the phrenic nerve and the zone of apposition wall thickness of the diaphragm (DT) using ultrasonography. We analyzed the differences in phCMAP (∆phCMAP) and DT (∆DT) between the end-inspiratory and end-expiratory phases and their correlation with forced vital capacity (FVC). The ΔphCMAP (mean 129.7 ± SD 204.7µV) and ∆DT (0.80 ± 0.88cm) in patients were significantly smaller than those in controls (348.6 ± 247.7µV, p = 0.0003 and 1.89 ± 1.10cm, p = 0.0002, respectively). Although ∆DT was significantly correlated with FVC, we found no correlation between ∆phCMAP and FVC. The phCMAP was paradoxically smaller during inspiration than during expiration in 35% of patients but in none of the controls. Dynamic parameters of the diaphragm were abnormal in early-stage ALS. The paradoxical reduction in phCMAP during inspiration may reflect early respiratory dysfunction. Assessment of dynamic abnormalities of the diaphragm may provide helpful information for respiratory management in patients with ALS.

Paradoxical Anxiety Level Reduction in Animal Chronic Stress: A Unique Role of Hippocampus Neurobiology.

A paradoxical reduction in anxiety levels in chronic predator stress paradigm (PS) in Sprague–Dawley rats has recently been shown in previous works. In this paper, we studied the possible neurobiological mechanism of this phenomenon. We segregated PS-exposed Sprague–Dawley rats into the high- and low-anxiety phenotypes. The long-lasting effects of PS on corticosterone levels, blood flow speed in the carotid arteries, diffusion coefficient, and 1H nuclear magnetic resonance spectra in the hippocampus were compared in the high-anxiety and low-anxiety rats. In addition, we evaluated the gene BDNF expression in the hippocampus which is considered to be a main factor of neuroplasticity. We demonstrated that in low-anxiety rats, the corticosterone level was decreased and carotid blood flow speed was increased. Moreover, in the hippocampus of low-anxiety rats compared to the control group and high-anxiety rats, the following changes were observed: (a) a decrease in N-acetyl aspartate levels with a simultaneous increase in phosphoryl ethanol amine levels; (b) an increase in lipid peroxidation levels; (c) a decrease in apparent diffusion coefficient value; (d) an increase in BDNF gene expression. Based on these findings, we proposed that stress-induced anxiety reduction is associated with the elevation of BDNF gene expression directly. Low corticosterone levels and a rise in carotid blood flow speed might facilitate BDNF gene expression. Meanwhile, the decrease in apparent diffusion coefficient value and decrease in N-acetyl aspartate levels, as well as an increase in the lipid peroxidation levels, in the hippocampus possibly reflected destructive changes in the hippocampus. We suggested that in Sprague–Dawley rats, these morphological alterations might be considered as an impetus for further increase in neuroplasticity in the hippocampus.

P232 EXERTIONAL BREATHLESSNESS IN HYPERTROPHIC CARDIOMYOPATHY: OBSTRUCTION–INDEPENDENT SYMPTOMS IN A “PARADOXICAL” RESPONSE TO EXERCISE

Abstract A 66–y.o. man with hypertrophic cardiomyopathy presented with residual exertional dyspnea NYHA III a few years after surgical myectomy, mitral valve repair and ICD implantation. Echocardiography showed residual mild septal hypertrophy and mitral regurgitation (MR), and a variable obstruction of left ventricular outflow tract (LVOT), witnessed by a pressure gradient ranging from 15 to 50–70 mmHg (Figure 1). Exercise echocardiography did not suggest exercise–induced LVOT obstruction (LVOTO) or functional MR. We thus performed a thorough invasive hemodynamic evaluation at rest and during exercise. LVOTO was present at rest, with a maximum pressure gradient of 90–100 mmHg and typical “spike–and–dome” configuration of the aortic pulse contour (Figure 2), with LV end–diastolic pressure (LVEDP) at the upper limit of normal (15 mmHg) and normal pulmonary hemodynamics. During exercise, we observed a paradoxical reduction of the LVOTO (30–40 mmHg at peak, Figure 2). Pulmonary hypertension developed during exercise, due to LV diastolic dysfunction, witnessed by a marked increase in pulmonary artery wedge pressure and LVEDP (up to 25 mmHg and 30 mmHg at peak, respectively). Cardiac output (CO) reserve was at the lower limits of normal, mainly due to chronotropic incompetence, responsible for a mildly reduced exercise capacity (peak oxygen consumption was 20 mL/Kg/min, 75% of predicted). Thus, cardiac catheterization confirmed the presence of a relevant LVOTO at rest, that was not directly related to exertional symptoms. These latter were mainly attributable to LV diastolic dysfunction and reduced CO reserve. These findings helped us driving treatment decision in a tailored way: beta–blockers were not uptitrated, because of their negative inotropic effect, and high–risk septal reduction therapies were excluded, since exertional symptoms were unrelated to LVOTO. However, an attempt to reduce LVOTO was done by DDD sequential pacing through the ICD. Pacing could induce mechanical dyssynchrony and reduce LVOTO by increasing the end–systolic LVOT diameter. The simultaneous echocardiographic monitoring highlighted an acute reduction of LVOT gradient from 50–70 mmHg to 20–30 mmHg (Figure 3). This case suggests that, in well–selected cases, patients’ management based on pathophysiological reasoning may help to define the etiopathogenetic mechanism underlying symptoms, and to drive treatment decision in a patient–centered way.

Serum aldosterone and urine electrolytes dynamics in response to DASH diet intervention - An inpatient mechanistic study.

Dietary approach to stop hypertension (DASH) diet reduces blood pressure (BP) as effectively as one antihypertensive drug, yet its mechanism of action was never fully characterized. We designed a translational inpatient trial to elucidate the biological pathway leading from nutritional change, through hormonal response, reversal of urine electrolytes ratio, to BP reduction. A single-center open-label interventional trial. Volunteers were admitted for 14 days, transitioning from an American-style diet to DASH diet. Vital signs, blood, and urine samples were collected daily. Participants completed two 24-hour ambulatory BP measurements (ABPM) and two 24-hour urine collections on days 1 and 10. Nine volunteers completed the protocol. During inpatient stay, serum aldosterone increased from day 0 (mean 8.3 ± 5.0) to day 5 (mean 17.8 ± 5.8) after intervention and decreased on day 11 (mean 11.5 ± 4.7) despite continuous exposure to the same diet (p-value = 0.002). Urine electrolyte ratio ([Na]/[K]) decreased significantly from a mean of 3.5 to 1.16 on day 4 (p < 0.001). BP by 24-hour ABPM decreased by a mean of 3.7 mmHg systolic BP and 2.3 mmHg diastolic BP from day 1 to 10. Shifting from a high-sodium/low-potassium diet to the opposite composition leads to aldosterone increase and paradoxical BP reduction. Urine electrolyte ratio reflects nutritional changes and should guide clinicians in assessing adherence to lifestyle modification.

Central volume shift in acute heart failure revealed by blood volume monitoring during haemodialysis

ABSTRACTCentral volume shift is one of the major pathophysiological mechanisms of acute pulmonary oedema in acute heart failure (AHF). Pathological vasoconstriction results in central volume shift; however, its onset and course have been rarely detected or recorded in clinical practice. We report an exceptional case of AHF developing during haemodialysis, with marked blood pressure (BP) elevation and paradoxical repeated reduction in blood volume (BV) detected by real-time BV monitoring, accompanied by worsening dyspnoea. This inverse correlation of BV and BP during haemodialysis indicates that the theoretical central volume shift was captured in real-world AHF.

Sex differences in the coronary vascular response to combined chemoreflex and metaboreflex stimulation in healthy humans.

What is the central question of this study? Coronary blood flow in healthy humans is controlled by both local metabolic signalling and adrenergic activity: does the integration of these signals during acute hypoxia and adrenergic activation differ between sexes? What are the main findings and its importance? Both males and females exhibit an increase in coronary blood velocity in response to acute hypoxia, a response that is constrained by adrenergic stimulation in males but not females. These findings suggest that coronary blood flow control differs between males and females. Coronary hyperaemia is mediated through multiple signalling pathways, including local metabolic messengers and adrenergic stimulation. This study aimed to determine whether the coronary vascular response to adrenergic stressors is different between sexes in normoxia and hypoxia. Young, healthy participants (n=32; 16F) underwent three randomized trials of isometric handgrip exercise followed by post-exercise circulatory occlusion (PECO) to activate the muscle metaboreflex. End-tidal was controlled at (1) normoxic levels throughout the trial, (2) 50mmHg for the duration of the trial (hypoxia trial), or (3) 50mmHg only during PECO (mixed trial). Mean left anterior descending coronary artery velocity (LADVmean ; transthoracic Doppler echocardiography), heart rate and blood pressure were assessed at baseline and during PECO. In normoxia, there was no change in LADVmean or cardiac workload induced by PECO in males and females. Acute hypoxia increased baseline LADVmean to a greater extent in males compared with females (P<0.05), despite a similar increase in cardiac workload. The change in LADVmean induced by PECO was similar between sexes in normoxia (P=0.31), greater in males during the mixed trial (male: 12.8 (7.7) cm/s vs. female: 8.1 (6.3) cm/s; P=0.02) and reduced in males but not females in acute hypoxia (male: -4.8 (4.5) cm/s vs. female: 0.8 (6.2) cm/s; P=0.006). In summary, sex differences in the coronary vasodilatory response to hypoxia were observed, and metaboreflex activation during hypoxia caused a paradoxical reduction in coronary blood velocity in males but not females.

Interleukin-1A May Illuminate Differential Effects of the Retinal Artery Caliber in HIV Patients

Background: Retinal artery caliber (RAC) is narrower in human immunodeficiency virus (HIV)-infected patients beginning antiretroviral therapy (ART). We aimed to assess associations between variations in genes encoding inflammatory mediators and natural killer receptors and retinal artery caliber (RAC) in HIV patients beginning ART.Materials and Methods: Seventy-nine HIV positive patients beginning ART with less than 200 cluster of differentiation (CD) 4 T-cells/μL were recruited. Examinations were performed before ART (V0) and at months 3, 6 and 12 (V3, V6, V12). The study was approved by ethics committees and informed consent was obtained from each subject.Results: Right and left RAC of the HIV patients were narrower than healthy controls (p=0.016 for right RAC) and narrowed further on ART, but demographic associations with the right and left RAC were not identical. Here we show that polymorphisms in genes encoding NK receptors or TNF activity had no significant impact, but right RAC was associated with carriage of allele 2 at IL1A+4845 (p=0.037 after 12 months on ART).Conclusion: Overall the paradoxical reduction in the RAC in HIV patients responding to ART was not modified by genotypes known to affect NK cell function or TNF responses, but IL1A genotype may modify the decline in the right RAC.Keywords: anti-retroviral therapy, CMV, HIV, IL1A, retinal artery caliber

Lower-body dynamic exercise reduces wave reflection in healthy young adults.

What is the central question of this study? There is a paradoxical reduction in augmentation index during lower-body dynamic (LBD) exercise in the face of an increase in central pressure. To determine causality, the amplitudes of forward and backward pressure waves were assessed separately using wave separation analysis. What is the main finding and its importance? Reflection magnitude decreased during LBD exercise in healthy young adults and was attributable to an increased forward pressure wave amplitude and decreased backward pressure wave amplitude. This vasoactive response might limit the adverse effects of wave reflection during LBD exercise, optimizing ventricular-arterial interactions. Acute lower-body dynamic (LBD) exercise decreases surrogate measures of wave reflection, such as the augmentation index. However, the augmentation index is influenced by the combined effects of wave reflection timing, magnitude and other confounding factors external to wave reflection, which make it difficult to discern the origin of changes in surrogate measures. The relative contributions of forward (Pf) and backward (Pb) pressure wave amplitudes to central pressure can be determined by wave separation analysis. Reflection magnitude (RM=Pb/Pf) and the timing of apparent wave reflection return can also be determined. We tested the hypothesis that acute LBD exercise decreases RM and reflected wave transit time (RWTT). Applanation tonometry was used to record radial artery pressure waveforms in 25 adults (24 ± 4 years of age) at baseline and during light-, moderate- and vigorous-intensity exercise. Wave separation analysis was conducted offline using a personalized physiological flow wave to determine Pf, Pb, RM and RWTT. The RM decreased during all intensities of exercise compared with baseline (all P<0.001; baseline, 43 ± 5%; light, 33 ± 6%; moderate, 23 ± 7%; vigorous, 17 ± 5%). The reduction in RM was attributable to the combined effect of increased Pf and decreased Pb during exercise. The RWTT decreased during all intensities of exercise compared with baseline (all P<0.04; baseline, 156 ± 17ms; light, 144 ± 15ms; moderate, 129 ± 16ms; vigorous, 121 ± 17ms). Lastly, in a stepwise multilinear regression, Pf, but not Pb and RWTT, contributed to increased central pulse pressure during LBD exercise. These data show that wave reflection decreased and that central pulse pressure is most influenced by Pf during LBD exercise.

Effects of Supplemental Oxygen During Mechanical Ventilation on Diaphragmatic Blood Flow

Introduction During mechanical ventilation (MV), supplemental oxygen is commonly administered to critically-ill patients to prevent hypoxemia. However, in ICU patients, hyperoxia during MV is associated with increased mortality and a decrease in ventilator free days. Hyperoxic MV can elicit a paradoxical reduction in O2 delivery to the heart, brain, and kidneys. Whereas MV in normoxia diminishes diaphragm perfusion and O2 delivery, the effect of MV with supplemental oxygen on diaphragm perfusion is unknown. Previous studies demonstrate that MV with hyperoxia substantially impairs diaphragm contractile function. Therefore, hyperoxia during MV may potentiate reductions in diaphragm perfusion with MV and predispose patients to problematic weaning. Purpose Using an established animal model of MV, we tested the following hypotheses: 1) MV supplemented with hyperoxic gas (FIO2 0.99) would reduce diaphragmatic blood flow compared to spontaneously breathing (SB) animals, and 2) hyperoxic MV would decrease diaphragmatic blood flow to a greater extent compared to MV with room air (normoxia, FIO2 0.21). Methods Using fluorescent microspheres, tissue blood flow was measured in adult female Sprague-Dawley rats (n = 4) during spontaneous breathing (SB), mechanical ventilation + hyperoxia (MV +O2), and mechanical ventilation + room air (MV + RA). Following microsphere infusion during SB, animals were intubated and immediately ventilated with supplemental hyperoxic gas for 30 min and an arterial blood sample (~100 ul) was collected to confirm hyperoxemia prior to the second microsphere infusion. Thereafter, animals were subjected to MV using room air for 30 min followed by a third infusion of microspheres. Following the final microsphere infusion, tissues were harvested for blood flow analysis. The diaphragm was sectioned into costal (ventral, medial, dorsal) and crural portions to determine blood flow distribution within the diaphragm. Results During MV + O2, average arterial PO2 (PaO2) was 370 ± 39 mmHg. Compared to SB, total diaphragm blood flow was significantly decreased with MV + O2 (50 ± 2 vs 17 ± 3 ml/min/100g; P<0.05) and MV + RA (30 ± 1 ml/min/100g; P<0.05 vs SB). Compared to SB, blood flow to the medial costal diaphragm was reduced during both MV + O2 (59 ± 5 vs 18 ± 4 ml/min/100g; P<0.05) and MV + RA (59 ± 5 vs 29 ± 6 ml/min/100g; P<0.05). During MV + RA, compared to MV + O2, blood flow to the whole diaphragm was higher (30 ± 1 vs 17 ± 3 ml/min/100g; P<0.05). Although not significant, medial costal diaphragm flow tended to be higher with MV + RA versus MV + O2 (P=0.09). Conclusion These data demonstrate that supplementing short term MV with hyperoxia versus room air reduces total diaphragmatic blood flow to a significantly greater degree, suggesting that hyperoxia during MV reduces diaphragmatic O2 delivery. This raises the likelihood that prolonged bouts of MV (i.e. 6+ h) with hyperoxia may accelerate MV-induced vascular dysfunction in the quiescent diaphragm thus exacerbating downstream contractile dysfunction.