IL-33 Enhances the Total Production of IgG, IgG1, and IgG3 in Angiostrongylus cantonensis-Infected Mice.

The purpose of this study is to clarify the role of IL-33 in the immune response to angiostrongyliasis, especially in terms of antibody production and isotype switching. In our experiment, C57BL/6 mice were each infected with 35 infectious larvae and were divided into groups that received an intraperitoneal injection of IL-33, anti-IL-33 monoclonal antibody (mAb), or anti-ST2 mAb 3 days post-infection (dpi) and were subsequently administered booster shots at 5-day intervals with the same dose. Serum samples from each group were collected weekly for ELISA assays. The levels of total IgG, IgG1, and IgG3 were significantly increased in A. cantonensis-infected mice that were treated with IL-33, and the levels decreased significantly in infected groups treated with anti-IL-33 or anti-ST2 mAb. These results suggest that IL-33 may play a critical role in the pathogenesis of human angiostrongyliasis and could be useful for understanding protective immunity against this parasitic infection.

Interruption of the tricuspid regurgitant jet: A possible consequence of reflected waves.

Reflected pressure waves can impact central aortic pressure, and can cause notching of the pulmonic valve Doppler signal. However, reflected waves in the venous system usually do not achieve a high enough velocity to alter Doppler flow patterns. Herein we report a case of systolic notching of the tricuspid regurgitant signal that likely resulted from reflected venous waves.

Excess pressure but not pulse wave velocity is associated with cognitive function impairment: a community-based study.

BACKGROUND: Carotid-femoral pulse wave velocity (cf-PWV), an index of mainly distal aortic stiffness, has been inconsistently associated with cognitive function. Excess pressure, derived from the arterial reservoir-excess pressure analysis, may integrate the pulsatile load of the proximal aorta. The present study examined whether increased excess pressure is associated with cognitive function impairment in community adults. METHODS: A total of 992 community participants (69.5% females; mean age: 67.3 years; education 13.6 years) without cerebrovascular disease or dementia received the Montreal Cognitive Assessment (MoCA) to evaluate global cognition. Arterial reservoir and excess pressure, arterial stiffness, and wave reflections were assessed, using carotid tonometry and aortic Doppler flowmetry. RESULTS: Excess pressure integral (XSPI), percentage XSPI, cf-PWV, characteristic impedance (Zc), and forward and backward pressure amplitude (Pf, Pb, respectively) were significantly higher in 197 participants (19.9%) with a low MoCA score (<26 or <25, depending on level of education). In multivariable analyses, XSPI (standardized odds ratio, 95% confidence interval, 1.30, 1.06-1.59), and percentage XSPI (1.27, 1.06-1.52) but not cf-PWV (1.04, 0.85-1.26) were significantly associated with a low MoCA. Further analysis revealed that Pf and Zc were the major determinants of XSPI (partial R2: Pf = 0.656, Zc = 0.467) and percentage XSPI (Pf = 0.459, Zc = 0.371). In contrast, age, instead of Pf and Zc, was the major determinant of cf-PWV (partial R2: age = 0.187). CONCLUSIONS: Excess pressure (XSPI/percentage XSPI), mainly determined by the pulsatile hemodynamics of the proximal aorta, was significantly associated with cognitive function impairment in middle-aged and elderly community adults.

Ibudilast, a Phosphodiesterase Inhibitor and Toll-Like Receptor-4 Antagonist, Improves Hemorrhagic Shock and Reperfusion-Induced Left Ventricular Dysfunction by Reducing Myocardial Tumor Necrosis Factor α.

OBJECTIVES: Rapid loss of blood volume causes ischemic injury to myocardial cells and impairs cardiac function. Subsequent reperfusion, although necessary to revitalize stunned tissues, can induce production of reactive oxygen species and inflammation, causing further tissue damages and weakening cardiac function. Ibudilast, a Toll-like receptor-4 (TLR4) antagonist and an inhibitor of phosphodiesterase-4, possesses antioxidative and anti-inflammatory capacities. In this study, we aim to examine the protective efficacy of ibudilast against hemorrhagic shock and reperfusion (HSR)-induced myocardial injury and cardiac dysfunction. METHODS: Studies were conducted on male Sprague-Dawley rats in 3 groups: sham-operated, HSR with, and HSR without pretreatment of ibudilast. Hemorrhagic shock was induced by withdrawing blood from the femoral artery until the mean aortic pressure dropped to around 40 mm Hg; reperfusion was conducted by replenishing blood after 120 minutes of hemorrhagic shock, and the observation continued for another 240 minutes. The left ventricular (LV) contractility, diastolic suction capacity, and ventricular stiffness were evaluated using simultaneous LV pressure, and volume was recorded during a temporary inferior vena cava constriction at the end of reperfusion. Ibudilast (10 mg/kg) was administered intraperitoneally 3 days and 20 minutes prior to HSR. Serum creatine kinase myocardial band (CK-MB) was examined at the end of both HSR, and serum CK-MB, myocardial TLR4 protein expression, and malondialdehyde (MDA) and tumor necrosis factor (TNF)-α levels at the end of reperfusion. RESULTS: HSR induced an increase in serum CK-MB. Subsequent reperfusion further increased serum CK-MB, upregulated myocardial TLR4 protein expression, and increased tissue levels MDA and TNF-α vs the sham (P < .05). HSR reduced LV contractility, prolonged LV relaxation time, and increased LV diastolic stiffness. Ibudilast pretreatment attenuated HSR-induced TLR4 protein expression, reduced myocardial MDA and TNF-α levels, and protected against cardiac dysfunction. CONCLUSIONS: Ibudilast pretreatment reduced myocardial TLR4 expression, decreased MDA and TNF-α levels, and protected against HSR-induced decrease in LV contractility, prolonged LV relaxation time, and increased diastolic stiffness.

Curcumin Attenuates Hemorrhagic Shock and Blood Replenish Resuscitation-induced Impairment of Pulmonary Barrier Function by Increasing SIRT1 and Reducing Malondialdehyde and TNF-α Contents and Neutrophil Infiltration in Lung in a Dose-Dependent Fashion.

OBJECTIVES: Acute lung injury (ALI) is a critical complication subsequent to hemorrhage shock and resuscitation (HSR) that frequently leads to multiple organ failure. Collective evidence suggested that the activation of pulmonary nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1) plays a critical role in inhibiting the production of reactive oxygen species (ROS) and tumor necrosis factor (TNF)-α, as well as the protection against ALI. Curcumin is a potent activator of SIRT1 and possesses antioxidative and anti-inflammatory effects. In this study, we aim to investigate the dose-dependent protective effectiveness of curcumin pretreatment against HSR-induced ALI. METHODS: Studies were conducted on Sprague-Dawley male rats in 5 groups: sham-operated, HSR, and HSR pretreated with 50, 200, or 400 mg/kg of curcumin. Curcumin was treated orally for 4 days and 1 hour before HSR induction. HSR was induced by decreasing the mean aortic pressure (MAP) to 40 mm Hg for 60 min through drawing blood from the left femoral artery, followed by blood replenish and leaving for another 120 min. At the end of HSR, the severity of ALI was assessed by pulmonary barrier function, via pulmonary filtration coefficient (Kfc) evaluated using isolated a perfused lung model, lung weight-to-body weight ratio (LW/BW), lung wet-to-dry weight ratio (W/D), and lavage protein concentration (PCBAL). We also examined the level of lung inflammation by lavage TNF-α and differential neutrophil count, and oxidative stress by lavage malondialdehyde (MDA). RESULTS: HSR significantly increased Kfc, LW/BW, W/D, and PCBAL; decreased pulmonary SIRT1; and increased lavage TNF-α and MDA contents and differential neutrophil count (P < .05). Curcumin pretreatment demonstrated lung protection efficacy with improved pulmonary barrier function, increased lung SIRT1, and reduced pulmonary oxidative stress and lung inflammation in a dose-dependent fashion. CONCLUSIONS: Curcumin pretreatment protects against HSR-induced pulmonary function impairment by increasing tissue SIRT1, which reduced lavage MDA and TNF-α and differential neutrophil count in a dose-dependent fashion.

2019 Consensus of the Taiwan Hypertension Society and Taiwan Society of Cardiology on the Clinical Application of Central Blood Pressure in the Management of Hypertension.

The Taiwan Society of Cardiology (TSOC) and the Taiwan Hypertension Society (THS) have appointed a joint consensus group for the 2019 Consensus of the TSOC and THS on the Clinical Application of Central blood pressure (BP) in the Management of Hypertension with the aim of formulating a management consensus on the clinical application of central BP in the management of hypertension. This consensus document focuses on the clinical application of central BP in the care of patients with hypertension. The major determinants of central BP are increased arterial stiffness and wave reflection, which are also the dominant hemodynamic manifestations of vascular aging. Central BP can be measured noninvasively using various techniques, including with convenient cuff-based oscillometric central BP monitors. Noninvasive central BP is better than conventional brachial BP to assess target organ damage and long-term cardiovascular outcomes. Based on the analysis of long-term events, a central BP threshold of 130/90 mmHg for defining hypertension has been proposed. Recent studies have suggested that a central BP strategy to confirm a diagnosis of hypertension may be more cost-effective than conventional strategies, and that guiding hypertension management with central BP may result in the use of fewer medications to achieve BP control. Although noninvasive measurements of brachial BP are inaccurate and central BP has been shown to carry superior prognostic value beyond brachial BP, the use of central BP should be justified in studies comparing central BP-guided therapeutic strategies with conventional care for cardiovascular events.

The Role of Vascular Calcification in Heart Failure and Cognitive Decline.

Vascular calcification is heterogeneous and triggered by multiple mechanisms. It has been implicated in the development of heart failure with preserved ejection fraction (HFpEF) and cognitive function impairment. Understanding the pathophysiology of vascular calcification may help us improve the management of HFpEF, atherosclerosis, accelerated arterial stiffness, hypertension, and cognitive dysfunction. Currently, there are no effective strategies for treating accelerated arterial stiffness. This may indicate that once arterial stiffness or vascular calcification has developed, it may be less likely to stop the ongoing pathophysiology. Therefore, earlier intervention targeting the probable pathways of vascular calcification may benefit the patients with vascular calcification and related pathological conditions. In this review, we briefly discuss the proposed pathophysiological roles of vascular calcification in the development of heart failure and cognitive decline, the animal models used to study the link between vascular calcification and cardiovascular diseases, and the possible corresponding management strategies.

Value of Excess Pressure Integral for Predicting 15-Year All-Cause and Cardiovascular Mortalities in End-Stage Renal Disease Patients.

BACKGROUND: The excess pressure integral (XSPI), derived from analysis of the arterial pressure curve, may be a significant predictor of cardiovascular events in high-risk patients. We comprehensively investigated the prognostic value of XSPI for predicting long-term mortality in end-stage renal disease patients undergoing regular hemodialysis. METHODS AND RESULTS: A total of 267 uremic patients (50.2% female; mean age 54.2±14.9 years) receiving regular hemodialysis for more than 6 months were enrolled. Cardiovascular parameters were obtained by echocardiography and applanation tonometry. Calibrated carotid arterial pressure waveforms were analyzed according to the wave-transmission and reservoir-wave theories. Multivariable Cox proportional hazard models were constructed to account for age, sex, diabetes mellitus, albumin, body mass index, and hemodialysis treatment adequacy. Incremental utility of the parameters to risk stratification was assessed by net reclassification improvement. During a median follow-up of 15.3 years, 124 deaths (46.4%) incurred. Baseline XSPI was significantly predictive of all-cause (hazard ratio per 1 SD 1.4, 95% confidence interval 1.15-1.70, P=0.0006) and cardiovascular mortalities (1.47, 1.18-1.84, P=0.0006) after accounting for the covariates. The addition of XSPI to the base prognostic model significantly improved prediction of both all-cause mortality (net reclassification improvement=0.1549, P=0.0012) and cardiovascular mortality (net reclassification improvement=0.1535, P=0.0033). XSPI was superior to carotid-pulse wave velocity, forward and backward wave amplitudes, and left ventricular ejection fraction in consideration of overall independent and incremental prognostics values. CONCLUSIONS: In end-stage renal disease patients undergoing regular hemodialysis, XSPI was significantly predictive of long-term mortality and demonstrated an incremental value to conventional prognostic factors.

Intravenous superoxide dismutase as a protective agent to prevent impairment of lung function induced by high tidal volume ventilation.

BACKGROUND: Positive-pressure mechanical ventilation is essential in assisting patients with respiratory failure in the intensive care unit and facilitating oxygenation in the operating room. However, it was also recognized as a primary factor leading to hospital-acquired pulmonary dysfunction, in which pulmonary oxidative stress and lung inflammation had been known to play important roles. Cu/Zn superoxide dismutase (SOD) is an important antioxidant, and possesses anti-inflammatory capacity. In this study, we aimed to study the efficacy of Cu/Zn SOD, administered intravenously during high tidal volume (HTV) ventilation, to prevent impairment of lung function. METHODS: Thirty-eight male Sprague-Dawley rats were divided into 3 groups: 5 h ventilation with (A) low tidal volume (LTV; 8 mL/kg; n = 10), (B) high tidal volume (HTV; 18 mL/kg; n = 14), or (C) HTV and intravenous treatment of Cu/Zn SOD at a dose of 1000 U/kg/h (HTV + SOD; n = 14). Lung function was evaluated both at baseline and after 5-h ventilation. Lung injury was assessed by histological examination, lung water and protein contents in the bronchoalveolar lavage fluid (BALF). Pulmonary oxidative stress was examined by concentrations of methylguanidine (MG) and malondialdehyde (MDA) in BALF, and antioxidative activity by protein expression of glutathione peroxidase-1 (GPx-1) in the lung. Severity of lung inflammation was evaluated by white blood cell and differential count in BALF, and protein expression of inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 (MMP-9), and mRNA expression of nuclear factor-κB (NF-κB) in the lung. We also examined protein expression of surfactant protein (SP)-A and D and we measured hourly changes in serum nitric oxide (NO) level. RESULTS: Five hours of LTV ventilation did not induce a major change in lung function, whereas 5 h of HTV ventilation induced apparent combined restrictive and obstructive lung disorder, together with increased pulmonary oxidative stress, decreased anti-oxidative activity and increased lung inflammation (P < 0.05). HTV ventilation also decreased SP-A and SP-D expression and suppressed serum NO level during the time course of ventilation. Cu/Zn SOD administered intravenously during HTV ventilation effectively reversed associated pulmonary oxidative stress and lung inflammation (P < 0.05); moreover, it preserved SP-A and SP-D expressions in the lung and increased serum nitric oxide (NO) level, enhancing vascular NO bioavailability. CONCLUSIONS: HTV ventilation can induce combined restrictive and obstructive lung disorders. Intravenous administration of Cu/Zn SOD during HTV ventilation can prevent lung function impairment and lung injury via reducing pulmonary oxidative stress and lung inflammation, preserving pulmonary surfactant expression, and enhancing vascular NO bioavailability.

Excess Pressure Integral Predicts Long-Term All-Cause Mortality in Stable Heart Failure Patients.

BACKGROUND: Excess pressure integral (XSPI) derived from reservoir-excess pressure analysis is proposed as a novel indicator of cardiovascular dysfunction in hypertensives. Our study investigated the prognostic value of XSPI for stable heart failure (HF) patients. METHODS: In total, 238 subjects (mean age 63 ± 18 years, 111 male), comprising 168 stable HF patients with either reduced (SHF; n = 64) left ventricular (LV) ejection fraction (EF) or isolated diastolic dysfunction (DHF, n = 104), and 70 healthy controls, were enrolled. Tonometry-derived carotid pressure waveforms were analyzed with the reservoir pressure theory. XSPI was calculated by subtracting the reservoir pressure from carotid pressure waveform. RESULTS: XSPI in SHF and DHF (14.01 ± 5.16 and 13.90 ± 5.05 mm Hg•s) were significantly higher than that in controls (11.01 ± 3.67 mm Hg•s, both P < 0.001). During a median follow-up of 9.9 years, 56 deaths occurred. XSPI was a significant independent predictor of total mortality after adjusting for age, sex, left ventricular ejection fraction (LVEF), glomerular filtration rate (GFR), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio = 4.37 per 1 SD, 95% confidence interval, 1.31-14.58). In subgroup analysis by different baseline characteristics including age, gender, NT-proBNP, LVEF, and GFR, higher XSPI was consistently associated with greater risk of total mortality. CONCLUSION: In patients with stable HF, XSPI, a novel maker of cardiovascular dysfunction, was associated with long-term risk of total mortality.

Prognostic significance of mechanical biomarkers derived from pulse wave analysis for predicting long-term cardiovascular mortality in two population-based cohorts.

BACKGROUND: Numerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts. METHODS: PWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI). RESULTS: In multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density- and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08-1.28, p<0.001; DC: 1.18 [1.09-1.28], p<0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI=0.049, p=0.0361), SC (NRI=0.043, p=0.0236) and DC (NRI=0.054, p=0.047). CONCLUSIONS: Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts.

Expanding application of the Wiggers diagram to teach cardiovascular physiology.

Dr. Carl Wiggers' careful observations have provided a meaningful resource for students to learn how the heart works. Throughout the many years from his initial reports, the Wiggers diagram has been used, in various degrees of complexity, as a fundamental tool for cardiovascular instruction. Often, the various electrical and mechanical plots are the novice learner's first exposure to simulated data. As the various temporal relationships throughout a heartbeat could simply be memorized, the challenge for the cardiovascular instructor is to engage the learner so the underlying mechanisms governing the changing electrical and mechanical events are truly understood. Based on experience, we suggest some additions to the Wiggers diagram that are not commonly used to enhance cardiovascular pedagogy. For example, these additions could be, but are not limited to, introducing the concept of energy waves and their role in influencing pressure and flow in health and disease. Also, integrating concepts of exercise physiology, and the differences in cardiac function and hemodynamics between an elite athlete and normal subject, can have a profound impact on student engagement. In describing the relationship between electrical and mechanical events, the instructor may find the introduction of premature ventricular contractions as a useful tool to further understanding of this important principle. It is our hope that these examples can aid cardiovascular instructors to engage their learners and promote fundamental understanding at the expense of simple memorization.

The case for the reservoir-wave approach.

The Reservoir-Wave Approach is an alternative, time-domain approach to arterial hemodynamics that is based on the assertion that measured pressure and flow can be resolved into their volume-related (i.e., reservoir) and wave-related (i.e., excess) components. The change in reservoir pressure is assumed to be proportional to the difference between measured inflow and calculated outflow. Wave intensity analysis of the excess components yields a pattern of aortic wave propagation and reflection in the dog that is novel and physiologically plausible: waves are reflected positively from a site in the femoral circulation and negatively from a site below the diaphragm, where the total "daughter-vessel" cross-sectional area exceeds the "mother-vessel" area. With vasodilatation, the negative reflection is augmented and with vasoconstriction, it is virtually eliminated. On the other hand, conventional hemodynamic analysis has been shown to yield a paradoxical "forward-going backward wave" and the impedance minimum, previously assumed to be an indicator of the source of wave reflection according to quarter-wave-length theory, has been shown to be due to the reservoir component. Clinical studies employing the Reservoir-Wave Approach should be undertaken to verify experimental observations and, perhaps, to gain new diagnostic and therapeutic insights.

Estimation of left ventricular stroke volume by impedance cardiography: its relation to the aortic reservoir.

Impedance cardiography is a non-invasive technique used to estimate left ventricular (LV) stroke volume (SV) using the change in thoracic impedance (ΔZ). It remains controversial, partly because impedance cardiographic parameters have not been successfully related to haemodynamic events. We hypothesized that the change in ΔZ may be proportional to the variation in thoracic (primarily aortic) blood volumes. Nine anaesthetized and ventilated dogs were divided into the following two groups: the 'aortic volume group' (n = 5), in which aortic and IVC (inferior vena caval) dimensions were measured ultrasonically; and the 'reservoir volume group', in which aortic and IVC reservoir volumes were calculated using the reservoir-wave model. Measurements were made in control conditions, in the presence of nitroprusside and methoxamine and after volume loading. In both the aortic volume group and the reservoir volume group, the maximal rate of increase in ΔZ [(dZ/dt)max] strongly correlated with the maximal rate of change in aortic/reservoir blood volume (R(2) = 0.85 and 0.95, respectively), which in turn was proportional to the LV SV. The LV and IVC contributions to ΔZ were small in control conditions (∼5 and 1%, respectively), but the LV contribution increased slightly (to 7%) with administration of methoxamine and after volume loading (to 10%). It is concluded that the change in thoracic impedance (ΔZ) during the cardiac cycle is proportional to the change in aortic reservoir (i.e. Windkessel) volume, which provides a mechanistic explanation for previously demonstrated good correlations with standard measures of cardiac output.

Alterations in aortic wave reflection with vasodilation and vasoconstriction in anaesthetized dogs.

BACKGROUND: Using the reservoir-wave approach, we studied wave propagation, reflection, and re-reflection in the canine aorta with administrations of sodium nitroprusside (NP) and methoxamine (Mtx). METHODS: In 8 anaesthetized dogs, excess pressures were calculated from pressure and flow measurements at 4 locations along the aorta; wave intensity analysis was employed to identify wavefronts and the type of waves. RESULTS: NP (intravenous; 14 µg/min) decreased mean aortic pressure from 80 ± 3 mm Hg to 48 ± 1 mm Hg; Mtx (intravenous; 10 µg/min) increased mean pressure from 80 ± 3 mm Hg to 104 ± 4 mm Hg. NP increased negative reflection near the kidneys (reflection coefficient: -0.33 vs -0.18; P < 0.01) and produced new negatively reflecting sites just beyond the arch and in the proximal femoral arteries, consistent with a vasodilating effects of nitrates on conducting arteries. Mtx negated negative reflection from near the kidneys (-0.02 vs -0.17; P < 0.01) and increased positive femoral reflection (0.38 vs 0.26; P < 0.01). The large reflected compression wave was re-reflected from the closed aortic valve to produce a prominent increase in middiastolic pressure in the distal aorta. CONCLUSIONS: The reservoir-wave approach explains decreasing diastolic pressure without positing waves that travel at near-infinite velocities and reveals the pressure changes that are uniquely due to wave motion.