Variable open-end wave reflection in the pulmonary arteries of anesthetized sheep

The aim of this study was to re-evaluate wave reflection in the healthy pulmonary arteries of sheep utilizing the time-domain-based method of wave intensity analysis. A thorough understanding of patterns of wave reflection during health and disease may provide future sensitive markers of early pulmonary vascular disease. Wave intensity was calculated from the simultaneous acquisition of proximal pulmonary arterial pressure and velocity in 12 anesthetized open-chest sheep. Normal pulmonary arterial wave speed was 2.1 ± 0.3 m s⁻¹. The incident forward compression wave generated by right ventricular systole was reflected in an open-end manner as a backward expansion wave from a site 3 cm downstream, corresponding to the main pulmonary bifurcation, and in a closed-end manner as a backward compression wave from a site 21 cm downstream, corresponding to the pulmonary microcirculation. The proximal open-end reflection site was not present throughout the entire cardiac cycle. Wave reflection was minimal with only 1% of the incident forward compression wave energy reflected as a backward expansion wave and 2% as a backward compression wave. The normal pulmonary artery in open-chest sheep is characterized by variable proximal open-end reflection from the main pulmonary bifurcation and fixed closed-end reflection from the microcirculation, generating backward-travelling waves of minimal intensity.     

Effect of nitroprusside on wave reflections in patients with heart failure

The relationship between wave reflections and ventricular-vascular coupling has been the subject of considerable speculation. Since we have previously shown that low-dose nitroprusside infusion improved ventricular-vascular coupling (as evidenced by increases in cardiac output and in aortic and pulmonary arterial total external power) in patients with severe left ventricular failure and secondary pulmonary hypertension, we chose to examine the changes in their aortic and pulmonary arterial wave reflections in this study. Wave reflection indexes examined included [1] calculated backward and forward pressure waves and the ratio of their magnitudes (reflection factor), [2] the reflection coefficient spectrum obtained by taking the ratios of the corresponding Fourier harmonics of the backward and forward waves, [3] two terminal reflection coefficients calculated as Γ _t =(R-Z _c )/R+Z _c ) where Z is characteristic impedance and R is either total resistance or vascular resistance, and [4] the difference between the maximum and minimum impedance moduli for frequencies of 4 to 15 Hz. In the systemic vasculature, nitroprusside produced large reductions in the elevated vascular resistances and decreased aortic reflections as indexed by the reflection factor and by both terminal reflection coefficients. In contrast, however, no significant changes were found in the pulmonary artery wave reflection indexes despite large reductions in the pulmonary resistances. Supported in part by Grant #P-50-HL17655 from the National Institutes of Health Ischemic Heart Disease Specialized Center on Research. Dr. Brin is a recipient of a Public Health Service Clinical Investigator Award (HL-01028) from the National Heart, Lung, and Blood Institute. Dr. Yin was a recipient of a Frank T. McClure Fellowship from the Johns Hopkins University Applied Physics Laboratory.     

Changes in central artery blood pressure and wave reflection during a cold pressor test in young adults

The relative contribution of sympathetic nervous system (SNS)-induced increase in peripheral vascular resistance on central artery blood pressure (BP) and aortic wave reflection (augmentation index; AIx) is not completely understood. Central BP and wave reflection characteristics were measured using radial artery applanation tonometry before, during a 3-min cold pressor test (CPT), and 90 and 180-s post-CPT in 15 young, healthy adults (25 +/- 1 years). The CPT resulted in a greater magnitude of change in the estimated aortic systolic (31 vs. 23%, P < 0.05) and pulse (31 vs. 13%, P < 0.05) BP compared with the change in brachial artery BP. Additionally, the CPT resulted in an increased mean arterial pressure (MAP) (P < 0.05) and AIx (10 +/- 2 vs. 26 +/- 2%, P < 0.05). The change in MAP during the CPT was correlated to the change in AIx (r = 0.73, P < 0.01) and inversely related to roundtrip duration of the reflected wave to the periphery and back (r = -0.57, P < 0.05). The present study suggests that cold pressor testing results in a significant increase in arterial wave reflection intensity, possibly due to an increased MAP. However, the greater increase in systolic and pulse BP in the central compared with the peripheral circulation suggests that increased central artery wave reflection intensity contributes to increased left ventricular myocardial oxygen demand during CPT-induced hypertension.     

sPAP/PAAT Ratio as a New Index of Pulmonary Vascular Load: A Study in Normal Subjects and Ssc Patients with and without PH

In pulmonary hypertension (PH), the development of right ventricular (RV) dilatation and RV failure are signs of accelerated progression of the disease, resulting in an increased risk of cardiac death. Even the noninvasive assessment of systolic blood pressure in the pulmonary artery undertaken by echocardiography does not provide a measure of ventricle–pulmonary interaction. Some studies have shown the potential for echocardiography to indirectly evaluate pulmonary vascular resistance (PVR) and the acceleration time of pulmonary outflow (PAAT). We used systolic pulmonary artery pressure (sPAP) and pulmonary vascular resistance to develop an sPAP/PAAT ratio (strength/surface unit)/(time) for this study. From January 2017 to December 2018, 60 healthy subjects and 63 patients with systemic scleroderma (Ssc) (60 females, 3 males), 27 with PH and 36 without PH at two-dimensional echocardiographic/Doppler, were screened. In normal subjects, the mean sPAP/PAAT ratio was 0.26 ± 0.063, which indicated optimal pulmonary arterial ventricle coupling and biventricular function. The data derived from the analysis of the Ssc patients showed that those presenting pre-capillary PH at cardiac catheterization had an sPAP/PAAT ratio of 0.40 ± 0.05. There was a significant correlation between sPAP/PAAT with Walk Distance (WD) and PVR, but not with TAPSE. Interobserver variability was less than 5%. The sPAP/PAAT ratio is a new parameter that may indicate pulmonary vascular afterload and interaction, both in normal subjects and in patients with Ssc and PH.     

Disappearance of molsidomine effects on pulmonary circulation of patients with chronic obstructive pulmonary disease after a three week treatment

The effect of oral molsidomine (M) on the pulmonary artery hypertension of patients with chronic obstructive pulmonary disease (COPD) was investigated during an acute study (4 mg once) and after a 3 week-treatment (3 times 4 mg a day), on a double-blind basis in 16 patients, 8 receiving a placebo, and 8 molsidomine. Ventilatory and cardiocirculatory indices were obtained at rest and during exercise. When acutely given, molsidomine reduces the mean pulmonary arterial pressure (PAP), the pulmonary vascular resistance (PVR) and the arterial O2 partial pressure (PaO2), increasing heart rate (HR) as well as the alveo-arterial O2 partial pressure difference (P(A-a)O2). During exercise, pulmonary arterial pressure and pulmonary vascular resistance decrease while heart rate increases without modification of arterial blood gases. After a 3-week treatment, molsidomine no more improves any index but significantly reduces cardiac output during exercise and consequently the O2 delivery to the tissues. The same feature has already been observed for other nitrates. It thus seems inappropriate to prescribe nitrates or nitrate-like drugs to chronic obstructive pulmonary disease patients with a view to lower their pulmonary hypertension.     

The role of platelets in the development and progression of pulmonary arterial hypertension

Pulmonary arterial hypertension is a multifactorial disease characterized by vasoconstriction, vascular remodeling, inflammation and thrombosis. Although an increasing number of research confirmed that pulmonary artery endothelial cells, pulmonary artery smooth muscle cells as well as platelets have a role in the pulmonary arterial hypertension pathogenesis, it is still unclear what integrates these factors. In this paper, we review the evidence that platelets through releasing a large variety of chemokines could actively impact the pulmonary arterial hypertension pathogenesis and development. A recent publication revealed that not only an excess of platelet derived cytokines, but also a deficiency may be associated with pulmonary arterial hypertension development and progression. Hence, a simple platelet blockade may not be a correct action to treat pulmonary arterial hypertension. Our review aims to analyse the interactions between the platelets and different types of cells involved in pulmonary arterial hypertension pathogenesis. This knowledge could help to find novel therapeutic options and improve prognosis in this devastating disease.     

Mental stress increases right heart afterload in severe pulmonary hypertension.

Little is known about mental stress effects on the pulmonary circulation in health and disease. The current study was conducted to investigate whether pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) would further increase during standardized mental stress testing in patients with severe pulmonary hypertension. The study was a prospective analysis of seven patients (average age: 40 years, range from 21 to 56 years) with severe pulmonary hypertension (primary: n = 4, secondary forms: n = 3; resting mean pulmonary artery pressure ranged between 48 and 65 mmHg). Right heart catheterization for the determination of PAP, pulmonary capillary wedge pressure (PCW) and cardiac output (CO) was clinically indicated (diagnostic workup, acute drug testing). Patients accomplished a standardized 10 min mental stress test (computer based, adaptive complex reaction-time task). Pulmonary haemodynamics during stress were compared to resting baseline. During mental stress mean PAP (+/- SEM) increased by 9.4 +/- 2.1 mmHg (P < 0.005). Pulmonary vascular resistance increased by 149 +/- 25 dyne s cm-5 (P < 0.001). Stroke volume decreased by 6.6 +/- 2.2 ml (P < 0.03). The data show that moderate mental stress increases right heart afterload in patients with severe pulmonary hypertension owing to elevation of PVR.     

脉搏波传播和血管顺应性对体循环和肺循环系统血流特性和心室功率的影响

本文采用耦合模型研究脉搏波传播和血管顺应性对体循环和肺循环血流特性和心室功率的影响。左心室和右心室均采用Ｅ－Ｒ模型,后负荷系统对于体动脉和肺动脉分别采用Ｔ－Ｙ管模型和稍微不对称Ｔ管模型,应用脉冲响应法将二者耦合起来。选取生理范围的参数,计算了两个系统的每搏输出量（ＳＶ）、每搏输出功（ＳＷ）、定常功率（Ｗs）、脉动功率（Ｗo)和总功率（Ｗt）等。详细分析了血管顺应性、脉搏波波速等对这些参量的影响。得到的主要结果是脉动功率对参数的变化比定常功率更敏感。因此,脉动功率百分比或许是评估心室效率的一个较好参数之一。     

Local and regional wave speed in the aorta: effects of arterial occlusion

Arterial wave speed is widely used to determine arterial distensibility and has been utilised as a surrogate marker for vascular disease. A comparison between the results of the traditional foot-to-foot method for measuring wave speed to those of the pressure-velocity loop (PU-loop) method is one of the primary objectives of this paper. We also investigate the regional wave speed along the aorta, and the effect of arterial occlusion on the PU-loop measured in the ascending aorta. In 11 anaesthetised dogs, a total occlusion lasting 3 min was produced at four sites: upper thoracic, diaphragm, abdominal and left iliac artery. Pressure and flow in the ascending aorta and pressure proximal to the occlusion site were measured, and data were collected before, during the occlusion and after the occlusion had been removed. In control conditions, the wave speeds determined by the PU-loop in the aortic root were systematically lower than those measured by the foot-to-foot method. During thoracic and diaphragm occlusions, mean aortic pressure and wave speed increased significantly but returned to control values after each occlusion had been removed. The PU-loop is an objective and easy to use method for determining wave speed and can be advantageous for use in short arterial segments when local measurements of pressure and velocity are available.     

Continuous air embolization into sheep causes sustained pulmonary hypertension and increased pulmonary vasoreactivity.

Baseline pulmonary arterial, left atrial and systemic artery pressures, cardiac output, and lung lymph flow were measured in seven chronically catheterized sheep before continuous air embolization into the pulmonary artery, which caused a two-to-threefold increase in pulmonary vascular resistance (PVR) for 12 days. Air embolization was discontinued on days 4, 8, and 12 and hemodynamic measurements were repeated. Thromboxane B2, 6-keto-PGF1 alpha, and protein were measured in lung lymph and blood plasma on days 0, 4, 8 and 12. Air embolization caused an acute, sustained rise in pulmonary artery pressure and PVR (baseline, 3.68 +/- 0.21; air, 8.32 +/- 0.62, mean +/- SE). By day 4, PVR was increased significantly even when air flow was interrupted (5.97 +/- 0.72) and by day 12, it was almost twice baseline; pulmonary artery pressure also remained elevated (baseline, 19 +/- 1 cm H2O; day 12, 31 +/- 3). Pulmonary vasoreactivity to PGH2-A was significantly increased on days 4, 8, and 12 (day 12, 285 +/- 41% of baseline response). Lung lymph flow, protein, and thromboxane clearance were increased throughout the study while clearance of 6-keto-PGF1 alpha was increased at day 4 and falling by day 8. At autopsy, morphometric analysis of the barium-injected pulmonary arterial bed revealed striking structural remodeling, extension of muscle into smaller arteries than normal: decreased peripheral arterial filling, increased medial thickness, and dilated large pulmonary arteries. Continuous air embolization into sheep causes the structural and functional changes of chronic pulmonary hypertension accompanied by increased pulmonary vasoreactivity to a bolus of PGH2-A. The abrupt onset of the sustained elevation in PVR induced by air embolization may account for the severity of the structural remodelling, particularly for the increased medial thickness.     

脉搏波速度在高血压病早期干预中的临床意义

目的探讨脉搏波传导速度（PWV）与高血压病早期干预的相关性及其相关因素。方法应用脉搏波速度自动测量系统对104例健康人和397例高血压病患者进行肱动脉-踝动脉脉搏波传导速度（baPWV）检测。结果高血压患者的脉搏波传导速度显著高于健康人（P〈0.01）。年龄是影响健康人大动脉弹性功能最主要的因素,年龄、收缩压和脉压与高血压患者的大动脉弹性功能密切相关。结论脉搏波传导速度是敏感反映高血压大动脉弹性的重要指标,年龄、收缩压和脉压是影响baPWV值的主要因素,可作为心血管疾病的一个危险信号,以指导早期预防干预。     

Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension

Neonatal calves exposed to chronic hypobaric hypoxia develop severe pulmonary hypertension associated with altered vascular reactivity, cellular proliferation, and increased elastin and collagen production. We hypothesized that prostaglandin (PG) production would be decreased in the pulmonary arterial vessel wall of these calves. Further, because of the possibility that the hemodynamic stresses of hypoxic pulmonary hypertension might change along the longitudinal axis of the pulmonary circulation, we measured prostaglandin synthetic capability in tissues isolated from proximal pulmonary artery, distal pulmonary artery, and pulmonary vein. We found that PGI2 production was decreased in both proximal and distal pulmonary artery rings isolated from pulmonary hypertensive calves compared to controls. PGI2 production was greater in distal than in proximal lobar pulmonary artery. In contrast, pulmonary veins from hypertensive calves, which are protected from the hemodynamic stress of pulmonary arterial hypertension, did not demonstrate altered PGI2 production compared to controls. PGE2 production was also decreased in proximal hypertensive pulmonary arterial rings as compared to controls. To determine if this decrease in vessel wall production of prostaglandins was due to changes in cellular prostaglandin production, we studied prostaglandin production by the three major cell types comprising hypertensive and control arteries. Endothelial cells cultured from hypertensive main pulmonary artery produced less PGI2 than did those from control artery, and there appeared to be a shift from PGI2 production to PGE2 production in endothelial cells isolated from hypertensive artery. Explanted advential fibroblasts from hypertensive artery produced less PGE2 than did controls. Smooth muscle cell PGI2 production did not differ between cells isolated from hypertensive and control arteries in these brief 30-min incubations. We conclude that there is a relative deficit in PGI2 and PGE2 production in the pulmonary arteries of calves with hypoxia-induced pulmonary hypertension and speculate that this contributes to altered vascular tone and vessel remodeling.     

Nitric oxide synthase expression in lungs of pulmonary hypertensive patients with heart disease.

Since little is known about the contribution of endothelial nitric oxide synthase (e-NOS) to the mechanism of pulmonary vasospasm and the development of pulmonary vascular occlusive disease, we elucidate how e-NOS is expressed in lung biopsy specimens obtained from operative patients with pulmonary hypertension. Lung biopsy specimens were obtained from 17 patients who underwent open-heart operations for various heart diseases. A piece of normal lung specimen was also obtained from the resected lungs of three lung cancer patients as a control. e-NOS expression was visualized with a monoclonal antibody against e-NOS, and the level of expression was partially quantified. Significantly high levels of e-NOS expression were seen in adult patients, whose preoperative mean pulmonary arterial pressures were greater than 20 mm Hg. In contrast, e-NOS expression in pediatric patients with the same levels of mean pulmonary arterial pressure was the same as that in the controls and in low pulmonary arterial pressure. There was a statistically significant positive correlation between the level of e-NOS expression and Heath--Edwards grading. These data suggest that the e-NOS expression in lung tissue is induced when pulmonary vascular obstructive diseases progress.     

Clinical usefulness of wave intensity analysis

Wave intensity (WI) is a hemodynamic index, which can evaluate the working condition of the heart interacting with the arterial system. It can be defined at any site in the circulatory system and provides a great deal of information. However, we need simultaneous measurements of blood pressure and velocity to obtain wave intensity, which has limited the clinical application of wave intensity, in spite of its potential. To expand the application of wave intensity in the clinical setting, we developed a real-time non-invasive measurement system for wave intensity based on a combined color Doppler and echo-tracking system. We measured carotid arterial WI in normal subjects and patients with various cardiovascular diseases. In the coronary artery disease group, the magnitude of the first peak of carotid arterial WI (W ₁) increased with LV max. dP/dt (r = 0.74, P < 0.001), and the amplitude of the second peak (W ₂) decreased with an increase in the time constant of LV pressure decay (r = −0.77, P < 0.001). In the dilated cardiomyopathy group, the values of W ₁ were much lower than those in the normal group (P < 0.0001). In the hypertrophic cardiomyopathy group, the values of W ₂ were much smaller than those in the normal group (P < 0.0001). In mitral regurgitation before surgery, W ₂ decreased or disappeared, but after surgery W ₂ appeared clearly. In the hypertension group, the magnitude of reflection from the head was considerably greater than that in the normal group (P < 0.0001). We also evaluated hemodynamic effects of sublingual nitroglycerin in normal subjects. Nitroglycerin increased W ₁ significantly (P < 0.001). WI can be obtained non-invasively using an echo-Doppler system in the clinical setting. This method will increase the clinical usefulness of wave intensity.     

右心室Tei指数监测肺动脉血栓内膜剥脱术前后患者血流动力学变化

目的应用右心室Tei指数监测肺动脉血栓内膜剥脱术(PEA)前后患者血流动力学改变情况,评价其临床应用价值。方法慢性血栓栓塞性肺动脉高压(CTEPH)患者23例,其中男性19例,女性4例;年龄17~64岁,平均年龄44.5岁。于PEA术前及术后3个月分别测量右心室Tei指数,并与对应检查时间点右心导管测量的肺动脉平均压(mPAP)、肺血管阻力(PVR)及右心排血量(RCO)间做相关性分析。结果 PEA术前患者右心室Tei指数增大(0.82±0.25),术后3个月超声心动图测量右心室Tei指数较术前明显减小(0.48±0.30;P0.01)。右心室Tei指数与PVR之间呈正相关(P0.001),与mPAP及RCO之间具有相关性(P0.05)。结论可以应用右心室Tei指数这一无创性检查参数监测PEA术前及术后CTEPH患者血流动力学改变情况。     

Blood pressure waveform analysis by means of wavelet transform

The assessment of cardiovascular function by means of arterial pulse wave analysis (PWA) is well established in clinical practice. PWA is applied to study risk stratification in hypertension, with emphasis on the measurement of the augmentation index as a measure of aortic pressure wave reflections. Despite the fact that the prognostic power of PWA, in its current form, still remains to be demonstrated in the general population, there is general agreement that analysis and interpretation of the waveform might provide a deeper insight in cardiovascular pathophysiology. We propose here the use of wavelet analysis (WA) as a tool to quantify arterial pressure waveform features, with a twofold aim. First, we discuss a specific use of wavelet transform in the study of pressure waveform morphology, and its potential role in ascertaining the dynamics of temporal properties of arterial pressure waveforms. Second, we apply WA to evaluate a database of carotid artery pressure waveforms of healthy middle-aged women and men. Wavelet analysis has the potential to extract specific features (wavelet details), related to wave reflection and aortic valve closure, from a measured waveform. Analysis showed that the fifth detail, one of the waveform features extracted applying the wavelet decomposition, appeared to be the most appropriate for the analysis of carotid artery pressure waveforms. What remains to be assessed is how the information embedded in this detail can be further processed and transformed into quantitative data, and how it can be rendered useful for automated waveform classification and arterial function parameters with potential clinical applications.     

Effect of resistance training on arterial wave reflection and brachial artery reactivity in normotensive postmenopausal women

Large elastic artery stiffness increases with age and menopause is a mitigating factor in women. High-intensity resistance training (RT) increases arterial stiffness in young men and women. However, the effects of moderate intensity RT on central aortic pressure wave reflection in healthy postmenopausal women are unknown. Healthy sedentary normotensive postmenopausal women were randomly assigned to either 18 weeks (2 days/week) of RT (RES n = 13) or aerobic training (AER n = 10). Central aortic pressure wave reflection and brachial artery reactivity were assessed before and after training. Central aortic pressure wave reflection was evaluated by measuring aortic augmentation index (AI_a) and round trip travel time (Δt _p) of the reflected arterial pressure wave using applanation tonometry. Brachial artery reactivity was assessed using brachial artery flow mediated dilation (FMD). Eighteen weeks of RT did not change AI_a (28.9 ± 1.9 vs. 28.5 ± 1.9%; mean ± S.E.M.) or Δt _p (140.6 ± 2.4 vs. 141.2 ± 2.1 ms). In contrast, the AER group showed a decrease in AI_a from 28.8 ± 2.1 to 25.1 ± 1.4% (P < 0.05) and an increase in Δt _p from 137.3 ± 2.5 to 144.6 ± 2.9 ms (P < 0.05). Brachial FMD did not significantly change in either group following training. This prospective, randomized study demonstrated that moderate intensity whole body RT in previously sedentary, normotensive postmenopausal women does not alter central aortic pressure wave reflection.     

Potential and limitations of wave intensity analysis in coronary arteries

Wave intensity analysis (WIA) is beginning to be applied to the coronary circulation both to better understand coronary physiology and as a diagnostic tool. Separation of wave intensity (WI) into forward and backward traveling components requires knowledge of pulse wave velocity at the point of measurement, which at present cannot accurately be determined in human coronary vessels. This prompted us to study the sensitivity of wave separation to variations in wave speed. An estimate of wave speed (SPc) was calculated based on measured distal intracoronary pressure and Doppler velocity in normal and diseased coronary vessels of patients during hyperemia. Changes of the area under separated WI waveforms were determined for a range of wave speeds from 25 to 200% of the calculated value. Variations in wave speed between half to twice the calculated value did not substantially alter separated WI. In conclusion, although SPc lacks accuracy in determining local coronary wave speed it is within limits still applicable for wave separation in coronary WIA.     

Nets,pulmonary arterial hypertension,and thrombo-inflammation

Journal of Molecular Medicine - Pulmonary arterial hypertension (PAH) is a progressive and fatal vascular disease in which high blood pressure in the pulmonary artery and remodeling of the...