Some Physical Properties of the Pulmonary Arterial Bed Deduced from Pulsatile Arterial Flow and Pressure

This study aimed to quantify changes of vascular compliance and resistance of the proximal and the peripheral pulmonary arterial vessels when vascular smooth muscle was stimulated. These above vascular characteristics were derived from registrations of pulsatile pressure and flow in the pulmonary artery (PA). An in situ cat lung preparation was used, with the right heart by-passed by a pulsatile blood pump. Vascular input impedance was derived from PA pulsatile pressure and flow recordings, and impedance characteristics were used for calculation of the variables of a simple lumped analog representation of the arterial bed. PA smooth muscle was stimulated by infusions of collagen suspension, by general hypoxia and by nor-adrenaline injections. Collagen caused 40% reduction of vascular compliance (C), no changes in proximal arterial resistance (Rl) and 18076 increase in peripheral vascular resistance (R2). Hypoxia caused 5096 reduced C, 20% increased R1 and 70% increased R2. Noradrenaline caused 20:6 reduced C and 30 % increased R1 and R2. These results, together with results derived from simulation of the observed impedance changes in a computer model of the lung arterial bed, indicated that collagen infusion elicited contraction of small and medium-sized arteries, with increased arterial volume as result of increased distending pressure. Hypoxia and noradrenaline, seemed both to cause contraction of the total arterial bed. This effect being most pronounced during hypoxia.     

人参皂苷Rg2对野百合碱诱导肺动脉高压模型大鼠的作用

目的 探讨人参皂苷Rg2(ginsenoside-Rg2)对野百合碱(monocrotaline,MCT) 诱导的肺动脉高压(pulmonary arterial hypertension,PAH) 模型大鼠的作用.方法 将48只雄性SD 大鼠随机分为对照组、模型组、人参皂苷Rg2 (20、40、80 mg/kg) 组和波生坦(Bos,200 mg /kg) 组,每组8只.一次性腹腔注射MCT(50 mg/kg) 复制PAH 模型,此后按分组灌胃给药,每天1 次,连续28d.通过颈总动脉和右心室用八道生理记录仪测定右心室收缩压(right ventricle systolic pressure,RVSP)、平均动脉压(mean arterial blood pressure,MBP)、心率(heart rate,HR).处死动物后采集血浆测定内皮素-1(endothelin-1,ET-1)和一氧化氮(nitric oxide,NO)的水平并测定右心肥大指数.结果 野百合碱注射后第28天时,与对照组比较,模型组右心室压力、右心肥大指数明显升高,心率和平均动脉压明显减小;血浆ET-1水平明显增加,NO水平明显降低.人参皂苷Rg2能明显缓解这些变化.结论 人参皂苷Rg2对野百合就所致的肺动脉高压模型大鼠具有改善作用.     

Impact of Acute Pulmonary Embolization on Arterial Stiffening and Right Ventricular Function in Dogs

Pulmonary hypertension (PH) can impact right ventricular (RV) function and alter pulmonary artery (PA) stiffness. The response of the RV to an acute increase in pulmonary pressure is unclear. In addition, the relation between total pulmonary arterial compliance and local PA stiffness has not been investigated. We used a combination of right heart catheterization (RHC) and magnetic resonance imaging (MRI) to assess PA stiffening and RV function in dogs before and after acute embolization. We hypothesized that in moderate, acute PH the RV is able to compensate for increased afterload, maintaining adequate coupling. Also, we hypothesized that in the absence of PA remodeling the relative area change in the proximal PA (RAC, a noninvasive index of local area strain) correlates with the total arterial compliance (stroke volume-to-pulse pressure ratio). Our results indicate that, after embolization, RV function is able to accommodate the demand for increased stroke work without uncoupling, albeit at the expense of a reduction of efficiency. In this acute model, RAC showed excellent correlation with total arterial compliance. We used this correlation to assess PA pulse pressure (PP) from noninvasive MRI measurements of stroke volume and RAC. We demonstrated that in acute pulmonary embolism MRI estimates of PP are remarkably close to measurements from RHC. These results, if confirmed in chronic PH and clinically, suggest that monitoring of PH progression by noninvasive methods may be possible.     

The Influence of Pulmonary Blood Flow Rate on Vascular Input Impedance and Hydraulic Power in the Sympathetically and Noradrenaline Stimulated Cat Lung

This study was designed to evaluate the influence of sympathetic nerve stimulation (NS) and α-adrenergic receptor stimulation (αS) on the pulmonary vascular input impedance and hydraulic power output of the right heart during variations of cardiac output (CO). An open chest cat preparation was used and pulsatile pressure and flow in the pulmonary artery were measured by high frequency response transducers. Calculations showed that vascular resistance (VR) was inversely dependent on CO, hut input impedance of the unstimulated lung was not influenced by CO variations. NS or αS increased VR and input impedance significantly, and the relation pulsatile hydraulic power/total hydraulic power (W_p/W_t) increased 40%, indicating that such stimulation has larger relative influence on impedance than on resistance. The reduction of arterial compliance during NS (maximal stimulus) was calculated to be 60%, independent of CO. Input impedance during NS or αS was reduced by CO elevations, probably because the concomitant distension of the arterial bed reduced arterial resistance and inertance. The ratio W_p/CO, which expresses the fraction of pulsatile hydraulic power lost per ml mean arterial flow, was found to be flow dependent both in control and stimulated conditions: W_p/CO was positively correlated to CO in control condition and weakly negatively correlated to CO during stimulation. At high CO the arterial vessels could he stimulated and stiffened without much extra load on the right heart.     

Determination of the effects of pulmonary arterial hypertension and therapy on the cardiovascular system of rats by impedance cardiography

Aim

To evaluate the effects of bosentan, sildenafil, and combined therapy on the cardiovascular system using impedance cardiography (ICG) in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH).

Methods

Seventy male Wistar-albino rats were randomized into five groups. A single dose of MCT was given to all rats, except to the control group. After 4 weeks, bosentan, sildenafil, and combined treatment was started and lasted for 3 weeks. The last group that developed PAH did not receive any medication. Echocardiographic evaluation was performed to determine the PAH development. Thoracic fluid content index (TFCI), stroke volume index (SI), heart rate (HR), cardiac index (CI), and myocardial contractility index (IC) were determined. All procedures were performed at the baseline and after 4 and 7 weeks.

Results

Echocardiographic parameters showed that the all MCT-injected rats developed PAH. There were no significant inter- and intra-group differences in TFCI, SI, and IC (P > 0.05), but at the 7th week, CI value in the sildenafil-treated PAH rats was significantly higher than in other groups and HR of PAH rats with combined therapy was significantly lower than in other groups.

Conclusion

PAH did not have an effect on LV function of rats, or if it did, the effect was compensated by physiological processes. Also, sildenafil treatment deteriorated the LV cardiac index.Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by increased pulmonary artery pressure, pulmonary vascular damage, and medial hypertrophy of pulmonary arterioles, leading to right ventricular (RV) hypertrophy, RV failure, and eventually death (1). The monocrotaline (MCT)-induced model of PAH is the most used model in rats. MCT is a pyrrolizidine alkaloid from the plant Crotalaria spectabilis. A single injection of MCT results in injury to the vascular endothelium of the lung, pulmonary hypertension, and RV hypertrophy and failure within 3 or 4 weeks (2-5).A key feature of PAH is deregulation of important vasodilatory mechanisms in the pulmonary circulation, including increased expression of phosphodiesterase 5 (PDE5) (6). Acute and chronic experimental models of PAH use PDE5 inhibitor sildenafil to reduce pulmonary pressure (7,8). Another important PAH treatment method is by endothelin (ET) receptor antagonist bosentan (9). The endothelin system is highly active in PAH and causes sustained vasoconstriction of pulmonary arteries. It increases the autogenic activity of smooth muscle cells and fibroblasts in the pulmonary vessel wall, thereby decreasing the lumen of pulmonary vessels and also contributing to increased pulmonary vascular resistance (10,11). It is also known that ET receptor expression in the RV myocardium increases due to PAH (12).Heart failure due to PAH can be identified by clinical symptoms that are linked to hemodynamic indices of right heart failure (3,13). Because of the major differences between left and right heart hemodynamics and potentially different responses to pressure overload, the data obtained for RV myocardium do not have to be applicable to the left ventricle (LV). In addition, although chronic pulmonary hypertension selectively overloads the RV, there also manifests LV dysfunction (14). However, hemodynamic indices of the left heart and treatment effects on them cannot be identified in this situation. The aim of this study is to evaluate the effects of PAH and bosentan, sildenafil, and combined treatments on the LV hemodynamic parameters by impedance cardiography (ICG) in rats with MCT-induced PAH.     

Methods for Measuring Right Ventricular Function and Hemodynamic Coupling with the Pulmonary Vasculature

The right ventricle (RV) is a pulsatile pump, the efficiency of which depends on proper hemodynamic coupling with the compliant pulmonary circulation. The RV and pulmonary circulation exhibit structural and functional differences with the more extensively investigated left ventricle (LV) and systemic circulation. In light of these differences, metrics of LV function and efficiency of coupling to the systemic circulation cannot be used without modification to characterize RV function and efficiency of coupling to the pulmonary circulation. In this article, we review RV physiology and mechanics, established and novel methods for measuring RV function and hemodynamic coupling, and findings from application of these methods to RV function and coupling changes with pulmonary hypertension. We especially focus on non-invasive measurements, as these may represent the future for clinical monitoring of disease progression and the effect of drug therapies.     

Impact of Pulmonary Hypertension on Tricuspid Valve Function

Pulmonary arterial hypertension (PAH) results in increased right ventricle (RV) afterload leading to RV remodeling, tricuspid regurgitation (TR), and RV failure. Though characterizing the mechanisms of TR in PAH may suggest new treatment strategies, the mechanisms leading to TR in PAH have not been characterized. In the present study, eleven porcine tricuspid valves were studied in an in vitro right heart simulator. Annular dilatations of 1.2 and 1.4 times normal area, papillary muscle (PM) displacement simulating concentric RV dilatation and eccentric RV dilatation due to concomitant left ventricle dysfunction, and two levels of PAH hemodynamics were simulated independently and in combination. Relative TR, tenting area (TA) along each coaptation line, and coaptation area (CA) of each leaflet were quantified. Results showed a significant increase (p ≤ 0.05) in TR with both increased mean pulmonary artery pressure (mPAP) and annular dilatation of 1.4 times normal. Increased mPAP significantly decreased TA but tended to increase CA, while PM displacement significantly increased TA but did not affect CA, suggesting competing effects of transvalvular pressure and leaflet tethering. Annular dilatation significantly decreased anterior and posterior CA but did not affect TA. These results may inform future TV repairs in PAH to reduce TR and improve RV hemodynamics.     

Acute Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension: Clinical and Serial CT Pulmonary Angiographic Features

In acute pulmonary embolism (PE), circulatory failure and systemic hypotension are important clinically for predicting poor prognosis. While pulmonary artery (PA) clot loads can be an indicator of the severity of current episode of PE or treatment effectiveness, they may not be used directly as an indicator of right ventricular (RV) failure or patient death. In other words, pulmonary vascular resistance or patient prognosis may not be determined only with mechanical obstruction of PAs and their branches by intravascular clot loads on computed tomography pulmonary angiography (CTPA), but determined also with vasoactive amines, reflex PA vasoconstriction, and systemic arterial hypoxemia occurring during acute PE. Large RV diameter with RV/left ventricle (LV) ratio > 1.0 and/or the presence of occlusive clot and pulmonary infarction on initial CTPA, and clinically determined high baseline PA pressure and RV dysfunction are independent predictors of oncoming chronic thromboembolic pulmonary hypertension (CTEPH). In this pictorial review, authors aimed to demonstrate clinical and serial CTPA features in patients with acute massive and submassive PE and to disclose acute CTPA and clinical features that are related to the prediction of oncoming CTEPH.     

Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by Monocrotaline

Mutations in the gene for the transforming growth factor (TGF)-β superfamily receptor, bone morphogenetic protein receptor II, underlie heritable forms of pulmonary arterial hypertension (PAH). Aberrant signaling via TGF-β receptor I/activin receptor-like kinase 5 may be important for both the development and progression of PAH. We investigated the therapeutic potential of a well-characterized and potent activin receptor-like kinase 5 inhibitor, SB525334 [6-(2-tert-butyl-5-{6-methyl-pyridin-2-yl}-1H-imidazol-4-yl)-quinoxaline] for the treatment of PAH. In this study, we demonstrate that pulmonary artery smooth muscle cells from patients with familial forms of idiopathic PAH exhibit heightened sensitivity to TGF-β1 in vitro, which can be attenuated after the administration of SB525334. We further demonstrate that SB525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. Immunohistochemical studies confirmed a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used experimentally to induce PAH) after treatment of rats with SB525334. Collectively, these data are consistent with a role for the activin receptor-like kinase 5 in the progression of idiopathic PAH and imply that strategies to inhibit activin receptor-like kinase 5 signaling may have therapeutic benefit.Pulmonary arterial hypertension (PAH) is a severe disease of the small pulmonary arteries characterized by vascular damage and narrowing of the vessels, leading to raised pulmonary artery pressure, right ventricular (RV) hypertrophy, and ultimately, right-sided heart failure and death. The combined effects of vasoconstriction, remodeling of the pulmonary vessel wall comprising abnormal endothelial and pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis, enhanced extracellular matrix deposition, and elevated thrombosis contribute to increased pulmonary vascular resistance and the resultant right-sided cardiac hypertrophy and mortality.¹ Although the exact molecular basis underlying the vascular damage remains unclear, genetic studies have linked germ-line mutations in a gene encoding the transforming growth factor β (TGF-β) superfamily receptor member bone morphogenetic protein receptor 2 (BMPR-II) to the development of heritable forms of idiopathic pulmonary arterial hypertension (iPAH), encompassing familial and a proportion of sporadic cases of the disease.²Studies to assess the consequences of loss of BMPR-II have been undertaken to help elucidate the functional role of this receptor in the human pathology. Data from in vitro studies have shown that TGF-β addition to PASMCs isolated from patients with iPAH results in an elevated proliferative response compared with the effects mediated by addition of this growth factor to PASMCs from normotensive individuals.³ These data suggest that BMPR-II may repress the activity of the TGF-β/activin-like kinase 5 (ALK5) pathway in PASMCs from healthy individuals and that loss of BMPR-II may lead to unregulated TGF-β/ALK5 activity in PASMCs from patients with iPAH. Indeed, elevated Smad2 phosphorylation, a marker of TGF-β/ALK5 activity, can also be observed in endothelial cells isolated from plexiform lesions of patients with iPAH indicative of pathway activation.⁴ Furthermore, analysis of the expression levels of TGF-β1, ALK5 and transforming growth factor-β receptor II (TGF-βRII) in leukocytes from patients with iPAH also reveals that the ratio of ALK5 expression to TGF-βRII is significantly higher in iPAH patients compared with normal controls, pointing toward an imbalance in expression patterns of components of the TGF-β pathway in circulating immune cells.⁵ Taken together, this evidence suggests that abnormal TGF-β/ALK5 signaling may be important in mediating the development and progression of iPAH.Evidence has accumulated that highlights an important role for TGF-β signaling in the development and progression of certain pathophysiological features observed in preclinical models of experimental PAH. For instance, elevated expression levels of TGF-β ligands have been reported in the rat monocrotaline (MCT)⁶ and hypoxia models.⁷ In addition, altered expression of TGF-β ligands and type I receptors have been described in the pulmonary vasculature of a lamb model of congenital heart disease after aortopulmonary vascular graft.⁸ Studies addressing the functional role of TGF-β signaling in preclinical rodent models of PAH have recently been reported. Transgenic mice engineered to express an inducible kinase-deficient TGF-βRII receptor appear to be refractory to PAH induced by low oxygen suggesting that intact TGF-β is required for induction of PAH by hypoxia.⁹ Controversy exists to the role played by TGF-β signaling in MCT-mediated PAH in rats. A study by Zakrzewicz and colleagues¹⁰ demonstrated that components of the TGF-β signaling pathway are down-regulated in rats after MCT treatment, whereas a more recent study has shown elevated TGF-β pathway activation in pulmonary vascular cells of MCT-treated rats.¹¹ Interestingly, the latter study also demonstrated the ALK5 inhibitor, SD-208 prevented the development of MCT-induced PAH in rats. In contrast, delaying administration of SD-208 until established PAH had occurred resulted in a less pronounced impact on the ensuing pathologies, leading the authors to conclude that TGF-β/ALK5 signaling may play an important role in the initiation of experimental PAH, but a limited role in progression of established disease. These data would naturally imply that strategies to inhibit ALK5 signaling in iPAH may have limited therapeutic benefit because patients will usually present at later stages of the disease.This study proposed to determine the validity of targeting the TGF-β pathway via a selective ALK5 inhibitor, SB525334. Here we demonstrate enhanced sensitivity to TGF-β in cells isolated from patients with familial iPAH, compared with normotensive controls, as shown by significantly higher expression levels of several TGF-β-regulated genes. We also show that abnormal TGF-β-mediated proliferation of PASMCs from patients with familial iPAH in vitro can be inhibited by the ALK5-selective compound, SB525334 with IC₅₀ values consistent with ALK5 inhibition. We have also tested the efficacy of SB525334 in reversing established PAH in the MCT rat model of disease. In contrast to the study using SD-208,¹¹ we demonstrate significant reversal of elevated mean pulmonary arterial pressure and inhibition of RV hypertrophy after MCT treatment using standard invasive readouts (right heart catheterization and Fulton index determination) or via noninvasive small animal echocardiography after oral administration of SB525334. Our computerized lung morphometry data suggest that small pulmonary artery remodeling induced after MCT insult is reversed by addition of SB525334 to rats and accounts for the significant improvement in hemodynamics after compound treatment. Our data support a role for ALK5 signaling in the latter stages of experimental PAH and implies that significant therapeutic benefit may be attained in the human pathology after systemic inhibition of the pathway.     

Urotensin Inhibition with Palosuran Could Be a Promising Alternative in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive and a life-threatening disease with its high morbidity and mortality ratios. On searching for new shining targets in pathogenesis, we noticed, in our previous studies, urotensin-II (UII) in systemic sclerosis with potent angiogenic and pro-fibrotic features. Owing to the mimicking properties of UII with endothelin-1 (ET1), we attempted to investigate the effect of palosuran in a PAH rat model. Thirty rats were randomly divided into three groups, with each group comprising 10 rats: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran group) received subcutaneous MCT and palosuran. Serum UII, ET1, transforming growth factor-β1 (TGF-β1) levels, pulmonary arteriolar pathology of different diameter vessels, and cardiac indices were evaluated. The ET1, TGF-β1, and UII levels were significantly diminished in the treatment group, similar to the controls (p?<?0.001). Right ventricular hypertrophy index and mean pulmonary arterial pressure scores were also significantly reduced in the treatment group (p?=?0.001). Finally, in the 50–125-μm diameter arterioles, in contrast to Groups 3 and 1, there was a statistically significant thickness (p?<?0.01) in the arteriolar walls of rats in Group 2. The treatment effect on arteries of more than 125-μm diameters was found to be valuable but not significant. Owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, palosuran as an antagonist of UII might be an optional treatment alternative for PAH.     

Influence of Moderate Vasoconstriction on the Wave Reflection Properties of the Pulmonary Arterial Bed

Increased transmural pressure in the pulmonary arterial bed may reduce vascular input impedance and reduce hydraulic power linked to pulsatile blood flow. Vascular impedance and pulsatile hydraulic power (Wp) levels of isolated perfused rabbit lungs were compared after similar rises of pulmonary arterial pressure (PAp), induced either by vasoconstriction or by left atrial pressure (LAp) elevation. Resulting Wp levels were significantly smaller after vasoconstriction than LAp elevation. Wp showed a minimum level at physiologic PAp (about 20 cm H₂O) irrespective of the cause of PAp elevation. Pressure pulse wave reflection coefficient (Γ) was calculated for control and test situations, and was found to be approximately doubled after vasoconstriction. Only minor changes in Γ were found after LAP elevation. Accordingly, moderate vasoconstriction (resulting PAp?20 cm H₂O) caused a backward traveling pressure wave of high amplitude, appearing in counter-phase to the forward pressure wave at the input site. The total pressure wave amplitude was thereby markedly lowered, resulting in a reduced Wp level. We assume that this effect of moderate vasoconstriction may be one reason for the existence of vascular smooth muscles in the pulmonary arteries.     

A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension

A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.Pulmonary arterial hypertension (PAH) remains a highly fatal syndrome, despite recent advancements in its treatment.^1,2 New candidate drugs, such as Rho kinase inhibitors^3–6 and tyrosine kinase inhibitors,^7,8 have shown promise in providing improved treatment for PAH. However, the clinical application of these agents has generally been hampered by their systemic toxicity/adverse effects.^9–12 Inhalation is a relatively selective drug delivery method for the lungs,¹³ but there are several problems with the clinical use of aerosol inhalation in the treatment of PAH.¹⁴ In fact, insufficient inhalation due to technical problems may be a major limitation for the effectiveness of inhaled Rho kinase inhibitor, fasudil, in patients with PAH.¹⁵In numerous diseases, the blood vessels in the affected organ express disease-specific cell surface markers (vascular zip codes).¹⁶ For example, tumor blood vessels express distinctive markers not present in vessels of normal tissues.¹⁶ These target organ–specific molecular structures are detectable by systemically administered homing peptides,^16,17 which find their way to the desired location by binding to their receptor expressed in the blood vessels of the target organ. Promising results are accumulating for the use of homing peptides to deliver drugs selectively to tumors.^16–18 This potentially useful targeting technology has not yet been applied to the treatment of PAH, although vascular selectivity would be desired in PAH.We have recently reported tumor-homing peptides that specifically bind to tumor vessels and then extravasate into the tumor tissue, carrying a payload with them.^18,19 Even more important, a tumor-penetrating peptide can transport co-administered drugs into the target tissue without chemically coupling the compound with the peptide (bystander effect).²⁰ This novel mechanism involves homing peptide–induced activation of an endocytic trans-tissue transport pathway, named CendR-pathway, in the target tissue of the peptide.^18–20 The bystander effect provides the advantage of promoting delivery of a drug to its target tissue without the coupling of the drug to the peptide required in conventional drug targeting.²⁰CARSKNKDC (CAR) is a vascular homing peptide originally identified as being capable of homing to the neovasculature in injured, regenerating tissues.²¹ CAR requires heparan sulfate on the target cells for cell binding and uptake into cells,²¹ suggesting that this peptide may recognize a unique sulfation pattern of heparan sulfate proteoglycans on the target cells. When CAR is fused together with the anti-fibrotic protein, decorin, as a recombinant fusion protein, it accumulates in the wound and penetrates deep into wound granulation tissue.^22,23 More recently, we have shown that CAR also selectively accumulates in the walls of hypertensive pulmonary arteries in monocrotaline- and Sugen5416/hypoxia/normoxia-induced (SU/Hx/Nx) PAH rats, but not in normotensive pulmonary arteries.²⁴ This study also showed that CAR penetrates beyond the vascular endothelium; it accumulates in the entire wall of hypertensive pulmonary arteries and in the surrounding lung parenchyma.²⁴The tissue-penetrating activity of CAR prompted us to examine whether CAR might also induce a bystander effect, and if it could be used to selectively transport co-administered drugs to CAR’s homing destination (ie, PAH tissue). We have tested the effect of CAR co-administration on three vasodilators: i) the Rho kinase inhibitor, fasudil; ii) the tyrosine kinase inhibitor, imatinib; and iii) the phosphodiesterase type 5 inhibitor, sildenafil. They were tested on blood pressure in PAH rats. We have also determined whether i.v. administration of CAR could be replaced by sublingual dosing.     

Influence of Vessel Distension and Myogenic Tone on Pulmonary Arterial Input Impedance. A Study using a Computer Model of Rabbit Lung

A computer model of the pulmonary arterial (PA) bed of rabbit lungs was designed in order to test experimental observations of changes in PA input impedance and pulsatile hydraulic power (cap.) during increased PA pressure. The computer model was based on a simple 3-component analog representation of single vessels (i.e. resistance, inertance and compliance). 16 generations of arterial vessels, from PA to 60 μm diameter, were combined to calculate PA input impedance. Input impedance was found to mimic closely that observed experimentally. Both venous pressure elevation and arteriolar constriction was found to reduce input impedance and Wp. By combining arteriolar constriction with increased myogenic tone of the larger arteries, Wp was found to show a minimum level at a certain PA pressure, dependent on the degree of arterial stiffening. Wp was found to follow changes in arterial volume and resistance during simulated vasoconstriction. Wp dissipation in arterial vessels was calculated to approx. 50% of total input Wp at physiological pressure conditions, and could be reduced by one half after PA pressure increase from 20 to 50 cm H₂O, despite a concurrent halving of arterial compliance. Arterial vessels smaller than 200 pm diameter were found to have negligible direct influence on PA input impedance.     

Quantification of pulsatility as a function of vascular input impedance: an in vitro study

The physiological benefits of pulsatility generated by ventricular assist device (VAD) support continue to be heavily debated as application of VAD support has been expanded to include destination and recovery therapies. In this study, the relationship between input impedance (Zart) and vascular pulsatility during continuous flow (CF) or pulsatile flow (PF) VAD support was investigated. Hemodynamic waveforms were recorded at baseline failure and with 50%, 75%, and 100% CF or PF VAD support for nine different Zart test conditions (combination of three different resistance and compliance settings) in a mock circulatory system simulating left ventricular failure. High-fidelity hemodynamic pressure and flow waveforms were recorded to calculate mean arterial pressure (MAP), Zart, energy equivalent pressure (EEP), and surplus hemodynamic energy (SHE) as metrics for quantifying vascular pulsatility. MAP and EEP were elevated with increasing resistance whereas SHE was reduced with increasing compliance. Vascular pulsatility was restored with increasing PF VAD support, but diminished by up to 90% with increasing CF VAD support. The nonpulsatile energy component (MAP) of the pressure waveform is dependent on resistance whereas the pulsatile energy component (SHE) is dependent on compliance. The impact of Zart and vascular pulsatility on patient recovery with VAD support warrants further investigation.     

Pulmonary Arterial Hypertension in Pediatric Patients with Hematopoietic Stem Cell Transplant–Associated Thrombotic Microangiopathy

Pulmonary arterial hypertension (PAH) is rarely included in the differential diagnosis of cardiorespiratory failure after pediatric hematopoietic stem cell transplant (HSCT) as the clinical presentation is nonspecific and may mimic other etiologies. The pathogenesis of PAH in HSCT is poorly understood and the diagnosis requires a high degree of suspicion. We describe 5 children diagnosed with PAH after allogeneic HSCT. All 5 patients had prolonged clinical signs of transplantation-associated thrombotic microangiopathy (TA-TMA) when they presented with hypoxemic respiratory failure and evidence of PAH. Four of the 5 patients had echocardiographic evidence of PAH, and 1 patient was diagnosed with PAH only on autopsy. PAH was diagnosed a median of 76 days (range, 56-101 days) after a diagnosis of TA-TMA. Despite aggressive medical management, including inhaled nitric oxide, 4 of the 5 patients died. One patient recovered from PAH after 11 months of sildenafil therapy. Three of the 4 deceased patients had an autopsy performed, demonstrating severe pulmonary vascular disease consistent with TA-TMA and severe PAH. We conclude that TA-TMA can be associated with significant pulmonary vascular injury presenting as hypoxemic respiratory failure with PAH after HSCT. Pediatric patients with unexplained hypoxemia after HSCT should be evaluated for both transplantation complications, TA-TMA and PAH, accordingly.     

Pulmonary Vascular Resistance and Impedance in Isolated Mouse Lungs: Effects of Pulmonary Emboli

To study pulsatile pressure-flow rate relationships in the intact pulmonary vascular network of mice, we developed a protocol for measuring pulmonary vascular resistance and impedance in isolated, ventilated, and perfused mouse lungs. We used pulmonary emboli to validate the effect of vascular obstruction on resistance and impedance. Main pulmonary artery and left atrial pressures and pulmonary vascular flow rate were measured under steady and pulsatile conditions in the lungs of C57BL/6J mice (n = 6) before and after two infusions with 25 μm-diameter microspheres (one million per infusion). After the first and second embolizations, pulmonary artery pressures increased approximately two-fold and three and a half-fold, respectively, compared to baseline, at a steady flow rate of 1 ml/min (P < 0.05). Pulmonary vascular resistance and 0 Hz impedance also increased after the first and second embolizations for all flow rates tested (P < 0.05). Frequency-dependent features of the pulmonary vascular impedance spectrum were suggestive of shifts in the major pulmonary vascular reflection sites with embolization. Our results demonstrate that pulmonary artery pressure, resistance, and impedance magnitude measured in this isolated lung setup changed in ways consistent with in vivo studies in larger animals and humans and demonstrate the usefulness of the isolated, ventilated, and perfused mouse lung for investigating steady and pulsatile pressure-flow rate relationships.     

The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle

Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK). We studied two complementary rat models: RVH?+?PAH (induced by monocrotaline) and RVH?+?without PAH (induced by pulmonary artery banding (PAB)). Monocrotaline RVH reduced RV O₂-consumption and enhanced glycolysis. RV 2-fluoro-2-deoxy-glucose uptake, Glut-1 expression, and pyruvate dehydrogenase phosphorylation increased in monocrotaline RVH. The RV monophasic action potential duration and QT_c interval were prolonged due to decreased expression of repolarizing voltage-gated K⁺ channels (Kv1.5, Kv4.2). In the RV working heart model, the PDK inhibitor, dichloroacetate, acutely increased glucose oxidation and cardiac work in monocrotaline RVH. Chronic dichloroacetate therapy improved RV repolarization and RV function in vivo and in the RV Langendorff model. In PAB-induced RVH, a similar reduction in cardiac output and glycolytic shift occurred and it too improved with dichloroacetate. In PAB-RVH, the benefit of dichloroacetate on cardiac output was approximately 1/3 that in monocrotaline RVH. The larger effects in monocrotaline RVH likely reflect dichloroacetate’s dual metabolic benefits in that model: regression of vascular disease and direct effects on the RV. Reduction in RV function and electrical remodeling in two models of RVH relevant to human disease (PAH and pulmonic stenosis) result, in part, from a PDK-mediated glycolytic shift in the RV. PDK inhibition partially restores RV function and regresses RVH by restoring RV repolarization and enhancing glucose oxidation. Recognition that a PDK-mediated metabolic shift contributes to contractile and ionic dysfunction in RVH offers insight into the pathophysiology and treatment of RVH.     

The Effect of Umbilical Cord Blood Derived Mesenchymal Stem Cells in Monocrotaline-induced Pulmonary Artery Hypertension Rats

Pulmonary arterial hypertension (PAH) causes right ventricular failure due to a gradual increase in pulmonary vascular resistance. The purposes of this study were to confirm the engraftment of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) placed in the correct place in the lung and research on changes of hemodynamics, pulmonary pathology, immunomodulation and several gene expressions in monocrotaline (MCT)-induced PAH rat models after hUCB-MSCs transfusion. The rats were grouped as follows: the control (C) group; the M group (MCT 60 mg/kg); the U group (hUCB-MSCs transfusion). They received transfusions via the external jugular vein a week after MCT injection. The mean right ventricular pressure (RVP) was significantly reduced in the U group after the 2 week. The indicators of RV hypertrophy were significantly reduced in the U group at week 4. Reduced medial wall thickness in the pulmonary arteriole was noted in the U group at week 4. Reduced number of intra-acinar muscular pulmonary arteries was observed in the U group after 2 week. Protein expressions such as endothelin (ET)-1, endothelin receptor A (ERA), endothelial nitric oxide synthase (eNOS) and matrix metalloproteinase (MMP)-2 significantly decreased at week 4. The decreased levels of ERA, eNOS and MMP-2 immunoreactivity were noted by immnohistochemical staining. After hUCB-MSCs were administered, there were the improvement of RVH and mean RVP. Reductions in several protein expressions and immunomodulation were also detected. It is suggested that hUCB-MSCs may be a promising therapeutic option for PAH.

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