Bosentan improved persistent pulmonary hypertension in a case after implantation of a left ventricular assist device

No medical treatment has been established to ameliorate pulmonary hypertension (PH) due to left heart disease. Heart transplantation (HTx) is thus far the definitive therapy for stage D heart failure, but concomitant PH is one of the major risk factors for death after HTx. Recently, implantation of a left ventricular assist device (LVAD) has been reported to improve PH and has become a major bridge tool for HTx. We experienced a rare case with persistent PH even after the implantation of a continuous-flow LVAD. The administration of an endothelin receptor antagonist, bosentan, significantly decreased pulmonary vascular resistance. Combination therapy with LVAD implantation and anti-PH medication may be useful for patients with stage D heart failure complicated with severe PH.     

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.     

Screening for precapillary pulmonary hypertension in chronic myeloproliferative disorders: the role of N-terminal pro-B-type natriuretic peptide and vascular endothelial growth factor – a pilot study

IntroductionPrecapillary pulmonary hypertension (PH) implies a worse prognosis in myeloproliferative neoplasms (MPN). N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in cardiopulmonary involvement. In MPN patients with precapillary PH, elevated vascular endothelial growth factor (VEGF) values, but in left heart (LH) disease patients, decreased values were reported. Our aim was to determine whether a combination of NT-proBNP and VEGF is suitable for the detection of the precapillary forms of PH in MPN patients.Material and methodsEighty-one MPN patients were investigated. Pulmonary hypertension was defined as Doppler-derived systolic pulmonary artery pressure (sPAP) ≥ 40 mm Hg. Patient groups with cardiopulmonary involvement (precapillary PH, PH due to LH disease, left ventricular ejection fraction < 50%, atrial fibrillation) or LH disease (PH due to LH disease, left ventricular ejection fraction < 50%, atrial fibrillation) were identified.ResultsIn 9 patients PH was associated with LH disease. In 2 patients precapillary PH was found with extremely high NT-proBNP values. NT-proBNP significantly correlated with sPAP (r = 0.550; p < 0.001). NT-proBNP ≥ 466 pg/ml was the best predictor of cardiopulmonary involvement (AUC: 0.962, sensitivity: 86.7%, specificity: 93.9%). No correlation was found between VEGF levels and sPAP values. VEGF ≤ 431 pg/ml was the best predictor of LH disease (AUC: 0.609, sensitivity: 76.9%, specificity: 62.7%).ConclusionsNT-proBNP levels reflect cardiopulmonary involvement with high accuracy, but the combination of NT-proBNP and VEGF is not suitable for the detection of precapillary PH as the diagnostic power of VEGF is limited. Highly elevated NT-proBNP levels may suggest precapillary PH but further investigation is necessary for the exclusion of LH disease or atrial fibrillation.     

Acute pulmonary vasoreactivity test with sildenafil or nitric monoxide before left ventricular assist device implantation

There has been no established medical therapy to ameliorate pulmonary hypertension (PH) owing to left heart disease (LHD-PH). It has recently been shown that the left ventricular assist device (LVAD) can improve LHD-PH and therefore has the potential to become a major bridge tool for heart transplantation (HTx). However, some patients still have persistent PH even after LVAD treatment. It is essential to demonstrate the reversibility of end-organ dysfunction, including PH, prior to implantable LVAD treatment, especially in Japan, because implantable LVAD treatment is indicated only as bridge to transplantation. Here we report a patient with LHD-PH whose PH was demonstrated to be reversible by the acute pulmonary vasoreactivity test (APVT) with nitrogen monoxide (NO) and the phosphodiesterase-5 inhibitor sildenafil. Both inhaled NO and sildenafil reduced pulmonary vascular resistance, but pulmonary capillary wedge pressure was increased by NO, which was conversely decreased under increased cardiac output by sildenafil. After the patient was listed as an HTx recipient, pulmonary vascular resistance recovered down to an acceptable range with LVAD treatment. Based on these findings, we suggest that the APVT with sildenafil may be a useful and safe tool to predict improvement of PH after LVAD treatment.     

肺动脉高压的肺动脉血管超声生物力学研究

目的采用超声成像技术与生物力学方法相结合的方法,对肺动脉高压(PH)进行了肺动脉(PA)的超声生物力学研究,试将PH患者肺动脉血管的生物力学性质参数用于临床评估PH。方法选择先天性心脏病室间隔缺损并肺动脉高压患者,同步记录肺动脉压力与肺动脉二维图像,从PA收缩加压与扩张开始点到PA达到压力或扩展最大程度时点,界定为10个测量时点、9个递增步骤,分别测量每个时点的PA内径值及收缩压数值及其递增量,然后使用血管生物力学数学模型分析其肺动脉应力-应变关系。结果随着PA压力的不断上升,PA血管内径的扩展性也逐渐受限,尤其是阻力型PH组的PA内径扩张明显受限制,阻力型PH组的肺动脉物质常数a值和b值的各个参数显著减小(P<0.001),表明肺动脉物质常数a值和b值在鉴别阻力型PH方面具有一定的预测作用。结论肺动脉超声生物力学方法在评估与选择先天性心脏病合并PH患者手术适应证方面具有一定的参考作用。     

肺动脉高压的肺动脉血管超声生物力学研究

目的采用超声成像技术与生物力学方法相结合的方法,对肺动脉高压(PH)进行了肺动脉(PA)的超声生物力学研究,试将PH患者肺动脉血管的生物力学性质参数用于临床评估PH。方法选择先天性心脏病室间隔缺损并肺动脉高压患者,同步记录肺动脉压力与肺动脉二维图像,从PA收缩加压与扩张开始点到PA达到压力或扩展最大程度时点,界定为10个测量时点、9个递增步骤,分别测量每个时点的PA内径值及收缩压数值及其递增量,然后使用血管生物力学数学模型分析其肺动脉应力-应变关系。结果随着PA压力的不断上升,PA血管内径的扩展性也逐渐受限,尤其是阻力型PH组的PA内径扩张明显受限制,阻力型PH组的肺动脉物质常数a值和b值的各个参数显著减小(P<0.001),表明肺动脉物质常数a值和b值在鉴别阻力型PH方面具有一定的预测作用。结论肺动脉超声生物力学方法在评估与选择先天性心脏病合并PH患者手术适应证方面具有一定的参考作用。     

Animal models of pulmonary hypertension due to left heart disease

Pulmonary hypertension due to left heart disease (PH‐LHD) is regarded as the most prevalent form of pulmonary hypertension (PH). Indeed, PH is an independent risk factor and predicts adverse prognosis for patients with left heart disease (LHD). Clinically, there are no drugs or treatments that directly address PH‐LHD, and treatment of LHD alone will not also ameliorate PH. To target the underlying physiopathological alterations of PH‐LHD and to develop novel therapeutic approaches for this population, animal models that simulate the pathophysiology of PH‐LHD are required. There are several available models for PH‐LHD that have been successfully employed in rodents or large animals by artificially provoking an elevated pressure load on the left heart, which by transduction elicits an escalated pressure in pulmonary artery. In addition, metabolic derangement combined with aortic banding or vascular endothelial growth factor receptor antagonist is also currently applied to reproduce the phenotype of PH‐LHD. As of today, none of the animal models exactly recapitulates the condition of patients with PH‐LHD. Nevertheless, the selection of an appropriate animal model is essential in basic and translational studies of PH‐LHD. Therefore, this review will summarize the characteristics of each PH‐LHD animal model and discuss the advantages and limitations of the different models.     

Gax在肺动脉高压大鼠肺动脉中的表达变化

目的:使用低氧及野百合碱(monocrotaline,MCT)诱导的两种肺动脉高压(pulmonary arterialhypertension,PAH)大鼠模型,观察生长终止特异性同源盒(growth arrest-specific homeobox,Gax)在肺动脉的表达变化。方法:Sprague Dawley大鼠随机分为四组:低氧模型组(n=16)、低氧对照组(n=16)、MCT模型组(n=16)及MCT对照组(n=16)。采用插管法测定大鼠的右心室压力及肺动脉压力。右心室质量除以左心室和室间隔质量,计算右心肥厚指数。采用定量RT-PCR法测定肺动脉主干及肺组织Gax mRNA表达;采用Western免疫印迹法测定肺动脉主干Gax蛋白表达;免疫组织化学染色观测Gax在肺内的分布及表达变化。结果:低氧模型组及MCT模型组大鼠的右心压力、肺动脉压力及右心肥厚指数均显著高于相应对照组(P<0.01),两种模型大鼠的肺动脉血管均出现明显重构。与对照组比较,Gax mRNA在两种模型组大鼠的肺组织表达降低(P<0.05),而在肺动脉主干表达升高(P<0.05)。Gax蛋白在肺内主要表达在微小动脉。与对照组比较,两种模型组大鼠的肺动脉主干和肺微小动脉Gax蛋白表达均升高(P<0.05),而肺组织Gax蛋白表达下降(P<0.05)。结论:Gax主要表达在肺微小动脉,在PAH发生时表达上调。     

Effect of chronic hypoxia on pulmonary artery blood velocity in rats as assessed by electrocardiography-triggered three-dimensional time-resolved MR angiography

Pulmonary arterial hypertension (PAH) is a severe disease that leads to increased pulmonary vascular resistance and right heart failure. Noninvasive methods are needed to detect changes in the pulmonary artery circulation during PAH establishment and/or treatment. Pulmonary blood flow velocity can be evaluated by dynamic MR angiography, although the relevance of such data in the context of PAH remains to be demonstrated. A novel dynamic MR angiography technique was used in this work to measure blood flow velocity in the pulmonary arteries of the same living animals, before and after the establishment of chronic hypoxia‐induced PAH. Chronic hypoxia decreased significantly the blood flow velocity (43.8 ± 4.9 vs 24.3 ± 8.7 cm/s) on electrocardiography‐triggered time‐resolved angiograms. In parallel, chronic hypoxia‐induced PAH was confirmed from invasive measurements of the mean pulmonary arterial pressure (32.1 ± 4.8 vs 12.5 ± 2.2 mmHg) and the ratio of the right ventricle weight to the left ventricle plus septum weight (Fulton index: 0.54 ± 0.06 vs 0.27 ± 0.04). This study demonstrates the potential interest of dynamic MR angiography for the investigation of experimental models and for the evaluation of treatment efficacy. Copyright © 2010 John Wiley & Sons, Ltd.     

A heart transplant candidate with severe pulmonary hypertension and extremely high pulmonary vascular resistance

Fixed pulmonary hypertension (PH) is a contraindication for heart transplantation (HTx). Several studies showed that use of a left ventricular assist device (LVAD) in patients with fixed PH who were initially deemed ineligible for HTx effectively decreased pulmonary arterial pressure (PAP), thus permitting HTx. We recently encountered a candidate for HTx who had severe PH with extremely high pulmonary vascular resistance (PVR). A 27-year-old female who had been diagnosed with dilated-phase hypertrophic cardiomyopathy and who was approved for HTx at age 25 was referred to our institute because of severe fatigability with moderate dyspnea even at rest due to severe bilateral heart failure. Despite continuous inotrope infusion, the patient’s symptoms were not relieved. Right heart catheterization (RHC) disclosed a PAP of 62/40 mmHg with severely reduced cardiac output (1.8 l/min). A PVR of 15.9 Wood units suggested progressive worsening of left ventricular function with almost irreversible remodeling of the pulmonary vasculature, and the patient was thought to be contraindicated for HTx. Following 3 weeks of aggressive medical treatment, repeat RHC demonstrated PVR lowering to 8.16 Wood units. This suggested it was likely that PVR could be reversed, and the patient underwent LVAD implantation. RHC performed after LVAD implantation showed a fall in PVR from the initial, extremely high measurement of 15.9 Wood units to 3.4 Wood units at 2 months postoperatively, and to 2.2 Wood units at 1 year. The patient is currently awaiting HTx with favorable LVAD support.     

Portopulmonary hypertension due to schistosomiasis in two Malagasy patients

Portopulmonary hypertension is characterized by a chronic liver disease associated with a mean pulmonary artery pressure >25 mmHg at rest, an increased pulmonary vascular resistance and a capillary pulmonary pressure <15 mmHg with portal hypertension. Schistosomiasis may be an aetiology of this syndrome, however, few cases have been reported. We describe the first cases of portopulmonary hypertension with schistosomiasis in Malagasy patients. There were 2 men aged of 18 and 20 from hyperendemic area of schistosomiasis in Madagascar Both had a history of repeated water contact. They presented a dyspnea associated with ascites and oedema. Clinical examination showed portal and pulmonary hypertension with right ventricular heart failure. Cardiac examination revealed a systolic murmur and splint of the second heart pulmonary Pulmonary hypertension was confirmed by cardiac ultrasonogaphy Serology of bilharzias was positive. Parasitological examination showed eggs of S. mansoni. The treatment based on salt-free diet, spironolactone and praziquantel led to a better evolution of symptoms (case 1). Symptoms of right heart failure remained for the second patient even though improvement was noted. In tropical countries, schistosomiasis may be one of the cause of portopulmonary hypertension and may appear in early age. Its treatment remains difficult as the drugs recommended are not affordable.     

Inhalation of Stachybotrys chartarum causes pulmonary arterial hypertension in mice

Inhalation of Stachybotrys chartarum, a ubiquitous fungus in our living environment, has been suspected as a cause of acute idiopathic pulmonary haemorrhage in infants, but its relation to human diseases is not yet known. The aim of present study was to investigate the effect of repeated intratracheal injection of the fungus into mice, paying special attention to the pulmonary vascular system. Spores of S. chartarum were injected into the trachea of mice from 6 to 18 times over 4-12 weeks, and the lungs were examined by histopathology, morphometrics and haemodynamics. When 1 x 10(4) spores/mouse were injected, histopathological examination showed the development of pulmonary arterial hypertension (PAH). Symmetrical thickening of the intima and media of the pulmonary arterial walls was seen after six injections over 4 weeks. Right ventricular hypertrophy was also evident after 12 injections. PAH was confirmed by the elevation of right ventricular systolic pressure (20.1 +/- 5.7 mmHg in the injected group vs. 12.0 +/- 2.4 mmHg in the control group, P < 0.01). This study showed that the inhalation of S. chartarum caused PAH in mice, suggesting a potential of S. chartarum as a cause of human health problem such as PAH.     

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction,pulmonary arterial remodelling and pulmonary hypertension

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation–perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right‐heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin‐1 and thromboxane A₂ may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase‐1 in acute hypoxia, but to cyclooxygenase‐2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5‐hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase‐5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.     

Left ventricular assist devices as bridge to heart transplantation in congestive heart failure with pulmonary hypertension

Severe pulmonary hypertension (PH) has been considered a significant contraindication to cardiac transplantation. Ongoing clinical experience, however, has shown that temporary support using left ventricular assist devices (LVADs) in these patients can result in significant reductions in PH. A comprehensive review of the available literature regarding the use of LVADs in heart failure patients with PH was conducted. The existing literature to date supports the use of LVADs in heart failure patients with PH and demonstrates that significant reductions in PH in these patients can be achieved. This subsequently allows for safe and effective cardiac transplantation in patients who were previously excluded from this modality. For heart failure patients with severe PH, the use of LVADs can provide significant benefits by significantly reducing PH and allowing subsequent staged transplantation.     

雷米普利通过调节细胞外调节激酶1/2的活性抑制肺动脉高压大鼠肺血管重构

目的探讨雷米普利抑制野百合碱（MCT）诱导的肺动脉高压（PAH）大鼠肺血管重构是否与调节细胞外调节激酶1/2（ERK1/2）活性有关。方法雄性Sprague-Dawley大鼠30只,质量280～320g,随机分为：正常对照组、PAH组、PAH＋雷米普利组。PAH组和PAH＋雷米普利组一次性颈部注射MCT60mg/kg后,PAH＋雷米普利组用雷米普利灌胃,PAH组用生理盐水灌胃。对照组颈部注射生理盐水后,用生理盐水灌胃。4周后,测定大鼠的右室收缩压（RVSP）和右心室肥厚指数（RVHI）,并用图像分析软件,测定肺小动脉管壁厚度（WT）占动脉外径（ED）的百分比（WT,%）及管壁面积（WA）占血管总面积的百分比（WA,%）。放射免疫法检测肺组织中血管紧张素Ⅱ（AngⅡ）浓度。Western免疫印迹分析肺组织中ERK1/2磷酸化水平。结果PAH组的RVSP、RVHI、WT（%）、WA（%）、肺组织AngⅡ浓度和ERK1/2磷酸化水平均显著高于正常对照组;雷米普利组RVSP、RVHI、WT（%）、WA（%）、肺组织AngⅡ浓度和ERK1/2磷酸化水平均明显低于PAH组。结论雷米普利抑制MCT诱导的肺血管重构的机制可能与降低肺组织ERK1/2磷酸化水平有关。     

Large animal models for diastolic dysfunction and diastolic heart failure—a review of the literature

Diastolic heart failure (DHF) or heart failure with preserved systolic left ventricular function is estimated to account for approximately 40% of heart failure cases. Medical treatment of patients with DHF is limited and mainly empirical. Device-based therapy has an increasing role in the treatment of systolic heart failure and may have a future role in the treatment of DHF patients. Diastolic dysfunction and DHF are associated with anatomical and physiological characteristics, which need to be modeled in large animals in order to allow evaluation of device-based therapies, prior to clinical studies. In this article, we will review the large animal models for diastolic dysfunction and heart failure.     

Left heart function in chronic obstructive lung disease

Summary In patients with varying degrees of chronic obstructive pulmonary disease (COPD), simultaneous measurements of central hemodynamics and left ventricular radionuclide ventriculograms at rest and during exercise were made. In 21 of these patients, satisfactory echocardiograms could be performed. In seven of the patients, arterial blood pressure at rest was increased. Decreased compliance of the left ventricle was thought to be present in patients with COPD and additional arterial hypertension. The left ventricular ejection fraction (LVEF) at rest was in the high normal range in all patients. During exercise, no further increase was observed. This pattern of LVEF response seems to be typical in patients with COPD. Because the highest values were observed in the more severe COPD and right ventricular hypertrophy, it is unlikely that an impairment of left ventricular function is caused by COPD. In five of 27 patients, an abnormal decrease of LVEF and regional hypokinesis occurred during exercise, thus suggesting additional coronary heart disease. The fact that at least 30% of the patients with COPD suffered from arterial hypertension and 20% of the patients exhibited unexpected ischemia detected by regional hypokinesis in RNV during exercise, but not in the ECG, may be of practical relevance. Coronary angiography was not indicated because most of these patients were over 65 and the factor limiting the working capacity was ventilatory impairment and not angina pectoris, in all patients. For this reason, a diagnostic uncertainty remains with regard to additional coronary heart disease in the older patients with advanced chronic obstructive pulmonary disease.Lung Function Parameters VC (1) inspiratory vital capacity - FEV1 (1) forced exspiratory volume in 1 sec - Raw (cmH20/l/s) airways resistance - RV/TLC (%) residual volume/total lung capacity - paO₂ (mm Hg) O₂ partial pressure Hemodynamic Parameters CI (1/min/sqm) cardiac index - SVI (ml/sqm) stroke volume index - PAP (mm Hg) pulmonary artery mean pressure - PwP (mm Hg) pulmonary capillary wedge pressure - RRs (mm Hg) systolic arterial pressure - RRd (mm Hg) diastolic arterial pressure (at the time of catheterization) - RR(WHO) (mm Hg) mean values measured at different days (at least 3 values). Parameters Derived from Combined Radionuclide Ventriculography and Central Hemodynamics LVEF (%) left ventricular ejection fraction - LVESVI (ml/sqm) left ventricular endsystolic volume index - P/V (mm Hg/ml/sqm) peak systolic pressure/endsystolic volume index - PFR (1/sec) peak filling rate: endsystolic volume/sec Echocardiographic Parameters RV d wth (mm) right ventricular enddiastolic wall thickness - LV d wth (mm) left ventricular enddiastolic wall thickness In honor to Prof. W.E. Adam's 60th birthday