Development Of Severe Pulmonary Hypertension Research Articles

Pulmonary alveolar microlithiasis: A rare cause of severe pulmonary hypertension

Pulmonary alveolar microlithiasis (PAM) is a rare disease, first described byHarbitz in 1918 [1]. Although its etiology and pathogenesis are not well described,more than half of the cases is considered to be familial. This condition is characterized by deposition of calcium and/or phosphate microliths within the alveolar air spaces secondary to disturbances in calcium and/or phosphate homeostasis. It is relatively more common in some countries as Turkey, Italy and USA [2,3]. Its clinical significance is related with the development of pulmonary hypertension and respiratory failure as a long-term consequence. Recently, Synetos et al. [4] have reported an interesting paper related with the development of severe pulmonary hypertension in a 55-year-old womanwith PAM, presented to the emergency department with dyspnea. They have documented the presence of PAM via chest X-ray and confirmed it by computerized tomography. Transthoracic echocardiographic examination has revealed the presence of severe pulmonary hypertension, and otherwise normal echocardiographic findings. They have ascribed the pulmonary hypertension to the chronic hypoxia which causes vascular remodeling since this disease demonstrates a slow and progressive impairment of lung architecture resulting in hypoxemia and restrictive pattern. Previously, we observed two similar cases in our clinic. After reading the article reported by Synetos et al. [4], we feel that the presentation of these two cases may provide some additional information to this clinically significant disease. In the first case, a 37-year-old man with a history of exertional dyspnea for about 10 years admitted to our clinic. His family history revealed that his brother died at 40 years of age due to

Endothelial Cell Activity in Chronic Obstructive Pulmonary Disease Without Severe Pulmonary Hypertension

Pulmonary hypertension is common in patients with chronic obstructive pulmonary disease (COPD), but the precise mechanism of vascular impairment in these patients is unknown. We, therefore, decided to investigate whether endothelial cell dysfunction is present in patients with COPD with a wide range of chronic airflow obstruction before the development of severe pulmonary hypertension. Selected plasma markers of endothelial cell activity were studied: nitrate+nitrite (NO-(2)/NO-(3)), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), soluble selectins (endothelium sES, leukocyte sLS, platelet sPS), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1). Twenty-five patients with COPD (forced expiratory volume in one second/vital capacity [FEV(1)/VC] < 88% predicted) and 29 healthy control subjects were recruited to the study. Among patients nine had a pulmonary artery systolic pressure (PASP) between 15 and 30 mmHg, 13 between 32 and 38 mmHg, 2 had a PASP of 41 and 42 mmHg, respectively. One patient had severe pulmonary hypertension with a PASP of 70 mmHg. The average FEV(1) of patients with COPD was 46 +/- 4% predicted. As compared to control subjects, patients with COPD showed a significant increase in plasma levels of TM and TFPI, indicating that their endothelial cells are still able to produce potent coagulation inhibitors. Levels of NO-(2)/NO-(3) were similar in the two groups of subjects examined, further suggesting preserved endothelial function in patients with COPD. In regard to adhesion molecules, patients with COPD showed a reduction in sLS, sPS, and sPECAM-1, and an increase in sICAM-1. This study shows that endothelial cell activity is largely preserved in patients with COPD without severe pulmonary hypertension, suggesting that these patients, despite quite severe airway obstruction, retain reasonably normal endothelial function until they develop severe pulmonary hypertension.

Long-term Clinical Course of a Patient with Anti PL-12 Antibody Accompanied by Interstitial Pneumonia and Severe Pulmonary Hypertension

We report a case of a patient with anti PL-12 antibody accompanied by interstitial pneumonia and severe pulmonary hypertension. At first presentation, hyperkeratotic skin lesions were found, although the diagnosis of CVD was not conclusive. Lung histology showed diffuse fibrosing interstitial pneumonia predominantly in the subpleural regions. During the seven-year follow-up period, severe pulmonary hypertension developed, although the progression of lung fibrosis was relatively limited. Anti-PL12 antibody was detected, and therefore the patient was diagnosed as having antisynthetase syndrome. Lung histology and pulmonary arteriogram suggested that vascular involvement of the disease contributed to the development of severe pulmonary hypertension.

Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats.

Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase-mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.

La coqueluche maligne du petit nourrisson

Pertussis remains in France the first cause of bacterial, infectious death in infant aged 10 days to 2 months. It is especially in this age group that malignant pertussis occurs. Case report. – A 40-day-old infant was admitted in the intensive care unit with symptoms of bronchiolitis along with a 200 bpm permanent tachycardia. He presented a marked leukocytosis with lymphocytosis. On the second day, convulsions and coma occurred, followed rapidly by respiratory failure, with a subsequent deterioration due to the development of severe pulmonary hypertension. Circulatory failure caused the infant’s death on the beginning of the 5th day. Pertussis was confirmed by PCR on nasopharyngeal swab. Intra-familial contamination was most likely. Comments. – Malignant pertussis is characterized by the very young age of patients, permanent tachycardia sine materia, dyspnea with early respiratory failure, frequent neurological symptoms, severe hyperleukocytosis and hyperlymphocytosis, and deep hyponatremia with oliguria and edema. Mortality remains superior to 75% despite the various treatments and life support measures that have been attempted. Adult pertussis, which represents one third of the cases of prolonged cough in this age group, is the main source of contamination of non-immunized young infants. This mode of transmission stresses the importance of the generalization of pertussis vaccine booster in early adolescence, which is recommended in France since 1998. Its extension towards the adult age is under study.

Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension.

Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.

Systemic lobar shunting induces advanced pulmonary vasculopathy

Objectives: We characterized the morphology and vasomotor responses of a localized, high-flow model of pulmonary hypertension. Methods: An end-to-side anastomosis was created between the left lower lobe pulmonary artery and the aorta in 23 piglets. Control animals had a thoracotomy alone or did not have an operation. Eight weeks later, hemodynamic measurements were made. Then shunted and/or nonshunted lobes were removed for determination of vascular resistance and compliance by occlusion techniques under conditions of normoxia, hypoxia (FIO2 = 0.03), and inspired nitric oxide administration. Quantitative histologic studies of vessel morphology were performed. Results: Eighty-three percent of animals having a shunt survived to final study. Aortic pressure, main pulmonary artery and wedge pressures, cardiac output, blood gases, and weight gain were not different between control pigs and those receiving a shunt. Six of 9 shunted lobes demonstrated systemic levels of pulmonary hypertension in vivo. Arterial resistance was higher (24.3 ± 12.0 vs 1.3 ± 0.2 mm Hg · mL–1 · s–1, P =.04) and arterial compliance was lower (0.05 ± 0.01 vs 0.16 ± 0.03 mL/mm Hg, P =.02) in shunted compared with nonshunted lobes. Hypoxic vasoconstriction was blunted in shunted lobes compared with nonshunted lobes (31% ± 13% vs 452% ± 107% change in arterial resistance, during hypoxia, P <.001). Vasodilation to inspired nitric oxide was evident only in shunted lobes (34% ± 6% vs 1.8% ± 8.2% change in arterial resistance during administration of inspired nitric oxide, P =.008). Neointimal and medial proliferation was found in shunted lobes with approximately a 10-fold increase in wall/luminal area ratio. Conclusions: An aorta–lobar pulmonary artery shunt produces striking vasculopathy. The development of severe pulmonary hypertension within a short time frame, low mortality, and localized nature of the vasculopathy make this model highly attractive for investigation of mechanisms that underlie pulmonary hypertension. (J Thorac Cardiovasc Surg 2000; 120:88-98)

Unusual Complications After Embolization of a Pulmonary Arteriovenous Malformation

A pulmonary arteriovenous malformation was embolized in a patient with hereditary hemorrhagic telangiectasia. Several unusual complications, including early deflation of a detachable balloon, migration of a coil, and development of severe pulmonary hypertension, occurred. Pulmonary hypertension was attributed to a coexistent left-to-right shunt caused by a large hepatic arteriovenous malformation.

Development of Pulmonary Hypertension After Placement of a Ventriculoatrial Shunt

The ventriculoatrial shunt (VAS) was developed to control hydrocephalic syndromes effectively. Several complications, however, have been described after the procedure. One of the most serious consequences is the development of severe pulmonary hypertension attributed to multiple and recurrent pulmonary embolization caused by the catheter of the VAS; however, the frequency is exceedingly low. Herein we describe the experience with three patients in whom severe pulmonary hypertension developed after a VAS procedure. In two patients, refractory heart failure developed, an outcome that caused death within a brief period. The third patient underwent atrial thrombectomy and then pulmonary thromboendarterectomy; recovery was complete. Scientific evidence shows that initial embolization predisposes pulmonary vessels to develop further in situ thrombosis; thus, the vascular lung disease progresses despite removal of the embolic source. A review of the literature revealed that in patients with a VAS, pulmonary embolism and pulmonary hypertension were clinically diagnosed in only 0.4% and 0.3% of the cases, respectively, whereas postmortem diagnoses of pulmonary embolism and pulmonary hypertension were established in 59.7% and 6.3%, respectively. These discrepancies point out the difficulty of establishing the diagnosis of these serious pulmonary vascular complications while the patient is alive.

Functional and structural adaptation of the yak pulmonary circulation to residence at high altitude

The high-altitude (HA) native yak (Bos grunniens) has successfully adapted to chronic hypoxia (CH) despite being in the same genus as domestic cows, which are known for their great hypoxic pulmonary vasoconstrictor responses (HPVRs), muscular pulmonary arteries, and development of severe pulmonary hypertension on exposure to CH. To determine possible mechanisms by which the pulmonary circulation may adapt to CH, yak pulmonary vascular reactivity to both vasoconstrictor and vasodilator stimuli and yak pulmonary artery structure were assessed. Hypoxia caused a small but significant HPVR, and norepinephrine infusion caused a greater rise in pulmonary arterial pressure (Ppa) than did hypoxia. Acetylcholine, an endothelium-dependent vasodilator, had no effect on Ppa but lowered pulmonary resistance (Rp) by causing an increase in cardiac output. Sodium nitroprusside, an endothelium-independent vasodilator, decreased both Ppa and Rp significantly. Yak small pulmonary arteries had a 4.1 +/- 0.1% medial thickness, with vessels < or = 100 microns devoid of smooth muscle. Yak pulmonary artery endothelial cells were much longer, wider, and rounder in appearance than those of domestic cows. Thus the yak has successfully adapted to HA conditions by maintaining both a blunted HPVR and thin-walled pulmonary vessels. Differences in both endothelial cell morphology and response to acetylcholine between the yak and those reported in the domestic cow suggest the adaptation to HA may include changes not only in the amount of pulmonary vascular smooth muscle but in endothelial cell function and structure as well.

睡眠時無呼吸症候群における循環障害 特に肺高血圧症に関して

Recently, it was recognized that cardiac arrythmia or pulmonary hypertension (PH) was occurred during apnea in patients with sleep apnea syndrome (SAS), and those cardiopulmonary disorders might influence the prognosis of SAS. But the frequency and the mechanisms of PH have not been well known. Therefore, we carried out a polysomnographic sleep study, including continuous recordings of pulmonary artery pressure, systemic artery pressure and cardiac output in 11 patients with obstructive SAS.Only 2 of 11 patients (19%) showed pulmonary hypertension during daytime (PPA≥20Torr). Blood gas analysis of these patients showed hypoxemia and hypercapnemia: PaO2 48.1Torr, PaCO2 48.6Torr and PaO2 57.9Torr, PaCO2 50.9Torr, respectively. It was suggested that only the SAS patient with hypoxemia and hypercapnemia during wakefullness was a candidate for pulmonary hypertension during daytime. Precise analysis of hemodynamic recordings during apneic phase from a case of primary alveolar hypoventilation syndrome and a case of obstructive sleep apnea syndrome showed significant contribution of hypoxic pulmonary vasoconsriction to the development of severe pulmonary hypertension during apnea in these patients. And the effect of intrathoracic pressure oscillations with distinct intrathoracic suction during obstructive apnea on the pulmonary hemodynamic changes was discussed.

Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m.

Some human newborns have a syndrome characterized by irreversible pulmonary hypertension and severe hypoxemia and by medial hypertrophy and adventitial thickening of pulmonary arteries. We considered that newborn calves made severely hypoxic might reproduce features of the human disease. When 2-day-old calves were placed at 4,300 m simulated altitude, pulmonary arterial pressure was increased and could be reversed by 100% O2. However, after 2 wk at 4,300 m, pulmonary arterial pressures were suprasystemic and there was right-to-left shunting probably through the foramen ovale and a patent but restrictive ductus arteriosus. Suprasystemic pulmonary pressure and hypoxemia persisted with 100% O2 breathing. Morphometrical examination of the lung arteries showed a markedly thickened adventitia with cellular proliferation and collagen and elastin deposition. There was increased medial thickness and distal muscularization of the pulmonary arteries associated with decreased luminal diameter. The rapid development of severe pulmonary hypertension and poor responsiveness to O2 was associated with increased arterial wall thickness, particularly involving the adventitia. Thus the pulmonary arterial circulation in these calves, which were placed at high altitude for 2 wk, exhibited features resembling persistent pulmonary hypertension in newborn infants.

Increase in Bronchial Resistance during Infusion of Thrombin into the Venous Circulation of Guinea Pigs

Bronchial resistance was measured by the lung overflow technique in guinea pigs. Intravenous infusion of thrombin produced a significant increase of bronchial resistance, induced by platelet constituents released from the thrombi and deposited in the arteries and capillaries of the lung. This was evidenced by increase of bronchial resistance and mortality having been aggravated by e-aminocaproic acid (inhibition of fibrinolysis), by infusion of gelatin (sludge phenomenon) as well as by catecholamines (stress effect) and significantly inhibited by massive doses of heparin and by experimental thrombocytopenia. Emphasis is laid on the significance of pulmonary microembolism in the development of severe pulmonary hypertension and edema, the cause of which is difficult to diagnose clinically, yet demonstrable at autopsy. The recommended method is held to be suitable for the objective study of the process in animal experiment.

Severe Pulmonary Hypertension after Blalock-Taussig Anastomosis in a Patient with Tetralogy of Fallot

Severe pulmonary hypertension and pulmonary vascular disease developed after unilateral Blalock-Taussig anastomosis (BTA) for tetralogy of Fallot in the case reported. Seven similar cases from the literature are reviewed. In contrast to experience after Potts' anastomosis, development of severe pulmonary hypertension and pulmonary vascular disease after BTA is very rare. Clinical signs include increasing cyanosis, loss of the continuous murmur, and a loud pulmonary-valve closure sound. The chest roentgenogram typically shows dilatation of the central pulmonary arteries. Cardiac catheterization with determination of pulmonary/systemic flow and resistance ratios is essential in evaluating operability. In all reported cases, the anastomosis was made at ages at which complete surgical repair would be offered now. The anastomosis in young children (less than five years old) has not been associated with development of pulmonary vascular disease.