Chronic thromboembolic pulmonary hypertension

Acute pulmonary hypertension has a high mortality at the onset. Patients surviving the first phase will usually recanalize the pulmonary arteries through intrinsic thrombolytic mechanisms and medical treatment. However, in some cases there is insufficient resolution of the emboli with subsequent thrombotic and fibrotic reorganization, leading to a worsening of the pulmonary obstruction. In the open pulmonary arteries the disease may lead to hypertrophy of the media and intimal proliferation, thus leading to a further increase in the pulmonary vascular resistance. This again leads to hypertrophy of the right ventricle and ultimately to right-sided heart failure. Untreated, chronic thromboembolic pulmonary hypertension has a five-year mortality approaching 100%, but extensive pulmonary thrombendarterectomy using extracorporeal circulation and deep hypothermia has been shown to lower the pulmonary vascular resistance and thereby improve the prognosis significantly. Operative treatment can now be offered in Denmark, and the purpose of this review is to draw attention to the disease, its symptoms, diagnosis and the surgical treatment.     

Thromboendarterectomy in chronic thromboembolic pulmonary hypertension. Hemodynamics and right-heart function over the long term

OBJECTIVE: To find out whether pulmonary thromboendarterectomy (PTE) can achieve lasting reduction of pulmonary vascular resistance in patients with pulmonary arterial hypertension due to chronic thromboembolism. PATIENTS AND METHODS: 45 patients (25 women, 20 men; mean age 45 +/- 24 [19-67] years) were re-investigated a mean of 21 (13-32) months after successful PTE. Two patients had then been in New York Heart Association (NYHA) stage II, 26 in stage III, and 17 in stage IV. In addition to clinical examination and chest radiogram 36 patients had right heart catheterization, 28 pulmonary angiography and 44 echocardiography. RESULTS: Definite improvement of symptoms had occurred in all. 34 were now in NYHA stage I, nine in stage II, and two in stage III. The pulmonary vascular resistance was significantly lower than before and immediately after PTE (pre-PTE: 1052 +/- 472 dyn.s.cm-5; post-PTE: 293 +/- 175 dyn.s.cm-5; at follow-up: 187 +/- 92 dyn.s.cm-5; P < 0.001 for follow-up vs pre-PTE; P < 0.05 for follow-up vs post-PTE). Correspondingly, cardiac index had significantly increased (3.0 +/- 0.5 vs 2.0 +/- 0.7 l/min.m2; P < 0.001). Radiological and echocardiographic examinations showed a definite decrease in right ventricular dimensions and improvement in right ventricular function. CONCLUSION: In patients with pulmonary arterial hypertension due to chronic pulmonary thromboembolism PTE can achieve a reduction in pulmonary vascular resistance with lasting improvement in right heart function and clinical symptoms.     

Chronic thromboembolic pulmonary hypertension associated with initial pulmonary involvement in Takayasu arteritis

We report a case of a 65-year-old man with intradipolic epidermoid cyst of the frontal bone. The patient presented with headache and swelling of the forehead. Skull x-ray showed massive destruction of the frontal bone. Magnetic resonance imaging (MRI) revealed an epidural mass without any encroachment of the dura mater. The cystic tumor was removed followed by cranipolasty with methylmethacrylate. Four years later, the tumor recurred in the same region. At the second surgery the bony defect was again replaced with methylemthacrylate plate. Four years after the second operation, the tumor reemerged with some subcutaneous fluid retention. At the third surgery, the remaining tumor capsule was removed as much as possible except for that part which adhered to the superior sagittal sinus. The authors discuss the relationship of tumor recurrence with utilization of methylmethacrylate for cranioplasty in this type of tumor.     

Predictors of mortality in pulmonary thromboendarterectomy

BACKGROUND: The operative mortality associated with surgical thromboendarterectomy of the pulmonary arteries has decreased at the University of California in San Diego with the application of new techniques. For universal performance of the procedure, however, those factors that contribute to the high operative mortality must be identified. We analyzed our results in 34 consecutive patients undergoing pulmonary thromboendarterectomy to determine those preoperative factors that contribute to operative mortality. METHODS: Since 1983, 34 patients with severe, surgically correctable chronic thromboembolic pulmonary hypertension who were judged to be operable by pulmonary arteriography underwent pulmonary thromboendarterectomy. No patient was excluded because of right ventricular failure or hemodynamic severity of disease; the mean pulmonary artery pressure (PAP) was 54 mm Hg, the mean pulmonary vascular resistance (PVR) was 1,094 dynes.s.cm-5, and all patients were in New York Heart Association functional class III or IV. RESULTS: Postoperative course was characterized either by swift recovery (mean length of stay, 13 days) or by rapid demise resulting from pulmonary or right ventricular failure, or both (overall operative mortality, 23%). In survivors, the mean PAP, PVR, cardiac output, and New York Heart Association functional class were significantly improved (p < 0.05). Patients who died had a significantly greater mean preoperative PAP than did those who survived (62.1 +/- 1.2 versus 49.5 +/- 2.3 mm Hg; p < 0.01) and significantly higher PVR (1,512 +/- 116 versus 949 +/- 85 dynes.s.cm-5; p < 0.01). In addition, both a PVR of more than 1,100 dynes.s.cm-5 and a mean PAP of more than 50 mm Hg could accurately predict operative mortality: operative mortality was six times greater in patients with a preoperative PVR of greater than 1,100 dynes.s.cm-5 (41% versus 5.85%) and almost five times greater in those with a mean PAP of greater than 50 mm Hg (37% versus 8%). No intraoperative factors, including the use or duration of circulatory arrest, affected outcome. CONCLUSIONS: Patients with severe hemodynamic disease (PVR > 1,100 dynes.s.cm-5 and PAP > 50 mm Hg) have a high likelihood of operative mortality and perhaps should not undergo pulmonary thromboendarterectomy, except at institutions where the operation is performed frequently.     

Chronic thromboembolic pulmonary hypertension: hemodynamic effects of selective pulmonary artery DSA with nonionic contrast media]

This paper examines the relationship in Escherichia coli between the in vivo content of 8-oxoguanine (8-oxoG) in chromosomal DNA and deficiencies of various key antioxidant defences. The structural genes for catalases (katG and katE), cytosolic superoxide dismutases (sodA and sodB) or formamidopyrimidine-DNA glycosylase (fpg) were inactivated to obtain bacterial strains lacking the scavenger enzymes for H2O2 or O2.- or the DNA repair protein for 8-oxoG. Wild-type bacteria showed 5-fold increased sensitivity to both lethality and mutagenesis by H2O2 in K medium (1% casamino acids and 1% glucose), as compared with nutrient broth. This higher sensitivity was associated with increased chromosomal oxidative damage, estimated as the 8-oxodG content, and with a marked decrease in both catalase and SOD activities. Bacteria lacking both cytosolic SODs (sodA sodB mutant) displayed increased 8-oxodG content in chromosomal DNA (2.8-fold that of the wild-type) when grown under standard aerated conditions. Comparatively, no significant difference in 8-oxodG content was observed in cells grown without aeration. Bacteria totally devoid of catalase activity (katG katE mutant) showed wild-type contents of 8-oxodG in chromosomal DNA when grown under aerated conditions. Nevertheless, the protective role of catalase in preventing formation of 8-oxodG in chromosomal DNA became evident under oxidative stress conditions: growth under hyperoxygenation and, particularly, following H2O2 exposure. Catalase deficiency resulted in a dramatic decrease in viability after H2O2 exposure. A deficiency of Fpg protein also sensitized E.coli to H2O2 lethality, though to lesser extent than a deficiency of catalase activity. However, the scavenger enzyme and the DNA repair protein protected equally against 8-oxoG formed in vivo upon H2O2 treatment.     

Improved exposure of the pulmonary arteries for thromboendarterectomy

Pulmonary thromboendarterectomy is a surgical technique for treating pulmonary hypertension caused by unresolved pulmonary embolism. It has been recommended to perform this procedure under deep hypothermic circulatory arrest. Here we describe two technical modifications: (1) improved exposure to the right pulmonary artery by division of the superior caval vein and (2) thromboendarterectomy in normothermic cardiopulmonary bypass, with beating heart or electrically induced ventricular fibrillation. These modifications allow complete endarterectomy of both pulmonary arteries under normothermic conditions, thus avoiding hypothermic circulatory arrest, which results in short cardiopulmonary bypass times and reduces the morbidity and mortality of this procedure.     

Pulmonary regurgitation in large atrial shunts without pulmonary hypertension

Seven patients with pulmonary regurgitation (PR), normal pulmonary artery (PA) pressures and large left-to-right atrial shunts are reported. Six had secundum atrial septal defects (ASD) and one had anomalous pulmonary venous drainage. These comprised 4% of 180 patients with atrial shunts and normal PA pressures. Pulmonary regurgitation was diagnosed clinically by mid-frequency diastolic decrescendo murmurs beginning after the pulmonic component of the second heart sound, and diagnoses were confirmed by catheterization. In two patients who had serial preoperative catheterizations over 8 and 16 years, PR progressed in one and was present only on the second study in the other. All patients underwent shunt correction, at which time the pulmonic anulus and artery appeared dilated, but the pulmonic valves were normal and did not require revision. In all patients the PR murmur disappeared after shunt correction alone, and on chest X-ray both PA and overall heart size decreased. Although it is known that pulmonary regurgitation occurs with atrial septal defects and pulmonary hypertension, the present study demonstrates that it also occurs with high flow atrial shunts, in which setting it has different implications and is reversible with shunt correction alone.     

Right ventricular pathology in chronic pulmonary hypertension

Right ventricular free wall biopsy specimens in 40 patients undergoing surgery for relief of chronic thromboembolic pulmonary hypertension were normal in 5%, disclosed only myocyte hypertrophy in 80%, mild focal fibrosis in 12.5%, and myocarditis in 2.5%. There was no relation between postsurgical functional or hemodynamic outcomes and the presence of focal fibrosis.     

Ketanserin in the treatment of protamine-induced pulmonary hypertension

The reversal of heparin by protamine may cause severe hemodynamic deterioration, characterized by systemic hypotension, pulmonary hypertension, and bronchoconstriction. A case report is presented concerning the administration of ketanserin in the treatment of pulmonary vasoconstriction and right ventricular failure following the infusion of protamine in a patient undergoing coronary artery bypass surgery and mitral valve replacement. The potential role of serotonin in the development of this serious complication is discussed.     

Reversibility of changes in left and right ventricular geometry and hemodynamics in pulmonary hypertension. Echocardiographic characteristics before and after pulmonary thromboendarterectomy

Pulmonary thromboendarterectomy (PTE) leads to an acute decrease of right ventricular (RV) afterload in patients with chronic thromboembolic pulmonary hypertension. We investigated the changes in right and left ventricular (LV) geometry and hemodynamics by means of transthoracic echocardiography. The prospective study was performed in 14 patients (8 female, 6 male; age 55 +/- 20 years) before and 18 +/- 12 days after PTE. Total pulmonary vascular resistance and systolic pulmonary artery pressure were significantly decreased (PVR: preoperative 986 +/- 318, postoperative 323 +/- 280 dyn x s/cm5, p < 0.05; PAP preoperative 71 +/- 40, postoperative 41 +/- 40 mm Hg + right atrial pressure, p < 0.05). End diastolic and end systolic RV area decreased from 33 +/- 12 to 23 +/- 8 cm2, respectively, from 26 +/- 10 to 16 +/- 6 cm2, p < 0.05. There was an increase in systolic RV fractional area change from 20 +/- 12 to 30 +/- 16%, p < 0.05. RV systolic pressure rise remained unchanged (516 +/- 166 vs. 556 +/- 128 mm Hg/sec). LV ejection fraction remained within normal ranges (64 +/- 16 vs. 62 +/- 12%). Echocardiographically determined cardiac index increased from 2.8 +/- 0.74 to 4.1 +/- 1.74 l/min/m2. A decrease in LV excentricity indices (end diastolic: 1.9 +/- 1 vs. 1.1 +/- 0.3, end systolic: 1.7 +/- 0.6 vs. 1.1 +/- 0.4, p < 0.05) proved a normalization of preoperatively altered septum motion. LV diastolic filling returned to normal limits: (E/A ratio: 0.62 +/- 0.34 vs. 1.3 +/- 0.8; p < 0.05); Peak E velocity: 0.51 +/- 0.34 vs. 0.88 +/- 0.28 m/sec, p < 0.05; Peak A velocity: 0.81 +/- 0.36 vs. 0.72 +/- 0.42 m/sec, ns; E deceleration velocity: 299 +/- 328 vs. 582 +/- 294 cm/sec2, p < 0.05; Isovolumic relaxation time: 134 +/- 40 vs. 83 +/- 38 m/sec, p < 0.05). We could show a marked decrease in RV afterload shortly after PTE with a profound recovery of right ventricular systolic function--even in case of severe pulmonary hypertension. A decrease in paradoxic motion of the interventricular septum and normalization of LV diastolic filling pattern resulted in a significant increase of cardiac index.     

Non-invasive estimation of pulmonary arterial hypertension in chronic obstructive pulmonary disease

The feasibility and reliability of the combination of several noninvasive methods using a multivariate method of analysis to predict pulmonary artery hypertension (PAH) is evaluated in 20 patients with chronic obstructive pulmonary disease. These methods comprised arterial blood gases (Pao2, Paco2), pulmonary functional parameters (FEV1), echo-Doppler parameters (tricuspid regurgitation jets, acceleration time on pulmonary valve), computed tomography measurements (transhilar distance, hilar thoracic index, and measurement of the descending branch of the right pulmonary artery to the lower lobe). A multiple stepwise regression analysis (including one Doppler parameter, two parameters of arterial blood gases, and one functional parameter) revealed a coefficient of determination (R2) equal to 0.954 for mean pulmonary artery pressure (MPAP) with a standard error of estimate (S.E.E.) of 5.25 mmHg. A stepwise regression analysis including computed tomography and radiographic parameters revealed an R2 equal to 0.970 for PAP with a S.E.E. of 4.26 mmHg. Logistical regression analysis classified correctly 80% of patients with PAH using noninvasive methods such as the diameter of the main pulmonary artery and the diameter of the left pulmonary arterial branch calculated by computed tomography. Not only the presence of PAH but also the level of MPAP can be estimated by the combination of multiple stepwise and logistical regression analyses.     

Lupus anticoagulant, high levels of anticardiolipin, and anti-beta2-glycoprotein I antibodies are associated with chronic thromboembolic pulmonary hypertension

OBJECTIVE: To evaluate the prevalence of lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), and that of anti-beta2- glycoprotein I (anti-beta2-GPI) and prothrombin antibodies in patients with pulmonary hypertension (PH). METHODS: Fifty-four consecutive patients with PH were studied: 23 with primary, 20 secondary, and 11 chronic thromboembolic PH. LAC was diagnosed by screening and confirmatory coagulation tests, while aCL, anti-beta2-GPI, and prothrombin antibodies were measured by ELISA. RESULTS: Prevalence of aPL was higher in patients with chronic thromboembolic PH compared to the other 2 groups. The prevalence in chronic thromboembolic PH vs primary and secondary PH was: LAC 63.6 vs 13.0 and 10.0%, p < 0.001; aCL-IgG 54.5 vs 17.4 and 15.0%, p < 0.02; anti-beta2-GPI-IgG 36.4 vs 0 and 0%, p < 0.001; and prothrombin antibodies-IgG 36.4 vs 8.7 and 5.0%, p < 0.05. No differences between groups were found for any antibody of IgM isotype. Antibodies detected in patients with primary and secondary PH were of low titer, so considering only moderate or high titers these differences were greater for aCL-IgG (odds ratio, OR 24.6, confidence interval, CI 3.0-282, p = 0.0004) and IgM (OR 35.0, CI 2.9-1692, p = 0.0007) and remained significant for anti-beta2-GPI-IgG (OR = undefined, p = 0.006). Multivariate analysis showed that only LAC and aCL-IgG at moderate or high levels were independent variables associated with chronic thromboembolic PH. CONCLUSION: The presence of LAC, moderate or high levels of aCL-IgG, or anti-beta2-GPI-IgG was strongly associated with that of chronic thromboembolic PH. These data are in agreement with the close relationship observed among these 3 variables and thromboembolism in patients with aPL.     

Idiopathic pulmonary hilar fibrosis: an unusual cause of pulmonary hypertension

A 37-year-old man with progressive exertional dyspnea had pulmonary hypertension associated with pulmonary arterial and venous obstruction. An autopsy revealed that the cause of death was idiopathic pulmonary hilar fibrosis, a variant of mediastinal fibrosis. Pulmonary hilar fibrosis can mimic thromboembolic pulmonary hypertension, pulmonary veno-occlusive disease, and pulmonary venous hypertension.     

Pulmonary artery structural changes in pulmonary hypertension complicating congenital diaphragmatic hernia

Primary pulmonary hypertension is characterized by the presence of smooth muscle cells in nonmuscular compartments or segments of the vessel and the abnormal deposition of collagen in both the small muscular arteries and arterioles and the large elastic arteries. Victorian blue van Gieson staining and Immunostaining with anti-alpha smooth muscle actin (ASMA) were performed on lung tissues obtained during autopsy from 21 patients who had congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) and 10 control patients who died of sudden infant death syndrome (SIDS). The degree of medial thickening and adventitial thickening was measured in pulmonary arteries by image analysis and compared statistically. There was a significant increase in adventitial as well as medial thickness in arteries of all sizes in CDH patients compared with control patients (P < .001). The most striking increase occurred in arteries with an external diameter (ED) of less than 75 microns. Calculation of the areas of the various components in the wall of each vessel showed that for smaller vessels (< 75 microns ED), the area of the lumen was smaller and the area of the media and adventitia was larger in CDH patients compared with control patients (P < < .001). In vessels greater than 75 microns ED, the areas of media in CDH was the same as in controls and the area of adventitia in CDH was significantly larger than controls (P < .001). The present study provides evidence that an increase in adventitial thickness and adventitial area occurs in pulmonary arteries in CDH patients complicated by PPH. The structural changes in the adventitia of the pulmonary arteries may be an important factor in the development of PPH in patients with CDH.     

The efficacy of pulmonary thromboendarterectomy on long-term gas exchange

It has not been delineated in detail how pulmonary thromboendarterectomy (PTE) affects gas exchange through long-term follow-up. In Japan, this surgery has been undertaken in a limited number of institutions, and the results of PTE have not been well publicized. A total of 25 patients were operated on during the period from 1985 to 1996 at our institution, and the overall mortality rate was 16%. Our criteria for PTE were based on the following: 1) thrombi surgically accessible as judged by angiographic study; 2) mean pulmonary arterial pressure > or = 30 mmHg. The efficacies of PTE were analysed on haemodynamics as well as gas exchange at one month postsurgery and during follow-up (6-24 months). Significant haemodynamic improvement was obtained as early as 1 month after surgery. Improvement of gas exchange lagged, but was then observed during follow-up, and the improvement level of pulmonary haemodynamics was sustained. The early postoperative restrictive impairment and ventilation-perfusion abnormality on lung perfusion scan resolved during the follow-up period. It was concluded that the early postoperative efficacy of pulmonary throm-boendarterectomy was mainly achieved due to the reduction of pulmonary hypertension, whereas improvement in gas exchange was obtained over the longer term.     

Milrinone improves pulmonary hemodynamics and right ventricular function in chronic pulmonary hypertension

BACKGROUND: Right ventricular failure after cardiac transplantation is commonly related to preexisting recipient pulmonary hypertension. This study was designed to investigate the effects of intravenous milrinone on pulmonary hemodynamic indices and right ventricular function in a canine model of monocrotaline pyrrole-induced chronic pulmonary hypertension. METHODS: Eight mongrel dogs underwent pulmonary artery catheterization to measure right-sided hemodynamic indices before and 6 weeks after a right atrial injection of monocrotaline pyrrole. Six weeks after injection, all hearts were instrumented with a pulmonary artery flow probe, ultrasonic dimension transducers, and micromanometers. Data were collected at baseline and after milrinone infusion. RESULTS: Six weeks after monocrotaline pyrrole injection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed. Milrinone led to significant increases in right ventricular function as well as significant improvements in pulmonary vascular resistance, pulmonary blood flow, and left ventricular filling. CONCLUSIONS: This investigation demonstrates the well-known hemodynamic and inotropic effects of milrinone which, in the setting of monocrotaline pyrrole-induced pulmonary hypertension, were also associated with significant increases in pulmonary blood flow and left ventricular filling.