Chronic Thromboembolism Research Articles

704-3 Relation of Neurohormonal Activation to Functional Class in Patients with Primary or Precapillary Secondary Pulmonary Hypertension

Intense neurohormonal activation has been demonstrated in patients with primary or precapillary secondary pulmonary hypertension (PH) but the relation of neurohormons to functional impairment is not well known. Plasma levels of atrial natriuretic peptide (ANP), aldosterone (ALD), renin activity (PRA), epinephrine (PE), norepinephrine (PNE) and endothelin (ET) were assessed from the antecubital vein in 12 patients with primary PH, 7 patients with precapillary secondary PH (2 connective tissue disease, 2 chronic thromboembolic, 3 closed atrial septal defect) and 10 control subjects. Twelve patients were in NYHA functional class II (PH-II) and 7 in class III/IV (PH-III/IV). Mean PA pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR) and right atrial pressure were assessed by heart catheterization: PAP CI PVR RAP (mmHg) (l/minlm 2 ) (RU) (mmHg) PH-II 53 ± 13 2.4 ± 0.4 12 ± 3 3 ± 2 PH-III/IV 61 ± 9 2.0 ± 05 18 ± 6 11 ±5 P 0.17 0.07 0.009 0.0001 Neurohormons plasma levels in control subjects (C), PH-II and PH-III/IV patients were as follows: ANP ALD PRA PE PNE ET (pg/ml) (pg/ml) (ng/ml/h) (pg/ml) (pg/ml) (pg/ml) C 58 ± 18 110 ± 65 0.7 ± 0.4 33 ± 19 220 ± 101 1.7 ± 0.3 PH-II 167 ± 96 * 144 ± 102 15 ± 2.0 298 ± 263 * 420 ± 294 * 3.6 ± 1.4 * PH-III/IV 276 ± 153 *† 209 ± 270 3.2 ± 3.9 * 462 ± 524 * 820 ± 693 *† 8.4 ± 3.9 *° * p < 0.05 vs C° p < 0.001 vs PH-II † P < 0.09 vs PH-II Neurohormonal activation in primary or precapillary secondary PH is detectable also in patients without overt clinical and hemodynamic signs of right heart failure (PH-II). Neurohormonal activation seems to be progressive and is more severe in functional class III/IV patients. ET shows the best statistically significant relation with functional impairment.

704-2 Comparative Relation of Neurohormonal Activation to Hemodynamics in Primary or Precapillary Secondary Pulmonary Hypertension

Primary (PPH) or precapillary secondary (SPH) pulmonary hypertension show similar hemodynamic abnormalities and an intense neurohormonal activation has been detected in both syndromes. Comparative analysis of the neurohormonal profile and its relation to hemodynamics of patients with PPH and SPH are not available. Plasma levels of atrial natriuretic peptide (ANP). aldosterone (ALD). renin activity (PRA). epinephrine (PE). norepinephrine (PNE) and endothelin (ET) were assessed from the antecubital vein in 12 patients with PPH and 7 patients with SPH (2 connective tissue disease, 2 chronic thromboembolic, 3 closed atrial septal defect). Hemodynamics were measured by heart catheterization. Between PPH and SPH patients no differences were assessed on cardiac index (CI) (2.2 ± 0.2 vs 2.3 ± 03 l/min/m 2 , ns), mean pulmonary artery pressure (PAP) (55 ± 12 vs 58 ± 12 mmHg, ns), pulmonary vascular resistance (PVR) (14 ± 6 vs 14 ± 4 RU, ns) right atrial pressure (RAP) (4 ± 4 vs 8 ± 7 mmHg, p = 0.13) and mixed venous blood oxygen saturation (vSat) (62 ± 7 vs 65 ± 9%, ns). Neurohormonal parameters in patients with PPH and patients with SPH were as follows ANP (pg/ml) ALD (pg/mi) PRA (ng/ml/h) PE (pg/ml) PNE (pg/ml) ET (pg/ml) PPH 203 ± 139 178 ± 132 1.8 ± 2.1 351 ± 420 426 ± 343 4.5 ± 3.1 SPH 210 ± 110 220 ± 262 2.5 ± 4.0 268 ± 333 637 ± 720 6.9 ± 3.7 p ns ns ns ns ns ns In patients with PPH, ET was correlated to RAP (r = 0.68, p < 0.02), to CI (r = 0.66, P < 0.02) and to PVR (r = 0.65, p < 0.02). In patients with SPH, ET was correlated to RAP (r = 0.96, P < 0.01), PNE was correlated to vSat (r = -0.80, P < 0.03) and ALD was correlated to RAP (r = 0.87, p < 0.02) No differences were observed on plasma levels of neurohormons between patients with PPH and SPH. In patients with PPH hemodynamic abnormalities were correlated only to ET plasma levels while in patients with SPH hemodynamics were correlated to ET, to PNE and to ALD plasma levels. Neuroendocrine activation shows a different pattern of association with hemodynamic abnormalities in patients with PPH compared to patients with SPH

Spiral CT of bronchial arteries in chronic thromboembolism.

Computed tomography study of bronchial artery anatomy and evaluation of dilatation and tortuousity as indicators for pulmonary hypertension and surgical risk in patients with chronic thromboembolism were performed. We retrospectively reviewed contrast-enhanced, thin section spiral CT scans of 39 patients undergoing pulmonary thromboendarterectomy. Findings were compared with mean pulmonary artery (PA) pressure in all, postoperative mortality in 33, and postoperative CT in 5 patients. Twenty patients without pulmonary hypertension served as controls. In the pulmonary hypertension group, 50 bronchial arteries were observed in 30 of 39 patients. Their prevalence was significantly higher than in the control group (p < 0.0001). Their proximal diameter measured > or = 1.5 mm in 20 patients (51%); a tortuous course was found in 14 (36%). The correlation between total bronchial artery diameter and mean PA pressure was poor (r = 0.2). Patients with dilated bronchial arteries had a significantly lower risk for postoperative death than patients without (p < 0.05); positive predictive value was 100% and confidence interval 0.79-1.0. Despite normal postoperative PA pressures, bronchial arteries were still visible on follow-up studies. The CT depiction of bronchial arteries, dilatation, and tortuousity provides indicators for chronic thromboembolic pulmonary hypertension. Its degree cannot be estimated. Dilated bronchial arteries are a significant predictor for survival of pulmonary thromboendarterectomy.

The management of pulmonary hypertension secondary to chronic thromboembolic disease

I N THE UNITED States it is estimated that 600,000 people experience pulmonary embolus each year. 1-3 Approximately 50,000 of these patients die, but in the vast majority, the pulmonary emboli resolve rapidly and substantially, resulting in no residual symptoms or hemodynamic sequelae. However, in a small minority of patients with extensive embolization, the emboli fail to resolve and undergo fibrovascular organization, causing chronic obstruction to pulmonary arterial blood flow. This can subsequently result in a condition known as chronic pulmonary thromboembolic hypertension (CPTH). The diagnosis, pathophysiology, and treatment of acute pulmonary embolism (PE) are discussed elsewhere in this symposium. The concept of chronic pulmonary thromboembolism (CPT) has been known to exist for many years, having been first suspected by Hart (1916) and Moller (1920). 4 An association of CPT with progressive respiratory insufficiency was made in 1928 by Ljungdahl. 5 However, for many years, the condition was regarded as an autopsy curiosity, and antemortem diagnosis was unusual. The small number of patients who were diagnosed with this condition received only medical management for the secondary pulmonary hypertension, including oxygen, vasodilator, fibrinolytic, and anticoagulant therapy. Long-term prognosis was very poor. This changed as advances in cardiac surgical techniques led to the ability to perform thromboendarterectomy which offered a surgical cure. With a potential cure available, there was an increased impetus toward making an early diagnosis. This was facilitated by advances in diagnostic techniques and an increased awareness of the characteristic clinical presentation. The diagnosis of CPT involving the major pulmonary vessels is now made more often during a patient's lifetime, and it has become apparent that CPTH is more common than was once previously thought. Although the exact incidence of pulmonary hypertension secondary to unresolved emboli is not known, Jamieson et al 6 have estimated that this sequel may develop in 0.1% to 0.2% of survivors of an acute embolic event, or in 540 to 1080 patients per year. The disorder is often amenable to surgical therapy, with successful thromboendarterectomy offering the best chance of long-term survival. 6-8 To date, there have been over 400 cases of pulmonary thromboendarterectomy reported, with the vast majority coming from the University of California at San Diego (UCSD) Medical Center (San Diego, California).

Pulmonary arteries and lung parenchyma in chronic pulmonary embolism: preoperative and postoperative CT findings.

To evaluate the role of computed tomography (CT) in diagnosis of chronic thromboembolic pulmonary hypertension, assessment of surgical operability, and follow-up after surgery. Seventy-five patients with chronic thromboembolism were examined with CT; 63 underwent thromboendarterectomy, and postoperative CT scans were acquired in 23. CT scans were analyzed for vascular and parenchymal changes, and findings were compared with those on lung scintigrams and with surgical results. CT findings allowed confirmation of the diagnosis of chronic thromboembolism and ensured technical operability (sensitivity, 77%; specificity, 100%; overall accuracy, 80%) by means of direct visualization of thrombi in central pulmonary arteries in 53 patients. CT enables demonstration of pulmonary thromboembolism with criteria pertaining to pulmonary arteries and to lung parenchyma and enables assessment of technical operatibility and confirmation of surgical success.

Effect of chronic thromboembolism on the pulmonary artery pressure-flow relationship in dogs.

To understand the hemodynamic alterations associated with chronic thromboembolic pulmonary hypertension, the large pulmonary arteries of mongrel dogs were chronically obstructed with lysis-resistant thrombi. Pulmonary hemodynamics were experimentally measured and described by multipoint pulmonary arterial pressure (PAP) vs. flow plots. In nine anesthetized chronically embolized dogs, but not in six control dogs, the PAP-flow line shifted significantly upward in a parallel fashion by 4.2 +/- 0.7 mmHg. The postembolic pulmonary circulation was further characterized by predictions from a morphometric-based elastic tube and sheet flow model of the canine pulmonary circulation. After model validation with the preembolic PAP-flow data, the derived postembolic PAP matched the in vivo results to within 1 mmHg. A detailed analysis of the model-derived PAP drop revealed that the PAP-flow line shift can be accounted for by a novel fixed resistor in the largest obstructed pulmonary artery.

Pulmonary Vascular Lesions Occurring in Patients With Chronic Major Vessel Thromboembolic Pulmonary Hypertension

The status of small pulmonary arteries may influence diagnosis, surgical selection and postoperative outcome of patients with chronic major vessel thromboembolic pulmonary hypertension (CTEPH). Therefore, in patients with the established diagnosis of CTEPH, lung tissue was obtained by biopsy (15 patients) or at autopsy (16 patients) to assess the histopathologic composition of small pulmonary arteries. Pathologic examination disclosed the full range of pulmonary hypertensive lesions in the small arteries, including plexogenic lesions. The type and extent of hypertensive lesions did not relate to preoperative hemodynamic values, to patient age, or to symptom duration. The findings indicate that primary pulmonary hypertension cannot be differentiated from potentially correctable CTEPH on the basis of histopathologic findings in small pulmonary arteries. Furthermore, none of the histologic findings preclude a positive hemodynamic and clinical result from pulmonary thromboendarterectomy. However, development of these hypertensive changes may explain the deterioration which these patients experience preoperatively over time.

Effectiveness and safety of bolus administration of alteplase in massive pulmonary embolism

Animal studies have demonstrated that thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) is accelerated and that bleeding is reduced when rt-PA is infused over a short period. Previous clinical studies in patients with venous thromboembolism have shown that rt-PA is an effective thrombolytic agent when administered by continuous infusion over 2 to 24 hours. Clinical experience of bonis rt-PA administration in patients with massive acute pulmonary embolism (PE) is, however, limited. A prospective open study was conducted in which 54 patients with massive PE (Miller index ≥20 of 34) received a 10-minute infusion of rt-PA at a dose of 1 mg/kg. Perfusion lung scanning was used to assess the change in pulmonary perfusion after drug administration. At 48 hours and 10 days, the mean absolute improvements in the perfusion defect were 11 and 31%, respectively. In addition, a significant clinical improvement occurred within 2 hours in 11 of the 15 shocked patients. Five patients died (9%) as a result of persistent shock (3 patients), neurologic damage (1 patient) or intracranial bleeding (1 patient). Major bleeding occurred in 8 patients (15%). Long-term follow-up information was available for 44 of the 49 discharged patients: 2 had died and 12 (27%) complained of persistent exertional dyspnea, 7 of whom had an associated heart or lung disease or chronic thromboembolism at admission. These results suggest that a bolus regimen of rt-PA could provide a convenient approach to thrombolytic therapy in patients with massive PE. However, further trials are necessary to assess the efficacy and safety of this regimen against currently recommended dosages.

Delayed thromboembolectomy for subacute limb ischemia

Arterial embolization frequently requires immediate operative intervention. Occasionally, embolic events produce subacute limb ischemia that may not be recognized as thromboembolic in origin. In October 1988, a prospective policy to attempt thromboembolectomy rather than infrainguinal bypass in all patients with delayed presentation of lower limb thromboembolism was initiated at our institution. Seven limbs in five patients were identified by history, physical examination, noninvasive study, and/or angiography as ischemic due to thromboembolism, which occurred from 3 to 10 weeks prior to presentation. Six of seven limbs were studied angiographically, and all seven were treated by femoral and/or popliteal thromboembolectomy with limb salvage. Six of seven limbs were restored to normal arterial hemodynamics as assessed by intra- and postoperative noninvasive study. One limb in a patient continued to have minimal residual occlusive disease that was recognized preoperatively. In all cases, chronic and fresh thromboemboli were found at surgery and confirmed by pathology. Chronic thromboembolism seems to be an underrecognized event. Limb salvage can be achieved readily even if extensive delay in diagnosis is present. Using preoperative angiography and intraoperative noninvasive techniques to measure the success of revascularization, as well as avoiding, when possible, complex infrainguinal reconstruction in these high-risk patients allows for an aggressive approach to limb salvage with gratifying results.

Transcatheter occlusion of pulmonary arterial circulation and collateral supply: failures, incidents, and complications.

Failures and complications were analyzed retrospectively in 45 patients treated with embolotherapy or occlusion of pulmonary arterial circulation. Pulmonary arterial branches were occluded with steel coils in 19 patients with pulmonary arteriovenous malformations, 17 with hemoptysis of pulmonary artery (PA) origin, and one with massive parenchymal shunt. Bronchial arterial supply to the lung was embolized with small particles in eight cases of hemoptysis and systemic to pulmonary arterial antegrade shunt secondary to chronic thromboembolism. Asymptomatic incidents included catheterization failures, vascular damage, partial occlusion, partial recanalization of the thrombus, ectopic deposition of a coil, and delayed bacterial contamination of the thrombus. A few cases of transient clinical and radiologic signs of pulmonary infarction were observed after complete occlusion of the PA and bronchial artery embolization. This complication was never observed after complete occlusion of main right or left PA, inferior right or left PA, or segmental branches. The management and prevention of these complications, the role of bronchial arterial collateral pathways, and the importance of the site of PA occlusion in the development of pulmonary infarction are discussed.

Chronic pulmonary thromboembolism in dogs treated with tranexamic acid.

Many questions remain regarding the pathogenesis, natural history, diagnosis, and treatment of chronic thromboembolic pulmonary hypertension in patients. To answer such questions, we developed an animal model of this disorder. The brisk thrombolytic response of canines to acute embolism has, previously, prevented the establishment of such a model. The fibrinolytic inhibitor tranexamic acid was given orally to canines before, and for intervals after, pulmonary emboli were released from venous thrombi formed in vivo in femoral veins or the inferior vena cava. Preliminary studies disclosed that embolic residuals from femoral vein thrombi were not sufficient to cause significant, persistent pulmonary hypertension. With repetitive, larger thrombi embolized from the inferior vena cava, however, persistent pulmonary hypertension was achieved in most animals. Resolution of emboli in the canine can be inhibited by tranexamic acid. As in humans, a spectrum of embolic residuals is encountered, and the perfusion lung scan consistently underestimates the extent of embolic residuals. Studies of this animal model continue.

Gas Exchange in Chronic Thromboembolism after Pulmonary Thromboendarterectomy

Thromboendarterectomy is the treatment of choice for chronic large vessel thromboembolic pulmonary hypertension. To identify the mechanisms responsible for the improvement in gas exchange following thromboendarterectomy, we studied nine patients with chronic thromboembolic pulmonary hypertension before and eight to 18 months after surgery using the multiple inert gas elimination technique. Preoperatively, all subjects had pulmonary hypertension and were hypoxemic or had an elevated P(A-a)O2. The VA/Q distribution was widened with an elevated VD/VT and a low cardiac index. After thromboendarterectomy, significant improvement had occurred. The VA/Q distribution had narrowed to near normal, and the cardiac index increased. It was concluded that thromboendarterectomy improved gas exchange both by improving VA/Q relationships and by increasing cardiac output.

Long‐Term Follow‐Up of Patients with Sick Sinus Syndrome: A Comparison of Clinical Aspects Among Unpaced, Ventricular Inhibited Paced, and Physiologically Paced Groups

To analyze the prognosis of the sick sinus syndrome (SSS), we compared the clinical aspects among unpaced, ventricular paced, and physiologically paced patients who were followed over a long period. Unpaced intrinsic SSS was not always progressive and patients did not necessarily require permanent pacing. The incidence of concomitant AV conduction disturbance was 65.6% before pharmacologic autonomic block, (PAB), but this was significantly reduced to 31.7% after PAB. Follow-up study of the physiologically paced groups revealed no development of either new or more than second degree AVB. The VVI group had significantly more complications (68%) than the physiologically paced groups, mainly chronic atrial fibrillation (36%) and thromboembolism (20%). In addition, cardiothoracic ratio (CTR) in the VVI group was significantly greater compared with that in the physiologic groups. Nine deaths occurred during the follow-up period in the pacing groups, including six with VVI and three with physiologic pacing. In the VVI pacing group, heart failure and thromboembolism were most commonly the causes of death, while in the physiologic pacing groups, the causes of death were noncardiac. Although the survival rate in the ventricular paced group was not significantly different from that in the physiologic pacing groups, cardiac deaths were fewer in the latter group. Considering our clinical data, the decision to use ventricular pacing needs to be carefully weighed in patients with sick sinus syndrome, and physiologic pacing is more highly recommended.

Operative predictors of delirium after pulmonary thromboendarterectomy: A model for postcardiotomy delirium?

Pulmonary thromboendarterectomy is an innovative surgical technique for treating pulmonary hypertension caused by chronic thromboembolism. The procedure uses cardiopulmonary bypass but necessitates dramatically longer bypass times than coronary artery bypass grafting or valve operations. We prospectively evaluated 22 patients undergoing pulmonary thromboendarterectomy to determine the incidence of delirium and its relationship to certain preoperative and postoperative medical variables as well as to duration of cardiopulmonary bypass, deep hypothermia, and circulatory arrest. Delirium occurred in 77% of patients with a peak incidence around 72 hours postoperatively. No preoperative or postoperative medical variable distinguished delirious from nondelirious patients. Total bypass time was not associated with delirium, but deep hypothermia time and total circulatory arrest time were both strongly associated. Overall prediction of delirium was 81% when total circulatory arrest time was considered. Further analysis suggested that a total circulatory arrest time greater than 55 minutes was both sensitive to (82%) and specific for (80%) delirium. Implications for the mechanism of postcardiotomy delirium and future research directions are discussed.

Junior hospital doctors and Europe

<b>Background:</b> Patients with pulmonary hypertension develop intimal plaques in large pulmonary arteries. <b>Objective:</b> To test the hypothesis that the composition of such plaques differs depending on whether the aetiology of the disease is thromboembolic or hypertensive. <b>Design:</b> Chronic thromboembolic and plexogenic pulmonary hypertension (primary and secondary (Eisenmenger syndrome)) were investigated. These are spontaneous human models and were used to examine the independent role of thrombus and hypertension in plaque composition. <b>Setting:</b> A national tertiary referral centre for lung transplantation and pulmonary thromboendoarterectomy. <b>Patients:</b> Thirty nine patients with chronic thromboembolic pulmonary hypertension who had undergone thromboendoarterectomy (n = 32) or lung transplantation (n = 7), 28 with plexogenic diseases (nine primary and 19 Eisenmenger), and three with Eisenmenger syndrome complicated by thromboembolic events. <b>Interventions:</b> The lung and thromboendoarterectomy samples were sectioned, stained with Movat pentachrome, and immunostained with antibodies for fibrin, platelets, inflammatory cells, smooth muscle cells, and erythrocyte membrane glycophorin A. <b>Main outcome measure:</b> Composition of the plaques affecting large pulmonary arteries. <b>Results:</b> Two types of intimal lesion were distinguished in chronic thromboembolic pulmonary hypertension: fibrous plaques with angioneogenesis; and core-rich atherosclerotic plaques with pultaceous cores largely consisting of glycophorin immunoreactive material, with cholesterol clefts (61.5%), CD68 positive macrophages (84.6%), T lymphocytes (87%), and calcification (46.1%). The samples from the patients with Eisenmenger syndrome and thromboembolic complications had similar characteristics, whereas those from patients with uncomplicated primary pulmonary hypertension had core-free fibrous plaques, spotted with macrophages and T lymphocytes. <b>Conclusions:</b> Chronic thromboembolic pulmonary hypertension is associated with atherosclerotic plaques with glycophorin-rich pultaceous cores, and plexogenic pulmonary hypertension with fibrous plaques. Thromboembolic material thus plays a critical role in the formation of pultaceous cores, of which erythrocyte membrane derived glycophorin is a major component.

Chronic pulmonary arterial embolization or thrombosis

The clinical picture and the management of 3 patients with chronic pulmonary thromboembolism are presented to illustrate several aspects of this syndrome. Our experience with these patients and the available data from the literature suggest that patients with chronic thromboembolic occlusion of a main right or left pulmonary artery who show no significant improvement of the pulmonary blood flow 2 to 3 months after embolization should be considered candidates for pulmonary thromboembolectomy before secondary changes of the involved thorax and lung occur. In patients in whom such chronic changes have already occurred, pneumonectomy may be necessary because of repeated hemoptysis and pulmonary infections, or bronchiectasis.

Effects of decreased aortic compliance on performance of the left ventricle.

Effects of decreased aortic compliance on performance of the left ventricle.

CHRONIC UNILATERAL PULMONARY-ARTERY THROMBOSIS: SUCCESSFUL THROMBENDARECTOMY WITH THIRTY-MONTH FOLLOW-UP OBSERVATION.

ACUTE, massive pulmonary embolism — always an event of major clinical concern and interest — has received increased attention in recent years as improved technics for accomplishing emergency embolectomy have been developed.1 2 3 In contrast, chronic, massive, pulmonary arterial thromboembolism has attracted less diagnostic and therapeutic enthusiasm. This disparity is undoubtedly related to the less dramatic clinical picture of chronic thromboembolism, the ease with which it masquerades as or is masked by diverse cardiopulmonary disorders and the concept that it is not amenable to surgical correction.4 5 6 7 In the past, chronic, massive thromboembolic pulmonary-artery occlusion has been recognized chiefly at the . . .