Pulmonary Vascular Pathology: A Clinical Update

Current knowledge on risk factors for venous thromboembolism (VTE) can still be largely explained within the framework of Virchow's classical concept on the pathogenesis of thrombosis. Genetic risk manifests as either a decrease in anticoagulant activity (deficiency of antithrombin, protein C or S) or an increase in procoagulant activity (factor V Leiden, prothrombin G20210A). The clinical impact of these factors is determined by their prevalence in the population and by the relative risk associated with each defect. The mutations in factor V and prothrombin are rather mild enhancers of thrombotic risk but are more common. The role of genetic variation in levels of some coagulation proteins as a risk factor for thrombosis needs further clarification.

Antiphospholipid antibodies are directed against phospholipid-binding proteins and enhance their affinity for phospholipid surfaces. They are detected as anticardiolipins or as lupus anticoagulants. Multiple effects may contribute to their thrombogenic character. Cancer cells also interact with several processes to shift the haemostatic balance towards a prothrombotic state; therapeutic intervention further augments the thrombotic risk. The need to search for occult malignancy in VTE is an open clinical debate. Epidemiological studies have clearly established the thrombotic risk in females on hormonal contraception or replacement.

Several studies argue for a lower risk of pulmonary embolism than of deep vein thrombosis in carriers of the factor V Leiden mutation, while the data on prothrombin G20210A are still less convincing. The observation is intriguing but unexplained.

Counselling patients and their family on thrombophilia testing is a delicate issue. Approaches may vary from almost unrestricted screening to tailoring to the individual's specific need.

Treatment of pulmonary embolism (PE) aims to prevent death and recurrent thromboembolism. This is primarily achieved with standard anticoagulation, heparin relayed with oral anticoagulants. In the initial phase of treatment unfractionated heparin could be replaced by low molecular weight heparin in stable patients. The optimal duration of anticoagulant treatment is uncertain since current evidence suggests that prolonged anticoagulation delays rather than suppresses the recurrence risk.

Initial thrombolytic treatment for acute PE is a debated issue. It is fairly well accepted for massive PE but controversial for submassive PE. A definite impact on mortality was never demonstrated and there is an increased bleeding risk. Current clinical practice prefers short-duration dosage schemes of thrombolytic agents. Embolectomy, if carried out, is a last resort intervention in a life-threatening situation.

Venous filters aim at preventing recurrent embolism when anticoagulation fails or is impractical. In general, the insertion of a filter should not modify the anticoagulant management. Filters favour the recurrence of deep vein thrombosis and may have additional drawbacks and therefore their use should remain restrictive.

Pulmonary arterial hypertension (PAH) is a life-threatening disease for which continuous intravenous prostaglandin (PG)I₂ or epoprostenol has been proven effective in significantly improving functional class, exercise capacity, haemodynamics and survival. When the functional class and haemodynamics are significantly improved after 3 months of therapy, which happens in one-third of the patients, the 5‐yr survival is excellent (90%). However, this treatment requires a permanent central venous catheter with the associated risk of serious complications, such as sepsis, thromboembolism or syncope and it is extremely expensive. As a consequence new derivatives have been developed that are more stable and easier to administer. Treprostinil was the first PGI₂ analogue developed for subcutaneous use. It has been shown to improve functionality, exercise capacity, and haemodynamics, but not survival over a 3‐month period. The most common side-effect is pain at the infusion site that can impair uptitration of the medication. Transition from intravenous epoprostenol to subcutaneous treprostinil can be safely achieved over a brief time period. Iloprost is the first PGI₂ analogue developed for intermittent aerosolisation. Again it has been proven effective and safe. However, transition from intravenous epoprostenol to inhaled iloprost seems to be much more difficult. Finally, beraprost is the first PGI₂ developed for enteral administration. It is relatively well tolerated, and has also been shown to improve exercise capacity.

Endothelin-receptor antagonists have also been developed recently. Bosentan is the first one that has demonstrated efficacy in patients with PAH. It is well tolerated and induces a reversible dose-related increase in liver enzymes in a minority of the patients. Combination of PGI₂ and anti-endothelins is currently under investigation.

Atrial septostomy has been shown to improve functionality, exercise capacity, haemodynamics and survival in patients with terminal pulmonary hypertension (PH). The working group recommends that it is performed in patients with persistent poor functionality under maximal medical therapy.

Single-, bilateral- and heart-lung transplantation (LTx) have been performed successfully in patients with primary PH. Right ventricular contractility seems intrinsically preserved as assessed by good recovery of systolic function after LTx, but the early postoperative period is often characterised by haemodynamic instability. There is no strong evidence to specify which is the optimal lung transplant procedure for PH. The choice largely depends on the local situation with organ donors and the experience of the transplant team. Single LTx is the preferred procedure in many US centres, while bilateral LTx is preferred at most European centres.

Pulmonary embolism is one of the most frequently encountered indications for diagnostic imaging. Standard techniques, such as chest radiology, lung scintigraphy and pulmonary angiography have been employed for many years. More recent developments have included helical computed tomography (CT) angiography and magnetic resonance imaging (MRI) techniques. However, the exact roles of these diagnostic modalities are still cause for debate, as these technical innovations have not yet been fully assessed.

The current chapter adresses the evidence for use of pulmonary angiography, lung scintigraphy and MRI. It briefly describes their techniques and their diagnostic accuracy. The topic of helical CT is discussed elsewhere, but the recent developments and the future use of MRI techniques that are currently undergoing clinical trials are discussed in this chapter. Finally, several possible diagnostic algorithms are outlined that may be at the heart of diagnostic work-up in the future.

The diagnostic and prognostic value of echocardiography in pulmonary embolism (PE) is increasingly recognised. Indeed, there are specific Doppler echocardiographic signs of acute PE. Direct visualisation of thrombi in systemic veins, the right heart and proximal pulmonary arteries is possible, which by itself justifies initiation of treatment. Indirect signs of PE and of the severity of it are those of right ventricular (RV) overload. The association with moderate elevation of velocity of the tricuspid insufficiency jet indicates a worse prognosis up to 1 yr; this is even more so if a patent foramen ovale with right-to-left shunting is documented. Conversely, a normal RV echogram consistently indicates a good prognosis in patients with PE treated with anticoagulants. To conclude, current data strongly indicate that echocardiography provides clinically relevant information both in patients with suspected or with confirmed PE.

Diagnosis of pulmonary embolism (PE) has undergone a major paradigm shift in recent years. No single noninvasive test has sufficient diagnostic accuracy to be used alone for diagnosing or ruling out PE. Even pulmonary angiography, a gold standard presently challenged by helical computed tomography (CT) scan, does not possess ideal diagnostic accuracy. Hence, modern diagnostic strategies for PE consist of combinations of non- or minimally invasive tests such as plasma D‐dimer measurement, lower limb venous compression ultrasonography, ventilation/perfusion lung scan and helical CT; pulmonary angiography being used only in rare cases of inconclusive noninvasive work-up. The value of clinical assessment in order to refine the interpretation of diagnostic tests is increasingly recognised and clinical probability of PE can be assessed with fair accuracy, either implicitly or by clinical prediction rules. Management studies in which patients deemed not to have PE are left untreated and followed up to assess their 3‐month thromboembolic risk have become the benchmark for the validation of diagnostic algorithms. Cost-effectiveness analysis allows the evaluation and comparison of the various diagnostic sequences. Finally, preliminary evidence shows that the implementation of evidence-based diagnostic algorithms is feasible and may increase the quality of care.

Pulmonary arterial hypertension (PAH) is a syndrome of dyspnoea, fatigue, chest pain and syncope defined by an increase in pulmonary vascular resistance of unknown cause. The clinical presentation of PAH is explained by the inability of the excessively afterloaded right ventricle to increase output in response to peripheral oxygen demand. This is related to the steepness of the pulmonary artery pressure/flow relationship, and increased right ventricular systolic pressure by the combined effects of increased pulmonary arterial resistance, elastance, and wave reflection. The pathobiological understanding of PAH is making rapid progress. The gene of the purely primary form of PAH has been located on chromosome 2, and shown to present in approximately one-third of patients' mutations of a sequence that encodes for a transforming growth factor receptor, bone morphogenetic protein receptor‐II. How this mutation accounts for the disease remains presently unclear. Biological abnormalities have been identified in all pulmonary arterial wall compartments. The endothelium produces an excess of endothelin (ET), a potent vasoconstrictor and mitogen, while synthesis and release of antagonistic prostaglandin (PG)I₂ and nitric oxide (NO) is decreased. Pulmonary vascular smooth muscle cells present with an increased expression of a serotonin transporter (5‐HTT), allowing for vasoconstrictive and mitogenic effects of circulating serotonin, and also show dysfunctional voltage-dependent potassium channels, which promote vasoreactivity and proliferation. The adventitial matrix-bound metalloproteases appear to be activated in relation to increased serine elastase, leading to increased production of tenascin, a potent mitogen. While none of these abnormalities solely explains PAH, their identification has already led to efficient therapeutic interventions, including the administration of PGI₂ derivatives and anti‐ET compounds. Studies are underway to test the possible benefit of NO, 5‐HTT inhibitors, and matrix metalloproteinase or serine elastase antagonists. Lack of complete understanding of the pathobiology of PAH explains why current therapeutic approaches remain palliative.

There is no sphygmomanometer for the pulmonary circulation. The consequence of this lack of a simple test to make the measurement of pulmonary artery blood pressure means that the diagnosis is often made late at a time where there is already structural remodelling of the pulmonary circulation. This in turn means that the circulation is already resistant to the effects of vasodilators. In the past there have been few treatments for severe pulmonary arterial hypertension (PAH) and therefore no pressure to make the diagnosis earlier. However, with the advent of prostaglandin (PG)I₂ and more recently a number of other drugs such as the PGI₂ analogues, endothelin antagonists and other compounds, it is clear that effective treatments are now available. It is also clear that these treatments are likely to be more effective if given earlier in the course of the disease, before the structural changes have occurred and hence there is greater pressure to make the diagnosis earlier and give the patients a greater chance of survival. An enormous leap forward was the discovery of the gene for familial primary pulmonary hypertension (PPH), which also appears to be present in a proportion of those with so-called sporadic pulmonary hypertension (PH). Furthermore, it is now known that in many other causes of PH, such as human immunodeficiency virus, portopulmonary hypertension, connective tissue disease-associated hypertension and anorectic drug-associated PH, the histology is similar to so-called unexplained PPH. This suggests a common biological path that is in the process of being unravelled by basic scientists. The understanding of this pathobiology will of course lead to the developments of new therapies, which are aimed not so much at the consequences of the biological process but at the fundamental causes of that process. New drugs would be expected to interfere with cellular transduction, cell-signalling systems and genetic transcription factors. Once again, however, it is likely that these compounds will only be effective if given early. The knowledge of the genetic basis of the disease with the possibility of genetic screening and new techniques for noninvasive assessment in the pulmonary circulation, in particular, amplified echocardiography, magnetic resonance imaging and sophisticated cardiopulmonary exercise testing, means that there is a greater possibility for screening the population without needing a right heart catheter. At present it is not clear who should be screened; neither is it clear whether those screened and found to have mild PH would benefit from early therapy. The author believes that the answers to these tricky ethical and medical questions will come in the next few years. Researchers are on the threshold of a golden era of the management of PAH.