Definitions and epidemiology
Pulmonary hypertension is defined as resting mean pulmonary artery pressure of ≥ 25 mm Hg.
Pulmonary hypertension is not in itself a diagnosis, but solely a hemodynamic state characterized by resting mean pulmonary artery pressure (PAPm) of ≥ 25 mm Hg. The term pulmonary arterial hypertension describes a subgroup that is hemodynamically distinguished by precapillary pulmonary hypertension with elevated pulmonary vascular resistance (PVR), i.e., PAPm ≥ 25 mm Hg with normal pulmonary arterial wedge pressure (PAWP) ≤ 15 mm Hg and PVR >240 dyn × s × cm-5 (1, 2).
For a diagnosis of pulmonary arterial hypertension, not only must these criteria be fulfilled, but other forms of precapillary pulmonary hypertension must be excluded. This applies particularly to lung disease and chronic thromboembolic pulmonary hypertension, but also to left heart disease with normalised PAWP. Figure 1 shows a simplified form of the currently prevailing classification of pulmonary hypertension.
Pulmonary hypertension is by no means uncommon; on the contrary, it probably affects around 1% of the global population. In those over 65 years of age, the prevalence of pulmonary hypertension is thought to be around 10% (3). However, the various forms of pulmonary hypertension differ considerably in incidence and prevalence. In Germany, the incidence of pulmonary arterial hypertension in 2014 was 3.9 per 1 million adults; the prevalence was 25.9 per 1 million adults (4). In the same year the incidence of chronic thromboembolic pulmonary hypertension was 4 per 1 million adults (3).
The second largest group of patients comprises those with lung disease, particularly chronic obstructive and fibrotic disease. Overall, the prevalence of pulmonary hypertension associated with lung disease is similar to that associated with left heart disease
Pulmonary arterial hypertension was originally thought to be a disease that mostly affected young women; however, the mean age of patients diagnosed with pulmonary arterial hypertension in Germany has risen steadily in recent years and is currently 65 years (4, 5). The reasons for this trend are complex, particularly since it cannot be assumed that the actual incidence of pulmonary arterial hypertension is increasing. Improvements in the quality of diagnosis are certainly behind the fact that many patients who not long ago would have been classified and treated as having cardiac insufficiency are now recognized to be suffering from pulmonary arterial hypertension. At the same time, many older patients in whom pulmonary arterial hypertension is diagnosed have cardiac or pulmonary comorbidities, a fact which often hampers precise classification. As a prominent example, up to 80% of patients with HFpEF (heart failure with preserved ejection fraction) develop a form of pulmonary hypertension (6) that is occasionally difficult to distinguish from “true” pulmonary arterial hypertension. This is the case when PAWP during treatment is in the normal range. In the absence of better terminology, pulmonary arterial hypertension in patients with significant cardiovascular risk factors is described as “atypical” to distinguish it from the “typical” pulmonary arterial hypertension in patients without significant cardiovascular risk factors or comorbidities (7). This differentiation may be of considerable relevance for treatment.
Despite the differing therapeutic implications, every form of pulmonary hypertension is clinically significant, because it is associated with increased symptoms and in nearly all cases with a higher risk of death (3). This is also true for the pulmonary hypertension in left heart disease or lung disease, although the consequences for treatment are not yet clear. The life expectancy of patients with pulmonary arterial hypertension has increased over the past three decades. The 3-year survival rate of this group is now 70 to 80% (5), compared with ca. 40% in the 1980s. The survival rates of patients with chronic thromboembolic pulmonary hypertension have also greatly improved. Before the introduction of effective treatment options the mortality associated with this disease was similar to that of pulmonary arterial hypertension, but properly treated patients now have a 3-year survival rate of 90% (8).
Symptoms and diagnosis of pulmonary hypertension
Early detection and precise classification of the disease are the essential goals of diagnosis in pulmonary hypertension. Together with physical examination, the basic diagnostic tests in every case of uncertain or progressive exercise dyspnea should include ECG and determination of brain natriuretic peptide (BNP) or the N-terminal fragment of its precursor (NT-proBNP). If both of these show no abnormality, pulmonary hypertension is highly unlikely to be present (9). Further diagnostic investigations are required only in the case of strong clinical suspicion of pulmonary hypertension or if the results of the above-mentioned tests are unclear. Pathologic ECG or BNP findings unequivocally indicate further cardiological investigation.
The crucial noninvasive procedure is generally echocardiography, which often arouses the first suspicion of pulmonary hypertension or right heart overload. Echocardiographic assessment of right ventricular pressure is frequently unreliable, but in combination with signs of right heart overload, echocardiography usually yields clear signs of pulmonary hypertension and thus indicates what kind of investigations should follow
Cardinal symptoms
The cardinal symptoms of pulmonary hypertension are increasing exercise dyspnea, dyspnea on bending down, fatigue, exercise-induced syncope, and edema.
The diagnosis of pulmonary hypertension can be confirmed only by right heart catheterization. However, this invasive procedure is not indicated in all patients thought to have pulmonary hypertension. While the indication is indisputable in the case of suspected pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, an invasive diagnostic procedure is usually not indicated in patients with chronic left heart disease or lung disease who show signs of pulmonary hypertension, because in most cases there would be no consequences for their treatment. The exceptions to this rule include patients planned for heart or lung transplantation and those with severe right heart overload or signs of severe pulmonary hypertension. This applies particularly in cases where the underlying disease is relatively mild and there is a discrepancy with the severity of the symptoms or that of the right heart overload. In the event of doubt the patient should be referred to a pulmonary hypertension center, particularly since right heart catheterization should in any case be carried out at a specialized institution. A list of pulmonary hypertension centers in Germany can be found on the website of the German self-help group pulmonale hypertonie e. v. (www.phev.de/professionals.html).
Echocardiography
Echocardiography can reveal signs of pulmonary hypertension or right heart overload.
In patients with idiopathic, hereditary, or drug-related pulmonary arterial hypertension, right heart catheterization is accompanied by vasoreactivity testing to identify so-called responders who might benefit from treatment with high-dose calcium antagonists (1, 2).
Confirmation of diagnosis
Right heart catheterization is necessary for confirmation of pulmonary hypertension.
An important follow-on investigation in patients with suspected or confirmed pulmonary hypertension is perfusion scintigraphy, to ensure that chronic thromboembolic pulmonary hypertension is not overlooked. Scintigraphy is thought to be more sensitive than angio-CT for this indication (1, 2). This may change with the universal introduction of dual-energy CT scanners, which as well as delivering conventional images also depict regional lung perfusion—without additional irradiation or contrast medium. However, this technique still requires further evaluation. Patients with signs of chronic thromboembolic pulmonary hypertension should be referred for further investigation to specialized centers, the only institutions equipped to decide on the best treatment in individual cases.
An algorithm for the Initial diagnostic work-up in the case of suspected
Pulmonary hypertension.
Treatment of pulmonary arterial hypertension
Specific treatment usually requires the combination of various medications and should be initiated at an expert center.
Drug treatment
Ten medications from five different substance classes are currently licensed for the treatment of pulmonary arterial hypertension in Germany.
Ten drugs from five different substance classes are currently licensed for the treatment of pulmonary arterial hypertension in Germany (etable 1). These drugs are used singly or in combination. The treatment strategy should be determined at specialized centers. Pulmonary arterial hypertension remains an incurable illness. The goal of treatment is containment of the disease, i.e., stabilization of the patient at a satisfactory clinical level (WHO functional class I or II) without signs of right heart failure and ideally without disease progression. In one randomized study using initial combination therapy (12), this goal was achieved in 40% of the patients. The choice of medication depends partly on the severity of the pulmonary arterial hypertension. The current guidelines (1, 2) recommend classification into low-, intermediate-, and high-risk disease, based on the expected 1-year mortality (etable 2). Patients with newly diagnosed “typical” pulmonary arterial hypertension and low or intermediate risk receive initial or early combination treatment comprising an endothelin receptor antagonist (ERA) with a phosphodiesterase-5 (PDE5) inhibitor or a soluble guanylate cyclase (sGC) stimulator (12– 14). The recommended initial treatment for high-risk patients is a triple combination of an ERA, a PDE5 inhibitor or an sGC stimulator, and an intravenously administered prostacyclin analog.
The patient’s reaction to treatment Is usually verified after 4 to 12 weeks and then at intervals of 3 to 6 months. How the treatment continues depends on the individual response. If the patient has not achieved the primary treatment goal, i.e., attainment of the low-risk category (etable 2), after the initial treatment, the next step is dual or triple combination treatment. A potential further option, switching from a PDE5 inhibitor to riociguat, is currently being evaluated (RESPITE; clinicaltrials.gov identifier NCT02007629).
Treatment goals
Pulmonary arterial hypertension is an incurable illness. The goal of treatment is containment of the disease, i.e., stabilization of the patient at a satisfactory clinical level without signs of right heart failure and ideally without disease progression.
Treatment recommendation
The recommended initial treatment for high-risk patients is a triple combination of an ERA, a PDE5 inhibitor or an sGC stimulator, and an intravenously administered prostacyclin analog.
If the treatment response still remains inadequate, evaluation for lung transplantation should be initiated without delay, because such patients may decompensate rapidly and without warning. Although nowadays the majority of patients with pulmonary arterial hypertension do not require transplantation, this measure is indispensable for those who are not helped by medication. Combined heart and lung transplantation is necessary only in exceptional cases, because right heart function is almost always restored to normal after lung transplantation (15). The outcome of lung transplantation has steadily improved in recent years, to the point where experienced centers now report 1-year survival rates of >90% (16).
The management of patients with “atypical” pulmonary arterial hypertension (table) is less standardized. The majority of these patients are first treated with a single agent, usually a PDE5 inhibitor (7). The further procedure depends on the response and on the individual circumstances; owing to the lack of data, no general recommendations can be given for these patients. On grounds of age and comorbidities most patients with “atypical” pulmonary arterial hypertension are usually not candidates for lung transplantation. Figure 3 shows the currently valid treatment algorithm for patients with pulmonary arterial hypertension.
Treatment of pulmonary hypertension in left heart disease and lung disease
Atypical pulmonary arterial hypertension
The management of patients with “atypical” pulmonary arterial hypertension is less standardized. The majority of these patients are first treated with a single agent, usually a PDE5 inhibitor.
The basic principles of the treatment of pulmonary hypertension in left heart disease and in lung disease are practically identical. None of the drugs licensed for the treatment of pulmonary arterial hypertension (etable 1) have any proven effect in patients with pulmonary hypertension on the basis of left heart disease or lung disease, so their use cannot be recommended in these indications. The randomized controlled multicenter studies conducted to test the action of drugs for pulmonary arterial hypertension in these groups of patients have all been negative, i.e., there was no sign of efficacy or the drug was actually harmful (17– 21). The potential risk entailed in using drugs for pulmonary arterial hypertension in patients with left heart disease or lung disease was emphasized by the recent discontinuation of a phase-II study of riociguat in patients with pulmonary hypertension based on fibrotic lung disease owing to signs of an elevated risk of mortality in the riociguat group (RISE-IIP, clinicaltrial.gov NCT02138825). The occasional patients with simultaneous left heart or lung disease and severe pulmonary (arterial) hypertension in whom the underlying disease does not explain the extent of pulmonary hypertension or right heart overload constitute an exception to the recommendation not to use pulmonary arterial hypertension drugs. The background to this recommendation is the observation that pulmonary arterial hypertension is increasingly also being diagnosed in the elderly, a category at high risk of other cardiopulmonary diseases. For example, the prevalence of chronic obstructive pulmonary disease in the over-70 age group is ca. 20% (22). Therefore, the same rate of chronic obstructive pulmonary disease can be expected in persons older than 70 years with “true” pulmonary arterial hypertension. The same is true for other common cardiopulmonary diseases. Differentiation between pulmonary hypertension due to left heart disease or lung disease and “true” pulmonary arterial hypertension coexisting with left heart or lung disease may be difficult and is a task for the experienced specialist. The therapeutic consequences are far-reaching, because only in the former case will specific treatment of pulmonary arterial hypertension be initiated.
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Chronic thromboembolic pulmonary hypertension
The treatment of chronic thromboembolic pulmonary hypertension is distinct from that of the other forms of pulmonary hypertension (figure 4). The preferred treatment is surgical pulmonary endarterectomy (1, 2), currently performed on a regular basis at three centers in Germany (Bad Nauheim, Hanover, and Homburg). This operation was developed in San Diego, California in the 1970s and the results have improved with the passage of time. The perioperative mortality at experienced centers is now 2 to 4% (8, 23). In nearly all cases, pulmonary endarterectomy yields substantial hemodynamic and clinical improvement (8, 23). In around 50% of cases the pulmonary blood pressure is restored to normal; the majority of the remaining patients end up with slight residual pulmonary hypertension that does not require treatment (8). In around 20% of patients treated with pulmonary endarterectomy, however, the residual pulmonary hypertension is clinically significant and has to be treated
The decision regarding operability”should logically be made at a center for chronic thromboembolic pulmonary hypertension, where the most suitable treatment procedure is determined in regular multidisciplinary discussions of the clinical and hemodynamic findings together with CT and angiography. Advanced age and relevant comorbidities do not per se contraindicate surgical pulmonary endarterectomy.
Treatment of chronic thromboembolic pulmonary hypertension
Surgical pulmonary endarterectomy is the treatment of choice.
Nowadays around 50 to 70% of patients with chronic thromboembolic pulmonary hypertension are operable (24). Riociguat is a licensed drug treatment for nonoperable patients and those with residual pulmonary hypertension after pulmonary endarterectomy (25, 26). In the event that riociguat does not achieve the desired improvement, the currently valid guidelines recommend the use of other medications for pulmonary arterial hypertension, although these have not been licensed for this indication (1, 2). In the past few years, moreover, some centers for chronic thromboembolic pulmonary hypertension have been evaluating pulmonary balloon angioplasty as a new interventional treatment option. This procedure can be used to recanalize obliterated pulmonary vessels at the peripheral, i.e., subsegmental level (27). The results to date are encouraging. For the time being, however, this method should be restricted to experienced centers for chronic thromboembolic pulmonary hypertension.
