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CLASSIFICATION, PATHOPHYSIOLOGY, AND DIAGNOSIS OF PULMONARY HYPERTENSION
Mathias M. Borst Department of Cardiology, Angiology and Pulmonology, University of Heidelberg Medical
Center
Key words: pulmonary hypertension, classification, pathophysiology, diagnosis.
Summary. In the article the newest classification of pulmonary hypertension is presented, which was confirmed
in 1998 in Evian. This classification is developed on the background of the etiology of the disease. The modern
developing conception of pulmonary hypertension and its diagnostic methods (clinical, echocardiographical and
intracardial) are presented. The medicine for testing of pulmonary hypertension is introduced, which allows
choosing the treatment in future. Seminars in Cardiology. 2001;7(l):53-56
Plautines hipertenzijos klasifikacija, patofiziologija ir diagnostika.
Raktazodziai: plautine hipertenzija, klasifikacija, patofiziologija, diagnostika.
Reziume. Straipsnyje pateikiama naujausia plautines hipertenzijos (PH) klasifikacija, patvirtinta 1998 metais
Eviane. Si klasifikacija sukurta atsižvelgiant j PH sukelusias priežastis. Pateikta moderni plautines hipertenzijos
vystymosi koncepcija, patofiziologijos ypatumai, PH diagnostikos metodai - klinikiniai, echokardiografiniai,
intrakardines hemodinamikos tyrimai. Pateiktas plautines hipertenzijos testavimas vaistais, apsprendziantis
tolesnę atskirij pacientu gydymo taktiką. Kardiologijos seminarai. 2001;7(l):53-56
Classification of pulmonary hypertension (PH)
In the past, PH has been classified in different ways, according to its main etiology or the primary site of vascular obstruction. Thus, PH was divided in primary and secondary forms or the in pre- and postcapillary form.
Although this way of classification was easier for the clinician, a new classification was established at a
WHO-sponsored international symposium in Evian, France, in 1998 (Table 1)
This classification takes into account that there are many similarities between primary and some secondary
forms of pulmonary arterial hypertension, and that treatment may be totally different in various groups. For instance, the treatment of pulmonary arterial hypertension differs fundamentally from that of pulmonary venous
hypertension, and the treatment of PH due to lung pa-renchymal or airway disease, to chronic hypoxic states, or
to thromboembolism is directed primarily at the underlying disease. Therefore, the Evian classification has
become a somewhat complicated but very useful tool for cardiologists and pulmonologists.
To assess the clinical severity of PH, the Classification of the New York Heart Association is useful.
By a hemodynamic definition, PH is present when the mean pulmonary artery pressure (PAPJ is > 20 mmHg at
rest. Latent PH is present when PAPm is normal at rest but rises to values > 24 mmHg during exercise. In mild
PH, PAPm is < 36 mmHg, in moderate PH < 50 mmHg, and in severe PH 3 50 mmHg. However, these
definitions are used inconsistently.
Pathophysiology of PH
The pathogenesis of PH is a rapidly evolving field of research. A modern concept of the pulmonary arterial type
of PH is summarized in figure 1 (modified from Gaine, JAMA 2000). Certain risk factors and associated conditions (Table 2) lead to vascular injury with changes in en-dothelial and vascular smooth muscle function.
This occurs not in all persons, but only in a small subgroup of susceptible patients. In familial primary PH
(PPH), aside from a mutation in the bone morphoge-netic protein receptor-2 (BMPR2) gene a second gene locus
(PPH2) on the same chromosome 2 has been identified in our group in affected families.
In the earlier state of initimal proliferation and vascular smooth muscle, pulmonary vasoconstriction is at least in
part reversible by vasodilators such as nitric oxide (NO), prostacyclin, and calcium channel blockers. Later, the
disease progresses and plexiform lesions (figure 2), in situ thrombosis, and advential proliferation occur. At this
stage, the effects of vasodilators often are limited.
Chronic PH implies an increase in right ventricular (RV) afterload, leading to RV hypertrophy (remodeling),
dilatation, and failure. As opposed to the left ventricle (LV), the RV may decompensate at modest increases in
preload and afterload. In addition, an increase in RV pressures and volume may disturb LV function. Due to
diastolic bulging of the interventricular septum into the LV lumen (figure 3), filling of the LV is hampered. RV
decompensation due to PH is part of a complex vicious cycle (figure 4). One of its most important mechanisms
is RV ischemia.
Table 1. Diagnostic Classification of PH (World
Symposium on Primary Pulmonary Hypertension, Evian,
France, 1998)
1. Pulmonary Arterial Hypertension
1.1 Primary Pulmonary Hypertension (PPH) (a) Sporadic
(b) Familial 1.2 1.2 Related to: (a) Collagen Vascular
Disease (b) Congenital Systemic to Pulmonary Shunts (c)
Portal Hypertension (d) HIV Infection (e) Drugs / Toxins
(1) Anorexigens (2) Other (f) Persistent Pulmonary
Hypertension of the Newborn (g) Other
2. Pulmonary Venous Hypertension
2.1 Left-Sided Atrial or Ventricular Heart Disease 2.2
Left-Sided Valvular Heart Disease
2.3 Extrinsic Compression of Central Pulmonary Veins
(a) Fibrosing Mediastinitis (b) Adenopathy / Tumors 2.4
Pulmonary Veno-Occlusive Disease 2.5 Other
3. Pulmonary Hypertension Associated with Disorders of
the Respiratory System and/or Hypoxemia
3.1 Chronic Obstructive Pulmonary Disease 3.2
Interstitial Lung Disease 3.3 Sleep Disordered Breathing
3.4 Alveolar Hypoventilation Disorders 3.5 Chronic
Exposure to High Altitude 3.6 Neonatal Lung Disease 3.7
Alveolar-Capillary Dysplasia 3.8 Other
4. Pulmonary Hypertension due to Chronic Thrombotic
and/or Embolic Disease
4.1 Thromboembolic Obstruction of Proximal Pulmonary
Arteries 4.2 Obstruction of Distal Pulmonary Arteries (a)
Pulmonary Embolism (Thrombus, Tumor, Ova and/or
parasites, Foreign Material) (b) In-situ Thrombosis (c)
Sickle Cell Disease
5. Pulmonary Hypertension due to Disorders Directly
Affecting the Pulmonary Vasculature
5.1 Inflammatory (a) Schistosomiasis (b) Sarcoidosis (c)
Other 5.2 Pulmonary Capillary Hemangiomatosis
Therefore, therapy of decompensated cor pulmonale must aim at an increase in systemic blood pressure.
Diagnosis of PH
The diagnosis of PH is very difficult clinical to make on clinical grounds, since its presenting symptoms are
quite unspecific: dyspnea, fatigue, chest tightness, syncope. The physical findings are subtle. Similarly, radiological, ECG, and blood gas findings have a rather low sensitivity and specificity in PH. Most importantly, the
attending physician must not forget to include PH in the differential diagnosis of patients with unexplained
car-diorespiratory symptoms, and specific investigations have
Table 2. Risk Factors and Associated Conditions for
PH
A. Drugs and Toxins
1. Definite • Aminorex • Fenfluramine •
Dexfenfluramine • Toxic Rapeseed Oil 2. Very Likely
• Amphetamines • L-tryptophan 3. Possible •
Meta-amphetamines • Cocaine • Chemotherapeutic
Agents 4. Unlikely • Antidepressants • Oral
Contraceptives • Estrogen Therapy • Cigarette
Smoking
B. Demographic and Medical Conditions
1. Definite • Female Gender 2. Possible • Pregnancy •
Systemic Hypertension 3. Unlikely • Obesity
C. Diseases
1. Definite • HIV Infection 2. Very likely • Portal
Hypertension / Liver Disease • Collagen Vascular
Diseases • Congenital Systemic-Pulmonary Cardiac
Shunts
Table 3. Routine Screening Echocardiogram for PH
Condition
Recommended
Scleroderma spectrum of
diseases
Asymptomatic and
symptomatic patients
Lupus erythematosus, RA Symptomatic patients
and other connective tissue
diseases
Family history of PPH
Symptomatic and 1st degree
relatives
Liver disease/portal
hypertension
Before liver transplantation
HIV infection
Symptomatic patients
History of i.v. drug use
Symptomatic patients
History of anorectic drug
use
Symptomatic patients
to be ordered. Once PH has been diagnosed, secondary forms (table 1) and associated conditions (table 2)
should excluded by thorough screening for treatable underlying diseases.
A modified diagnostic strategy according to the Evian consensus is outlined below.
Screening for Pulmonary Hypertension
Screening tests should be noninvasive and low risk, if possible, and have a relatively high sensitivity and specificity for detecting pulmonary hypertension. A transtho-racic echocardiogram is currently the preferred screening test for the presence of pulmonary hypertension in groups of patients at increased risk. After a through clinical examination, it should be performed according to the following recommendations (table 3) which are based
on the prevalence of PH in the respective groups.
The role of stress Doppler echocardiography in the detection of latent PH and PPH is currently being evaluated
in Heidelberg.
Evaluation of mild PH
In asymptomatic individuals with incidental discovery of mild PH, Doppler echocardiogram should be repeated
in six months along with a detailed history and physical examination. In symptomatic individuals right heart
cath-eterization is warranted for confirmation of the hemody-namic findings. If the right heart catheterization
does not reveal pulmonary hypertension at rest, it is recommended that pulmonary hemodynamics be measured
during exercise. Patients in whom mild pulmonary hypertension exists at rest, or develops with exercise, should
be managed like other patients with pulmonary hypertension. Individuals who are asymptomatic but at high risk
of developing pulmonary hypertension should have a Doppler echocar-diographic exam repeated in six months.
If the presence of mild pulmonary hypertension is confirmed, they should undergo the same evaluation, as do
patients with symptomatic pulmonary hypertension.
Medical testing to characterize PH
Echocardiography with Doppler measurement of tri-cuspid regurgitant velocity and determination of right
ventricular function may be useful in the follow-up of patients with pulmonary hypertension to monitor progression of the disease and/or the response to therapy.
Other useful techniques to determine right heart and pulmonary vascular morphology are magnetic resonance
imaging (MRI) and computed tomography (CT) of the chest. It is recommended that a high-resolution chest CT
scan also be performed to evaluate the lung parenchyma and to detect the presence of pulmonary veno-occlusive
disease. The value of serial chest CT scans in following the course of patients is not established.
A six-minute walk test or a cardiopulmonary exercise test is recommended in patients at the time of diagnosis
and follow-up. Exercise tests best characterize the functional impairment of patients with PPH and their response to therapy.
Right heart catheterization is recommended for all patients who are undergoing an evaluation of pulmonary hypertension. Measurements during catheterization should include RA, RV, PA, and PC pressures, SaO,,
SvO2, and CO.
It is recommended that all patients undergo acute testing with a short-acting vasodilator (intravenous or inhaled
prostacyclin, inhaled nitric oxide, or intravenous adenosine) to determine vasodilator responsive-ness at the time
of their initial right heart catheterization. Patients who appear responsive to acute vasodilator testing may have a
favorable response to treatment with oral calcium channel blockers. A minimum acceptable response would be a
reduction in PAPm of 10 mm/ Hg associated with either no change or an increase in CO. Other widely used
criteria are a > 20% drop in either PVR or in PAPm (partial responder), or a > 20% drop in both parameters
(responder). Patients who do not manifest responsiveness to acute vasodilator challenge are unlikely to have
clinical benefit from oral calcium channel blocker therapy.
Lung biopsy entails a risk and there is little evidence that it provides additional clinically useful information
over careful noninvasive and hemodynamic assessment in most patients. Lung biopsy cannot be recommended
as a part of the routine evaluation of patients with suspected PPH. It should be considered when there appears to
be a specific indication, such as a diagnosis of active vasculitis.
Serological markers
Recently, there has been some interest in blood tests that may help to assess the prognosis and the response to
therapy in patients with PH. These include plasma levels of uric acid, a marker of poor prognosis, and of
brain natriuretic peptide (BNP and pro-BNP), a marker of right ventricular strain or failure. Finally, testing for
the genetic susceptibility to PH may in the future help to assess the individual risk of patients in high-risk groups
such as familial PPH.