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Primary pulmonary hypertension

In medicine, pulmonary hypertension (PH) or pulmonary artery hypertension (PAH) is an increase in blood pressure in the pulmonary artery or lung vasculature. more...

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Depending on the cause, it can be a severe disease with a markedly decreased exercise tolerance and right-sided heart failure. It was first identified by Dr Ernst von Romberg in 1891.

Signs and symptoms

A history usually reveals gradual onset of shortness of breath, fatigue, angina pectoris, syncope (fainting) and peripheral edema.

In order to establish the cause, the physician will generally conduct a thorough medical history and physical examination. A detailed family history is taken to determine whether the disease might be familial.


Normal pulmonary arterial pressure in a person living at sea level has a mean value of 12-16mmHg. Definite pulmonary hypertension is present when mean pressures at rest exceed 25 mmHg. Although pulmonary arterial pressure can be estimated on the basis of echocardiography, pressure sampling with a Swan-Ganz catheter provides the most definite measurement.

Diagnostic tests generally involve blood tests, electrocardiography, arterial blood gas measurements, X-rays of the chest (generally followed by high-resolution CT scanning). Biopsy of the lung is usually not indicated unless the pulmonary hypertension is thought to be secondary to an underlying intrinsic lung disease. Clinical improvement is often measured in a "six-minute walking test", i.e. the distance a patient can walk in six minutes, and stability and improvements in this measurement correlate with reduced mortality.

Causes and mechanisms

Pulmonary hypertension can be primary (occurring without an obvious cause) or secondary (a result of other disease processes.)

Primary PH

Primary pulmonary hypertension (PPH) is considered a genetic disorder. Certain forms of PPH have been linked to mutations in the BMPR2 gene, which encodes a receptor for bone morphogenic proteins, as well as the 5-HT(2B) gene, which codes for a serotonin receptor. Recently, characteristic proteins of human herpesvirus 8 (also known for causing Kaposi sarcoma) were identified in vascular lesions of PPH patients. However, it is not understood what roles these genes and viral particles play in PPH. PPH has also been associated to the use of appetite suppressants (e.g. Fen-phen). While genetic susceptibility to adverse drug reactions is suspected, the cause of the disease is still largely unknown.


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Electrocardiography to define clinical status in primary pulmonary hypertension and pulmonary arterial hypertension secondary to collagen vascular disease
From CHEST, 8/1/02 by Gregory S. Ahearn

Study objectives: To determine the utility of the ECG for predicting clinical status in adults with primary pulmonary hypertension (PPH) or pulmonary arterial hypertension (PAH) secondary to collagen vascular disease.

Design: Retrospective study.

Setting: Outpatient clinic in a tertiary referral center.

Patients: Adult outpatients with PPH or PAH secondary to collagen vascular disease who underwent electrocardiography within 30 days of undergoing right-heart catheterization, echocardiography, and 6-min walk testing.

Interventions: None.

Measurements and results: The following measurements were recorded from each ECG: P-wave amplitude in lead II; mean frontal QRS axis; QRS duration; R-wave and S-wave deflections in leads I and V6; and the T-wave configurations in the precordial leads. These ECG variables were correlated with hemodynamic variables, RV size, and exercise capacity. Of the 61 patients included in this study, 56 (92%) were women. Eight of 61 patients (13%) had normal findings on ECGs. There was no significant difference in the demographics or hemodynamics when comparing groups with normal vs abnormal ECGs. All ECG parameters had no more than moderate correlation with hemodynamic variables, ventricular size measured by echocardiogram, and exercise capacity as measured by a 6-min walk. The best correlation was between mean the frontal QRS axis and cardiac index (r = -0.46).

Conclusions: The ECG is an inadequate screening tool to rule out the presence of clinically relevant pulmonary hypertension, either primary or secondary to collagen vascular disease. The mean frontal QRS axis correlated best with the severity of hemodynamic impairment.

Key words: diagnosis; echocardiography; electrocardiography; exercise testing; hemodynamics; pulmonary arterial hypertension; pulmonary vascular disease

Abbreviations: MPAP = mean pulmonary artery pressure; NPV = negative predictive value; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; PPV = positive predictive value; PVR = pulmonary vascular resistance; RA = right atrial; RV = right ventricle ventricular; RVH = right ventricular hypertrophy


Primary pulmonary hypertension (PPH) and pulmonary hypertension in the setting of collagen vascular disease (collectively called pulmonary arterial hypertension [PAH]) both result from progressive obliteration of the pulmonary vascular bed. While the pathogenesis is not understood, these uncommon conditions generally result in death from progressive right-sided heart failure. The therapy for PAH has improved (1,2); however, in some patients the disease is progressive and may require lung transplantation. (3-6) It is possible that vasodilator treatment may be more effective if it is started earlier in the clinical course while the pulmonary vasculature retains some vasoreactivity. Patients with advanced PAH do not respond to acute vasodilator testing, suggesting that extensive vascular remodeling has occurred. The prognosis in this setting is poor.

The early diagnosis of PAH is difficult because presenting symptoms are often mild and nonspecific. By the time patients develop significant dyspnea, the disease is usually advanced. Accurate diagnosis depends on right-heart catheterization; however, this is an invasive and costly test and, thus, is not appropriate for screening. Right ventricular (RV) dysfunction and pulmonary hypertension often are diagnosed serendipitously by echocardiography; however, echocardiography may not detect pulmonary hypertension unless the diagnosis is specifically sought or if there is not adequate tricuspid regurgitation. The latter scenario may occur in up to 10% of patients with pulmonary hypertension (Ahearn and Tapson; unpublished data). The ECG is easily performed, is inexpensive, and is widely available. Its diagnostic utility has been established for ischemic heart disease, but it has not been widely evaluated as a screening tool with which to exclude pulmonary vascular disease associated with PAH.

Previous studies (7) have suggested that ECG parameters may be predictive of the severity of RV dysfunction in patients with pulmonary emboli. Also, changes in ECG parameters reflect improvement in RV function after single-lung transplantation. (8) The role of the ECG has not been well-established in evaluating patients with PAH, perhaps because of its perceived clinical utility. Thus, we sought to determine the sensitivity of standard ECG parameters of RV hypertrophy (RVH) in a cohort of patients with PAH. Furthermore, we hypothesized that the degree of ECG abnormalities may be predictive of hemodynamic parameters, echocardiographic findings, and exercise capacity.


Sixty-one patients with PPH or pulmonary hypertension secondary to collagen vascular disease were identified retrospectively. The diagnosis of PPH or pulmonary hypertension was established according to standard criteria. (9) Only patients who had undergone echocardiograms and cardiac catheterizations within 30 days of undergoing a 12-lead ECG were included in this study. Right-heart catheterizations were performed according to standard procedures. Cardiac outputs were calculated using the estimated Fick principle. Pulmonary vascular resistance (PVR) was calculated using standard formulas and was expressed as Wood units. All echocardiograms included standard two-dimensional parasternal (long-axis and short-axis views), apical (2-chamber and 4-chamber views), and subcostal windows. Peak RV systolic pressures were estimated from tricuspid regurgitation jet velocities as assessed by continuous-wave Doppler echocardiography. All ECGs were read by an attending cardiologist who was blinded to the clinical status of the patient. The amplitude of the P wave in lead II, QRS axis, QRS duration, R-wave/S-wave ratios in leads I and V6, and the T-wave configuration in the precordial leads. "Positive" was defined as the major deflection above the isoelectric point, "negative" was defined as being the predominant deflection below the isoelectric point, and "equivocal" was defined as having no predominant deflection. The isoelectric point was defined as the PR interval. The configuration of the QRS complex in lead V1 was recorded as Q, QR, R, RS, or RSR'. The magnitude of each of these deflections was recorded. The R and S waves in lead I and lead V6 were recorded. RVH was defined as present if the frontal plane QRS axis was > 80[degrees], if the R-wave/S-wave ratio in lead V1 was > 1, and the R wave in lead V1 was > 0.5 mV.

Statistical Analysis

Relationships between the ECG parameters and the hemodynamic and echocardiogram parameters are expressed as Spearman correlation coefficients. Hemodynamic data were analyzed using nonparametric analysis because it was not normally distributed. A p value of < 0.05 was considered to be significant. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy all were calculated using standard formulas.


Of the 61 patients studied, 56 (92%) were women. Baseline patient information is presented in Table 1. Eight of 61 ECGs (13%) were read as being completely normal. There was a trend toward lower PVR and pulmonary artery pressure as well as toward a higher cardiac index in patients who had normal ECG findings; however, there were no significant differences in this limited patient sample.

Correlations of selected ECG parameters with hemodynamic, echocardiographic, and exercise capacity are shown in Table 2. No ECG parameter correlated well with hemodynamic or echocardiographic findings. The amplitude of the P wave in lead II had a negative correlation, with cardiac index of 0.3. It correlated poorly with other hemodynamic, echocardiographic, and exercise parameters, with correlation coefficients ranging from 0.26 to 0.39. The frontal QRS axis correlated best of all the ECG parameters with hemodynamic and echocardiographic parameters. It correlated best with cardiac index, with a coefficient of -0.46 (Fig 1). Other correlation coefficients ranged from 0.38 to 0.42. Frontal QRS axis correlated poorly with the 6-min walk distance (r = 0.15). QRS duration was poorly correlated with all the parameters that were tested, as was the R-wave/S-wave ratio in lead V6. The R-wave/S-wave ratio in lead I correlated moderately with the cardiac index (r = 0.49), but only moderately to poorly with other hemodynamic, echocardiographic, and exercise parameters. The presence of an inverted T wave in lead V4 was not predictive of hemodynamic, echocardiographic, or exercise parameters. When ECGs that had been read as normal were excluded from the analysis, the correlations did not improved (data not shown).


Defining a cutoff value of > 100[degrees] for the frontal QRS axis as abnormal, Table 3 depicts the sensitivity, specificity, PPV, and NPV for detecting hemodynamic, echocardiographic, and exercise results. A QRS axis of > 100[degrees] was 89% sensitive for detecting RV enlargement. It was 100% specific for a PVR of >5 Wood units and was 83% specific for RV enlargement. The sensitivity and specificity were moderate for mean pulmonary artery pressure (MPAP) and cardiac index. The sensitivity and specificity were poor for the 6-min walk distance. The PPV for MPAP of > 50 mm Hg, PVR of > 5 Wood units, and RV enlargement were 84%, 100%, and 97%, respectively. The PPV was poor for patients with a cardiac index of < 2.0 L/min and a 6-min walk distance of < 1,000 feet. The NPV of a QRS axis of > 100[degrees] was greatest for a cardiac index of < 2.0 L/min at 79%.

Using RVH, as judged by a blinded attending cardiologist, Table 4 shows sensitivity, specificity, PPV, and NPV for detecting hemodynamic, echocardiographic, and exercise results. The sensitivity was uniformly poor. A reading of RVH was 83% specific for both PVR of > 5 Wood units and RV enlargement. The PPV was excellent for PVR of > 5.0 Wood units and RV enlargement. The PPV for an MPAP of > 50 mm Hg was 81%. The NPV was greatest for RV enlargement (84%).


An elevated right atrial (RA) pressure is an ominous finding in patients with PAH and is predictive of mortality. (10-12) A markedly elevated RA pressure, however, occurs late in the course of the disease when there is marked functional impairment. Ideally, ECG parameters would be both sensitive and specific in identifying patients early in the course of the disease when symptoms are mild. It is possible that therapy would be more efficacious if instituted early in the course of the disease before there has been irreversible damage to the pulmonary vasculature.

The most striking result of our study is that 13% of patients with significant pulmonary hypertension who had been referred to a tertiary medical center had normal ECG findings, which cast serious doubt on the utility of the ECG as a general screening tool. Compared with patients with abnormal ECG findings, there was a trend toward less severe pulmonary hypertension. Small numbers limit the statistical power of the analysis. Furthermore, our results show that traditional ECG measures of RVH do not correlate well with derangement of the pulmonary circulation and do not correlate well with exercise capacity as measured by 6-min walk distance. The frontal plane QRS axis correlated the best of all the parameters tested. Interestingly, when patients with normal ECGs were removed from the analysis, there was no improvement in the correlation between the QRS axis and the severity of pulmonary hypertension.

When defining a cutoff of > 100[degrees], the sensitivities were still low (Table 2); however, a QRS axis of > 100[degrees] was highly predictive of RV enlargement and a PVR of > 5 Wood units, suggesting that this finding is of diagnostic value. Similarly, the presence of RVH had a PPV of 96% for an elevated PVR. The sensitivity and specificity were inadequate for other parameters (Table 3).

Kanemoto (13) reported that an R wave in lead V1 of > 1.2 mV was 93% sensitive for detecting a systolic MPAP of > 90 mm Hg. However, this parameter was relatively nonspecific (47%). Kanemoto also found no more than moderate correlation between the R waves and S waves in leads V1 and V6 and the hemodynamic parameters.

In a series of patients with pulmonary hypertension secondary to mitral stenosis, Gupta et al (14) found that there was a moderate correlation between the mean QRS axis and pulmonary artery pressure (r = 0.51). They were able to distinguish three groups. Patients with a mean QRS axis of < 70[degrees] were unlikely to have elevated MPAP. Almost all patients with a QRS axis of > 100[degrees] had moderate-to-severe pulmonary hypertension. In our series, all patients had pulmonary hypertension, so it is not possible to calculate such a cutoff. However, we found a similar correlation between QRS axis and MPAP.

In conclusion, the frontal plane QRS axis is the ECG parameter that correlates the best with severity of hemodynamic derangement. The magnitude of the correlation, however, is only moderate. A QRS axis of > 100[degrees] is highly predictive of RV enlargement. The ECG will have a limited role in ruling out PPH or pulmonary hypertension secondary to collagen vascular disease. It is important to note that these findings should not be extrapolated to evaluating PAH from other causes such as mitral stenosis, left ventricular dysfunction, or parenchymal lung disease.


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(2) Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000; 132:425-434

(3) Barst RJ, Rubin LJ, McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121:409-415

(4) Rich S. Medical treatment of primary pulmonary hypertension: a bridge to transplantation? Am J Cardiol 1995; 75:63A-66A

(5) Conte JV, Gaine SP, Orens JB, et al. The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation. J Heart Lung Transplant 1998; 17:679-685

(6) Barst RJ. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin. Heart 1997; 77:299-301

(7) Ferrari E, Imbert A, Chevalier T, et al. The ECG in pulmonary embolism: predictive value of negative T waves in precordial leads; 80 case reports. Chest 1997; 111:537-543

(8) Kramer MR, Valantine HA, Marshall SE, et al. Recovery of the right ventricle after single-lung transplantation in pulmonary hypertension. Am J Cardiol 1994; 73:494-500

(9) Jezek V, Widimsky J. Non-invasive diagnosis of pulmonary hypertension and activities pursued by a working group of the World Health Organization. Cor Vasa 1990; 32:178-182

(10) Okada O, Tanabe N, Yasuda J, et al. Prediction of life expectancy in patients with primary pulmonary hypertension: a retrospective nationwide survey from 1980-1990. Intern Med 1999; 38:12-16

(11) Chapman PJ, Bateman ED, Benatar SR. Prognostic and therapeutic considerations in clinical primary pulmonary hypertension. Respir Med 1990; 84:489-494

(12) Rich S, Levy PS. Characteristics of surviving and nonsurviving patients with primary pulmonary hypertension. Am J Med 1984; 76:573-578

(13) Kanemoto N. Electrocardiographic and hemodynamic correlations in primary pulmonary hypertension. Angiology 1988; 39:781-787

(14) Gupta SR, Gupta SK, Sudhir K, et al. Mean frontal QRS axis and pulmonary artery pressures in rheumatic mitral stenosis. J Indian Med Assoc 1989; 87:180-182

* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Ahearn and Tapson) and Cardiology (Drs. Rebeiz and Greenfield), Department of Medicine, Duke University Medical Center, Durham, NC.

Manuscript received August 13, 2001; revision accepted January 16, 2002.

Correspondence to: Victor F. Tapson, MD, FCCP, Associate Professor of Medicine, Division of Pulmonary and Critical Care, Duke University Medical Center, Box 31175, Durham, NC 27710; e-mail:

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2002 Gale Group

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