(Chest. 2003;123:711-715.)
© 2003
American College of Chest Physicians
Unexplained Pulmonary Hypertension Is Associated With Systolic Arterial Hypertension in Patients Undergoing Routine Doppler Echocardiography*
Robert S. Finkelhor, MD;
Shawn X. Yang, MD;
Georgene Bosich, RN and
Robert C. Bahler, MD, FCCP
* From the Case Western Reserve University at MetroHealth Medical Center, Cleveland, OH.
Correspondence to: Robert S. Finkelhor, MD, Division of Cardiology, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109-1900; e-mail: rfinkelhor{at}metrohealth.org
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Abstract
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Study objective: To determine the validity of the association between systemic hypertension (HTN) and unexplained pulmonary hypertension (PHTN) as identified with Doppler echocardiography.
Methods: All patients with a reported systolic pulmonary artery pressure (SPAP) on routine Doppler echocardiography from our 1997 echocardiographic database were identified. Exclusions included all diseases known to be associated with PHTN. Of 1,174 patients, 503 had PHTN (defined as a SPAP of 
40 mm Hg), of whom 42 (8.4%) had unexplained PHTN. These PHTN patients were matched for age (mean [± SD] age, 70 ± 11 years) with 84 randomly selected patients from the same database who had normal SPAP values and no diseases associated with PHTN.
Results: The mean SPAP of those patients with unexplained PHTN was 48 ± 9 mm Hg vs 31 ± 5 mm Hg for those without unexplained PHTN. HTN was more prevalent in those with PHTN (98% vs 72%, respectively; p = 0.0008). Patients with unexplained PHTN had significantly higher mean systolic BP, as routinely measured at the end of the echo (154 ± 26 vs 138 ± 21 mm Hg, respectively; p = 0.0006), but they did not differ in diastolic BP (80 ± 14 vs 78 ± 11 mm Hg, respectively; p = 0.39). PHTN patients and control subjects did not differ with respect to gender (women, 74% vs 70%, respectively), race (white, 64% vs 65%, respectively), body mass index (30 ± 8 vs 28 ± 8 kg/m2, respectively), or left ventricular ejection fraction (64 ± 6% vs 63 ± 7%, respectively). When only those with known HTN were considered, PHTN patients still had higher systolic arterial BP (155 ± 25 vs 143 ± 21 mm Hg, respectively; p = 0.013) and tended to be on more BP medications (1.6 ± 1.1 vs 1.2 ± 0.9, respectively; p = 0.09).
Conclusions: Unexplained PHTN occurs mostly in the elderly, is associated with systolic HTN, and those hypertensive patients with concomitant PHTN have higher systolic arterial pressures.
Key Words: echocardiography • hypertension • pulmonary hypertension
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Introduction
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Until the advent of Doppler echocardiography, pulmonary artery pressure could be measured only by right heart catheterization, limiting its assessment either to those persons who were ill enough to warrant invasive measurements or to selected subjects in research protocols. Doppler echocardiography allows a wider population to undergo the safe and accurate estimation of pulmonary pressure.1
2
3
4
From routine echocardiographic studies, we observed that systemic hypertension (HTN) and pulmonary hypertension (PHTN) were frequently associated. Our objective was to determine the validity of this observation and to better define the clinical characteristics of patients with unexplained PHTN.
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Materials and Methods
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Pulmonary artery pressure is routinely sought in patients undergoing echocardiographic studies. From our laboratory computer database, all patients in 1997 with PHTN were identified. Patients were excluded by an extensive retrospective database search (ie, the echocardiographic laboratory, the pulmonary function laboratory, and radiology databases) and a review of patient clinical records. Exclusionary criteria included diseases known to be associated with PHTN (International Primary Pulmonary Hypertension Study5
modified by the addition of fenfluramine-phentermine, known as fen-phen) [Table 1
]. Echocardiographic criteria for exclusion were global or focal systolic dysfunction, diastolic left ventricular dysfunction, valvular heart disease with moderate or greater lesion severity, or the presence of an intracardiac shunt. Diastolic dysfunction was based on well-defined criteria for the Doppler assessment of the mitral inflow and pulmonary veins,6
7
and included clear restrictive, abnormal relaxation or pseudonormal filling patterns. Saline solution contrast studies are routinely performed in our laboratory when either the referral diagnosis is stroke or transient ischemic attack or when there is any evidence of right ventricular dilatation.
Systolic pulmonary artery pressure (SPAP) was reported as the sum of the Doppler echocardiography-derived right ventricular-right atrial Doppler gradient1
2
3
and right atrial pressure. Right atrial pressure was estimated from the inferior vena caval diameter and its respiratory variation. The values used were 5 mm Hg if the inferior vena cava was not dilated (ie, to 
12 mm in diameter), 10 mm Hg if it was dilated but varied by 50% with respiration, and 15 mm Hg if it was dilated and varied < 50% with respiration.4
The upper limit of SPAP in a young, healthy population using an empiric right atrial pressure of 10 mm Hg has been 35 mm Hg.8
As the estimation of right atrial pressure can vary by ± 5 mm Hg, we defined PHTN as a SPAP of 40 mm Hg. This noninvasive method has been validated in our laboratory in 16 patients who underwent right heart catheterization < 6 months after the echocardiographic study with a good correlation for pulmonary artery systolic pressure (r = 0.88; y = 1.03x + 3.4; standard error of the estimate, 9.0 mm Hg; p < 0.001).
Since normal pulmonary artery pressure increases with age,9
10
each patient with unexplained PHTN was matched by age with two randomly chosen patients without PHTN who were screened by the same type of database and clinical record review.
Systemic HTN was defined as follows: (1) medical record diagnosis of hypertension plus the use of antihypertensive medication; (2) at least two elevated BP measurements of 140 mm Hg systolic and/or 90 mm Hg diastolic, as recorded in the patient chart in the absence of hypertensive medication; or (3) an elevated BP at the time of the echocardiographic study. In our laboratory, the sonographers routinely perform BP measurements at the end of the echocardiogram. A manual mercury sphygmomanometer is used with the patient in a sitting position.
Between-group comparisons used the unpaired t test for continuous data and 
2 analysis for discrete data. Where appropriate, least-squares linear regression analysis was employed. Continuous data were expressed as the mean ± SD. Statistical significance was set at p < 0.05.
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Results
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A numerical value for SPAP was reported in 1,174 of 3,064 patients (38%), of whom 503 had PHTN. Unexplained PHTN was present in 42 patients. The mean ages of the PHTN patients and the age-matched control subjects were similar (70 ± 11 years; age range, 45 to 97 years). The reasons for study referral were also similar (Table 2
). The mean SPAP was 48 ± 9 mm Hg in the PHTN group (range, 40 to 75 mm Hg), and 31 ± 5 mm Hg in the control population (p < 0.0001). HTN was present in 98% of patients with unexplained PHTN, but in only 72% of those without PHTN (p = 0.0008). The systolic arterial BP, as measured at the end of the echocardiogram, was higher for patients with unexplained PHTN (154 ± 26 vs 138 ± 21 mm Hg, respectively; p = 0.0006), but diastolic pressures were not (80 ± 14 vs 78 ± 11, respectively; p = 0.39). The two groups were similar with respect to gender, race, body mass index, prevalence of atrial fibrillation, and left ventricular ejection fraction (Table 3
). Regression analysis showed a weak but significant correlation between the systolic BP measured at the end of the echocardiographic study and SPAP (r = 0.27; p = 0.002).
The results of this study were little changed if a narrower definition of systemic HTN was used. When systemic HTN was defined either as the use of antihypertensive medication or at least two elevated pressure measurements in the patient record, HTN was present in 78% of those with unexplained PHTN vs 54% in patients without PHTN (p = 0.009). When only those patients with a history of hypertension plus the use of antihypertensive medication were considered in order to eliminate those patients who might be labeled as having white coat hypertension, there was still a strong trend toward more hypertension in those with PHTN (76% vs 61%, respectively; p = 0.06).
Since the proportion of patients with HTN was greater in the group with PHTN, it would be expected that the group with PHTN would have a higher BP than the control subjects (Table 3)
. However, when the analysis was restricted to the patients with HTN, systolic arterial BPs were significantly different (155 ± 25 vs 143 ± 21 mm Hg, respectively; p = 0.013), but the diastolic pressures were not (Table 4
). There was also a trend toward the use of a greater number of antihypertensive medications in the PHTN group (1.6 ± 1.1 vs 1.2 ± 0.9 per patient; p = 0.09) [Table 4
]. When narrowing the analysis even further to hypertensive patients on medication, there was still a significantly greater systolic arterial BP for those with unexplained PHTN (Table 5
).
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Discussion
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We found that unexplained PHTN occurred in 8% of the patients in whom PHTN was detected during a clinical echocardiographic study. Patients with unexplained PHTN were elderly, almost all had systemic HTN, and their HTN was more severe.
Our patients with unexplained PHTN clearly differ from those with primary PHTN. They were on average 3 decades older, their PHTN was less severe, and they had systolic HTN. As with primary PHTN, these patients were mostly women, but this is probably only a reflection of the larger proportion of women in an older population. Thus, an overlap of our population with primary PHTN seems very unlikely. Considering the size of our hospital referral population and the incidence of primary PHTN of one to two persons per million, we would expect to see at most one patient with primary PHTN per year.
Our study was not designed to address the mechanism for the association of HTN and PHTN. One possible mechanism is that left ventricular diastolic dysfunction could lead to upstream reactive PHTN.11
12
13
Although we had excluded a priori all patients with clear Doppler evidence of left ventricular diastolic dysfunction using published criteria,6
7
this does not exclude the possibility of more subtle diastolic dysfunction as a mechanism leading to PHTN. More contemporary ultrasonographic techniques such as tissue Doppler or color M-mode now have now been proposed to enhance the diagnosis of diastolic dysfunction.14
Another possible mechanism for the association of HTN and PHTN is an exaggerated endothelial response to vasoconstrictor stimuli existing in both the systemic and pulmonary vasculature of hypertensive patients.15
16
This response has been demonstrated with mental stress and cold pressor stimulation, and can be reproduced with exogenous catecholamines. These changes occurred in the absence of either a baseline elevation or a significant rise in pulmonary capillary wedge pressure, arguing against marked resting left ventricular diastolic dysfunction as being the cause for these upstream changes.
Systolic HTN is more common in the elderly, is caused by poor arterial compliance, is associated with a worse prognosis, and correlates better with left ventricular hypertrophy than does diastolic pressure.17
Thus, it could be argued that the association of PHTN and systolic HTN might be related either to increased pulmonary arterial stiffness, to diastolic left ventricular dysfunction, or both.
The rigorous definition of PHTN requires invasive measurements of mean arterial pressure and pulmonary vascular resistance, which are not readily available by present noninvasive techniques. The Doppler echocardiographic measure of SPAP should be able to serve as a reliable screening test to determine who may need to have invasive measurements. Assuming an upper normal mean pulmonary artery pressure of 20 mm Hg and an upper normal diastolic pulmonary artery pressure of 10 mm Hg (the mean pressure equals one third of the difference between the diastolic and systolic pressures plus the diastolic pressure), the upper normal value for peak systolic pressure should be 40 mm Hg rather than the often-quoted 30 mm Hg. This is consistent with the upper normal value that we used and is supported by studies using rigorously screened young healthy subjects.8
Subsequent to the completion of our study, the mean SPAP, as derived by the Doppler tricuspid regurgitation velocity, in a healthy population that was 50 years of age, was reported as 33 ± 7 mm Hg.18
Our study is limited by its retrospective nature. Screening for diseases causing PHTN was at the discretion of the referring physician. Nevertheless, the thorough chart review for recognized causes of PHTN was carried out in the same manner for both the patient group and the control subjects. It is unclear whether routine testing for subclinical disease (ie, pulmonary function testing to exclude obstructive lung disease, sleep studies to detect sleep apnea, or exercise testing to detect myocardial ischemia) would change these results. Another limitation of our study is that our analysis was limited to those patients in whom a tricuspid regurgitant Doppler velocity could be obtained in order to determine the pulmonary artery pressure. As this may occur more frequently in patients with PHTN, our control group may be different from those in whom a pulmonary artery pressure could not be estimated.
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Acknowledgements
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We thank Lee Biblo, MD, for a critical review of this manuscript.
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Footnotes
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Abbreviations: HTN = systemic hypertension; PHTN = pulmonary hypertension; SPAP = systolic pulmonary artery pressure
Received for publication December 5, 2000.
Accepted for publication July 16, 2002.
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References
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Abstract
Introduction
