Pulmonary Venous Hypertension: A Diagnostic and Therapeutic Dilemma

Francisco J. Soto, MD, MS
Assistant Professor Director, Pulmonary Hypertension Program Medical College of Wisconsin Milwaukee, Wisconsin

Introduction

Current data suggest that patients with pulmonary arterial hypertension (PAH)—those with involvement of the pulmonary circulation at the precapillary level—can experience a significant clinical and hemodynamic benefit from available treatments such as prostacyclin, endothelin-receptor antagonists, or phosphodiesterase-5 inhibitors.1 Data are lacking as to whether other categories of pulmonary hypertension,2 such as pulmonary venous hypertension (PVH), which involves the pulmonary circulation at the postcapillary level, enjoy a similar treatment benefit. It is even possible that those with PVH may experience worsening of their symptoms when such therapies are administered by increasing the leftsided filling volume and pressure.

Figure 1. Four-chamber apical view on transthoracic echocardiography. Normal right and left ventricular chamber size. Normal right atrium size. Borderline normal-mild left atrium enlargement.Based on current guidelines,3 a diagnosis of PAH is established once a resting mean pulmonary arterial pressure (mPAP) greater than 25 mmHg and a left atrial or left ventricular pressure of 15 mmHg or less is documented. On the other hand, the same mPAP value cutoff in the presence of left-sided pressure greater than 15 mmHg would fulfill the definition of PVH. Such simple distinction criteria based on left-sided filling pressures is helpful in discriminating between clear cut cases of PAH and PVH. Unfortunately, clinicians are frequently faced with more complex diagnostic case scenarios that require additional workup and interventions. One such case is presented here to provide some diagnostic insights that may help better discriminate between the two categories.

Case Description

The patient is a 62-year-old woman with a past medical history significant for 20 years of systemic hypertension (Table 1). She was referred to our pulmonary hypertension program for progressive dyspnea on exertion and an echocardiogram that suggested the presence of pulmonary hypertension. Her primary physician ordered the test based on her complaints of 2 years of progressive dyspnea on exertion that was not clearly explained by other etiologies. Her outside echocardiogram revealed an estimated right ventricular systolic pressure of at least 54 mmHg (estimated right atrial pressure 5 mmHg). A thorough evaluation and diagnostic workup (Table 2) was performed at our institution. These tests were unremarkable for such secondary causes of pulmonary hypertension as thromboembolic disease, parenchymal lung disease, congenital heart disease, and collagen vascular disease. Transthoracic echocardiography (Figure 1) with a specific pulmonary hypertension protocol was repeated at our institution and confirmed the outside echocardiographic findings (Table 2).

Clinical suspicion for idiopathic PAH was present in her case based on a negative workup for secondary causes. However, her age, her long history of systemic hypertension, and her echocardiographic findings, including left-sided changes plus unremarkable right-cardiac structures, raised suspicion also for undetected left heart disease in the form of left ventricular diastolic dysfunction. This entity can lead to PVH and generate symptoms and findings similar to those in PAH. The lack of right-sided abnormalities on echocardiography certainly mitigates strongly against PAH. In general, one would expect to see some right-sided strain findings after 2 years of progressive dyspnea if PAH were to be the explanation for her symptoms.

She subsequently underwent diagnostic right and left cardiac catheterization at our institution (Table 3) to confirm the presence of pulmonary hypertension and to obtain additional hemodynamic data that could help discriminate between PAH and PVH. Her right heart catheterization numbers were consistent with a diagnosis of PAH given her elevated mPAP and a pulmonary capillary wedge pressure (PCWP) of 15 mmHg or less (Figures 2 and 3). However, a simultaneous left ventricular end-diastolic pressure (LVEDP) measurement—a number that is routinely obtained at our institution during initial diagnostic catheterizations4 —was elevated at 22 mmHg. Her baseline PCWP forms did reveal a prominent v wave, something that can be found in the presence of mitral regurgitation or in impaired relaxation of the left ventricle. None of the two echocardiograms revealed evidence of significant mitral valve disease.

After reviewing her right heart catheterization numbers, we decided to perform an intravenous epoprostenol vasodilator trial to assess for the presence of vasoreactivity (Table 3). This led to only a minimal decrease in mPAP consistent with a negative vasodilator trial.

An exercise challenge was also conducted based on the suspicion for left heart disease trying to unmask impaired relaxation of the left ventricle. A 5-minute upper body exercise protocol, a flat dumbbell fly routine, led to a significant increase in pulmonary pressures with a concomitant LVEDP increase (Table 3).

Figure 2. Sample tracing: mean pulmonary capillary wedge pressure at baseline. Peak a wave 20; mean a wave 15; v wave 40. Electronic mean reported as 13. All pressures reported as mmHg.Based on the presence of an elevated LVEDP, long-standing systemic hypertension history, plus the hemodynamic response observed during an exercise challenge, the suspicion for PVH remained strong in her case. We then proceed with an intravenous nitroprusside infusion at a starting dose of 1 mc/kg/min.5 Our goal was to decrease her systemic systolic blood pressure (to around 100 to 110 mmHg) and/or decrease her LVEDP to less than 15 mmHg while simultaneously monitoring for pulmonary artery pressure changes. A pig tail catheter was kept in the left ventricle during the nitroprusside infusion to directly follow the left ventricular systolic pressure and the LVEDP.6 Once the LVEDP and systemic systolic blood pressure normalized, a dramatic improvement in pulmonary arterial pressures was documented (Table 3). Right heart catheterization numbers revealed complete normalization of her pressures (Figure 4).

Figure 3. Sample tracing: pulmonary artery pressure (PAP) and left ventricular end-diastolic pressure (LVEDP) at baseline. Left ventricular systolic pressure: 154; LVEDP: 22; PAP: systolic 55, diastolic 22, mean 35. All pressures reported as mmHg.With the above hemodynamic findings plus a strong clinical suspicion for postcapillary pulmonary hypertension, her case was labeled as PVH secondary to left ventricular diastolic dysfunction. In an attempt to replicate the vascular effects of nitroprusside in the outpatient setting (direct preload and afterload reduction), treatment was started with a combination regimen of oral nitrates and hydralazine. Doses of these two agents were escalated during a period of several weeks aiming to reach a systemic systolic blood pressure in the 100 to 110 mmHg range as tolerated by side effects.

Follow-up

Figure 4. Sample tracing: pulmonary artery pressure (PAP) and left ventricular end-diastolic pressure (LVEDP) after nitroprusside. PAP: systolic 34, diastolic 10, mean 17; LVEDP: 8-10. All pressures reported as mmHg.After more than 2 years from her cardiac catheterization and initiation of this therapeutic approach, the patient has continued to tolerate this regimen well without significant side effects. Her diuretics regimen has been adjusted based on a close follow-up of her brain natriuretic peptide (BNP) numbers and basic chemistry.

We have documented improvement between her baseline data and the most recent follow-up 2 and a half years later. Her BNP level decreased from 86 pg/mL at baseline to 42. Her functional status improved from a baseline World Health Organization (WHO) functional class III to an early II (mainly bothered by going up inclines and bending over). Her 6- minute walk test distance improved from 398 to 450 meters. Echocardiographic values have remained stable. No evidence of right ventricular dysfunction or dilatation has been documented. She has not experienced any signs of clinical deterioration throughout her follow-up visits (conducted approximately every 4 months). Given her stable clinical course, we have not introduced any pulmonary vasodilator agents to her regimen.

Discussion

Our case represents a common scenario that most physicians treating pulmonary hypertension currently face in their practice. Based on the increased awareness of pulmonary hypertension in the general public and health providers, large numbers of patients are being referred to be evaluated on the basis of dyspnea and an elevated pulmonary artery pressure on echocardiography. Many of these patients are older individuals with comorbidities such as systemic hypertension, diabetes mellitus, coronary artery disease, or obstructive sleep apnea. While some of them could and will have PAH, patients with those characteristics are more likely to have left ventricular diastolic dysfunction manifesting itself as PVH. Accordingly, given their underlying symptoms, a thorough evaluation is frequently indicated.

Since the available therapies to treat PAH are not only expensive but also may potentially worsen the symptoms in patients with PVH, it is very important to establish the proper diagnosis. To our knowledge, besides the use of a left ventricular filling pressure cutoff (> or ≤15 mmHg), there are no standardized protocols that allow the clinician to clearly discriminate between a diagnosis of PAH (especially idiopathic PAH) and PVH in complex cases like the one presented here.

Utilization of some of the interventions described above has allowed our group to better assess the more difficult cases. However, until any of these interventions is prospectively validated in large clinical trials, our practice is to have a very close follow-up for the first 6 to 12 months (or longer) on those patients being labeled as PVH to make sure that there are no obvious clinical, echocardiographic, or hemodynamic signs of deterioration. When in doubt, we promptly proceed with a repeat cardiac catheterization to assess cardiopulmonary hemodynamics in more detail.

With regard to the therapeutic management of pulmonary hypertension in the presence of left ventricular diastolic dysfunction, especially when the diastolic dysfunction can not be completely attributed to systemic hypertension, it is not clear whether PAH therapies could play a role. Some benefit has been suggested through anecdotal description in small case series. It will be interesting to see whether a potential benefit of these drugs in improving myocardial relaxation can overcome the likely increase in right-to-left blood flow that may result from their pulmonary vasodilation properties. This issue is under investigation at this time.7

Given the potential for abrupt systemic vasodilation, it is our practice to perform nitroprusside vasodilator trials while simultaneously monitoring LVEDP and systemic arterial pressures. In general, we would recommend avoiding nitroprusside trials in obvious PAH cases or those with significant right ventricular impairment since those patients might have an impaired hemodynamic response and not be able to adequately increase their cardiac output in the event of systemic hypotension. If left ventricular diastolic dysfunction is suspected in these types of cases, other safer alternatives such as an exercise challenge or a fluid bolus could be considered in order to evaluate the left ventricular pressure response to extra volume or an increase in blood flow. Unfortunately, none of those interventions has been validated either.

Finally, our case also illustrates the value of measuring both PCWP and LVEDP during the initial diagnostic catheterization, especially in those patients with comorbidities that can lead to PVH. Important discrepancies between the two hemodynamic measurements can occur. If present, they could significantly alter the therapeutic approach and will have important implications on establishing the longterm prognosis of these patients. In addition, we recommend following the available guidelines for interpretation of hemodynamic tracings and pressure measurement.8 The electronic mean measurements provided by catheterization laboratory software programs might not be completely accurate and could lead to initiation of therapies that are not clinically indicated.

Key Words—Pulmonary venous hypertension diagnosis, pulmonary arterial hypertension, right heart catheterization, left heart catheterization, LVEDP.

Address for reprint requests and other correspondence: Francisco J. Soto, MD, Director, Pulmonary Hypertension Program, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite 5200, Milwaukee, WI 53226, HYPERLINK "mailto:fsoto@mcw.edu" fsoto@mcw.edu.

Commentary

Vallerie V. McLaughlin, MD
Associate Professor of Medicine
Director, Pulmonary Hypertension Program
University of Michigan Health System
Ann Arbor, Michigan

Dr Soto’s case presentation and discussion elegantly highlight an increasingly common challenge that we are faced with in practice, the diagnosis and treatment of left heart etiologies of pulmonary hypertension. As the population ages, and as the prevalence of other comorbid diseases such as diabetes, systemic hypertension, obesity, and obstructive sleep apnea increase, we are going to be faced with this dilemma with greater frequency. While well summarized in Dr Soto’s case and discussion, I would like to highlight a few pearls at different points in the evaluation of such patients.

History
The clinician’s index of suspicion for left heart disease as the etiology of the pulmonary hypertension should be increased in patients who have a past medical history of systemic hypertension, particularly if it has not been optimally controlled; diabetes; obesity; coronary artery disease; and obstructive sleep apnea; or symptoms of paroxysmal nocturnal dyspnea or orthopnea. Although paroxysmal nocturnal dyspnea and orthopnea can occur in very late stages of PAH, that diagnosis is generally clear cut at this stage.

Noninvasive Testing
Atrial fibrillation is uncommon in PAH and its presence should sway one toward a left heart etiology of pulmonary hypertension. If electrocardiography does not show right axis deviation, left heart disease also moves up on the differential.

There are many echocardiographic features that should raise the index of suspicion of left heart disease as the etiology of the pulmonary hypertension. These include absence of right heart chamber enlargement; left atrial enlargement; left ventricular hypertrophy; impaired diastolic relaxation by Doppler indices; and modest elevation of pulmonary arterial pressures (ie, 50’s rather than 90’s).

If the index of suspicion is high after the initial evaluation and noninvasive testing, it might be appropriate to optimize medical therapies and repeat an echocardiogram prior to moving on to invasive testing. In some situations, with optimal blood pressure and fluid management, symptoms and evidence of pulmonary hypertension on echocardiography will improve and this might obviate the need to proceed to cardiac catheterization.

Cardiac Catheterization
The most important points here were emphasized in Dr Soto’s case and discussion, but I will briefly reiterate.

It is critical to obtain an accurate measurement of left heart filling pressure. In many instances, it is difficult to obtain a perfect wedge pressure tracing in these patients. Over or underinflating the balloon even just a bit can dramatically alter the wedge pressure tracing. Like Dr Soto, we generally obtain a direct measurement of left ventricular end diastolic pressure in patients in whom we suspect pulmonary venous hypertension. In the absence of mitral stenosis (which should be apparent on echocardiography) the left ventricular end diastolic pressure is an accurate reflection of left heart filling pressure, and of the pulmonary venous pressure.

Often the left heart filling pressure is substantially elevated in such patients, and the transpulmonary gradient is normal or just mildly elevated, and the diagnosis is clear. Nothing further may be required in these cases to confirm the diagnosis. However, it is not uncommon to see an upper normal or just mildly elevated left heart filling pressure, particularly in patients who has been well diuresed. In these instances, either a fluid challenge or exercise will help clinch the diagnosis. Dr Soto used exercise in his case. By increasing heart rate one reduces the diastolic filling time, which in a patient with impaired diastolic function can substantially increase the filling pressures. A volume load in the catheterization laboratory challenges the impaired left ventricle in a similar fashion. An important cautionary note to remember here is that although exercise echocardiography may demonstrate an increase in pulmonary arterial pressures, it is often difficult to delineate how much of this increase is a result of elevated left heart filling pressures given the increased heart rate and reduced diastolic filling time.

Dr Soto also nicely demonstrated the reduction in pulmonary artery pressures that occurred as the result of the reduction in systemic arterial pressures in this case with nitroprusside. This is also my drug of choice to delineate the physiology in a patient with severe systemic hypertension in the catheterization laboratory. Typical agents used to test for vasoreactivity, epoprostenol, adenosine, and nitric oxide, may increase pulmonary blood flow and result in increased filling pressures in those with a left ventricle that is unable to accommodate that increased venous return.

Treatment
As in Dr Soto’s case, treatment should be directed toward the underlying pathology, which at times is difficult. Optimal blood pressure control, sodium restriction, and volume management are key in most patients. Treatment of atrial fibrillation may be of benefit (if possible) as restoring atrial kick is crucial in those with diastolic dysfunction. If this is not possible, rate control should be emphasized, to allow adequate time for diastolic filling. Weight loss should also be encouraged in the obese patient, and compliance with treatment of other comorbid diseases, such as sleep apnea, is crucial. Dr Soto’s patient had a very nice response to this approach, but sadly, this is not always the case. Often patients are still symptomatic despite this approach, or are not compliant with these therapies. There is very little evidence on how to approach treatment of pulmonary hypertension in such a patient. As Dr Soto highlights, there is no evidence that any PAH-specific therapy is helpful in such a patient, and there is the theoretic risk of increasing pulmonary blood flow and inducing pulmonary edema. It would be interesting to see a controlled clinical trial in this population.

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