Pulmonary Venous Hypertension: A Diagnostic and Therapeutic Dilemma

Introduction

Current data suggest that patients with pulmonary arterial hypertension (PAH)—those with involvement of the pulmon- ary circulation at the precapillary level—can experience a significant clinical and hemodynamic benefit from available treatments such as prostacyclin, endothelin-receptor antag- onists, or phosphodiesterase-5 inhibitors.1 Data are lacking as to whether other categories of pulmonary hypertension,2 such as pulmonary venous hypertension (PVH), which in- volves 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 left- sided filling volume and pressure.

Based on current guidelines,3 a diagnosis of PAH is esta- blished once a resting mean pulmonary arterial pressure (mPAP) greater than 25 mmHg and a left atrial or left ven- tricular 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 be- tween clear cut cases of PAH and PVH. Unfortunately, clini- cians are frequently faced with more complex diagnostic case scenarios that require additional workup and interven- tions. One such case is presented here to provide some diag- nostic insights that may help better discriminate between the two categories.

Case Description

The patient is a 62-year-old woman with a past medical his- tory 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 pri- mary 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 echocar- diogram revealed an estimated right ventricular systolic pressure of at least 54 mmHg (estimated right atrial pres- sure 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 dis- ease. Transthoracic echocardiography (Figure 1) with a spe- cific pulmonary hypertension protocol was repeated at our institution and confirmed the outside echocardiographic findings (Table 2).

Table 1. Baseline Demographics.

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Table 2. Relevant Pulmonary Hypertension Workup.

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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 echocar- diography certainly mitigates strongly against PAH. In gen- eral, one would expect to see some right-sided strain find- ings 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 addi- tional hemodynamic data that could help discriminate between PAH and PVH. Her right heart catheterization num- bers were consistent with a diagnosis of PAH given her ele- vated 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.

Table 3. Results of Cardiac Catheterization, Exercise Challenge, Vasodilator Trial, and Nitroprusside.

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After reviewing her right heart catheterization numbers, we decided to perform an intravenous epoprostenol vasodila- tor 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 exer- cise protocol, a flat dumbbell fly routine, led to a significant increase in pulmonary pressures with a concomitant LVEDP increase (Table 3).

Based on the presence of an elevated LVEDP, long-stand- ing systemic hypertension history, plus the hemodynamic response observed during an exercise challenge, the suspi- cion for PVH remained strong in her case. We then proceeded 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.5 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).

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With the above hemodynamic findings plus a strong clin- ical suspicion for postcapillary pulmonary hypertension, her case was labeled as PVH secondary to left ventricular dias- tolic dysfunction. In an attempt to replicate the vascular effects of nitroprusside in the outpatient setting (direct pre- load 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 sever- al weeks aiming to reach a systemic systolic blood pressure in the 100 to 110 mmHg range as tolerated by side effects. Diuretics were also up-titrated to achieve additional reduction in preload. We continued her other antihypertensive agents.

Follow-up

After more than 2 years from her cardiac catheterization and initiation of this therapeutic approach, the patient has con- tinued 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) num- bers 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 (main- ly 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 (con- ducted 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 physi- cians 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 hyper- tension, diabetes mellitus, coronary artery disease, or obstructive sleep apnea. While some of them could and will have PAH, patients with those characteristics are more like- ly 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 prop- er diagnosis. To our knowledge, besides the use of a left ven- tricular filling pressure cutoff (> or £15 mmHg), there are no standardized protocols that allow the clinician to clearly dis- criminate 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 prospec- tively 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 hemo- dynamic signs of deterioration. When in doubt, we promptly proceed with a repeat cardiac catheterization to assess car- diopulmonary hemodynamics in more detail.

With regard to the therapeutic management of pulmonary hypertension in the presence of left ventricular diastolic dys- function, 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 bene- fit 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.6

Given the potential for abrupt systemic vasodilation, it is our practice to perform nitroprusside vasodilator trials while simultaneously monitoring LVEDP and systemic arterial pres- sures. In general, we would recommend avoiding nitroprus- side 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 ade- quately 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 comorbidi- ties 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 long- term prognosis of these patients. In addition, we recom- mend following the available guidelines for interpretation of hemodynamic tracings and pressure measurement.7 The electronic mean measurements provided by catheterization laboratory software programs might not be completely accu- rate and could lead to initiation of therapies that are not clinically indicated.