Pulmonary Hypertension in Older Adults: PAH or PH due to LHD?

Pulmonary hypertension (PH) is an entity that is actually a heterogeneous group of diseases classified into five groups per the World Health Organization (WHO).¹ WHO Group 1 pulmonary arterial hypertension (PAH) is a specific condition characterized by pathological remodeling of the pulmonary arterioles that has gained much attention because of the recent prolific development of effective pharmacologic therapies. It was once thought to affect mostly women in the third to fifth decade of life, but recent observations demonstrate that the PAH population is older, often with cardiovascular risk factors.² As such, there is a growing population of older patients with dyspnea and suspected PH who are referred to subspecialty care with the goal of receiving impactful PAH therapy. This has given rise to an important diagnostic dilemma; a significant proportion of these patients may in actuality suffer PH due to heart failure with preserved ejection fraction (HFpEF).^3,4 These patients belong to a subset of WHO Group 2 PH due to left heart disease (PH-LHD). PH-LHD and HFpEF also afflict older patients with a predilection for women who harbor a high prevalence of cardiovascular risk factors. Unfortunately, PAH-specific therapy does not confer benefit, and in fact could potentially cause harm, in PH-LHD.⁵

The gold standard for diagnosis of PH is the measurement of a mean pulmonary artery pressure (mPAP) ≥25 mmHg at the time of right heart catheterization (RHC).¹ After confirming PH, the hemodynamic criteria differentiating PAH from PH-LHD is dependent on the measurement of the pulmonary artery wedge pressure (PAWP). Currently, PAH is defined by the presence of PH and a PAWP ≤15 mmHg, a threshold that suggests that pulmonary venous hypertension from left heart disease is not present. However, it is increasingly apparent that a single PAWP measurement is often insufficient to confidently exclude left heart disease. The current practice is to perform RHC in the supine position after an overnight fast, which can result in normal PAWP, particularly if patients are treated with diuretics.⁶ AMBITION (A Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects With Pulmonary Arterial Hypertension) illustrated the limitations of contemporary hemodynamic criteria for PH.³ Despite confirmation of PAH by RHC, a significant proportion of patients were suspected of having PH-LHD related to HFpEF based on multiple cardiovascular risk factors (obesity, diabetes mellitus, and hypertension) and were ultimately excluded from the final analysis. This population is described as atypical PAH or PAH with cardiovascular risk factors, for whom there remains significant equipoise regarding the efficacy of PAH-specific pharmacotherapy.

The Rationale for Provocative Testing During RHC

There is currently interest in the use of provocative maneuvers during RHC as tools to address the clinical challenges presented by atypical PAH. The rationale for these interventions is to elicit dynamic responses of the PAWP that may either suggest the presence of left heart dysfunction or, conversely, confirm that responses of the left heart are within normal limits. Ideally, interpretation of PAWP responses to provocative maneuvers should occur relative to a comparative reference range derived from healthy subjects matched for age and sex.

Infusion of Normal Saline

Preload manipulation by the infusion of normal saline is appealing given the ease of administration and requires minimal preparation and no equipment.⁷ A series of elegant experiments in humans have demonstrated a monoexponential increase of the PAWP in response to carefully timed infusions of warmed normal saline at relatively large volumes (up to 150 ml/kg), which describes the compliance relationship of the left ventricle.⁸ The curve shifts upwards and toward the left in sedentary and aged adults, denoting loss of left ventricular compliance. The linear slope of PAWP increase relative to the volume of normal saline infused can also be calculated, ranging from approximately 6 mmHg/L in younger men to 9 mmHg/L in older women.⁸ As such, even in healthy individuals, the PAWP attains high values depending on the volume of normal saline infused and the subject's characteristics.

Not surprisingly, the prevalence of patients who fulfill the hemodynamic criteria for PAH but then exhibit abnormal PAWP responses to the infusion of normal saline is affected by the PAWP threshold employed. Both Robbins et al.⁷ and Fox et al.⁹ demonstrated that the PAWP exceeds a threshold of 15 mmHg after infusion of 0.5 L of normal saline in approximately 20% of patients with hemodynamically confirmed PAH. More recently D'Alto et al.¹⁰ addressed the concern that employing a threshold of 15 mmHg would likely include a proportion of patients with normal physiology, particularly in older adults. These investigators conducted the only prospective study available in which 0.5 L of normal saline was administered to patients undergoing RHC for suspected PAH. Using an a priori defined cut-point of 18 mmHg, 8% of patients without PH and 7% of patients with hemodynamically confirmed PAH have a PAWP >18 mmHg. Although there may be concerns regarding normal saline infusion in patients at risk of marked elevations in PAWP, volumes in the range of 0.5 L are safe even in patients with established HFpEF.^8,11

Exercise

Exercise is another intervention by which left heart response can be further classified; however, it is more burdensome than volume loading.¹² In recent years, information has become available concerning the hemodynamic response to exercise in healthy, sedentary older adults.^13,14 It is clear that aging augments the PAWP response to exercise. Older individuals also demonstrate a characteristic pattern with an early peak in PAWP responses after the initiation of exercise.^15,16 Although a threshold value of a PAWP >25 mmHg during exercise is employed to identify left heart disease,¹⁷ this approach may be limited by 1) the potential for false positives in healthy older adults and 2) the reliance on single PAWP values assessed at peak effort that may be confounded by measurement artifacts. Exercise provides the opportunity to perform multiple measurements. Importantly, increases in PAWP during exercise are dependent on the increases in cardiac output, and the slope of this relationship does not exceed 2 mmHg/L/min in healthy adults.^13,16 In older adults, this threshold remains intact as long as exercise can be sustained for >3 minutes, beyond the early peak in PAWP. A similar approach is employed to define the normal mPAP response to exercise related to cardiac output, which does not exceed 3 mmHg/L/min in healthy patients.^18,19

In exercise hemodynamic assessments, procedures and criteria for interpretation are not standardized among institutions.^20-23 It is essential to develop systematic local procedures with trained personnel. Some guiding principles for the conduct of exercise hemodynamic testing include 1) use of purpose-built exercise equipment with capacity for measurement of work-rate, 2) rational exercise protocols adjusted for patient tolerance, and 3) processes to ensure quality of hemodynamic recordings and reliable repeated measurements of cardiac output. Hemodynamic measurements should be performed concurrent with semi-upright or upright exercise because effects dissipate very quickly after cessation of exercise. There is valuable information, along with increased complexity, in procedures that incorporate invasive hemodynamics with cardiopulmonary exercise testing.²⁰ The published experience from select centers demonstrates the relative safety of exercise hemodynamic testing.

Provocative Testing in Current Practice and Future Directions

It is important to note that, currently, neither exercise nor the infusion of normal saline has garnered a recommendation as guideline-directed practice for the evaluation of PH.^1,24 Compared with the infusion of normal saline, cycle ergometry is a more potent stressor to elicit abnormal PAWP responses in the setting of known HFpEF.¹¹ It would be tempting to suggest that exercise may also be favored to elicit responses confirming the presence of PH-LHD among patients with apparent PAH. However, prior to recommending provocative testing for this indication, it is necessary to clearly establish demographic and/or hemodynamic selection criteria for the population with a pre-test probability of unmasking PH-LHD high enough to warrant testing. Provocative maneuvers are likely not required in younger patients with unequivocal PAH hemodynamics or, conversely, patients with obvious PH-LHD and HFpEF. A fundamental problem is that the impetus to perform provocative testing is based on doubt in the diagnostic performance of the current gold standard (supine resting RHC). As such, there is no gold standard by which to determine whether exercise or an infusion of normal saline can appropriately reclassify PAH as PH-LHD. On the other hand, the current understanding of physiologic responses to provocative maneuvers should enable clinicians to confirm responses of the left heart that are within normal limits.

There is tremendous opportunity to conduct research addressing the challenges described herein. It will be important to prospectively document the frequency of these exercise phenotypes and whether they are more or less useful than resting RHC in predicting the response to PAH therapy. Although further research is needed, provocative maneuvers performed during RHC offer comprehensive phenotyping based on physiological markers that may improve diagnosis of patients with PH and provide new targets for therapy.

References

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2. Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137:376-87.
3. Galiè N, Barberà JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015;373:834-44.
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19. Naeije R, Vanderpool R, Dhakal BP, et al. Exercise-induced pulmonary hypertension: physiological basis and methodological concerns. Am J Respir Crit Care Med 2013;187:576-83.
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Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Pulmonary Hypertension, Hypertension

Keywords: Pulmonary Wedge Pressure, Diuretics, Heart Ventricles, Hypertension, Hypertension, Pulmonary, Cardiac Catheterization, Diabetes Mellitus, Heart Diseases, Heart Failure, Risk Factors, Stroke Volume

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