INTRODUCTION

In the latter part of the 20th century, Drs Jeremy Swan and William Ganz introduced the use of balloon-tipped, flow-directed catheters, and the modern era of right heart catheterization (RHC) began. It remains the “gold standard” for diagnosis and management of a wide spectrum of cardiopulmonary diseases, and accordingly, the techniques of the procedure have continued to evolve into the 21st century. This review will discuss the modern practice of RHC, including best practices in procedure technique, updated hemodynamic definitions of disease states, and recent developments in the interpretation of provocative maneuvers.

INDICATIONS FOR RHC

RHC may be performed to confirm a diagnosis of pulmonary hypertension (PH) when its presence has been suggested by noninvasive imaging or clinical suspicion. Hemodynamic evaluation is critical to properly phenotype PH patients, and this information is crucial before initiation of pulmonary vasodilator therapy. RHC is also standard in those being considered for advanced heart failure (HF) therapies. In the most recent mechanical sup port and cardiac transplant guidelines, RHC has a class 1 indication to include measurement of the pulmonary vascular resistance (PVR). Pre–heart transplant candidates should undergo RHC every 3 to 6 months, especially if reversible PH is present or HF symptoms are worsening.1,,2 This screening may be omitted in stable patients with a left ventricular assist device who had no evidence of PH before implant.3 

The routine use of pulmonary artery (PA) catheter-guided therapy in patients admitted with HF and symptomatic congestion has failed to reduce hospital length of stay or mortality and may increase adverse events.4 Therefore, RHC should only be performed in those whose hemodynamics are unclear. A commonly encountered clinical situation is that of worsening renal function while attempting diuresis, a situation in which knowing filling pressures and cardiac output (CO) can guide medical therapy or the need to initiate inotropic or mechanical support.

BEFORE YOU BEGIN

Preparation is the key to success. Even before entering the catheterization lab, the operator should have a suspicion of what will be found on the hemodynamic evaluation. Do the findings fit the clinical scenario? For example, if a 26-year-old woman without risk factors for left heart disease, normal left atrial (LA) size, a severely dilated right ventricle (RV) with D-shaped septum, and an estimated RV systolic pressure of 100 mm Hg is found to have a significantly elevated PA wedge pressure (PAWP), the measurement accuracy should be questioned (and confirmed). Issues with patient positioning, calibration, leveling, zeroing, and measurement technique can all contribute to these errors.

Whenever possible, RHC should be performed in stable, noncritical patients who are able to lay supine with their legs flat. Operators should have an unobstructed view of hemodynamic monitors, real-time electrocardiogram, and waveforms. Pressure measurements should be recorded during spontaneous breathing without breath-hold maneuvers, which can lead to inadvertent Valsalva and pre-load alteration. To avoid altered breathing patterns associated with sedation, use of topical and subcutaneous local anesthetics is favored over intravenous sedation. If premedication is required for particularly anxious patients, oral conscious sedation should be considered.

The pressure transducer should be zeroed to atmospheric pressure at the level of the LA. To help ascertain LA position using external landmarks, Kovacs et al. retrospectively compared commonly cited anatomic landmarks to computed tomography–derived biatrial levels. They found that the right atrium (RA) was one-third of the thoracic diameter posterior to the anterior thorax surface in 98.5% of patients. The LA was located in the midthorax level (halfway between the anterior sternum and the table surface, ie, midchest) in 97.4% of patients. Deviations from these points can significantly alter the number of patients classified as having PH and elevated LV pressure.5 Therefore, it is advisable to use a measuring stick to accurately place the transducer at the midthoracic level as an estimation of the LA location.

In addition to inspecting the waveform to determine the current location of the catheter, operators should examine the pressure tracing quality, looking for signs of overdampening or underdampening (see Figures 1A and 1B). Overdampening can occur when air is introduced into the catheter or tubing and may result in the loss of a dicrotic notch in the PA tracing, a blunted RV end-diastolic inflection point, or reduction in the overall amplitude of the pressure tracing (Figure 1A) with concurrent decrease in measured systolic pressure and increase in diastolic pressure (therefore, the mean pressure is usually not affected).6 This can be addressed by fastidiously flushing the catheter or tubing. Catheter ringing (underdampening; Figure 1B) may occur when the frequency of the transmitted waveform (heart rate) approximates the natural resonance frequency of the transducer system and falsely increases the amplitude of the resultant waveform. Similar to overdampening, mean pressure is usually not affected.6 Ringing may be exacerbated by microbubbles in the system; therefore, flushing the system or the introduction of a denser fluid, such as blood or contrast, into the catheter to alter the resonant frequency of the system may reduce this artifact.7 Reducing the length of tubing between the transducer and the fluid-filled catheter may also ameliorate catheter ringing. Pressure lines and transducers should always be inspected for bubbles, which should be removed via adequate flushing before beginning.

Figure 1:

(A) Overdampening. Three separate examples are shown. Overdampening is usually caused by air in the catheter or tubing and may result in loss of the right ventricle (RV) inflection point at end diastole (blue arrow) and loss of the dicrotic notch in the downslope of the pulmonary artery (PA) tracing (red arrow). Overall waveform amplitude is reduced, with falsely low systolic and high diastolic measurements; however, mean pressure is usually not affected. (B) Underdampening. Contiguous tracings in a posttransplant patient with “catheter ringing,” which occurs when the heart rate approaches natural resonance frequency of the transducer system. Sharp, jutting peaks and troughs are seen. The peaks are falsely elevated and troughs falsely lowered. Ringing can be addressed by flushing the system or introducing more dense fluid into the catheter to lower compliance. RA = right atrial; PAWP = pulmonary artery wedge pressure.

Figure 1:

(A) Overdampening. Three separate examples are shown. Overdampening is usually caused by air in the catheter or tubing and may result in loss of the right ventricle (RV) inflection point at end diastole (blue arrow) and loss of the dicrotic notch in the downslope of the pulmonary artery (PA) tracing (red arrow). Overall waveform amplitude is reduced, with falsely low systolic and high diastolic measurements; however, mean pressure is usually not affected. (B) Underdampening. Contiguous tracings in a posttransplant patient with “catheter ringing,” which occurs when the heart rate approaches natural resonance frequency of the transducer system. Sharp, jutting peaks and troughs are seen. The peaks are falsely elevated and troughs falsely lowered. Ringing can be addressed by flushing the system or introducing more dense fluid into the catheter to lower compliance. RA = right atrial; PAWP = pulmonary artery wedge pressure.

WHAT AND HOW TO MEASURE

Antecubital or internal jugular venous access under ultrasound guidance is generally preferred and associated with a better safety profile. Once the venous sheath has been placed, we recommend documenting an oxygen saturation from the high superior vena cava. This allows for an immediate assessment of perfusion status and, importantly, will be compared to the PA saturation to rule out left-to-right intracardiac shunting. A significant step up in oxygenation should prompt further investigation. With the balloon inflated, the PA catheter is then advanced into the RA. A typical RA pressure (RAP) tracing is shown in Figure 2A, consisting of a and v waves with x and y descents.

Figure 2:

(A) Typical right atrial pressure (RAP) tracing. The a-wave represents a rise in atrial pressure due to atrial contraction and temporarily occurs after the P-wave on electrocardiogram. The c-wave represents closure of the tricuspid valve (akin to a dicrotic notch) and occurs in the downslope of the x-descent, which represents atrial relaxation. Therefore, the pre–c-point represents the end of ventricular diastolic filling, just before tricuspid valve closure. The v-wave is a rise in atrial pressure due to ventricular contraction and temporally occurs after the QRS complex on electrocardiogram. The y-descent represents ventricular relaxation. (B) RAP tracing with positive Kussmaul sign and steep y-descents. Kussmaul sign is a paradoxical increase (or a lack of decline) in overall RAP with inspiration (onset starting at red arrow). Steep y-descents are also seen (blue arrows) in which the downslope may be sharper and the nadir lower than the x-descent. (C) Typical right ventricle (RV) tracing. A ventricular waveform is now clearly seen, with step up in peak systolic pressure as compared to RAP. (D) Typical pulmonary artery (PA) tracing. Advancement of the PA catheter past the pulmonic valve is indicated by a step up in diastolic pressure as compared to the RV diastolic pressure and the appearance of a dicrotic notch in the downslope (red arrow). (E) End-diastolic PA wedge pressure (PAWP). Further advancement of the PA catheter into the wedge position will cause overall pressure to decline, and reappearance of a-x-v-y waves. The end-diastolic PAWP is the best surrogate for left ventricular enddiastolic pressure and occurs just before the c-wave (blue arrow). If the c-wave is absent or difficult to identify, an average of the peak and trough of the a-wave is a surrogate. In atrial fibrillation, no a-wave is present, so end-diastole is 130 to 160 milliseconds after the QRS complex and before the v-wave. (F) Mean PAWP. The mean PAWP is often computer generated (black line), represents an average pressure over the entire cardiac cycle, and can be thought of as the totality of pressure the pulmonary circulation “feels” from the left heart. Although enddiastolic and mean PAWP are often similar, in the presence of large v-waves or in atrial fibrillation, the mean PAWP may be higher than the end-diastolic PAWP (blue arrow). This has contributed to “negative diastolic pressure gradients.”

Figure 2:

(A) Typical right atrial pressure (RAP) tracing. The a-wave represents a rise in atrial pressure due to atrial contraction and temporarily occurs after the P-wave on electrocardiogram. The c-wave represents closure of the tricuspid valve (akin to a dicrotic notch) and occurs in the downslope of the x-descent, which represents atrial relaxation. Therefore, the pre–c-point represents the end of ventricular diastolic filling, just before tricuspid valve closure. The v-wave is a rise in atrial pressure due to ventricular contraction and temporally occurs after the QRS complex on electrocardiogram. The y-descent represents ventricular relaxation. (B) RAP tracing with positive Kussmaul sign and steep y-descents. Kussmaul sign is a paradoxical increase (or a lack of decline) in overall RAP with inspiration (onset starting at red arrow). Steep y-descents are also seen (blue arrows) in which the downslope may be sharper and the nadir lower than the x-descent. (C) Typical right ventricle (RV) tracing. A ventricular waveform is now clearly seen, with step up in peak systolic pressure as compared to RAP. (D) Typical pulmonary artery (PA) tracing. Advancement of the PA catheter past the pulmonic valve is indicated by a step up in diastolic pressure as compared to the RV diastolic pressure and the appearance of a dicrotic notch in the downslope (red arrow). (E) End-diastolic PA wedge pressure (PAWP). Further advancement of the PA catheter into the wedge position will cause overall pressure to decline, and reappearance of a-x-v-y waves. The end-diastolic PAWP is the best surrogate for left ventricular enddiastolic pressure and occurs just before the c-wave (blue arrow). If the c-wave is absent or difficult to identify, an average of the peak and trough of the a-wave is a surrogate. In atrial fibrillation, no a-wave is present, so end-diastole is 130 to 160 milliseconds after the QRS complex and before the v-wave. (F) Mean PAWP. The mean PAWP is often computer generated (black line), represents an average pressure over the entire cardiac cycle, and can be thought of as the totality of pressure the pulmonary circulation “feels” from the left heart. Although enddiastolic and mean PAWP are often similar, in the presence of large v-waves or in atrial fibrillation, the mean PAWP may be higher than the end-diastolic PAWP (blue arrow). This has contributed to “negative diastolic pressure gradients.”

During RAP assessment, the presence or absence of the Kussmaul sign should be documented (Figure 2B). This paradoxical increase in pressure (or failure to fall) during inspiration is indicative of a noncompliant RV and can be seen in constrictive pericarditis and advanced HF, including dilated, ischemic, or restrictive cardiomyopathies. In a single-center study, the Kussmaul sign was found in 43% of patients referred for transplantation and was associated with worse hemodynamics, echocardiographic parameters, higher natriuretic peptide levels, higher diuretic doses, lower sodium levels, and worse clinical outcomes.8 The RAP tracing may show prominenty descents, in which the downward slope is more prominent than that of the x wave and the nadir usually deeper (Figure 2B). This suggests a less distensible RV from a variety of causes. Recent work by Harada et al. suggests that this finding, in combination with elevated RV systolic pressure, may predict worse outcomes in HF patients with preserved ejection fraction (HFpEF).9 

A step up in systolic pressure occurs with advancement of the catheter into the RV (Figure 2C). Occasionally, a square root (or dip-and-plateau) sign may be present, which can be seen with severe tricuspid regurgitation, pericardial constriction, and restrictive physiology.10 As the catheter passes the pulmonic valve and enters the PA, a step up in diastolic pressure and a characteristic dicrotic notch in the downslope of the PA tracing are seen (Figure 2D). Finally, when the catheter is advanced into the distal PA, pressure will fall as the catheter achieves a wedge position (Figures 2E and 2F). The PAWP tracing is achieved when a static column of blood is created between the occlusive balloon, the distal pulmonary arterial and venous vasculature, and the LA. The PAWP serves as a surrogate for LA pressure and—in the absence of mitral stenosis—LV end diastolic pressure (LVEDP).

Because of the diagnostic and therapeutic implications of the PAWP, it is of paramount importance to measure it in a standardized fashion with regard to the respiratory and cardiac cycle. In most situations, pressure measurements should be recorded at end expiration, when intrathoracic pressure closely approximates 0 and has the least impact on intracardiac pressures.11 In some situations, particularly severe lung disease or morbid obesity, large respiratory pressure variation may be present, and intrathoracic pressure at end expiration may be higher than 0. Esophageal pressure–transducing balloon catheters can be used to estimate intrathoracic pressure, thus allowing for more exact determination of intracardiac pressures by subtracting the esophageal pressure.12 As these instruments are not routinely available, reporting an average pressure over the respiratory cycle may be preferred.13 We typically report both end expiratory and averaged values when significant respiratory variation is present. Additionally, Cheyne-Stokes breathing may be present in patients referred for RHC. Operators should be careful to measure all pressures during the same phase of the breath cycle (hyperpnea versus apnea).

Recent work has also highlighted the importance of standardization of PAWP measurement with regard to the cardiac cycle. At end diastole, the mitral valve is open, and thus LA pressure (and PAWP) should be equal to LVEDP. On the PAWP tracing, end diastole occurs just before the c-wave (mitral valve closure). Because the c-wave may be difficult to identify on a fluid-filled catheter tracing, the peak and trough of the a-wave is averaged and correlates with the pre–c-wave value (Figure 2E). This value is the best estimate of LVEDP. Because no a-wave exists when atrial fibrillation is present, end-diastolic PAWP is measured 130 to160 milliseconds after the onset of QRS and before the v-wave.11,14,15 Mean PAWP, or PAWP averaged over the cardiac cycle, encompasses the pressure waveform during both systole and diastole. This may best represent the pressure “felt” by the pulmonary circulation from the left heart. Although in many instances mean PAWP approximates end-expiratory PAWP, the presence of large v-waves and atrial fibrillation lead to a mean PAWP greater than end-diastolic PAWP (Figure 2F). The use of mean PAWP rather than end-diastolic PAWP contributes to the phenomenon of “negative” diastolic pulmonary gradients.16–18 The presence of large v-waves suggests a contribution of left heart disease (significant mitral regurgitation or stiff LA syndrome) regardless of the measured PAWP and should always be noted as part of the hemodynamic report. Frequently, large v-waves resolve during systemic vasodilator challenge.

Whenever a PAWP tracing is atypical or if a diagnosis of PH is being considered and measured PAWP is greater than 15 mm Hg, a PAWP saturation should be obtained to confirm complete occlusion and an accurate measurement.11 An inadequately wedged balloon allows the transduction of higher pressure from the more proximal PA into the wedge tracing, falsely elevating it. It also allows leakage of deoxygenated blood into the static column distal to the balloon. To obtain a wedge saturation, slowly withdraw and waste a sample of blood from the distal port of the PA catheter with the balloon inflated in wedge position until the blood appears bright red, then withdraw another 1- to 2-mL sample for oxygen saturation measurement. A truly wedged catheter should yield an oxygen saturation reflective of the postcapillary pulmonary bed, typically >90% or within 5% of systemic oxygen saturation. Lower values should prompt repeat attempts to wedge or consideration of a direct LVEDP measurement.

CO MEASUREMENTS

The direct Fick method remains the “gold standard” for estimating CO. However, the technique requires specialized equipment to properly measure oxygen consumption, which is generally not feasible in most catheterization laboratories. Therefore, thermodilution (TD) and the indirect Fick method are more commonly used. The indirect Fick method uses estimated values for oxygen uptake originally derived from the TD method in patient populations that were highly selected, lean, and homogeneous with regards to age and race. Therefore, extrapolating oxygen consumption to a population of patients with HF, PH, or obesity is likely to induce error.19 

When measuring TD CO, injection of saline should occur at the same point of the respiratory cycle.20 Although TD is commonly cited to be less accurate in the setting of tricuspid regurgitation and extremes of CO, studies have shown good correlation with TD and Fick in these situations.21,,22 TD is the preferred method of measuring CO,23 with one caveat being the presence of an intracardiac shunt, in which TD should not be used. An analysis of over 15 000 patients undergoing RHC showed a poor correlation between TD and indirect Fick methods, with one-third of the cohort differing by greater than 20%. Low cardiac index as measured by the TD method was superior in predicting 90-day mortality to the Fick method; therefore, TD should be favored in clinical practice.24 This was recently corroborated in a cohort of pulmonary arterial hypertension (PAH) patients in which the TD and indirect Fick indices (with oxygen consumption estimated by 3 different formulas) were compared against direct Fick indices. The TD method and indirect Fick using the Dehmer formula had high accuracy (but poor precision) as compared to direct Fick, whereas indirect Fick using the Bergstra or La-Farge-Miettinen methods overestimated and underestimated oxygen consumption, respectively. Also notable in this study was the lack of effect of tricuspid regurgitation, even when severe, on TD accuracy.25 

APPLICATION OF HEMODYNAMICS TO CLINICAL DIAGNOSES

The current hemodynamic definition of PH is a mean PA pressure (mPAP) >20 mm Hg.26 Additional hemodynamic classification is based on the PAWP, with >15 mm Hg considered consistent with Group 2 PH, or PH due to left heart disease (PH-LHD). PH-LHD encompasses a spectrum of widely varying pathologies and clinical diagnoses, including HF with reduced (HFrEF) or preserved ejection fraction (HFpEF), valvular disease, restrictive cardiomyopathy or constrictive pericarditis, and congenital or acquired cardiovascular conditions associated with left-to-right shunting.

PH-LHD can be further dichotomized into isolated postcapillary PH (IpcPH)—in which elevated PA pressure is a result of (and proportional to) the degree of chronic passive elevation of LV filling pressure—and combined postcapillary and precapillary PH (CpcPH), in which PA pressure is often higher than expected (“out of proportion”) to the degree of LV filling pressure.

How to define the precapillary component remains debated. The Fifth World Symposium on Pulmonary Hypertension (WSPH) proposed that the diastolic pressure gradient (DPG) alone should differentiate these 2 entities (with DPG < 7 mm Hg in IpcPH and ≥7 mm Hg in CpcPH), but subsequent controversy over its prognostic ability and concerns related to measurement fidelity led to its abandonment in favor of PVR in the Sixth WSPH position statement. Thus, IpcPH is currently defined as PAWP > 15, mPAP > 20 mm Hg, and PVR < 3 Wood units (WU), and CpcPH is defined as PAWP > 15, mPAP > 20 mm Hg, and PVR ≥ 3 WU.11 Because the use of PAH-specific therapies is not recommended in the CpcPH population, this differentiation is more relevant for risk stratification, assessment of candidacy for advanced HF therapies, and clinical trial enrollment rather than to specifically guide treatment.

Other hemodynamic parameters useful in risk stratification are shown in Table 1.

Table 1.

Derived Hemodynamic Parameters a

Derived Hemodynamic Parameters a
Derived Hemodynamic Parameters a

PROVOCATIVE TESTING

In the early stages of cardiopulmonary disease, resting pressures may be normal, with abnormalities in hemodynamics only becoming apparent with provocation.27 Diuretics may also lower LV filling pressures into the normal range despite the presence of LHD. This practice can make PH-LHD in the setting of HFpEF particularly difficult to differentiate from PAH. Therefore, saline loading or dynamic exercise can be important additional tools in the evaluation of undifferentiated dyspnea. These provocative maneuvers may unmask occult PH-LHD, differentiate PAH from HFpEF, or diagnose exercise PH (EPH). Vasodilator challenges can be performed to assess reactivity of the pulmonary vasculature in select patients with Group 1 PAH or Group 2 PH as part of cardiac transplant candidacy evaluation.

SALINE LOADING: WHAT CONSTITUTES AN ABNORMAL RESPONSE?

Patients undergoing RHC are in a fasting state, and many have undergone diuresis prior to the procedure. Therefore, resting PAWP can be normal even in the setting of LHD and perhaps lead to an erroneous diagnosis. In a cohort of 207 patients labeled as PAH, 22% were reclassified to occult PH-LHD when normal resting PAWP increased to >15 mm Hg after an infusion of 0.5 L of saline over 5 to 10 minutes.28 However, one criticism of this study is that a rise in PAWP to >15 mm Hg with saline infusion can be seen even in healthy controls, as suggested by Fujimoto et al.29 and Borlaug.30 In their study of healthy young and older subjects, several increased PAWP to >15 mm Hg, but none reached a PAWP >18 mm Hg after 500 cc of normal saline.

Data further confirming a cutpoint of 18 mm Hg as an abnormal response to saline loading come from D'Alto et al., who infused 7 mL/kg of saline (mean volume infused 478 mL, and 40% of the cohort received >500 mL) into a cohort of 212 patients referred for RHC. The authors found that 6% of those with baseline precapillary PH and 8% of those with no PH at baseline were relabeled as postcapillary (hidden) PH. Prediction bands derived from quadratic fits of the individual responses in no-PH and precapillary PH patients confirmed 18 mm Hg as an abnormal response to saline loading (see Figure 3).31 

Figure 3:

Pulmonary artery wedge pressure (PAWP) relative to saline infusion. Data from D'Alto et al.31 showing increases in PAWP with 500 mL saline bolus in those with no baseline pulmonary hypertension (PH; left), baseline precapillary PH (middle), and baseline postcapillary PH (right). The shaded areas represent quadratic fits of the pooled responses and indicate that 18 mm Hg is a reasonable cut point for abnormal PAWP response to saline infusion. Black dots represent patients with hidden left heart disease, defined by PAWP > 18 mm Hg after fluid challenge. Used with permission.

Figure 3:

Pulmonary artery wedge pressure (PAWP) relative to saline infusion. Data from D'Alto et al.31 showing increases in PAWP with 500 mL saline bolus in those with no baseline pulmonary hypertension (PH; left), baseline precapillary PH (middle), and baseline postcapillary PH (right). The shaded areas represent quadratic fits of the pooled responses and indicate that 18 mm Hg is a reasonable cut point for abnormal PAWP response to saline infusion. Black dots represent patients with hidden left heart disease, defined by PAWP > 18 mm Hg after fluid challenge. Used with permission.

Finally, Andersen et al. recently explored the effects of both saline loading (150 mL/min to total 10 mL/kg) and exercise during the same procedure in a cohort of healthy and HFpEF patients. With saline loading, healthy controls had a baseline mean PAWP of 7 mm Hg and rose to a mean of 13 ± 6 mm Hg (ie, less than 19 mm Hg), while patients with known HFpEF had a baseline mean PAWP of 14 mm Hg which rose to 21 ± 4 mm Hg with saline.27 

In summary, a PAWP > 18 mm Hg immediately after a 500-mL saline bolus over 5 minutes is likely abnormal and may be consistent with LHD.11 Data are lacking about optimal treatment for these individuals, whom we are likely including in PAH clinical trials.

EXERCISE: HEMODYNAMIC INTERPRETATION

Exercise RHC is more challenging to perform and interpret than resting hemodynamic assessment. Large swings in intrathoracic pressure are common and end-expiratory pressure may be an overestimate.13 Because of this, it is recommended to take the average pressure over several respiratory cycles (respiratory mean) during exercise maneuvers.32 Exercise increases catheter ringing and motion artifacts, which are known to amplify the peaks and troughs of waveforms. Therefore, only the mean of the individual waveforms for RAP, mPAP, and PAWP are typically reported.

Exercise positioning is another important consideration. It may be performed supine, semi-upright, or upright. Many operators feel upright exercise reproduces symptoms more consistently. Exercise duration is longer and chronotropic response is more significant in the upright position compared with supine.33 However, upright positioning may also be more difficult to perform, requires additional equipment and personnel, and may not always be feasible. Thus, it is important to understand the impact of positioning on hemodynamic data. At rest, an upright patient will have a lower mPAP, PAWP, stroke volume, and CO, and a higher heart rate, PVR, and arteriovenous oxygen difference as compared with a supine patient. With exercise, these positional differences diminish, and at maximal exercise, there are likely no major differences.32 The PAWP increases linearly with CO in either supine or upright exercise,34,,35 although typically supine PAWP is ~5 mm Hg higher than upright.11 During exercise a supine patient will have a slight reduction in PVR, thought to be due to the increased distensibility of pulmonary resistive vessels in zone 3 when fully recruited in supine position. PVR also declines in upright exercise, but as the resting PVR is generally higher than supine, the decline in exercise PVR is more marked.34 

The duration of exercise is also relevant. Older but otherwise healthy individuals may have delayed pulmonary vascular accommodation to exercise-induced increases in CO, as manifested by marked early increase in PA pressure and PAWP that may decline within several minutes of sustained exercise. In a cohort of healthy volunteers, Wright et al. saw that with light semi-upright exercise, the mean baseline PAWP of 11 mm Hg significantly increased to 22 mm Hg at 2 minutes but declined to 17 mm Hg by 7 minutes (still significantly higher than baseline). With continued exercise to a higher workload, the PAWP increased again to 20 mm Hg at 2 minutes and again declined to 15 mm Hg by 7 minutes. Therefore, even healthy patients may routinely exceed 20 mm Hg early in exercise, but decline within several minutes.36 The most recent position statement from the European Respiratory Society (ERS) recognizes that, while 3 to 5 minutes per stage is ideal to achieve steady-state oxygen uptake, for practical purposes, a shorter interval of 2 minutes is reasonable, with an exercise duration goal of 10 minutes total.32 

Oxygen consumption for Fick estimation of exercise CO must be directly measured and cannot be derived from standard formulas as is done with indirect Fick at rest. Given the rapidity of obtainment during an exercise protocol, the TD method is a reasonable alternative and should be collected. However, data from Hsu et al. suggest that, as CO increases, TD may significantly underestimate the CO obtained via the direct Fick method (9.0 L/min versus 11.3 L/min at peak exercise). The lower TD CO estimates subsequently led to significant overdiagnoses of EPH when applied to 2 newer criteria (described below).37 

EXERCISE: WHAT CONSTITUTES AN ABNORMAL RESPONSE

The most recent ERS position statement does not identify a widely accepted hemodynamic definition of EPH.32 A prior guideline threshold of mPAP > 30 mm Hg was abandoned at the Fourth WSPH, as it was realized that the pulmonary response to exercise depends on multiple variables, and no single value threshold would suffice to define pathology. This decision was influenced by a large meta-analysis of almost 1200 healthy patients showing the age dependency of mPAP during exercise: the upper limit of normal for those <50 years old was 29 mm Hg, but was 46 mm Hg for those >50 years old; almost 50% of healthy patients >50 years old achieved an mPAP > 30 mm Hg with exercise.38 

Furthermore, pressure is a flow-dependent variable that may be elevated due to high CO in the absence of pathology. Therefore, more recently proposed criteria for EPH have focused on the pressure-output slope relationship. Naeije et al. suggested that the normal limits of total pulmonary resistance (TPR, mPAP/CO) are between 0.5 and 3.0 mm Hg·min·L−1 and that a multipoint slope of this relationship at progressive time points of >3 corresponds to a diagnosis of EPH.35 Ho et al. recently showed reduced cardiovascular event-free survival among individuals with normal resting pressures, but who met this criteria during exercise.39 

Herve et al. investigated a simpler approach in a cohort of 169 patients comprised of normal controls, those with known pulmonary vascular disease, and those with known LHD—but all with a resting mPAP ≤ 20 mm Hg. In the normal controls, the upper limits of exercise PAWP and mPAP were 19 and 37 mm Hg, respectively, and a quarter (26%) had mPAP > 30 mm Hg. The diagnostic accuracy of resting and exercise mPAP, PVR, and TPR was assessed. All resting hemodynamic parameters had low diagnostic specificity, but exercise TPR and mPAP had high diagnostic accuracy at optimal values of 2.97 WU and 31 mm Hg, respectively. As seen in Figure 4, using cutoff lines at these approximate values, the controls were clearly able to be discriminated from the 2 pathological groups. Finally, the authors noted that the combined criteria were met at low workloads (CO) in most patients, implying that, if an mPAP > 30 mm Hg is reached before 10 L/min is reached, the test can be terminated even at low workload, having already met the aforementioned criteria.40 Most recently, 2 retrospective studies have suggested the Herve method (combination of mPAP > 30 mm Hg and TPR > 3 WU) is more sensitive than the mPAP-CO slope method.41,,42 

Figure 4:

Relationship between exercise mean pulmonary artery pressure (mPAP) and cardiac output (CO). Data from Herve et al.40 showing that the exercise response in known left heart disease (LHD) or pulmonary vascular disease (PVD) was accurately discriminated from controls and healthy volunteers using cutoff values of 30 mm Hg for mPAP (horizontal dashed line), 3 Woods units (WU) for total pulmonary resistance (TPR; mPAP/CO, sloped dashed line). This relationship implies that reaching an mPAP > 30 mm Hg at CO < 10 L/min is pathologically abnormal. Used with permission.

Figure 4:

Relationship between exercise mean pulmonary artery pressure (mPAP) and cardiac output (CO). Data from Herve et al.40 showing that the exercise response in known left heart disease (LHD) or pulmonary vascular disease (PVD) was accurately discriminated from controls and healthy volunteers using cutoff values of 30 mm Hg for mPAP (horizontal dashed line), 3 Woods units (WU) for total pulmonary resistance (TPR; mPAP/CO, sloped dashed line). This relationship implies that reaching an mPAP > 30 mm Hg at CO < 10 L/min is pathologically abnormal. Used with permission.

The criteria defining an abnormal PAWP response to exercise have been similarly debated. The ERS position statement suggests that a PAWP of 20 (upright) or 25 mm Hg (supine) may be considered the upper limit of normal, but also points out that evidence supporting these thresholds is scarce. Wolsk et al. showed that, in a cohort of healthy patients, no subject aged 20 to 39 years had PAWP > 25 mm Hg at peak exertion, but 30% of those aged 60 to 79 years exceeded this value.43 

Similar to the above discussion with mPAP, the inadequacy of a single time-point PAWP and the flow-dependency of the wedge pressure have also been recognized. In a cohort of 175 patients comprised of controls, HFpEF patients, and those with exertional dyspnea but normal PAWP and LVEF, Eisman et al. found that PAWP rose linearly with CO, with the lowest PAWP/CO slope in the control group and the highest in the HFpEF group (1.2 versus 3.6 mm Hg·min·L−1). When a PAWP/CO slope of 2 mm Hg·min·L−1 was defined as abnormal (2 standard deviations above the control mean), approximately 40% of the dyspneic patients with normal PAWP and normal LVEF were found to have abnormal PAWP/CO slope. More importantly, these patients were found to have a 3.4-fold higher risk for cardiovascular death, incident HF hospitalization, or subsequent RHC with PAWP ≥ 15 mm Hg. 44 In the aforementioned Wright et al. cohort of healthy patients, PAWP/CO slopes were <2 mm Hg·min·L−1 with both sustained light and moderate exercise.36 

OTHER EXERCISE CONSIDERATIONS

Oldham et al. described a cohort of 49 patients consisting primarily of young women with exertional intolerance, normal biventricular ejection fractions, no PH, and impaired oxygen consumption due to decreased CO in the face of low biventricular filling pressures during upright exercise testing. After infusion with normal saline, this cohort still had lower peak exercise RAP and PAWP compared with normal subjects, resulting in lower stroke volume augmentation and suggesting preload insufficiency as a cause of impaired exercise output. Almost 20% of the cohort had evidence of abnormal neuroendocrine testing (postural orthostatic tachycardia syndrome, adrenal insufficiency, autonomic neuropathy). The group termed this syndrome “preload insufficiency” and suggested that the diagnosis should be considered when maximal exercise RAP is <6.5 mm Hg, maximal PAWP is <12.5 mm Hg, or when the increase in RAP is <5.5 mm Hg or PAWP increase is <6.75 mm Hg, particularly when other causes of impaired output have not been identified.45 

Operators should be aware that development of an RV outflow tract (OT) gradient may occur during exercise. In a cohort of almost 300 patients without congenital heart disease, Van Riel et al. described a mean RVOT gradient of 8.8 mm Hg at rest and 18.7 mm Hg with exercise. High gradients were more commonly found in younger males with higher peak oxygen consumptions. Subsequent work showed that a high RVOT gradient was not associated with HF but in fact the opposite: lower biventricular filling pressures, higher CO, and higher peak oxygen consumption. Given that these patients were referred for exertional symptoms, it is unclear at present whether development of an RVOT gradient with exercise can be a normal finding or is pathological.46,,47 This may also have important implications for using stress echocardiography as a diagnostic tool.

COMPARISON OF EXERCISE AND SALINE LOADING

Both saline loading and exercise increase venous return to the heart; however, saline loading has minimal effects on blood pressure and heart rate as compared with exercise testing29 and thus theoretically isolates ventricular compliance as the sole variable being tested. Alternatively, exercise testing is more physiologic and induces other stresses on the heart, such as increased heart rate with shorter diastolic filling time and increased contractility with resultant increased myocardial wall stress and oxygen demand.27 Exercise testing may be more sensitive than saline loading for the detection of occult LHD.27 

While exercise testing may provide a more accurate reflection of exertional physiology, it requires more specialized equipment and expertise. Saline infusion is less technically difficult to perform, requires less preparation and specialized equipment, and is more widely available. As mentioned, exercise causes more dramatic respiratory variation and thus a higher likelihood of error in waveform interpretation. For these reasons, the Sixth WSPH has recommended that patients with intermediate to high pretest probability of PH-LHD and PAWP 13 to 15 mm Hg undergo a fluid challenge over exercise testing.11 

VASODILATOR CHALLENGES

A vasoreactive challenge should be performed in individuals with idiopathic or anorexigen-associated PAH. This maneuver is typically performed with inhaled nitric oxide at 10 to 80 ppm. Other vasodilators may also be used, including intravenous epoprostenol or adenosine, or inhaled iloprost. A positive vasoreactive response is defined as a decrease in mPAP ≥ 10 mm Hg to an absolute value ≤40 mm Hg with unchanged or increased CO. It is not recommended in other forms of PAH, as a positive test is not associated with a long-term response to calcium channel monotherapy.48 Conversely, the presence of vasoreactivity has been associated with improved survival in a cohort of PH patients regardless of etiology, and therefore, a vasoreactive challenge may be considered for prognostic purposes.49 

Vasoreactivity testing is typically not indicated in PH-LHD, unless it is being performed in the context of heart transplantation evaluation. Heart transplant candidates with a PVR > 5 WU and transpulmonary gradient >15 mm Hg are at higher risk of early mortality.50 However, if PVR can be reduced to <2.5 WU while maintaining a systolic aortic pressure of 85 mm Hg, risk appears mitigated.51 Nitroprusside is the most commonly used and has the added safety benefit of a short half-life. Inhaled nitric oxide may increase LA pressure and cause pulmonary edema.52 Other agents like intravenous nitroglycerin, milrinone, intravenous prostacyclin, and prostaglandin E1 have also been used to test for reversibility. Although prior guidelines suggest testing only when PA systolic pressure is >50 mm Hg, a recent study by Crawford et al. found that elevated PVR in those with mPAP < 25 mm Hg had similar postoperative risk.53 Therefore, we recommend testing in any candidate with PVR > 3 WU regardless of PA pressure.

CONCLUSIONS

Invasive hemodynamics are critical for diagnosis and treatment of cardiopulmonary disease. The modern era has seen substantial progress in the standardization of procedural techniques and waveform interpretation. Provocative maneuvers are increasingly being used to refine diagnosis and assess for early pathology.

Disclosure: There are no conflicts of interest or disclosures to report.

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