Passive Leg Raise: A Leg Up in the Diagnosis of Heart Failure With Preserved Ejection Fraction?

The diagnosis of heart failure with preserved ejection fraction (HFpEF) relies on typical heart failure symptoms coupled with evidence of elevated left ventricular filling pressures despite an left ventricular ejection fraction ≥50%. While seemingly straightforward, establishing this diagnosis can often prove challenging. By now, it is well appreciated that clinical, laboratory, and echocardiographic indicators of HFpEF have sub-optimal sensitivity and specificity, and that the diagnosis of HFpEF should be confirmed hemodynamically when necessary.¹ But even among patients who go on to diagnostic right heart catheterization (RHC), HFpEF can be missed in patients on diuretics who are euvolemic. Moreover, RHC can easily miss HFpEF in its early stages, during which intracardiac filling pressures only rise during physiological stress—so-called occult HFpEF. In such cases, hemodynamic assessment of the unstressed cardiovascular system falls short, leaving a substantial subset of patients without a clear diagnosis.²

In these cases, invasive exercise hemodynamic testing has emerged as the gold standard to clarify the diagnosis of HFpEF.³ In a seminal 2010 study, Borlaug et al described the utility of invasive exercise hemodynamic testing in the evaluation of HFpEF.⁴ Based on comparison between patients with HFpEF versus noncardiac dyspnea, a threshold exercise pulmonary capillary wedge pressure (PCWP_Exercise) ≥25 mm Hg emerged as ideal for discriminating HFpEF.⁴ This threshold has held steady over a decade of subsequent investigation,² even taking into account the natural rise of peak PCWP_Exercise with age in healthy controls.⁵ A complementary hemodynamic parameter involves measuring PCWP and cardiac output throughout exercise to generate a PCWP/cardiac output slope; a slope >2 mm Hg·min·L⁻¹ is indicative of HFpEF.⁶ Together, these studies have established invasive exercise hemodynamic testing as the ideal means to identify occult HFpEF.^3,6-8

While definitive, invasive exercise hemodynamic testing requires additional equipment, expertise, and procedural time, and its execution can vary among performing centers. Together, these factors preclude more widespread use. Thus, more accessible methods of uncovering occult HFpEF would indeed prove beneficial. Two such alternatives include rapid saline infusion and passive leg raise (PLR). Rapid saline infusion during RHC (500 mL of normal saline or ≈7 mL/kg) is simpler to execute than exercise RHC.⁹ However, the discriminatory capability of rapid saline infusion for HFpEF remains unclear. While it is clear that a rapid infusion of saline results in a higher PCWP in HFpEF patients versus healthy subjects, its diagnostic sensitivity remains inferior to exercise in the identification of HFpEF.¹⁰ Moreover, execution of something as simple as a saline infusion can still vary among various centers, due to variable preferences for venous access site, the caliber of the introducer sheath, and the duration of saline infusion. Therefore, even a fluid challenge can leave something to be desired in the hemodynamic diagnosis of HFpEF. Overall, PLR would be a very available yet simpler way to volume load the heart. However, whether PLR during RHC can reliably diagnose occult HFpEF has remained unclear.

In this issue of Circulation: Heart Failure, Dr van de Bovenkamp et al¹¹ sought to determine the diagnostic accuracy and cutoff values of PLR PCWP during RHC as compared to exercise RHC for the diagnosis of occult HFpEF. The investigators first studied a derivation cohort referred for RHC for evaluation of unexplained dyspnea or pulmonary hypertension. This cohort included 109 patients who underwent routine RHC, PLR (50 degrees for up to 3 minutes), then standard supine bike exercise. Patients were grouped by resting and exercise PCWP into non-HFpEF (n=39; PCWP_rest <15, PCWP_exercise <25 mm Hg), occult HFpEF (n=33; PCWP_rest <15, PCWP_exercise ≥25 mm Hg), and manifest-HFpEF (n=37; PCWP_rest ≥15 mm Hg) groups. In the derivation cohort, PCWP_PLR demonstrated excellent concordance with exercise in the diagnosis of HFpEF. PCWP_PLR demonstrated an area under the receiver operating characteristic of 0.91 for the diagnosis of HFpEF among the entire cohort and 0.82 for the diagnosis of occult HFpEF (manifest-HFpEF group excluded). Cutoff values of PCWP_PLR ≥19 and >11 mm Hg achieved specificity and sensitivity of 100%, respectively. Importantly, these cutoffs were externally validated in a cohort of 74 patients (including 18 occult HFpEF and 24 non-HFpEF), where PCWP_PLR sensitivity and specificity were confirmed. In fact, PCWP_PLR demonstrated an even higher overall area under the receiver operating characteristic of 0.95 for the diagnosis of occult HFpEF.

We commend Dr van de Bovenkamp et al for their rigorous study of PLR during RHC for the diagnosis of occult HFpEF. The findings build upon prior studies of PCWP_PLR,^4,12 but this is now the largest study to date and the first to externally validate its initial results while also establishing potential diagnostic cutoffs. While the derivation cohort was a retrospective one, these results were validated in a separate cohort that was prospectively studied.⁷ That 2 distinct HFpEF cohorts, each from its own continent, yielded such similar cutoffs helps with the generalizability of these findings. Methodologically, patients were even studied on their baseline diuretic medications during nonfasting conditions, thereby mimicking their basal physiological state with good fidelity. Moreover, the authors prospectively measured PCWP_PLR over time, showing that mean time to max PCWP_PLR was only ≈20 seconds. This observation may reveal yet another advantage of PLR over rapid saline infusion, since in practice there can be occasional delays between infusion completion and subsequent PCWP measurement. The addition of RHC PCWP_PLR to our HFpEF diagnostic armamentarium has strong potential to benefit future HFpEF evaluation algorithms. It could certainly be considered as an easier, viable alternative at centers that employ rapid saline infusion and should also be considered at centers with invasive exercise RHC capability. Moreover, it would be an easy maneuver that could help confirm the diagnosis of group I pulmonary arterial hypertension when a borderline resting PCWP may blur the line with group II disease.

Strengths aside, there were some important limitations worth considering in the present study. First, mean baseline PCWP in the manifest-HFpEF group was significantly elevated at 18±3 mmHg, greatly increasing the likelihood that this group would surpass the diagnostic cutoff established for PCWP_PLR. As such, this contributed strongly to the impressive PCWP_PLR area under the receiver operating characteristic of 0.91 in the overall cohort. In practice, with manifest-HFpEF excluded, the area under the receiver operating characteristic of this diagnostic maneuver fell to a more modest 0.82. Second, using the cutoffs recommended by the authors would have left approximately two-thirds of patients still in need invasive exercise testing. This reflects the weaker effect on PCWP of rapid volume expansion, whether by PLR or saline infusion, when compared with exercise—an observation which has been previously shown.¹⁰ Thus, while PLR could save some time, some centers may prefer to commit to exercise RHC in all subjects. Practically speaking, an exercise ergometer still has to be loaded in advance onto the cath lab table for all cases. Thus, the omission of exercise does not save much time once the patient is already on the table, and exercise affords additional diagnostic information beyond the identification of occult HFpEF. Instead, the utility of PCWP_PLR may be most useful at centers that do not have invasive exercise RHC capability. Perhaps a comprehensive diagnostic score, incorporating RHC PCWP_PLR with clinical and echocardiographic features obtained before catheterization, could fully obviate the need for exercise RHC? Or, maybe imaging done at time of PLR could help clarify further: HFpEF patients have indeed been shown to demonstrate reduced echocardiographic left atrial strain in response to PLR.¹³ Lastly, it remains unclear if PCWP_PLR is superior to rapid saline infusion. Hopefully, future studies will directly compare the 2, since the latter is already used at many centers. Certainly, the former would generally be preferred, as it is faster, more physiological, can be performed regardless of introducer sheath and catheter position, and avoids the introduction of a significant amount of fluid. But that would only be true if PLR was at least noninferior.

Dr van de Bovenkamp et al have contributed a valuable study that externally validates the PLR PCWP and defines diagnostic cutoffs for use in its evaluation of occult HFpEF. As the authors suggest in the proposed diagnostic algorithm, PCWP_PLR could be incorporated into a HFpEF hemodynamic diagnostic algorithm, with PCWP_PLR ≥19 mm Hg ruling in HFpEF and <11 mm Hg ruling out HFpEF. Exercise testing would then only be required in the intermediate cases. PCWP_PLR seems to be an important diagnostic tool that warrants consideration in future hemodynamic diagnostic algorithms for HFpEF. If it can perhaps replace rapid saline infusion, or, better yet, fully eliminate the need for exercise, then PCWP_PLR could significantly improve the diagnostic rigor of HFpEF at many more centers.