Invasive Exercise Haemodynamics: An Oracle in Heart Failure with Preserved Ejection Fraction Diagnosis and Prognostication

This article refers to ‘Central haemodynamic abnormalities and outcome in patients with unexplained dyspnoea’ by K. Omote et al., published in this issue on pages 185–196. Patients with unexplained dyspnoea on exertion represent a diagnostically challenging population. Reliance on cardiopulmonary diagnostic testing solely performed at rest poses significant risk of overlooking physiologic abnormalities unmasked by exercise. Exercise invasive haemodynamic measurements have emerged as an important modality for assessment and differentiation of cardiac versus non-cardiac dyspnoea and their value is increasingly recognized by guidelines and major consensus documents.1-3 In the current issue of the Journal, Omote et al.4 expand the knowledge base underlying the importance of pulmonary arterial catheter-based haemodynamic measurements in the evaluation of suspected heart failure with preserved ejection fraction (HFpEF). The authors investigated whether abnormal invasive haemodynamic parameters derived during clinically-indicated supine cardiopulmonary exercise testing (CPET) predict heart failure-related hospitalizations or death. This retrospective analysis of 764 patients with unexplained dyspnoea included three groups: (i) patients with haemodynamic evidence of HFpEF at rest based on pulmonary arterial wedge pressure ≥15 mmHg (rPAWP≥15, n = 384); (ii) patients with haemodynamic evidence of HFpEF defined by a supine peak exercise PAWP ≥25 mmHg (exPAWP≥25, n = 187); and (iii) patients with ‘non-cardiac dyspnoea’ (NCD) based on not only having rPAWP <15 mmHg and exPAWP <25 mmHg but also having resting mean pulmonary arterial pressure (PAP) <20 mmHg as well as pulmonary vascular resistance (PVR) <3 Wood units (WU) at rest and mean PAP ≤30 mmHg or PVR <3 WU with exercise. This grouping clusters those with abnormal pre-capillary pulmonary haemodynamics exclusively with the two elevated PAWP groups, arguably enriching for adverse outcomes in comparison to the NCD group. Over a median follow-up period of 2.7 years, 117 events were identified. The authors found that: (i) the rPAWP≥15 group demonstrated increased risk of combined outcomes compared to rPAWP <15 mmHg with exPAWP≥25 (hazard ratio [HR] 2.24; 95% confidence interval [CI] 1.38–3.65), and (ii) the exPAWP≥25 group demonstrated increased risk for adverse events compared to NCD (HR 2.44; 95% CI 1.11–5.36). Importantly, lower cardiac output (CO) during exercise also predicted increased risk for adverse outcomes (HR 2.35; 95% CI 1.50–3.68; p = 0.0002). When examined as continuous variables, one standard deviation increase in exPAWP and decrease in exercise CO resulted in 30% (HR 1.30; 95% CI 1.05–1.62) and 33% (HR 0.67; 95% CI 0.51–0.89) increase in combined outcomes, respectively. The integrated measure PAWP/CO slope also predicted adverse outcomes (log PAWP/CO slope, HR 1.20; 95% CI 1.02–1.41). Overall, the authors should be commended on this comprehensive and in-depth analysis. First, they extensively evaluated the prognostic impact of multiple pertinent haemodynamic parameters including PAWP, PAP, right atrial pressure (RAP), PVR, pulmonary artery compliance (PAC), CO, as well as PAWP/CO and mean PAP/CO slopes, more parameters than any previous exercise haemodynamic study.4-8 In addition, they used echocardiography to exclude patients with underlying conditions that could manifest with HFpEF symptoms, thus further refining the focus on HFpEF. The present study further establishes the role of exercise haemodynamic measurements to both diagnose and risk stratify patients with suspected HFpEF. This analysis complements previous studies (Table 1) in which normal rPAWP with a steep increment in PAWP in response to exercise purports an intermediate prognosis between those with normal rest and exPAWP and those with elevated resting and exPAWP.5-7, 9 NYHA class II or III 61.2 ± 11 years, 33.8% male BMI 27.8 ± 4.5 kg/m2 rPAWP >12 PAWPL >25.5 Both 2.21 [1.14–4.17]a 5.44 [2.88–10.29] 4.75 [1.90–11.84] Peak work 74 ± 33 W Peak RER N/R Unexplained dyspnoea 56 ± 17 years, 37% male BMI 29.0 ± 6.7 kg/m2 Peak work N/R Peak RER 1.14 ± 0.12 3.4 [1.2–10.4]a 11 HF hospitalizations 4 deaths 7 RHC Unexplained dyspnoea 56 ± 17 years, 41% male BMI 29.2 ± 6.5 kg/m2 Peak work 102 ± 46 W Peak RER 1.17 ± 0.13 1.28 [1.17–1.41]a 167 CV hospitalizations 80 deaths (3.7 years) Unexplained dyspnoea 65 ± 12 years, 57% male BMI 27.5 ± 4.7 kg/m2 Peak work 64 ± 38 Wb Peak RER N/R rPAWP >12 PAWPL >25.5 mmHg/W/kg 1.73 [1.32–2.26]b 4.48 [2.64–7.61] 170 deaths (8.5 years) Unexplained dyspnoea 65 ± 12 years, 43% male BMI 31.7 ± 7.2 kg/m2 Peak work 50 ± 32 W Peak RER 1.01 ± 0.11 rPAWP exPAWP PAWP/CO slope (log) 1.50 [1.22–1.83]a 1.30 [1.05–1.62]a 1.20 [1.02–1.41]a 56 HF hospitalizations 61 deaths (2.7 years) It is important to highlight the similarities and differences in how exercise haemodynamic measurements were ascertained by Omote et al. in comparison to other studies establishing the prognostic significance of exPAWP. First, the studies by Omote et al.4 and those by Eisman et al.7 and Ho et al.6 each utilized gas exchange measurement with artero-venous blood gas measurements to directly measure Fick CO whereas Dorfs et al.5 and Ahlgrim et al.9 indexed PAWP to workload but did not directly measure CO. Direct Fick CO measurement is a clear strength in exercise haemodynamic studies as temporal matching of oxygen uptake (VO2) to arteriovenous oxygen content to derive CO measurements is simple and can be done repeatedly during exercise either at individual stages or by taking advantage of the linearity in VO2 augmentation during incremental ramp exercise. One major difference in the approach by Omote et al. versus Eisman/Ho is reliance on supine versus upright exercise, respectively. While the supine position is attractive in that resting measures can simply be extended to accommodate exercise without having to move the patient or transducers, there are inherent limitations. Supine exercise provides a compact window to evaluate exercise response patterns because achievable workloads are truncated particularly when overweight patients with large abdominal girth and predisposition to orthopnoea at rest exercise while lying flat with their legs raised. Compared to both groups (HFpEF and NCD) studied by Omote et al., upright exercise haemodynamic studies (Table 1) resulted in at least 65% higher peak workload achieved, greater likelihood of achieving respiratory exchange ratio above 1.05 to delineate maximum volitional effort and closer proximity to expected peak heart rates and peak peripheral oxygen extraction values. These differences extend well beyond what would be expected on the basis of slightly younger age of populations studied.6, 7 The ability to perform maximum level exercise becomes particularly important when assigning causality and rank order to physiologic deficits (beyond elevated PAWP alone) responsible for exercise intolerance in the multi-organ system disorder of HFpEF.10 The more compact window afforded by supine stepwise exercise also leads to fewer matched measures of PAWP and CO compared to upright studies. Omote et al. started exercise at 20 W and used 20 W steps, permitting only an average −2–3 exercise haemodynamic assessments among HFpEF patients based on average peak workloads of 40–50 W (Figure 1). Omote et al. derived PAWP/CO slopes only by subtracting peak from resting values of PAWP and CO. However, reliance on peak measurements alone to define exercise pressure–flow responses renders measures sensitive to the presence of wide respirophasic variation in some individuals but not others at peak exercise. Studies with upright exercise with minute-by-minute assessments included an average of >10 matched PAWP and CO measurements spanning the spectrum of loading conditions at rest, low- and intermediate-level exercise and peak exercise (Figure 1).3, 11 Furthermore, the authors found that in 3% of individuals exercise CO fell unexpectedly during exercise prompting substitution with +0.1 L/min for the change in CO. Such small changes in CO will predispose to very high PAWP/CO slopes with particularly skewed distribution of variables and requisite log-transformation of the data for appropriate interpretation in regression analyses. A potential advantage of coupling supine exercise and a single PAWP threshold cut-point is that supine exercise may ‘normalize’ the exercise intensity exposure. PAWP≥25 is more likely to perform well in predicting outcomes in patient groups performing low-level exercise than if a wider spread in exercise exposure was rendered possible by upright exercise or a more heterogeneous population with higher fitness levels presenting with exertional dyspnoea. Data regarding pulmonary exercise haemodynamics in healthy subjects are limited to small studies due to the need for invasive measurements, limiting our understanding of appropriate thresholds for normal and abnormal exercise haemodynamics. In the Operation Everest study, exPAWP≥25 was present in 3/8 fit young individuals and those with the highest exPAWP values also had the highest exercise COs.12 In the study by Ahlgrim et al.,9 higher average workloads were achieved than in Omote et al. despite supine exercise. Survivors had an average peak PAWP of 27 mmHg whereas non-survivors had an average peak PAWP of 29 mmHg, and exPAWP indexed to workload outperformed exPAWP in predicting survival in a HFpEF-predominant population.9 Thus, individuals capable of high exercise CO and workload can exceed 25 mmHg of PAWP at maximum exercise. These observations are obviously population-specific. At the 2008 4th World symposium on pulmonary hypertension held in Dana Point, the established mean PAP value in excess of 30 mmHg as a solitary cut-point for defining pulmonary hypertension was abandoned. More recent meta-analyses and consensus statements emphasize indexing PAWP and PAP to CO to account for the amount of blood flow and the ‘dose’ of exercise.3, 13, 14 Hence, application of solitary cut-points may pertain to instances where exercise is limited due to body position/mechanical constraints. Nevertheless, the generalizability of such cut-points to younger patients, milder symptoms, and upright exercise may be limited. While these considerations frame the need for further investigation of exercise haemodynamic patterns in broad populations with direct comparison of supine and upright positions, clearly the findings by Omote et al. represent a significant step forward in use of supine exercise to aid in diagnosis and prognostication of HFpEF with simple threshold parameters. Beyond diagnostic and prognostic relevance, whether lowering exPAWP improves functional capacity and clinical outcomes in HFpEF remains incompletely understood. A recent study by Sarma et al.15 showed that acute reduction of PAWP during peak exercise with sublingual nitroglycerin did not immediately augment peak VO2. These findings are not surprising in light of the numerous contributions to the oxygen pathway during exercise beyond PAWP alone, all of which may be abnormal in HFpEF.10 However, the question of whether detection of the pathophysiologic hallmark of HFpEF (elevated filling pressures and/or reduced CO) during exercise could permit earlier detection of more treatable forms of HFpEF allowing for earlier initiation of emerging potentially disease-modifying therapies such as sodium–glucose cotransporter 2 inhibitors, remains of high interest. Finally, whether chronic lowering of exPAWP may permit greater ability to perform habitual physical activity, which is known to be deficient in pre-HFpEF and HFpEF, also remains an important question. Joseph Campain is a research fellow supported by Sarnoff Cardiovascular Research Foundation. Gregory Lewis is supported by NIH R01-HL 151841, R01-HL131029, R01-HL159514, U01- HL160278. Conflict of interest: none declared.