Pulmonary haemodynamics during recovery from maximum incremental cycling exercise

Sensitivity and specificity of haemodynamic measurements during recovery

We observed sensitivity ≤25% for PH-related haemodynamic measurements following peak exercise in diagnosing ePH and ePVH (table 5). Our results confirm previous noninvasive observations [22] and provide further invasive data to support the notion that PH-related measurements during recovery from exercise are not sufficiently sensitive to exclude PH, even in early phases of recovery. This observation is of major importance not only for invasive haemodynamic measurements, but likely also for noninvasive techniques such as exercise echocardiography and exercise cardiac magnetic resonance.

Exercise echocardiography is commonly used to access the dynamic pulmonary vascular response to exercise [23, 24]. However, similar to invasive CPET, exercise echocardiography is technically demanding, leading some centres to perform echocardiographic measurements during recovery from peak exercise, given the lack of specific PH-related recommendations in current guidelines [25, 26]. With respect to gated cardiac magnetic resonance-derived haemodynamic measurements, the technical challenge imposed by the acquisition of images suitable for analysis during high-intensity exercise is a major limitation [27]. Additionally, exercising within the narrow diameter of the magnetic resonance imaging bore can be an issue in some cases, making the acquisition of images during recovery more tempting. However, our findings suggest that PH-related haemodynamic measurements acquired solely during recovery miss the majority of ePH and ePVH diagnoses and, therefore, should not be used as a substitute of peak exercise measurements to exclude the presence of ePH and ePVH.

ePH versus ePVH haemodynamic recovery patterns

PVR and PVC recovery patterns were different for ePH and ePVH. PVR remained elevated and PVC remained low in ePH throughout recovery compared to ePVH (figure 2), suggesting differences in the underlying PH pathophysiology.

The pulmonary circulation is influenced by both passive and active factors at rest and during exercise. Passive factors include increases in transmural pressure driven by input (PAP) and outflow pressures (PAWP) that assist in ventilation and perfusion matching, especially in the upright position [28]. Active factors include nitric oxide (NO)-mediated mechanisms, regional alveolar hypoxia and sympathetic nervous system stimulation, which dynamically regulate vasoconstriction and vasodilation, further affecting PVR, recruitment and distension during exercise [29–31]. We observed that ePH PVR elevation persisted during recovery (figure 2a), differing from controls and ePVH, and suggesting underlying dynamic pulmonary artery vasoconstriction and/or pulmonary vascular structural remodelling.

PVC represents an early marker of pulmonary vascular remodelling, reflecting the ability of the pulmonary vasculature to distend during systole and recoil during diastole [32]. Therefore, persistently low PVC may indicate intrinsic changes of vessel wall function/structure (stiffness) that can ultimately impact right ventricular performance, as is the case for resting precapillary PH [33]. In our study, low PVC throughout recovery provides evidence of pathological pulmonary vascular stiffness in ePH. Conversely, in ePVH, PVC returned to its baseline resting value by 1-min recovery (figure 2b), indicating that ePVH mechanisms are likely to be largely passive (i.e. passive increased transmural pressure due to increased PAWP). Therefore, as PAWP rapidly returns to its baseline value during recovery, PVC is quickly restored. Along these lines, we observed that stroke volume did not decay as fast as PAWP during recovery in ePVH (table 4), suggesting that their high filling pressures are not mandatory in order to maintain forward flow and consequently that ePVH might tolerate some degree of preload reduction without compromising systemic perfusion.

Interestingly, the sub-analysis of ePVH according to peak PVR revealed a blunted PVC recovery in patients with a peak PVR ≥120 dyn·s·cm⁻⁵ despite the same pattern of PAWP recovery in both subgroups (table S1), suggesting that ePVH PVC changes are not strictly related to PAWP changes as previously thought [34]. Additionally, we observed that PVC recovery pattern was also not solely explained by heart rate, since both PVC and heart rate were reduced in ePVH with a peak PVR ≥120 dyn·s·cm⁻⁵ (table S1). These observations possibly reflect a subgroup of ePVH, in which a sustained increased intravascular pressure led to changes in vascular wall structure [35] and subsequent decrease in pulmonary vascular compliance, as a marker of early pulmonary vascular remodelling and disease severity. In this context, ePVH with peak PVR ≥120 dyn·s·cm⁻⁵ also had lower CO and lower peak V′_O2 compared to ePVH with peak PVR <120 dyn·s·cm⁻⁵ (table S1), suggesting that dynamic increases in right ventricle afterload (PVR and PVC) are physiologically and clinically relevant.

We observed that ePH failed to increase RC-time during recovery compared to ePVH and controls (table 4) due to equal contributions from abnormal PVR and PVC recovery patterns. The observed RC-time pattern is analogous to the dynamic changes in RC-time described for chronic thromboembolic PH [36], and suggests that an early pulmonary vasculopathy (i.e. ePH) has its origins in concordant abnormalities of resistance and compliance. As a result, pulmonary vascular bed dilatation and recruitment during exercise is impaired, subsequently compromising right ventricular function and exercise capacity.

Our ePH findings are in accordance with previously published noninvasive data that demonstrated evidence of pulmonary vascular stiffness by resting cardiac magnetic resonance in ePH [37]. Sanz et al. [37] suggested that, in addition to increases in transmural pressure, changes in intrinsic elastic properties of the pulmonary circulation play a major role in determining pulmonary vascular stiffness and its association with PH severity. Hence, our findings provide additional direct evidence that ePH represents an early and mild stage of resting PH, possibly presenting similar mechanisms of pulmonary vascular remodelling such as pulmonary vascular wall thickening, smooth muscle cell proliferation and collagen and extracellular matrix deposition.

Heart rate at peak exercise was significantly lower in ePVH (table 4). However, this is unlikely to be solely related to β-adrenergic blockade, because β-blocker usage frequency was not different between ePH and ePVH. One possible explanation for this finding might be the presence of chronic sympathetic overstimulation and downregulation of β-adrenergic receptors, resulting in chronotropic incompetence, which is commonly observed in chronic heart failure. The rate of heart rate recovery was not different among groups (data not shown), which differs from prior reports in established PH [38] and heart failure [39]. However, our study evaluated only ePH and ePVH, in which delayed heart rate recovery might not be present due to the early/mild stage of disease.

Finally, the rapid decrease in pulmonary pressures during recovery emphasises the ephemeral nature of haemodynamic derangement in ePH and ePVH and highlights the potential role of specific therapies targeting the exercise phase. This approach has recently been reported for HFpEF using acutely infused sodium nitrite, which is converted to NO during exercise boosted by hypoxia and acidosis [40]. By targeting active factors of the pulmonary circulation (NO-mediated mechanisms), Borlaug et al. [40] demonstrated the beneficial effects of nitrite on exercise haemodynamics by the reduction in PAWP and PAP during exercise, and improvements in exercise CO reserve, with less effect on resting haemodynamics. However, whether or not this approach might also be applicable to ePH or ePVH with evidence of pulmonary vascular remodelling (i.e. elevated PVR and reduced PVC) needs further investigation.

Limitations

Studied patients were derived from a single tertiary dyspnoea centre, and likely represent an early/mild stage of disease. Therefore, they may not represent an overall community-based population and the generalisation of our findings to other PH populations should be done with caution. The control group was symptomatic and, therefore, may not represent a completely normal population. However, controls had normal exercise capacity and exercise haemodynamics. The sample studied included overweight patients, whose exercise haemodynamics measurements may show some degree of inaccuracy. However, a sub-analysis of patients with a body mass index >35 kg·m⁻² (table S2) revealed similar pulmonary haemodynamics to the entire study population, demonstrating that elevated body mass index did not affect ePH and ePVH recovery patterns.

For the ePH group, we used a mPAP ≥30 mmHg associated with a PVR ≥120 dyn·s·cm⁻⁵, in the absence of elevated filling pressures during exercise, based on a prior report using a similar maximum incremental cycling protocol [17]. This ePH definition essentially describes the same exercise haemodynamic phenotype as the approach that uses a peak TPR >240 dyn·s·cm⁻⁵ after a PAWP >20 mmHg is first excluded [9]. In our study, the majority of the ePH population (22 out of 36) met both criteria (PVR ≥120 dyn·s·cm⁻⁵ and TPR >240 dyn·s·cm⁻⁵). Furthermore, our ePH group represents a population with clinically relevant pulmonary vascular dysfunction, because the presence of ePH clearly impacted their exercise capacity (as measured by peak V′_O2) compared to controls (table 2). For ePVH, we used a peak PAWP ≥20 mmHg. We acknowledge that there remains no consensus on the optimal cut-off value to categorise elevated filling pressures during exercise; however, the 20 mmHg threshold is in accordance with previous studies of post-capillary PH during exercise [4, 9, 12, 13], and in a similar manner to ePH, the presence of ePVH was associated with a reduced exercise capacity (tables 2 and S1).

Elevation of intrathoracic pressures during exercise might influence exercise haemodynamics; however, this influence is expected to be of equal magnitude on right atrial pressure and PAWP [15]. Using V′_E as a surrogate of intrathoracic pressure (and pleural pressure in our subjects without parenchymal lung disease) we found that intrathoracic pressures did not play a major role on PAWP. The increased peak PAWP and peak PAWP minus RAP in ePVH (table 4) occurred at the same V′_E (and presumably same pleural pressure) in the ePH group (table 2). This suggests that ePVH PAWP changes during exercise are related to intrinsic changes in lusitropy rather than changes in pleural pressure itself. Additionally, the low filling pressures during exercise in controls (table 4) were observed at elevated V′_E (and presumably elevated pleural pressure) compared to ePH and ePVH (table 2), reinforcing the notion that intrathoracic pressures were not the main forces influencing PAWP patterns in ePVH.

For patient's safety, our clinical exercise protocol required 1 min of freewheeling during recovery to prevent systemic hypotension. The freewheeling hypothetically could have masked differences in recovery; however, all of our key findings were already observed at 1-min recovery despite the freewheeling stage. Another limitation is the relatively small sample size of ePVH subgroups, which might decrease study power with regard to the comparison of ePVH with and without elevated peak PVR. Finally, this was an observational study and, therefore, we are not able to comment on data reproducibility and further (interventional) studies will be necessary to determine the exact mechanisms behind the different ePH and ePVH recovery patterns and their clinical relevance.

Conclusions

Our study demonstrated that mPAP and PAWP decline quickly during recovery from peak exercise in ePH and ePVH, resulting in a low sensitivity of PH-related haemodynamic measurements during recovery in diagnosing PH. We also observed that PVR and PVC recovery patterns differ between ePH and ePVH, suggesting differences in the underlying PH pathophysiology. The high PVR and low PVC observed throughout recovery in ePH suggest that fixed pulmonary vascular remodelling and/or sustained pulmonary vascular dysfunction underlie the abnormal ePH pulmonary haemodynamic response to exercise. We speculate that for similar reasons, ePVH with a high peak PVR exhibits analogous pulmonary haemodynamic recovery pattern to that observed for ePH.