In this study, we investigated CPX parameters in patients with non-PH, Ipc-PH, and Cpc-PH. In our cohort, 35% of the patients who underwent RHC had PH-LHD, with Cpc-PH accounting for only 13% of the entire cohort. Therefore, Cpc-PH appears to be a relatively uncommon condition, which is consistent with previous findings. The present study’s results also revealed that peak PETCO2 was the optimal predictor of Cpc-PH, thus corroborating the findings of previous reports in which ventilatory variables proved useful in differentiating Cpc-PH[17, 18]; however, the high detection power of peak PETCO2 has not been previously reported.
PH is a common complication of LHD, and it develops in response to a passive increase in left-sided filling pressures, more specifically left atrial pressure, and is associated with a poor prognosis. Cpc-PH is known to have an even worse prognosis.
Genetically, Cpc-PH resembles PAH. Assad et al. found that patients with Cpc-PH had genetic abnormalities in pathways that were highly active in the lungs and known to contribute to the pathophysiology of PAH. These exploratory genetic findings suggest that Cpc-PH may have a pathophysiology distinct from that of Ipc-PH.
In pathological aspects, progressive thickening and collagen proliferation of the lamina densa occur in order to protect against fluid accumulation in the interstitium of the endothelium and vascular wall as well as in the alveoli[4, 5, 23]. In Ipc-PH, small arteries exhibit endothelial dysfunction and vasoconstriction, despite no defined changes in the composition of small pulmonary arteries, and the pulmonary veins show a certain degree of thickness and tendency toward arteriolarization. Moreover, in Cpc-PH, the venous system becomes fully arteriolarized, and the small arteries exhibit a clear muscularization process and remodeling; impairment of gas exchange diffusion or lengthening of the path between air and the red blood cells is prominent.
In an effort to differentiate Cpc-PH from Ipc-PH in a non-invasive manner, an approach based on physiology is important to detect this pathological change. In our cohort, the low peak-PETCO2 value, which is one of the ventilatory variables in CPX, was an indicator of Cpc-PH with the optimal predictive value, thus potentially reflecting a marked impairment of gas exchange diffusion.
The differentiation of Cpc-PH using CPX was reported by Cariviate et al.. They found VE/VCO2 at the AT to be useful in detecting Cpc-PH, and Cpc-PH was intermediate between PAH and Ipc-PH in terms of gas exchange. Among the ventilatory parameters obtained using the submaximal exercise test, low PETCO2, high VE/VCO2, and high VD/VT were reportedly characteristic of Cpc-PH. Moreover, the exacerbation of pulmonary gas exchange abnormalities in patients with Cpc-PH was related to an excessive rise in pulmonary vascular pressures. Zhong et al. also reported that VE/VCO2-related parameters were diagnostic variables for the presence of pre-capillary components in patients with PH-LHD. Among the ventilatory variables, the lowest VE/VCO2%pred, which was obtained from the submaximal exercise test, was the optimal predictor of Cpc-PH, as demonstrated by an AUC of 0.77. From our data, peak PETCO2 is also particularly useful in detecting Cpc-PH, as demonstrated by an AUC of 0.75. This is comparable to that reported by Zhong et al. In the maximal exercise test, peak PETCO2 was the optimal diagnostic variable.
In the HF population, the PETCO2 is a known CPX variable that potentially possesses prognostic information. In particular, Arena et al. reported that PETCO2 change from rest to the respiratory compensation (RC) point, PETCO2 at the RC point, and PETCO2 at peak exercise were all significant predictors of cardiac-related events. Low PETCO2 levels during exercise have classically been considered to strongly reflect low CO during exercise. Matsumoto et al. found that PETCO2 at the RC point was significantly correlated with CO at peak exercise in patients with cardiac disease. In addition, they concluded that decreased CO2 production, abnormal ventilatory patterns, and compensatory hyperventilation did not appear to explain the lower PETCO2 values during exercise in patients with cardiac disease, thus further confirming lower CO as the underlying cause. Moreover, Tanabe et al. revealed a significant correlation between the PETCO2 and cardiac index at peak exercise in patients with HF.
In patients with PAH, the PETCO2 decline associated with exercise was more distinct than that in those with LHD. Hemnes et al. demonstrated that the measurement of resting PETCO2 at the bedside may discriminate PAH patients from those with pulmonary venous hypertension or no PH. Moreover, Welch et al. also demonstrated that this readily available resting PETCO2 may be a physiologically relevant marker of poor prognosis in PAH. They reported that lung diffusion for carbon monoxide (DLCO) correlates with resting PETCO2, suggesting that these variables could provide potentially similar insight into the degree of pulmonary vasculopathy in patients with PAH. DLCO measures the ability of a gas to diffuse from the alveoli to the red blood cells in the pulmonary capillaries and depends on alveolar–capillary membrane diffusive capacity and capillary volume, which is the amount of blood flowing through the ventilated alveolar–capillary units over a period of time, that is, a few seconds. Because alveoli that are affected by dead-space ventilation have no blood flow, they are unlikely to participate in absorbing gas into the alveolar capillaries. The correlation between the PETCO2 and DLCO could be explained by the fact that both are markers of dead-space ventilation. The PETCO2, as well as DLCO, may also reflect capillary membrane diffusive capacity and capillary volume (i.e., CO). Peak PETCO2 may better capture pathological changes in Cpc-PH whereby the venous system becomes fully arteriolarized and gas exchange is strongly impaired.
This study has certain limitations. First, our study population only included patients who were able to undergo the exercise stress test. Second, PH-LHD was classified according to the previous criteria of the 6th World Symposium on Pulmonary Hypertension in 2019. Finally, our cohort comprised a heterogeneous population of patients with cardiac disease.
In conclusion, peak PETCO2 was associated with Cpc-PH in patients with LHD.