Heart failure (HF) is the most common cause of pulmonary hypertension (PH) ¹ and is associated with increased morbidity and mortality. ^{1 , 2} Exertional dyspnea and reduced exercise capacity are the most frequent concerns in patients with PH due to HF (PH-HF), ² The key physiological mechanism in PH-related exertional dyspnea is a lung vasculature abnormality due to excessive pulmonary vascular resistance, which attenuates cardiac output response to exercise. ³ Noteworthy, patients with PH show a sharp increase in physiologic dead space and hence reduced gas exchange efficiency. ³ Indeed, patients with HF often display ventilatory abnormalities likely related to dysregulation in peripheral control (i.e., impaired skeletal muscle ergoreflex and increased peripheral chemoreceptor sensitivity). ^{4 - 6}

Cardiopulmonary exercise testing (CPX) is an useful tool for assessing severity and prognosis in cardiorespiratory disease. ⁷ Carbon dioxide end-tidal partial pressure (PETCO ₂ ) during CPX is a well-established noninvasive marker of ventilation/perfusion ratio in patients with lung and heart diseases. ⁸ Indeed, the PETCO ₂ decrease from rest to ventilatory anaerobic threshold (VAT) during CPX is associated with pulmonary gas exchange abnormalities in patients with PH. ⁹

Therapeutic strategies are available for treating primary PH; however, the same does not occur for PH-HF, whereas target therapy agents have failed to demonstrate benefit or have even been harmful. ^{1 , 2} Although exercise training is a well-established non-pharmacological therapy for HF, ¹⁰ its effect on patients with PH-HF, particularly on PETCO ₂ response during exercise, is unknown. Therefore, our aim was to report the effect of aerobic exercise training on PETCO ₂ response during exercise in a patient with PH-HF.

Progressive increase in PETCO ₂ from resting to VAT (nearly 5-8 mmHg), followed by its maintenance or slight increase up to the onset of respiratory compensation point and its progressive decrease from respiratory compensation point to maximal effort, is expected in healthy subjects during CPX. ¹² In contrast, our data showed progressive decreases in PETCO ₂ from resting to VAT and maximal effort at baseline ( Figures 1A and 1B ), which is in accordance with a previous study assessing the PETCO ₂ response in patients with primary PH. ⁹ Indeed, the abnormal PETCO ₂ response was directly associated with disease severity. ⁹

Physiological mechanisms involved in the altered PETCO ₂ pattern found at baseline may include: (1) ventilation-perfusion inequalities due to ventilated alveoli hypoperfusion, resulting in increased physiologic dead space (V _D /V _T ) and (2) increased acidosis at lower work rates, resulting in augmentation of ventilation drive induced by higher levels of hydrogen ion (H ⁺ ). ⁹ For instance, the increased pulmonary vascular resistance in patients with PH may blunt cardiac output response during exercise, which results in reduced O ₂ transport to working muscle, thereby increasing the contribution of anaerobic glycolysis to exercise. Indeed, patients with HF demonstrate impaired skeletal muscle metabolism, which reduces mitochondrial oxidative capacity. ¹³ Thus, it is possible that both pulmonary gas exchange and muscle metabolism abnormalities may be involved in the impaired baseline PETCO ₂ response during exercise in the patient with PH-HF.

In contrast, to the best of our knowledge, the present report showed for the first time that three months of aerobic exercise training might improve PETCO ₂ response to exercise in a patient with PH-HF, as shown by the sharp increase in PETCO ₂ from rest to VAT ( Figure 1B ), as well as by the increased PETCO ₂ levels at both VAT and peak of exercise (Table 1). This result is in line with a previous study demonstrating the effectiveness of aerobic exercise training for improving PETCO ₂ response in coronary artery disease patients. ¹³

It is known that exercise training improves muscle oxidative metabolism during exercise in individuals with HF (e.g., increased O ₂ uptake and arteriovenous O ₂ difference, lower phosphocreatine depletion, lower increase in adenosine diphosphate, and decreased lactate accumulation). ¹⁴ In addition, training-induced improvements in ventilation efficiency during exercise are, at least in part, due to improvements in muscle receptor reflexes and skeletal muscle metabolism in individuals with HF. ^{15 , 16} In this context, it can be suggested that a training-induced improvement in muscle aerobic metabolism may be reduced acidosis-related ventilatory stimulus during CPX, and thus may be associated with the improved PETCO ₂ response after training in the present study. The improvements in both VO ₂ at VAT and OUES suggest an increase in muscle aerobic capacity and thus support this hypothesis.

Improvements in gas exchange efficiency and breathing pattern may be induced by the reduction of physiologic dead space ventilation and may also be involved in the improved PETCO ₂ response after training. ¹² In this context, the reduced V _E VCO ₂ slope, V _D /V _T , and tachypneic (BF) and shallow pattern of breathing (T _E and T _I ) after training support this hypothesis. In fact, the reduced V _T /T _I and V _T /T _E after training indicate a decrease in neuromuscular inspiratory and expiratory drive, respectively. It is important to note that breathing pattern has a significant influence in the V _D /V _T ratio during exercise. Specifically, a tachypneic breathing pattern during exercise increases V _D /V _T ratio and decreases PETCO ₂ levels. ¹⁷ Moreoever, higher levels of breathing frequency are closely related to decreases in expiratory time and, as a consequence, in premature cessation and greater PETCO ₂ increase during progressive exercise. ¹⁷ Thus, the decrease in breathing frequency and the increase in expiratory time found after exercise training may also be associated with the improved PETCO ₂ response during follow-up in the present study. Interestingly, peripheral chemoreflex control was normalized after exercise training in a rabbit model of heart failure, ¹⁸ suggesting that it may be associated with the improvement in ventilation efficiency.

It is noteworthy that the patient also reported an improvement in exertional dyspnea sense after training, which is in line with the improved exercise capacity, as shown by the training-induced increase in exercise time during CPX. In conjunction, these improvements may result in an increased quality of life.

The echocardiography used for assessing PH is a limitation of the present study. However, we used sequential assessments to confirm the diagnosis. The assessment of only one patient during the follow-up is also a limitation that should be acknowledged.

In summary, this case report showed for the first time that the impaired PETCO ₂ response to exercise in PH-HF might be improved by three months of a thrice-weekly aerobic exercise training program. Given that PETCO ₂ is a noninvasive marker of ventilation/perfusion ratio ⁸ and that its abnormal response during CPX is associated with pulmonary gas exchange abnormalities in patients with PH, ⁹ the present results suggest that aerobic exercise training may be an important tool for improving pulmonary gas exchange abnormalities in patients with PH-HF.