Despite improvements in our understanding of the pathophysiology of pulmonary arterial hypertension (PAH), it remains a disease of significant morbidity and mortality.
PAH is characterized by dyspnea/fatigue, a common presentation among patients with heart failure. A diagnosis of PAH can only be made when other cardiac/pulmonary causes of increased pulmonary arterial pressure have been ruled out.
In a study published in the Journal of Clinical Medicine, Nishizaki and colleagues conducted a literature review on the effects of exercise training on the right ventricle and pulmonary vasculature in patients with PAH. Study of the impact of exercise is particularly pertinent in PAH because diastolic dysfunction results in reduced cardiac output, which is more prominently observed during periods of exertion.
Physical activity requires the coordination of various systems in the body, such as the cardiopulmonary system and the skeletomuscular system. For the most part, exercise entails aerobic metabolism, which requires continuous oxygen intake. However, in PAH, due to an imbalance of pulmonary vasodilators and vasoconstrictors, the reserve capacity of the pulmonary circulation is compromised. The result is an ineffective hemodynamic response to physical activity. A ventilation/perfusion mismatch and a reduced pulmonary capillary bed both result in exertional dyspnea.
Read more about PAH etiology
“Right ventricular contractility increases at rest, whereas right ventricular contractile reserve decreases,” Nishizaki and colleagues wrote. “Left ventricular diastolic dysfunction due to ventricular septal displacement also occurs due to the increased right ventricular afterload.”
This in turn reduces the aerobic capacity of skeletal muscles. An early switch from aerobic to anaerobic metabolism occurs, leading to increased fatigability and ultimately exercise intolerance. An insufficient supply of oxygen creates a vicious cycle, causing individuals with PAH to have a markedly reduced capacity to perform strenuous physical activity.
A study carried out on rat models used monocrotaline to induce PAH-like conditions and found that exercise can drive right ventricular inflammation and pulmonary vascular remodeling. This significantly cut the survival rate of the rat models studied, especially those that were administered higher doses of monocrotaline. It is clear that right ventricular maladaptation leads to increased afterload, further driving disease progression.
The Effects of Reducing Afterload
“In PAH, right ventricular dysfunction develops mainly because of an uncoupling of the right ventricular function from the pulmonary arterial afterload (ie, afterload mismatch),” Vizza and colleagues wrote in the American Journal of Respiratory and Critical Care Medicine.
Because of this, researchers are proposing that the reduction of the right ventricular afterload can go a long way to improving right ventricular function and securing better outcomes.
Vizza et al compared the effects of different PAH therapies on right ventricular afterload. They found that oral monotherapy has minimal impact on afterload reduction; a 16-week period of bosentan therapy achieves only negligible changes in right ventricular areas as determined by echocardiography.
Initial oral combination therapy fares better. Studies indicate it can achieve a 27%-59% reduction in pulmonary vascular resistance (PVR) from baseline and a 10%-23% reduction in mean pulmonary arterial pressure (mPAP). However, patients on oral combination therapy are still unable to achieve low-risk status and require additional treatment.
Interestingly, the addition of parenteral prostanoids appears to significantly reduce right ventricular afterload. Parenteral prostanoids were the first drugs approved to treat PAH as they can reduce mPAP by 8%-16% and PVR by 14%-39% from baseline.
A study investigating the merits of various treatment strategies for PAH reported that single oral therapy with parenteral prostanoids achieves a significant improvement in hemodynamics. When parenteral prostanoids were used in combination with triple combination therapy, studies indicate they can reduce PVR by 70% and mPAP by 30%. In addition, triple combination therapy and parenteral prostanoids can significantly reduce mortality risk among patients with PAH.
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It should be noted that parenteral prostanoids are known to cause significant adverse effects, especially with continuous infusion. These include nausea and vomiting, diarrhea, flushing, and myalgia. Because the treatment is administered intravenously, the risk of local pain and systemic infection is always present. As a result, patients are often reluctant to be started on this form of therapy. The rate of nonadherence among patients already on parenteral prostanoids is high.
Nevertheless, it is clear from various studies that the reduction of the right ventricular afterload is the right approach to improving clinical outcomes. By aggressively reducing afterload via a hemodynamics-guided strategy, a profound reverse remodeling of the right ventricle may occur.
In keeping with the available evidence, a number of policy changes should be made. For example, monotherapy without parenteral prostanoids should be avoided, given that it rarely achieves meaningful outcomes. Instead, triple therapy including prostanoids should be offered to all patients diagnosed with PAH. Given that triple therapy is not available in poorer corners of the globe, relevant healthcare authorities should channel funding for the acquisition of the individual drugs necessary.
“This treatment paradigm needs to be tested prospectively in patients with PAH, particularly those with an intermediate- or high-risk status at early follow-up,” Vizza and colleagues wrote.
Nishizaki M, Ogawa A, Matsubara H. High right ventricular afterload during exercise in patients with pulmonary arterial hypertension. J Clin Med. 2021;10(9):2024. doi:10.3390/jcm10092024
Vizza CD, Lang IM, Badagliacca R, et al. Aggressive afterload lowering to improve the right ventricle: a new target for medical therapy in pulmonary arterial hypertension? Am J Respir Crit Care Med. 2022;205(7):751-760. doi:10.1164/rccm.202109-2079PP