The success of pulmonary hypertension treatment: improved cardiac function by reducing the arterial load

The function of the right ventricle (RV) determines the fate of patients with pulmonary hypertension (PH). This already became apparent from the first registry of patients with pulmonary arterial hypertension (PAH) showing that right ventricular parameters rather than (arterial) load parameters determine prognosis. ¹ In more recent years it has been recognized that load dependent right ventricular function parameters (e.g. ventricular volumes, stroke volume [SV], and RV ejection fraction [RVEF]) rather than load-independent ventricular parameters (e.g. end-systolic ventricular elastance), are the most sensitive for the assessment of patient during follow-up. ² This is of no surprise since the ability of the right ventricle to adapt to the load rather than the load itself determines outcome. ³ Consequently, parameters such as SV and RVEF are the parameters of choice to determine prognosis. ⁴ In addition, it was recognized that poor adaptation of the RV to its load is accompanied with a prolonged right ventricular contraction time, so that volume changes over time of both the RV and left ventricle (LV) provide essential information to evaluate the state of the RV in PH. At the myocyte level, strain (relative shortening of the myocardium) and strain rate (myocardial shortening as function of time) correspond to the global imaging parameters volume, and volume changes over the cardiac cycle. ⁵

These parameters were evaluated for both the RV and LV using the data of the recently published trial on Ambrisentan and Tadalafil upfront combination therapy in systemic sclerosis associated PAH. ⁶ In the paper by Hassoun et al. the MRI strain analysis performed in this study are presented. ⁷ The outcomes of this paper show that longitudinal and circumferential strain and strain rate of both the RV and LV improved after initiation of upfront combination therapy and that these changes were paralleled by well-known treatment outcome parameters such as cardiac index, 6-min walking distance, and NT-proBNP.

How do these improvements in strain and strain rate explain the success of upfront combination therapy? When we translate volume changes to the myocyte level, a larger SV for a given RV end-diastolic volume corresponds with a higher strain (and with a larger RVEF); a faster right ventricular contraction time corresponds to an increased strain rate. In that sense, the findings are not surprising; they directly correspond to the global ventricular parameters (e.g. SV). The Ambition trial was the first trial showing that initial combination treatment prevents clinical worsening in comparison to sequential treatment. In this study, it was shown that NT-proBNP dropped, ⁸ suggesting a lower right ventricular wall stress. The force-velocity relation of cardiac muscle is an inversed one; ⁹ thus, higher strain rate implies smaller force of contraction and lower wall stress with lower NT-proBNP.

In the study currently under discussion, a decrease in NT-proBNP was related to LV peak early global longitudinal strain. Also, other parameters of LV systolic and diastolic function were improved. Data from Manders et al. showed that contractile dysfunction of the LV in PAH is common and can be explained as a consequence of underfilling. ¹⁰ Improved filling of the LV as a consequence of upfront combination therapy will move the LV to a better working point on the Frank-Starling curve, thereby improving cardiac function.

Finally, as the authors observe, the medication given in this trial could have a direct effect on cardiomyocyte function. This cannot be excluded; however the most likely assumption is that the improvement of RV function is related to the reduction of its load. In conclusion, the study by Hassoun et al. demonstrated the relevance of strain and strain rate and explains the success of initial combination therapy in scleroderma-related PH at the myocardium level. How these parameters compare to other well established hemodynamic and cardiac parameters needs to be established in future studies.