Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function

Area of Science:

• Cardiovascular Biology
• Pulmonary Hypertension Pathophysiology
• Cellular Pharmacology

Background:

• Pulmonary hypertension (PH)-associated right ventricular (RV) failure is a critical complication linked to reduced pulmonary vasodilators.
• Treprostinil shows promise in PAH patients with cardiac decompensation, suggesting potential cardiac benefits.
• RV structural changes in cardiomyocytes are hypothesized to impair contractile responses and cAMP/PKA signaling.

Purpose of the Study:

• To investigate the synergistic effects of treprostinil and isoprenaline on RV and LV cardiomyocytes in a rat model of PH.
• To determine if disease-related structural changes in RV cardiomyocytes reduce contractile responses and cAMP/PKA signaling activity.
• To assess the therapeutic potential of combined treprostinil and isoprenaline in PH-induced RV dysfunction.

Main Methods:

• PH was induced in rats using monocrotaline; ventricular cardiomyocytes were isolated.
• In vitro stimulation with treprostinil and isoprenaline assessed cardiomyocyte contraction.
• FRET microscopy evaluated PKA activity in response to treprostinil in biosensor-expressing cells.

Main Results:

• PH RV cardiomyocytes displayed maladaptive remodeling, including hypertrophy and impaired contractility and calcium transients.
• Combined treprostinil and isoprenaline failed to enhance inotropy or correct aberrant contractile behavior in PH RV cardiomyocytes.
• Treprostinil treatment in PH RV cardiomyocytes led to decreased PKA activity.

Conclusions:

• PH-associated RV cardiomyocyte remodeling diminishes treprostinil sensitivity, inotropic support, and impairs relaxation.
• The complexity of RV dysfunction in advanced PH necessitates the exploration of alternative therapeutic strategies.
• Current combination therapies may not be effective in rectifying advanced PH-induced RV cardiomyocyte dysfunction.