The effect of Riociguat on cardiovascular function and efficiency in healthy, juvenile pigs

Abstract

Introduction: Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary hypertension. Its effect on cardiometabolic efficiency is unknown. A potential cardiac energy sparing effect of this drug could imply a positive prognostic effect, particularly in patients with right heart failure from pulmonary hypertension.

Method: We infused Riociguat in six healthy juvenile pigs and measured the integrated cardiovascular effect and myocardial oxygen consumption. To assess the interplay with NO-blockade on cardiac function and efficiency we also administered the NO-blocker L- NAME to the animals after Riociguat.

Results and discussion: Infusion of 100 µg/kg Riociguat gave modest systemic vasodilatation seen as a drop in coronary and systemic vascular resistance of 36% and 26%, respectively. Right and left ventriculoarterial coupling index (Ees/Ea), stroke work efficiency (SWeff), and the relationship between left ventricular myocardial oxygen consumption (MVO₂ ) and total mechanical work (pressure-volume area; PVA) were unaffected by Riociguat. In contrast, systemic and pulmonary vasoconstriction induced by L-NAME (15 mg/kg) shifted the Ees/Ea ratio toward reduced SWeff in both systemic and pulmonary circulation. However, there was no surplus oxygen consumption, that was measured by the MVO₂ /PVA relationship after L-NAME in Riociguat-treated pigs. This suggests that Riociguat can reduce the NO-related cardiometabolic inefficiency previously observed by blocking the NO pathway.

Figure 1

Schematic drawing of the sonometric crystal positions used for assessing right and left ventricular volumes (see equation 1 and 2). The placements of the crystals are in the subendocardial position. Crystal no. 8 is placed in the posterior wall of the left ventricle adjacent to crystal no. 5 in the anterior wall. “Flow” indicates time transit flow probes, RCA is the right coronary artery, LCX is the left circumflex coronary artery, LAD is the left anterior descending artery, C1 to C8 are sonometric crystals placed in the subendocardium. Balloon catheters are drawn in the right ventricle and pulmonary artery

Figure 2

General hemodynamic measurements at baseline (Baseline), after a bolus of 100 µg/kg Riociguat (Rio) and finally after adding 15 mg/kg L‐NAME. MAP is the mean systemic arterial pressure, MPAP is the mean pulmonary arterial pressure, CO is the cardiac output. SVR, PVR, and CVR are the systemic, pulmonary and coronary arterial resistances. dP/dT_max is the maximum slope of left ventricular pressure development. Tau is the time constant of isovolumetric relaxation. EF is the left ventricular ejection fraction. N = 6, ** denotes p < .01 compared to the previous phase of the experiment

Figure 3

Ventriculoarterial coupling (VA coupling) and stroke work efficiency (SWeff) in both the left (LV) and right (RV) ventricles after subsequent boluses of Riociguat and L‐NAME (see Figure 2). Left column displays data from the systemic circulation and right column from the pulmonary vasculature. VA coupling was calculated as the ratio of ventricular end‐systolic and arterial elastance (Ees/Ea). SWeff is the portion of total ventricular mechanical work (pressure–volume area, PVA) measured as external pressure and volume work (SW). N = 6, * p < .05, ** p < .01 compared to the previous measuring point in the experiment

Figure 4

Screenshot of actual recordings from one pig. Pressure–volume loops and calculated preload recruitable stroke work (PRSW) during reduction in preload by inflation of the Fogarty balloon catheter in the inferior caval vein. Left panels are from the left ventricle. Right panels are from the right ventricle. Top panels are the pressure–volume loops with linear curve fitting to the maximum pressure/volume relationship (ESPVR) and curvilinear curve fitting of the end‐diastolic pressure/volume relationship (EDPVR). The lower panels show the preload recruitable stroke work for the left and right ventricles, respectively

Figure 5

Ventriculoarterial coupling, left ventricle. Schematic pressure–volume curves for the left ventricle based on the average values of the end diastolic pressure–volume relationship (EDPVR), the pressure–volume relationship after isovolumetric contraction, the end systolic pressure–volume relationship, and the pressure–volume relationship at the start of diastole. Curves are fitted through these four points. Also shown is the average volume at the x‐axis intercept of the ESPVR line at baseline, V0. Left ventricular elastance is the slope of the ESPVR line (Ees). The slope from the end systolic pressure–volume point to the X‐axis intercept of the end‐diastolic volume is the aortic elastance (Ea). Error bars are standard deviation for pressures and volumes. N = 6

Figure 6

Ventriculoarterial coupling, right ventricle. Schematic pressure–volume curves for the right ventricle based on the average values of the end diastolic pressure–volume relationship (EDPVR), the maximum systolic pressure–volume relationship, and the pressure–volume relationship at the start of diastole. Curves are fitted through these three points. Also shown is the average volume at the x‐axis intercept of the end systolic pressure–volume line (ESPVR line) at baseline, V0. The slope of the ESPVR line is the right ventricular elastance (Ees) and the slope from the maximum systolic pressure–volume point to the X‐axis intercept of the end diastolic volume is the pulmonary arterial elastance (Ea). Error bars are standard deviation for pressures and volumes. N = 6

Figure 7

Mechanoenergetic efficiency of the left ventricle. Mechanoenergetic efficiency was calculated as the pressure–volume area (PVA) related to myocardial oxygen consumption (MVO₂) at a range of workloads. The panels display the pooled scatter and linear regression of MVO₂/PVA recordings from six pigs