Objectives and Background: Decisions based on invasive functional diagnostic measurements are often made in the setting of fluctuating hemodynamic variables that may alter resting or hyperemic measurements. The purpose of this investigation is to analyze the effect of myocardial contractility (CY) on invasive functional parameters. We hypothesize that the pressure drop coefficient (CDP e; ratio of pressure drop to distal dynamic pressure) and fractional flow reserve (FFR; ratio of average pressures distal and proximal to a stenosis) are not affected by fluctuations in CY and can distinguish between different severities of epicardial stenosis. Methods: Simultaneous measurements of distal coronary-arterial pressure and velocity were performed in 10 pigs using a dual-sensor tipped guidewire for heart rate (HR) <110 bpm and HR >110 bpm, in the presence of coronary lesions of <50% area stenosis (AS) and >50% AS. Variations in myocardial function and vascular resistance were induced by atrial pacing, papaverine and balloon obstruction, respectively. The maximum rate of rise of left ventricular pressure ([dp/dt] max) was the index of contractility. The contractile function of the heart was empirically defined as CY >900 mm Hg/sec (higher) and CY <900 mm Hg/sec (normal). Results: For CY >900 mm Hg/sec, under AS <50% and AS >50%, the mean values of FFR (0.91 ± 0.02 and 0.78 ± 0.02), and CDP e (15.6 ± 5.3 and 70.7 ± 24.7) were significantly different (P<.05). Similarly, for CY <900 mm Hg/sec, under AS <50% and AS >50%, the mean values of FFR (0.83 ± 0.04 and 0.63 ± 0.04), and CDP e (43.8 ± 14.9 and 191.8 ± 61.4) were also significantly different (P<.05). Conclusions: Both FFR and CDP e could effectively distinguish between stenosis severity at normal and higher levels of myocardial contractility.