FFR, from myocardial strips to the echo lab. Isolated cardiomyocytes (upper panel): upregulation of Ca2+ entry through Ca2+ channels by high rates of beating is involved in the frequency-dependent regulation of contractility. The effect of increasing contractility by increasing heart rate ("pure" Bowditch treppe) is intrinsic to myocardium and takes a few seconds to occur, while the β-adrenergic amplification of the force-frequency relation (FFR) takes longer, i.e., 30–40 seconds, the time it takes for β-receptor activation and cAMP synthesis (on the right: FFR + ISO). (Modified from: Piot C, Circ 1996 ). Middle panel: measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts: the FFR of these failing groups both exhibit a negative treppe at contraction frequencies above about 100 bpm. The contraction frequency at which the FFR begins its descending limb ("optimum stimulation frequency") declines progressively in the order: ASD (atrial septal defect), CAD (coronary artery disease), IDDM (diabetic myopathy), MR (mitral regurgitation), DCM (dilated cardiomyopathy). (Modified from: Mulieri LA. R.A. Howarth Ed. 1997). Lower panel: time sequence during stress echo; the force-frequency relation is built off line. The force-frequency relation is defined as up-sloping when the peak stress systolic pressure/end-systolic volume index (SP/ESV index) is higher than baseline and intermediate stress values; biphasic, with an initial up-sloping followed by a later down-sloping trend, when the peak stress SP/ESV index is lower than intermediate stress values; flat or negative, when the peak stress SP/ESV index is equal to or lower than baseline stress values. The critical heart rate (or optimum stimulation frequency) is the human counterpart of the treppe phenomenon in isolated myocardial strips (Modified from Bombardini T, CU 2005 ).