Cardiac Resynchronization Therapy and Cardiac Reserve

One of the primary mechanisms by which a heart can increase its pump performance is beating more frequently. Elevating heart rate enhances net cardiac output by the simple algebra of having more stroke volumes ejected per minute but also by an intrinsic effect of stimulation frequency on contractility. The latter, known as the force-frequency relation (FFR), relates to rate-dependent increases in calcium entry into a myocyte (more action potentials and thus Ca2+ channel openings per minute) coupled with greater Ca2+ uptake into the sarcoplasmic reticulum.1–3 The net effect is an increase in calcium released to the myofilaments with each stimulation, resulting in a “positive staircase” as heart rate rises from normal basal levels to fast physiological rates (&180 bpm in normal humans). This process has a limit, as calcium becomes effectively trapped within the sarcoplasmic reticulum when heart rate is faster than the kinetics of Ca2+ cycling can accommodate, leading to a “negative staircase” at more rapid rates.1,3Article p 953 The FFR plays an important role in normal contractile reserve under stress, yielding a near 100% rise in cardiac chamber contractility in healthy adults when heart rate is varied from 60 to 150 bpm.4 As with many features of contractile regulation, however, the FFR becomes abnormal in the failing heart, characterized by both blunting of the peak response and a shift to a lower heart rate at which the maximal response is observed.1,5–7 In a patient with heart failure, this could result in a flat or even negative response, as heart rate varies over the physiological range. A number of factors are thought responsible for this, including downregulation of adrenergic responsiveness,8 depression, and/or reduced activation of critical proteins involved with excitation-contraction coupling, such the sarcoplasmic reticular ATPase, phospholamban,9–11 sodium/calcium exchanger, …