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Cardiac Myosin Binding Protein-C (cMyBP-C) is highly phosphorylated under basal conditions. However, its phosphorylation level is decreased in patients with heart failure. The necessity of cMyBP-C phosphorylation for proper contractile function is established, but the physiological and pathological consequences of decreased cMyBP-C phosphorylation in the heart are not clear.Herein, we report that cMyBP-C dephosphorylation is sufficient to reduce contractile parameters and calcium kinetics associated with a prolonged decay time of the calcium transient and increased diastolic calcium levels. This finding is based on the use of intact adult cardiomyocytes from mouse models expressing phospho-ablated (AAA) and phospho-mimetic (DDD) cMyBP-C, as well as controls. Isoproterenol stimulation reversed the depressive contractile and Ca-kinetic parameters.In addition, caffeine-induced calcium release indicated no difference between AAA/DDD and controls in sarcoplasmic-reticulum calcium content. On the other hand, sodium-calcium exchanger function and phosphorylation levels of calcium handling proteins were significantly decreased in AAA hearts compared to controls. Stress conditions resulted in increases in both spontaneous after-contractions in AAA cardiomyocytes and the incidence of arrhythmias in vivo, compared to controls. Treatment with omecamtiv mecarbil, a positive cardiac inotropic drug, rescued contractile deficit in AAA cardiomyocytes, but not calcium handling abnormalities. Taken together, these findings indicate a cascade effect whereby dephosphorylation of cMyBP-C causes contractile defects, which then lead to calcium cycling abnormalities, finally resulting in after-contractions and increased incidence of cardiac arrhythmias under stress conditions.As an essential lynchpin in this cascade of pathophysiological events, the present study has elucidated the link between impairment in sarcomere contractility and abnormal Ca2+ cycling, thus presenting an opportunity to study sarcomere contractility and Ca2+ cycling as one functional (or dysfunctional) system, suggesting a unitary therapeutic target for the dual treatment of patients with HF and arrhythmia.