An implantable medical device comprising: a plurality of electrodes comprising: a right atrial electrode positionable within the right atrium to deliver cardiac therapy to, or sense electrical activity of, the right atrium of a patient's heart, and a tissue-piercing electrode implantable through the right atrial endocardium and central fibrous body to deliver cardiac therapy to, or sense electrical activity of, the left ventricle of a patient's heart; a therapy delivery circuit operably coupled to the plurality of electrodes to deliver cardiac therapy to the patient's heart; a sensing circuit operably coupled to the plurality of electrodes to sense electrical activity of the patient's heart; and a controller comprising processing circuitry operably coupled to the therapy delivery circuit and the sensing circuit, the controller configured to: calibrate a pacing therapy for a plurality of heartrates and a plurality of AV delays based on measured physiological response information, and deliver the calibrated pacing therapy using one or both of the tissue-piercing electrode and the right atrial electrode; wherein the tissue-piercing electrode is implantable from the triangle of Koch region of the right atrium through the right atrial endocardium and central fibrous body to deliver cardiac therapy to or sense electrical activity in the basal and/or septal region of the left ventricular myocardium of the left ventricle of the patient's heart. a plurality of electrodes comprising: a right atrial electrode positionable within the right atrium to deliver cardiac therapy to, or sense electrical activity of, the right atrium of a patient's heart, and a tissue-piercing electrode implantable through the right atrial endocardium and central fibrous body to deliver cardiac therapy to, or sense electrical activity of, the left ventricle of a patient's heart; a right atrial electrode positionable within the right atrium to deliver cardiac therapy to, or sense electrical activity of, the right atrium of a patient's heart, and a tissue-piercing electrode implantable through the right atrial endocardium and central fibrous body to deliver cardiac therapy to, or sense electrical activity of, the left ventricle of a patient's heart; a therapy delivery circuit operably coupled to the plurality of electrodes to deliver cardiac therapy to the patient's heart; a sensing circuit operably coupled to the plurality of electrodes to sense electrical activity of the patient's heart; and a controller comprising processing circuitry operably coupled to the therapy delivery circuit and the sensing circuit, the controller configured to: calibrate a pacing therapy for a plurality of heartrates and a plurality of AV delays based on measured physiological response information, and deliver the calibrated pacing therapy using one or both of the tissue-piercing electrode and the right atrial electrode; wherein the tissue-piercing electrode is implantable from the triangle of Koch region of the right atrium through the right atrial endocardium and central fibrous body to deliver cardiac therapy to or sense electrical activity in the basal and/or septal region of the left ventricular myocardium of the left ventricle of the patient's heart. calibrate a pacing therapy for a plurality of heartrates and a plurality of AV delays based on measured physiological response information, and deliver the calibrated pacing therapy using one or both of the tissue-piercing electrode and the right atrial electrode; wherein the tissue-piercing electrode is implantable from the triangle of Koch region of the right atrium through the right atrial endocardium and central fibrous body to deliver cardiac therapy to or sense electrical activity in the basal and/or septal region of the left ventricular myocardium of the left ventricle of the patient's heart.