TY - JOUR

T1 - The neonatal but not the mature heart adapts to acute tachycardia by beneficial modification of the force-frequency relationship

AU - Schmidt, M R

AU - White, P A

AU - Khambadkone, S

AU - Gross, G J

AU - Bøtker, H E

AU - Vogel, M

AU - Hjortdal, V E

AU - Sørensen, K E

AU - Redington, A N

PY - 2011/6

Y1 - 2011/6

N2 - The force-frequency relationship (FFR) reflects alterations in intracellular calcium cycling during changing heart rate (HR). Tachycardia-induced heart failure is associated with depletion of intracellular calcium. We hypothesized (1) that the relative resistance to tachycardia-induced heart failure seen in neonatal pigs is related to differences in calcium cycling, resulting in different FFR responses and (2) that pretreatment with digoxin to increase intracellular calcium would modifies these changes. LV +dP/dt was measured during incremental right atrial pacing in 16 neonatal and 14 adult pigs. FFR was measured as the change in +dP/dt as HR was increased. Animals were randomized to control or intravenous bolus digoxin (n = 8 neonate pigs in the 0.05 mg/kg group and n = 7 adult pigs in the 0.025 mg/kg group) and paced for 90 min at 25 bpm greater than the rate of peak +dP/dt. Repeat FFR was then obtained. The postpacing FFR in neonatal control pigs shifted rightward, with peak force occurring 30 bpm greater than baseline (P < 0.03). There was no vertical shift; thus, force at 150 bpm decreased (P < 0.03) and force at 300 beats/min increased (P < 0.08). In adult control pigs, FFR shifted downward (P < 0.01), with decreased force generation at all HRs. In both neonates and adult pigs, digoxin increased +dP/dt at all HRs; however, in neonate pigs digoxin decreased the contractile reserve by abrogation of the rightward shift of FFR. An adaptive response to tachycardia in the neonate pig leads to improved force generation at greater HRs. Conversely, the response of the mature pig heart is maladaptive with decreased force generation. Pretreatment with digoxin modifies these responses.

AB - The force-frequency relationship (FFR) reflects alterations in intracellular calcium cycling during changing heart rate (HR). Tachycardia-induced heart failure is associated with depletion of intracellular calcium. We hypothesized (1) that the relative resistance to tachycardia-induced heart failure seen in neonatal pigs is related to differences in calcium cycling, resulting in different FFR responses and (2) that pretreatment with digoxin to increase intracellular calcium would modifies these changes. LV +dP/dt was measured during incremental right atrial pacing in 16 neonatal and 14 adult pigs. FFR was measured as the change in +dP/dt as HR was increased. Animals were randomized to control or intravenous bolus digoxin (n = 8 neonate pigs in the 0.05 mg/kg group and n = 7 adult pigs in the 0.025 mg/kg group) and paced for 90 min at 25 bpm greater than the rate of peak +dP/dt. Repeat FFR was then obtained. The postpacing FFR in neonatal control pigs shifted rightward, with peak force occurring 30 bpm greater than baseline (P < 0.03). There was no vertical shift; thus, force at 150 bpm decreased (P < 0.03) and force at 300 beats/min increased (P < 0.08). In adult control pigs, FFR shifted downward (P < 0.01), with decreased force generation at all HRs. In both neonates and adult pigs, digoxin increased +dP/dt at all HRs; however, in neonate pigs digoxin decreased the contractile reserve by abrogation of the rightward shift of FFR. An adaptive response to tachycardia in the neonate pig leads to improved force generation at greater HRs. Conversely, the response of the mature pig heart is maladaptive with decreased force generation. Pretreatment with digoxin modifies these responses.

KW - Age Factors

KW - Animals

KW - Animals, Newborn

KW - Calcium Channels/drug effects

KW - Cardiac Pacing, Artificial

KW - Cardiotonic Agents/pharmacology

KW - Cytoplasm/drug effects

KW - Cytosol/drug effects

KW - Digoxin/pharmacology

KW - Electrocardiography/drug effects

KW - Heart Failure/physiopathology

KW - Heart Rate/drug effects

KW - Models, Theoretical

KW - Myocardial Contraction/drug effects

KW - Sarcoplasmic Reticulum/drug effects

KW - Swine

KW - Tachycardia/physiopathology

KW - Ventricular Function, Left/drug effects

U2 - 10.1007/s00246-011-9899-6

DO - 10.1007/s00246-011-9899-6

M3 - Journal article

C2 - 21394656

VL - 32

SP - 562

EP - 567

JO - Pediatric Cardiology

JF - Pediatric Cardiology

SN - 0172-0643

IS - 5

ER -