Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction

Abstract

Objectives: The purpose of this study is to evaluate tachycardia-induced relaxation abnormalities in myocardium from patients with a normal ejection fraction.

Background: Diastolic dysfunction and left ventricular (LV) hypertrophy are closely linked. Tachycardia can induce heart failure symptoms in otherwise asymptomatic patients. To study the effects of tachycardia on myocardial contractility and relaxation, we evaluated the effects of increasing pacing rates in myocardial biopsy samples obtained from patients with a normal ejection fraction.

Methods: LV biopsy samples were obtained during coronary bypass surgery. Myocardial strip preparations were electrically paced at rates from 60 to 180 beats/min. Diastolic resting tone was assessed by cross-bridge deactivation. Calcium transporting systems were functionally examined, and myofilament calcium sensitivity was studied.

Results: Incomplete relaxation developed in 7 preparations, with increased diastolic tension development at increasing pacing rates. This was absent in the remaining 7 preparations. Incomplete relaxation was found to be associated with increased LV mass and left atrial volume. Cross-bridge deactivation showed that these preparations also had a significant resting tone. Additional functional analyses suggest that incomplete relaxation is associated with disproportionately elevated cellular calcium loads due to a reduced sarcolemmal calcium extrusion reserve.

Conclusions: Tachycardia-induced incomplete relaxation was associated with increased LV mass and left atrial volumes. We also found a disproportionately increased calcium load at high rates and a substantial resting tone due to diastolic cross-bridge cycling. These observations may play a role in reduced exercise tolerance and tachycardia-induced diastolic dysfunction.

Figure 1

Panel A depicts two force tracings of paced human myocardial strips. The upper tracing shows a normal relaxation up to the highest rate. The lower tracing demonstrates incomplete relaxation that is first apparent at 120/min (circle). At 180/min diastolic tension is markedly increased resulting in a diastolic contracture. Panel B shows average peak systolic force (■) and average diastolic tension (●) after grouping the experiments according to their relaxation behavior (normal vs. incomplete). The group of preparations that displayed incomplete relaxation showed a rise in diastolic tension as the rate was increased (p<0.05). Rates typical for tachycardia are in red.

Figure 2. Tracings from two preparations with normal and incomplete relaxation

Both preparations were paced at 180/min when the stimulation was stopped. After allowing the preparation to establish a stable resting tension, BDM, a reversible crossbridge inhibitor, was added to the circulating solution. This revealed a substantial resting tone in the preparation with incomplete relaxation. No resting tone was found in preparations that showed normal relaxation characteristics with tachycardia.

Figure 3. Calcium-force relationship in skinned preparations from the preparations with normal and incomplete relaxation

There was no difference in the calcium concentrations at half maximal force (EC50). This indicates that calcium sensitivity is unchanged in preparations that display incomplete relaxation.

Figure 4

Panel A. Post-Rest Contractions (PRCs) and the time dependent decay of PRCs at two preceding pacing rates (60/min and 180/min). The rest intervals were incrementally increased as indicated. The developed tension of the post-rest contraction is a measure of sarcoplasmic reticulum (SR) calcium release. This data demonstrates an increase in SR mediated contractility in the group that displays incomplete relaxation. Panel B. Rapid Cooling Contractures (RCCs) as a measure of the total SR calcium content at 60/min and 180/min in the normal and incomplete relaxation group. Rapid switching to a solution at 1°C releases all calcium from the SR which then activates the myofilaments. The group with incomplete relaxation demonstrates a disproportional increase in SR calcium content at 180/min that recovers to more normal levels after a prolonged resting interval. * indicates p<0.05 for between group comparisons at the respective rates.

Figure 5. Contractile consequences of complete sarcoplasmatic reticulum (SR) inhibition in preparations with normal and incomplete relaxation

The preparation that exemplifies normal relaxation shows a small increase in diastolic tension after SR removal when paced at 180/min. This rise in diastolic tension is much more pronounced in the preparation that displays incomplete relaxation at baseline.

Figure 6. Incomplete relaxation and contracture onset-rates in patients with concentric LV hypertrophy versus patients with a normal LV mass

The onset of incomplete relaxation at rates that are just above physiological resting heart rates is demonstrated in myocardium from patients with hypertrophy. Error bars represent confidence intervals.