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Mild Metabolic Acidosis Impairs the β-Adrenergic Response in Isolated Human Failing Myocardium

Mild Metabolic Acidosis Impairs the β-Adrenergic Response in Isolated Human Failing Myocardium

Hanna Schotola et al. Crit Care.


Introduction: Pronounced extracellular acidosis reduces both cardiac contractility and the β-adrenergic response. In the past, this was shown in some studies using animal models. However, few data exist regarding how the human end-stage failing myocardium, in which compensatory mechanisms are exhausted, reacts to acute mild metabolic acidosis. The aim of this study was to investigate the effect of mild metabolic acidosis on contractility and the β-adrenergic response of isolated trabeculae from human end-stage failing hearts.

Methods: Intact isometrically twitching trabeculae isolated from patients with end-stage heart failure were exposed to mild metabolic acidosis (pH 7.20). Trabeculae were stimulated at increasing frequencies and finally exposed to increasing concentrations of isoproterenol (0 to 1 × 10(-6) M).

Results: A mild metabolic acidosis caused a depression in twitch-force amplitude of 26% (12.1 ± 1.9 to 9.0 ± 1.5 mN/mm(2); n = 12; P < 0.01) as compared with pH 7.40. Force-frequency relation measurements yielded no further significant differences of twitch force. At the maximal isoproterenol concentration, the force amplitude was comparable in each of the two groups (pH 7.40 versus pH 7.20). However, the half-maximal effective concentration (EC50) was significantly increased in the acidosis group, with an EC50 of 5.834 × 10(-8) M (confidence interval (CI), 3.48 × 10(-8) to 9.779 × 10(-8); n = 9), compared with the control group, which had an EC50 of 1.056 × 10(-8) M (CI, 2.626 × 10(-9) to 4.243 × 10(-8); n = 10; P < 0.05), indicating an impaired β-adrenergic force response.

Conclusions: Our data show that mild metabolic acidosis reduces cardiac contractility and significantly impairs the β-adrenergic force response in human failing myocardium. Thus, our results could contribute to the still-controversial discussion about the therapy regimen of acidosis in patients with critical heart failure.


Figure 1
Figure 1
Immediate changes in pH. (A) Representative single twitches before and after changing extracellular pH. No obvious reduction of developed tension is visible. (B) Representative single twitches after an acute pH change show a decrease of absolute developed tension due to mild metabolic acidosis. (C) Mean values of relative force amplitude before and after pH change show a significant decrease of force amplitude after changing to the mild acidotic solution. (D) Time to 90% relaxation before and after pH solution change yielded no statistical difference.
Figure 2
Figure 2
Force-frequency relation. (A, B) Representative single twitches show a decrease of force amplitude and an increase of diastolic tension in both groups. (C) Relative force amplitudes at frequencies between 1 Hz and 3 Hz show a negatively shaped force-frequency relation. (D) Diastolic tension normalized to the values recorded at the lowest frequency revealed no differences between the two groups. (E) Mean values of time to 90% of relaxation do not differ significantly between the two pH groups.
Figure 3
Figure 3
β-Adrenergic response. (A, B) Representative single twitches show an increase of force amplitude with increasing isoproterenol concentrations in both groups, but faster in the pH 7.4 group. (C) Relative force amplitudes normalized to baseline force showed a sigmoid shape with increasing isoproterenol. (D) Diastolic tension normalized to baseline revealed no differences between the groups: the tension decreased minimally with increasing isoproterenol. (E) Time to 90% of relaxation was statistically significantly slower in the mild acidotic group than in the control group with pH 7.40. (F) Half-maximal effective concentration (EC50) was statistically significantly different between the pH groups.

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