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. 2015 Dec 15;309(12):H2077-86.
doi: 10.1152/ajpheart.00685.2015. Epub 2015 Oct 9.

The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium

Nima Milani-Nejad  1 , Benjamin D Canan  2 , Mohammad T Elnakish  3 , Jonathan P Davis  2 , Jae-Hoon Chung  4 , Vadim V Fedorov  2 , Philip F Binkley  5 , Robert S D Higgins  6 , Ahmet Kilic  6 , Peter J Mohler  7 , Paul M L Janssen  8
Affiliations

The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium

Nima Milani-Nejad et al. Am J Physiol Heart Circ Physiol. .

Abstract

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.

Keywords: cross-bridge cycling kinetics; heart failure; muscle length; relaxation; trabeculae.

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Figures

Fig. 1.
Fig. 1.
A: typical K+ contracture in a human trabecula (heart 328163, muscle RV1). Arrowhead shows when maximum rate of cross-bridge reattachment (ktr,max) was measured. Arrows show the approximate time of assessment of ktr during submaximal activation levels; note that these varied highly from muscle to muscle. No ktr maneuver was performed in this particular contracture. B: representative ktr tracing in a human trabecula (heart 618200, muscle RV4). The movement of the motor is shown at top. Note the transient overshoot during force redevelopment while the position of the motor is constant. All ktr tracings were fit to the equation described in methods from the residual tension after the maneuver to the onset of maximum tension during the overshoot. C: ktr measurements are temperature dependent in intact human right ventricular trabeculae. All measurements were made during the maximal tension level of the K+ contracture. n = 4 hearts (1 trabeculae per heart). P < 0.05: *vs. 27°C, #vs. 32°C. D: typical twitch tracing of a human right ventricular trabeculae (heart 685884, muscle RV1) at optimal length. Developed force (Fdev) corresponds to the tension that is generated during muscle contraction, and resting force (Fres) corresponds to the passive tension of the trabeculae. Time to peak (TTP) is the time it takes for the muscle to reach peak force development from onset of stimulation. RT50 is the time it takes for the muscle to relax from peak developed force to 50% of the force. +dF/dt and −dF/dt are the maximal velocity of force development and relaxation, respectively (expressed as mN·mm−2·s−1). +dF/dt and −dF/dt can be normalized to the developed force, resulting in +dF/dt/Fmax and −dF/dt/Fmax, respectively (not shown). The unit of these measurements is second−1.
Fig. 2.
Fig. 2.
Length-tension relationship, force-frequency relationship, and β-adrenergic stimulation in nonfailing vs. failing right ventricular myocardium. A: length-tension relationship is not different (at 0.5 Hz stimulation frequency) between nonfailing and failing myocardium (ANOVA, P > 0.05). Lopt, optimal length; L90, 90% of Lopt; L95, 95% of Lopt. B: force-frequency relationship is negative in failing myocardium. C: β-adrenergic response is shifted to the right in failing myocardium. D: EC50 is significantly greater in failing myocardium. *P < 0.05 as determined with 2-way ANOVA; $post hoc t-test indicating a significant difference of P < 0.05 between failing and nonfailing groups; #P < 0.05 as determined with unpaired t-test between nonfailing and failing groups. n = 8 nonfailing hearts, n = 8–9 failing hearts (1–3 trabeculae/heart).
Fig. 3.
Fig. 3.
Contraction and relaxation parameters from the muscles in Fig. 2A. A: original representative recordings of single twitches (normalized) in failing and nonfailing human myocardium stimulated at 0.5 Hz at Lopt and L90. B: the kinetic parameter +dF/dt/Fdev corresponding to the kinetics of contraction speed-up at muscle length is decreased, while there is no difference between nonfailing and failing myocardium at each length. C: the kinetic parameter −dF/dt/Fdev corresponding to the kinetics of twitch relaxation at multiple muscle lengths. Measurements made at stimulation frequency of 0.5 Hz. *P < 0.05 vs. Lopt of same heart group. N.S., P > 0.05 between nonfailing and failing at each length. n = 8 nonfailing hearts, n = 9 failing hearts (1–3 trabeculae/heart).
Fig. 4.
Fig. 4.
Muscle length regulates kinetics of contraction and relaxation in both nonfailing and failing right ventricular myocardium. A: original representative recordings of single twitches (normalized) in failing and nonfailing human myocardium stimulated at 1 Hz at Lopt and L90. B: the contraction kinetic parameter +dF/dt/Fdev is accelerated as muscle length is decreased in both groups. C: the relaxation kinetic parameter −dF/dt/Fdev is accelerated as muscle length is decreased in both groups. There is no difference in either kinetic parameter between nonfailing and failing human myocardium at each respective muscle length. Measurements made at stimulation frequency of 1 Hz. P < 0.05: *vs. Lopt, #vs. L95, $vs. Lopt,repeat of same heart group. N.S., P > 0.05 between nonfailing and failing at each length. n = 9 nonfailing hearts, n = 10 failing hearts (1 trabecula/heart).
Fig. 5.
Fig. 5.
There is no difference in ktr,max during maximal activation between nonfailing and failing myocardium. A: decreasing muscle length results in a decrease in developed tension during the K+ contracture. B: representative force-redevelopment recordings in failing and nonfailing human myocardium at Lopt and L90. C: decreasing muscle length accelerates ktr in both nonfailing and failing myocardium. However, there is no difference between nonfailing and failing myocardium at each length. P < 0.05: *vs. Lopt, #vs. L95, $vs. Lopt,repeat of same heart group. N.S., P > 0.05 between nonfailing and failing human myocardium at each respective muscle length. n = 9 nonfailing hearts, n = 10 failing hearts (1 trabecula/heart).
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