Effects of increased preload on the force-frequency response and contractile kinetics in early stages of cardiac muscle hypertrophy

Abstract

Haizlip KM, Bupha-Intr T, Biesiadecki BJ, Janssen PM. Effects of increased preload on the force-frequency response and contractile kinetics in early stages of cardiac muscle hypertrophy. Am J Physiol Heart Circ Physiol 302: H2509 -H2517, 2012. First published March 30, 2012 doi:10.1152/ajpheart.00660.2011.-Numerous studies have aimed to elucidate markers for the onset of decompensatory hypertrophy and heart failure in vivo and in vitro. Alterations in the force-frequency relationship are commonly used as markers for heart failure with a negative staircase being a hallmark of decompensated cardiac function. Here we aim to determine the functional and molecular alterations in the very early stages of compensatory hypertrophy through analysis of the force-frequency relationship, using a novel isolated muscle culture system that allows assessment of forcefrequency relationship during the development of hypertrophy. New Zealand white male rabbit trabeculae excised from the right ventricular free wall were utilized for all experiments. Briefly, muscles held at constant preload and contracting isometrically were stimulated to contract in culture for 24 h, and in a subset up to 48 h. We found that, upon an increase in the preload and maintaining the muscles in culture for up to 24 h, there was an increase in baseline force produced by isolated trabeculae over time. This suggests a gradual compensatory response to the impact of increased preload. Temporal analysis of the force-frequency response during this progression revealed a significant blunting (at 12 h) and then reversal of the positive staircase as culture time increased (at 24 h). Phosphorylation analysis revealed a significant decrease in desmin and troponin (Tn)I phosphorylation from 12 to 24 h in culture. These results show that even very early on in the compensatory hypertrophy state, the force-frequency relationship is already affected. This effect on force-frequency relationship may, in addition to protein expression changes, be partially attributed to the alterations in myofilament protein phosphorylation. contractility; culture; myofilaments; rabbit; trabeculae HEART DISEASE IS THE NUMBER ONE killer in the western world, emphasizing the need for understanding the progression to failure and the development of different treatment strategies. There are numerous causes of heart failure, but a rather common denominator is the presence of some type of hypertrophic maladaptive growth of the myocardium. Cardiac hypertrophy is, most generally, caused by an increase in cardiac load, induced by elevated blood pressure (5,31,38). Normally, hypertrophy occurs as a compensatory mechanism to ameliorate the immediate effects of hypertension. This increased load, ultimately, leads to a deficiency in pump function of the heart. If this deficiency chronically remains, a hypertrophic response occurs, which is almost always irreversible.Hypertrophy is characterized by an increase in the size of the cardiomyocyte, through the addition of sarcomeres in series and/or in parall...

Comparison of Biomechanical Properties and Microstructure of Trabeculae Carneae, Papillary Muscles, and Myocardium in the Human Heart

“…Trabeculae carneae and papillary muscles are often used in mechanical tests as a surrogate of the myocardium Fig. 1 Photograph of a human heart opened by a frontal incision illustrating the trabeculae carneae and papillary muscles 1 to understand its mechanical behavior [22,23]. For example, papillary muscles from rat and rabbit hearts have been used extensively in mechanical testing to understand the mechanical properties of the myocardium [24,25].…”

Role of Endothelin in the Induction of Cardiac Hypertrophy In Vitro

“…These observations were made in a multicellular preparation, containing cardiomyocytes, fibroblasts, and endothelial cells. In this system, muscles have the ability to react to biochemical and mechanical stimuli and can remodel and adapt contractile function in a 24–48 hour time span [13] , [15] , [16] , [17] , [18] , [20] , [21] , [37] . Thus, results from this model may differ from other in vitro models in which isolated cardiomyocytes alone are investigated, or from whole-animal models where systemic regulation is present.…”

“…Our lab and those of others have shown that these cultured multicellular preparations muscles remain stable in their protein expression/generation [15] and contractile function for up to 5 days [16] . Multicellular preparations can be used from various species [14] , [17] , including human [16] , and this system allows for functional protein product expression of virus-mediated gene transfer [18] , [19] and the observation of slow process such as load-induced changes in protein expression [13] , [20] or apoptosis [21] , [22] . Briefly, New Zealand White rabbits (1.5–2.0 kg) were heparinized and anesthetized by infusion of pentobarbital sodium (50 mg/kg) into the ear vein.…”

Accounting for Material Changes in Decellularized Tissue with Underutilized Methodologies

“…The load imposed on the cell in turn determines force of contraction and modulates phosphorylation and expression of myofilament proteins such as troponin I and desmin. Because of this relationship between tissue mechanical forces and the cardiac cell, chronic changes in elasticity and stiffness may subsequently lead to maladaptive growth [ 41 , 42 ].…”