Abstract 1581: Extension of Titin as a Function of Filling Pressure and Sarcomere Length in the Porcine Left Ventricle

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Martin M LeWinter ◽  
Joseph Popper ◽  
Lori Nyland ◽  
Stephen B Bell ◽  
Henk Granzier
Keyword(s):  
Left Ventricle ◽  
Sarcomere Length ◽  
Filling Pressure ◽  
Passive Tension ◽  
Large Mammals ◽  
Myocardial Stiffness ◽  
Sarcomeric Protein ◽  
Equilibrium Volume ◽  
Slack Length

The giant sarcomeric protein titin is a molecular spring that is the chief source of cardiomyocyte passive tension and a major determinant of myocardial stiffness. The spring portion is located in the I band and consists of PEVK, Ig repeat and N2B and N2A elements. Titin occurs as two isoforms. N2B is a smaller and stiffer isoform that contains only the N2B element and predominates in the left ventricle (LV) of rodents. N2BA titin contains both N2A and N2B elements. N2B and N2BA are co-expressed in the sarcomere of large mammals (~60:40 ratio). As a result, passive cardiomyocyte and myocardial stiffness in large mammals is less than in rodents. Details of titin extension as a function of sarcomere length (SL) have been elucidated in rodents but not in large mammals, where the presence of both isoforms would be expected to modify extension and passive tension. Accordingly, we studied titin extension in miniswine. We first established the relation between filling pressure and SL in the anterior LV wall of the in situ, freshly arrested (KCl) heart. SL was determined over a range of filling pressures using a light microscopic method that minimizes shrinkage. At equilibrium volume (transmural pressure 0 mmHg), SL was between 2.00–2.10 μm, longer than slack length of ~1.85 μm in muscle strips. SL reached a maximum of ~2.50 βm when the LV was over-distended (filling pressure >40 mmHg). We then examined extension of titin in myocardial strips using electron microscopy and immuno-labeling of selected epitopes. The chief difference between isoforms was that the N2B-Us epitope segment in N2B titin lengthened ~four times more than the N2B-Us segment in N2BA titin over SLs from ~1.80 to ~2.50 μm. This difference remained large over the SL range present in the in situ LV. Linear fits of the measured end-to-end length of N2B-Us segments were used to estimate the force-SL relation of single N2B and N2BA molecules. This analysis predicted a much steeper relation for N2B titin. Thus, over the range of SLs present in the in situ LV the most prominent difference in extension of N2B and N2BA titin is greater lengthening of the N2B segment of N2B titin. This predicts a much greater in situ stiffness for N2B titin and demonstrates how passive stiffness can be exquisitely controlled by varying isoform expression.

scholarly journals Sarcomere length–dependent effects on Ca2+-troponin regulation in myocardium expressing compliant titin

2018 ◽  
Vol 151 (1) ◽  
pp. 30-41 ◽  
Author(s):  
King-Lun Li ◽  
Mei Methawasin ◽  
Bertrand C.W. Tanner ◽  
Henk L. Granzier ◽  
R. John Solaro ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Sarcomere Length ◽  
Mechanical Stretch ◽  
Passive Tension ◽  
Wild Type ◽  
Time Resolved ◽  
Complex Interactions ◽  
Donor And Acceptor ◽  
Myocardial Fibers

Cardiac performance is tightly regulated at the cardiomyocyte level by sarcomere length, such that increases in sarcomere length lead to sharply enhanced force generation at the same Ca2+ concentration. Length-dependent activation of myofilaments involves dynamic and complex interactions between a multitude of thick- and thin-filament components. Among these components, troponin, myosin, and the giant protein titin are likely to be key players, but the mechanism by which these proteins are functionally linked has been elusive. Here, we investigate this link in the mouse myocardium using in situ FRET techniques. Our objective was to monitor how length-dependent Ca2+-induced conformational changes in the N domain of cardiac troponin C (cTnC) are modulated by myosin–actin cross-bridge (XB) interactions and increased titin compliance. We reconstitute FRET donor- and acceptor-modified cTnC(13C/51C)AEDANS-DDPM into chemically skinned myocardial fibers from wild-type and RBM20-deletion mice. The Ca2+-induced conformational changes in cTnC are quantified and characterized using time-resolved FRET measurements as XB state and sarcomere length are varied. The RBM20-deficient mouse expresses a more compliant N2BA titin isoform, leading to reduced passive tension in the myocardium. This provides a molecular tool to investigate how altered titin-based passive tension affects Ca2+-troponin regulation in response to mechanical stretch. In wild-type myocardium, we observe a direct association of sarcomere length–dependent enhancement of troponin regulation with both Ca2+ activation and strongly bound XB states. In comparison, measurements from titin RBM20-deficient animals show blunted sarcomere length–dependent effects. These results suggest that titin-based passive tension contributes to sarcomere length–dependent Ca2+-troponin regulation. We also conclude that strong XB binding plays an important role in linking the modulatory effect of titin compliance to Ca2+-troponin regulation of the myocardium.

scholarly journals Titin isoform expression in aortic stenosis

2009 ◽  
Vol 117 (6) ◽  
pp. 237-242 ◽  
Author(s):  
Lynne WILLIAMS ◽  
Neil Howell ◽  
Domenico Pagano ◽  
Peter Andreka ◽  
Marton Vertesaljai ◽  
...  
Keyword(s):  
Left Ventricle ◽  
Aortic Stenosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Normal Donor ◽  
Myocardial Stiffness ◽  
Hypertrophic Response ◽  
Cardiac Titin ◽  
Sarcomeric Protein ◽  
Artery Disease

Titin is a giant sarcomeric protein that plays a major role in determining passive myocardial stiffness. The shorter N2B isoform results in a higher passive myocardial stiffness than the longer N2BA isoform. We hypothesised that the expression of the short N2B isoform would be increased in patients with aortic stenosis compared with healthy controls in response to pressure overload, in order to act as a modulator for the increased demand placed on the left ventricle during the early stages of the hypertrophic response. Myocardial biopsies were obtained from the left ventricle of 19 patients undergoing aortic valve replacement for aortic stenosis who had no significant co-existing coronary artery disease. Left ventricular biopsies were also obtained from 13 donor hearts for comparison. SDS-agarose gels revealed small N2B and large N2BA cardiac titin isoforms, with a mean N2BA/N2B ratio that was significantly decreased in the 19 aortic stenotic patients compared with the 13 controls (0.66±0.04 in the normal donor hearts compared with 0.48±0.03 in patients with aortic stenosis; P=0.02). However, total titin remained unchanged (0.28±0.02 compared with 0.24±0.02 respectively; P=0.29). In conclusion, the expression of less N2BA and more N2B titin in response to pressure overload may result in the generation of higher passive tension upon stretch to a given sarcomere length and this might affect cardiac performance.

Increased regional myocardial stiffness of the left ventricle during angina pectoris

1982 ◽  
Vol 49 (4) ◽  
pp. 1042
Author(s):  
Patrick D. Bourdillon ◽  
Beverly H. Lorell ◽  
Walter J. Paulus ◽  
Israel Mirsky ◽  
Joshua Wynne ◽  
...  
Keyword(s):  
Angina Pectoris ◽  
Left Ventricle ◽  
Myocardial Stiffness

Rhythm effects on contractility of the beating isovolumic left ventricle

1960 ◽  
Vol 199 (6) ◽  
pp. 1115-1120 ◽  
Author(s):  
B. Lendrum ◽  
H. Feinberg ◽  
E. Boyd ◽  
L. N. Katz
Keyword(s):  
Heart Rate ◽  
Left Ventricle ◽  
Systolic Pressure ◽  
Ventricular Volume ◽  
Contractile Force ◽  
Postextrasystolic Potentiation ◽  
Pressure Development ◽  
Induced Changes ◽  
Electrical Alternans

Variation in contractile force of the isovolumic contracting left ventricle of the dog was studied in open-chested in situ hearts. The electrocardiogram and intraventricular pressures were recorded at various heart volumes. Spontaneous changes in heart rate and rhythm occurred at all volumes. Isovolumic systolic pressure development (contractile force) varied with rate and rhythm. Contractile force increased with heart rate (treppe) regardless of pacemaker origin. When a premature beat was followed by a compensatory pause, the premature beat showed a decrease and the next beat an increase in contractile force (postextrasystolic potentiation). The magnitude of the changes varied directly with the prematurity of the beat. Mechanical alternans was observed with electrical alternans, despite the absence of significant volume change. Rate-induced changes, postextrasystolic potentiation and mechanical alternans were additive when they occurred simultaneously. For practical purposes, ventricular volume (filling), hence muscle fiber length, remained constant during these rate and rhythm change, therefore could not affect the strength of contraction. Contractile force changes directly attributable to rate and rhythm changes do, therefore, occur in the intact mammalian heart.

Influence of insulin resistance on the structural and functional state of myocardium of the left ventricle in males with uncomplicated hypertension

2014 ◽  
Vol 18 (4 (72)) ◽  
Author(s):  
M. Y. Kolesnyk
Keyword(s):  
Insulin Resistance ◽  
Left Ventricle ◽  
Left Atrium ◽  
Functional State ◽  
Filling Pressure ◽  
High Index ◽  
Homa Index ◽  
Uncomplicated Hypertension ◽  
High Insulin

The influence of insulin resistance on structural and functional state of the myocardium in 172 males with uncomplicated hypertension has been analyzed. The patients with high insulin resistance (HOMA index was above median) have higher left atrium dimension and tend to concentric remodeling of the left ventricle. Patients with high index HOMA values have echocardiographic signs of increased left ventricle filling pressure after exercise.

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