Myofilament Ca2+ sensitivity correlates with left ventricular contractility during the progression of pressure overload-induced left ventricular myocardial hypertrophy in rats
█ Original article
Ruppert Mihály1,2*, Bódi Beáta3*, Nagy Dávid1, Korkmaz-Icöz Sevil2, Loganathan Sivakkanan2, Oláh Attila1, Barta Bálint András1, Sayour Alex Ali1,2, Benke Kálmán1, Karck Matthias2, Merkely Béla1, Papp Zoltán3,4, Szabó Gábor2*, Radovits Tamás1*
1Semmelweis Egyetem, Városmajori Szív- és Érgyógyászati Klinika, Budapest
2Ruprecht-Karls Egyetem, Szívsebészeti Klinika, Kísérleti Kutató Laboratórium, Heidelberg
3Debreceni Egyetem, Klinikai Fiziológiai tanszék, Debrecen
4MTA-DE, Vaszkuláris Biológia és Miokardium Patofiziológiai Kutatócsoport, Debrecen
Aim: Here we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH).
Methods: Abdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes.
Results: AB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LVmass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca2+ sensitivity (pCa50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca2+-sensitivity among the study groups.
Conclusion: Changes in myofilament Ca2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.