Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice

Abstract

XP. Progressive troponin I loss impairs cardiac relaxation and causes heart failure in mice. Am J Physiol Heart Circ Physiol 293: H1273-H1281, 2007. First published May 25, 2007; doi:10.1152/ajpheart.01379.2006.-Cardiac troponin I (TnI) knockout mice exhibit a phenotype of sudden death at 17-18 days after birth due to a progressive loss of TnI. The objective of this study was to gain insight into the physiological consequences of TnI depletion and the cause of death in these mice. Cardiac function was monitored serially between 12 and 17 days of age by using high-resolution ultrasonic imaging and Doppler echocardiography. Two-dimensional B-mode and anatomical M-mode imaging and Doppler echocardiography were performed using a high-frequency (ϳ20 -45 MHz) ultrasound imaging system on homozygous cardiac TnI mutant mice (cTnI Ϫ/Ϫ ) and wild-type littermates. On day 12, cTnI Ϫ/Ϫ mice were indistinguishable from wildtype mice in terms of heart rate, atrial and LV (LV) chamber dimensions, LV posterior wall thickness, and body weight. By days 16 through 17, wild-type mice showed up to a 40% increase in chamber dimensions due to normal growth, whereas cTnI Ϫ/Ϫ mice showed increases in atrial dimensions of up to 97% but decreases in ventricular dimensions of up to 70%. Mitral Doppler analysis revealed prolonged isovolumic relaxation time and pronounced inversion of the mitral E/A ratio (early ventricular filling wave-to-late atrial contraction filling wave) only in cTnI Ϫ/Ϫ mice indicative of impaired LV relaxation. cTnI Ϫ/Ϫ mouse hearts showed clear signs of failure on day 17, characterized by Ͼ50% declines in cardiac output, ejection fraction, and fractional shortening. B-mode echocardiography showed a profoundly narrowed tube-like LV and enlarged atria at this time. Our data are consistent with TnI deficiency causing impaired LV relaxation, which leads to diastolic heart failure in this model. damaged relaxation; echocardiography; Doppler analysis THE CONTRACTILE SARCOMERIC PROTEINS consist of a highly ordered arrangement of myosin thick filaments, actin thin filaments, and associated proteins, such as the troponin-tropomyosin complex. Contractile sarcomeric protein mutations, truncations, and deletions have been identified for various cardiac disorders in humans and experimental animals (8,16,18,23,25,28

High-Frequency Ultrasound Assessment of the Murine Heart From Embryo Through to Juvenile

“…Prolonged IRT and reversal of E/A wave ratio indicating impaired LV relaxation was recorded in cardiac troponin I (TnI) knockout (KO) mice and not in wild types. 17 Decreased and even reversal of E/A ratio was also shown in Tbx5 del/þ mice (model of Holt-Oram syndrome). This later model demonstrated reduced diastolic capabilities while systolic properties remained normal.…”

Troponin Mutation Caused Diastolic Dysfunction and Experimental Treatment in Transgenic Mice with Cardiomyopathy

“…The histological and functional measurement results clearly showed that TnI depletion altered both resting and active mechanical properties of ventricular myocytes and caused a lethal phenotype with shortened sarcomere length and a restricted ventricle due to a severe diastolic dysfunction [2,11]. The results also showed for the first time that expression of the adult cTnI isoform is not an essential component of the switch that terminates expression of the fetal ssTnI expression in the developing heart.…”

Functional characterization of mouse fetal TnI gene promoters in myocardial cells

“…It is clinically important because troponin I can dramatically decrease in postinfarction left ventricular remodeled myocardium remote from the infarct zone [25] and the content of TnI in left ventricular myocardium may significantly decrease in older men with or without cardiac disease [26]. In addition, progressive troponin I loss can cause diastolic dysfunction and heart failure [27]. The similarities in regulation of TnI in lower and higher mammals and the down-regulation of slow skeletal TnI mRNA even in hypertrophied human heart imply tight genetic control of the expression of TnI gene in the heart.…”