Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Abstract

Wilson K, Guggilam A, West TA, Zhang X, Trask AJ, Cismowski MJ, de Tombe P, Sadayappan S, Lucchesi PA. Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure. Am J Physiol Heart Circ Physiol 307: H1605-H1617, 2014. First published September 26, 2014 doi:10.1152/ajpheart.00423.2014.-Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca 2ϩ sensitizer would improve VOinduced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200 -240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca 2ϩ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca 2ϩ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4 -8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (, dP/ dt min) function in ACF and REV. Levo improved Ca 2ϩ sensitivity without altering the amplitude and kinetics of the intracellular Ca 2ϩ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased ␣-to-␤-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function. myofilament dysfunction; myofilament Ca 2ϩ sensitization; levosimendan; myosin-binding protein-C; troponin I MITRAL REGURGITATION (MR) is the most and second most common valve lesion in the United States and Europe, respectively, affecting Ͼ2 million Americans (10, 16). The pathophysiological consequences of MR include chronic left ventricular (LV) hemodynamic volume overload (VO) followed by LV chamber dilation, progressive LV contractile dysfunction, and heart failure (HF). Despite the clinical importance of VO, few models mimic the pathophysiological progression of chronic VO with and without hemodynamic load reduction. The aortocaval fistula (ACF) model of VO HF in the rodent mimics increased hemodynamic preload observed in human disease, irrespective of etiology. In this model, chronically increased LV preload leads to progressive LV pump failure, which is classified into t...

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat

“…Accordingly, the worsened time constant of isovolumic relaxation (τ) and rate of the LV pressure decrease ( dP/dt min ) reflected impaired diastolic performance after i.v. OM administration in rats with volume overload HF (Wilson et al ., ).…”

Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats

“…1,2,5 Various animal models have been used in the study of LVDD, including the mRen2.Lewis rats, 9,10 deoxycorticosterone acetate-hypertensive rats, 30 spontaneously hypertensive rats (SHR), 31 streptozotocin and a high-fat diet-induced diabetic rats and mice, 32,33 lipopolysaccharide-induced high inflammation and LVDD, 34 and aortocaval fistula-induced volume overload model. 35 However, all these animal models are pathological models and may not reflect the biological conditions of LVDD that exist in healthy, aging women after the cessation of ovarian estrogen production.…”

Cardiovascular effects in rats after intratracheal instillation of metal welding particles

“…In the current study, the mechanism of impaired diastolic function d P /d t min in response to β-adrenoceptor stimuli after MMA-HS treatment is not known. However, it could be due to the intrinsic changes of myocyte function, which may include alterations in calcium handling, myofilament function and the sensitivities of the receptors (Engelhardt et al, 2001; Wilson et al, 2014). …”