Authors: | Wilson, K.; Guggilam, A.; West, T. A.; Zhang, X; Trask, A. J.; Cismowski, M. J.; De Tombe, P; Sadayappan, S; Lucchesi, P. A. |
Article Title: | Effects of a Myofilament Calcium Sensitizer on Left Ventricular Systolic and Diastolic Function in Rats with Volume Overload Heart Failure |
Abstract: | Background. Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 weeks 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 Ca2+ sensitizer would improve VO-induced myofilament dysfunction in ACF and REV. Methods and Results. Following the initial Sham or ACF surgery in male Sprague-Dawley rats (200-240g) 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 Ca2+ sensitivity, while in REV, impaired LV function is accompanied by decreased Ca2+ sensitivity. IV Levo elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (Veh; water) or Levo (1 mg/kg) in drinking water from Weeks 4-8. Levo improved systolic (%FS, Ees, PRSW) and diastolic (tau, dP/dtmin) function in ACF and REV. Levo improved Ca2+ sensitivity without altering the amplitude and kinetics of the intracellular Ca2+ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cTnI Ser-23/24 phosphorylation correlated with improved diastolic relaxation, while in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased alpha-to-beta-MHC correlated with improved diastolic relaxation. Conclusion. Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function. |
Journal Title: | American journal of physiology.Heart and circulatory physiology |
Volume: | 307 |
Issue: | 11 |
ISSN: | 1522-1539; 0363-6135 |
Publisher: | American Journal of Physiology - Heart and Circulatory Physiology |
Date Published: | 2014 |
Start Page: | H1605 |
End Page: | 17 |
Language: | ENG |
DOI/URL: |
ajpheart.00423.2014 |
Notes: | LR: 20150416; CI: Copyright (c) 2014; GR: K02 HL 114749/HL/NHLBI NIH HHS/United States; GR: K99 HL116769/HL/NHLBI NIH HHS/United States; GR: R01 HL-056046/HL/NHLBI NIH HHS/United States; GR: R01 HL-62426/HL/NHLBI NIH HHS/United States; GR: R01 HL105826/HL/NHLBI NIH HHS/United States; GR: T32 HL-098039/HL/NHLBI NIH HHS/United States; JID: 100901228; 0 (Cardiotonic Agents); 0 (Hydrazones); 0 (Pyridazines); 349552KRHK (simendan); OID: NLM: PMC4255015 [Available on 12/01/15]; OTO: NOTNLM; PMCR: 2015/12/01 00:00; 2014/09/26 [aheadofprint]; ppublish |