In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

Guggilam, Anuradha; Hutchinson, Kirk R.; West, T. Aaron; Kelly, Amy; Galantowicz, Maarten L.; Davidoff, Amy J.; Sadayappan, Sakthivel; Lucchesi, Pamela A.

doi:10.1016/j.yjmcc.2012.11.013

Cited by 26 publications

(41 citation statements)

References 51 publications

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“…At week 0, VO was induced under isoflurane anesthesia (2-2.5%) as described (17,19). Following abdominal incision, the abdominal aorta and caudal vena cava were exposed.…”

Section: Methodsmentioning

confidence: 99%

“…Transthoracic echocardiograms were performed biweekly (8.5-MHz, Xario; Toshiba Medical Systems, Tustin, CA) under isoflurane anesthesia (1.5-2.0%) (17,19). Midwall parasternal short-axis M-mode images were obtained to assess chamber diameters in end-systole (LVESD) and end-diastole (LVEDD) and LV posterior wall thickness in systole (PWTs) and diastole (PWTd).…”

Section: Methodsmentioning

confidence: 99%

“…Hearts were removed from anesthetized rats for LV myocyte isolation (17). The heart, mounted on a Langendorff apparatus, was perfused with Tyrode's solution supplemented with 10 mM 2,3-butanedione monoxime, followed by perfusion buffer and then digestion with trypsin/Liberase-TH.…”

Section: Methodsmentioning

confidence: 99%

“…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 three clinically relevant stages: 1) pre-HF [4-wk ACF; marked LV dilation, increased LV wall stress, mild LV dysfunction (ϳ10% decrease in % fractional shortening, %FS); no pulmonary congestion/edema], 2) established HF [8-wk ACF; severe LV dilation, significant LV systolic (25% decrease in %FS, ϳ50% decrease in end-systolic elastance, Ees, and preload-recruitable stroke work, PRSW) and diastolic dysfunction (10 -27% increase in and dP/dt min , respectively); no pulmonary congestion or edema], and 3) end-stage HF (15-21-wk ACF; LV pump failure with pulmonary congestion/edema) (17,19,34). This model is commonly used to identify molecular and cellular mechanisms driving disease progression and to test novel therapeutic approaches for improving LV structure and function (13,21,40).…”

mentioning

confidence: 99%

“…Although this mirrors human data where structure, but not function, returns postsurgically in 17% of patients with MR (27), the mechanism underlying the delayed functional recovery remains elusive. Although the cellular mechanisms that control excitation-contraction coupling have been studied at end-stage HF (17), less is known about cellular dysfunction at earlier stages of HF. Specifically, myocyte and myofilament function has not previously been evaluated in ACF or REV, and our model provides an attractive system for studying the physical and biochemical mechanics of VO before and after surgical intervention.…”

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confidence: 99%

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

Wilson

Guggilam

West

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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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...

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“…At week 0, VO was induced under isoflurane anesthesia (2-2.5%) as described (17,19). Following abdominal incision, the abdominal aorta and caudal vena cava were exposed.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Wilson

Guggilam

West

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Ca2+/calmodulin‐dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model

et al. 2022

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Aims Volume overload (VO) induced hypertrophy is one of the hallmarks to the development of heart diseases. Understanding the compensatory mechanisms involved in this process might help preventing the disease progression. Methods and resultsTherefore, the present study used 2 months old Wistar rats, which underwent an aortocaval fistula to develop VO-induced hypertrophy. The animals were subdivided into four different groups, two sham operated animals served as age-matched controls and two groups with aortocaval fistula. Echocardiography was performed prior termination after 4and 8-month. Functional and molecular changes of several sarcomeric proteins and their signalling pathways involved in the regulation and modulation of cardiomyocyte function were investigated. ResultsThe model was characterized with preserved ejection fraction in all groups and with elevated heart/body weight ratio, left/right ventricular and atrial weight at 4-and 8-month, which indicates VO-induced hypertrophy. In addition, 8-months groups showed increased left ventricular internal diameter during diastole, RV internal diameter, stroke volume and velocity-time index compared with their age-matched controls. These changes were accompanied by increased Ca 2+ sensitivity and titin-based cardiomyocyte stiffness in 8-month VO rats compared with other groups. The altered cardiomyocyte mechanics was associated with phosphorylation deficit of sarcomeric proteins cardiac troponin I, myosin binding protein C and titin, also accompanied with impaired signalling pathways involved in phosphorylation of these sarcomeric proteins in 8-month VO rats compared with age-matched control group. Impaired protein phosphorylation status and dysregulated signalling pathways were associated with significant alterations in the oxidative status of both kinases CaMKII and PKG explaining by this the elevated Ca 2+ sensitivity and titin-based cardiomyocyte stiffness and perhaps the development of hypertrophy. Conclusions Our findings showed VO-induced cardiomyocyte dysfunction via deranged phosphorylation of myofilament proteins and signalling pathways due to increased oxidative state of CaMKII and PKG and this might contribute to the development of hypertrophy.

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Myofilament dysfunction as an emerging mechanism of volume overload heart failure

Wilson

Lucchesi

2014

Pflugers Arch - Eur J Physiol

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Two main hemodynamic overload mechanisms [i.e., volume and pressure overload (VO and PO, respectively] result in heart failure (HF), and these two mechanisms have divergent pathologic alterations and different pathophysiological mechanisms. Extensive evidence from animal models and human studies of PO demonstrate a clear association with alterations in Ca(2+) homeostasis. By contrast, emerging evidence from animal models and patients with regurgitant valve disease and dilated cardiomyopathy point toward a more prominent role of myofilament dysfunction. With respect to VO HF, key features of excitation-contraction coupling defects, myofilament dysfunction, and extracellular matrix composition will be discussed.

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In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

Cited by 26 publications

References 51 publications

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

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

Ca2+/calmodulin‐dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model

Myofilament dysfunction as an emerging mechanism of volume overload heart failure

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