Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

Miura, Makoto; Hirose, Masao; Endoh, Hideaki; Wakayama, Yuji; Sugai, Yoshinao; Fukuda, Koji; Shindoh, Chiyohiko; Shirato, Kunio; Shimokawa, Hiroaki

doi:10.1253/circj.cj-10-1050

Cited by 11 publications

(8 citation statements)

References 40 publications

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“…In addition to SERCA2a, Kogler et al, found that other calcium-handling proteins such as phospholamban and ryanodine receptor were also downregulated only in the RV, but not in the LV of MCT-treated rats 26 . In a recent study Miura et al suggested that an increase in diastolic [Ca 2+ ]i and an increase in Ca 2+ sensitivity of the sarcoplasmic reticulum Ca 2+ release channel accelerate Ca 2+ waves in ventricular hypertrophy, thereby causing arrhythmogenesis in the RV of MCT-induced PH 33 .…”

Section: Discussionmentioning

confidence: 99%

Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension

Umar¹,

Lee²,

Lange³

et al. 2012

Circ: Arrhythmia and Electrophysiology

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Background Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. Here we test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality. Methods and Results Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (CTRL, n=17). Activation pattern of RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day-21 and progressed to RVF by ~day-30. Rats manifested increased mortality and ~30% rats died suddenly and precipitously during 23–32 days post-MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV which was subsequently maintained by both focal and incomplete re-entrant wavefronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization (EAD)-mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the LV cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the CTRL hearts. RVF was associated with significantly reduced RV ejection fraction (p<0.001), RV hypertrophy (p<0.001) and RV fibrosis (p<0.01). The hemodynamic function of the LV and its structure were preserved. Conclusions PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an EAD-mediated triggered activity.

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Section: Discussionmentioning

confidence: 99%

Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension

Umar¹,

Lee²,

Lange³

et al. 2012

Circ: Arrhythmia and Electrophysiology

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“…Benoist and collaborators (4) have described a proarrhytmogenic substrate in the hearts of MCTtreated animals. Whether MCT-induced myocarditis or arrhythmias (4,42) are the cause of death in rats, which can tolerate higher levels of RV afterload, remains undetermined but should be considered.…”

Section: Mct-induced Myocarditismentioning

confidence: 99%

The monocrotaline model of pulmonary hypertension in perspective

Gomez-Arroyo

Farkas

Alhussaini

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

351

291

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Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

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“…; Miura et al . ; Lookin et al . ), and (iv) decreased expression of the sarcoplasmic reticulum Ca 2+ ‐ATPase (Kogler et al .…”

Section: Introductionmentioning

confidence: 99%

Pulmonary arterial hypertension reduces energy efficiency of right, but not left, rat ventricular trabeculae

Pham

Nisbet

Taberner

et al. 2018

The Journal of Physiology

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Pulmonary arterial hypertension (PAH) greatly increases the afterload on the right ventricle (RV), triggering RV hypertrophy, which progressively leads to RV failure. In contrast, the disease reduces the passive filling pressure of the left ventricle (LV), resulting in LV atrophy. We investigated whether these distinct structural and functional consequences to the ventricles affect their respective energy efficiencies. We studied trabeculae isolated from both ventricles of Wistar rats with monocrotaline-induced PAH and their respective Control groups. Trabeculae were mounted in a calorimeter at 37°C. While contracting at 5 Hz, they were subjected to stress-length work-loops over a wide range of afterloads. They were subsequently required to undergo a series of isometric contractions at various muscle lengths. In both protocols, stress production, length change and suprabasal heat output were simultaneously measured. We found that RV trabeculae from PAH rats generated higher activation heat, but developed normal active stress. Their peak external work output was lower due to reduced extent and velocity of shortening. Despite lower peak work output, suprabasal enthalpy was unaffected, thereby rendering suprabasal efficiency lower. Crossbridge efficiency, however, was unaffected. In contrast, LV trabeculae from PAH rats maintained normal mechano-energetic performance. Pulmonary arterial hypertension reduces the suprabasal energy efficiency of hypertrophied right ventricular tissues as a consequence of the increased energy cost of Ca cycling.

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Acceleration of Ca2+ Waves in Monocrotaline-Induced Right Ventricular Hypertrophy in the Rat

Cited by 11 publications

References 40 publications

Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension

Spontaneous Ventricular Fibrillation in Right Ventricular Failure Secondary to Chronic Pulmonary Hypertension

The monocrotaline model of pulmonary hypertension in perspective

Pulmonary arterial hypertension reduces energy efficiency of right, but not left, rat ventricular trabeculae

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