Pulmonary artery pulsatility index predicts right ventricular myofilament dysfunction in advanced human heart failure

Aslam, Mohammed; Jani, Vivek; Lin, Brian L.; Dunkerly‐Eyring, Brittany; Livingston, Carissa E.; Ramachandran, Abhinay; Ranek, Mark J.; Bedi, Kenneth; Margulies, Kenneth B.; Kass, David A.; Hsu, Steven

doi:10.1002/ejhf.2084

Cited by 17 publications

(17 citation statements)

References 7 publications

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“…Depression of the myocardial contractility, independent of the ejection fraction, is commonly seen in failing hearts [ 1 , 2 , 3 , 4 , 5 , 41 ]. Current inotropic therapies that directly augment the contractility are problematic, clinically, as they are pro-arrhythmic and increase mortality and, as such, are restricted to acute decompensation.…”

Section: Discussionmentioning

confidence: 99%

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

Jani

Yuan

et al. 2022

IJMS

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Sufficient cardiac contractility is necessary to ensure the sufficient cardiac output to provide an adequate end-organ perfusion. Inadequate cardiac output and the diminished perfusion of vital organs from depressed myocardium contractility is a hallmark end-stage of heart failure. There are no available therapeutics that directly target contractile proteins to improve the myocardium contractility and reduce mortality. The purpose of this study is to present a proof of concept to aid in the development of muscle activators (myotropes) for augmenting the contractility in clinical heart failure. Here we use a combination of cardiomyocyte mechanics, the biochemical quantification of the ATP turnover, and small angle X-ray diffraction on a permeabilized porcine myocardium to study the mechanisms of EMD-57033 (EMD) for activating myosin. We show that EMD increases the contractility in a porcine myocardium at submaximal and systolic calcium concentrations. Biochemical assays show that EMD decreases the proportion of myosin heads in the energy sparing super-relaxed (SRX) state under relaxing conditions, which are less likely to interact with actin during contraction. Structural assays show that EMD moves the myosin heads in relaxed muscles from a structurally ordered state close to the thick filament backbone, to a disordered state closer to the actin filament, while simultaneously inducing structural changes in the troponin complex on the actin filament. The dual effects of EMD on activating myosin heads and the troponin complex provides a proof of concept for the use of small molecule muscle activators for augmenting the contractility in heart failure.

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Section: Discussionmentioning

confidence: 99%

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

Jani

Yuan

et al. 2022

IJMS

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“…For any PAP, RVD is also more severe among patients with HFrEF than HFpEF 31. Additionally, the PAPi is an excellent predictor of RV sarcomere contractile dysfunction in patients with HFrEF 32. In a cross-sectional analysis of patients with HFpEF (n=219) and HFrEF (n=219), after controlling for PASP, the ratio of RV longitudinal strain to PASP was lower in HFrEF versus HFpEF (−0.53±0.36 vs −0.75±0.32) 31…”

Section: Rv Function In Heart Failure With Reduced Ejection Fractionmentioning

confidence: 97%

Right ventricular function across the spectrum of health and disease

Edward

Banchs

Parker

et al. 2022

Heart

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Knowledge of right ventricular (RV) structure and function has historically lagged behind that of the left ventricle (LV). However, advancements in invasive and non-invasive evaluations, combined with epidemiological analyses, have advanced the current understanding of RV (patho)physiology across the spectrum of health and disease, and reinforce the centrality of the RV in contributing to clinical outcomes. In the healthy heart, ventricular-arterial coupling is preserved during rest and in response to increased myocardial demand (eg, exercise) due to substantial RV contractile reserve. However, prolonged exposure to increased myocardial demand, such as endurance exercise, may precipitate RV dysfunction, suggesting that unlike the LV, the RV is unable to sustain high levels of contractility for extended periods of time. Emerging data increasingly indicate that both LV and RV function contribute to clinical heart failure. Reductions in quality-of-life, functional capacity and overall clinical outcomes are worsened among patients with heart failure when there is evidence of RV dysfunction. In addition, the RV is adversely impacted by pulmonary vascular disease, and among affected patients, overall RV function differs based on mechanisms of the underlying pulmonary hypertension, which may result from variations in sarcomere function within RV cardiomyocytes.

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“…Multiple hemodynamic indices are used to characterize the physiology of the RV, including RV afterload, right atrial pressure (RAP), the RAP-to-pulmonary artery wedge pressure (RAP/PAWP) ratio, RV stroke work index, the pulmonary artery pulsatility index (PAPi), and tricuspid annular plane systolic excursion (TAPSE) ( 37 , 38 ). While all correlate with RHF, their sensitivity and specificity for predicting outcomes can be quite variable.…”

Section: Pathophysiology Of Right Heart Failure In Cardiac Surgerymentioning

confidence: 99%

Supporting the “forgotten” ventricle: The evolution of percutaneous RVADs

James

Smith

2023

Front. Cardiovasc. Med.

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Right heart failure (RHF) can occur as the result of an acute or chronic disease process and is a challenging clinical condition for surgeons and interventionalists to treat. RHF occurs in approximately 0.1% of patients after cardiac surgery, in 2–3% of patients following heart transplantation, and in up to 42% of patients after LVAD implantation. Regardless of the cause, RHF portends high morbidity and mortality and is associated with longer hospital stays and higher healthcare costs. The mainstays of traditional therapy for severe RHF have included pharmacological support, such as inotropes and vasopressors, and surgical right ventricular (RV) assist devices. However, in recent years catheter-based mechanical circulatory support (MCS) strategies have offered novel solutions for addressing RHF without the morbidity of open surgery. This manuscript will review the pathophysiology of RHF, including the molecular underpinnings, gross structural mechanisms, and hemodynamic consequences. The evolution of techniques for supporting the right ventricle will be explored, with a focus on various institutional experiences with percutaneous ventricular assist devices.

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Pulmonary artery pulsatility index predicts right ventricular myofilament dysfunction in advanced human heart failure

Cited by 17 publications

References 7 publications

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

EMD-57033 Augments the Contractility in Porcine Myocardium by Promoting the Activation of Myosin in Thick Filaments

Right ventricular function across the spectrum of health and disease

Supporting the “forgotten” ventricle: The evolution of percutaneous RVADs

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