Original Article[11C]meta-hydroxyephedrine PET evaluation in experimental pulmonary arterial hypertension: Effects of carvedilol of right ventricular sympathetic function
Introduction
Drugs that target neurohormonal activation, once thought to be contraindicated, are now a cornerstone of management for patients with left ventricular (LV) systolic dysfunction. Our understanding of right heart failure (RHF) has lagged behind and its management remains largely symptomatic and often palliative. Many proven targeted therapies for left heart failure (LHF) either do not appear to provide similar benefits or have not been rigorously tested in RHF. Indeed, this is particularly relevant for patients with pulmonary arterial hypertension (PAH), where chronic pressure overload heralds RHF and represents the leading cause of morbidity and mortality.1
There is little doubt that LHF is a state of chronic sympathetic nervous system (SNS) activation, perpetuating the cycle of pathological remodeling and further LV dysfunction.2 SNS hyperactivation is also thought to be implicated in PAH3; however, the role of similar mechanisms in progression of RV failure is not well understood. Pharmacologic blockade of the SNS with β-adrenergic receptor blockers (β-blockers) remains one of the most efficacious therapies for patients with LV systolic dysfunction.4 There is interest in whether any similar efficacy exists for the failing RV, but β-blocker therapy is generally believed to be contraindicated unless required to treat a comorbidity.5 Results from experimental models of PAH have suggested that if given early in disease progression prior to development of RV dysfunction, β-blocker therapy can prevent pathological RV remodeling and preserve systolic function.6,7 However, given the insidious nature of progressive pulmonary remodeling, patients often present late in the disease once RV dysfunction has developed. It remains to be determined whether these therapies can reverse established RV dysfunction later in disease progression, at a time that is clinically relevant. Several early-phase clinical studies using β-blockers in patients with PAH have produced conflicting findings suggesting no improvement in RV function or even harm.8, 9, 10 These disparate results necessitate further rigorous preclinical studies to shed light on this important clinical question. Furthermore, no previous study has evaluated the effects of beta blocker on RV sympathetic integrity and function.
The objectives of the present study were to evaluate whether [11C]HED PET imaging can be used to non-invasively assess RV sympathetic function and to correlate RV [11C]HED imaging with histochemical evaluation of RV sympathetic and parasympathetic nerve density. We also aimed to determine if chronic β-blocker therapy can (1) reverse RV dysfunction and pathological remodeling and (2) improve RV SNS integrity in the Sugen chronic hypoxia (SuHx) model of PAH using PET imaging. The present study is the first to comprehensively assess sympathetic function within the failing RV using non-invasive PET imaging, which has the unique ability to be translated from preclinical studies to clinical patients.
Section snippets
Methods
All animals received humane care and procedures conformed to the guiding principles of the National Institute of Health’s Guide for the Care and Use of Laboratory Animals, and were approved by the University of Ottawa Heart Institute Animal Care Committee.
Development of PAH
Pulmonary artery acceleration time (PAAT), an echocardiographic index of pulmonary artery pressure, was significantly decreased in PAH rats compared to healthy controls at week 5 prior to treatment randomization (P < .0001, Figure 2C). Representative doppler waveforms demonstrate decreased PAAT and reveal a mid-systolic notch in PAH rats compared to healthy control (Figure 2D). There was no difference in PAAT between rats subsequently assigned to vehicle and carvedilol treatment at 5 weeks,
PAH Severity and Autonomic Innervation
DBH-positive nerve area within the RV decreased proportional to increasing RVSP (Figure 7F). A moderate correlation was observed for the LV septum that approached statistical significance (Figure 7D). LV lateral wall DBH+ nerve area was unaffected by increasing RV pressure (Figure 7B). A significant negative correlation was also found between increasing RVSP and [11C]HED VD in the LV septum and RV, but not the LV lateral wall by PET imaging (Figure 7A, C, E). Importantly, DBH-positive nerve
Discussion
This study investigated the effects of long-term carvedilol administration on ventricular and cardiac SNS function in an animal model of PAH and RHF (Supplemental Figure 4). Major findings reveal: (1) carvedilol did not demonstrate any beneficial effects on RV remodeling or function; (2) carvedilol increased sympathetic function in the LV but not the RV, an effect that may be due to chronically suppressing sympathetic activation; (3) increasing PAH severity resulted in selective regional
Limitations
We did not titrate carvedilol to the desired dose, as is mandated in clinical practice. It is likely that titrating the β-blocker may have increased tolerability; but, to date, this dosing regime has not been adopted in the preclinical field. While our data, in the context of previously published studies, suggests the timing of therapy is critically important, the present study was not intended to compare a prevention versus reversal model. Future studies should also aim to explore the temporal
Conclusion
The use of β-blockers to selectively target SNS activation in patients with PAH and RHF remains widely contested. Our study suggests that when given at a clinically relevant time-point, carvedilol fails to recover RV function, and in fact tended to worsen RV and LV function. The potential deleterious effects of carvedilol in our study illustrates the potential dangers of administering therapy later in the progression to maladaptive RV remodeling when the negative inotropic and chronotropic
New Knowledge Gained
Our study is the first to use [11C]hydroxyephedrine PET to non-invasively characterize the RV’s sympathetic nervous system (SNS) in PAH. Using complimentary immunohistochemistry, we validate the use of HED to quantify the burden of sympathetic denervation within the failing RV. These imaging findings have the unique ability to be directly translated from our animal model to clinical patients.
Acknowledgments
We would like to thank Julia Petryk and Richard Seymour for their technical assistance with the nuclear imaging, hemodynamic assessments, respectively.
Disclosures
RdK is a consultant for- and has received grant funding from Jubilant DraxImage. RdK receives revenues from Rubidium-82 generator technology licensed to Jubilant DraxImage, and from sales of FlowQuant software. RSB is or has been a consultant for- and has received grant funding from GE Healthcare, Lantheus Medical Imaging, and Jubilant DraxImage.
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