signature=991f47b135cea06880bba82aa7fba460,Creation of clinically relevant model of chronic heart fa...

Heart failure (HF) remains a major cause of mortality and morbidity in the world.1 Despite significant improvement in both medical and surgical therapies for HF, the mortality rate persists in excess of 50% after 5 years.2 Ischemic heart disease remains a leading cause of HF, and has a complex and incompletely understood pathophysiology with acute ischemic injury evolving to progressive left ventricular (LV) dysfunction and structural remodeling. These chronic functional and structural changes are associated with compensatory neurohormonal and metabolic alterations.

The complex natural progress of atherosclerosis in humans can lead to either acute or slowly progressive coronary occlusion with the initial ischemic insult not easily emulated in an animal model. Pre-clinical approaches and large animal models to mimic ischemic heart disease have included single and multi-step catheter-based and surgical interventions.3-17 Generally, these interventions are performed in normal animals without the same pathophysiological substrate that leads to atherosclerosis or modulates the repair processes in humans. Therefore, the initial injury, repair, and remodeling processes may not be completely comparable to the clinical scenario. However, robust large animal models have tried to reproduce the fundamental characteristics of the process of repair and LV remodeling, including changes in LV geometry and dilatation, eccentric hypertrophy, infarct expansion, alterations in regional and global LV systolic and diastolic performance and functional reserve under stress, alterations in LV mass, and changes in regional wall thickness.7 Ideally, these animal models should have a mortality rate that is comparable to the clinical scenario and be highly reproducible in order to provide proper predicative value for clinical investigations into the pathophysiological mechanisms, and evaluation of novel therapeutics and interventions.

While several large animal models have been employed to model ischemic heart disease in humans (including canine, porcine, and ovine), the coronary and gross cardiac anatomy in swine is fairly equivocal to humans. Unlike canine models, that have a significant native collateral circulation, swine have less native preformed collateral circulation in the mid-myocardium and sub-endocardium.18 Therefore, the porcine model is frequently used to test devices and therapies in models of acute ischemic heart disease, as well as models of chronic ventricular remodeling post-ischemic injury, and HF. The size of swine also allow for the use of standardized clinical investigational tools and equipment, including advanced clinical imaging systems. Recent reviews have summarized the animal models of HF,5,7,19 and some have even focused specifically on porcine models.4

Large animal models of HF with preserved ejection fraction (HFpEF) have been more difficult to establish partly due to the incomplete pathological understanding of HFpEF.20 There is one proposed swine model that is thought to mimic HFpEF that involves staged banding of the aorta.21 Other investigators recently have developed an ovine model that may approximate the conditions of HFpEF.10 As such, the majority of pre-clinical studies focus on systolic HF and employ permanent or transient surgical ligation of coronary arteries to produce a HF model with decreased ejection fraction. These models are highly dependent on the size of the ischemic insult. Percutaneous approaches are an alternative to surgical models where inflammation and development of fibrotic tissue at the surgical site can interfere with imaging techniques. However, these percutaneous models can have reduced reproducibility, as intracoronary placement of the occluding balloon, coil, or stent can be highly dependent on the gross coronary anatomy and navigation through the coronary arteries under fluoroscopy. Ischemia-reperfusion via balloon angioplasty provides a means to emulate acute ischemic injury and subsequent remodeling following revascularization.15,17,22 However, further to the placement of the balloon and subsequent size of ischemic zone, fatal arrhythmias during the reperfusion period can contribute to a high percentage of the overall mortality. Investigators have devised other percutaneous approaches using coronary microembolization, intracoronary thrombogenic coil deployment,13 and placement of bottleneck stents16 to produce ischemic injury with decreases in LV EF and mortality between 13% and 37%.

Surgical ligation models have the advantages of a reduction in overall procedure time, improved accuracy in the selection of the location of the ligation, and reproducibility of the extent of ischemic injury. In a permanent surgical occlusion model, the level (proximal, distal, and mid) and location (left anterior descending (LAD) vs left circumflex (LCX) or branches) have been shown to dramatically alter the MI size (0%-21%) and mortality rate (0%->70%).6,14 While a more distal ligation and subsequent smaller MI size serves to ensure a high survival rate, these smaller infarcts result is minimal LV remodeling and do not induce significant HF.14 Ameroid constrictor models have been widely used, and conceptually due to the slow occlusion of the coronary artery, result in a low attrition rate (approximately 26%).4 This surgical intervention is well established and leads to a classic model of hibernating myocardium.4,11,12,23

Teramato and colleagues3 previously reported a swine model of HF induced by permanent ligation on the distal portion of the LAD, followed by proximal placement an ameroid constrictor to occlude the proximal portion. This study was able to demonstrate a high survival rate out to 4-month post-surgery (75%), and characterized LV remodeling in the setting of reduced EF, and increased end-diastolic and end-systolic volumes with initial development of fibrosis in the remote regions.

In this issue of the Journal of Nuclear Cardiology, Tarkia and colleagues, recapitulated the porcine model of staged coronary occlusion initially reported by Teramato3 and characterized the LV remodeling process structurally, functionally, and metabolically by PET/CT imaging with [15O]water and [11C]acetate at 3-month post-surgical intervention. They apply PET/CT imaging, as well as echocardiography to understand the changes in myocardial rest/stress perfusion, metabolism, wall stress, regional and global work, and efficiency in the remote areas of heart following myocardial infarction. Their utilization of clinically available imaging tools creates an easily translatable methodology between pre-clinical and clinical in predictions of HF outcomes. Additionally, due to the non-invasive technique of these imaging tools, their model and imaging approach can provide a means to evaluate the progression of HF and to quantify the temporal changes in flow and metabolism. In addition to the information provided on perfusion and metabolic outcomes, additional imaging could be applied to interrogate regional activation of critical receptors or enzymes within the myocardium,24-28 neurohormonal changes,29-33 along with regional changes in myocardial hypoxia,34 apoptosis,35,36 necrosis,37 and fibrosis.38

Unfortunately, the current study reported a high attrition (overall survival rate of 26%) with a major cause of death attributable to lethal arrhythmias during the perioperative period. However, chronic telemetry was not performed in these studies to establish an arrhythmic cause of death during the chronic experimental period. Resting flow and inducible ischemia are critical parameters with regard to assessing risk for arrhythmias in this model, although these risks factors were not critically evaluated in the current study. It is not clear if the late deaths were due to the primary distal injury and substrate for reentrant ventricular tachycardia, or resting ischemia, or stress-induced ischemia associated with activity of these animals and ischemia-induced arrhythmia, or possibly even pump failure. The use of telemetry, additional imaging of the animals at an earlier time point, or evaluation of the infarct size ex vivo after death may have helped to determine the cause of death in these animals.

However, the researchers were able to demonstrate robust endpoints for characterization of LV remodeling at the 3-month follow-up time point. The overall mass of the LV was tending to an increase as measured by in vivo contrast x-ray CT angiography in the pigs with HF vsd controls (HF: 193 ± 42; control: 160 ± 29 g, P = .07), and this corresponded to an increase in LV end-diastolic volumes (HF: 252 ± 84 mL; control: 145 ± 17 mL, P = .003) and end-systolic volumes (HF: 154 ± 68 mL; control: 53 ± 7 mL, P = .001). At the experimental endpoint, these animals did not have significant fibrosis in the remote zone; however, the myocardium in these remote regions displayed a significant increase in cardiomyocyte diameter. Functionally, these animals demonstrated a decreased LVEF, cardiac output, and global LV work, with an increase in systolic wall stress. The novelty in this study, is the application of [11C]acetate to this clinically relevant porcine model of HF. The primary application of [11C]acetate was to measure oxidative metabolism in the context of remodeling and changes in regional LV energetics, and to determine mechanical efficiency or the increase in energy expenditure in relation to work.39 As applied by these investigators, [11C]acetate could be used to assess the temporal progression of the metabolic LV remodeling, in association with the functional remodeling that leads to HF. However, in this study, [11C]acetate was studied only at the 3-month time point, limiting the evaluation of metabolic and/or functional remodeling throughout the period that led to progressive HF. The investigators were able to demonstrate that although myocardial perfusion in the remote zone was the same at both rest and stress in the HF animals compared to controls, the global myocardial efficiency was decreased while the regional efficiency in the remote area was increased.

With new therapies currently under testing for treatment of HF,40 the development of clinically relevant animal models that can recapitulate the pathology of human ischemic heart disease and techniques that can be used to monitor temporal progression are of increased importance. We look forward to further pre-clinical investigation with this porcine model with the application of conventional physiological imaging, as well as more advanced molecular imaging modalities in order to better define the underlying pathophysiology of HF. The proposed model and multi-modality imaging can also be used to evaluate novel therapeutics designed to reduce the adverse remodeling following ischemic injury, and to prevent and treat associated HF.

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The authors have no conflict of interest to disclose.Author information

AffiliationsSection of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208017, New Haven, CT, 06520-8017, USA

Stephanie Thorn PhD & Albert J. Sinusas MD

Yale Translational Research Imaging Center, Yale University School of Medicine, New Haven, USA

Stephanie Thorn PhD & Albert J. Sinusas MD

Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, USA

Albert J. Sinusas MD

AuthorsStephanie Thorn PhD

Albert J. Sinusas MD

Corresponding authorAdditional information

See related article, doi:10.1007/s12350-015-0068-9.About this article

Cite this article

Thorn, S., Sinusas, A.J. Creation of clinically relevant model of chronic heart failure: Application of multi-modality imaging to define physiology.

J. Nucl. Cardiol. 22,673–676 (2015). https://doi.org/10.1007/s12350-015-0081-zReceived:20 January 2015

Accepted:20 January 2015

Published:20 February 2015

Issue Date:August 2015