Frebus J. van Slochteren

A Fast pH‐Switchable and Self‐Healing Supramolecular Hydrogel Carrier for Guided, Local Catheter Injection in the Infarcted Myocardium

Minimally invasive intervention strategies after myocardial infarction use state-of-the-art catheter systems that are able to combine mapping of the infarcted area with precise, local injection of drugs. To this end, catheter delivery of drugs that are not immediately pumped out of the heart is still challenging, and requires a carrier matrix that in the solution state can be injected through a long catheter, and instantaneously gelates at the site of injection. To address this unmet need, a pH-switchable supramolecular hydrogel is developed. The supramolecular hydrogel is switched into a liquid at pH > 8.5, with a viscosity low enough to enable passage through a 1-m long catheter while rapidly forming a hydrogel in contact with tissue. The hydrogel has self-healing properties taking care of adjustment to the injection site. Growth factors are delivered from the hydrogel thereby clearly showing a reduction of infarct scar in a pig myocardial infarction model.

Concise Review: Heart Regeneration and the Role of Cardiac Stem Cells

Acute myocardial infarction leads to irreversible loss of cardiac myocytes, thereby diminishing the pump function of the heart. As a result, the strenuous workload imposed on the remaining cardiac myocytes often gives rise to subsequent cell loss until the vicious circle ends in chronic heart failure (CHF). Thus, we are in need of a therapy that could ameliorate or even reverse the disease progression of CHF. Endogenous regeneration of the mammalian heart has been shown in the neonatal heart, and the discovery that it may still persist in adulthood sparked hope for novel cardioregenerative therapies. As the basis for cardiomyocyte renewal, multipotent cardiac stem/progenitor cells (CSCs) that reside in the heart have been shown to differentiate into cardiac myocytes, smooth muscle cells, and vascular endothelial cells. These CSCs do have the potential to actively regenerate the heart but clearly fail to do so after abundant and segmental loss of cells, such as what occurs with myocardial infarction. Therefore, it is vital to continue research for the most optimal therapy based on the use or in situ stimulation of these CSCs. In this review, we discuss the current status of the cardioregenerative field. In particular, we summarize the current knowledge of CSCs as the regenerative substrate in the adult heart and their use in preclinical and clinical studies to repair the injured myocardium.

Assessment of coronary microvascular resistance in the chronic infarcted pig heart

Pre‐clinical studies aimed at treating ischemic heart disease (i.e. stem cell‐ and growth factor therapy) often consider restoration of the impaired microvascular circulation as an important treatment goal. However, serial in vivo measurement hereof is often lacking. The purpose of this study was to evaluate the applicability of intracoronary pressure and flow velocity as a measure of microvascular resistance in a large animal model of chronic myocardial infarction (MI). Myocardial infarction was induced in Dalland Landrace pigs (n = 13; 68.9 ± 4.1 kg) by a 75‐min. balloon occlusion of the left circumflex artery (LCX). Intracoronary pressure and flow velocity parameters were measured simultaneously at rest and during adenosine‐induced hyperemia, using the Combowire (Volcano) before and 4 weeks after MI. Various pressure‐ and/or flow‐derived indices were evaluated. Hyperemic microvascular resistance (HMR) was significantly increased by 28% in the infarct‐related artery, based on a significantly decreased peak average peak flow velocity (pAPV) by 20% at 4 weeks post‐MI (P = 0.03). Capillary density in the infarct zone was decreased compared to the remote area (658 ± 207/mm2 versus 1650 ± 304/mm2, P = 0.017). In addition, arterioles in the infarct zone showed excessive thickening of the alpha smooth muscle actin (αSMA) positive cell layer compared to the remote area (33.55 ± 4.25 μm versus 14.64 ± 1.39 μm, P = 0.002). Intracoronary measurement of HMR successfully detected increased microvascular resistance that might be caused by the loss of capillaries and arteriolar remodelling in the chronic infarcted pig heart. Thus, HMR may serve as a novel outcome measure in pre‐clinical studies for serial assessment of microvascular circulation.

Advanced measurement techniques of regional myocardial function to assess the effects of cardiac regenerative therapy in different models of ischaemic cardiomyopathy

Cardiac regenerative therapy is still not used in daily clinical practice. A reason for this might be the modest effect on relevant global clinical endpoints [i.e. ejection fraction (EF)] in preclinical studies. To introduce proper improvement strategies, it is important to extend the focus from clinical endpoints to more detailed local measures of cardiac function. In this review, we discuss the measurement principles of all invasive and non-invasive techniques that are used to assess the local effects of cardiac regenerative therapy in order to improve feedback to researchers unravelling the dominant pathways that lead to effective cardiac regeneration. Generally adopted mechanisms of cardiac regenerative therapy are: (i) vasculogenesis, (ii) cardiomyogenesis, and (iii) matrix-assisted myocardium stabilization. Since direct in vivo measures of these mechanisms do not exist, we discuss the measurement techniques of local microvascular resistance, myocardial perfusion, viability, fibrosis, and deformation imaging. The ability of these techniques to reflect the mechanism of cardiac regenerative therapy, and the results of applications in stem cell studies are discussed, and critically commented upon. Special attention is given to applications of deformation imaging, since this has recently been suggested and used as a potential new technique to assess local changes of cardiac biomechanics, which requires special knowledge about cardiac physiology. We conclude that besides the clinically relevant EF measurements, detailed measures of local cardiac function provide information about the local changes induced by cardiac regenerative therapy. In particular, combination of deformation imaging, by ultrasound or magnetic resonance imaging, with simultaneously measured local geometry and pressure measurements is a promising approach to assess the effects of cardiac regenerative therapy on local cardiac biomechanics. This approach provides information about local tissue contractility, stiffness, and thereby remodelling. We recommend that researchers use this comprehensive approach in future studies.

Cardiac motion estimation using ultrafast ultrasound imaging tested in a finite element model of cardiac mechanics

Recent developments in ultrafast ultrasound imaging allow accurate assessment of 3D cardiac deformation in cardiac phases with high deformation rates. This paper investigates the performance of a multiple spherical wave (SW) ultrasound transmission scheme in combination with a motion estimation algorithm for cardiac deformation assessment at high frame rates. Ultrasound element data of a realistically deforming 3D cardiac finite element model were simulated for a phased array transducer, transmitting five SWs (PRF 2500 Hz). After delay-and-sum beamforming, coherent compounding of multiple SW transmissions was performed to generate radiofrequency data (frame rate 500 Hz). Axial and lateral displacements were determined using a normalized cross-correlation-based technique. Good agreement was obtained between estimated and ground truth displacements derived from the model over the cardiac cycle. This study indicates that high frame rate displacement estimation using multiple SWs is feasible and serves as an important step towards high frame rate 3D cardiac deformation imaging.

Retrograde Coronary Venous Infusion as a Delivery Strategy in Regenerative Cardiac Therapy: an Overview of Preclinical and Clinical Data

An important aspect of cell therapy in the field of cardiac disease is safe and effective delivery of cells. Commonly used delivery strategies such as intramyocardial injection and intracoronary infusion both present with advantages and disadvantages. Therefore, alternative delivery routes are explored, such as retrograde coronary venous infusion (RCVI). Our aim is to evaluate safety and efficiency of RCVI by providing a complete overview of preclinical and clinical studies applying RCVI in a broad range of disease types and experimental models. Available data on technical and safety aspects of RCVI are incomplete and insufficient. Improvement of cardiac function is seen after cell delivery via RCVI. However, cell retention in the heart after RCVI appears inferior compared to intracoronary infusion and intramyocardial injection. Adequately powered confirmatory studies on retention rates and safety are needed to proceed with RCVI in the future.

MRI Visualization of Injectable Ureidopyrimidinone Hydrogelators by Supramolecular Contrast Agent Labeling

Information about the in vivo location, shape, degradation, or erosion rate of injected in situ gelating hydrogels can be obtained with magnetic resonance imaging (MRI). Herein, an injectable supramolecular ureidopyrimidinone-based hydrogel (UPy-PEG) is functionalized with a modified Gadolinium(III)-DOTA complex (UPy-Gd) for contrast enhanced MRI. The contrast agent is designed to supramolecularly interact with the hydrogel network to enable high-quality imaging of this hydrogel. The applicability of the approach is demonstrated with successful visualization of the Gd-labeled UPy-PEG hydrogel after targeted intramyocardial catheter injection in a pig heart.

3D Hybrid Imaging for Structural and Congenital Heart Interventions in the Cath Lab

ABSTRACT Hybrid imaging (HI) during cardiovascular interventions enables the peri-procedural visualization of the organs and tissues by means of integrating different imaging modalities. HI can improve the procedural efficacy and safety. This review provides an overview of different systems, their possibilities and the current clinical use and benefits focused on structural and congenital heart diseases. We have performed a literature search and linked the software options to the clinical use in cardiology to gain insight into the clinical use of the systems. In this review, we focus on radiation and contrast exposure, complication rate and procedure time. We found that currently available studies are limited by small cohorts. Nevertheless, HI systems for valvular procedures result in a significant decrease of radiation and contrast exposure. The largest benefit hereof is observed when HI is used in combination with rotational angiography. Furthermore, automatically determined optimal implant angle for transcatheter aortic valve implantation decreases the complication rate significantly. Congenital heart disease interventions that require 2D/3D Transoesophageal echocardiography (TEE) such as septal defects show a significant decrease in radiation and contrast exposure and procedural time when using TEE-Mono- and bi-plane cine angiography and fluoroscopy (XRF) fusion software. MitraClip procedures using these HI systems, however, show only a trend in decrease of these effects. In conclusion, major interventional X-ray vendors offer HI software solutions which are safe and can aid the planning and image guidance of cardiovascular interventions. Even though current HI technologies have limitations, HI provides support in the increasingly complex cardiac interventional procedures to provide better patient care.

3D Whole-heart Myocardial Tissue Analysis

Cardiac regenerative therapies aim to protect and repair the injured heart in patients with ischemic heart disease. By injecting stem cells or other biologicals that enhance angio- or vasculogenesis into the infarct border zone (IBZ), tissue perfusion is improved, and the myocardium can be protected from further damage. For maximum therapeutic effect, it is hypothesized that the regenerative substance is best delivered to the IBZ. This requires accurate injections and has led to the development of new injection techniques. To validate these new techniques, we have designed a validation protocol based on myocardial tissue analysis. This protocol includes whole-heart myocardial tissue processing that enables detailed two-dimensional (2D) and three-dimensional (3D) analysis of the cardiac anatomy and intramyocardial injections. In a pig, myocardial infarction was created by a 90-min occlusion of the left anterior descending coronary artery. Four weeks later, a mixture of a hydrogel with superparamagnetic iron oxide particles (SPIOs) and fluorescent beads was injected in the IBZ using a minimally-invasive endocardial approach. 1 h after the injection procedure, the pig was euthanized, and the heart was excised and embedded in agarose (agar). After the solidification of the agar, magnetic resonance imaging (MRI), slicing of the heart, and fluorescence imaging were performed. After image post-processing, 3D analysis was performed to assess the IBZ targeting accuracy. This protocol provides a structured and reproducible method for the assessment of the targeting accuracy of intramyocardial injections into the IBZ. The protocol can be easily used when the processing of scar tissue and/or validation of the injection accuracy of the whole heart is desired.

Surgical left ventricular radius enlargement by patch insertion on the beating heart: a new experimental aneurysm model

We presented a novel experimental aneurysm model for studies in left ventricular (LV) reconstruction techniques and assessed LV function. In eight pigs, the LV radius and geometry were enlarged surgically on the beating heart by inserting an aortic allograft construct. Haemodynamics and LV dimensions were assessed by echocardiography at baseline and under dobutamine stress. Surgery was successfully performed without lethal blood loss or arrhythmias. LV end-diastolic and end-systolic short-axis areas increased from 13.0 ± 1.7 to 17.0 ± 4.3 cm(2) (P = 0.001) and from 4.0 ± 0.9 to 13.0 ± 2.6 cm(2) (P = 0.001), respectively. Stroke volume decreased from 56 ± 11 to 33 ± 16 ml (P = 0.001). Incremental dobutamine infusion concurred with a biphasic response on fractional area shortening. Mitral valve insufficiency ranging from grades 2 to 4 was observed. In the pig, a novel, reproducible aneurysm model for acute cardiac dysfunction was created on the beating heart. Innovative (surgical) strategies for (staged) reconfiguration of the ventricle, e.g. adjustable Dor procedures and stepwise volume restraining cardiac support devices, can be tested for efficacy using this acute model.