Access routes, devices and guidance methods for intrapericardial delivery in cardiac conditions
Introduction
There is increased interest in exploring advanced drug delivery routes to achieve localized or targeted delivery of therapeutic agents that minimise side effects experienced by patients. Localised delivery, by definition, is a form of targeted delivery where the delivered drug resides mainly at a certain site, resulting in reduced movement and absorption into the bloodstream. Two main approaches exist to maintain localised delivery – (i) delivering the drug to a naturally enclosed site, such as pericardium and myocardium in the heart, bladder, synovial space between joints, etc.; (ii) through dosage forms where the drug has limited ability to translocate, such as patches, gels and implants [1]. Localized cardiac delivery is difficult to achieve via conventional delivery routes [1] such as intravenous (IV) and oral delivery, as these result in the drug being introduced into the bloodstream and systemic circulation, hence being subject to typical distribution and plasma protein binding effects which render specific localisation in the heart difficult.
Unmet clinical needs exist for localised and targeted delivery of drugs, cells and genes to the heart, especially for cardiac regeneration post-myocardial infarction and post-operation atrial fibrillation. Common approaches used for localised delivery of drugs to the heart include intramyocardial, intrapericardial and intracoronary routes. Intramyocardial delivery involves direct administration of material into the myocardium, which consists of the thick muscle layer of the heart wall. This approach is suggested to improve the residence time of cells in the myocardium [1]. Thus, it is widely used in cell therapy for delivery of stem cells and derived cells into the heart, but it might precipitate ventricular fibrillation [2]. Meanwhile, intracoronary delivery involves injection or infusion in the coronary artery, which is used preferably post-MI and with percutaneous cardiac intervention (PCI) [3], but the use is limited due to occlusion of the artery [4].
Intrapericardial delivery involves the administration of pharmacological agents into the pericardium, a bilaminar sac surrounding the heart. Hence, much larger volumes can be administered via intrapericardial delivery. Drugs or cells that have been delivered into the intrapericardial space have been shown to diffuse across epicardium into the endocardium, penetrate the myocardium, spread from the atrium to ventricle [5,6] and achieve localized and targeted action on the heart[5], [6], [7], [8]. Moreover, owing to the slow clearance of the pericardial fluid [9], the pericardial escape of drug is low and thus the pericardium can act as a reservoir for the drug and prolong the half-life in the heart [10], and reduce peripheral side effects [11]. Furthermore, desired drug concentration in the myocardial tissue can be achieved with a lower dose compared with other routes, such as oral, intravenous or intracoronary delivery [8,[12], [13], [14]]. Thus, intrapericardial delivery offers key benefits over other methods of localised cardiac delivery making it a preferred route for drug delivery to the heart.
The pericardium is subdivided into the parietal and visceral pericardium, as shown in Fig 1. The parietal pericardium is the outer layer, which is made up of a fibrous laminar (fibrosa) and serous laminar (serosa). The two layers in the parietal pericardium are inseparable. The luminal surface of the visceral pericardium is a monolayer of mesothelial cells and exists in continuity with the serous layer of the parietal pericardium [15]. The space contained between the two layers of the serous pericardium is the pericardial space, which contains pericardial fluid to lubricate the membrane and ease the movement of the heart [15]. Volumetric studies of pericardial fluid in adult humans indicate a typical volume of 20 – 60 mL[16], [17], [18], [19]. Pericardial fluid is predominately formed by plasma ultrafiltration through epicardial capillaries, with the addition of a small amount of myocardial interstitial fluid, which has similar characteristics to pleural fluid [16,17]. The fluid is drained through the parietal pericardium lymphatic capillaries [20]. Pericardial fluid contains electrolytes, metabolites, albumin and nutrients including glucose, triglycerides and cholesterol [17,21].
Since intrapericardial drug delivery remains at a relatively early stage of development, this literature review aims to explore recent advances in access methods and devices, as well as the guidance methods. Drug delivery directly onto the epicardium (also known as the visceral pericardium) is also included in this review. This review will highlight the potential applications of these techniques for the treatment of cardiac conditions not involving the pericardium, such as myocardial infarction, arrhythmias and vascular damage. The choice of route and mode of delivery will also be discussed further in this article.
Section snippets
Thoracotomy
Thoracotomy is a procedure that involves incising the pleural space of the chest. There are two common approaches to thoracotomy adopted in studies for intrapericardial delivery. Medial sternotomy accesses the pleural cavity and heart via an opening of the sternum, which is used in open-heart surgery. Lateral thoracotomy involves an incision on the intercoastal space, with the opening widened by a rib retractor placed between the ribs. Both approaches may be used for not only surgical access
Guidance methods for intrapericardial access
Apart from thoracotomies, which allow direct visualisation of the pericardium, other intrapericardial access techniques require guidance methods to confirm the position and successful entry into the pericardium. Four main types of guidance method have been investigated in clinical trials and experimental studies to assist the pericardial access. Fluoroscopy has been predominantly used in experimental studies whereas echocardiography has been the most common guidance adopted in the clinical
Cardiac arrhythmia
Cardiac arrhythmia refers to conditions that cause the heart to beat irregularly and includes sub-categories such as tachycardia and bradycardia, where atrial fibrillation is one of the most common types of arrhythmia. Intrapericardial delivery of anti-fibrillatory drugs has been investigated for the alleviation of electrical and adrenergic induced atrial fibrillation and prevent postoperative atrial fibrillation (POAF). Most anti-arrhythmic drugs have been delivered in the form of a solution
Conclusions
Pericardial access provides an alternative route for delivering therapeutics to the heart. Encouraging results have been reported when using this route for delivery of cells, drugs and protein for a variety of conditions to induce regeneration of myocardium after acute myocardial infarction, mitigating cardiac arrhythmias, or preventing platelet aggregation and restenosis after reperfusion via the coronary artery. Although current concerns exist regarding invasiveness and associated
Declaration of Competing Interest
No conflict of interest.
Acknowledgment
This work was supported by the EPSRC Centre in Doctoral Training for Nanomedicine and Advanced therapeutics [EP\L01646X]. The authors would like to express their appreciation for the continuous and kind support from the funder EPSRC.
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