Eric S. Richardson

Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias

Basic and clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) decrease fatal arrhythmias and infarct sizes. This study investigated if pericardial delivery of n-3 PUFAs would protect the myocardium from ischemic damages and arrhythmias. Acute myocardial infarctions were induced in 23 pigs with either 45 min balloon inflations or clamp occlusions of the left anterior descending coronary arteries and 180 min reperfusion. Docosahexaenoic acid (C22:6n-3, DHA, 45 mg), one of the main n-3 PUFAs in fish oil, was infused within the pericardial space only during the 40-min stabilizing phase, 45 min ischemia and initial 5 min reperfusion. Hemodynamics and cardiac functions were very similar between the DHA-treated and control groups. However, DHA therapy significantly reduced infarct sizes from 56.8 +/- 4.9% for controls (n = 12) to 28.8 +/- 7.9% (P < 0.01) for DHA-treated animals (n = 11). Compared with controls, DHA-treated animals significantly decreased heart rates and reduced ventricular arrhythmia scores during ischemia. Furthermore, three (25%) control animals experienced eight episodes of ventricular fibrillation (VF), and two died subsequent to unsuccessful defibrillation. In contrast, only 1 (9%) of 11 DHA-treated pigs elicited one episode of VF that was successfully converted via defibrillation to normal rhythm; thus, mortality was reduced from 17% in the controls to 0% in the DHA-treated animals. These data demonstrate that pericardial infusion of n-3 PUFA DHA can significantly reduce both malignant arrhythmias and infarct sizes in a porcine infarct model. Pericardial administration of n-3 PUFAs could represent a novel approach to treating or preventing myocardial infarctions.

Electrophysiological Mechanisms of the Anti-arrhythmic Effects of Omega-3 Fatty Acids

Heart rhythm disorders, or arrhythmias, are a leading cause of morbidity and mortality worldwide. Omega-3 polyunsaturated fatty acids (ω3PUFAs), commonly found in fish oils and plant seeds, have recently emerged as potential anti-arrhythmic agents. The purpose of this review is to summarize the electrophysiological basis of the anti-arrhythmic properties of ω3PUFAs from clinical, animal, and cellular research. Evidence of the anti-arrhythmic effects of ω3PUFAs originated from epidemiological studies that correlated a low incidence of sudden cardiac death with high dietary ω3PUFA intake. Subsequently, multiple clinical trials have confirmed the therapeutic effects of ω3PUFAs in preventing sudden cardiac death and multiple other arrhythmia-related disorders. This has led basic scientists to investigate the effects of ω3PUFAs on several ion channels including sodium, potassium, and calcium channels, as well as Na/Ca exchangers. Therefore, ω3PUFAs may hold promise as safe and effective anti-arrhythmic agents. Nevertheless, further research is needed in areas such as: (1) identifying which form(s) of ω3PUFAs (i.e., phospholipid, triglyceride, or free) is (are) responsible for anti-arrhythmic actions; and (2) developing reproducible methods for delivery so that the appropriate form and concentration may be present at the target site to prevent and treat arrhythmias.

Not Every Bulb Is a Rose: A Functional Comparison of Bulb Suction Devices

BACKGROUND Not all closed drainage suction bulbs are equivalent, and there may be a discrepancy between purported and observed clinical efficacy. We evaluated four popular bulb suction apparati to directly compare their maximum attainable suction, maximum volume collected, and negative pressure maintained relative to volume collected. METHODS Employing a developed-calibrated digital collection system, the relative function of the Surgidyne 100cc (SD100), Jackson-Pratt 100cc (JP100), Jackson-Pratt 400cc (JP400), and HemoVac 400cc (HV400) drains were compared. For these analyses, three separate drains of each type (JP100 utilized 6 drains) were tested in triplicate (alpha =0.05). RESULTS The SD100 bulbs achieved the greatest negative pressure (-167.4 mmHg) while the HV400s the least (-80.5mm Hg). Only the SD100s pulled at or above purported volume. All other types obtained volumes significantly less than their described volumes: for each bulb type, the obtained volumes were statistically different. Of note, 66.7% (4 of 6) of JP100 bulbs collected only half the purported volume. CONCLUSIONS The use of the SD100 bulb demonstrated superior maximum attainable suction, maintained suction to a higher volume; they were the only bulbs tested that collected volumes at or above those purported. The HV400 bulbs demonstrated the lowest suction and volume collected. Nevertheless, when used clinically, all such drain bulbs must be emptied long before achieving maximum volume to maintain reliable suction.

Design of a Novel Perfusion System to Perform MR Imaging of an Isolated Beating Heart

Isolated mammalian hearts have been used to study cardiac physiology, pharmacology, and biomedical devices in order to separate myocardial characteristics from the milieu of the intact animal and to allow for increased control over experimental conditions. Considering these benefits and that MRI is the “gold” standard for measuring myocardial function, it was considered desirable to have a system which would allow simultaneous MR imaging of an isolated beating heart. Here we describe a unique portable system, which enables physiologic perfusion of an isolated heart during simultaneous MR imaging. A two unit system was designed to physiologically support a large mammalian isolated heart during MR imaging were a modified Krebs-Henseleit perfusate was used as a blood substitute. The first unit, which resides in an adjacent support room next to the scanner, contains all electronically powered equipment and components (with ferromagnetic materials) which cannot operate safely near the magnet, including (1) a thermal module and custom tube in tube heat exchanger warming the perfusate to 38°C; (2) a carbogen tank (95% O2 5% CO2) and hollow fiber oxygenator; and (3) two centrifugal blood pumps which circulates and pressurizes the left and right atrial filling chambers. The second unit, which resides next to the magnet and is free of ferromagnetic materials, receives warmed, oxygenated perfusate from the first unit via PVC tubing. The isolated hearts were connected to the second unit via four cannulae sutured to the great vessels. A support system placed inside the scanner on the patient bed secured the hearts and cannulae in the correct anatomical position. To date, this system was tested in a 1.5 T Siemens scanner using swine hearts (n=2). The hearts were arrested with St. Thomas cardioplegia and removed via a medial sternotomy. After cannulation of the great vessels, reperfusion, and defibrillation, four-chamber and tagged short-axis cine loops were acquired using standard ECG gating. Tagged short-axis images obtained at the base, mid-ventricle, and apex were used to measure the following functional parameters for one heart: LV end-diastolic volume=38.84 ml, LV end-systolic volume=23.23 ml, LV stroke volume=15.6 ml, LV ejection fraction=40.18%, and peak LV circumferential strain=16%. The feasibility of MR imaging an isolated, four-chamber working large mammalian heart was demonstrated using a custom designed and built portable MRI compatible perfusion system. This system will be useful in studying in vitro cardiac function (including human hearts) and developing MRI safe biomedical devices and MRI guided therapies in a controlled setting.

Animal Models for Cardiac Valve Research

In the current regulatory climate, the Food and Drug Administration requires that all invasive cardiac devices are subjected to in vivo testing prior to human clinical trials and/or medical use. The most effective method for assessing the in vivo performance, durability, and biocompatibility of a novel heart valve therapy is through testing within the appropriate animal model. For replacement heart valves, preclinical testing is performed under strict regulatory guidelines to critically assess the performance of the device and the response of the host, by accurately replicating the intended human implantation procedure. This ensures the collection of relevant data and minimizes the potential for distress or discomfort to the test subject. The fundamental goals of a preclinical study are to report any detectable pathological consequences of the procedure, to report any macro- or microscopically detectable structural alterations in the device itself, and to histologically assess any thromboembolic material, inflammatory reactions, or degenerative processes. The success of a preclinical trial relies on careful protocol design, choosing the appropriate animal model, and adhering to the regulatory guidelines for Good Laboratory Practices. Importantly, the continued use of animal models in cardiac research has also benefited the field of veterinary science and, until in vitro and in silico methods provide suitable alternatives, will continue to be the most accurate assessment for the next generations of valve therapies.

Use of Large Animal Models for Cardiac Electrophysiology Studies

Large animal models can be utilized to recreate many cardiac electrophysiological disease states and procedures and to test new devices and imaging techniques. In this chapter, a brief summary of regulatory principles regarding animal models is presented. Factors for choosing an animal model, such as growth rate, ease of handling, and comparative cardiac anatomy, are detailed, with the cardiac anatomy presented in terms of common electrophysiologic procedures: lead placement, His pacing, and ablation studies. General anesthesia information is then provided, along with common methods of accessing the heart and invasive monitoring techniques. Finally, common electrophysiologic interventions are discussed such as different techniques for creating common pathologies including congestive heart failure models, acute and chronic atrial fibrillation models, ventricular fibrillation, and myocardial infarction (ischemia).

A Novel Combination Therapy for Post-Operative Arrhythmias

Atrial fibrillation (AF) is a common heart rhythm disorder, effecting about 20% of cardiac surgical patients. While often benign, it leads to a prolonged hospital stay, and potentially to malignant arrhythimas. Many anti-arrhythmic drugs have been used to both prevent and treat post-operative AF and other post-operative arrhythmias; however, they have potentially harmful side-effects (e.g., hypotension, pulmonary fibrosis). Cardioversion is often the therapy of last resort to restore a perfusable rhythm. We propose a novel, innovative concept that allows for local pharmacological and electrical therapy of the heart. We have shown in animal models that such delivery increases the efficacy of the therapy and reduces side effects. Several variations of the device have been conceived and prototypes are currently being developed. The simplest version is a multi-port infusion catheter incorporated into a temporary pacing lead. Placement of the device would be trivial for surgeons, who routinely place temporary pacing leads prior to closing the chest. Removal of the device post-operatively would be equally simple. More complex iterations include an expandable wick to maintain the infused drug in a desired location. Designs may also include epicardial defibrillation capabilities, which would lower the energy required for defibrillation. To demonstrate proof of principle, cadaver and animal investigations were performed. In a fresh cadaver, a sternotomy and pericardiotomy was performed. A catheter was placed in the pericardium, and an infusion of radio-opaque contrast was administered under fluoroscopy. The majority of the contrast collected near the pulmonary veins, which are often the origin of atrial arrhythmias. To evaluate the efficacy of drugs administered into the pericardium as compared with drugs administered through the conventional route (intravenously), animal studies in swine were performed. Results demonstrated that pericardially administered metoprolol had a greater and more lasting effect on heart rate than when given intravenously. Additionally, during pericardial delivery myocardial contractility was better preserved. Only trace amounts of metoprolol were found in the circulation. Thus pericardial delivery may enhance certain therapeutic effects of drugs while limiting side effects. Currently, studies are underway to evaluate the efficacy other pharmacologic agents delivered into the pericardium. Should our animal studies continue to show promising results, we anticipate moving into clinical trials. Development and refinement of prototype delivery devices will also continue as we pursue this promising new therapy for post-operative arrhythmias.