ISOLATED HEART STAND: APPLICATIONS IN EX VIVO CARDIOVASCULAR DRUG AND DEVICE TESTING
The isolated perfused heart system, conceived by Oscar Langendorff almost 100 years ago, has become a mainstay of pharmacological, device application and physiological live heart research. This in vitro heart assay allows the study of contractile force, heart rate, coronary resistance and other parameters of the heart under known and controlled physiological conditions. Importantly, this preparation allows the addition of drugs and observation of their effect on the heart without the complications involved with in vivo experimentation.
To achieve the optimum use of the isolated heart system, it is important to give a careful thought to the design of the experiment, the donor heart, its maintenance and instrumentation. The selection of the heart is often based on the typical or unique response of the donor organ to pharmacological or physiological stimuli or on selected metabolic or biochemical events. Noble Life Sciences’ knowledgeable scientists can provide guidance with the study design and in choosing the best model for specific application. The most common donors for assessment of hearts used in the isolated heart system are rats, guinea pigs, rabbits, dog and pigs.
Since the components of the blood may be damaged by peristaltic pump action, instead of donor’s whole blood, saline-based media containing glucose, or other substrates such as pyruvate, lactate, fatty acids, and amino acids, are more commonly used as the perfusate. The perfusate feeds nutrients and oxygen to the cardiac muscle, allowing it to continue beating for several hours after its extraction from the donor. Of the ionic components in the perfusate, potassium and calcium are the most variable and critical. Temperature of the perfusate is regulated because the cardiac electrical, contractile and metabolic activity and stability of the preparation are temperature-dependent. In addition, collagenase can be added to the perfusate to harvest single cells from the donor heart and measure treatment effects at the cellular level.
Utilizing an isolated heart decouples the organ from the hormonal and autonomic nervous responses and otherwise very complex in vivo factors. The decoupling allows for basic analysis of fundamental cardiac properties such as:
• Investigating cardiac muscle physiology
• Testing of pharmacological compounds
• Unmasking potential action of investigative compounds
• Direct induction of ischemia or arrhythmias
• Precise mapping of the conduction pathways
• Coronary blood flow regulation
• Cardiac metabolism
• Electrostimulation waveform testing
The original Langendorff isolated heart preparation uses retrograde perfusion through the aorta. This set up is very important to discern mechanical behavior of smooth vascular muscle cells in the coronary vasculature expressed as changes in the vessel radius. Langendorff isolated heart assay has evolved to encompass both constant pressure and constant flow mode as well as “Working Heart.” Each of these modes and their applications are explained below:
• Constant pressure mode: The perfusate is released from a gravity-fed reservoir and a fixed, known pressure is held constant. Changes in coronary resistance is detected as changes in blood flow and measured volumetrically.
• Constant flow mode: Peristaltic pumps hold the perfusate flow at a fixed rate (ml/min) and changes in coronary resistance are detected as changes in pressure. This set up is predominantly used when studying coronary vascular tone (constrictors and dilators), and smooth muscle or endothelial function.
• “Working Heart” mode: Antegrade perfusion occurs as the perfusate enters through the mitral valve and is ejected through the aortic valve. The beating heart pumps the fluid from the left ventricle out of the aorta under experimentally controlled preload (atrial pressure) and afterload (aortic resistance) conditions. This allows the measurement and calculation of additional parameters under work conditions.
Noble Life Sciences now offers isolated heart stand is capable of both Langendorff constant flow and constant pressure testing along with Working Heart mode. Our rig is complete with pressure sensors, microelectrodes, and fully supported by a software package to capture the data for further analysis. Whether testing pharmaceuticals, cell therapy, device therapy or harvesting cells, our knowledgeable scientists can help with study design and also guide each step of the decision process ensuring your success.
After the initial exploration to the direct effect on the heart organ, preclinical trials can further be continued in vivo, using Noble’s vivarium services and our wide range of animal models and imaging (MRI, CT scan, etc.) capabilities that support cardiovascular drug and/or device development.
Noble Life Sciences is dedicated to your continued success with our team of experienced scientists, physicians, surgeons, veterinarians, and technical staff to assist your preclinical program development. From pharmaceutical testing to prototype development to GLP studies, Noble Life Sciences is your Smart Solution for preclinical development.
For more information regarding isolated heart research, cardiovascular animal models and our vivarium services, Contact us today.