The author would like to acknowledge funding from NHLBI (K08 HL102066 and R01 HL114832).

Before performing any of the procedures described in this protocol, obtain approval by the local institutional animal care and use committee.
1. Setting Up the Experimental Rig
Note: This procedure is performed on anesthetized animals and the quality of the data is proportional to the quality of the anesthetic support offered to the animal. This first section will detail the equipment and procedures necessary to provide anesthesia to the mouse while p...

<ol>
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There are three critical steps in this procedure: 1) the placement of the endotracheal tube and appropriate ventilation, 2) placement of the jugular IV catheter, and 3) the proper placement of the PV catheter in the left ventricle. Determining the appropriate respiratory rate is an important part of providing ventilatory support. Conscious mice generally maintain alveolar ventilation with rapid shallow breaths. In general, ventilated mice will have much larger tidal volumes. Thus a slower respiratory rate is required. Th...

Cardiovascular disease continues to be a significant cause of mortality and morbidity throughout the world 1. Diseases of the heart present particularly difficult challenges in developing new therapies. Advances in genetics provide for the possibility to identify a multitude of potential genetic contributors to the development of heart disease. The integrative nature of the cardiovascular system requires that these genetic targets be validated in intact animal models. The genetic flexibility and low housing costs of the mouse have brought it to the forefront for the assessment of the physiological role of a given gene. The small size of the mouse presents some unique challenges for the assessment of cardiac function. There are several modalities that can provide information regarding cardiac function, but only the simultaneous measurement of ventricular pressure and volume allows pressure-volume (PV) loop analysis of ventricular function. PV loops allow cardiac function to be analyzed independent of its connection to the vasculature; an important factor in determining the functional role of a particular genetic element.
The assessment of pressure-volume loops has been used both experimentally and clinically for many years and extensive literature exists regarding the analysis of these data sets 2,3. The adaptation of PV loop technology to the mouse has been an important advancement for the understanding of murine cardiac physiology 4-6. Catheter based PV loop technologies couple a pressure transducer and the use of conductance to estimate ventricular volume. The ventricular volume is determined by examining changes in an electrical field generated by the catheter. This method models the ventricle as a cylinder, the height of which is defined by the distance between the electrodes on the catheter and the radius is calculated from conduction of an electrical field through the blood in the ventricle 7-9. The conductance signal measured by the catheter has two components. The first is the conduction through the blood; this varies with the volume of the ventricle and constitutes the primary signal used to determine ventricular volume. The second component results from conduction through and along the wall of the ventricle. This is called parallel conductance and must be removed in order to determine the absolute ventricular volume. There are two commercially available systems for the collection of pressure-volume data in the research laboratory and the method used to calculate and remove the parallel conductance is the primary difference between them 6,10,11. Conductance catheters require the injection of hypertonic saline for the calculation of parallel conductance. This injection transiently changes the conductivity of the blood in the ventricle, while the conductivity of the wall remains constant. From this data it is possible to determine the component of the conductance signal that originates from the blood and what comes from the ventricular wall. This approach assumes that parallel conductance does not vary during the cardiac cycle. The admittance method relies on phase changes in the electrical field to assess the contribution of the ventricular wall to the overall volume signal. This method relies on a variety of predetermined constants for the conductivity of the blood and myocardium to determine the final volume, but makes continuous measures of parallel conductance during the cardiac cycle. Both of these systems provide good estimates of left ventricular volume and the differences between them are not likely to be physiologically significant. The cylindrical model of the ventricle and other assumptions render these catheter-based approaches not as accurate as other modalities, but this data is provided on a beat-by-beat basis that is essential for the assessment of load independent measures of cardiac function.
The procedure outlined here is used in my laboratory and has provided data for a large number of studies examining the basic pathophysiological mechanisms of dystrophic cardiomyopathy 12-18. The procedure outlined below is one of two that can be used to obtain PV loop data. While many of the principles are applicable for either approach, this protocol will focus on an open-chest apical approach; a closed chest protocol has been detailed elsewhere 19,20. While the procedure will be described in detail, the important overarching principles are to expose the heart with minimal damage to either the heart or the lungs. Throughout the protocol it is important to remember that this is a non-survival procedure and that having a good exposure of the heart is critically important for the proper placement of the catheter.

<table border="0" cellpadding="0" cellspacing="0" width="523">
	<tbody>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Dumont 5/45 (2)</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">11251-33</td>
			<td style="width:63px;"></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Vessel Dilating Forceps</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">18153-11</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Castroviejo Micro Dissecting Spring Scissor</td>
			<td style="width:127px;">Roboz Instruments</td>
			<td style="width:119px;">RS-5668</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Octogon Forceps - Serrated/Curved</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">11041-08</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Octogon Forceps - Serrated/Straight</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">11040-08</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Dissector Scissors- Heavy Blade</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">14082-09</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Transpore Surgical Tape</td>
			<td style="width:127px;">3M</td>
			<td style="width:119px;">1527-1</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">3-0 Silk Suture</td>
			<td style="width:127px;">Fine Science Tools</td>
			<td style="width:119px;">18020-30</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">TOPO Ventilator</td>
			<td style="width:127px;">Kent Scientific</td>
			<td style="width:119px;">TOPO</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Martin ME 102 Electrosurgical Unit</td>
			<td style="width:127px;">Harvard Apparatus</td>
			<td style="width:119px;">PY2 72-2484</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Syringe Pump</td>
			<td style="width:127px;">Lucca Technologies</td>
			<td style="width:119px;">GenieTouch</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Stereomicroscope with boom stand</td>
			<td style="width:127px;">Nikon</td>
			<td style="width:119px;">SMZ-800N</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Thermocouple Thermometer</td>
			<td style="width:127px;">Cole Parmer</td>
			<td style="width:119px;">EW-91100-40</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">T/Pump Warm Water Recirculator</td>
			<td style="width:127px;">Kent Scientific</td>
			<td style="width:119px;">TP-700</td>
			<td></td>
		</tr>
		<tr height="20">
			<td height="20" style="height:20px;width:216px;">ADVantage Pressure-Volume System</td>
			<td style="width:127px;">Transonic</td>
			<td style="width:119px;">ADV500</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Data Acquision and Analysis</td>
			<td style="width:127px;">DSI</td>
			<td style="width:119px;">Ponemah ACQ-16</td>
			<td></td>
		</tr>
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measuring pressure volume loops in the mouse

Understanding the causes and progression of heart disease presents a significant challenge to the biomedical community. The genetic flexibility of the mouse provides great potential to explore cardiac function at the molecular level. The mouse&#39;s small size does present some challenges in regards to performing detailed cardiac phenotyping. Miniaturization and other advancements in technology have made many methods of cardiac assessment possible in the mouse. Of these, the simultaneous collection of pressure and volume data provides a detailed picture of cardiac function that is not available through any other modality. Here a detailed procedure for the collection of pressure-volume loop data is described. Included is a discussion of the principles underlying the measurements and the potential sources of error. Anesthetic management and surgical approaches are discussed in great detail as they are both critical to obtaining high quality hemodynamic measurements. The principles of hemodynamic protocol development and relevant aspects of data analysis are also addressed.

By convention, volume is plotted on the X-axis and pressure on the Y-axis as in Figure 1. The pressure-volume loops resulting from plotting pressure against volume should resemble a rectangle, the vertical edges representing isovolumic changes in pressure (i.e., when both mitral and aortic valves are closed). The bottom horizontal represents ventricular filling through the mitral valve and the upper horizontal portion represents ventricular emptying through the a...

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Measuring Pressure Volume Loops in the Mouse

This manuscript describes a detailed protocol for the collection of pressure-volume data from the mouse.

Understanding the causes and progression of heart disease presents a significant challenge to the biomedical community. The genetic flexibility of the ...

The overall goal of measuring pressure volume loops in the mouse is to obtain a detailed assessment of cardiac function. This method is useful for the physiological characterization of mice harboring specific genetic manipulations, which in turn can produce insights into the role of specific proteins in cardiac function. The main advantage of this technique is that it provides a detailed assessment of contractile function that is not available through other methodologies.Once the mouse is prepped for surgery, begin by making an incision at the sternal notch extending from about five millimeters right of the midline to about five millimeters left of the midline. Make a second incision extending along the right edge of the first rostrally to about two millimeters coddled to the end of the mandible. Then make a third incision extending from the rostral end of the second incision to about five millimeters right of midline.And retract the resulting skin flap to the right to expose the underlined tissues. Next, under a dissecting microscope, blunt dissect the parotide and sub-mandibular salivary glands at the midline to expose the underlining musculature overlining the trachea. Then bluntly separate the right and left sternal hyoideus muscles.When the trachea is visible, pass a ten centimeter piece of three-zero silk suture under the throat tissue, taking care not to include the esophagus. Using a 20 gauge needle, make a wide incision in the gap just coddle to the larynx before the first tracheal ring. Then immediately remove the anesthesia mask from the animal, and carefully insert the endotracheal tube into the trachea.Once the tube has been secured, extend the left edge of the original skin incision down to the xiphoid process and across the midline to about one point five centimeters right of the midline. Next, use blunt dissection to retract the skin flap laterally exposing the underline musculature. And use vessel dilating forceps to isolate the insertion of the pectoralis major on the right side near the coddle aspect of the sternum.Cauterize and cut the muscle. Then cut through the pectoralis major along its attachment to the sternum. And undermine the latissimus dorsi on the same side.Retract the cut end cranially to reveal the ribs. And use a pair of sharp forceps to carefully dissect down through the intercostal muscle layers to enter the chest. Once the plural space has been opened, carefully insert the blunt tip vessel dilators and lift the chest wall with gentle upward force.Now, cut laterally along the intercostal muscles taking care not to cut the lung lobe and extend the incision medially, keeping three to four millimeters lateral of the midline to avoid the internal mammary artery running parallel to the sternum. Then place a saline-soaked small cotton-tipped applicator through the incision toward the midline and provide a gentle upward traction to pull the chest wall away from the underline structures. Carefully use a cautery to cut through the chest wall beginning at the medial edge of the incision and ending about one centimeter lateral of the midline on the left side.Once the tissue has been thoroughly cauterized, use scissors to carefully cut through the sternum. The apex of the heart should be clearly visible. Then, using blunt dissection, disrupt the pericardium and identify the caudal vena cava.To place the jugular vein catheter, orient a 30-gauge needle catheter attached to a syringe containing ten percent albumin such that the needle lies upon the jugular vein on its own, bevel side up. To visualize the jugular vein, grasp the needle with forceps in one hand and retract the salivary gland with tissue forceps in the other. Apply gentle traction to the tissue surrounding the diesel jugular vein to create tension on the vessel wall.Then, using a shallow angle of approach, carefully insert the needle into the vein and advance the tip three to four millimeters into the vessel. When the catheter is in position, secure the needle to the underline salivary glands using surgical glue and begin infusing the albumin solution. To place the pressure volume catheter, first, move a syringe containing equilibrated saline solution and the pressure volume catheter next to the mouse with the catheter tip at roughly the same height as the heart and zero the pressure reading.Next, using a saline-soaked small cotton-tipped applicator, maneuver the heart to visualize the apex and use a 25-gauge needle to make a stab incision as close to the center of the apex as possible. Following the removal of the needle, quickly but gently insert the catheter through the incision. The ventricular pressure volume loops can then be measured.Following the placement of the catheter, turn the anesthesia down to illuminate the cardio dipressive effects that the anesthesia may be having. If there was excessive blood loss during the procedure, you can simply increase the volume of albumin infused. By convention, the volume is plotted on the X-axis and the pressure on the y-axis.Pressure volume loops resulting from plotting the pressure against the volume should resemble a rectangle with the vertical edges representing the isovolumic changes in the pressure. The bottom horizontal side representing the ventricular filling through the mitral valve and the upper horizontal side representing the ventricular emptying through the aortic valve. In a healthy wild type mouse, left ventricular pressures of 90 to 110 millimeters of mercury are expected with a maximal rate of a maximum derivative of pressure of 8000 to 12000 millimeters of mercury per second.Further, one of the most common artifacts of measurement that can complicate the analysis of pressure volume data is catheter entrapment which is evident as a spike in pressure at the end of systole likely resulting from the direct compression of the pressure transducer by a papillary muscle or other dynamic structure within the ventricle. While performing this procedure, it is important to remember to continuously monitor the mouse to ensure a sufficient anesthetic depth. Once mastered, this technique can be completed in roughly an hour depending on the protocol used after the catheter placement.Following the completion of this procedure, infusions of experimental compounds can be used to assess their affects on cardiac function. After watching this video, you should have a good understanding of how to surgically place a pressure volume catheter in the left ventricle of the mouse and obtain high quality pressure volume loops for cardiac analysis.

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JoVE Journal

Biology

16.1K visualizações.  University of Minnesota. The overall goal of measuring pressure volume loops in the mouse is to obtain a detailed assessment of cardiac function. This method is useful for the physiological characterization of mice harboring specific genetic manipulations, which in turn can produce insights into the role of specific proteins in cardiac function. The main advantage of this technique is that it provides a detailed assessment of contractile function that is not available through other methodologies.Once the mouse...