Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension

This model of acute right heart failure in the context of coronary pulmonary hypertension can help to better understand the pathophysiology of this clinically relevant situation. Induction of acute right heart failure by the mean of volume and pressure overload is easily reproducible and duplicates the main pathophysiological aspects of the corresponding clinical situation. After confirming an appropriate level of sedation, place a central venous catheter through the jugular vein up to the superior vena cava using the Seldinger method.

Next, make a four centimeter transverse incision at the groin and insert a Beckman retractor into the incision. Using Debakey forceps and Metzenbaum scissors, divide the anterior face of the femoral vein and artery and place a 20 gauge catheter into the femoral artery. Then connect the catheter to a disposable transducer with a fluid-filled catheter to obtain systemic and central venous blood pressure.

Using an 18 gauge catheter and a fluoroscope with a C-arm and an interior-posterior view, insert a guidewire into the femoral vein through the inferior vena cava. Place a balloon dilation catheter over the guidewire at the intrapericardial level and place the visible markers of the balloon immediately above the diaphragm level. Then remove the guidewire.

Immediately after the catheters have been placed, acquire an apical five-chamber view under the xiphoid process in two dimensions and in the tissue Doppler mode. Acquire the parasternal short and long axis views on the right side of the sternum in 2D and tissue Doppler modes and an image of the valvular flow using continuous and pulsed Doppler modes. Then acquire tissue Doppler signals of the lateral tricuspid annulus and the lateral and septal mitral annulus.

For catheterization of the right heart, introduce the Swan-Ganz catheter into the jugular 8 French sheath inserted into the jugular vein and acquire the mean right atrial, right ventricular, and pulmonary artery pressures. Next, measure the cardiac output with the thermodilution method according to the manufacturer's instructions while simultaneously measuring the heart rate for the stroke volume calculation. Connect the disposable transducer to the pressure volume loop workstation for live acquisitions of the pressures derived from the fluid-filled catheters and use fluoroscopy to introduce the conductance catheter into the right ventricle.

Then verify the quality signal using in live acquisition of the pressure volume loops and acquire pressure volume loop families in the steady state and during acute preload reduction induced by inflating the balloon inserted into the inferior vena cava during end expiratory apnea. To induce acute right heart failure, first use a free flow infusion output to start a 15 milliliters per kilogram saline infusion. Five minutes after hemodynamic stabilization and at the end of each infusion, obtain the right heart catheterism, pressure volume loop, and echocardiographic measurements.

Then start the second infusion of 15 milliliters per kilogram of saline immediately after the end of the measurements and start the third infusion of 30 milliliters per kilogram of saline immediately after the end of the second set of measurements. To induce hemodynamic pressure overload, use the fluoroscope to insert a 5 French angiographic catheter through the jugular sheath into the right lower lobe pulmonary artery. Embolize the right lower lobe pulmonary artery with a 150 microliter bolus containing n-butyl-2-cyanoacrylate lipidic contrast dye, washing out the catheter with 10 milliliters of saline once the bolus has been delivered.

Two minutes after the embolization, measure the systemic and pulmonary artery pressures to evaluate the hemodynamic response, then repeat the bolus delivery every two minutes until hemodynamic compromise is achieved. After reaching hemodynamic compromise, acquire pressure volume loop and echocardiographic measurements before starting a dobutamine infusion at 2.5 micrograms per kilogram per minute. Wait 10-15 minutes for hemodynamic stabilization before performing right heart catheterization, pressure volume loop, and echocardiographic measurements.

When all of the measurements have been acquired, increase the dobutamine infusion dose to five micrograms per kilogram per minute and repeat the right heart catheterization, pressure volume loop, and echocardiographic measurements once hemodynamic stabilization has been achieved as just demonstrated. Then increase the dobutamine infusion dose to 7.5 micrograms per kilogram per minute. Acute volume loading does not induce acute right heart failure, but rather highlights the adaptive phenotype of the chronic pulmonary hypertension model.

With volume loading, the cardiac output increases without an increase in the right atrial pressure and with ventriculo-arterial coupling remaining stable. Hemodynamic compromise is associated with a significant decrease in cardiac output, stroke volume, and ventriculo-arterial coupling, whereas right ventricle contractility remained stable. A twofold increase in the right atrial pressure and mean pulmonary artery pressure are also typically observed.

Dobutamine delivery as demonstrated restores cardiac output, stroke volume, and ventriculo-arterial coupling within the normal range. Echocardiography can be used to quantify dynamic changes in right ventricle size and function throughout the experiment. Pressure volume loop analysis allows the dynamic quantification of right ventricle end-systolic elastins and ventriculo-arterial coupling.

In this representative study, the two deaths that occurred immediately after acute pulmonary embolism were associated with acute thrombosis of the right heart cavities. After hematoxylin eosin and saffron staining, right ventricular ischemic lesions characterized by clusters of hypereosinophilic cardiomyositis with pyknotic nuclei can be observed in the sub-endocardial and sub-pericardial layers of the right ventricle free wall. The magnitude of acute volume and pressure overload required to induce acute right heart failure phenotype of the right ventricle in the context of pulmonary hypertension.

Hemodynamic restoration could be used by drugs or intervention in order to determine the best therapeutic option.