Fiberoptic Confoncal Microscopy (FCM): A new surgical approach to identifying conduction tissue

The inability to identify the location of conduction tissue in congenitally deformed hearts can lead inadvertent injury of the conduction system during surgery and, in some patients, postoperative heart block. These patients then require placement of an artificial pacemaker in an additional procedure with added risk of morbidity.

This problem has led A.K. Kaza, MD, cardiac surgeon and director of the Neonatal Cardiac Surgery Program at Boston Children’s Hospital, to develop a novel way to locate this tissue more easily during surgery using real-time fiberoptic confocal microscopy (FCM) inside the heart.

Adopting technology for use in the heart

“Fiberoptic confocal microscopy is a low power laser light that comes through a fiberoptic microscope and shines at the tissue, enabling detailed imaging of tissue microstructure,” says Kaza. “Initially, the company that manufactures the microscope, Mauna Kea Technologies, developed it to look for cancer in the esophagus and stomach.

“When I heard about it, I thought we might be able to adapt it to look at conduction tissue inside the human heart. The microscope is very small, so we can take it inside the heart, using a tower to house the laser source and image detectors.”

Kaza began working on the research in 2008, collaborating with Frank B. Sachse, PhD, a basic science researcher, and Robert Hitchcock, PhD, a bioengineer, both from the University of Utah. One of their first steps was to validate the method with a conventional confocal microscope, before working on methodology to use a fiberoptic scope.

To aid in identifying conduction tissue, Kaza wanted to find a dye to use in conjunction with the microscope. “All tissues have a certain degree of inherent fluorescence, but dyes can help elicit fluorescence that can clarify the specific architecture of the cardiac tissue,” he says.

After some initial trials, they landed on fluorescein, a dye that was already approved by the FDA for other applications, which they found effective at very low concentrations.

“We performed some tests in the lab where we applied it topically to the heart tissue and found that it produced good images,” says Kaza. “After a series of safety validation experiments, we received approval from the FDA to use it in humans.”

Kaza and his research team study a test subject’s conduction with fiberoptic confocal microscopy

Moving the research into the operating room

After experimenting with the FCM system using fluorescein in animal models, Kaza moved on to test it in six patients with simple atrial septal defects to see how well he could maneuver the microscope and how well he could image regions of cardiac tissue.

“We found it works just as well in humans as in animals,” he says. “We were initially concerned about how difficult it would be to steer the microscope through the human heart, but it’s actually pretty flexible.”

Kaza says that he and his team will continue to adapt the tool to give it more flexibility and make it easier to use.

In the operating room, Kaza sets aside two to five minutes to perform the imaging procedure. After the heart is stopped and the bypass machine is on he applies the dye on the surface of the heart and uses the fiberoptic probe to find the conduction tissue. The image is displayed on the monitor so he can capture the recording and go back and re-check the area if he needs to.

“The first phase of this trial is to ensure that it’s safe and not causing any significant risk,” says Kaza. “The grant is for another three years, so we plan to use that time to show it’s effective. Our goal is to enroll patients and then randomize. We’ll do surgery and see if this system causes less risk of residual defects over the traditional way. If it’s successful, it has the potential to become a part of every open-heart surgery we do.”

A collaborative effort

Looking even further ahead, Kaza envisions creating an automated way of analyzing the confocal images to make it simpler for clinicians to identify the conduction tissue.

“This is a true collaborative effort,” he says. “I’m the clinician, Bob is the engineer, and Frank is the basic scientist. We all bring our individual strengths to the table to solve these problems and improve outcomes for our kids.”

Research Highlights

A sample of recently-published research by Heart Center faculty.

Hickey PA, Gauvreau K, Porter C, Connor, JA. “The Impact of Critical Care Nursing Certification on Pediatric Patient Outcomes.” Pediatric Critical Care Medicine. 2018

Hinsley K, Evans-Langhorst M, Porter C, Chandler S, VanderPluym C, Triedman J, Bezzerides VJ. “Low Molecular Weight Heparin as an Anticoagulation Strategy for Left-sided Ablation Procedures.” Congenital Heart Disease. 2017.

McCully JD, Cowan DB, Emani SM, del Nido PJ, “Mitochondrial Transplantation: From Animal Models to Clinical Use in Humans. Mitochondrion. 2017; 34:127-34.

Rosa B, Machaidze Z, Mencattelli M, Manjila S, Shin B, Price K, Borger MA, Thourani V, del Nido P, Brown DW, Baird CW, Mayer JE, Dupon PE. “Cardioscopically Guided Beating Heart Surgery: Paravalvular Leak Repair.” The Annals of Thoracic Surgery. 2017; 104(3):1074-9.

Newburger JW, Sleeper LA, Gaynor JW, Hollenbeck-Pringle D, Frommelt PC, Li JS, Mahle W T, Williams IA, Atz AM, Burns KM, Chen S, Cnota J, Dunbar-Masterson C, Ghanayem NS, Goldberg CS, Jacobs JP, Lewis AB, Mital S, Pizarro C, Eckhauser A, Stark P, Ohye RG. “Pediatric Heart Network, Investigators. Transplant-Free Survival and Interventions at 6 Years in the Single Ventricle Reconstruction Trial.” Circulation. 2018.

Rollins CK, Asaro LA, Akhondi-Asl A, Kussman BD, Rivkin MJ, Bellinger DC, Warfield SK, Wypij D, Newburger JW, Soul JS. “White Matter Volume Predicts Language Development in Congenital Heart Disease.” The Journal of Pediatrics. 2017; 181:42-8 e2.

Rollins CK, Newburger JW, Roberts AE. “Genetic Contribution to Neurodevelopmental Outcomes in Congenital Heart Disease: Are Some Patients Predetermined to Have Developmental Delay?” Current Opinion in Pediatrics. 2017; 29(5):529-33.

Son MBF, Gauvreau K, Kim S, Tang A, Dedeoglu F, Fulton DR, Lo MS, Baker AL, Sundel RP, Newburger JW. “Predicting Coronary Artery Aneurysms in Kawasaki Disease at a North American Center: An Assessment of Baseline z Scores.” Journal of the American Heart Association. 2017; 6(6).

Tishler B, Gauvreau K, Colan SD, del Nido PJ, Nathan M. “Technical Performance Score Predicts Partial/Transitional Atrioventricular Septal Defect Outcomes.” The Annals of Thoracic Surgery. 2017.

Zhang D, Li Y, Heims-Waldron D, Bezzerides V, Guatimosim S, Guo Y, Gu F, Zhou P, Lin Z, Ma Q, Liu J, Wang DZ, Pu WT. “Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.” Circulation Research. 2018; 122(1):74-87.

Balasubramanya S, Zurakowski D, Borisuk M, Kaza AK, Emani SM, del Nido PJ, Baird CW. “Right Ventricular Outflow Tract Reintervention After Primary Tetralogy of Fallot Repair in Neonates and Young Infants.” Journal of Thoracic Cardiovascular Surgery. 2018; 155(2):726-34.

Fang ZA, Ghelani SJ, Koutsogiannaki S, DiNardo JA, Yuki K. “Validation of a Mathematical Model of Bidirectional Glenn Circulation With Aortopulmonary Collaterals and the Implications for QP/QS Calculation.” Journal of Cardiothoracic Vascular Anesthesia. 2018; 32(1):395-401

Hawkins B, Ventresco C, VanderPluym C. Developing an app for patients on ventricular assist devices: The VADKids app. Prog Pediatr Cardiol. 2017;47:37-8.

Hofferberth SC, Nathan M, Marx GR, Lu M, Sleeper LA, Marshall AC, Baird CW, Mayer, JE, del Nido PJ, Emani SM. “Valve-sparing Repair With Intraoperative Balloon Dilation in Tetralogy of Fallot: Midterm Results and Therapeutic Implications.” Journal of Thoracic Cardiovascular Surgery. 2018; 155(3):1163-73 e4.

Balkin EM, Sleeper LA, Kirkpatrick JN, Swetz KM, Coggins MK, Wolfe J, Blume ED. “Physician Perspectives on Palliative Care for Children with Advanced Heart Disease: A Comparison Between Pediatric Cardiology and Palliative Care Physicians.” Journal of Palliative Medicine. 2018: 7.

Bucholz EM, Rodday AM, Kolor K, Khoury MJ, de Ferranti SD. “Prevalence and Predictors of Cholesterol Screening, Awareness, and Statin Treatment Among US Adults With Familial Hypercholesterolemia or Other Forms of Severe Dyslipidemia (1999-2014).” Circulation. 2018.

Callahan R, Kieran MW, Baird CW, Colan SD, Gauvreau K, Ireland CM, Marshall AC, Sena LM, Vargas SO, Jenkins, KJ. “Adjunct Targeted Biologic Inhibition Agents to Treat Aggressive Multivessel Intraluminal Pediatric Pulmonary Vein Stenosis.” The Journal of Pediatrics. 2018.

Godfrey ME, Rathod RH, Keenan E, Gauvreau K, Powell AJ, Geva T, Prakash, A. “Inefficient Ventriculoarterial Coupling in Fontan Patients: A Cardiac Magnetic Resonance Study.” Pediatric Cardiology. 2018; 39(4):763-73.

Hoganson DM, Cooper DA, Rich KN, Piekarski BL, Gui L, Gaut JP, Mayer JE, Aikawa E, Niklason LE, Emani SM. “Flow Preservation of Umbilical Vein for Autologous Shunt and Cardiovascular Reconstruction.” The Annals of Thoracic Surgery. 2018

Kuebler JD, Shivapour J,Yaroglu Kazanci S, Gauvreau K, Colan SD,McElhinney DB, Brown DW. “Longitudinal Assessment of the Doppler-Estimated Maximum Gradient in Patients With Congenital Valvar Aortic Stenosis Pre- and Post-Balloon Valvuloplasty.” Circulation Cardiovascular Imaging. 2018; 11(3):e006708.

Mahle WT, Hu C, Trachtenberg F, Menteer J, Kindel SJ, Dipchand AI, Richmond ME, Daly, KP, Henderson HT, Lin KY, McCulloch M, Lal AK, Schumacher KR, Jacobs JP, Atz AM, Villa CR, Burns KM, Newburger JW. “Pediatric Heart Network, Investigators. Heart Failure after the Norwood Procedure: An Analysis of the Single Ventricle Reconstruction Trial.” The Journal of Heart and Lung Transplantation: The Official Publication of the International Society for Heart Transplantation. 2018.

Nair AG, Oladunjoye OO, Trenor CC, LaRonde M, van den Bosch SJ, Sleeper LA, Emani, SM, Kheir JN. “An Anticoagulation Protocol for Use After Congenital Cardiac Surgery.” The Journal of Thoracic and Cardiovascular Surgery. 2018.

Oladunjoye OO, Piekarski B, Banka P, Marx G, Breitbart RE, del Nido PJ, Emani SM. “Staged Ventricular Recruitment in Patients with Borderline Ventricles and Large Ventricular Septal Defects.” The Journal of Thoracic and Cardiovascular Surgery. 2018.

Opotowsky AR, Rhodes J, Landzberg MJ, Bhatt AB, Shafer KM, Yeh DD, Crouter SE, Ubeda Tikkanen A. “A Randomized Trial Comparing Cardiac Rehabilitation to Standard of Care for Adults With Congenital Heart Disease.” World Journal for Pediatric & Congenital Heart Surgery. 2018; 9(2):185-93.

Prosnitz AR, Drogosz M, Marshall AC, Wilkins-Haug LE, Benson CB, Sleeper LA, Tworetzky W, Friedman KG. “Early Hemodynamic Changes After Fetal Aortic Stenosis Valvuloplasty Predict Biventricular Circulation at Birth.” Prenatal Diagnosis. 2018; 38(4):286-92.

Rajpal S, Alshawabkeh L, Almaddah N, Joyce CM, Shafer K, Gurvitz M, Waikar SS, Mc Causland FR, Landzberg MJ, Opotowsky AR. “Association of Albuminuria With Major Adverse Outcomes in Adults With Congenital Heart Disease: Results From the Boston Adult Congenital Heart Biobank.” JAMA Cardiology. 2018; 3(4):308-16.

Callahan R, Lock JE, Shah PB, Marshall AC. “Transcatheter Intervention of Coronary Obstructions in Infants, Children, and Young Adults.” Pediatric Cardiology. 2018.

Pickard SS, Gauvreau K, Gurvitz M, Gagne JJ, Opotowsky AR, Jenkins KJ, Prakash A. Stroke in Adults With Coarctation of the Aorta: A National Population-Based Study. Journal of the American Heart Association. 2018; 7(11).

Singh TP, Gauvreau K. “Center Effect on Post-Transplant Survival among Currently Active United States Pediatric Heart Transplant Centers.” American Journal of Transplantation. 2018.