Researchers say that cardiac ultrasound microbubble contrast agents can do much more than just enhance echocardiogram images. In fact, they may hold the key to helping start the revascularization of heart attack patients before they reach the hospital and enabling a more efficient delivery of gene and drug therapies.
Echo contrast agents are composed of a lipid shell that contains gas inside, and each bubble is about the size of a platelet cell. When ultrasound waves hit the bubbles, they bounce back and can greatly enhance the blood inside the heart on echo imaging. But if the frequency of the sound waves are turned up, it causes these bubbles to cavitate and oscillate their size and eventually burst. Researchers say this has unique physiological effects on the walls of blood vessels, causing a push and pull effect on the cell walls that leads to openings in the cells and between them, creating microjets and radial forces. These effects are being researched as a new way to breakdown clots faster and to deliver drugs genes and stem cells deeper into tissues beyond the cell walls.
Jonathan Lindner, MD, is a lead researcher in this area. He offered an update on the technology in an interview with Cardiovascular Business at the American College of Cardiology (ACC) 2023 meeting. Lindner, a former president for the American Society of Echocardiography (ASE), is the Frances Myers Ball Endowed Professor of Medicine and vice-chief for research for the cardiovascular division at the University of Virginia at the Robert M. Berne Cardiovascular Research Center.
"Ultrasound is the only imaging modality that causes a physical effect on tissues. We are investigating how ultrasound effects blood flow and how it effects drug and gene delivery," Lindner explained. "The microbubbles in an ultrasound field ring, essentially like a musical instrument, and when they do that, they actually produce a lot of biophysical effects on surrounding tissues. This includes the generation of pressure waves."
Lindner's lab has been working on how much energy is required to get the intended therapeutic effects in the vessels and the adjacent cells. He said stable cavitation can be used to expand and contract the bubbles to enable a push-pull effect, microstreaming and acoustic radial force against the cells in the vessel wall. Inertial cavitation happens at higher energies, causing the bubbles to oscillate wildly and then burst. This produces shockwaves, stronger microjets and the formation of free radicals that all can penetrate between cells in the vessel wall.
"That produces a tremendous amount of very brief energy that can result in a lot of sheer and microporation of the surrounding cells," Lindner said.
Ultrasound to help revascularize heart attack patients
A study between 2014 and 2015 tested the use of bubble contrast and higher frequency ultrasound in ST-elevation myocardial infarction (STEMI) patients. The goal was to see if the method of bursting the bubbles in the clot could create enough mechanical force to break up the clot prior to percutaneous coronary intervention (PCI).[1] Researchers found high mechanical index impulses from a diagnostic transducer, combined with a commercial microbubble infusion, can prevent microvascular obstruction and improve functional outcomes in STEMI patients.
Linder wrote an accompanying editorial to the study, and pointed out that it looked like there was a lot more going on physiologically beyond just breaking up the clot with microbubble cavitation.
"A lot of the effects seen in that study were not from dissolving blood clots, but possibly from other effects it was having on the tissue," Lindner explained. "And that actually led us to some areas where we are looking at how the vibration of the microbubbles, which creates a lot of sheer about 1,000 times higher that than you get physiologically in the heart or the limbs. When you have this very high sheer, it triggers a lot of biochemical responses that cause vasodilation and increases blood flow."
His lab took that idea to focus efforts on understanding these pathways, which include nitric oxide and purinergic signaling.
"The vibration of these clinically used microbubbles can markedly improve blood flow in limbs with peripheral artery disease and in patients with ischemic heart disease," Lindner said.
This research has culminated in an ongoing first-in-human study led by Lindner using this technology to help improve perfusion in patients with critical limb ischemia. This includes patients with non-healing ulcers who have no recourse to conventional revascularization. Lindner said the study is looking to see if ultrasound therapy alone can improve the patients' condition enough to improve symptoms and allow wounds to heal.
Use of ultrasound to facilitate more efficient drug and gene delivery to cells
Lindner said ultrasound-mediated drug and gene delivery has been used for years to get better tissue penetration. He said the cavitation of the bubbles helps deliver these therapies in two ways. First, there is poration of the cells where holes facilitate transfer. But second, he said the cavitation and the sheer also triggers cells to essentially draw in drugs or the DNA through endocytosis. He said these forces also help open up tight junctions between cells.
However, researchers are finding these effects, and possibly others yet to be discovered, are enabling gene delivery in cells far away from the vessel walls where there is initial uptake of the DNA.
"With gene delivery, it is all about delivering it to the right cells and getting it in there safely and in amounts that are enough to have an effect," Linder said. "In cardiomyopathies, you essentially need to transfect the vast majority of myocytes in order to have the intended biological effect, and that is what we are trying to attack."
Lindner is chairing a session on microbubble contrast at the ASE 2023 meeting in National Harbor, Maryland, on Monday, June 26, at 10:30 a.m. It will include a detailed discussion of these novel clinical approaches.
Dave Fornell has covered healthcare for more than 17 years, with a focus in cardiology and radiology. Fornell is a 5-time winner of a Jesse H. Neal Award, the most prestigious editorial honors in the field of specialized journalism. The wins included best technical content, best use of social media and best COVID-19 coverage. Fornell was also a three-time Neal finalist for best range of work by a single author. He produces more than 100 editorial videos each year, most of them interviews with key opinion leaders in medicine. He also writes technical articles, covers key trends, conducts video hospital site visits, and is very involved with social media. E-mail: dfornell@innovatehealthcare.com