A new strategy to restore blood flow to the heart walls and reduce heart muscle death due to a heart attack is being tested at the Heart Institute (InCor) of the University of São Paulo (USP). Those who suffer a first heart attack and arrive at the Heart Institute within six hours of the onset of chest pain may be asked to undergo an extra and innovative procedure that promises to decrease heart damage.
The treatment is called sonotrombolysis and is an adaptation of cardiac ultrasound, an imaging test that allows observation of the movements and integrity of the heart. Painless, except for a needle prick in the arm, the therapy consists of injecting 3 to 5 milliliters of an opaque fluid containing billions of gas microbubbles into the bloodstream and seconds later applying a very brief and high intensity sequence of ultrasound pulses to the heart—the difference between the ultrasound used in testing and the one used in sonotrombolysis lies in the intensity of the pulses, which is higher in the latter case.
Though inaudible to humans, acoustic ultrasound waves make the microbubbles vibrate until they explode. When they break, they produce pressure that, without damaging the artery, dissolves the clot into pieces smaller than the erythrocytes, the cells that deliver oxygen throughout the body and circulate even through the narrowest blood vessels, the capillaries (see infographic). Once the clot is gone, blood resumes its normal flow and restores oxygen and nutrients to the heart muscle.
“It’s like using dynamite to shatter a concrete wall on a microscopic scale,” says cardiologist Wilson Mathias Júnior, director of InCor’s Echocardiography Service and the clinical trial coordinator who evaluated the safety and effectiveness of sonotrombolysis. “This is the first time the treatment has been tested in humans.”
At the Institute, Mathias’s team selected 30 patients who had experienced their first heart attack and asked them to participate in an evaluation of the technique. As soon as they arrived at the hospital, they all received the medication traditionally used to reduce clot formation: heparin, acetylsalicylic acid and clopidogrel. Then, while awaiting catheterization, participants underwent one of two possible interventions. Twenty received the microbubble injection followed by high-intensity ultrasound pulses. The other 10 also received the bubbles, but they were accompanied by low-intensity pulses used to produce images of the heart. The researchers measured the performance of the sonotrombolysis, comparing data from these 30 patients with data from a group of 70 who had received only anticoagulant medication and had undergone catheterization for the implantation of a stent—a wire mesh cylinder that keeps the artery open.
Half of the patients in the first group showed improvement in heart circulation before stent implantation. One month later circulation in the heart muscle remained good in 12 of the 20 patients (60%) treated with microbubbles and ultrasound. The same result was achieved by only one of 10 patients who had received the less intense pulses, and by only 16 of 70 (23%) in the control group, according to an article published in the May 2016 issue of the Journal of the American College of Cardiology.
Since this first phase, another 15 people have gone through the procedure at InCor, and Mathias’s team is hoping to soon reach 100. Mathias knows that only after evaluating more cases will he have a more accurate idea of the effectiveness of the technique. “Right now the most important thing is to show that the safety and benefits of the procedure,” he says. “Later on we will have to do larger clinical trials with other centers.”
“The pre-clinical tests had already demonstrated that high-intensity ultrasound was able to recanalize the coronary arteries and the smaller blood vessels that comprise microcirculation,” says the cardiologist Thomas Porter of the University of Nebraska Medical Center, a co-author of the study. Dr. Porter coordinates the U.S. team collaborating with the Institute. It was during a stay in Nebraska in 2006 that Brazilian physician Jeane Mike Tsutsui from Mathias’ group, showed that high-intensity ultrasound pulses dissolved clots in the hearts of dogs subjected to an experimental model simulating a heart attack. “We are pleased to see a similar result in this initial study with humans,” says Porter. “So far we have seen no complications,” Dr. Tsutsui adds.
Sonotrombolysis has encouraged researchers to try to solve a problem that neither catheterization nor stenting could solve: restoring microcirculation to the heart, i.e., blood flow in the smaller vessels, which are in close contact with cells, allowing oxygen and nutrients to reach them. Previous studies have shown that half of those who undergo catheterization and receive stents continue to experience clots that block microcirculation. “This issue has not yet been resolved by the therapies that make up state-of-the-art heart attack treatment,” says Porter. “Now ultrasound using microbubbles is helping to solve the problem.”
Mathias and Porter have already begun negotiations with an ultrasound equipment manufacturer to try to make the devices portable. A reduction in size would allow the use of sonotrombolysis in ambulances and basic health units and initiate treatment earlier for heart attack patients. Mathias believes that disseminating such devices could help reduce the damage from heart attacks in countries like Brazil, where there are about 250,000 cases per year. “Here in Brazil,” says Mathias, “only 30% of people who experience heart attacks have access to drugs that prevent clot formation, and only 5% have access to catheterization.”
Therapeutic use of ultrasound in acute and chronic coronary artery disease (nº 2010/52114-1); Grant Mechanism Research Support – Thematic Project; Principal Investigator Wilson Mathias Júnior (InCor-USP); Investment R$1,295,020.45.
MATHIAS JR., W. et al. Diagnostic ultrasound impulses improve microvascular flow in patients with STEMI receiving intravenous microbubbles. Journal of the American College of Cardiology. 67; 21. 2016.