Author + information
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
- Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon
- ↵∗Address for correspondence:
Dr. Jonathan R. Lindner, Knight Cardiovascular Institute UHN62, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239.
Ultrasound (US) over a wide range of frequencies is used for a variety of therapeutic applications. As just 1 example, high-intensity focused US, which relies on the targeting of a deep tissue through convergence of high-pressure US pulses, is an approved therapy for ablation of certain types of tumors and has been used to eliminate seizure foci in the brain. The biological effects of US that are leveraged for therapy can be classified as either thermal or nonthermal. In cardiovascular medicine, thermal effects are key to the investigational use of intracardiac US catheters that are designed for ventricular arrhythmia ablation (1). Nonthermal effects of large pressure fluctuations during high-power US or shock-wave therapy include cavitation (the formation of unstable bubbles) and acoustically driven shear and convective motion (1). Ongoing research is examining how transthoracic high-intensity focused US can combine thermal and nonthermal effects to induce histotripsy in order to noninvasively create palliative shunts (2), or to reduce obstructive septal hypertrophy. The added effects of cavitation nuclei in the form of microbubble contrast agents has been an area of particularly intense research interest.
The study by Mathias et al. (3) in this issue of the Journal represents the first large randomized clinical trial using contrast echocardiography to restore perfusion and reduce infarct size in patients with acute ST-segment elevation myocardial infarction (MI). There is a solid foundation for the use of ultrasound to: 1) lyse thrombus; and 2) directly increase tissue perfusion through vascular modulation. High-power intravascular US catheters approved by the United States Food and Drug Administration are currently in use for accelerating resolution of venous thrombosis or pulmonary emboli (4). In preclinical models, US performed at frequencies and pressures traditionally used for diagnostic echocardiography can accelerate clot lysis when combined with microbubble contrast agents, particularly when pressures are sufficiently high to produce inertial cavitation (violent collapse of microbubbles) rather than stable cavitation (volumetric oscillation without destruction) (5,6). Putative mechanisms of “sonothrombolysis” include clot fragmentation and augmented penetration of endogenous or drug-based thrombolytic agents.
US also influences tissue perfusion. US at low (<100 KHz) and diagnostic (1 to 2 MHz) frequencies can be used to vasodilate large vessels and reduce microvascular tone through the shear-mediated release of endothelial-derived vasodilators such as nitric oxide and prostaglandins (7,8). Microbubble contrast agents that focally produce very large vascular shear stress when they undergo inertial cavitation amplify the release of vasodilators, resulting in a much greater augmentation in tissue perfusion than US alone (8). Flow augmentation during inertial cavitation is attributable to the massive release of adenosine triphosphate from endothelial and erythrocyte sources which secondarily signals endothelial nitric oxide and prostaglandin formation, and relaxes smooth muscle cells through metabolic conversion to adenosine (9). The latter is an important consideration in MI because adenosine has both antiplatelet and anti-inflammatory effects.
On the basis of the preceding information, improvements in myocardial perfusion and infarct size in patients exposed to microbubble cavitation in the study by Mathias et al. (3) could be mediated by any of the mechanisms illustrated in Figure 1. It is safe to say that their protocol was intended to be clinically feasible with current technology because they used a commercially available contrast agent, US settings already approved for diagnostic echocardiography, and standard apical imaging planes. Although the duration of exposure to contrast US before percutaneous coronary intervention (PCI) was not standardized, the investigators instead modeled clinical scenarios by giving as much cavitation as possible before PCI, then using the rest of the study product for post-PCI cavitation, which may have been important for microvascular reflow. They also used myocardial contrast echocardiography perfusion imaging to guide the time interval between destructive high-power pulses, thereby guaranteeing microbubble cavitation, not only in the coronary arteries, but in the microcirculation as well.
One curious design issue is that the investigators did not use imaging planes that specifically targeted the predicted location of the epicardial infarct-related artery. Yet, recanalization on pre-PCI angiography was much more frequent in the contrast US treatment group, and was nearly 50%, which is substantially greater than that commonly observed in primary PCI trials. It is worth noting that major coronary arteries are often within the standard apical imaging planes with the notable exception of a large portion of the right coronary artery. Separate analysis based on whether the segment of the infarct-related artery was predicted to be within the imaging plane was not performed and would have been difficult to judge.
One of the most intriguing findings was that in those receiving contrast US, neither improvement in microvascular perfusion post-PCI nor reduction in infarct size required recanalization of the epicardial infarct-related artery. These findings are similar to those in preclinical porcine models of coronary sonothrombolysis with contrast US (10), and imply that effects at the microvascular level were critical for benefit. To further address this idea, it would have been valuable in the current study to measure dynamic changes in perfusion while receiving US before PCI, and to evaluate whether the beneficial effects of contrast US were skewed according to whether patients received most of their exposure pre- versus post-PCI.
The study by Mathias et al. (3) is a landmark in the use of therapeutic contrast US for acute MI. The aims were bold, and the investigators employed protocols that are practical for clinical implementation. There are still many important unanswered questions to answer, including: 1) is it more important to expose the microcirculation or the epicardial coronary arteries; 2) is pre-PCI contrast US an essential component, or is most of the benefit from microvascular exposure post-PCI; 3) how much of the improvement in perfusion is attributable to clot lysis versus reduction in microvascular tone versus reduction in post-reperfusion thromboinflammatory response; and 4) does clot age influence its susceptibility to sonothrombolysis? The results from the current study certainly justify future efforts to answer these questions.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Lindner is supported by National Institutes of Health grants R01-HL078610, R01-HL130046, and P51-OD011092.
- 2019 American College of Cardiology Foundation
- Mathias W. Jr..,
- Tsutsui J.M.,
- Tavares B.G.,
- et al.
- Zarghouni M.,
- Charles H.W.,
- Maldonado T.S.,
- Deipolyi A.R.
- Belcik J.T.,
- Davidson B.P.,
- Foster T.,
- et al.
- Belcik J.T.,
- Davidson B.P.,
- Xie A.,
- et al.
- Xie F.,
- Gao S.,
- Wu J.,
- et al.