Can Upper Torso Vibro Acoustic Stimulation Treat No Reflow Following STEMI-Directed PPCI? Rationale and Literature Review. What’s the Buzzzzzzz?

Introduction 

No-reflow following primary percutaneous coronary intervention (PPCI) in ST-elevation myocardial infarction (STEMI) occurs in up to 40% of cases, carries a poor prognosis, and at present, there are no consistently reliable strategies for treating this condition.  Low sonic vibroacoustic stimulation (VAS) has shown to enhance clot disruption and stimulate vasodilation. Moreover, transthoracic diastolic timed VAS (tdVAS) (50 Hz, 2 mm) has shown to enhance myocardial relaxation, improve left ventricular (LV) output, and augment coronary flow in volunteers including those with coronary artery disease (CAD), all factors which may assist the no-reflow patient. We are not aware of any substantial review or analysis that has yet been done to address whether tdVAS could enhance emptying of an ischemic microvascular region following STEMI-directed coronary stenting. We have therefore performed a literature review on relatable data and provided mechanisms in consideration of this hypothesis.    

Background

PPCI is the preferred reperfusion strategy in STEMI; however, there are times when myocardial reperfusion (or more precisely, coronary microvascular flow) does not restore to its optimal level, even following successful stenting of an infarct artery. This condition, known as slow or “no reflow”, has plagued PPCI in 10 to 40% of STEMI cases^1-4, and carries with it an unacceptable increased risk of morbidity and mortality². No reflow results in part from micro-embolization of athero-thrombotic material following balloon inflations into the arterioles and microcirculation which causes additional necrosis, inflammation, and microvascular dysfunction.^2,4 Present treatment/prevention options include delivery of a variety of pharmaceuticals, as well as employment of distal protection and thrombus aspiration techniques — all of which have shown, at best, limited to mixed results in promotion of normalized reflow and/or clinical benefit.^2,5-9 Indeed, there remains no consistently efficacious strategy for preventing or treating no reflow^2,3, so the search continues for therapeutic options.

Transcutaneous ultrasound has been studied to improve STEMI reperfusion. However, the PLUS trial (27 kHz)¹⁰ failed to show efficacy, probably due to the problematic shielding of ultrasound by lung (which covers a substantial portion of the coronaries and does not transmit ultrasound) and a relatively thick, attenuating, chest wall.¹¹ Since then, the need for skilled ultrasonic targeting across an acoustic penetration window was deduced and high mechanical index echocardiographic imaging, with clot-disruptive intravenous (IV) micro bubbles has since surged as a preferred investigative strategy in promoting reflow (or treating no reflow) in STEMI cases before and immediately after PPCI.^3,12-14 However, results of a recent study regarding this technique were confusing, with 3 of 6 patients experiencing unresolved no reflow following stenting in patients pre-treated with ultrasound (an admitted safety concern requiring discontinuation of the study*).¹⁵ Ultrasound, especially when delivered at higher than standard duty factor or intensity, harbors a propensity to increase platelet adhesion16, promote bleeding^17,18, and damage blood vessels.^19-24 Studies in epicardial coronary arteries have in particular showed that ultrasonic energy alters endothelial function at high power and disrupts nitric oxide (NO)-dependent vasodilation²⁵, and most recently, promotes vasoconstriction.¹⁵ Moreover, challenging acoustic imaging windows make it difficult to ensure ultrasonic penetration to a culprit coronary vessel¹¹, and this problem is magnified by a paucity of microbubbles expected to actually reach an occlusive thrombosis site where there is absent flow.²⁶ 

All in all, evidence for damage to membrane proteins and/or cytoskeletal fibers, complete membrane disruption, and irreversible cellular damage (including rupture of vascular endothelial cells resulting in capillary hemorrhage)²⁷, along with difficulties in transcutaneously targeting ultrasound (and delivering microbubbles) to vascular targets, has been gradually mounting to disqualify ultrasound as a practical emergency reperfusive candidate.

Our group has been working on utilizing endothelial membrane ability to directly transform low sonic frequency VibroAcoustic Stimulation (VAS) into mechanical energy at the subcellular and cellular level. Unlike ultrasound, VAS does not promote violent cavitational air voids and bubbles in the tissue, and overall, can avoid damaging micro-stresses and strains to the cells caused by higher frequency ultrasonic waves. VAS stimulation has a long history of safe use in vascular stimulation and vasodilation. It has been proposed for treatment of a wide range of blood flow disorders, including improving the speed and quality of reperfusion in STEMI.^11,28-31 VAS has been shown in vitro and in vivo to provide reliable transmissibility from the upper torso to the heart^32,33, a clot-dissipating effect^{28,30,31,34-37}, improvements in circulation, including microcirculation^38-40, and a localized vasodilatory response^41-44, particularly effective in vessels with spasm^45,46.  

Transthoracic “diastolic timed” VAS (tdVAS), delivered in avoidance of the early- to mid-force generation period of LV systole, has, in particular, shown to provide an enhancement of left ventricular (LV) relaxation and coronary flow in CAD patients^32,33,47, as well as a positive inotropic effect in ischemic heart failure^48,49. VAS also provides unique internal transmission characteristics through bodily tissue, including arteries and the epi-myocardium^50-52, which suggests a less imperative need for perfect upper torso device positioning and skill-based targeting to ensure coronary stimulation¹¹. 

Potentially treatable components of no reflow include microcirculatory spasm, platelet aggregation, and micro-vascular thrombus⁵³, which are all at least mechanistically treatable by tdVAS. Moreover, we have found no evidence that acute short-term exposures of VAS in the sonic frequency range poses harm to blood vessels**.  

A review of the data

tdVAS augments coronary flow in volunteers with CAD 

The response of coronary blood flow (CBF) velocity as measured by left main transesophageal Doppler in 10 healthy volunteers (8 men, 2 women; 50.6 ± 12.8 years old, mean ± SD) and 10 CAD patients (8 men, 2 women; 66.4 ± 8.0 years old) was compared immediately before, during and after tdVAS† (50 Hz, 2 mm amplitude) applied to the patient’s precordium.³² CBF velocity was also assessed by intracoronary Doppler flow wire in three CAD patients (2 men, 1 woman; 60.3 ± 10.5 years old). tdVAS was demonstrated to reliably transmit to the ventricle by observance of fluctuating perturbations in the LV pressure wave form and by transesophageal accelerometer. tdVAS was shown to immediately cause a statistically significant increase in LV (dP/dt) relaxation rate and diastolic CBF velocity (with no change in systolic flow, and independent from changes in heart rate or blood pressure) in all patients (Figure 1), with the most pronounced changes in CAD patients. The investigators concluded that tdVAS increased coronary flow by enhancing diastolic relaxation, likely by facilitated myocardial cross-bridge detachment in ischemic regions. The procedure was reported as safe, without any complications.  

Diastolic timed VAS and positive inotropy

The effects of diastolic timed VAS (in this case applied directly to the epi-myocardial surface, 50 Hz, 1 mm) in an open chest canine model of ischemic impaired LV relaxation was assessed.⁴⁹ In 10 preparations, pacing tachycardia and administration of propranolol were imposed to induce various levels of incomplete relaxation. A flow probe was placed around the ascending aorta to measure stroke volume (SV). At resting heart rates, diastolic VAS caused an immediate decrease in the time constant (negative dP/dt) of LV pressure fall (T) without any influence on heart rate, LV peak systolic pressure (peak LVP), SV, and total systemic vascular resistance. With pacing tachycardia, diastolic VAS increased both peak LVP and SV at 160 beats per minute (before) and 120 beats per minute (after propranolol), simultaneously decreasing both T and LV diastolic pressures. The increase in peak LVP and SV caused by diastolic VAS correlated with the T diastolic interval (r=0.82), the assumed index of severity of incomplete relaxation. The investigators concluded that diastolic timed VAS accelerates LV relaxation rate and that this improves systolic function through the Frank-Starling mechanism. Figure 2 shows how diastolic timed VAS affected LV pressure in this study. 

Systolic VAS and negative inotropy

Precordial VAS stimulation (100 Hz, 2 mm) applied throughout the cardiac cycle (including systole) was shown to induce a mild depression of LV function in volunteers with known ischemic heart disease.⁵⁴ This was discussed as potentially caused by VAS’s interference of LV cross-bridge kinetics during systole, and may therefore lead to decreased systemic blood pressures and elevated LV diastolic pressures (which may provoke heart failure, and/or increased levels of angina), should the technique be used clinically.

While this is not an expected problem for “diastolic timed” emissions, potential negative inotropy is a valid safety concern (and would need to be monitored for) should tdVAS be applied to the ischemic heart in future clinical trials.   

VAS promotes clot dissipation

An in vitro study was performed³¹ to assess whether intermittent, 50 Hz VAS (VAS applied during diastolic-like pressure and halted during systolic-like pressure) applied for 20 minutes over a 4 cm attenuating barrier would provide a clot-dissipating effect in a clotted, fluid-filled soft-flow catheter (lumen sized to resemble an epicardial coronary artery).VAS was shown to provide a substantial clot disruptive effect in all samples versus controls (Figure 3).  

Clot dissipation by VAS is not surprising in view of the Trellis catheter (Medtronic) which uses oscillations in the 50 Hz range to disrupt deep vein thrombosis.³⁵ The use of VAS has also been shown to disrupt blood coagula endoscopically³⁷ and external tapping of acutely thrombosed coronary arteries in open animal models have shown to immediately restore flow³⁶. We also published a study showing how externally delivered 50 Hz VAS causes fluid turbulence which leads to clot erosion³⁰, and have contributed to other studies showing how 24 Hz and 100 Hz VAS delivered, even remote from a thrombosis site, assists clearance of clotted flow systems^34,28.

VAS enhances blood flow   

It has been well established that low sonic VAS enhances regional circulation (including micro-circulation)^38-40 and carries potent vasodilatory capabilities, particularly for arteries in spasm^45,46. Cyclic stress and strain exerted on the endothelial lining of arteries can cause endogenous liberation of  nitric oxide (NO), a potent vasodilator^42-44, and tissue plasmin activator⁵⁵, both factors predictive for stimulating regional blood flow.  

In recent studies at Technion-Israel Institute of Technology (Haifa, Israel), it was shown that “sonophore” effect is responsible for bilayer membrane oscillation and translation of acoustic pressure wave into intracellular cyclic deformations, which in turn activates mechano-sensitive proteins.²⁷

Researchers at Mt. Sinai Medical Center (Miami, Florida) have recently studied low sonic VAS to the chest wall of rats. This study showed enhanced endothelial NO release, which in addition to its vasodilatory properties, was discussed as a potential cardioprotective mechanism in limitation of ischemic reperfusion injury.⁴¹

Discussion/Conclusion

tdVAS may promote myocardial microvascular reflow following PPCI in STEMI cases. In view of favorable correlative data, pilot testing in no reflow appears compassionately warranted.  
In Part 2 to this work, the authors will unveil a pilot protocol in use of a diastolic timed vibro-acoustic stimulator (Parallel Biotechnologies) to enable assessment of this technique.

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^*See discussion of results regarding use of high mechanical index ultrasound with microbubbles pre and post cath in PPCI STEMI cases (the ROMIUS trial) by the following link: https://www.livemedia.gr/video/179544 (presentation by Professor Otto Kamp, from the 30th Annual Advances in Contrast Ultrasound - Bubble Conference 2015, Chicago).

^**According to years of internet (including patent) searches by the authors, with search words including vibration, acoustics, percussion, hertz, sonic, infrasonic, artery, vein, thrombosis, coronary, cerebral, blood, blood flow, damage, endothelium, cavitation, bleeding, hemorrhage.  

^†VAS timed from late systole (i.e., peak contraction of the anterior wall by m-mode) to the following P wave.

¹CEO, Parallel Biotechnologies LLC, Miami Beach, Florida; ²In-Vitro Laboratories, Burnaby, British Columbia, Canada; ³Ahof Biophysical Systems Inc., Burnaby, British Columbia, Canada.

Disclosures: This review was sponsored by a grant awarded by Ahof Biophysical Systems Inc., an entity holding patents relating to vibration for promoting coronary flow. Andrew Hoffmann holds shares in Ahof Biophysical Systems Inc. Material support was provided by Parallel Biotechnologies LLC. Arkady Uryash, MD, holds shares in Parallel Biotechnologies LLC, an entity also holding patents relating to vibration for treatment of blood flow disorders. Harjit Gill, PhD, has received funding from Ahof Biophysical Systems Inc. for this and other assignments. 

Arkady Uryash, MD, can be contacted at auryashmd@parallelbiotech.com. Harjit Gill, PhD, can be contacted at h-gill7@hotmail.com. Andrew Hoffmann, BSc, can be contacted at andrew.hoffmann11@gmail.com.