Upper Torso Vibroacoustic Stimulation for Treatment of No-Reflow Following STEMI-Directed PPCI: A Device and Pilot Study Protocol — Shake, Rattle, and Rock`n Reflow!

Abstract

There is presently no consistently effective strategy for treatment of no-reflow following ST elevation myocardial infarction-directed primary percutaneous coronary intervention. Transthoracic, Diastolic timed, VibroAcoustic Stimulation (tdVAS) has shown to enhance myocardial relaxation, improve left ventricular output, and augment coronary flow in volunteers including with coronary artery disease. We therefore present a prospective, double-blinded, randomized, controlled pilot study protocol to test whether tdVAS (50 Hz, 2mm), by 30-minute session directly following primary percutaneous coronary intervention, is feasible, safe, and may enhance myocardial perfusion, decrease infarct size, and improve clinical outcomes in the no-reflow patient.  

Background

The no-reflow phenomenon (coronary microvascular obstruction) occurs in 10 to 40% of ST-elevation myocardial infarction (STEMI)-directed primary percutaneous coronary intervention (PPCI) cases^1-3, and carries a poor prognosis². Present treatment options have shown, at best, limited to mixed results in restoring flow and adding clinical benefit², so the search continues for new therapies.   

Upper torso transthoracic diastolic timed vibroacoustic stimulation (tdVAS), with emissions timed in avoidance of the early to mid left ventricular (LV) force generation period, has shown in clinical studies to enhance LV relaxation, stroke volume (purportedly by the Frank Starling mechanism), and coronary flow, including in coronary artery disease patients.^4-8   

We have, therefore, taken a first step to investigate whether tdVAS is feasible, safe, effective, and may ameliorate no reflow by providing a phase 1, randomized, double blind, controlled protocol in study of a sonic stimulator, the “YES REFLOW” Vibro-Acoustic Therapy (VAT) System (Parallel Biotechnologies). Experience gained by this pilot study should begin to fill the evidence gap as to whether tdVAS may improve myocardial perfusion and clinical outcomes in the no-reflow patient.  

Methods/Design

Scientific title: Transthoracic diastolic timed VibroAcoustic Therapy in treatment of NO-REFLOW following emergency STEMI-directed PPCI.   

Acronym: VAT-NO-REFLOW trial

Purpose: To assess feasibility, safety and efficacy of tdVAS in treatment of no-reflow in STEMI patients following PPCI. 

Study type: A prospective, double blind, randomized controlled pilot study. 

Principal investigator: TBA.

Interventional model: One test group, one control. 

Masking: Double blind (assessor and patient)

Conditions to be treated: Acute STEMI with TIMI 1 or 0 flow, and ECG evidence of unresolved ischemic injury (i.e., ST elevation ≥1 mm in at least one lead, or persistent left bundle branch block [LBBB]ⁱ) following completion of PPCI, despite successful recanalization of the culprit epicardial artery.

Study location: Cardiac cath lab. Hospital location TBA.

Hypothesis: Chest wall-applied 50 Hz, ~2mm tdVAS sonic stimulation administered immediately following no-reflow STEMI-directed PPCI via the YES REFLOW VAT system is feasible, safe, and will enhance myocardial perfusion, decrease infarct size, preserve LV function, and improve clinical outcomes. 

Medical device to be evaluated:  “YES REFLOW” VAT System (Figure 1). The YES REFLOW VAT system is comprised of a powerful, high fidelity sonic actuator with harness/belt assembly, placed over the chest where the oscillations are directed towards the heart.  

The system is equipped with an “ECG/IBP smart trigger” (Parallel Biotech) enabling cessation of acoustic stimulation prior to the onset of systole in avoidance of the iso-volumetric contraction period (IVCP), and by use of a heart rate-dependent algorithm (and optional manual control), providing re-initiation of stimulation in late systole just prior to the iso-volumetric relaxation period (IVRP). The VAT system thereby allows for real-time assessment and modulation of diastolic timing.   

Intervention type: No-reflow patients (n=15) randomized to receive 30 minutes of tdVAS (50 Hz, ~ 2 mm) to either their chest wall (n=10) or sham therapy (n=5).  

Methods to monitor vibratory penetration: LV pressure perturbation (LVPP) test: tdVAS cardiac penetration is shown by pressure fluctuations in the LV pressure waveform as measured by a catheter-tipped manometer (PC 370 Millar Instruments).  

“Ahhhhh” test: Thoracic cavity penetration is assessed by vocal undulations from the patientⁱⁱ while saying “ahhhhhhhhhhhhhhh” (for demonstration video:
https://youtu.be/JmCIz9oq4Xo
https://vimeo.com/184754356 
[Password: Ahhh])

The ability of the “Ahhhhh” test to predict direct cardiac penetration is an additional investigative point of this study. 

Methods to monitor diastolic timing: tdVAS should be initiated in late systole (prior to the steep downslope of the LV pressure waveform) and be halted prior to the left ventricular end diastolic pressure (LVEDP) at initiation of the waveform’s steep upslope.

If an LV pressure waveform cannot be maintained (because of ectopy, etc.) the catheter may be withdrawn to the aortic root, where the dichrotic notch may substitute as a diastolic timing marker. We also suggest marking the timing of the LVEDP in relation to a monitored QRS complex. Figure 2 illustrates the methods for monitoring tdVAS penetration and diastolic timing.     

Patient inclusion criteria:

1. Adults (≥30 years), either gender.
2. Patient weight: ≤125 kg.
3. First STEMI — with persistent ST elevation (at least 1 mm in one lead), or presumed new onset and persistent LBBB, with TIMI 0 or 1 flow following PPCI in an otherwise successfully recanalized culprit coronary artery.
4. Ability to pass tdVAS cardiac penetration test (i.e., the LVPP test), with VAT system applied to the chest wall. 
5. Hemodynamically stable following PPCI (blood pressure >90 mm Hg systolic, O₂ sat ≥ 95% with O₂ administered), free of unstable brady- or tachy- arrhythmias (i.e., salvos of premature ventricular complexes [PVCs] — triplets or greater, with rates of >120 bpm). 

Patient exclusion criteria:

1. Patient has a pacemaker or internal cardiac defibrillator.ⁱⁱⁱ 
2. New-onset atrial fibrillation for greater than 48 hours without adequate anticoagulation.  
3. Severe aortic stenosis (valve area ≤ 1.0 cm2).^iv
4. Patient’s weight is >125 kg.
5. Presence of LV clot noted or suspected on LV angiography.
6. Late presenter, with first evidence of unabating chest discomfort >12 hours prior to initiation of PPCI.
7. Open sores or musculoskeletal concerns questioning safe use of upper torso sonic stimulation. 
8. No evidence for tdVAS to cardiac penetration by LVPP test.    

Groups/Cohorts    

Group I (chest wall). Patients to receive 30 minutes of chest wall tdVAS with the sonic stimulator engaged over the chest wall by an elastic adjustable harness encircling the upper torso (Figure 1). A flexible, molding to the chest wall^v “VAT transmission interface” should be placed on the left and right sternal borders at the level of the 3rd and 4th intercostal spaces (Figure 3) to focus the oscillations over the base of the heart. If failed evidence for cardiac penetration, or if patient is unable to tolerate chest wall tdVAS (due to pain, anxiety, or breathing difficulties), discontinue the trial run and document as a treatment failure.  

Group II (sham) – optional^vi. Patients to receive 30 minutes of sham treatment with the device at minimum power gently placed over the chest wall (with no transmission interface). Device makes a noise, is marginally palpable, and is not measurably penetrative to the thoracic cavity.

Potential adverse events. The YES REFLOW VAT system (an FDA class 1 non-invasive device) is configured with an electrocardiographic (ECG)/invasive blood pressure (IBP) smart trigger to enable diastolic-timed emissions. Device labeling states: “To seek doctor’s advisement prior to use for the following conditions: if pregnant or have a pacemaker. Do not use the device directly on swollen or inflamed areas, or skin eruptions”. 

Potential adverse events could theoretically occur, as sonic stimulation during the LV force generation period has been suggested to promote a negative inotropic effect (i.e., a decreased strength of LV contraction) in the ischemic heart.⁹ This may be caused by mechanical interference of LV cross-bridge kinetics, and could lead to decreased systemic blood pressures and elevated LV end diastolic pressures (in provocation of heart failure or increased levels of angina).

This is not an expected problem, however, as the VAT system has been expressly configured to cease emissions before or at the peak of the R wave (which we have shown to reliably precede initiation of the IVCP), and reinitiate in late systole, typically just before the terminal downslope of an identifiable T wave (which we have shown to reliably precede the IVRP).¹⁰ Sonic emissions are thereby substantially halted in avoidance of the LV force generation to peak output period to preserve systolic myocardial cross-bridge kinetics. Nevertheless, cath lab staff will monitor the subjects for evidence of hemodynamic compromise, worsening ischemia, shortness of breath, arrhythmia, and provocation of chest pain during tdVAS, with termination of a session mandated in case of dangerous effects during therapy.

The need for tdVAS timing in complete avoidance of systole is not deemed a critical safety factor, as by far, the highest myocardial stress, pressure generation, and contribution of blood flow ejected from the heart occurs during early to mid-systole¹¹, which is expressly avoided by the VAT system.

Methods to ensure “diastolic timing”. In sinus rhythm, tdVAS termination is accomplished firstly by use of a monitored history of prior R – R intervals to predict the timing of a following QRS complex, thereby providing an electronic “OFF” command typically within the P – R interval of an upcoming beat. In case of an earlier-than-expected beat (e.g., a PVC or if atrial fibrillation), the “OFF” command will be triggered upon recognition of the upslope of the R wave.

An electronic “ON” command will, by an automated heart rate-dependent linear regression equation derived from Simonson et al¹², typically fall within the ST segment prior to the terminal downslope of the T wave. The “ON” command may also be manually fine-tuned to ensure emissions begin just prior to the onset of diastole.  

Figure 4 illustrates of appropriate vibratory timing with respect to the ECG.

Primary Outcome Measures

• Change in culprit vessel TIMI flow and myocardial blush grade (timeframe: during and immediate post therapy). Serial angiography Q 5 minutes and immediate post over a 30-minute session.^vii  
• Change in ST elevation (or resolution of LBBB) (timeframe: during and immediate post therapy). Continuous 12-lead or 12-lead ECG Q 5 minutes and immediate post over a 30-minute session.^viii 
• Percentage of patients who remain hemodynamically stable (timeframe: at time of therapy). Hemodynamic instability^ix includes:

A)     Evidence for tdVAS-induced heart failure —> a BP drop below 93 mm Hg systolic and/or O₂ saturation drop ≤93% despite O₂ administration should be documented as a safety concern and lead to discontinuation of the therapy session.
B)     New-onset ventricular arrhythmia (salvos of PVCs, triplets or ventricular tachycardia at a rate of >120 bpm^x) concomitant with therapy.

• Salvagability index (timeframe: 72-96 hours post infarction). Percentage of myocardium with viability within the risk area obtained by magnetic resonance imaging.^xi
• Left ventricular function and perfusion parameters (timeframe: 72-96 hours and at 6 months) —> left ventricular volumes, ejection fraction, longitudinal strain, and infarct size by myocardial contrast echocardiography.^xii

Secondary Outcome Measures: 

• Thirty-day survival (timeframe: 30 days post infarction).
• Incidences of documented congestive heart failure requiring administration of a diuretic (timeframe: 72-96 hours post infarction and by 6 months).
• Incidences of documented ventricular tachycardia — 4 beats ≥120 bpm (timeframe: 72-96 hours post infarction and by 6 months).
• Incidences of patient bruising and/or ribcage injury to the chest wall (timeframe: during and within 24 hrs following therapy).
• Correlative ability of the Ahhhhh test to match LVPP test (calculated as a percentage).

Detailed Protocol

Immediately following STEMI-directed PPCI, the interventionist will determine whether the no-reflow angiographic, electrocardiographic, and safety inclusion criteria have been met, whereby the patient will be offered consent for study enrollment.    

No-reflow patients (n=15) will be randomized to receive 30 minutes of tdVAS therapy to their anterior chest wall (n=10) or sham treatment (n=5). 

Treatment is planned on the cath lab table to enable serial angiographic assessment of the no-reflow vessel, as well as monitoring of diastolic timing and cardiac penetration of the acoustic stimulus. Angiography and 12-lead ECGs should be administered in 5-minute intervals to inspect for changes in TIMI flow, blush grade, and ST elevation (or if acute LBBB, changes in QRS morphology) during and immediately following therapy. tdVAS should be temporally discontinued during catheter engagement within the coronary artery and 12-lead acquisitions. Vital signs should be documented continuously, or as a minimum, taken in 5-minute intervals, with patient comments and/or symptoms recorded.  Provocation or worsening signs of heart failure (i.e., a sustained blood pressure drop to below 90 mm Hg, or sustained drop in O₂ sat below 93%), or increased levels of angina pectoris and/or ST elevation (despite administration of oxygen and/or nitroglycerine) during tdVAS should be documented and lead to termination of the session.    

Device positioning and assessment of diastolic timing. The YES REFLOW VAT system should be engaged over the anterior chest wall, with the pliable VAT transmission interface overlying the left and right sternal margins of the 3rd and 4th ICS. The weight, contour and elastic adjustable straps of the VAT system provide a hands-free, stable upper torso engagement to enable optimal transthoracic sonic transmission. 

The limb leads of the ECG/IBP smart trigger should be applied to the ankles and wrists (preferably far from the torso), with the V lead placed to the second left ICS. Pressure catheter should be advanced to the LV or central arterial line, with the VAT system activated at minimum power just to assess diastolic timing with cessation of stimulation noted on or before the steep LV pressure rise, and re-initiation just prior to the steep LV pressure fall (as per Figure 2). Once appropriate diastolic timing is confirmed, the system may be turned on to maximum power to enable transthoracic cardiac acoustic penetration. Patients should be instructed to relax during therapy to avoid fatigue and musculoskeletal artifact.  

Monitoring tdVAS penetration. In all cases, the best possible cardiac acoustic penetration should be obtained and then continuously monitored by assessment of the LVPP test (Figure 2). Penetration should also, when possible, be periodically evaluated (initially, and thereafter in 5-minute intervals) by the Ahhhhh test, with the success or failure (in affirming cardiac penetration in view of the LVPP test) documented. Minor adjustments of the VAT system may be attempted (moving the device slightly cranial or caudal, or adding engagement force by pressing down or adding a weight to the device against the patient’s upper torso) to optimize appearance of LV pressure fluctuations, and/or the strength of vocal undulations throughout the procedure.^xiii  Topical lidocaine to the chest wall surface may be considered to provide additional comfort (particularly in females) during the procedure.

If transthoracic cardiac penetration cannot be established by the LVPP test, the session should be documented as a penetration failure and cancelled.

WARNING: If oscillations fail to terminate prior to end diastole, document as a “diastolic timing failure” — and cancel the procedure at first evidence of significant hemodynamic compromise (i.e., systolic pressure drops below 90 mm Hg, or evidence of worsening heart failure).   

Comparative Analysis

Comparisons between study groups will be made based on changes in angiographic TIMI flow and blush grade, changes in ST elevation (or QRS morphology), and reduction in infarct size determined by salvagability index (SI) at magnetic resonance imaging 72-96 hours post STEMI. LV function and perfusion parameters will also be evaluated at 72-96 hours and at 6 months by echocardiography in all surviving subjects. Patients will return for 6-month follow-up to assess for mortality and any post-infarct hospital admissions, including documented arrhythmia.

We recommend image evaluation be performed by two blinded accredited physicians experienced in interpretation of the modality. In case of their disagreement, the reviewers can re-evaluate or invite a third, blinded physician as arbitrator.    

Ethics

Ethical consideration of this study is argued based on compassionate grounds, as unresolved no-reflow carries a poor prognosis, and there are presently no reliable treatment options in treatment of the affliction. The study shall ensure:

• Informed consent.
• Confidentiality and anonymity will be maintained as per participant’s request.
• Adequate safety measures to ensure no harm is done to the participants (i.e., cath lab with continuous vital sign monitoring)
• Institutional Review Board ethical and safety acceptance by the accredited medical center to run the study.^xiv

Results Dissemination Plan

Results will be presented for peer review in view to publication in a respected cardiovascular journal. 

Future Work

It would be interesting to assess whether the YES REFLOW VAT system could be administered in-ambulance to accelerate and ensure successful pre-hospital thrombolysis for the acute STEMI patient.

Summary

tdVAS may be effective in ameliorating no-reflow following STEMI-directed PPCI. Evidence by third party clinical testing has shown that tdVAS safely augments coronary flow in coronary artery disease patients, hence pilot testing in the acute no-reflow scenario (where all other measures to promote reflow have failed) appears compassionately warranted. To this end, a prospective, randomized, controlled pilot study in use of the YES REFLOW VAT system for treatment of no-reflow is herein presented.  

Acknowledgements. We thank Arianna Hoffmann for her assistance in photography, and Bella Sandman, and Michelle and Ronald Uryash for their technical assistance.

References 

1. Soeda T, Higuma T, Abe N, Yamada M, Yokoyama H, Shibutani S, et al. Morphological predictors for no reflow phenomenon after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction caused by plaque rupture. Eur Heart J Cardiovasc Imaging. 2016 Jan 22. pii: jev341. [Epub ahead of print].
2. Lim SY. No-reflow phoenomenon by intracoronary thrombus in acute myocardial infarction. Chonnam Med J. 2016 Jan; 52(1): 38-44. 
3. Galasso G, Schiekofer S, D’Anna C, Gioia GD, Piccolo R, Niglio T, et al. No-reflow phenomenon: pathophysiology, diagnosis, prevention, and treatment. A review of the current literature and future perspectives. Angiology. 2014 Mar; 65(3): 180-189. 
4. Naya T, Koiwa Y, Honda H et al Diastolic vibration from the precordium increases coronary blood flow in humans. J Cardiovasc Diagn Procedures. 1994; Abstract (FRI – POS07) 12:110.
5. Koiwa Y, Honda H, Naya T, Shirato K. Precordial or epicardial input of phase-controlled minute vibration: effect on the coronary flow rate in regional ischemia. In: New horizons for failing heart syndrome. Sasayama S, editor. Springer, Tokyo; New York; 1996. 
6. Koiwa Y, Honda H, Takagi T, Kikuchi J, Hoshi N, Takishima T. Modification of human left ventricular relaxation by small-amplitude, phase-controlled mechanical vibration on the chest wall. Circulation. 1997; 95:156-162. doi 10.1161/01.CIR.95.1.156 
7. Takagi T, Koiwa Y, Kikuchi J, et al. Diastolic vibration improves systolic function in cases of incomplete relaxation. Circulation. 1992, 86: 1955-1964. 
8. Koiwa Y, Takagi T, Kikuchi H, Honda H, Hoshi N, Takishima T. The improvement of systolic function of depressed left ventricle by external vibration at diastole. Tohoku J Exp Med. 1989; 159: 169-170. doi: 10.1620/tjem.159.169
9. Koiwa Y, Ohyama T, Takagi T, Takishima T. Clinical demonstration of vibration-induced depression of left ventricular function. Tohoku J Exp Med. 1989 Nov; 159(3): 247-248. doi: 10.1620/tjem.159.247.
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Footnotes

i. Believed to be “new-onset” LBBB resulting from the STEMI.
ii. Assuming patient is awake and able to comply.
iii. The effects of VAT on ICDs and pacemakers has not been well studied. Moreover, it is difficult to assess electrocardiographic injury during ventricular pacing. 
iv. Or unable to pass guidewire across aortic valve. 
v. Thereby enabling flush rib-space engagement.
vi. Given the small planned enrollment, a control group may be optional given this early stage of enquiry.
vii. Worsening TIMI flow (from 1 to 0) with tdVAS should be documented as a safety concern and lead to discontinuation of the therapy session. A statistically relevant worsening in TIMI flow in treatment groups will prompt discontinuation of the study.
viii. Worsening ST elevation by ≥1 mm in any lead with tdVAS should be documented as a safety concern and lead to a discontinuation of the therapy session. A statistically relevant worsening in ST elevation in treatment groups will prompt discontinuation of the study.
ix. Worsening hemodynamic instability during tdVAS should be documented as a safety concern and lead to discontinuation of the therapy session.
x. Hemodynamically stable, accelerated idioventricular rhythms (deemed as reperfusion arrhythmias, ≤120 beats per minute) are acceptable for continuing tdVAS therapy. 
xi. A statistically relevant worsening in salvagability index in treatment groups will prompt discontinuation of the study.    
xii. A statistically relevant worsening in infract size in treatment groups will prompt discontinuation of the study.
xiii. There is typically a “sweet spot”, whereby a particular position of the device against the patient’s chest wall will provide most pronounced acoustic fluctuations in the LVPP and Ahhhhh test.    
xiv. An Investigational Device Exemption from the FDA may be required.

Disclosures: The protocol for this study was sponsored in part by a grant awarded by Ahof Biophysical Systems Inc., an entity holding patents relating to medical uses for vibration. The author (AH) holds shares in Ahof Biophysical Systems Inc.  

Material support was provided by Parallel Biotechnologies LLC. The author (AU) holds shares in Parallel Biotechnologies LLC, the device developer and entity also holding patents relating to vibroacoustics in treatment of blood flow disorders. 

The author (HG) has received funding from Ahof Biophysical Systems Inc. for this and other assignments. Otherwise no conflicts of interest are declared.  

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.