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Diagnostic Ultrasound Impulses ImproveMicrovascular Flow in Patients With STEMIReceiving Intravenous Microbubbles

Wilson Mathias, JR, MD,a Jeane M. Tsutsui, MD,a Bruno G. Tavares, MD,a Feng Xie, MD,b Miguel O.D. Aguiar, MD,a

Diego R. Garcia, MD,a Mucio T. Oliveira, JR, MD,a Alexandre Soeiro, MD,a Jose C. Nicolau, MD,a

Pedro A. Lemos, NETO, MD,a Carlos E. Rochitte, MD,a José A.F. Ramires, MD,a Roberto Kalil, FILHO, MD,a

Thomas R. Porter, MDb

ABSTRACT

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BACKGROUND Pre-clinical trials have demonstrated that, during intravenous microbubble infusion, high mechanical

index (HMI) impulses from a diagnostic ultrasound (DUS) transducer might restore epicardial and microvascular flow in

acute ST-segment elevation myocardial infarction (STEMI).

OBJECTIVES The purpose of this study was to test the safety and efficacy of this adjunctive approach in humans.

METHODS From May 2014 through September 2015, patients arriving with their first STEMI were randomized to either

DUS intermittent HMI impulses (n ¼ 20) just prior to emergent percutaneous coronary intervention (PCI) and for an

additional 30 min post-PCI (HMI þ PCI), or low mechanical index (LMI) imaging only (n ¼ 10) for perfusion assessments

before and after PCI (LMI þ PCI). All studies were conducted during an intravenous perflutren lipid microsphere infusion.

A control reference group (n ¼ 70) arrived outside of the time window of ultrasound availability and received emergent

PCI alone (PCI only). Initial epicardial recanalization rates prior to emergent PCI and improvements in microvascular flow

were compared between ultrasound-treated groups.

RESULTS Median door-to-dilation times were 82 � 26 min in the LMI þ PCI group, 72 � 15 min in the HMI þ PCI group,

and 103 � 42 min in the PCI-only group (p ¼ NS). Angiographic recanalization prior to PCI was seen in 12 of 20 HMI þ PCI

patients (60%) compared with 10% of LMI þ PCI and 23% of PCI-only patients (p ¼ 0.002). There were no differences in

microvascular obstructed segments prior to treatment, but there were significantly smaller proportions of obstructed

segments in the HMI þ PCI group at 1 month (p ¼ 0.001) and significant improvements in left ventricular ejection fraction

(p < 0.005).

CONCLUSIONS HMI impulses from a diagnostic transducer, combined with a commercial microbubble infusion, can

prevent microvascular obstruction and improve functional outcome when added to the contemporary PCI management of

acute STEMI. (Therapeutic Use of Ultrasound in Acute Coronary Artery Disease; NCT02410330) (J Am Coll Cardiol

2016;67:2506–15) © 2016 by the American College of Cardiology Foundation.

I t is estimated that more than 1.1 million patientsin the United States alone were discharged fromhospitals in 2010 with the diagnosis of acute cor-

onary syndrome, of whom 813,000 were classified

m the aHeart Institute (InCor), University of São Paulo, Medical School,

dicine, University of Nebraska Medical Center, Omaha, Nebraska. This

iversity of São Paulo Medical School ethics committee, and received finan

ency; FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo);

. Nicolau has received speaker/consulting honoraria and/or research/ed

yer, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck

nt funding and equipment support from Lantheus Medical Imaging and

rted that they have no relationships relevant to the contents of this pape

nuscript received March 10, 2016; accepted March 17, 2016.

as having acute myocardial infarction (1). Currentrecanalization therapies in acute ST-segment eleva-tion myocardial infarction (STEMI) are pharma-cological thrombolysis or percutaneous coronary

São Paulo, Brazil; and the bDepartment of Internal

study was approved by the Clinics Hospital of the

cial support from the Brazilian government research

and the Theodore F. Hubbard Foundation at UNMC.

ucational grant support from Amgen, AstraZeneca,

, Novartis, Pfizer, and Sanofi. Dr. Porter has received

Philips Medical Systems. All other authors have re-

r to disclose.

AB BR E V I A T I O N S

AND ACRONYM S

DUS = diagnostic ultrasound

HMI = high mechanical index

LAD = left anterior descending

artery

LMI = low mechanical index

MPSI = microvascular

perfusion score index

MVO = microvascular

obstruction

RCA = right coronary artery

STEMI = ST-segment elevation

myocardial infarction

WMSI = wall motion score

J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6 Mathias, Jr., et al.M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5 Ultrasound Therapy in Acute STEMI

2507

intervention (PCI), both of which have improved theprognosis of these patients (2,3). These approachesare meant to restore epicardial flow as soon aspossible after symptom onset. Despite major effortsto reduce this time interval, unavoidable delays stillexist in developed countries due to patient factorsand delays in transport to appropriate hospitals (3).This problem is even greater in developing countries,where other factors frequently compromise access toprimary PCI or even lytic therapy (4).

An even greater problem with current STEMI ther-apy is persistent microvascular obstruction (MVO).Even with timely epicardial revascularization, signifi-cant MVO may still exist in more than 50% of patientsafter epicardial recanalization, resulting in highernecrotic area, adverse left ventricular (LV) remodel-ing, and worse prognosis (5–8). Although severalpharmacological agents have been employed to reduceMVO in STEMImanagement, they are typically utilizedduring or after PCI, well after MVO has occurred.

SEE PAGE 2516

Although transthoracic high mechanical index(HMI) impulses from a diagnostic ultrasound (DUS)transducer have been utilized to diagnose MVO anddetect myocardial perfusion during a continuousmicrobubble infusion (5,6,9–11), the microbubblecavitation induced by these HMI impulses (12) createsshear forces capable of dissolving epicardial andmicrovascular thrombi in animal models of acuteSTEMI (13–15). These same HMI impulses, whenapplied to the microvasculature, also induce nitricoxide (NO) release (16), which may further augmentmicrovascular flow.

Although these effects have been demonstratedand verified in animal models, the utility of DUS inthis context has never been studied in humans duringthe contemporary management of STEMI, whereemergent PCI is routinely employed with such speedthat only brief applications of ultrasound may bepossible prior to interventional therapies. The pur-pose of this study was to examine what effect addingemergent DUS-guided HMI impulses applied bothbefore and after PCI during intravenous commerciallyavailable microbubble infusion, a therapy knownas sonothrombolysis, has on early coronary arterypatency rates, microvascular recovery, and LV func-tion in patients presenting with their first STEMI.

METHODS

The trial was designed to investigate whetherapplying HMI impulses from a DUS transducer using

a commercially available microbubble infu-sion (5% Definity, Lantheus Medical Imaging,Inc., North Billerica, Massachusetts) runningat 3 to 5 ml/min in patients with a first STEMIwould improve early epicardial patency rates,microvascular flow, and recovery of LV sys-tolic function.

Exclusion criteria were a history of priormyocardial infarction or PCI, known cardio-myopathy, severe valvular heart disease,fibrinolytic therapy prior to arrival in theemergency department, allergy to perflutren,chest pain onset >12 h from arrival, orreduced life expectancy (6 months) fromother comorbidity.

From May 2014 to September 2015, a total

of 887 STEMI patients arrived at the Heart Institute(InCor) University of São Paulo Emergency Depart-ment; of these, 100 met inclusion criteria for thestudy protocol, and 30 arrived within the time win-dow when emergent DUS could be applied prior toand after PCI (Figure 1). The remaining 70 STEMI pa-tients who fell outside of the time window in whichultrasound was available (7:00 AM to 7:00 PM, Mondaythrough Friday) served as a control reference group(PCI only) for evaluation of door-to-dilation times andangiographic recanalization rates.

All patients received immediate aspirin (300 mg),clopidogrel (600 mg), heparin, and emergent PCIprotocols as outlined within the 2014 STEMI guide-lines (3).

The 30 ultrasound-treated patients were random-ized in a 1:2 fashion to either 1 of 2 DUS algorithms:1) a low mechanical index (LMI)–only 1.8 MHz DUSgroup (n ¼ 10) consisting of LMI (0.18) imaging only at25-Hz frame rates with limited (no more than 3)diagnostic HMI impulses to assess regional wall mo-tion and microvascular perfusion before and afterPCI (LMI þ PCI group); and 2) DUS therapeutic groups(n ¼ 20) that received either multiple image-guideddiagnostic HMI (1.8 MHz; 1.1 to 1.3 mechanical in-dex; 3-ms pulse duration) impulses applied in theapical 4-, 2-, and 3-chamber views or HMI longer-pulse duration impulses (1.3 MHz transmit, 5-mspulse duration in 5 patients, and 1.8 MHz transmit,20-ms pulse duration in 5 patients) applied to theapical windows that contained the risk area. Thesepatients (n ¼ 20 total) were referred to as the HMI þPCI group, who received HMI impulses applied for 5-sintervals repeatedly after LMI imaging detectedmicrobubbles within the myocardial microvascula-ture. The intervals between HMI impulses variedfrom 5 to 15 s depending on the time required for

index

FIGURE 1 Patient Selection

887 patients with AMI at Emergency Departmentfrom May 2014 to September 2015

418 with Non STEMI

369 exclusion criteria

469 with STEMI

100 with STEMI meet inclusion criteria

30 patients with STEMI randomized to 3 groups

70 arrived at night or weekends

Of the 887 patients with acute myocardial infarction (AMI) potentially

available for inclusion, only 30 with ST-segment elevation myocardial

infarction (STEMI) were able to be randomized for study inclusion.

Mathias, Jr., et al. J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6

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myocardial contrast replenishment. The focus wasset at the mitral valve level for all studies.

Table 1 describes the different ultrasound regimensused. Transmit line spacings were 2� apart for allimaging and therapeutic modalities, resulting in 132lines/frame for diagnostic LMI and HMI impulses(3 ms), 132 lines/frame for HMI (5 ms), and 120 lines/frame for HMI (20 ms).

There were 2 time periods in the acute setting inwhich the HMI impulses were applied. The firsttreatment was for whatever time period was possibleprior to emergent PCI. The second time period wasfor 30 min after PCI. LMI imaging was used tocompute biplane-derived measurements of left ven-tricular ejection fraction (LVEF) and assess micro-vascular perfusion before randomized treatment andimmediately after the second ultrasound treatment.Diagnostic LMI imaging with ultrasound contrast wasalso utilized to examine microvascular perfusion,regional wall motion, and ejection fraction at hospitaldischarge and finally at 1 month post-PCI.

ASSESSMENT OF TREATMENT OUTCOMES. All coro-nary angiograms were analyzed offline by an inde-pendent interventional cardiologist (P.A.L.) who wasblinded to clinical characteristics or allocated treat-ment. The initial (pre-PCI, before any coronarymanipulation) and final angiograms (post-PCI, afterguidewire removal) were examined for epicardialTIMI (Thrombolysis In Myocardial Infarction) flowgrading (17). Angiographic recanalization was definedas the presence of TIMI flow grade 2 or 3 in the infarctvessel. Maximum ST-segment resolution (percentage

of maximal baseline elevation), using previously de-scribed definitions (18), was assessed by an indepen-dent operator (M.T.O.) who compared the initial12-lead electrocardiogram performed during emer-gency department assessment with the 12-lead elec-trocardiogram obtained just after the first ultrasoundtreatment but prior to PCI, and again following thesecond ultrasound treatment post PCI.

Wall motion score index (WMSI) was computed byanalyzing wall thickening in all 3 contrast-enhancedapical windows and computing the index usinga 17-segment model as recommended in the 2015American Society of Echocardiography guidelines(19). Contrast-enhanced images were used to com-pute biplane measurements of LVEF before and afterrandomized treatments, at 48 h prior to hospitaldischarge, and finally at 1 month. The microvascularperfusion score index (MPSI) within the same17-segment model was assessed by a blinded experi-enced reviewer (W.M.) using a scoring system of 1 formyocardial contrast replenishment within 4 s of theapplied HMI impulse (as demonstrated in Figure 2,MPS1 panels); a score of 2 (mildly reduced) whencomplete replenishment within the risk area wasdelayed longer than 4 s after the HMI impulse; or ascore of 3, which was defined as virtually no replen-ishment of myocardial contrast over 10 s after theHMI impulse (Figure 2, MPS3 panels). A score of 3 wasconsidered to indicate MVO. The score index wascomputed as total score divided by total number ofsegments analyzed. Attenuated basal segments werenot included in the calculation.

All LVEF, wall motion, and microvascular perfu-sion assessments were made by an independentexperienced echocardiographic reviewer (W.M.) whowas blinded to treatment assignment at the time ofthese measurements.

STATISTICAL ANALYSIS. Paired Student t testingwas used to compare blood pressure, heart rate, andoxygen saturation before or after contrast adminis-tration and ultrasound treatments. Proportional dif-ferences in angiographic recanalization rates beforeand after PCI were compared using contingencytables (chi-square testing using 3 � 2 contingencytables). Door-to-dilation times and hemodynamicmeasurements between the 3 groups were comparedwith analysis of variance. In the ultrasound-treatedpatients, changes in MPSI, regional WMSI, and ejec-tion fraction from baseline to subsequent measure-ments at 1 month were compared using pairedStudent t testing within groups. Differences in thesemeasurements between ultrasound-treated groupsat these time points were made with unpaired

TABLE 1 Ultrasound Treatment Regimens

HMIPulse

Frequency/PulseDuration

FR(Hz)

Number ofPulses per Line

SectorSize (�)

Number ofLines per Frame

Duration of TherapyPre-PCI (min)

Short pulse: HMI þ PCI(n ¼ 10)

1.1–1.3 1.8 MHz/3 ms 25 3 90 132 12 � 10

Long pulse: HMI þ PCI(n ¼ 5)

1.3 1.3 MHz/5 ms 10 3 90 132 20 � 8

Long pulse: HMI þ PCI(n ¼ 5)

1.3 1.8 MHz/20 ms 5 4 60 120 19 � 14

LMI þ PCI(n ¼ 10)

0.18 1.8 MHz/3 ms 25 3 90 132 <2*

*Time required to obtain LMI perfusion images.

FR ¼ frame rate; HMI ¼ high mechanical index; LMI ¼ low mechanical index; PCI ¼ percutaneous coronary intervention.

J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6 Mathias, Jr., et al.M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5 Ultrasound Therapy in Acute STEMI

2509

Student t testing. Contingency tables in theultrasound-treated groups were used to compare theproportion of patients exhibiting >20% ST-segmentresolution prior to PCI, as well as the proportion ofsegments exhibiting MVO before ultrasound treat-ments and at 1-month follow-up. The comparison ofsegments exhibiting MVO was tested without ad-justments for multiple comparisons within in-dividuals at each time point. Nonparametric testing(Mann-Whitney U and Friedman tests) was used ifdata were not normally distributed. The PCI-onlygroup received no ultrasound or contrast agentinfusion and was not included in the 30-day

FIGURE 2 Microvascular Perfusion Assessments

MPS1

MPS3

A B

Microvascular replenishment is seen (A) before and (B) immediately follo

10 s. In these examples of microvascular perfusion scores (MPS) of 1 (top

in the patient with a score of 1, but still had not replenished at 10 s in

echocardiographic contrast follow-up study. All ana-lyses were performed with the assistance of SPSS 17.0for Windows (SPSS Inc., Chicago, Illinois).

RESULTS

The mean age of the DUS-treated patients was 59 � 10years compared with 60 � 13 years in the PCI-onlygroup. There were slight differences in the propor-tion of patients with a history of hypertension(37% DUS-treated vs. 59% PCI-only; p ¼ 0.052) andproportion of those with a history of smoking(57% DUS-treated vs. 36% PCI-only; p ¼ 0.076).

C D

wing high mechanical index (HMI) impulses, as well as at (C) 4 and (D)

) and 3 (bottom), microvascular replenishment occurred at 4 s (C, top)

the patient with a score of 3 (D, bottom).

TABLE 2 Pre- and Post-PCI Characteristics in STEMI Patients

SBP Pre(mm Hg)

SBP Post(mm Hg)

Heart Rate Pre(beats/min)

Heart Rate Post(beats/min)

O2 Saturation Pre(%)

O2 Saturation Post(%)

Short pulse: HMI þ PCI(n ¼ 10)

141 � 27 131 � 23 81 � 15 83 � 12 96 � 3 96 � 3

Long pulse: HMI þ PCI(n ¼ 10)

142 � 35 129 � 19 80 � 15 85 � 10 96 � 1 95 � 4

LMI þ PCI(n ¼ 10)

135 � 19 123 � 31 83 � 15 83 � 11 96 � 2 95 � 2

PCI-only(n ¼ 70)

137 � 27 125 � 17* 77 � 15 78 � 19 97 � 2 96 � 2

Values are mean � SD. *p < 0.05 between pre- and post-PCI.

SBP ¼ systolic blood pressure; STEMI ¼ ST-segment elevation myocardial infarction; other abbreviations as in Table 1.

Mathias, Jr., et al. J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6

Ultrasound Therapy in Acute STEMI M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5

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There were no differences in the prevalence of dia-betes (30% DUS-treated vs. 29% PCI-only; p ¼ 1.000)or hyperlipidemia (37% DUS-treated vs. 27% PCI-only; p ¼ 0.35). There were no differences betweengroups in blood pressure, heart rate, or oxygen satu-ration before or after PCI (Table 2). Table 3 comparesdoor-to-dilation times, as well as culprit artery loca-tions, angiographic disease extent, and percentageof patients with collateral flow to the infarct vessel.Door-to-dilation times were not affected by theaddition of ultrasound treatment, which actuallytended to be longer in the PCI-only group (p ¼ 0.05)due to overnight and weekend arrival times.

The average period of DUS therapy time for theHMI þ PCI groups prior to PCI was 14 � 10 min (range4 to 44 min). Post-PCI ultrasound DUS treatmenttimes for the HMI þ PCI groups were all 30 min. Inthe 30 ultrasound-randomized patients, the infarct-related vessel was left anterior descending (LAD)/diagonal in 18 cases, right coronary artery in 8, andleft circumflex in 4. The LAD territory was the infarctvessel in 8 of 10 LMI þ PCI patients and 13 of 20 HMI þPCI patients. Infarct locations in the 70 PCI-onlypatients were 30 LAD, 26 right coronary artery, and14 left circumflex territories.

In the HMI þ PCI-treated patients, $20% ST-segment resolution was seen prior to PCI (after the

TABLE 3 Angiographic Variables and Troponin Levels in STEMI Patie

Group

Culprit Artery Atherosclerotic Burden

LAD(%)

LCX(%)

RCA(%)

1 Vessel(%)

2 Vessels(%)

3 Vesse(%)

Short pulse: HMI þ PCI 80 10 10 50 0 50

Long pulse: HMI þ PCI 60 40 0 60 20 20

LMI þ PCI 80 10 10 50 20 30

PCI-only 44 36 20 40 33 27

Values are % or mean � SD. *p < 0.05 between groups.

LAD ¼ left anterior descending coronary artery; LCX ¼ left circumflex coronary arother abbreviations as in Tables 1 and 2.

first ultrasound treatment) in 10 of 20 (50%) patients,but in only 1 in 10 patients randomized to LMI þ PCI(p ¼ 0.03). Following PCI and at hospital discharge,there were no differences in ST-segment resolutionbetween these groups.

TIMI flow grade 2 or 3 recanalization on theangiogram prior to PCI was seen in 12 of 20 HMI-treated patients, compared with 1 of 10 patients ran-domized to LMI and 16 of 70 patients undergoing PCIonly (p ¼ 0.002). A total of 8 of 10 patients (80%)treated with short-pulse diagnostic HMI impulses hadepicardial recanalization prior to PCI, compared with4 of 10 in the longer-pulse duration HMI-treated pa-tients (2 of 5 in the 5-ms pulse duration and 2 of 5 inthe 20-ms pulse duration groups). An example of LADrecanalization prior to PCI in an HMI þ PCI patient isshown in Figure 3.

Multivessel coronary artery disease (2 or moreepicardial vessels having >50% diameter stenoses)was present in 5 of 10 (50%) LMI þ PCI patients, 11 of20 (55%) HMI þ PCI-treated patients, and 41 of 70(59%) PCI-only treated patients (Table 3). After PCI,TIMI flow grade 2 or 3 in the culprit vessel was ach-ieved in 29 of 30 patients undergoing ultrasoundtreatments (1 LMI þ PCI patient had TIMI flow grade 1following PCI). TIMI flow grade 2 or 3 following PCIwas seen in 68 of the 70 patients receiving PCI only

nts

Patients WithCollaterals (%)

Door-to-DilationTime (min)

Percent WithPeak Troponin>50 ng/ml

Percent WithTIMI Flow Grade2–3 Flow Pre-PCI

ls

10 72 � 16 80 80*

40 76 � 31 80 40*

40 89 � 24 90 10*

24 101 � 42 83 23*

tery; RCA ¼ right coronary artery; TIMI ¼ Thrombolysis In Myocardial Infarction;

FIGURE 3 Sonothrombolysis

In this example of a patient with successful sonothrombolysis, changes in the 12-lead electrocardiogram (A and B) and microvascular

perfusion (C and D) are seen following pre–percutaneous coronary intervention treatment with guided high mechanical index (HMI)

impulses during an intravenous microsphere infusion. The green box in A and B indicates reduction in ST segments. Microvascular

replenishment improved in the left anterior descending (LAD) territory (C and D, arrow) after repeated diagnostic HMI impulses. In this

case, the LAD was open prior to emergent percutaneous coronary intervention (E); the residual stenosis was stented and the angiogram

was repeated (F).

J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6 Mathias, Jr., et al.M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5 Ultrasound Therapy in Acute STEMI

2511

(p > 0.10 between groups). At 1-month follow-up, 1patient died in the DUS-treated group and 1 patientdied in the PCI-only group.

CHANGES IN MICROVASCULAR PERFUSION. Theproportion of segments exhibiting MVO (score of 3)before ultrasound treatment was not different be-tween groups (33% of HMI þ PCI segments and 40% ofLMI þ PCI segments; p ¼ 0.11). After PCI, the pro-portion of segments still exhibiting MVO was signifi-cantly lower in the HMI þ PCI group compared to theLMI þ PCI group (21% vs. 31%; p ¼ 0.01). At 1 month,follow-up was possible in 28 of the 30 DUS-treatedpatients. The proportion still exhibiting MVOwas substantially lower in the HMI þ PCI group

(12% vs. 30%; p < 0.001). This translated into a sig-nificant difference in the change in MPSI over thistime period, with the HMI þ PCI group having thegreatest improvement (p ¼ 0.04) (Central Illustration).

Table 4 demonstrates wall motion and microvas-cular perfusion results for each of the different DUStherapeutic mechanical index settings. The diag-nostic HMI impulses had equivalent epicardialrecanalization rates to the 5- and 20-ms pulse durationimpulses and higher numbers of segments exhibitingmicrovascular recovery at 1 month.

CHANGES IN REGIONAL AND GLOBAL WALL

MOTION. WMSI improved significantly (p < 0.001compared with baseline WMSI) at 1 month in the

CENTRAL ILLUSTRATION Diagnostic Ultrasound Therapy in Acute STEMI

Mathias, Jr., W. et al. J Am Coll Cardiol. 2016;67(21):2506–15.

This study considered whether the addition of high mechanical index (HMI), compared with low mechanical index (LMI), impulses from a diagnostic ultrasound

transducer before and after emergent percutaneous coronary intervention (PCI) might restore epicardial and microvascular flow in acute ST-segment elevation

myocardial infarction (STEMI). At 1 month post-STEMI and PCI, the HMI þ PCI group experienced significantly greater improvement in the myocardial perfusion score

index (MPSI) (p < 0.05), as well as significant improvement in left ventricular ejection fraction (p < 0.005) and smaller proportions of microvascular obstructed

segments (p ¼ 0.001).

Mathias, Jr., et al. J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6

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HMI þ PCI group (Table 4). There was a smaller, butsignificant, improvement in the LMI þ PCI group overthis time period (p ¼ 0.03). LVEF increased(compared with pre-treatment values) only in theHMI þ PCI group (Table 4).

DISCUSSION

This is the first human study to demonstrate atherapeutic effect of DUS-guided cavitation of intra-venously administered, commercially available ul-trasound contrast agents during acute STEMI. Earlyepicardial recanalization rates were significantlyhigher with the intermittent brief application of

HMI impulses to the microcirculation through theapical windows. More importantly, these beneficialeffects were evident at the microvascular level, withimproved capillary flow already observed immedi-ately following PCI. The improvement in microvas-cular perfusion was even more demonstrable at1-month follow-up. Because microvascular perfusionfrequently remains abnormal following PCI alone inacute STEMI, adding emergency DUS before and afterPCI may be a vital supplement that will prevent MVOand its complications.

The HMI impulses used to improve epicardial andmicrovascular recanalization in the current study arepart of a standard feature on an ultrasound system

TABLE 4 Changes in LV Function and Myocardial Perfusion*

LVEF (%)Pre-Treatment

LVEF (%)1 Month

WMSIPre-Treatment

WMSI1 Month

MPSIPre-Treatment

MPSI1 Month

Percentage of SegmentsWith MVO Pre-PCI

Percentage of SegmentsWith MVO Post-PCI

HMI þ PCI 44 � 10 50 � 10† 1.90 � 0.31 1.69 � 0.39† 1.89 � 0.34 1.52 � 0.35†‡ 33 12‡

LMI þ PCI 38 � 8 42 � 12 2.09 � 0.25 1.83 � 0.47† 2.03 � 0.24 1.85 � 0.39 40 30

Values are mean � SD or %. *Change is seen between randomized ultrasound treatment and 1-month follow-up visit. †p < 0.05 compared with pre-treatment. ‡p < 0.005between HMI þ PCI and LMI þ PCI.

LVEF ¼ left ventricular ejection fraction; MPSI ¼ myocardial perfusion score index; MVO ¼ microvascular obstruction; WMSI ¼ wall motion score index; other abbreviationsas in Table 1.

J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6 Mathias, Jr., et al.M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5 Ultrasound Therapy in Acute STEMI

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that is normally used to assess myocardial perfusionand regional wall motion (20–22). These HMI im-pulses cause microbubbles to cavitate (grow andcollapse) during the period of insonation, which ul-timately disrupts them (15). This growth and collapsecauses shear stress in regions near the microbubble,which, in the case of a thrombus, results in dissolu-tion (12). In 10 of 20 patients treated with HMI pulses,we were able to prolong the pulse duration to slightlylonger intervals (5 and 20 ms) than those used fordiagnostic imaging (3 ms), which should prolongthe duration of shear induced by microbubble cavi-tation. These longer pulse durations have been shownto be more effective than shorter ones in dissolvingin vitro thrombi (23); indeed, others have shown thatlonger pulse durations were required for in vitrothrombus dissolution in microvascular models ofthrombosis (24,25). These slightly longer pulse dura-tions were also effective in improving epicardialrecanalization rates in larger animal studies ofcontrolled infarctions (15).

Despite these findings in animals, we found thatthe frequent transthoracic application of shorter-pulse duration HMI impulses routinely used withmyocardial perfusion imaging were just as effectiveas longer-pulse duration impulses in restoringepicardial and microvascular flow. Although largerstudies are needed to confirm this, these findingswould imply that current diagnostic systems usingthe standard short-pulse duration HMI impulsesshould be capable of achieving this thrombus-dissolving effect without software modifications. Itwould also appear that longer pulse durations thanthose used for diagnostic imaging may not be neces-sary to improve microvascular recovery in STEMI,which may improve the safety profile of this appli-cation and reduce the possibility of unwanted bio-effects related to prolonged microbubble cavitation(26,27).

The reason for the acute microvascular benefits inthe HMI þ PCI group may be multifactorial. Although

a significant part of this may be related to mechanicalthrombus dissolution at the microvascular level,other ultrasound-induced bioeffects may be playing arole as well. It is possible that the HMI impulses,when applied to the heart, elicit NO release that im-proves microvascular perfusion and augmentsthe thrombus-dissolving effects of cavitation. In ani-mal models of epicardial vessel ligation, directlyapplied low-frequency ultrasound has improveddownstream perfusion. This effect was reversed fol-lowing NO synthase inhibitor use (28). HMI DUS im-pulses, applied during an intravenous microbubbleinfusion, have been shown to improve microvascularflow in ischemic hind limbs following upstream largevessel ligation (16). This phenomenon was shown tobe mediated in part by NO release. We have observedbeneficial microvascular effects of short-pulse dura-tion (<5 ms) DUS in animal models of acute STEMIwithout epicardial recanalization (12), which resultedin improvements in wall thickening within the riskarea. These findings all suggest that part of thebeneficial effects we observed at the microvascularlevel may be related to factors other than thrombusdissolution.

Another purpose of this initial study was todemonstrate safety of DUS in this setting. Weanalyzed whether any potential harm would occurusing DUS-induced cavitation impulses in the earlysetting of an acute STEMI, and we observed no clin-ically relevant differences of any measured hemo-dynamic parameter (Table 2). Also, we sought todetermine whether the addition of an emergency-response ultrasound team applying the impulseswould interfere with standard of care, which isbest assessed by door-to-dilation time. We sawno differences in this critical quality parameterwhen compared with a reference group that hadno ultrasound interventions at the time of presenta-tion (PCI-only). This is particularly encouraging inthat a larger commercial system was used forthis study, which could be improved further with

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: In

patients with acute STEMI undergoing primary PCI,

ultrasonic impulses from a diagnostic transthoracic

transducer with an HMI, when applied concurrently

with intravenous microbubble infusion, increase

microvascular myocardial perfusion.

TRANSLATIONAL OUTLOOK: Large-scale clinical

trials are needed to assess whether HMI ultrasound

impulses can be employed therapeutically to improve

ventricular function and clinical outcomes in patients

with acute STEMI undergoing PCI.

Mathias, Jr., et al. J A C C V O L . 6 7 , N O . 2 1 , 2 0 1 6

Ultrasound Therapy in Acute STEMI M A Y 3 1 , 2 0 1 6 : 2 5 0 6 – 1 5

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more portable systems allowing better access to pa-tients even in ambulances. One limitation of thecomparative group was it included patients arrivingovernight and on weekends, which may have pro-longed their door-to-dilation times and explain whythere was a wide variation in door-to-dilation times(Table 3).

STUDY LIMITATIONS. Due to financial restrictions,we could not obtain 1-month follow-up contrastechocardiographic data on the PCI-only patients. Theobjective of this initial investigation was to determinewhat effect intermittent HMI impulses would have onejection fraction and microvascular recovery whencompared with LMI imaging only. Unless one as-sumes the brief duration of LMI imaging aloneto assess regional wall motion and microvascularperfusion was adversely affecting microvascularrecovery, there would be no expectation that micro-vascular recovery in the 70 patients treated with PCIonly would be different than the LMI þ PCI group(Central Illustration, Table 4).

CLINICAL IMPLICATIONS. Early treatment with HMIdiagnostic impulses resulted in an improvement inejection fraction and wall motion scores at 1-monthfollow-up. This improvement may be related tothe long-term effects of restoring microvascularflow early in the treatment period. Persistent micro-vascular flow abnormalities at hospital discharge,whether observed by magnetic resonance imaging orcontrast echocardiography, have been associatedwith increased morbidity and mortality followingSTEMI (5–8). By acutely improving microvascular flowin acute STEMI, DUS also may play a critical supple-mental role in preventing the remodeling that leadsto further reductions in ejection fraction andincreased risk for arrhythmic and heart failurecomplications (29). Our initial study was too smallto examine these differences, but larger trials arewarranted to study whether this improvement inmicrovascular outcome with DUS translates intoreduced morbidity and mortality at longer-termfollow-up.

CONCLUSIONS

Intermittent diagnostic HMI transthoracic impulses,administered during an intravenous commerciallyavailable ultrasound contrast agent infusion, cansafely improve early epicardial patency rates and re-covery of microvascular function when utilized in theemergent contemporary management of patients withacute STEMI.

ACKNOWLEDGMENTS The authors thank Carol Gouldfor her assistance in manuscript preparation, NadiaLuana de Melo Batista and Erica Prado Viana for theircoordination of all studies and assistance with datacollection, Pat Rafter at Philips Healthcare for hisassistance with software modifications on the scannerused in this study, Dr. Evan Unger from MicrovascularTherapeutics for support with microbubble importa-tion, and The Theodore F. Hubbard and FAPESPFoundations for providing research coordinatorsupport and financial sponsorship for this study.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Wilson Mathias, Jr., Heart Institute (InCor), TheUniversity of São Paulo, Avenida Doutor Enéas deCarvalho Aguiar, 44, Cerqueira Cesar, São Paulo, SP05403-000, Brazil. E-mail: wmathias@incor.usp.br.

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KEY WORDS acute myocardial infarction,microvascular obstruction, ultrasoundtherapy