Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

Clinical factors and echocardiographic techniques related to the presence, size, and location of acoustic windows for leadless cardiac pacing.

AIMS: Temporary leadless cardiac pacing using ultrasound energy is feasible in patients. An implantable left ventricular stimulation system being developed for cardiac resynchronization therapy transfers energy from a subcutaneous transmitter to an endocardial receiver through tissue free of interfering lung or rib ('acoustic window'). The aim was to use transthoracic echocardiography to evaluate acoustic window (AW) locations and sizes to determine the implant site for a transmitter, and to investigate clinical predictors of AW location and size. METHODS AND RESULTS: Inclusion criteria were ejection fraction ≤35%, and New York Heart Association functional class III or IV. Acoustic windows were evaluated in intercostal spaces (ICSs) measured in the supine, right lateral, sitting, and standing position during normal respiration and held inspiration. Among 42 patients, at least one adequate AW (≥2 cm(2)) was identified in 41, 19 patients had adequate AWs in 2 ICSs and 20 patients had adequate AWs in 3. Acoustic window areas were generally smallest in the lateral position with held inspiration and largest in the standing position with normal respiration. Patients with ischaemic cardiomyopathy compared with non-ischaemic cardiomyopathy had smaller heart size [left ventricular end-systolic volume index (LVESVI) 78 ± 38 mL/m(2) vs. 104 ± 46 mL/m(2), P = 0.03] but larger AWs in the right lateral position (11.4 ± 6.5 cm(2) vs. 7.3 ± 3.4 cm(2), P = 0.01) and standing position (14.0 ± 7.2 cm(2) vs. 9.4 ± 3.3 cm(2), P = 0.02). CONCLUSIONS: Adequate AWs were present in nearly all patients. Despite smaller hearts, ischaemic cardiomyopathy patients had adequate AWs. A simple procedure performed as an adjunct to pre-implant echocardiography can screen patients and identify transmitter implant locations for an ultrasound-mediated leadless pacing system.

Use of Flecainide for the Treatment of Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with substantial morbidity and impairment of quality of life. Restoration and maintenance of normal sinus rhythm is a desirable goal for many patients with AF; however, this strategy is limited by the relatively small number of antiarrhythmic drugs (AADs) available for AF rhythm control. Although it is recommended in current medical guidelines as first-line therapy for patients without structural heart disease, the use of flecainide has been curtailed since the completion of the Cardiac Arrhythmia Suppression Trial. In clinical trials and real-world use, flecainide has proven to be more effective than other AADs for the acute termination of recent onset AF. Flecainide is also moderately effective and, with the exception of amiodarone, equivalent to other AADs for the chronic suppression of paroxysmal and persistent AF. In patients without structural heart disease, flecainide has been demonstrated to be safe and well tolerated relative to other AADs. Despite this favorable profile, flecainide is underutilized, likely due to a perceived risk of ventricular proarrhythmia, a concern that has not been borne out in patients without underlying structural heart disease. Guidelines for administration and use of flecainide are summarized in this review.

Designation and distribution of events in the Multicenter UnSustained Tachycardia Trial (MUSTT).

Patients with coronary artery disease, depressed left ventricular ejection fraction, and nonsustained ventricular tachycardia (VT) have a high mortality rate due to arrhythmic (arrhythmic death/cardiac arrest) and other cardiac causes. The Multicenter UnSustained Tachycardia Trial (MUSTT) investigated whether electrophysiologic study (EPS) was helpful in choosing drug or defibrillator therapy in patients induced into sustained VT. The events committee attempted to categorize follow-up events in patients in MUSTT and to present a detailed breakdown of events. A derivative of the Hinkle-Thaler classification was used, incorporating lessons from other multicenter studies. The committee was blinded to results of EPS and implantable cardioverter-defibrillator (ICD) or other antiarrhythmic therapy status of patients. The primary end point was cardiac arrest or death from arrhythmia. Secondary end points were death from all causes, cardiac causes, and spontaneous sustained VT. Classifications were death and cardiac arrest. Each was similarly divided as arrhythmic with 14 subcategories, e.g., unwitnessed or related to EPS and nonarrhythmic with 10 subcategories, e.g., ischemia. Terminal VF in progressive heart failure was considered nonarrhythmic. Events were reviewed by 2 members. Disagreements were resolved by the 2 members or, if needed, by the full committee. Of the 2,202 patients in MUSTT, there were 902 deaths. Sustained VT requiring cardioversion occurred in 182 patients. An additional 94 patients had resuscitated cardiac arrests. Events occurred in 1,027 patients, and all were reviewed. The 3 leading events were deaths that were classed as sudden/unwitnessed (23% of 902), due to progressive heart failure (22%), or due to noncardiovascular causes (18%). Arrhythmic deaths or cardiac arrests were highest in inducible patients randomized to no antiarrhythmic therapy; next were inducible patients receiving an ICD; and lowest were in patients who were noninducible. In conclusion, the classification system provided a detailed breakdown of events in consistent categories, showing utility for event analysis and interpretation and development of therapeutic strategies. The classifications assigned by the committee were used in all MUSTT outcomes reports, thus affecting all reported outcomes and overall interpretations of the MUSTT.

Feasibility and safety of a novel technology for pacing without leads.

BACKGROUND: Pacemaker lead complications and failures remain clinical problems. New devices incorporating three leads are associated with even greater limitations. OBJECTIVES: The purpose of this study was to investigate the feasibility and safety of a technology enabling cardiac pacing without leads in an acute porcine model. METHODS: The system is composed of an ultrasound transmitter delivering energy from the chest wall to a receiver-electrode in contact with the myocardium that then converts the ultrasound energy to electrical energy sufficient to pace. In five feasibility studies, the receiver-electrodes were attached to the tip of a catheter to facilitate intracardiac positioning at pacing sites. In six safety studies (five treatment and one sham), ultrasound energy was transmitted to both chest walls, and histopathologic examinations were performed to evaluate bioeffects due to ultrasound energy transmission. RESULTS: In five feasibility studies, direct and ultrasound-mediated electrical pacing was demonstrated at 30 sites in the right atrium, right ventricle, and left ventricle, at direct electrical pacing outputs of 1.4 +/- 0.6 V and ultrasound-mediated electrical pacing outputs of 1.8 +/- 0.9 V. The mechanical index was 0.6 +/- 0.4 at the receiver site during ultrasound-mediated pacing at a depth of 11.2 +/- 2.4 cm from the chest wall. Using two receiver-electrode catheters, biventricular pacing was demonstrated in all studies. In five safety study treatment animals at a similar depth, the peak mechanical index was 2.3, and the thermal index was 0.4. Microscopic evaluation revealed no evidence of mechanical or thermal bioeffects. CONCLUSION: The feasibility and safety of this novel technology for pacing without leads has been demonstrated acutely in animals.

Ultrasound energy improves myocardial perfusion in the presence of coronary occlusion.

OBJECTIVES: We evaluated whether ultrasound improves myocardial tissue perfusion in 14 animals with coronary artery occlusion. BACKGROUND: A recent study demonstrated that low-frequency ultrasound improves tissue perfusion in the rabbit ischemic limb, but there are no data on ultrasound enhancement of myocardial perfusion. METHODS: Fourteen animals (9 dogs, 5 pigs) underwent thoracotomy and occlusion of a diagonal branch of the left anterior descending coronary artery. Myocardial tissue perfusion units (TPUs) and pH were measured before coronary occlusion, after occlusion, and after direct exposure of the ischemic myocardium in the presence of fixed occlusion to low-frequency ultrasound (27 kHz). RESULTS: The TPU decreased from 100.9 +/- 13 at baseline to 71.1 +/- 13 (p < 0.01) after 60 min occlusion but rose by 19.7% to 85.1 +/- 8 (p < 0.01) after ultrasound exposure for 60 min. After 60-min coronary occlusion, myocardial pH fell from 7.43 +/- 14 to 7.05 +/- 0.15 (p < 0.01) but then improved to normal (7.46 +/- 0.32) after ultrasound for 60 min. Administration of L-Nomega-nitro-arginine methyl esther (L-NAME), an inhibitor of nitric oxide synthase, before ultrasound exposure, blocked improvement in myocardial tissue perfusion and pH by ultrasound. Quantitative histomorphology showed a significant increase in the capillary area of myocardium exposed to ultrasound versus non-exposed myocardium (16.2 +/- 7.9 vs. 8.2 +/- 2.1, p < 0.02). CONCLUSIONS: Low-frequency, low-intensity ultrasound improves myocardial tissue perfusion and pH in the presence of a fixed coronary artery occlusion.

Coronary vasodilation by noninvasive transcutaneous ultrasound: an in vivo canine study.

OBJECTIVES: We evaluated the coronary vasodilatory effects of transcutaneous low-frequency (27-kHz) ultrasound (USD). BACKGROUND: Ultrasound has been shown to affect vascular function. METHODS: Ultrasound energy was administered transcutaneously to 12 dogs. Coronary arterial dimensions were assessed using intravascular coronary ultrasound (IVUS) and quantitative coronary angiography (QCA). RESULTS: The IVUS mid-left anterior descending (LAD) luminal area was 6.77 +/- 1.27 mm(2) at baseline. After 30 s of ultrasound, this area increased by 9% (7.40 +/- 1.44 mm(2), p < 0.05), after 3 min by 19% (8.05 +/- 1.72 mm(2), p < 0.05) and after 5 min increased by 21% (8.16 +/- 1.29 mm(2), p < 0.05). The mean coronary diameter (2.69 +/- 0.33 mm) at baseline (QCA of three segments of LAD and three segments of left circumflex coronary artery) increased by 19.3% (3.21 +/- 0.28 mm) after 5 min of USD exposure. After a 90-min observation period there was a return to baseline values (p = NS). Intracoronary nitroglycerin (NTG) administered to five dogs revealed a similar magnitude of vasodilation as USD. CONCLUSIONS: Noninvasive, transthoracic low-frequency USD energy results in coronary artery vasodilation within seconds of exposure. The vasodilation is reversible and is similar in magnitude to that induced by NTG. Further evaluation is needed to assess its potential applications in humans.

Transcutaneous ultrasound-facilitated coronary thrombolysis during acute myocardial infarction.

In preclinical experiments, the combination of transcutaneous, low-frequency ultrasound and thrombolytic therapy has shown improved patency rates over thrombolytics alone. A total of 25 patients with myocardial infarction were treated with a thrombolytic agent and adjunctive transcutaneous ultrasound. No unanticipated major adverse events were observed.

Adjunctive transcutaneous ultrasound with thrombolysis: results of the PLUS (Perfusion by ThromboLytic and UltraSound) trial.

OBJECTIVES: We investigated whether transcutaneous ultrasound (TUS) augments coronary thrombolysis and achieves higher rates of Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 and ST-segment resolution in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: In animal coronary and peripheral artery thrombosis models, low-frequency TUS enhances and accelerates thrombolysis. METHODS: In a double-blind, randomized, controlled international clinical trial, 396 patients with STEMI < or =6 h were randomized to thrombolysis alone or thrombolysis plus TUS. The 60 minute TIMI flow grade, ST-segment resolution (primary end points) and other angiographic, electrocardiographic, and clinical outcomes were compared between treatment groups. RESULTS: The trial was halted after Safety and Efficacy Monitoring Committee interim analysis that demonstrated lack of treatment efficacy. In total, 360 patients were evaluable for angiographic, electrocardiographic, or clinical end points. Sixty minutes after thrombolytic administration, the proportion of patients achieving TIMI flow grade 3 did not differ between TUS and control groups (40.7% vs. 48.5%, respectively; p = 0.10). Achievement of >50% ST-segment resolution at 60 min did not differ between TUS and control groups (53.2% vs. 50.0%; p = 0.93). Thirty-day mortality and composite clinical events-death, reinfarction, recurrent ischemia, stroke, major bleed, left ventricular rupture (9.7 % vs. 10.2%; p = 0.88)-did not differ between TUS and control patients. CONCLUSIONS: Thrombolysis plus TUS failed to improve 60-min TIMI flow grade or ST-segment resolution versus thrombolysis alone.

Temporary leadless pacing in heart failure patients with ultrasound-mediated stimulation energy and effects on the acoustic window.

BACKGROUND: Left ventricular stimulation for cardiac resynchronization therapy is largely limited by access and anatomy of coronary veins. OBJECTIVE: This study sought to apply ultrasound-mediated leadless pacing technology in heart failure patients and to evaluate the effects of respiration and body posture on the acoustic window. METHODS: Patients with advanced heart failure and ejection fraction

First human demonstration of cardiac stimulation with transcutaneous ultrasound energy delivery: implications for wireless pacing with implantable devices.

OBJECTIVES: The purpose of this study was to evaluate the feasibility and safety of a novel technology that uses energy transfer from an ultrasound transmitter to achieve cardiac stimulation without the use of a pacing lead in humans. BACKGROUND: To overcome the limitations of pacemaker leads, a new technology enabling stimulation without the use of a lead is desirable. METHODS: A steerable bipolar electrophysiology catheter incorporating a receiver electrode into the tip and circuitry to convert ultrasound energy to electrical energy was inserted transvenously into the heart. An ultrasound transmitting transducer was placed on the chest wall with ultrasound gel. Ultrasound energy was amplitude-adjusted and transmitted at 313 to 385 kHz. The output waveform of the receiver electrode was monitored while the transmitter was moved on the chest wall to target the receiver. The ultrasound transmission amplitude was limited to a mechanical index of 1.9, the maximum allowed for ultrasound imaging systems. Ultrasound-mediated pacing with minimum voltage but consistent capture was obtained for 12 s. RESULTS: Twenty-four patients (48 +/- 12 years) were tested during or after completion of clinical electrophysiology procedures. A total of 80 pacing sites were tested (mean 3.3 sites/patient): 12 right atrial, 35 right ventricular, and 33 left ventricular (31 endocardial) sites. The transmit-to-receive distance was 11.3 +/- 3.2 cm (range 5.3 to 22.5 cm). Ultrasound-mediated pacing was achieved at all 80 test sites, with consistent capture at 77 sites. The mechanical index during pacing was 0.5 +/- 0.3 (range 0.1 to 1.5). The mean ultrasound-mediated capture threshold was 1.01 +/- 0.64 V. There was no adverse event related to ultrasound pacing. No patient experienced discomfort during pacing. CONCLUSIONS: The feasibility and safety of pacing usng ultrasound energy has been shown acutely.