Rationale and design of the AngeLmed for Early Recognition and Treatment of STEMI trial: a randomized, prospective clinical investigation.

Significant improvements in door-to-balloon times have led to a reduction in mortality in ST-segment elevation myocardial infarction; however, mean symptom-to-door times remain at 2 to 3 hours. An intracardiac electrogram monitoring device may be beneficial in high-risk patients by alerting them to rapidly progressive ST-segment changes indicative of acute coronary occlusion. The Cardiosaver and DETECT phase I clinical studies demonstrated the safety, feasibility, and potential benefit of using an intracardiac electrogram monitoring device to alert the patient to seek medical attention. The goal of the randomized, prospective ALERTS Trial (Clinicaltrials.gov no. NCT00781118) is to evaluate the efficacy of an implantable monitoring device (IMD) in reducing the composite of either cardiac or unexplained death, new Q-wave myocardial infarction, or symptom-to-door time of >2 hours for confirmed thrombotic events. The IMD alerts the patient in real time when ST-segment deviation from a personalized baseline exceeds the trigger threshold. The trial is designed to enroll high-risk post-acute coronary syndrome patients or patients with previous multivessel coronary artery bypass surgery. All patients have the IMD implanted, with 1:1 unblinded randomization to the alerting feature being either turned on versus turned off for the first 6 months. Randomization occurs at the first follow-up visit, 7 to 14 days after the implantation of the IMD. Subjects then return for follow-up visits at months 1, 3, and 6 and thereafter every 6 months until closure of the investigational device exemption. Subjects who cannot be implanted successfully or who have the device explanted are removed from the study and followed up for a minimum of 30 days post-procedure. If a subject experiences a device-related complication and/or adverse experience, the subject is followed up until resolution or until the condition becomes stable and no further change is anticipated.

The Guardian: an implantable system for chronic ambulatory monitoring of acute myocardial infarction.

The AngelMed Guardian is an implantable medical device that records cardiac data and detects ischemic events using a standard pacemaker intracardiac lead positioned in the right ventricular apex. The Guardian has been implanted in 55 people in the United States and Brazil and is currently undergoing a Food and Drug Administration phase 2 pivotal trial in the United States. The Guardian detects acute ischemic events by analyzing ST-segment shifts. The ST-segment shifts are calculated as the difference between the ST deviation of a current 10-second electrogram window and a baseline ST deviation value. If the ST-segment shift is greater than a heart rate-dependent programmable threshold, then the device generates an emergency alert signal. Results thus far have demonstrated that (i) the intracardiac electrogram is relatively noise-free and (ii) the ST-shift technique used by the Guardian is effective for detecting acute ischemic events.

Implanted Monitor Alerting to Reduce Treatment Delay in Patients With Acute Coronary Syndrome Events.

BACKGROUND: Increased pre-hospital delay during acute coronary syndrome (ACS) events contributes to worse outcome. OBJECTIVES: The purpose of this study was to assess the effectiveness of an implanted cardiac monitor with real-time alarms for abnormal ST-segment shifts to reduce pre-hospital delay during ACS events. METHODS: In the ALERTS (AngeLmed Early Recognition and Treatment of STEMI) pivotal study, subjects at high risk for recurrent ACS events (n = 907) were randomized to control (Alarms OFF) or treatment groups for 6 months, after which alarms were activated in all subjects (Alarms ON). Emergency department (ED) visits with standard-of-care cardiac test results were independently adjudicated as true- or false-positive ACS events. Alarm-to-door (A2D) and symptom-to-door (S2D) times were calculated for true-positive ACS ED visits triggered by 3 possible prompts: alarm only, alarms + symptoms, or symptoms only. RESULTS: The Alarms ON group showed reduced delays, with 55% (95% confidence interval [CI]: 46% to 63%) of ED visits for ACS events <2 h compared with 10% (95% CI: 2% to 27%) in the Alarms OFF group (p < 0.0001). Results were similar when restricted to myocardial infarction (MI) events. Median pre-hospital delay for MI was 12.7 h for Alarms OFF and 1.6 h in Alarms ON subjects (p < 0.0089). Median A2D delay was 1.4 h for asymptomatic MI. Median S2D delay for symptoms-only MI (no alarm) in Alarms ON was 4.3 h. CONCLUSIONS: Intracardiac monitoring with real-time alarms for ST-segment shift that exceeds a subject's self-normative ischemia threshold level significantly reduced the proportion of pre-hospital delays >2 h for ACS events, including asymptomatic MI, compared with symptoms-only ED visits in Alarms OFF. (AngeLmed for Early Recognition and Treatment of STEMI [ALERTS]; NCT00781118).

Potential of an intracardiac electrogram for the rapid detection of coronary artery occlusion.

BACKGROUND: Early identification of acute MI and prompt intervention can improve clinical outcomes. It would be valuable to identify a method that could allow the earliest possible detection of myocardial injury or ischemia. METHODS AND RESULTS: This article reports one of the first clinical investigations to examine the ability of an intracardiac right ventricular (RV) electrode to identify the early onset of myocardial ischemia/injury in a cohort of patients undergoing balloon occlusion of a coronary artery during percutaneous transluminal coronary angioplasty. The primary data set for analysis included observations from 14 patients with 17 lesions, with a matched comparison of a V6 surface lead and the RV to left upper chest, "intracardiac" lead. The intracardiac lead was sensitive in detecting myocardial injury current/ischemia. There was a 36.4+/-5.6% ST-segment shift, relative to the amplitude of the QRS complex, in the intracardiac lead at 2 min, compared with a 10.1+/-1.9% ST shift from a surface lead (P=.00011). The RV to left upper chest lead detected a >10% shift in ST segment within 2 min in 17 (100%) of 17 cases vs. 8 (47%) of 17 for a V6 surface lead. The intracardiac lead provided detection of ischemia in all three major epicardial coronary distributions. CONCLUSIONS: This study demonstrates the ability of an intracardiac (RV apex to left upper chest) lead to rapidly detect myocardial ischemia/injury during acute coronary occlusion in the setting of balloon angioplasty. The results of this study suggest that a simple implantable system resembling a ventricular pacemaker could be programmed to assist in the very early diagnosis of acute myocardial infarction.

Next generation renal denervation: chemical "perivascular" renal denervation with alcohol using a novel drug infusion catheter.

BACKGROUND/PURPOSE: We update the pre-clinical and early clinical results using a novel endovascular approach, to perform chemical renal denervation, via peri-adventitial injection of micro-doses of dehydrated alcohol (ethanol-EtOH). METHODS/MATERIALS: A novel, three-needle delivery device (Peregrine™) was used to denervate the renal arteries of adult swine (n = 17) and in a first-in-man feasibility study (n = 18). In the pre-clinical testing EtOH was infused bilaterally with one infusion per renal artery into to the perivascular space, using EtOH doses of 0.3 ml/artery (n = 8), and 0.6 ml/artery (n = 9), and with saline sham control (0.4 ml/artery n = 3). Renal parenchymal norepinephrine (NE) concentration (performed blindly), and safety were the primary endpoints. Data from the first-in-man study (n = 18) to evaluate device performance, safety and peri-procedural pain are reported. RESULTS: In the pre-clinical testing renal function was unchanged at 3-month follow-up. Angiography at 90 days (n = 34 arteries) demonstrated normal appearing renal arteries, unchanged from baseline, and without stenosis or other abnormalities. The reductions in mean renal parenchymal NE reductions at 3 months were 68% and 88% at doses of 0.3 and 0.6 ml, respectively (p < 0.001 vs. controls). In the first-in-man study, there was 100% device success, no complications, a mean treatment time of 4.3 ± 3 minutes/artery, and minimal or no patient discomfort during treatment. Angiography at 6-months showed no evidence of renal artery stenosis, and evidence of a reduction of blood pressure from baseline. CONCLUSION: Perivascular RDN using micro-doses of alcohol is a promising alternative to energy-based systems to achieve dose-dependent, predictable, safe and essentially painless renal denervation. Further clinical evaluation is warranted. SUMMARY: (For annotated table of contents) This paper describes the preclinical results, in a porcine model, and the early first-in-man results, using the Peregrine™ chemical renal denervation catheter to perform renal sympathetic denervation using micro-doses of alcohol.

Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model.

AIMS: We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation. METHODS AND RESULTS: A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8). CONCLUSIONS: Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted.

Initial clinical results using intracardiac electrogram monitoring to detect and alert patients during coronary plaque rupture and ischemia.

OBJECTIVES: We report the first clinical studies of intracardiac ST-segment monitoring in ambulatory humans to alert them to significant ST-segment shifts associated with thrombotic occlusion. BACKGROUND: Despite improvements in door-to-balloon times, delays in symptom-to-door times of 2 to 3 h remain. Early alerting of the presence of acute myocardial infarction could prompt patients to seek immediate medical evaluation. METHODS: Intracardiac monitoring was performed in 37 patients at high risk for acute coronary syndromes. The implanted monitor continuously evaluated the patients' ST segments sensed from a conventional pacemaker right ventricle apical lead, and alerted patients to detected ischemic events. RESULTS: During follow-up (median 1.52 years, range 126 to 974 days), 4 patients had ST-segment changes of ≥3 SDs of their normal daily range, in the absence of an elevated heart rate. This in combination with immediate hospital monitoring led to angiogram and/or intravascular ultrasonography, which confirmed thrombotic coronary occlusion/ruptured plaque. The median alarm-to-door time was 19.5 min (6, 18, 21, and 60 min, respectively). Alerting for demand-related ischemia at elevated heart rates, reflective of flow-limiting coronary obstructions, occurred in 4 patients. There were 2 false-positive ischemia alarms related to arrhythmias, and 1 alarm due to a programming error that did not prompt cardiac catheterization. CONCLUSIONS: Shifts exceeding 3 SD from a patient's daily intracardiac ST-segment range may be a sensitive/specific marker for thrombotic coronary occlusion. Patient alerting was associated with a median alert-to-door time of 19.5 min for patients at high risk of recurrent coronary syndromes who typically present with 2- to 3-h delays.

Real-time detection and alerting for acute ST-segment elevation myocardial ischemia using an implantable, high-fidelity, intracardiac electrogram monitoring system with long-range telemetry in an ambulatory porcine model.

OBJECTIVES: The purpose of this study was to evaluate feasibility of using real-time, high-fidelity, intracardiac electrogram monitoring from a permanently implantable ischemia detection system (IIDS), with long-range telemetry capability to detect ST-segment shifts associated with acute or subacute coronary occlusion in a porcine model. BACKGROUND: Early identification of coronary occlusion with ST-segment elevation could profoundly accelerate the timing of revascularization and improve clinical outcomes. METHODS: This paper reports the first investigation using real-time, high-fidelity, intracardiac electrogram monitoring from a permanently IIDS, with long-range telemetry capability. This IIDS was tested in an ambulatory porcine model, with acute coronary occlusion precipitated by stent thrombosis. Two overlapping copper stents were implanted in the left anterior descending (n = 3), the circumflex (n = 3), or the right coronary artery (n = 2) of juvenile farm pigs. Monitoring was carried using telemetry from the IIDS. RESULTS: All stented pigs had acute ST-segment elevation event(s) triggering the alerting thresholds of the IIDS. All triggered events were confirmed to be caused by thrombosis of the copper stent(s), and well correlated to infarct age and location. Four of the 8 pigs died from ventricular fibrillation, recorded by the IIDS at a mean time of 70 +/- 121 h after ST-segment alert. The sensitivity and specificity of alerting for ST-segment shift, associated with thrombotic coronary occlusion, were 100% and 100%, respectively. CONCLUSIONS: This study demonstrates the ability of an implantable ischemia detection system to detect ST-segment elevation from coronary occlusion in a porcine model of ST-segment elevation myocardial infarction. ST-segment elevation was sufficient to trigger alerting thresholds in all 3 epicardial coronary distributions. Such a system, with real-time alerting capability, could advance the time frame of reperfusion therapy and potentially prevent, rather than interrupt, acute myocardial infarction in patients with coronary artery disease.