Mini Micronan Cardiology’s ‘Fantastic Journey’ to Miniaturization
Miniaturization continues to recalibrate medicine. For example, itty bitty implants are being used to diagnose, monitor, and treat various cardiovascular conditions. It’s not just shtick: miniaturization has already shown real benefit for patients, with much more to come.
Designing and building ever-smaller medical implants is hardly a new idea; patients are already profiting in big ways. In a recent JACC Interventions State-of-the-Art Paper of same-day discharge after percutaneous coronary intervention (PCI), the authors note that over the past decade, continuous refinements of PCI procedures, including the miniaturization of interventional equipment, have substantially increased success rates, improved short- and long-term safety, and reduced post-procedural length of stay.1
Back in 2009, Bloomberg Business predicted that the miniaturization of medical equipment would be one of the 20 most important inventions of the next 10 years. Six years on from this prediction and miniaturization remains on track as an area of highly productive innovation. New products are racing through development and coming to market almost daily.
Piggy-Backing on Consumer Electronics
In this day of ultra-convenient portable consumer electronics that do pretty much everything, practitioners expect similar convenience and functionality from their medical devices. Also, the push for shorter hospital stays has increased the need for upgraded portable diagnostic and monitoring equipment that can follow the patient into recovery and, in some cases, after discharge. Furthermore, with minimally invasive devices comes greater possibility for minimally invasive surgeries, with shorter hospital stays, easier recovery, and fewer complications.
Thankfully, the technologies developed from other industries have laid the foundation for the evolution of miniaturization within the medical device market. Cell phones and laptops use high-performing chip technologies that offer more functions and greater processing capacity, all at half the size of even a few years ago. Add in sensors that are nearly microscopic, wireless connectivity, and high amounts of data storage capacity, and the possibilities are nearly endless.
Not that miniaturization hasn’t been a goal in the field of implantable devices since their advent, but the technologies and advances we’re seeing today are exciting and real, both in cardiology and well beyond through the wider medical world.
Make it Smaller and Better
Some of the earliest adopters of miniaturization included pacemaker manufacturers. They used semiconductor technology to combine both analog and digital signals into a single-chip pacemaker, contributing to reductions in size and weight while improving patient comfort and functionality. Hard to believe that a design that was the size of a microwave oven in 1951 evolved into a device about the size of a standard Oreo® cookie. (We say ‘standard’ because even Oreo® cookies today have a “mini” version.)
Since a large proportion of the acute and chronic problems associated with pacemakers are related to either the pacing leads or the pacemaker pocket, newer devices are trying to get rid of both.
In April, Medtronic announced it had received a CE Mark for its Micra® Transcatheter Pacing System (TPS). The Micra compares in size to a large vitamin (think, horse pill) and has no leads; instead, after being fed through the femoral vein, it sits inside the right ventricle, attached to the heart via small tines. Able to pace a single chamber only, the device does so through an electrode protruding from one end rather than leads. It has a 10-year estimated battery life. However, not everything is mini today; certainly not the 27F catheter delivery from the groin that’s used to place the Micra. Yet, based on soon-to-be-published data (Ritter P et al. in the European Heart Journal),2 the approach is safe, with just one pericardial effusion (without tamponade) occurring after 18 device deployments.
At the June 2015 European Heart Rhythm Association EUROPACE-CARDIOSTIM meeting, early safety and performance data on the Micra TPS showed that the device was implanted successfully in 100% of 140 patients. At 1- and 3-month follow-ups, all patients had mean electrical pacing measurements within expected ranges. The adverse event rate was comparable to that seen with other pacemakers (1.4%), with no infections or device dislodgments, and no events requiring repeat procedures or resulting in death. Further, there were zero unanticipated serious adverse device events.
The Micra TPS won the top innovation award for practice improvement at that recent EHRA meeting in Milan.
Boston Scientific Corp and St. Jude are working on their own miniature pacemakers, and all three companies are focused on adding functionality that will allow the devices to pace multiple chambers. The Nanostim™, St. Jude’s device, also has CE mark approval and is currently being tested in the LEADLESS 2 trial. (We should note that the Nanostim leadless pacemaker was awarded the Innovation Award at Cardiostim 2014.)
But I Swear There Was a Rattle
Another area rich with miniaturization opportunities is arrhythmias, which can be sneaky little buggers. They can be kind of like that rattle the car makes that stops the second you get to the mechanic. Subclinical AF is often intermittent or paroxysmal in nature, so unless the heart opts to misbehave while the EKG or Holter monitor is attached, it’s hard to know what’s going on. And it is not fun to finally receive confirmation of an AF problem in a particular patient because they’ve had a stroke. Not when anticoagulation can reduce the risk by nearly 50%.
The cause of stroke remains unexplained after routine evaluation in about 30% of patients, resulting in the classification, by exclusion, of cryptogenic stroke. AF is recognized to be the cause of a significant percentage of cryptogenic strokes, but in the absence of documented AF, anticoagulants are not usually used. And given that much AF is paroxysmal or asymptomatic in nature, short-term monitoring often misses it.
With the prevalence of diagnosed AF on the tear, it would seem foolhardy to not assume that subclinical or silent AF prevalence isn’t also increasing. There are tiny implanted and stick on devices that now allow physicians to get a better picture what the true incidence is.
Medtronic’s miniaturization effort began about 10 years ago and has operated separately from its conventional research group to enable its scientists to disrupt the company’s current product pipeline. The Cryptogenic Stroke and Underlying AF (CRYSTAL AF) trial was a parallel-group, randomized, controlled trial to compare the time to detection of AF with an implantable cardiac monitor versus conventional cardiac monitoring in patients with cryptogenic stroke or transient ischemic attack (TIA).3 Patients were enrolled only after undergoing a thorough evaluation to determine their stroke classification. The trial used the Medtronic REVEAL XT implantable cardiac monitor (ICM). Those assigned to the control group underwent assessment at scheduled and unscheduled visits, with ECG monitoring performed at the discretion of the patient’s physician.
By 6 months, AF had been detected in 8.9% of ICM patients, as compared to 1.4% of controls (hazard ratio [HR], 6.4; p < 0.001). The corresponding rates at 1 year were even wider apart at 12.4% in the ICM group and 2.0% in the control group (HR, 7.3; p < 0.001). Of note, 84 days was the median time to AF detection, indicating a potential shortfall in detection with short-term monitoring. Of those in whom AF was detected, 97% were prescribed oral anticoagulants.
Of the 208 devices inserted for rhythm detection, 5 (2.4%) were removed because of infection at the insertion site or pocket erosion. The ICM remained implanted in 96.6% of patients at 12 months.
The REVEAL XT device, which is the size of a USB flash drive, isn’t even considered miniature anymore, but a newer insertable cardiac monitor called the REVEAL LINQ most definitely is. The LINQ makes the XT look positively clumsy. It is 87% smaller than the XT but has 20% more data memory, improved atrial fibrillation (AF)-detection algorithms, and a battery that lasts 3 years (same as the XT). Insertion of the device is almost ridiculously simple—a 1 cm incision and the device comes pre-loaded on an insertion tool that the operator slides into place, preferably in the “best location,” which, according to Medtronic, lies at a 45 degree tilt to the sternum over the fourth intercostal space, 2 cm from the left lateral edge of the sternum.
In another recent study, this one presented at the International Stroke Conference in Nashville in February of this year, investigators took a “real-world” look into how the newer generation Medtronic ICM, the REVEAL LINQ, performs in patients with cryptogenic stroke. At a median of 182 days, the ICM had an AF detection rate of 12.2%, or fully 37% higher than the rate observed in CRYSTAL-AF at the same time point.
“These were patients who had just been labeled as cryptogenic stroke but didn’t have to go through the same gauntlet of tests and things that the CRYSTAL-AF patients had to go through to exclude other reasons for their stroke,” explained investigator John Rogers, MD, FACC, from Scripps Clinic Torrey Pines in La Jolla, CA.
On July 16, 2015, Medtronic announced the first in-office implant of its miniaturized cardiac monitor as part of its Reveal LINQ In-Office 2 (RIO 2) Study. Dr. Rogers successfully implanted the device. Now, RIO 2 will determine if the procedure is as safe as those performed in a more traditional setting, such as an operating room, cardiac catheterization laboratory, or electrophysiology laboratory.
At the same time the main CRYSTAL-AF results were published, a second study, this one called EMBRACE, tested a slightly less high-tech or invasive technique for longer-term monitoring. Gladstone et al compared a 30-day event-triggered loop recorder to conventional 24-hour monitoring in 572 patients without known AF who had had a cryptogenic stroke or TIA. They found AF (30 seconds or longer) in 16.1% of the intervention group versus 3.2% of the control group (p<0.001). AF lasting 2.5 minute or longer was seen in 9.9% and 2.5%, respectively (p < 0.001).
In an editorial discussing both studies, Hooman Kamel, MD, from the Weill Cornell Medical College, NY, suggested that while the most patients with cryptogenic stroke or TIA should undergo “at least several weeks of rhythm monitoring,” the loop recorders like those used in the EMBRACE trial will likely be cost-effective, while “the value of more expensive implantable loop recorders is less clear.”4
One argument against prolonged cardiac monitoring is that the clinical significance of brief episodes of AF detected by implanted devices is unknown, nor is the role of anticoagulation. This issue was addressed in a January 2015 JACC State-of-the-art Review authored by Carol Chen-Scarabelli, PhD, from the University of Michigan, Ann Arbor, MI, and colleagues.5
Current AF guidelines either lack specific recommendations for device-detected AF or recommend further investigation of device-detected AF to clarify its connection with stroke risk. Chen-Scarabelli and colleagues, however, fundamentally object to the ambiguity in the guidelines and instead suggest that device-detected AF offers “a unique opportunity” to intervene early and prevent stroke or lessen its severity. They go further and suggest that clinicians have “an inherent responsibility to act on such information gleaned from device diagnostics, with potential legal ramifications for those who fail to act.”
They concluded: “The reluctance of clinicians to act on device-detected AF is bewildering, as many would not hesitate to act on a single standard 12-lead ECG that records 10 s of rhythm… Such failure represents a lost opportunity.”
In case you thought your equipment has reached its size limitations already in terms of being as small as possible, interventional cardiology will continue to benefit from the giant miniaturization boom. Or better said, patients will continue to gain from smaller equipment.
In transcatheter aortic valve replacement (TAVR), miniaturization already has improved patient outcomes. In an April 2015 editorial by Blasé Carabello, MD, FACC, from Mount Sinai Beth Israel Hospital, New York, NY, he noted, “Progressive miniaturization, valve designs that limit paravalvular leak (PVL), and devices that protect patients from cerebral embolism will almost surely facilitate the use of TAVR in lower risk patients and facilitate enhanced outcomes with lower complication rates.”6
Worldwide each year, we’re now seeing more left ventricular assist devices (LVADs) implanted than hearts transplanted. Even the devices already being placed are a far cry from the console on wheels that drove the pneumatic assist devices of the 1990s. LVAD next gen units are characterized by continuous miniaturization and enhanced pump performance, providing increased device durability and—potentially—prolonged survival of the patients.7 Indeed, a next generation of these devices are referred to as MVADs, meaning mini versions of LVADs. In the case of the HeartWare (Framingham, Massachusetts) miniature hybrid or “HVAD” pump, it weighs 160 g compared with the company’s preclinical MVAD pump, which pumps you up at only 78 g.
By reducing the required thoracic space and pump footprint, smaller patients may become candidates for device implantation, which will still support large-framed or obese patients.8 Plus, an MVAD may permit more minimally invasive surgical techniques, especially since the MVAD pump does not require the creation of a pump pocket, which may reduce invasiveness of surgery, length of stay, and complications such as bleeding, hematoma, and infections. According to the Center for Artificial Organs and Transplantation, as miniaturization of LVADs continue, minimally invasive techniques likely will be used for most implantations in the future.9
LVAD miniaturization and ease of implantation may ultimately lead to a paradigm shift in clinical practice, resulting in the treatment of a less ill cohort of patients. Indeed, as Donna Mancini, MD, and Paolo C. Colombo, MD, FACC, put it this summer in a JACC State-of-the-Art review, with the continued expansion of LVAD therapy, “cardiac transplantation may eventually become the future bailout strategy for device patients who develop complications.”10
Sometimes “miniature” is relative. The Cardiohelp by Maquet is the world’s smallest veno-arterial extracorporeal membrane oxygenation (vaECMO) system. They call it miniaturized because it is far more portable than standard ECMO machines, weighing only 11.5 kg and can readily be carried by only one person. Not to belittle this piece of engineering magic, having it around was shown in one 2012 “Best of the Best” AHA abstract (Shah AP, et al.) to increase utilization of ECMO, particularly for the treatment of patients successfully resuscitated from cardiac arrest to ameliorate the effects of post-resuscitation myocardial dysfunction. It also allows continued ECMO therapy during inter-hospital transfer in patients with cardiopulmonary failure.11
A Gold Star for a Sticker
It’s been a full year now since the U.S. Food and Drug Administration (FDA) approved the CardioMEMS HF System, the first permanently implantable wireless system to provide pulmonary artery (PA) pressure measurements, including systolic, diastolic, and mean PA pressures. The PA pressure data are reviewed by physicians who can make decisions regarding the status of the patient and, if necessary, initiate changes in medical therapy, with the goal of reducing hospitalization due to heart failure.
After the small sensor is implanted into the PA, Bluetooth technology permits PA pressures to be read easily to evaluate early HF decompensation. At home, users take readings from a bedside monitor and then send them to a physician through an antennae embedded in a pillow. Users must lie face up on the pillow to send the data. This system can also help physicians keep track of reactions to medications and dosages and make changes accordingly.
Let’s say a 24-hour Holter isn’t sufficient but an implanted device isn’t warranted. Well, creative minds have devised a tiny solution to that, too. It’s a stick-on heart monitor called the Zio Patch made by digital health care company iRhythm. Their “wearable sensors” record the patient’s rhythm for 14 days. Then the device is returned to the company, the data are analyzed via proprietary algorithms, and the clinician is sent a focused report.
“The adhesives are very comfortable to wear so the device can be worn for 14 days,” said Judy Lenane, RN, MHA, executive vice president and chief clinical officer for iRhythm in an interview with CSWN. “They can shower, exercise, live their life, and have the data collected.”
In a study of 146 patients who underwent simultaneous ambulatory electrocardiogram (ECG) recording with a 24-hour Holter monitor and a 14-day adhesive patch monitor, the patch monitor detected 96 arrhythmia events compared with 61 events detected by the Holter (p < 0.001). Not surprisingly, patients found the patch more comfortable to wear.12
“On the basis of these findings, novel, single-lead, prolonged-duration, low-profile devices may soon replace conventional Holter monitoring platforms for the detection of arrhythmia events in patients referred for ambulatory ECG monitoring,” said the Scripps Translation Science Institute researchers, led by Eric J. Topol, MD, FACC.
Referring to a recent study of the iRhythm device, Sunil Kumar Agarwal, MD, PhD, stressed: “The interesting part is that… about 50% of the people we identified with atrial fibrillation had paroxysmal AF, meaning we will not capture them on a 10-second ECG. Five out of seven patients who had paroxysmal AF were not on anticoagulation.” Dr. Agarwal is a fellow in cardiology at Mt. Sinai School of Medicine, New York. (Scan the QR to see our interview with Dr. Agarwal.)
According to the company’s website, more than 300,000 patients have used the patch at more than 800 US institutions and it is widely reimbursed.
Does it really matter? After all, a just-published population-based cohort study in Lancet Neurology questioned the presumed importance of paroxysmal AF as the major cause of cryptogenic stroke.13 However, in an accompanying editorial, Jose M. Ferro, MD, from the University of Lisbon, Portugal, questioned the authors’ conclusion because the main study did not use the new devices that allow for prolonged heart rhythm monitoring. In other words, if you don’t look carefully for AF, you may not find it, but that doesn’t mean it wasn’t there.14
With their purchase of Corventis, Medtronic also has a mobile cardiac telemetry system that uses a peel and stick patch.
InfoBionic (Lowell, Massachusetts) is set to commercialize its remote patient monitoring system, the MoMe Kardia, which is designed to help detect cardiac arrhythmias in patients by sensing electrical acitivity, respiration, and motion. The device can be worn as a necklace or belt attachment and transmits data to a cloud-based platform where the data are analyzed then sent on to the physician. The device works as a Holter, event, and mobile cardiac telemetry monitor. If a physician feels that the patient’s cardiac symptoms call for a different type of monitoring technology, they can switch the device remotely to any one of three main monitoring modes. A physician can access the patient’s MoMe Kardia data via web or iPad app.
In May 2015, toSense announced FDA clearance for its CoVa™ Monitoring System, which features a novel sensor, also worn like a conventional necklace for just a few minutes each day. The sensor measures bioimpedance and ECG waveforms, and from these calculates thoracic impedance, heart rate, heart rate variability, and respiration rate. It can track thoracic fluid levels, an early predictor of heart failure that isn’t currently monitored by most connected sensors.
AliveCor has a novel technology that incorporates electrodes into an iPhone case that records an ECG tracing. It was recently evaluated in 55 patients following AF ablation done at the Cleveland Clinic.15 All the study participants also used traditional transtelephonic monitoring (TTM), using a beeper-sized device that collects ECG data, stores it internally, and it can then be transmitted to a doctor over a landline. Patients were asked to record their rhythm using both monitors simultaneously whenever they had symptoms or at least once a week.
“The clinical value of these findings are important, as the current options for monitoring patients after AF ablation vary between institutions and are usually patient-specific,” Khaldoun G. Tarakji, MD, FACC, who led the iTransmit study, said in a statement. “Capturing AF and monitoring someone’s heart after an ablation can be extremely challenging and it is imperative to have an easy-to-use monitor that patients can have access to anywhere and at any time after an ablation.”
Importantly, patients found the AliveCor device easy to use: 92% of participants said they would rather use the AliveCor Heart Monitor than the TTM.
And you can’t get much smaller than an app—and AstraZeneca has partnered with a mobile health coaching company (Vida) to launch an app, called Day-by-Day, which helps patients recovering from myocardial infarction. The app is designed to speed up the patient’s recovery and help patients deal with any trauma they may feel after experiencing a heart attack. The app is currently part of a trial program at Duke University.
Research in the Cloud
Prolonged cardiac monitoring may have tremendous research potential. The vast amounts of data collected and stored by these devices offer researchers a potential goldmine of data into when, how, and why people get into trouble and have an event.
The EMBRACE investigators, for example, published a follow-up analysis of the 30-day event monitoring data showing that patients who experienced higher baseline Holter-detected atrial premature beat (APB) counts were significantly more likely to have prevalent subclinical AF.16 In fact, APB count was the only significant predictor of AF detection by 30-day ECG (p < 0.0001) and at 90 days (p = 0.002) and 2 years (p = 0.003).
The makers of the Zio patch monitor, iRhythm, aspires to be the world leader in the management of cardiac arrhythmia information. They may make good on that aspiration as they already have (by their own admission) the largest ECG database in the world, containing more than 51 million hours (or 5,400 years) of continuous ECG recording. The company is actively engaged in mining their “big data” for interesting tidbits. For example, the GIRAFFE (Genomic Risk Markers for Atrial Fibrillation Following Extended Cardiac Rhythm Monitoring) study will investigate the association between a set of single nucleotide polymorphisms and AF in patients at high risk for the arrhythmia, focusing on SNPs previously shown to be associated with AF.
Continuing the Voyage
A diplomat with secret knowledge is injured in an assassination attempt, suffering a blood clot in his brain that threatens to keep those secrets from getting into the “right” hands. In a never before attempted procedure, a group of scientists is miniaturized and has 1 hour to get in, destroy the clot (with a laser), and get out before returning to normal size.
The year was 1966, the film “Fantastic Voyage”—and at the time, we marveled at this concept of vast miniaturization, even if we knew we were watching science fiction.
Fast forward nearly 50 years to the 2015 summer hit, Ant-Man. Ever since Ant-Man’s debut in Marvel Comics, we have known his super powers involved packing super strength and other abilities into a tiny package. But at some point in the film (spoiler alert), the question looms whether it is possible to get too small, too microscopic to do any good. With sequels at the ready, we may get that answer—at least in the Marvel Universe.
Fortunately, in the real world of medicine, miniaturization straddles the best of both of these worlds: smaller and smaller devices incorporate complicated miniaturized technology and complex algorithms to provide powerful, real-time information coupled with more comfortable, user-friendly portability. But we are also learning our limits as to how small is too small (such as with catheters). Where we go from here will continue to be another fantastic voyage.
Editor’s Note: Some of this material also appears in the current issue of CardioSource WorldNews: Interventions.
- Abdelaal E, Rao SV, Gilchrist IC, et al.
- JACC Cardiovasc Interv. 2013;6:99-112.
- Ritter P(1), Duray GZ(2), Steinwender C(3), et al.
- Eur Heart J. 2015 Jun 4. [Epub ahead of print]
- Sanna T, Diener HC, Passman RS, et al. N Engl J Med. 2014;370:2478-86.
- Kamel H. N Engl J Med. 2014 Jun 26;370(26):2532-3.
- Chen-Scarabelli C, Scarabelli TM, Ellenbogen KA, et al.
- J Am Coll Cardiol. 2015;65(3):281-94.
- Carabello B. JACC Cardiovasc Interv. 2015;8:678-80.
- Hanke JS, Rojas SV, Avsar M, et al. Curr Cardiol Rev. 2015;11:246-51.
- Cheung A, Chorpenning K, Tamez D, et al. Innovations (Phila). 2015;10:151-6.
- Rojas SV, Avsar M, Hanke JS, et al. Artif Organs. 2015;39:473-9.
- Mancini D, Colombo PC. J Am Coll Cardiol.
- Raspé C, Rückert F, Metz D, et al. Perfusion. 2015;30:52-9.
- Barrett PM, Komatireddy R, Haaser S, et al. Am J Med. 2014;127:95.e11-7.
- Li L, Yiin GS, Geraghty OC, et al. Lancet Neurol. 2015 Jul 27. [Epub ahead of print]
- Ferro JM. Lancet Neurol. 2015 Jul 27. [Epub ahead of print]
- Tarakji KG, Wazni OM, Callahan T, et al. Heart Rhythm. 2015;12:554-9.
- Gladstone DJ, Dorian P, Spring M, et al. Stroke. 2015;46:936-41.
Clinical Topics: Invasive Cardiovascular Angiography and Intervention
Keywords: CardioSource WorldNews, Inventions, Monitoring, Physiologic, Patient Discharge, Percutaneous Coronary Intervention
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