Recent innovations in technology are expanding the pacemaker vertical.
Pacemaker technologies have advanced dramatically over the decades since they were first introduced, and every year many thousands of new implants are performed worldwide. Many of the improvements in pacing technology over the past five decades are incremental, but some have certainly been game-changing or revolutionary advances, including dual-chamber pacing to allow maintenance of atrioventricular synchrony, rate responsive pacing, and cardiac resynchronization therapy, with or without defibrillation backup. Despite these developments, certain problems have persisted. Complications that result from the use of implantable devices are the most prominent issues that have persisted over the years. These complications include acute problems involving the implantation procedure, such as pneumothorax and hematoma, as well as more subacute and chronic problems including infection and lead failure. Similar problems have plagued the use of all cardiac implantable electronic devices (CIEDs), although the solutions have differed.
Recent innovations in pacemaker technology, spurred by low-power electronics, high-density batteries, improved catheter delivery systems, and innovative software design, have emerged with the hope of obviating these concerns.
Global Market Dynamics
The global pacemaker market is expected to reach USD 12.3 billion by 2025, predicts Grand View Research, Inc. Heightening prevalence of cardiac conditions coupled with the availability of medical coverage is a key driving factor governing the growth of pacemaker globally. In addition, technological enhancements in these devices are supporting the expansion of this vertical.
Increasing prevalence of cardiovascular diseases (CVDs) is a high-impact growth-rendering driver for this market. Currently, the high occurrence of CVDs is one of the key concern areas, to address which government organizations and market participants are channelizing funds and efforts to offer the best possible cure. This is anticipated to foster R&D initiatives and increase the influx of advanced products in this space.
Additionally, increasing awareness about cardiovascular disorders and their long-term impact is increasing the preference of patients for advanced treatment options. This is expected to bolster the usage rate of these products.
On the other hand, these devices are cost-prohibitive with the cost of a pacemaker ranging from USD 10,000 to USD 30,000. The high price is likely to restrain the growth of the pacemaker market.
North America held more than 40 percent share of the global pacemaker market in 2016. Developed healthcare infrastructure, presence of planned reimbursement structure, greater per capita healthcare spending, and higher awareness among the population about advanced technologies supported the significant growth of this regional segment.
Asia-Pacific is anticipated to exhibit sturdy growth over the next eight years. Several government initiatives are anticipated to create a free and open economy. For instance, implementation of goods and services tax (GST) in India to avoid the tax cascading effect is anticipated to bring down the tax rate, thus improving the ease-of-doing business in the country. Also, recently introduced economic reforms in China, promoting a well-balanced and open economy, have had a significant impact in shaping the global economy in 2017, thus presenting more investment opportunities for multinational players in this region.
Some of the key players in this space are Medtronic, Biotronik Inc., Boston Scientific Corporation, St. Jude Medical, Zoll Medical Corporation, Medico S.p.A., Vitatron, Pacetronix, and Cordis, Inc.
New product development, geographical expansion, collaboration, mergers and acquisitions, and pricing strategies are key undertakings of the players in this space. For Instance, in July 2016, St. Jude Medical received the US FDA approval for SyncAV, a CRT software compatible with the company’s multiPoint pacing technology. The software was approved earlier in the European market in June 2016.
Recent Technological Advances
Since the first cardiac pacemaker was implanted in 1958, improvements in pacing technology have been coupled to advances in engineering, material design, and computer sciences. The past decade has been particularly fruitful for these fields and the cardiac pacemaker has reaped the benefits. Most notably, advances in very-large-scale integration (VLSI) circuitry have resulted in highly compact circuit design (<65 nm) with low power consumption. New techniques in circuit fabrication have lowered semiconductor node sizes to 14 nm and processers using this technology are currently available in today’s mobile phones and laptop computers and will likely be an integral part of future pacemaker design. In addition to more efficient hardware, pacing lead construction has also aimed to lessen current drain. High-impedance leads are designed with a very-small-diameter electrode at the tip of the lead that maximizes current density while keeping pacing thresholds at or below those of a standard lead. Although initial studies of high-impendence leads extended battery life, the real-life gains of device longevity have been questioned. Lightweight lithium/carbon monofluoride batteries have been used for the past decade and provide higher current densities to support onboard processes as well as pacing without dips in voltage that were seen in lithium/iodine batteries. Finally, MRI-conditional pacemakers have been developed using redesigned components to minimize heating potential, dislodgement, current induction, and electromagnetic interference. Currently, all major manufacturers offer an MRI-conditional device.
Leadless pacemakers. The design of the transvenous permanent pacemaker (PPM) is simple yet reliable, comprised of a pulse generator and one or more transvenous leads. This basic design has seen iterative changes resulting in improved battery life, lead performance, and device programming; however, the general makeup of the PPM is mostly unchanged. Despite their dependability, contemporary cardiac pacemakers still have several liabilities such as device infection, lead failure requiring replacement, or extraction and secondary tricuspid regurgitation. Because of these limitations, the leadless cardiac pacemaker (LCP) has long been of interest to cardiologists. Recent technologic advances have made the dream of the leadless cardiac pacemaker a reality. Currently single component LCPs (available for commercial use in Europe and under clinical investigation in the United States) and multicomponent leadless left ventricular (LV) endocardial pacing system for delivery of CRT are available.
Biological pacing. Electronic pacemakers have been used for more than 50 years to successfully treat symptomatic bradycardia and other diseases of the conduction system. Despite serial improvements in design, complications such as pocket infections, lead fracture, and adverse cardiac remodeling persist. Ideally, the pacemaker would be free of such complications and, accordingly, a biological pacemaker – developed by either cellular implantation or gene therapy – has been proposed as the panacea for pacing. Recent successes in translational research have created excitement about the future of biological pacing.
Over the past 20 years, cell therapy and gene therapy have emerged as the predominant approaches to biological pacing. Both modalities have demonstrated an ability to increase pacemaker rate; however, gene therapy has been the most successful at approximating ideal pacemaker function. Hybrid therapy, a combination of the two modalities, has also been used with success.
Cellular therapies are those that use embryonic stem cells or induced pluripotent stem cells to develop a biological pacemaker. Human embryonic stem cells have been transformed into spontaneously excitable cardiomyocytes that integrated structurally, electrically, and mechanically in vitro in rats and functioned as pacemaker cells in vivo in pigs with complete heart block. Adult human mesenchymal stem cells (hMSCs) have been used successfully as a delivery system to carry pacemaker genes. Although these approaches have shown viable pace- making potential for up to six weeks in vivo, the use of epicardial sites for the injection of pacemaker cells and lower heart rates in the range of 60 beats per minute limit clinical utility.
Gene therapies have used viral vectors or other means to increase myocardial excitability, induce diastolic depolarization, or induce a sinus node phenotype at the cellular level. Approaches that increase inward current aim to overexpress the ion channels of the hyperpolarization-activated, cyclic nucleotide-gated channel (HCN) pacemaker family, the skeletal-muscle sodium channel (SkM1), and the beta-2 receptor or adenylyl cyclase. Overexpression of the potassium-channel Kir2.1AAA has been used to decrease outward current during diastole. Various combinations of these approaches have also been evaluated. Recently, scientists delivered percutaneous injections of TBX18, a human embryonic transcription factor for T-box 18 capable of reprograming cardiomyocytes into pacemaker cells, into a porcine model of heart block to achieve in vivo somatic reprogramming. This method resulted in a sinus-node-like phenotype, which generated ventricular pacemaker activity with heart rates in the mid-70s that were responsive to autonomic regulation during activity. The pacemaker activity persisted for two weeks and was not associated with increased arrhythmia. The minimally invasive nature of TBX18 injections to deliver gene therapy is tantalizing in clinical scenarios that require temporary pacing such as infective endocarditis or pacemaker infection. Although further study is needed, gene therapy remains promising for both temporary and permanent biological pace making.
Although each of these novel technologies was developed to deal with limitations of traditional pacing devices, each carries their own limitations. As previously discussed, leadless pacemakers in their current iteration carry the theoretical risk of embolization, inability to retrieve due to encapsulation, and have limited available pacing modes. Ultrasound-based leadless systems are restricted by available acoustic windows, limiting their usefulness in some patients. Effective multisite endocardial pacing requires a trans-septal approach that necessitates anticoagulation and may result in mitral valve pathology, possibly causing more harm than benefit. Newer pacing algorithms carry the potential to increase battery consumption, leading to shortened generator lifespan. And finally, little is known about the risk of gene or cellular therapy for biological pacemakers in human subjects. These factors will be better delineated in the near future as experience with these technologies grows.
Recent advancements in pacing technology have allowed cardiologists to imagine a future in which pacemaker leads and pocket infections are part of electrophysiology folklore; atrial fibrillation is treated or outright suppressed by pacing algorithms, ultrasound beams eliminate LV activation delay, or perhaps, gene therapy provides a device-free, permanent solution to all cardiac conduction disorders. Clearly, there remains room for growth and innovation in the fields of cardiology and electrophysiology; however, the current wave of innovation provides the clinician with a toolbox full of new therapies to treat the rapidly aging population.