Shinshu University

Participants in front of the logo of the European Society of Cardiology at a previous meeting. The 2024 conference was held in London 30 August-2 September. Image credit: Shutterstock/hydebrink The results of two subanalyses of the PACMAN-AMI trial were presented on the final day (2 September) of the European Society of Cardiology (ESC) 2024 Congress. Coronary heart disease is the most frequent cause of mortality in the industrialised world, and hypercholesterolaemia is a major risk factor. Statins are the first-line therapy, but are often not wholly effective. Several studies have demonstrated low-density lipoprotein cholesterol (LDL-C) reduction with PCSK9 inhibition, in addition to decreased adverse cardiovascular events. The Phase III PACMAN-AMI trial (NCT03067844) investigated the effect of Regeneron Pharmaceutials’ PCSK9 inhibitor Praluent (alirocumab), a PCSK9 inhibitor, in patients with acute myocardial infarction (AMI). Some data from the study was presented earlier at the conference during a session outlining the efficacy of antibodies like Praluent in reducing LDL-C levels . In the study, patients received Praluent or placebo every two weeks alongside statin therapy. After 52 weeks, PCSK9 inhibition significantly reduced percent atheroma volume (PAV), the difference between vessel and lumen volumes, and other measures of blood vessel occlusion compared to statin therapy alone. See Also: Novavax wins FDA emergency approval for updated Covid-19 vaccine Global Calcium hit with Form 483 after Indian factory inspection Subanalyses provide more insights Dr. Yasushi Ueki from Shinshu University Hospital in Japan first presented a subanalysis of the PACMAN-AMI trial. His team used risk stratification to identify patients with the greatest potential for benefit from plaque regression. Ueki explained his group divided patients into three groups based on risk factors for chronic coronary disease—those with none, with one, or with two or more major risk factors. Blood vessel imaging for these patients was compared before and after 52 weeks of Praluent treatment or placebo between risk-stratified groups. Ueki’s team found PAV was only significantly reduced among patients with one or no risk factors, with, “no significant difference between patients with two or more risk factors”. This was also true regarding changes in maximum lipid core burden index and macrophage angle. According to Ueki, “among AMI patients with no or one atherothrombotic risk factors, the addition of alirocumab to high-intensity statin demonstrated greater coronary plaque regression; patients with fewer risk factors thus appear to be more susceptible for atheroma regression”. Dr. Flavio Biccirè from the University Hospital of Bern in Switzerland then spoke about his team’s subanalysis. They focused on vessel lesions, regions at which plaque buildup is most pronounced, as opposed to the PACMAN-AMI trial’s wider, vessel-level analysis. Identifying vessel lesions using imaging data from 245 patients, Biccirè and his colleagues remeasured clinical outcomes. They found that at the lesion level, PAV change with Praluent at 52 weeks was -4.9 compared to placebo, far greater than the -2.1 change stated in the original analysis. Biccirè concluded, “LDL-C lowering induced an extensive atheroma burden reduction at lesion-level”, and that, “significant changes in coronary lesions, rather than mild effects described at vessel-level, underlie the protective vascular effects of contemporary lipid-lowering therapies”.

Flexible piezoelectric sensors are essential to monitor the motions of both humans and humanoid robots. However, existing designs are either are costly or have limited sensitivity. In a recent study, researchers tackled these issues by developing a novel piezoelectric composite material made from electrospun polyvinylidene fluoride nanofibers combined with dopamine. Sensors made from this material showed significant performance and stability improvements at a low cost, promising advancements in medicine, healthcare, and robotics. Flexible piezoelectric sensors are essential to monitor the motions of both humans and humanoid robots. However, existing designs are either are costly or have limited sensitivity. In a recent study, researchers from Japan tackled these issues by developing a novel piezoelectric composite material made from electrospun polyvinylidene fluoride nanofibers combined with dopamine. Sensors made from this material showed significant performance and stability improvements at a low cost, promising advancements in medicine, healthcare, and robotics. The world is accelerating rapidly towards the intelligent era -- a stage in history marked by increased automation and interconnectivity by leveraging technologies such as artificial intelligence and robotics. As a sometimes-overlooked foundational requirement in this transformation, sensors represent an essential interface between humans, machines, and their environment. However, now that robots are becoming more agile and wearable electronics are no longer confined to science fiction, traditional silicon-based sensors won't make the cut in many applications. Thus, flexible sensors, which provide better comfort and higher versatility, have become a very active area of study. Piezoelectric sensors are particularly important in this regard, as they can convert mechanical stress and stretching into an electrical signal. Despite numerous promising approaches, there remains a lack of environmentally sustainable methods for mass-producing flexible, high-performance piezoelectric sensors at a low cost. Against this backdrop, a research team from Shinshu University, Japan, decided to step up to the challenge and improve flexible piezoelectric sensor design using a well-established manufacturing technique: electrospinning. Their latest study, which was led by Distinguished Professor Ick Soo Kim in association with Junpeng Xiong, Ling Wang, Mayakrishnan Gopiraman, and Jian Shi, was published on 2 May, 2024, in the journal Nature Communications. The proposed flexible sensor design involves the stepwise electrospinning of a composite 2D nanofiber membrane. First, polyvinylidene fluoride (PVDF) nanofibers with diameters in the order of 200 nm are spun, forming a strong uniform network that acts as the base for the piezoelectric sensor. Then, ultrafine PVDF nanofibers with diameters smaller than 35 nm are spun onto the preexisting base. These fibers become automatically interweaved between the gaps of the base network, creating a particular 2D topology. After characterization via experiments, simulations, and theoretical analyses, the researchers found that the resulting composite PVDF network had enhanced beta crystal orientation. By enhancing this polar phase, which is responsible for the piezoelectric effect observed in PVDF materials, the piezoelectric performance of the sensors was significantly improved. To increase the stability of the material further, the researchers introduced dopamine (DA) during the electrospinning process, which created a protective core-shell structure. "Sensor fabricated from using PVDF/DA composite membranes exhibited superb performance, including a wide response range of 1.5-40 N, high sensitivity of 7.29 V/N to weak forces in the range of 0-4 N, and excellent operational durability," remarks Kim. These exceptional qualities were demonstrated practically using wearable sensors to measure a wide variety of human movements and actions. More specifically, the proposed sensors, when worn by a human, could produce an easily distinguishable voltage response to natural motions and physiological signals. This included finger tapping, knee and elbow bending, foot stamping, and even speaking and wrist pulses. Given the potential low-cost mass production of these piezoelectric sensors, combined with their use of environmentally friendly organic materials instead of harmful inorganics, this study could have important technological implications not only for health monitoring and diagnostics, but also robotics. "Despite the current challenges, humanoid robots are poised to play an increasingly integral role in the very near future. For instance, the well-known Tesla robot 'Optimus' can already mimic human motions and walk like a human," muses Kim, "Considering high-tech sensors are currently being used to monitor robot motions, our proposed nanofiber-based superior piezoelectric sensors hold much potential not only for monitoring human movements, but also in the field of humanoid robotics." To make the adoption of these sensors easier, the research team will be focusing on improving the material's electrical output properties so that flexible electronic components can be driven without the need for an external power source. Hopefully, further progress in this area will accelerate our stride towards the intelligent era, leading to more comfortable and sustainable lives.

Regenerative heart therapies involve transplanting cardiac muscle cells into damaged areas of the heart to recover lost function. However, the risk of arrhythmias following this procedure is reportedly high. In a recent study, researchers tested a novel approach that involves injecting 'cardiac spheroids,' cultured from human stem cells, directly into damaged ventricles. The highly positive outcomes observed in primate models highlight the potential of this strategy. Regenerative heart therapies involve transplanting cardiac muscle cells into damaged areas of the heart to recover lost function. However, the risk of arrhythmias following this procedure is reportedly high. In a recent study, researchers from Japan tested a novel approach that involves injecting 'cardiac spheroids,' cultured from human stem cells, directly into damaged ventricles. The highly positive outcomes observed in primate models highlight the potential of this strategy. Cardiovascular diseases are still among the top causes of death worldwide, and especially prevalent in developed countries. Myocardial infarctions, commonly known as "heart attacks," are on the rise, resulting in a significant number of deaths each year. Heart attacks typically kill millions of cardiac muscle cells, leaving the heart in a weakened state. Since mammals cannot regenerate cardiac muscle cells on their own, heart transplants are currently the only clinically viable option for patients suffering (or likely to suffer) heart failure. Given that full heart transplants are expensive and donors difficult to come by, it is no surprise that alternative therapies are highly sought after by the medical community. One promising strategy that has been steadily gaining traction is using human induced pluripotent stem cells (HiPSCs) for regenerative heart therapy. Simply put, HiPSCs are cells derived from mature cells that can be effectively 'reprogrammed' into a completely different cell type, such as cardiac muscle cells (cardiomyocytes). By transplanting or injecting cardiomyocytes derived from HiPSCs into damaged areas of the heart, it is possible to recover some lost functionality. Unfortunately, studies have reported that this approach can increase the risk of arrythmias, posing a major hurdle to clinical trials. In a recent study, a Japanese research team from Shinshu University and Keio University School of Medicine, tested a new strategy for regenerative heart therapy that involves injecting 'cardiac spheroids' derived from HiPSCs into monkeys with myocardial infarction. This study, published on April 26, 2024, in the journal Circulation, was led by Professor Yuji Shiba from the Department of Regenerative Science and Medicine, Shinshu University. The team included Hideki Kobayashi, the first author, and Koichiro Kuwahara from the Department of Cardiovascular Medicine, Shinshu University School of Medicine, as well as Shugo Tohyama, and Keiichi Fukuda from the Department of Cardiology, Keio University School of Medicine, among others. In their novel approach, the researchers cultivated HiPSCs in a medium that led to their differentiation into cardiomyocytes. After carefully extracting and purifying cardiac spheroids (three-dimensional clusters of cardiac cells) from the cultures, they injected approximately 6 × 107 cells into the damaged hearts of crab-eating macaques (Macaca fascicularis). They monitored the condition of the animals for twelve weeks, taking regular measurements of cardiac function. Following this, they analyzed the monkeys' hearts at the tissue level to assess whether cardiac spheroids could regenerate the damaged heart muscles. First, the team verified the correct reprogramming of HiPSCs into cardiomyocytes. They observed, via cellular-level electrical measurements, that the cultured cells exhibited potential patterns typical of ventricular cells. The cells also responded as expected to various known drugs. Most importantly, they found that the cells abundantly expressed adhesive proteins such as connexin 43 and N-cadherin, which would promote their vascular integration into an existing heart. Afterwards, the cells were transported from the production facility at Keio University to Shinshu University, located 230 km away. The cardiac spheroids, which were preserved at 4 °C in standard containers, withstood the four-hour journey without problem. This means that no extreme cryogenic measures would be needed when transporting the cells to clinics, which would make the proposed approach less expensive and easier to adopt. Finally, the monkeys received injections of either cardiac spheroids or a placebo directly into the damaged heart ventricle. During the observation period, the researchers noted that arrythmias were very uncommon, with only two individuals experiencing transient tachycardia (fast pulse) in the first two weeks among the treatment group. Through echocardiography and computed tomography exams, the team confirmed that the hearts of monkeys that received treatment had better left ventricular ejection after four weeks compared to the control group, indicating a superior blood pumping capability. Histological analysis ultimately revealed that the cardiac grafts were mature and properly connected to pre-existing existing tissue, cementing the results of previous observations. "HiPSC-derived cardiac spheroids could potentially serve as an optimal form of cardiomyocyte products for heart regeneration, given their straightforward generation process and effectiveness," remarks Assistant Professor Kobayashi. "We believe that the results of this research will help solve the major issue of ventricular arrhythmia that occurs after cell transplantation and will greatly accelerate the realization of cardiac regenerative therapy," he further adds. Although tested in monkeys, it is worth noting that the cardiac spheroid production protocol used in this study was designed for clinical application in humans. "The favorable results obtained thus far are sufficient to provide a green light for our clinical trial, called the LAPiS trial. We are already employing the same cardiac spheroids on patients with ischemic cardiomyopathy," comments Asst. Prof. Kobayashi. Let us all hope for a resounding success in the LAPiS trial, paving the way for expanded and effective treatment avenues for people suffering from heart problems.