What’s New in Research – June 2018
New Cardiac Pump Device More Effective, Less Costly Than Standard Pump
Analysis of data from MOMENTUM 3 trial finds Heartmate 3 can minimize cost of care over time for heart failure patients
In a presentation at the annual meeting of the Heart Failure Association of the European Society of Cardiology, and in a simultaneous publication in Circulation, investigators from Brigham and Women’s Hospital presented evidence that a next-generation cardiac pump device not only improves long-term outcomes but may also decrease cost of care over time for heart failure patients. The research team analyzed results from the MOMENTUM 3 trial, which compared two devices: The HeartMate II (current generation) and HeartMate 3 (a novel, centrifugal-flow pump), both manufactured by Abbott, Inc., which sponsored the study.
“The HeartMate 3 left-ventricular assist device (LVAD) is a more forgiving pump in terms of clinical adverse events, and now we can confirm that its increased effectiveness is associated with decreased costs,” said Mandeep Mehra, MD, executive director of the Center for Advanced Heart Disease and medical director of the Heart & Vascular Center at Brigham and Women’s Hospital. “In medicine, most often, a therapy that demonstrates increased effectiveness usually comes at a higher price, and we are able to show that this new technology actually decreases costs to payers and patients over time.”
Mehra and colleagues found that the newer device reduced costs due to re-hospitalization by 51 percent, largely driven by a decrease in stroke and pump malfunction requiring reoperation due to pump thrombosis. Patients who received the HeartMate 3 experienced fewer hospitalizations and, on average, spent 8.3 fewer days in the hospital per year than those who received the HeartMate II. The authors note that it may be possible to further reduce costs by decreasing outlier complications and reducing hospital length of stay, and decrease early complications by improving patient selection criteria and considering this therapy before patients get too sick.
In April, Abbott Inc. issued a field safety notice regarding HeartMate 3 outflow graft twist complications with an incidence rate of 0.72 percent. The FDA issued a Class I recall but did not recommend the return of LVADs or avoidance of use in new patients. The current study re-reviewed 20 hospitalizations (five in the HeartMate 3 and 15 in the HeartMate II populations) and in a conservative analysis, classified them as being device-related for the purposes of this analysis. Nonetheless, the data still demonstrated a reduction in re-hospitalization related hospital days and significant cost savings for the HeartMate 3 compared to the HeartMate II.
The MOMENTUM 3 trial (NCT02224755), its conduct and analyses, are funded by Abbott, Abbott Park, IL, USA. Authors’ disclosures of potential conflicts of interest and acknowledgements can be found in Circulation.
Paper cited: Mehra, M et al. “Health Care Resource Use and Cost Implications in the MOMENTUM 3 Long-term Outcome Study: A Randomized Controlled Trial of a Magnetically Levitated Cardiac Pump in Advanced Heart Failure” Circulation DOI: 10.1161/CIRCULATIONAHA.118.035722
Case Study: Innovative Ewing Amputation Restores Proprioception
Results indicate novel procedure allows amputee to control and interpret feedback from the prosthesis
In its uninjured state, the human body is a dynamic machine comprised of many moving parts that function in balance and enable us to perform complex movements – such as running and dancing – through the coordinated interaction of our brains and our muscles. Traditional amputations disrupt this dynamic state. Lower limb amputees lose the ability to finely control the muscles in their residual leg and, more importantly, the ability to perceive where their limb is in space without looking at it. Without this intercommunication, actions such as walking on uneven ground or balancing on one leg become impossible. These limitations have, in the past, made it difficult for surgery to restore proprioception – or the sense of the position, speed and torque of a limb – in lower limb amputees.
In July 2016, Jim Ewing became the first person to undergo a fundamentally new kind of amputation procedure, as designed by a clinical team led by Matthew Carty, MD, at Brigham and Women’s Hospital, in collaboration with Hugh Herr, PhD, and his team of biomechatronics experts at the MIT Media Lab Center for Extreme Bionics. A paper published this week in Science Translational Medicine details biomechatronic outcomes and describes the dexterity with which Ewing can use a special prosthesis that was specifically designed to take advantage of the surgical innovations present in his modified residual limb.
“We are excited to see the results of this work in Jim’s ability to interface with the prosthetic to restore proprioception and perform complex movements, which are far beyond what we typically witness in patients with standard amputations,” said Carty, of the BWH Division of Plastic and Reconstructive Surgery. “His progress is enabling us to transform limb salvage and leverage all that is technically possible to restore function.”
In the new publication, Carty and colleagues describe an agonist-antagonist myoneural interface (AMI). The new neural interface and communication paradigm, invented by researchers at the Center for Extreme Bionics at the MIT Media Lab, is able to send movement commands from the central nervous system to a robotic prosthesis, and relay proprioceptive feedback describing movement of the joint back to the central nervous system in return. The AMI involves a novel surgical approach to limb amputation in which dynamic muscle relationships are preserved within the amputated limb. Made up of two muscle-tendons (agonist and antagonist) that are surgically connected to allow one muscle to contract while the other muscle stretches, the AMI allows an amputee to control and interpret feedback from their prosthesis, including speed, location and more, based on feedback from a bionic joint.
The AMI was validated in extensive pre-clinical experimentation at MIT, prior to its first surgical implementation in a human patient at Brigham and Women’s Faulkner Hospital.
To measure the AMI’s ability to preserve dynamic muscle relationships and restore proprioception, the MIT and BWH team evaluated Ewing’s ability to control and manipulate his prosthesis in free space. The team used a functional electrical stimulation (FES) modality and also conducted interviews, comparing responses for Ewing with those of patients who had received a traditional amputation.
The team found that Ewing performed better on a variety of tasks that required controlling the prosthesis, as compared to four subjects who underwent a traditional amputation. For instance, when climbing and descending stairs, Ewing was able to flex his prosthetic foot and place it on each step in a manner that he described as “automatic” while his counterparts could not.
Based on their findings, the research team hypothesizes that the AMI provides feedback to the patient that allows them to correct and adjust limb position, speed and torque. Each time Ewing sought to moved his phantom limb, he received confirmation of correct muscle activation as stretch receptors within the AMI muscles sent signals to his brain.
The current study has its roots in a research project that received initial funding in 2014, when Carty was selected as the winner of the inaugural Stepping Strong Innovator Awards granted by The Gillian Reny Stepping Strong Center for Trauma Innovation. The awards and center were established by a family that survived the Boston Marathon bombings and committed to support groundbreaking projects in innovative trauma research and care. This support allowed the team to quickly focus on all of the foundational work that was necessary to prepare in advance of taking this innovation to the operating room.
Funding for this work was also provided by MIT Media Lab Consortia and a generous gift from Google, Inc. Prosthetic design and fabrication funded in part by US Army MRMC (W81XWH-14-C-0111).
Unlocking the Secrets of HIV’s Persistence
Researchers find that cells infected with HIV can activate a cellular program for long-term survival
Thanks to advances in the development of anti-retroviral therapy (ART), patients with HIV are living longer than ever before. And yet, even in patients on very effective, long-term ART, HIV persists, requiring patients to take antiviral medication life-long. It’s thought that the virus establishes a “persistent reservoir” of infected cells that can survive almost indefinitely. A new study by investigators at Brigham and Women’s Hospital explores how the virus gets this foothold, identifying cellular survival programs that become activated in infected cells, and providing a potential target for future therapy. Their results are published this week in Immunity.
“Our work shows that these HIV reservoir cells upregulate anti-apoptosis molecules (molecules that are otherwise expressed in cancer) that maintain their long-term survival,” said Mathias Lichterfeld, MD, PhD, of BWH’s Division for Infectious Diseases. “These findings point to clinical strategies that may reduce persisting viral reservoirs.”
In collaboration with a group led by Steve Carr, PhD, from the Broad Institute of MIT and Harvard, Lichterfeld and colleagues used quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics to take a detailed look at the proteins that were increased in cells infected with HIV. They found that BIRC5 and its partner OX40 were both involved in these cells’ long-term survival. BIRC5, also known as “survivin” is part of a family of molecules involved in cell death. It is naturally expressed in stem cells during embryonic development but generally turned off in adult cells. One exception to this generality is cancer: cancer cells frequently turn BIRC5 back on and its presence is associated with resistance to chemotherapy. The new study shows BIRC5 may also help HIV-1-infected cells to escape cell death, and contribute to the ability of viral reservoir cells to persist for decades despite effective antiretroviral therapy.
In recent years, clinicians have reported cases of patients with HIV who have had aggressive chemotherapy that has temporarily reduced viral levels to undetectable levels, but HIV has rebounded in these patients. The current study points to a new approach: inhibition of the BIRC5-OX40 pathway may help reduce reservoirs of infected cells, and potentially offer a path forward to eliminating these persisting cells.
Funding for this work was provided by This work is supported by the National Institutes of Health (AI130005, AI098487, AI117841, AI120008, AI124776, AI116228, AI078799, HL134539, AI125109, AI060354), the Harvard University Center for AIDS Research (CFAR), NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, and NCCAM.
Paper cited: Kuo HH et al. “Anti-apoptotic Protein BIRC5 Maintains Survival of HIV-1-Infected CD4+ T Cells” Immunity DOI: https://doi.org/10.1016/j.immuni.2018.04.004
Another Potential Mechanism Linking Androgen Deprivation Therapy to Cardiovascular Mortality
Study finds that androgen deprivation therapy for prostate cancer causes prolongation of QTc interval duration which could explain part of the increased risk of cardiovascular mortality and sudden cardiac death in these patients
Prostate cancer is the most common cancer in men in the US. As the prostate is a testosterone-responsive gland, androgen deprivation therapy (ADT) is the cornerstone of treatment in these men, with approximately 50 percent of prostate cancer patients starting ADT within a year of diagnosis. This therapy works by suppressing testosterone production, which in turn slows the growth of the cancer. Although ADT results in improved survival in a subset of these patients, it has many side effects, including increased risk of cardiovascular disease and sudden death. The mechanisms by which ADT may lead to an increased risk of sudden death were unclear. Now, a team of researchers from BWH has shed some light on this issue and their findings are published findings in the Journal of the Endocrine Society.
“We showed that ADT results in electrophysiological changes in the heart,” said first author Thiago Gagliano-Jucá, MD, PhD, a research fellow in the Section on Men’s Health at BWH. “The time it takes for these cells to be able to contract again after each beat increased following ADT, and prolongation of this time is a known risk factor of ventricular arrhythmias. We are trying to piece together how ADT might be resulting in sudden deaths in some men.”
Testosterone is known to shorten the time necessary for the cardiac cells (cardiomyocytes) to be able to contract again after a previous contraction. Reduced testosterone levels as a result of ADT prolongs this time, which is known as the QTc interval on the electrocardiogram. This prospective study of over 70 men found that men receiving ADT experience a prolongation of their QTc interval duration compared with those men with prostate cancer who were not receiving ADT. QTc prolongation is well established to be associated with a higher risk of arrhythmia, suggesting that the prolongation of the QTc interval during ADT might be the mechanism behind some of these cardiac events.
“Oncologists should monitor QTc interval in patients receiving ADT, especially those patients who are taking medications that also prolong QTc interval” said Gagliano-Jucá.
This study was supported by a grant from the National Cancer Institute.
Paper cited: Thiago Gagliano-Jucá et al. “Androgen Deprivation Therapy Is Associated with Prolongation of QTc Interval in Men with Prostate Cancer” Journal of the Endocrine Society DOI: 10.1210/js.2018-00039
Patients with High Lipoprotein(a) Levels May Especially Benefit from Taking PCSK9 Inhibitors
Study finds that cholesterol-lowering evolocumab treatment effectively reduces lipoprotein(a) levels, a known risk factor for heart disease
Lipoprotein(a) is a variant of LDL (low-density lipoprotein) cholesterol, and large amounts of data have shown that higher lipoprotein(a) levels are associated with an increased risk of cardiovascular events. Atherosclerosis patients with higher baseline lipoprotein(a) levels have a 26 percent greater risk of coronary death from heart attack than patients with the lowest lipoprotein(a) levels. To date, there have been limited therapies available that can effectively reduce lipoprotein(a) levels and reduce risk of cardiovascular events. In the latest analysis from the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, researchers found that PCSK9 inhibitors reduced lipoprotein(a) levels and that patients starting with higher Lp(a) levels appeared to derive greater absolute benefit from taking PSCK9 inhibitors. Their results were reported at the 86th Annual Congress of the European Atherosclerosis Society.
“In addition to its effects for reducing LDL cholesterol, PCSK9 inhibition may emerge as an important option for patients with elevated lipoprotein(a) concentration,” said first author Michelle L. O’Donoghue, MD, of the Department of Cardiovascular Medicine at Brigham and Women’s Hospital. “We have identified a therapy, evolocumab treatment, that effectively reduces lipoprotein(a) concentration.”
The FOURIER trial was a randomized, double-blind, placebo-controlled trial, which evaluated adding evolocumab to the treatment regimen in over 27,000 patients with high LDL cholesterol levels.
Evolocumab was found to significantly reduce Lp(a) levels and reduce risk of cardiovascular events. Patients with the higher baseline lipoprotein(a) levels benefited the most from evolocumab treatment, with a 24 percent decrease in the risk of heart attack, stroke or cardiovascular death. Patients with lower baseline lipoprotein(a) levels had a 15 percent reduction in risk with evolocumab treatment.
“PSCK9 inhibitors may help us achieve a dual goal in treating cardiovascular patients: We might be able to reduce both LDL cholesterol levels and lipoprotein(a) levels with this treatment,” said O’Donoghue. “This treatment was particularly effective for patients with higher Lp(a) levels, as these patients derived a greater absolute reduction in risk after evolocumab treatment.”
The FOURIER trial received grant support from Amgen. O’Donoghue has received grant funding from Amgen for an unrelated project.
Study cited: Michelle L. O’Donoghue et al. “Lipoprotein(a), PCKS9 Inhibition and Cardiovascular Risk: Insights from the FOURIER Trial” 86th Annual Congress of the European Atherosclerosis Society. May 5-8th 2018, Lisbon, Portugal