“By inducing proliferation in cardiac heart muscle cells, we hope to be able to treat this deadly disease.” Mohamed said. “In this study, we have demonstrated preliminary efficacy of the transient gene therapy we call 4F in the treatment of ischemic heart failure.” 

The most common form of heart disease, ischemic heart disease affects about 18.2 million adults in the United States and caused 360,900 deaths in 2019. Also called coronary heart disease, it is characterized by reduced blood and oxygen flow to the heart due to narrowed arteries, usually caused by a buildup of plaque. When the blood flow to the heart muscle is completely blocked, the patient experiences a heart attack and millions of heart muscle cells die.

Since heart muscle cells do not reproduce readily and limited medical options exist to repair heart muscle, a heart attack often leads to progressive heart failure.

The therapy developed by Mohamed’s team involves a combination of four cell-cycle regulator genes, cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1, known collectively as 4F, or four factors. Using 4F, the UofL-led team was able to stimulate the proliferation of heart muscle cells in the lab, leading to improved heart function in animal models for up to four months.

In addition, the proliferation was limited to onecycle, avoiding adverse effects resulting from uncontrolled proliferation, thereby increasing clinical feasibility of the process.

Mohamed was part of a team that first identified the potential of the of heart muscle cells in 2018. In this most recent work, he and his team further refined the process to use these genes, bringing the technology to treat ischemic heart disease closer to testing in humans. was published Jan. 21 in the journal Circulation.

In October, Mohamed and Bradford Hill, professor in the Division of Environmental Medicine, led a team that showing that two common food supplements, Nicotinamide (Vitamin B3) and N-acetyl glucosamine (GlcNAc), are essential for heart cell division and improve cardiomyocyte proliferation when included as part of treatment with 4F.

“This discovery will facilitate new avenues to use metabolites which are naturally in our food to regenerate the diseased heart and treat heart failure,” Mohamed said.

The study utilized a  developed at UofL by Mohamed that keeps slices of human hearts alive for a longer period of time for research. The system mimics the environment of a living organ through continuous electrical stimulation and oxygenation, maintaining viability and functionality of the heart segments for six days, allowing more extensive testing. The  for use by researchers outside UofL.

The investigational device, currently intended as a bridge to heart transplant, is part of an Early Feasibility Study (EFS) sponsored by CARMAT, a French medical device company, in partnership with UofL, UofL Health – Jewish Hospital and the UofL Health – Trager Transplant Center.

Led by cardiothoracic surgeons Mark Slaughter and Siddharth Pahwa, both of UofL Health – UofL Physicians and the UofL School of Medicine, the team performed the implant of the device on Sept. 14, 2021 at UofL Health – Jewish Hospital. The same team completed the nation’s second implantation in a male patient last month, also at Jewish Hospital.

“For the other half of the world’s population, completion of this procedure by the Jewish Hospital team brings new hope for extended life,” said Slaughter, UofL Health surgical director of heart transplant and professor and chair of the Department of Cardiovascular and Thoracic Surgery in the UofL School of Medicine. “Size limitations can make it harder to implant artificial hearts in women, but the Aeson artificial heart is compact enough to fit inside the smaller chest cavities more frequently found in women, which gives hope to a wider variety of men and women waiting for a heart transplant and increases the chances for success.”

More than 3,500 individuals are awaiting a heart transplant in the U.S. and 900 of them are women. There are few treatment options for patients with biventricular heart disease, meaning both the left and right sides of the heart are not pumping blood adequately. The Aeson device is designed to solve the limitations of current left-ventricular assist devices, which pump blood in just one chamber, by pumping blood in both heart chambers.

Aeson also contains pressure sensors that estimate the patient’s blood pressure and automatically adapts cardiac output according to the sensor information. It is fully implanted as a heart replacement and powered by a portable external power supply.

During this procedure, the Aeson total artificial heart was implanted into a 57-year-old Kentucky woman with severe biventricular heart failure during an eight-hour surgery. The recipient, whose identity is being withheld upon request, was referred to the Advanced Heart Failure Therapies Program at Jewish Hospital earlier this year with end-stage heart failure and had undergone cardiac surgery years before. The patient is recovering well in the cardiovascular intensive care unit. Jewish Hospital is just one of four programs in the nation approved to perform this clinical trial procedure.

“The varying pumping ability of the Aeson device increases its viability among more patients,” said Pahwa, UofL Physicians cardiothoracic surgeon and assistant professor in the UofL Department of Cardiovascular and Thoracic Surgery. “While other devices are set at a fixed rate or create a continuous flow, CARMAT has developed the Aeson to automatically adjust the flow, creating an improved performance to meet the body’s changing blood flow needs.”

Currently, the Aeson artificial heart is tested as a bridge to transplant for patients with end-stage biventricular heart failure, allowing more time for the patient to receive a permanent heart organ transplant. The device already has been approved for such use in Europe, where approximately 20 devices have been implanted. It currently is being tested in the U.S. as part of a feasibility study approved by the Food and Drug Administration. The first Aeson artificial heart in North America was implanted in a male patient in July at Duke University Medical Center. The second implantation, also in a male patient, was performed at Jewish Hospital in August. This third North American implantation is the first to involve a female patient.

“Even as we have fought this deadly pandemic, our researchers and health care providers have also been on the front lines of improving care and quality of life for not only Kentuckians, but for people around the world,” said Kentucky Gov. Andy Beshear. “I am proud that UofL, Jewish Hospital and their doctors are leading the world in implanting this promising and innovative device that could offer hope and time to thousands of people, including our wives, mothers and other loved ones, in coming years.”

Stéphane Piat, chief executive officer of CARMAT, said, “This third implant in the U.S. was a landmark event not only because it allowed us to finalize the enrollment of the first cohort of patients of the EFS, but very importantly because it is the first time ever that our device has helped a woman suffering from heart failure. This achievement confirms that the size limitations for adults are minimal, which makes us very confident in Aeson’s potential to become a therapy of choice for a broad patient population.”

Preclinical research for CARMAT’s artificial heart began at UofL more than five years ago. Researchers at UofL’s Cardiovascular Innovation Institute tested Aeson’s autoregulation capability, which allows the device to adapt its flows according to the patient’s needs by detecting changes of pressure in the device. UofL researchers have conducted preclinical testing of artificial heart components and mechanical assist devices at CII for many years, testing some portion of nearly every mechanical assist device that is commercially available today.

Jewish Hospital and the University of Louisville share a storied history in advancing heart care. Highlights include:

• Aug. 24, 1984: Kentucky’s first heart transplant performed at Jewish Hospital by UofL physicians
• July 2, 2001: The world’s first AbioCor artificial heart was implanted at Jewish Hospital by UofL physicians, led by cardiothoracic surgeon Laman Gray
• Dec. 21, 2011: Kentucky’s first transcatheter aortic-valve replacement performed at Jewish Hospital by UofL physicians
• Jan. 18, 2015: Kentucky’s first HeartMate 3 left ventricular assist device implanted at Jewish Hospital by UofL physicians
• Feb. 21, 2018: UofL Health – Trager Transplant Center’s 500^th heart transplant performed at Jewish Hospital
• June 14, 2019: The first EvaHeart2 LVAD implanted as bridge to transplant at UofL Health – Trager Transplant Center
• April 22, 2021: UofL Health – Trager Transplant Center’s 1000^th TAVR performed at Jewish Hospital

“This world-first artificial heart implant into a female patient is another demonstration of UofL Health’s commitment to provide both the world-class care of today and develop the world-class standards of tomorrow,” said John Walsh, chief administrative officer of Jewish Hospital. “We celebrate this first as a milestone and recognize the hard work of Drs. Slaughter and Pahwa and the entire team. The true impact of their work will be measured in the dozens, hundreds and thousands of lives improved in the years to come.”

The patient who received the nation’s second Aeson implant, on Aug. 20, 2021, continues to improve at Jewish Hospital. An update is expected in the coming weeks.

“This is a very important advance in the field of cell therapy and in the management of heart failure. It suggests that a treatment, given only once, can produce long-term beneficial effects on the quality of life and prognosis of these patients,” said Roberto Bolli, director of the UofL Institute of Molecular Cardiology, who led the study at UofL. “The results pave the way for a larger, Phase 3 trial of cell therapy in heart failure.”

UofL led enrollment among seven institutions participating in CONCERT-HF, a Phase 2 clinical trial testing the safety, feasibility and efficacy of two types of adult cells, used alone and in combination, in patients with heart failure.

CONCERT-HF evaluated the use of two types of cells – autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs) – alone or in combination, in patients with heart failure caused by chronic ischemic cardiomyopathy, a decrease in heart pumping effectiveness due to heart attacks and a lack of blood getting to the heart. Autologous MSCs are derived from the patient’s bone marrow and CPCs are from the patient’s heart tissue. Both are known as “autologous” cells because they come from the same patient in whom they are returned for the treatment.

In the study, patients treated with CPC cells alone had a significant reduction in major adverse cardiac events, particularly hospitalization. Patients treated with MSC cells alone and with a combination of both types of cells experienced significantly improved quality of life compared with patients who received no treatment. Quality of life was assessed using patient responses to the Minnesota Living with Heart Failure Questionnaire, which gauges the degree to which physical, emotional and socioeconomic effects of heart failure adversely affect the patient’s life and the extent to which they prevented the patient from living as they wanted to live.

“The results of this trial show for the first time that cell therapy reduces hospitalization for heart failure and improves clinical outcome, providing a cogent rationale for undertaking a pivotal Phase 3 trial” that could be the next step on the pathway to FDA approval, Bolli said.

The results of the were published in the . The Phase 2, randomized, placebo-controlled trial, funded by NIH National Heart, Lung and Blood Institute, was conducted by the Cardiovascular Cell Therapy Research Network, a network of clinical trial researchers involved in cell therapy for heart disease that includes UofL. UofL led enrollment in the study, accounting for 25% of the 125 trial participants.

Bolli’s expertise and long career in successful cardiac research led to the establishment of the CCTRN center at UofL in 2011. This consortium of leading cardiovascular research organizations includes Stanford University, the University of Miami, Indiana University, the Texas Heart Institute, the University of Florida and the Minneapolis Heart Institute Foundation, in addition to UofL. The School of Public Health at the University of Texas Health Science Center at Houston serves as the data coordinating center.

Bolli is a pioneer in research using adult stem cells for cardiac disease. Over the past two decades, he has shown that CPCs are beneficial in many preclinical models of heart failure, thus paving the way for the CONCERT-HF trial. He also led the recent – the first study to show safety and potential efficacy of cell therapy in cancer survivors with heart failure caused by anticancer therapy.

Roberto Bolli, MD, director of the University of Louisville Institute of Molecular Cardiology, announced today that a new research trial funded by NIH National Heart, Lung and Blood Institute, the CONCERT-HF Study, is now open to enroll patients. The study is a Phase II, randomized, placebo-controlled trial of the safety, feasibility and efficacy of two types of adult stem cells used alone and in combination in patients with heart failure.

In addition to UofL, the study centers are Stanford University, the University of Miami, Indiana University, the Texas Heart Institute, the University of Florida and the Minneapolis Heart Institute Foundation. The School of Public Health at the University of Texas Health Science Center at Houston will serve as the data coordinating center.

In the study, two types of stem cells will be studied. Both are known as “autologous” stem cells because they come from the same patient in whom they are returned. The two types of adult stem cells used are autologous mesenchymal stem cells (MSCs) and c-kit+ cardiac stem cells (CSCs). MSCs will be manufactured from the patients’ own bone marrow while CSCs will be manufactured from the patients’ own heart tissue.

Bolli, who also serves as scientific director of the Cardiovascular Innovation Institute at UofL, is a pioneer in research using adult stem cells for cardiac disease. In the landmark 2011 SCIPIO trial, he and his research team were the first to successfully show the safety and potential efficacy of autologous c-kit+ stem cells taken via cardiac biopsy from patients who had suffered a previous heart attack.

SCIPIO enrolled 20 stem cell-treated patients with heart failure at UofL; four of the 20 patients discontinued the trial. Although definitive conclusions cannot be made because of the small number of patients, the results suggest a remarkable efficacy of autologous cardiac stem cells. After one year, the 16 patients in the study showed a 40 percent increase in the amount of blood their hearts were pumping. Moreover, MRIs in some patients showed significantly less dead heart tissue after the trial therapy, suggesting that the adult stem cell therapy was regenerative in nature.

Bolli practices with UofL Physicians. His success with the SCIPIO trial and his overall body of work, comprising more than 30 years of cardiac research, led to his successful grant application to establish a (CCTRN) center at UofL. This consortium of leading cardiovascular research organizations is sponsored by the National Heart, Lung, and Blood Institute and conducts early clinical trials of adult stem cell therapies in patients with cardiovascular disease.

“I continue to believe that adult stem cells could be the greatest advancement in cardiovascular medicine in my lifetime,” Bolli said. “CONCERT-HF is very important because it will help determine whether c-kit cardiac stem cells are effective and whether combining two stem cell types is more effective than giving one cell type alone.”