Isolated Noncompaction of the Ventricular Myocardium

By Seth Bogner, HeartPoint Global In pediatric cardiology, a persistent challenge revolves around ensuring accessible and effective care for children grappling with congenital heart disease (CHD). CHD affects approximately 1.7% of newborns globally, or 2.4 million, of which 90% have the urgent need for affordable and specialized treatments that call for innovative solutions. According to a recent article in The Journal of the American College of Cardiology (JACC), economic constraints in many developing nations contribute to delayed diagnosis and treatment for up to 90% of children with CHD, leading to severe consequences such as organ dysfunction and complications like profound cyanosis and polycythemia. A few years ago, I met with an interventional cardiologist in his office. I couldn’t help but notice a cardiac guidewire displayed on the wall behind his desk. When I asked about it, he shared an astonishing fact — it had been used in surgeries over 200 times in Myanmar. This highlighted the severe shortage of medical supplies and expertise in many developing nations. Typically, a guidewire is a single-use item meant to be discarded after one use. The cardiologist, amazed by the guidewire’s extensive use, felt the need to commemorate this as a testament to the challenges faced in those regions. This encounter sparked my inspiration and determination to bring easily accessible technology to the developing world, especially for individuals who often lack the means or access to surgeries that we take for granted in Western countries. Developing IntelliStent The journey with my team began in the lab, focusing on innovation around a transcatheter pulmonary artery band, an intervention that can be placed and adjusted without the risks associated with surgery. A transformation in pediatric cardiac care emerged with IntelliStent — a transcatheter device designed to regulate blood flow within the intravascular space , addressing the urgent need for affordable and specialized care. With traditional therapeutic strategies, the emphasis is on symptom improvement, leaving a significant unmet clinical need, especially in the pediatric population, where heart transplantation is the only life-saving option for end-stage dilated cardiomyopathy (DCM). IntelliStent introduces a paradigm shift, especially concerning existing therapies for pediatric dilated cardiomyopathy. Current treatments often fall short, leading to considerations of left ventricular assist devices (LVAD) and transplantation which is not available for patients that don’t live in a country with a well-developed and funded healthcare system This presents significant challenges, especially in the pediatric age range. IntelliStent emerges as a viable and cost-effective alternative, providing a temporary bridge to improve left ventricle function. When pharmaceutical interventions fall short; the next step may be the use of a LVAD and transplantation, but these options are not widely available, creating challenges even in the U.S. due to the scarcity of organ transplants in the pediatric age group. Consequently, the rationale behind placing a band into the pulmonary arteries becomes evident — a strategy to elevate the pressure in the right ventricle and reshape the interventricular septum’s morphology. This approach proves beneficial for infants, either leading to improvement with the band alone or serving as a bridge to transplant. The placement procedure is straightforward and has minimal risk compared to installing an artificial heart. IntelliStent, a specific arrangement of stents applicable throughout the vascular system, holds the potential for various scenarios requiring pressure or flow reduction in vessels. Looking ahead, there is a growing interest in exploring the translation of this experience for adults. Notably, the cost comparison is striking. While an LVAD in the U.S. incurs a million-dollar annual expense per patient, IntelliStent, by an order of magnitude, is significantly more cost-effective, with costs centered around the intervention rather than an annual basis. The ability to place and adjust this band without resorting to surgical procedures is a highly sought-after advancement. While pulmonary artery band surgery is an option for specific cases, the global limitations in congenital cardiac surgery often mean that complete repair or pulmonary artery band placement is not readily available, especially for left-to-right shunts resulting from common congenital defects. The introduction of a transcatheter pulmonary artery band becomes crucial in regions where access to congenital cardiac surgery is restricted, offering a potential lifeline for children at risk of developing Eisenmenger syndrome. This approach serves as a means of safeguarding the lungs from excess flow and pressure in the presence of unrepaired congenital cardiac defects, providing a life-saving option for both children and adults with congenital heart malformations. The timing of pulmonary artery band placement hinges on preventing progression to the irreversible stage of shunting, offering flexibility for intervention at any age for those at risk of Eisenmenger syndrome. IntelliStent’s global impact Once granted public approval, this groundbreaking device will be disseminated globally, catering to both the developing and developed worlds. The immediate focus lies on meeting the unmet needs, providing access to cardiac care for pediatric patients currently devoid of such resources in the U.S., marking a pivotal step in extending life-saving interventions to those in need. In developing nations, left ventricular dilated cardiomyopathy is left untreated. Collaborations with organizations like the Eurasia Heart Foundation aim to make a significant impact globally, focusing on working closely with the FDA to bring affordable and specialized care to those in need. The significance of transcatheter procedures becomes clear when considering the risks associated with general anesthesia during surgery. IntelliStent offers a safer alternative with the ability to conduct transcatheter procedures under moderate sedation. The flexibility to adjust flow and pressure over time, its lower cost, and reduced risk of complications position IntelliStent as a groundbreaking solution. The unique adaptability of IntelliStent is highlighted by its adjustability, allowing modifications that are not only available during the initial intervention but also at later stages as patient conditions evolve. The importance of accurate restriction of flow is paramount, with the capability to adjust allowing it to be a patient-centric approach with minimal risks. Imaging studies can be conducted while the patient is awake and follow-ups are less frequent, reducing the burden on both patients and healthcare resources. Four successful rounds of preclinical studies have laid the foundation for IntelliStent’s safety and efficacy. The system’s ability to achieve the desired effect at a lower rate of pressure reduction enhances patient safety. In-human clinical trials are imminent, focusing on evaluating safety before exploring applications in small children. The future looks bright, with cardiovascular medtech innovation as a beacon of hope for improved and affordable pediatric cardiac care globally. Seth Bogner is chair and CEO of HeartPoint Global Inc., which provides global, breakthrough medical solutions for cutting-edge cardiac care that are affordable, safe, and minimally invasive. Heartpoint Global is the Cardiovascular Research Foundation (CRF) TCT 2023 Shark Tank (Innovation) Competition winner. How to submit a contribution to MDO The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design & Outsourcing or its employees.

SAN FRANCISCO, May 31, 2019 /PRNewswire/ -- Congenital heart disease occurs in up to 1 percent of live births, and the affected infants may require multiple surgeries, life-long medication, or heart transplants. In many patients, the exact cause of congenital heart disease is unknown. While it is becoming increasingly clear that these heart defects can be caused by genetic mutations, it is not well understood which genes are involved and how they interact. Genetic mutations, also called genetic variants, can also cause poor heart function, but the type and severity of dysfunction varies widely even among those with the same mutation. Although the Human Genome project allowed scientists to identify rare cases of disease caused by severe mutations of a single gene, scientists believe that more common forms of disease may result from a combination of subtle genetic mutations acting together. Yet experimental proof for this concept of human disease has remained elusive—until now. In a paper published in the journal Science, scientists from the Gladstone Institutes and the University of California, San Francisco (UCSF) used technological advances to prove that three subtle genetic mutations inherited within a family worked together to cause heart disease in multiple siblings at a very young age. "The idea that several genetic variants are necessary to cause most complex diseases has been around for a long time, but proving it has been difficult," said Casey Gifford, PhD, a staff scientist at Gladstone who is the first author on the paper. "With the advent of CRISPR genome editing and improvements in human pluripotent stem cell technology, we felt that we finally had the right tools to test this hypothesis once we found the right case to study." The right case turned out to be a family in which multiple children suffered from the same form of severe congenital heart disease that resulted in poor pumping of the heart. Deepak Srivastava, MD, first encountered the family over a decade ago when he treated a 2-month-old child for left ventricular noncompaction, a type of heart disease where the cells in the left ventricle don't mature fully and therefore can't contract well, leading to heart failure. While this child survived after requiring emergency life-support, she had a sibling who died from the same condition as a fetus in the third trimester, and her 4-year-old sister also had a similar condition. After running tests on both parents' hearts, the researchers learned that the father also had a milder, adult-onset version of the disease, while the mother's heart was normal. "Given the severity of the disease in the children and the fact that one of the parents had an asymptomatic form, we suspected that the condition in the children was caused by a combination of the mother and the father's genes," says Srivastava, Gladstone president and cardiologist at UCSF Benioff Children's Hospitals, who is the senior author on the paper. To test this theory, the researchers sequenced the genome of the family and discovered that the father had mutations in two genes, MKL2 and MYH7, that placed him at risk for heart disease. There are normally two copies of each gene in our genome, and in this case, only one copy of MKL2 and MYH7 was mutated, resulting in a change of just one of hundreds of amino acids. All three children not only inherited both of these mutations from their father, but also a third mutation from the mother disrupting one copy of the gene NKX2-5. This mutation affected only one amino acid and has been reported in the general population without heart disease. But the children also shared many other genetic variants in common, so whether altering just one copy of these three genes was enough to cause disease remained an open question. Using CRISPR genome editing, Srivastava's team created the exact same mutations on one copy of each gene in mice. The mice that only harbored one copy of the father's two variants or the mother's variant didn't show any signs of heart disease. Remarkably, mice that had all three mutations showed heart defects that mimicked those observed in the children. There was not only damage to the structure and function of the heart similar to the human disease, but also changes in the expression of hundreds of other genes essential for development of the heart and coronary vasculature. "Our findings suggest that the gene inherited from the mother exacerbated the problem caused by the father's genes, resulting in a much more severe form of heart disease in the children," explained Gifford, who was a Damon Runyon Cancer Research Foundation Fellow when she performed the research. In a final step, the researchers generated induced pluripotent stem cells from each of the family members and then turned the stem cells into beating heart cells. The cells from the children, which carried all three mutations, showed signs of disease, while the parents' cells did not. The researchers say the study answers an important question about how people with the same gene mutation can have different forms of the disease. For example, mutations of the gene MYH7 have previously been implicated in several different types of both congenital and adult-onset heart disease. The new data suggest that a modifier gene, in this case, NKX2-5, influences the effect of MYH7 mutations to change how disease manifests. "This work finally provides experimental proof of how a modifier gene might be functioning to influence the disease process in humans, and how multiple genes work together to cause human disease," said Srivastava, who is also a professor of pediatrics and biochemistry and biophysics at UCSF. "It points us to a way that you could make a mutation in a gene better or worse depending on what it's combined with. This discovery opens the door to identifying genetic modifiers of disease and using them as targets to develop novel therapeutics." About the Research Project The paper, "Oligogenic inheritance of a human heart disease involving a genetic modifier," was published online in Science on May 31, 2019. The work was funded by grants from the Damon Runyon Cancer Research Foundation, the California Institute of Regenerative Medicine, the National Institutes of Health, The Roddenberry Foundation, the L.K. Whittier Foundation, and the Younger Family Fund. Additional study participants and co-authors are Sanjeev S. Ranade, Ryan Samarakoon, Hazel T. Salunga, T. Yvanka de Soysa, Yu Huang, Ping Zhou, Aryé Elfenbein, Stacia K. Wyman, Yen Kim Bui, Kimberly R. Cordes Metzler, and Kathryn N. Ivey from Gladstone, as well as Philip Ursell from UCSF. About the Gladstone Institutes To ensure our work does the greatest good, the Gladstone Institutes focuses on conditions with profound medical, economic, and social impact—unsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. It has an academic affiliation with the University of California, San Francisco. Media Contact: Julie Langelier | Assistant Director, Communications | julie.langelier@gladstone.org | 415.734.5000