Heart failure is a very common and chronic condition defined by an inability of the heart to pump blood effectively. Over half of cases of heart failure are caused by a condition called dilated cardiomyopathy, which involves dilation of the heart cavity and weakening of the muscle. Importantly, many cases of this disease do not have a known cause and are called “idiopathic” (i.e., physicians do not know why). Over the past 2 decades, doctors and scientists started realizing the disease can cluster in families, leading them to think there is a genetic cause to the disease. This resulted in discovering multiple genes that cause this disease. Nonetheless, the majority of cases of dilated hearts that cluster in families do not have a known genetic cause. Now scientists can turn blood and skin cells into heart cells by genetically manipulating them and creating engineered stem cells called “induced pluripotent stem cells” or iPSCs. This approach enables the scientists to study what chemical or genetic changes are happening to cause the problem. Also because these cells behave similar to the cells in the heart, scientists can now test new medicines on these cells first before trying them in patients. Here we aim to collect tissue from 800 patients without a known cause for their dilated hearts (and 200 control individuals) to help accelerate our understanding of this debilitating disease and hopefully offer new and better treatments.
Heart failure is a significant health burden in California with rising hospitalization and death rates in the state. We have a very limited understanding of the disease and so far the existing treatments only slow down the disease and the changes that happen rather than target the root cause. By studying a subgroup of the dilated cardiomyopathy patients who have no identified cause, we can work on identifying genetic causes of the disease, some of the biology happening inside the heart cell, and provide new treatments that can prevent the disease from happening or progressing. Improving the outcome of this debilitating disease and providing new treatments will go a long way to helping a large group of Californians lead healthier and longer lives. There are estimates that the US economy loses $10 billion (not counting medical costs), because heart failure patients are unable to work. Hence new knowledge and developments gained from this research can go a long way to ameliorating that cost. Finally, heart failure is the most common chronic disease patients in California are hospitalized for. This research targets over half of those admissions. If this research is able to cut the hospitalization rate even by 1%, this would translate to millions of dollars in savings to the state. Continuing to invest in innovation will make our state a hotbed for the biotechnology industry, which in turn advances the state’s economic and educational status.
The proposal describes the collection of tissues to enable study of idiopathic familial dilated cardiomyopathy (IFDCM), a significant cause of heart failure. The applicant plans to collect tissue samples from 800 affected individuals with IFDCM, as well as 200 control individuals including unaffected familial members, healthy individuals and individuals with DCM of known causes, through a multicenter effort. After conversion into induced pluripotent cells (iPSC) and iPSC-derived cardiomyocytes, the applicant envisions the samples can be utilized to model the DCM in vitro to understand human disease mechanisms, to identify novel genetic causes of DCM, and to perform drug screens for identification of new therapeutic targets.
Impact and Significance
- Heart failure caused by DCM presents a substantial economic and medical burden for which treatment options are few.
- Many cases of idiopathic DCM are familial, suggesting a genetic component. The applicant’s familial sampling approach presents an opportunity to understand genetic causes of IFDCM.
- Understanding of the disease has been limited by access to human cardiomyocytes. iPSC-derived cardiomyocytes provide an otherwise unavailable, relevant cell source that enables both human disease modeling and testing of potential therapies.
- The application’s compelling rationale for studying the selected disease includes the demonstration that monogenic forms of DCM can already be modeled in vitro.
- The selection of familial cohorts for study is a strength of the application and obviates much of the concern that a given case may be driven (solely) by environmental factors.
- Evidence suggests that IFDCM is polygenic and supports the applicant’s proposed use of large patient numbers for study.
Quality of the Proposed Protocols
- The proposed protocols are excellent. They are well written with appropriate donor consent; no constraints are placed upon use of the cells and consent includes the possibility of donor follow up. Further, the PI already has similar protocols in place at the host institution.
- Reviewers praised the data management system’s strength and appropriateness for managing (de-identified) patient data. Further, the level of relevant clinical data the applicant plans to collect and the well considered plans for managing this information were impressive.
- Reviewers had some questions regarding integration of the ancillary sites with respect to transfer of patient samples and information.
- Excellent. The panel has no concerns regarding the ability to complete the proposed work as the PI is a leader in this field and enrollment at the host institution is already ongoing.
- A compelling case was made for patient recruitment at additional sites, including those outside of California.
- The budget was deemed appropriate overall.
- The panel felt a full time technician at the host institution was not justified given the anticipated daily patient workload.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- As a practicing cardiologist and leader with a relevant track record in the iPSC field, the PI is extremely well qualified to lead the proposed project.
- The strong multidisciplinary team includes qualified recruiting physicians at all sites and a capable project manager.
- PROGRAMMATIC DISCUSSION
- - A reviewer indicated that it was difficult to determine, based on current genetic understanding, if the IFDCM patient sample size should be 800, as proposed, or could be 600. Reviewers supported reducing the patient sample size to 600 in order to ensure broader disease representation among the 3000 samples planned for collection for development of the iPSC resource.
- Stephen L Minger