Multi-omics Approach Sheds Light on the Leading
Inherited Cause of Heart Failure
by Adrienne Mueller, PhD
December 6, 2021
Hypertrophic cardiomyopathy, or HCM, is the leading inherited cause of heart failure and sudden death- affecting 1 in 500 individuals. Gene mutations associated with HCM cause the heart walls to thicken to such an extent that the heart’s ability to pump blood is impaired. Long-term consequences of HCM include sudden death and heart failure. There is currently no available treatment to slow disease progression, although several new drugs are in clinical trials.
Over the last two decades, we have discovered over 1000 genetic mutations associated with HCM – most of which in genes coding the contractile elements of heart muscle cells, the sarcomere. Sarcomeres, complex structures composed of a multitude of proteins, are the driving force behind heart muscle cell contraction. Studies have shown that the majority of HCM-related changes in sarcomere genes cause an abnormal increase in contractile force. To create more force, the heart muscle needs more energy. It is not known how the heart muscle copes with this increase in energy demand, and whether this results in cellular stress that contributes to HCM clinical outcomes (sudden death and heart failure)?
To address these questions, a multi-disciplinary team of Stanford researchers led by post-doctoral fellow Sara Ranjbarvaziri, PhD and her mentor Daniel Bernstein, MD used a novel multi-omics approach to profile all cellular metabolic pathways, and to determine which specific mechanisms are dysfunctional in patients with HCM. The investigators collected multiple types of data from the heart muscle cells of 27 HCM patients and 15 healthy controls, one of the largest of this type of clinical study to date. Their broad multi-omics approach consisted of a coordinated analysis of the gene expression, protein expression, lipids and metabolites, as well as microscopic tissue analysis, and tests of mitochondrial structure and function (the source of cellular energy). The authors wanted to determine whether there is a common set of metabolic problems in heart muscle cells that is shared across all HCM patients with different genetic backgrounds.
In their study, just published in Circulation, the investigators identified several key differences between HCM and control hearts; among the most striking were that HCM heart muscle cells had 1) markedly perturbed metabolic function across nearly all metabolite classes, and 2) an increase in severely defective mitochondria.
Adult heart muscle cells consume lipids to produce energy in the form of ATP, and HCM patients showed very different lipid profiles than controls. Ranjbarvaziri et al. found an accumulation of lipid-processing intermediates in HCM heart cells, suggesting that even though the cells were attempting to meet the increased sarcomeric energy demand by consuming more lipids, the cells could not fully process them. Many of these intermediates are toxic to cells, and thus the accumulation of toxic lipid intermediates may directly contribute to heart failure in HCM patients.
The investigators also showed that the mitochondria of HCM heart muscle cells were damaged and therefore unlikely to be able to meet the high energy demands of over-active sarcomeres. Normally, the heart has a mechanism (mitophagy) for removing damaged mitochondria, however, this study shows that in HCM these damaged mitochondria are not being effectively cleared by the cells’ quality control systems, further exacerbating heart failure.
In summary, Ranjbarvaziri et al. have identified several common mechanisms underlying heart muscle cell pathology in HCM: altered metabolic signaling and mitochondrial dysfunction. This severity of metabolic derangement has not been previously suspected at this early stage of HCM, since all of the patients in this study still had increased heart function, and were not in end-stage heart failure. This study also demonstrates the benefits of using an unbiased multi-omics approach to identify convergent processes in a disease with diverse underlying genetics. Finally, this study suggests that new therapeutics could treat HCM early in the course of the disease by directly acting on the shared pathologies: improving metabolic function and reducing mitochondrial injury.
Additional Stanford Cardiovascular-Institute affiliated authors who contributed to this study include Mathew Ellenberger, Giovanni Fajardo, Mingming Zhao, Alison Schroer Vander Roest, Rahel A Woldeyes, Tiffany T Koyano, Robyn Fong, Ning Ma, Lei Tian, Gavin M Traber, Frandics Chan, John Perrino, Sushma Reddy, Wah Chiu, Joseph C Wu, Joseph Y Woo, Kathleen M Ruppel, James A Spudich, Michael P Snyder, and Kévin Contrepois.