The urgency for establishing methods to predict major adverse cardiovascular events caused by hypertrophic cardiomyopathy (HCM) is undeniable. HCM, which affects one out of 200 to 500 people in the United States, is not only a common disease but it is the most common cause of sudden cardiac death in the United States in young athletes and young adults under 30 years old. HCM is also culpable in the development of severe cardiac disorders such as arrhythmias, stroke, and heart failure.
According to a 2018 study based on the Sarcomeric Human Cardiomyopathy Registry (SHaRe), “...among patients with HCM diagnosed <40 years of age (about one-third of the HCM population), 90 percent experience a major adverse cardiovascular event during their lifetime, 70 percent develop atrial fibrillation, 65 percent have heart failure symptoms limiting their daily life, and 30 percent develop ventricular tachycardia/ventricular fibrillation or sudden cardiac death.”
Dr. Yuichi Shimada
“Sudden cardiac death can be the first manifestation of HCM,” says Yuichi J. Shimada, MD, MPH, a cardiologist with NewYork-Presbyterian/
Dr. Shimada was introduced to HCM’s potential for a sudden death scenario during his first month as a resident fresh out of medical school. “My first rotation was on the cardiology floor. I was so enthusiastic and motivated that I stayed in the hospital on the cardiology unit every night,” recalls Dr. Shimada. “One evening, a patient who was known to have hypertrophic cardiomyopathy came into the emergency room because of sustained ventricular tachycardia. Knowing that this dangerous, potentially lethal arrhythmia could deteriorate into ventricular fibrillation, we treated him with a number of medications such as beta blocker and sotalol, but he continued to have episodes of nonsustained VT. We couldn't suppress them.”
Dr. Shimada began to notice that the patient’s episodes occurred most often during the night inspiring a revelation that the patient could have sleep apnea, which is known to worsen certain symptoms such as sympathetic nerve surge, hypoxia, and arrhythmias. “Usually sleep apnea affects people with a high BMI, but his BMI was about 19, so sleep apnea as a trigger was not top of mind,” continues Dr. Shimada. “A polysomnography showed that he had central sleep apnea, a subtype of sleep apnea not related to obesity but that does affect people with heart failure, for example. We treated the sleep apnea with CPAP therapy and that eradicated his arrhythmias.”
The case, which was published in the Annals of Noninvasive Electrocardiology in 2009, was a turning point in Dr. Shimada’s choice to pursue cardiology as a specialty. Following his residency, Dr. Shimada completed a cardiology fellowship at Brigham & Women’s Hospital, Harvard Medical School, along with specialized training in HCM at Massachusetts General Hospital, Harvard Medical School, followed by an advanced fellowship in echocardiology at Columbia. To this day, hypertrophic cardiomyopathy remains his priority focus, which he believes “is the most interesting heart disease.”
Clinical Risk Factors for Sudden Cardiac Death
According to Dr. Shimada, currently there are five major risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy as follows:
- Family history of sudden cardiac death
- Personal history of unexplained syncope over five years
- Greater than 30 millimeter left ventricular hypertrophy
- Apical aneurysm
- Left ventricular ejection fraction equal to or lower than 50 percent
“If the patient has one of these five major risk factors or more, then the 2020 American College of Cardiology guidelines for HCM indicated that ICD implantation is reasonable,” notes Dr. Shimada. “In terms of LV ejection fraction, patients with hypertrophic cardiomyopathy usually have a normal, an upper limit of normal, or even hyperdynamic left ventricular function and therefore it would be very unusual for them to have abnormally low LV ejection fraction. If the patient does not have any of these five major risk factors, then we assess two minor risk factors or predictors of sudden cardiac death – extensive late gadolinium enhancement on cardiac MRI, which clinically represents myocardial fibrosis in the left ventricle, and nonsustained ventricle tachycardia on Holter monitoring. In these cases, the guidelines also say that ICD implantation may be considered.”
A Role for Proteomics Profiling in Predicting MACE
With hypertrophic cardiomyopathy frequently implicated in major adverse cardiovascular events (MACE), Dr. Shimada and his colleagues in the Columbia Hypertrophic Cardiomyopathy Center sought to identify underlying mechanisms that lead to the development of HCM and, importantly, to uncover novel biomarkers in the blood predictive for MACE.
“Over 1,500 mutations in more than a dozen genes have been discovered to be pathogenic for HCM,” says Dr. Shimada. “Most of the time, we can find mutations in familial cases and early onset sporadic non-familial cases, however, the detection rate decreases to as low as 20 percent in late onset sporadic cases. And about 50 percent or more of patients with HCM have no identifiable mutations. Additionally, there are several limitations in the clinical application of genetic testing data in hypertrophic cardiomyopathy. The sheer number of genes and different kinds of mutations sometimes make it challenging for us to interpret the significance of each mutation. The genetic clinical correlations are weak so even family members who share the same mutation may have different phenotypes probably due to modifier genes and environmental factors. Finally, each individual gene mutation does not offer prediction of major cardiovascular events. So, we applied a new approach of measuring several thousands of proteins to see if we could improve prediction compared to the conventional clinical markers.”
With this in mind, Dr. Shimada and his HCM Center colleagues at Columbia designed a two-part study to develop a machine learning prediction model for HCM and to elucidate the molecular biological process that causes sudden cardiac death and other major cardiovascular events. Key to their study was the application of proteomics profiling, a novel technology that enables the simultaneous measurement of thousands of protein concentrations in tissue or fluid. The technology has been used in investigations of a number of cardiovascular diseases, but not in a prospective cohort of patients with HCM.
“Proteomics profiling allows us to reveal proteins that are involved in the pathological process leading to the development of, for example, sudden cardiac death, dangerous arrhythmias, or heart failure,” explains Dr. Shimada. “By analyzing the top important proteins to predict the adverse cardiovascular event, we can also gain insights into signaling pathways differentially regulated in patients who subsequently develop MACE and those who do not.”
The prospective cohort study of 245 patients with HCM involved plasma proteomics profiling of 4,979 proteins upon patient enrollment using a proteomics-based model the Columbia researchers developed to predict MACE. The analytic cohort was distributed into a training set of 174 patients followed at Massachusetts General Hospital and the predictive ability of the model was verified in an independent test set of 71 patients with HCM followed at NewYork-Presbyterian/
The study’s findings, published online in the October 11, 2022, issue of Circulation: Genomic and Precision Medicine, showed:
- In the test set, the high-risk group determined by the proteomics-based predictive model had a significantly higher rate of developing MACE.
- The Ras-MAPK (mitogen-activated protein kinase) pathway was upregulated in patients who subsequently developed MACE.
- Pathways known to be involved in inflammation and fibrosis, for example, the TGF (transforming growth factor)-β pathway, were also upregulated.
This study serves as the first to demonstrate the ability of proteomics profiling to predict MACE in hypertrophic cardiomyopathy, exhibiting both novel and known pathways differentially regulated in patients who subsequently experience MACE.
— Dr. Yuichi Shimada, et al. Circulation: Genomic and Precision Medicine
“Our study analyzed the largest number of patients with HCM undergoing proteomics profiling with the most comprehensive proteomics profiling to date,” says Dr. Shimada. “Plasma proteomics profiling makes it possible to simultaneously measure the concentrations of thousands of proteins with one blood draw of a 0.05 milliliter of blood. We were able to identify a set of proteins that can predict adverse cardiac events with a high degree of accuracy. While we examined the broader concept of cardiovascular events with outcomes related to heart failure, sudden cardiac death, arrhythmias, et cetera, each type of adverse event has its own prevention strategy. If we can predict who is likely to experience which adverse event, then we can prioritize these patients for more frequent surveillance or an intervention to prevent the adverse event from occurring.”
“Results of this study not only exhibit the utility of proteomics profiling for clinical risk stratification, but also suggest mechanisms underlying the development of adverse events,” says Dr. Shimada. “Our work in proteomics is a good example of our efforts to achieve precision medicine in HCM. That is the theme of my lab. Importantly these efforts and other research could not be done without the contribution of the patients. Their willingness to participate in research enable us to pursue better methods to use in clinical practice for predicting adverse events and developing targeted therapeutics for prevention and treatment.”
