In this study, we compared the myocardial metabolism between patients with clinically severe and mild HCM using DESI-IMS. We revealed that the myocardium in the clinically severe HCM group had significantly higher levels of DHA.
Our study is unique because it used the DESI-IMS to highlight the details of FA metabolic disorders. To date, the following studies have been conducted on this topic: one used resected myocardium from patients with severe HF in whom heart transplant was indicated  and the other used resected myocardium from patients with hypertrophic obstructive cardiomyopathy in whom septal myectomy was indicated . However, only the severe cases were examined, and IMS was not used for analysis in both studies. Although EMB is an invasive procedure, it is a validated method for diagnosing cardiomyopathies [7, 12]. EMB can be performed irrespective of the presence of clinical symptoms and their degree of severity, to differentiate even the early or mild phase of other cardiomyopathies from HCM. Therefore, this study could include the mild cases. However, a non-invasive method will be required to accurately determine if DHA accumulates in the myocardium or not, especially in asymptomatic or mildly symptomatic patients with HCM.
Adenosine triphosphate (ATP) production in the myocardium mainly relies on the mitochondrial oxidation of FA, carbohydrates, ketone bodies, and amino acids. The remaining ATP is produced through aerobic glycolysis . In normal hearts, FAs account for the majority of oxidative metabolism. However, in hypertrophied hearts, FA oxidation is reduced, and glucose utilization is increased . Therefore, it can be assumed that FA pooling is enhanced in hypertrophied myocardium. Ranjbarvaziri et al. reported that free FA accumulation in HCM myocardium was significantly higher than that in normal myocardium . Additionally, they stated that the dysregulation in FA metabolism in HCM myocardium may be caused by mitochondrial damage and reduced citrate synthase activity which was associated with increased reactive oxygen species, based on the findings from electron microscopy and integrated molecular pathway level analysis. This report supports the hypothesis that some free FAs, including DHA, are not properly metabolized, and are abnormally pooled in the hypertrophied myocardium.
However, the fact that the intensity of DHA was higher in the myocardium obtained from the severe HCM group shows that DHA could have some implications, rather than decreased FA oxidation in hypertrophied hearts.
DHA is an omega-3 polyunsaturated fatty acid (PUFA), that has been reported to have several beneficial effects on the human body, such as anti-inflammatory and anti-atherosclerotic effects. Omega-3 PUFAs have been reported to have anti-remodeling and anti-fibrotic effects on the myocardium in mice . DHA in particular has been reported to accumulate in cardiac tissues compared to other omega-3 PUFAs (regardless of supplementation). DHA rather than EPA supplementation reduces vulnerability to atrial fibrillation . In this study, the signal intensity of DHA in the clinically severe HCM group was significantly higher than that of the clinically mild HCM group, even though all the patients did not receive DHA supplementation. Previous studies reported DHA to have an inhibiting effect on phenylephrine-induced cardiac hypertrophy under in-vitro situations [17, 18]. However, another report from an in-vivo animal investigation documented the serum DHA concentration in HCM was not higher than the control . Integrating these results, DHA itself has cardioprotective effects; however, its utilization might be dysregulated under the condition of severe HCM with mitochondrial damage.
Although the precise mechanism of upregulation of DHA in severe HCM myocardium is unknown, we could hypothesize that higher oxidative stress in severely hypertrophied myocardium induces the accumulation of DHA.
From the analysis using DESI-IMS, the intensity of DHA was significantly higher in the EMB samples from the clinically severe HCM group than in those from the mild HCM group. DHA may play an important role in the pathophysiology of worsening HF in patients with HCM.