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Layer-specific proteomic analysis of human hearts in patients with sudden cardiac death
Yu Kakimoto1, Xueting Guan1, Atsushi Ueda1
1Department of Forensic Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Insights
Decreased levels of mitochondrial and calcium-handling proteins in the inner heart layer, including PKP2 and RYR2, are linked to sudden cardiac death (SCD) in cardiac hypertrophy (CH) patients. These proteomic changes may aid in postmortem SCD diagnosis.
Area of Science:
- Cardiology
- Proteomics
- Molecular Biology
Background:
- Decreased longitudinal strain predicts sudden cardiac death (SCD) in cardiac hypertrophy (CH) patients.
- The heart wall has distinct inner longitudinal, middle circular, and outer longitudinal layers.
- Layer-specific proteomic changes may influence SCD risk.
Purpose of the Study:
- To investigate layer-specific proteomic differences in the left ventricular wall.
- To identify potential proteomic biomarkers for sudden cardiac death (SCD) in cardiac hypertrophy (CH).
Main Methods:
- Human cardiac tissues from SCD, CH, and control cases were analyzed.
- Cardiomyocytes were isolated from three distinct left ventricular wall layers using laser microdissection.
- Proteomic analysis was performed using liquid chromatography-tandem mass spectrometry and label-free quantification.
Main Results:
- Cardiomyocytes were enlarged in SCD and CH cases; myocardial fibrosis did not significantly progress.
- Proteomic profiles differed between control and SCD/CH cases, particularly in the inner layer.
- Mitochondrial and calcium-handling proteins, including PKP2 and RYR2, were decreased in SCD hearts, showing stepwise reduction from control to CH to SCD.
Conclusions:
- Proteomic alterations, especially in the inner heart layer, precede myocardial fibrosis progression.
- Decreased PKP2 and RYR2 levels in arrhythmogenic pathways were observed.
- Proteomic analysis may improve postmortem diagnosis of SCD in asymptomatic individuals with CH.
Background:
Recent studies have shown that decreased longitudinal strain in speckle-tracking echography can predict sudden cardiac death (SCD) in patients with cardiac hypertrophy (CH). Histologically, the heart wall consists of the inner longitudinal, middle circular, and outer longitudinal layers. Thus, layer-specific proteomic changes may contribute to SCD risk.
Methods:
The three layers in human cardiac tissues were obtained during autopsies of SCD, compensated CH, and control cases (18 cases aged > 40 years, 54 samples in total). SCD cases consisted of patients with ischemic or hypertensive heart failure, whereas CH and control cases were accidental deaths. After histological analysis, cardiomyocytes were collected separately from the three layers of the left ventricular wall using laser microdissection. The extracted proteins were analyzed using liquid chromatography-tandem mass spectrometry, followed by label-free quantification.
Results And Discussion:
Histologically, cardiomyocytes were enlarged in all layers of SCD and CH cases without significant progression of myocardial fibrosis. The proteomic profiles of SCD and CH cases were distinguishable from those of control cases, especially in the inner layer. The levels of mitochondrial and calcium-handling proteins were significantly decreased in SCD hearts. Arrhythmogenic changes, including decreased PKP2 and RYR2 levels, developed in a stepwise manner from control through CH to SCD, most prominently in the inner layer. Immunohistochemical analysis showed reduced levels of PKP2 in intercalated disks and RYR2 in sarcomeres. Because proteomic alterations precede the progression of myocardial fibrosis, their detection may enhance the accuracy of postmortem diagnosis of SCD in middle-aged and older asymptomatic individuals with CH.
