Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited cardiomyopathy, with an adult incidence rate of 1:500 to 1:200.^1,2 Up to 75% of patients with HCM have left ventricular outflow tract (LVOT) obstruction under resting conditions (defined as gradients ≥30 mm Hg) or with provocation (<30 mm Hg at rest and ≥30 mm Hg with physiologic provocation).¹ Dynamic LVOT hypertrophic obstructive cardiomyopathy (HOCM) is the key mechanism leading to clinical symptoms in patients and significantly increased mortality.³ Asymmetric myocardial hypertrophy with systolic anterior motion of the mitral valve is the pathophysiologic cause of LVOT obstruction.⁴ Although medical treatment with β-blockers, nondihydropyridine calcium channel blockers, and disopyramide have a class I indication in current guidelines,¹ they are effective in reducing LVOT obstruction in less than 50% of patients resulting in a large patient population with drug-refractory sypmtoms.⁵ Therefore, effective ventricular septal reduction with either surgical myectomy or alcohol septal ablation (ASA) is the main invasive treatment for LVOT obstruction. Unfortunately, the success of ASA is limited by septal coronary anatomy and alternative nonsurgical techniques have had limited success.^6,7

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease. Although HCM has been reported to be associated with many variants of genes involved in sarcomeric protein biomechanics, pathogenic genes have not been identified in patients with partial HCM. FARS2 (the mitochondrial phenylalanyl-tRNA synthetase), a type of mitochondrial aminoacyl-tRNA synthetase, plays a role in the mitochondrial translation machinery. Several variants of FARS2 have been suggested to cause neurological disorders; however, FARS2-associated diseases involving other organs have not been reported. We identified FARS2 as a potential novel pathogenic gene in cardiomyopathy and investigated its effects on mitochondrial homeostasis and the cardiomyopathy phenotype. METHODS: FARS2 variants in patients with HCM were identified using whole-exome sequencing, Sanger sequencing, molecular docking analyses, and cell model investigation. Fars2 conditional mutant (p.R415L) or knockout mice, fars2 -knockdown zebrafish, and Fars2 -knockdown neonatal rat ventricular myocytes were engineered to construct FARS2 deficiency models both in vivo and in vitro. The effects of FARS2 and its role in mitochondrial homeostasis were subsequently evaluated using RNA sequencing and mitochondrial functional analyses. Myocardial tissues from patients were used for further verification. RESULTS: We identified 7 unreported FARS2 variants in patients with HCM. Heart-specific Fars2 -deficient mice presented cardiac hypertrophy, left ventricular dilation, progressive heart failure accompanied by myocardial and mitochondrial dysfunction, and a short life span. Heterozygous cardiac-specific Fars2 ^R415L mice displayed a tendency to cardiac hypertrophy at age 4 weeks, accompanied by myocardial dysfunction. In addition, fars2 -knockdown zebrafish presented pericardial edema and heart failure. FARS2 deficiency impaired mitochondrial homeostasis by directly blocking the aminoacylation of mt-tRNA ^Phe and inhibiting the synthesis of mitochondrial proteins, ultimately contributing to an imbalanced mitochondrial quality control system by accelerating mitochondrial hyperfragmentation and disrupting mitochondrion-related autophagy. Interfering with the mitochondrial quality control system using adeno-associated virus 9 or specific inhibitors mitigated the cardiac and mitochondrial dysfunction triggered by FARS2 deficiency by restoring mitochondrial homeostasis. CONCLUSIONS: Our findings unveil the previously unrecognized role of FARS2 in heart and mitochondrial homeostasis. This study may provide new insights into the molecular diagnosis and prevention of heritable cardiomyopathy as well as therapeutic options for FARS2-associated cardiomyopathy.

Both the second-reading mode and concurrent-reading mode have the potential to improve novice readers’ performance for breast cancer screening on an automated breast US. BackgroundComputer-aided detection (CAD) systems may be used to help radiologists interpret automated breast (AB) US images. However, the optimal use of CAD with AB US has, to the knowledge of the ...

Background: Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis with poor prognosis. Currently, the predictors of cardiac involvement and prognostic staging systems are primarily based on conventional echocardiography and serological biomarkers. We used three-dimensional speckle tracking echocardiography (STE-3D) measurements of strain, hypothesizing that it could detect cardiac involvement and aid in prediction of mortality. Methods: We retrospectively analysed 74 consecutive patients with biopsy-proven AL amyloidosis. Among them, 42 showed possible cardiac involvement and 32 without cardiac involvement. LV global longitudinal strain (GLS), global radial strain, global circumferential strain and global area strain (GAS) measurements were obtained. Results: The GLS and GAS were considered significant predictors of cardiac involvement. The cut-off values discriminating cardiac involvement were 16.10% for GLS, 32.95% for GAS. During the median follow-up of 12.5 months (interquartile range 4–25 months), 20 (27%) patients died. For the Cox proportional model survival analysis, heart rate, cardiac troponin T, NT-proBNP levels, E/e’, GLS, and GAS were univariate predictors of death. Multivariate Cox model showed that GLS ≤ 14.78% and cardiac troponin T ≥ 0.049 mg/l levels were independent predictors of survival. Conclusions: STE-3D measurements of LV myocardial mechanics could detect cardiac involvement in patients with AL amyloidosis; GLS and cardiac biomarkers can provided prognostic information for mortality prediction.