Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

A rterial stiffness is well-recognized as an important predictor of development of cardiovascular disease (CVD), 1,2 and meta-analyses of prospective cohort studies have revealed that increase in the carotid-femoral pulse wave velocity (cfPWV) is associated with an increase in the risk of development of CVD. 3,4 However, the cfPWV is measured by tonometry or Doppler, which requires specialized training and exposure of the inguinal region. 5,6Abstract-An individual participant data meta-analysis was conducted in the data of 14 673 Japanese participants without a history of cardiovascular disease (CVD) to examine the association of the brachial-ankle pulse wave velocity (baPWV) with the risk of development of CVD. During the average 6.4-year follow-up period, 687 participants died and 735 developed cardiovascular events. A higher baPWV was significantly associated with a higher risk of CVD, even after adjustments for conventional risk factors (P for trend <0.001). When the baPWV values were classified into quintiles, the multivariableadjusted hazard ratio for CVD increased significantly as the baPWV quintile increased. The hazard ratio in the subjects with baPWV values in quintile 5 versus that in those with the values in quintile 1 was 3.50 (2.14-5.74; P<0.001). Correspondence to Hirofumi Tomiyama, Department of Cardiology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Tokyo, Japan. E-mail tomiyama@ tokyo-med.ac.jp In the early 2000s, a simple device for measurement of the brachial-ankle pulse wave velocity (baPWV) was launched for clinical use. Brachial-Ankle Pulse Wave Velocity and the Risk Prediction of Cardiovascular Disease An Individual Participant Data Meta-Analysis7 baPWV is automatically measured using a separate cuff for each of the 4 limbs by an oscillometric method. baPWV may be more easily applied in clinical practice than the cfPWV because of the simplicity and ease of its measurement.7,8 baPWV has been reported to be closely correlated with the directly measured aortic PWV and cfPWV. 9 A recent meta-analysis using summary data from the literature has demonstrated that higher levels of baPWV were associated with an increased risk of development of CVD.10 However, most of the studies included in the meta-analyses were conducted in patients with a high CVD risk (patients with CVD or end-stage renal disease), and thus, the usefulness of baPWV to assess the risk of development of CVD in subjects with a low to intermediate CVD risk as assessed using the Framingham risk score (FRS) had not been clearly elucidated. Furthermore, these studies did not determine the predictive ability for CVD over that of the traditional risk factors. Therefore, we conducted a meta-analysis using individual participant data (IPD) from prospective cohort studies to clarify whether baPWV could be used as an independent marker to predict the risk of development of CVD in subjects without preexisting CVD. Methods Study PopulationJ-BAVEL (Japan Brachial-Ankle Pulse Wave Velocity Individual Participant Data Meta-Analysis of Pros...

Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, lipotoxicity, and mitochondrial dysfunction. How mitochondrial function is regulated in diabetic cardiomyopathy remains poorly understood. Mice were fed either a normal diet (ND) or a high fat diet (HFD, 60 kcal % fat). Mitophagy, evaluated with Mito‐Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with ND and 12.4% with HFD) and continued to increase after 20 weeks (p<0.05). Although we have shown recently that mitophagy during the early phase of HFD feeding is mediated by Atg7‐dependent mechanisms, the mechanisms mediating mitophagy in the heart during the chronic phase of HFD feeding remain poorly understood. Phosphorylation of ULK1 was activated and Rab9 protein level was increased in the mitochondrial fraction within 20 weeks of HFD consumption (p<0.05). By isolating adult cardiomyocytes from GFP‐Rab9 transgenic mice fed HFD, we discovered that mitochondria were sequestrated by Rab9‐positive ring‐like structures. Since ULK1 regulates Rab9‐dependent mitophagy, we fed ULK1 cKO mice with HFD for 20 weeks. In wild type (WT) mice, cardiac hypertrophy and diastolic dysfunction (EDPVR = 0.051±0.009 in ND and 0.115±0.006 in HFD) were induced after 20 weeks of HFD feeding (p<0.05). By crossing Tg‐Mito‐Keima mice with ULK1 cKO mice, we found that downregulation of ULK1 impaired mitophagy in response to ND or 20 weeks of HFD consumption (p<0.05). Deletion of ULK1 exacerbated diastolic dysfunction (EDPVR=0.115±0.006 in WT and 0.162±0.021 in ULK1 cKO, p<0.05) and even induced systolic dysfunction (ESPVR=22.74±2.13 in WT and 16.78±2.12 in ULK1 cKO, p<0.05) during HFD feeding. Electron microscopic analyses indicated that the mitochondrial cristae structure was disrupted more severely in ULK1 cKO mice with HFD feeding than control mice (p<0.05). In summary, genetic disruption of ULK1‐Rab9‐dependent mitophagy during the chronic phase of HFD feeding exacerbates mitochondrial dysfunction, thereby facilitating the development of diabetic cardiomyopathy. ULK1‐Rab9‐dependent mitophagy serves as an essential quality control mechanism for cardiac mitochondria during HFD feeding. Support or Funding Information The project was supported by AHA and NIH (5R01HL138720‐02). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia and increased plasma levels of fatty acids, which are taken up and stored in lipid droplets in the heart. Intramyocardial lipids

The Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown. Objective: We investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO). Methods and Results: We used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM. Conclusions: Although activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.