Abstract Dysregulation of autophagy in cardiomyocytes is implicated in various heart disease conditions. Beclin 1, a mammalian ortholog of yeast Atg6 and a core component of the autophagy machinery, ...plays a central role in the regulation of autophagy through activation of Vps34. Beclin 1's ability to activate Vps34 is tightly regulated via transcriptional regulation, miRNA, post-translational modification, and interaction with Beclin 1 binding proteins. Of these mechanisms, binding of Beclin 1 with Bcl-2 family proteins (Bcl-2/XL ) that negatively regulate autophagy activity has been shown to be both positively and negatively regulated by various kinases, including DAPK, ROCK1, Mst1 and JNK1, in response to external stimuli. Beclin 1's interaction with Bcl-2/XL also secondarily affects apoptosis through regulation of pro-apoptotic BH3 domain containing proteins. Thus, modulation of Beclin 1 significantly influences both autophagy and apoptosis, thereby deeply affecting the survival and death of cardiomyocytes in the heart. In this review, we discuss the signaling mechanism of autophagy modulation through Beclin 1 and therapeutic potential of Beclin 1 in heart diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Sarcoidosis is a systemic disease characterized by the development of noncaseating epithelioid granulomas in multiple organs. Despite extensive investigations over a long period of time, the ...etiology of this disease remains unknown. Cardiac involvement of this disease is the most ominous complication leading to fatal outcome. Recently, attention has been focused on isolated cardiac sarcoidosis, which exists without clinically apparent sarcoidosis elsewhere. One of the critical issues of isolated cardiac sarcoidosis is difficulty in diagnosis, since existence of the cardiac lesion should be detected from cardiac manifestations alone. Because specificity of biomarkers or sensitivity of histological examination of biopsied sample is very low, diagnosis of isolated cardiac sarcoidosis mainly depends on imaging modalities. In this review article we summarized current knowledge on the pathogenesis of sarcoidosis, clinical features of cardiac sarcoidosis especially that isolated to the heart by showing some typical cases. Utilities and problems of diagnostic imaging tests for this condition including echocardiography, cardiac magnetic resonance imaging, and fluorodeoxyglucose–positron emission tomography are discussed. Advances in pharmacological and nonpharmacological treatment for cardiac sarcoidosis have improved the prognosis of cardiac sarcoidosis to a great deal; however, there are many issues that remain to be solved in the management of isolated cardiac sarcoidosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background:Various frailty markers have been developed to guide better patient selection for transcatheter aortic valve implantation (TAVI). This study aimed to investigate the frequency and specific ...causes of unplanned hospital readmission after TAVI, and to investigate which frailty markers better predicted outcomes.Methods and Results:We retrospectively reviewed 155 patients for whom we calculated their Short Physical-Performance Battery (SPPB), Placement of AoRTic TraNscathetER Valve (PARTNER) frailty scale, frailty index, clinical frailty scale, modified Fried scale, and gait speed. The primary endpoint was unplanned readmission following TAVI. The clinical model was established using variables that were identified as independent predictors in multivariate analysis. Incremental values were assessed after adding each frailty marker to the clinical model, and were compared between frailty markers. Although unplanned readmission <30 days was 1.9%, 23% of patients had an unplanned readmission following TAVI mainly because of heart failure and pneumonia within 1 year. Frailty markers other than the modified Fried scale were independently associated with unplanned readmission. The SPPB and the PARTNER frailty scale significantly increased discriminatory performance for predicting unplanned readmission.Conclusions:Unplanned readmissions following TAVI in the present study were fewer than previously reported. There seems to be a difference between frailty markers in their predictive performance. Precise frailty assessment may result in reducing unplanned admissions after TAVI and therefore better quality of life.
Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and ...survival. Here, we show that mitophagy during myocardial ischemia was mediated predominantly through autophagy characterized by Rab9-associated autophagosomes, rather than the well-characterized form of autophagy that is dependent on the autophagy-related 7 (Atg) conjugation system and LC3. This form of mitophagy played an essential role in protecting the heart against ischemia and was mediated by a protein complex consisting of unc-51 like kinase 1 (Ulk1), Rab9, receptor-interacting serine/thronine protein kinase 1 (Rip1), and dynamin-related protein 1 (Drp1). This complex allowed the recruitment of trans-Golgi membranes associated with Rab9 to damaged mitochondria through S179 phosphorylation of Rab9 by Ulk1 and S616 phosphorylation of Drp1 by Rip1. Knockin of Rab9 (S179A) abolished mitophagy and exacerbated the injury in response to myocardial ischemia, without affecting conventional autophagy. Mitophagy mediated through the Ulk1/Rab9/Rip1/Drp1 pathway protected the heart against ischemia by maintaining healthy mitochondria.
Background:This study aimed to assess the relationship between hospital-acquired functional decline and the risk of mid-term all-cause death in older patients undergoing transcatheter aortic valve ...implantation (TAVI).Methods and Results:In total, 463 patients (mean age 85 years, interquartile range IQR: 82, 88) undergoing elective TAVI at Sakakibara Heart Institute between 2010 and 2018, who were followed up for 3 years, were enrolled in the study. Hospital-acquired functional decline after TAVI, which was defined by at least a 1-point decrease on the Short Physical Performance Battery before discharge compared to the preoperative score, was assessed. A total of 113 patients (24.4%) showed hospital-acquired functional decline after TAVI, and 50 (11.3%) patients died over a mean follow-up period of 1.9±0.8 years. Kaplan-Meier survival curves indicated that hospital-acquired functional decline was significantly associated with all-cause mortality (log-rank test, P=0.001). On multivariate Cox regression analysis, hospital-acquired functional decline was associated with a higher risk of all-cause mortality (OR 2.108, 95% CI 1.119–3.968, P=0.021) independent of sex, body mass index, advanced chronic kidney disease, and preoperative frailty, as assessed by the modified essential frail toolkit.Conclusions:Hospital-acquired functional decline is associated with mid-term all-cause mortality in older patients following TAVI. Trajectory of functional status is a vital sign, and it is useful for risk stratification in older patients following TAVI.
Heart failure pandemic is rapidly approaching in Japan, requiring nationwide actions. In particular, the Japanese Circulation Society and related societies launched the Stroke and Cardiovascular ...Disease Control Act, which was passed by the National Diet, as the first ever legislative policy measure against stroke and cardiovascular disease. In association with this, actions against heart failure pandemic from the scientific field are also important. Because heart failure pandemic is a critical problem not only in Japan but also in many developed countries, we believe the nationwide approach, as summarized here, will greatly contribute to the development of cardiovascular medicine, particularly the management and treatment of heart failure worldwide.
Background:Atrial fibrillation (AF) is a common cardiac arrhythmia, associated with increased cardiovascular morbidity and mortality including thromboembolic events. The aims of this study were to ...assess the prevalence of left atrial appendage (LAA) thrombi in Japanese non-valvular atrial fibrillation (NVAF) patients undergoing preprocedural transesophageal echocardiography (TEE) during anticoagulation therapy, and to compare the efficacy of warfarin and direct oral anticoagulants (DOAC).Methods and Results:This retrospective study reviewed records of 559 consecutive NVAF patients (445 men; age, 62±11 years) undergoing preprocedural TEE following at least 3 weeks of anticoagulation therapy. Of these, 275 patients had non-paroxysmal AF (49%). LAA thrombus was observed in 15 patients (2.7%). The prevalence of LAA thrombi was similar between the DOAC group (2.6%) and the warfarin group (2.8%, P=0.86). No patients with CHA2DS2-VASc score=0, or paroxysmal AF without prior stroke or transient ischemic attack, had LAA thrombi. On univariate analysis, non-paroxysmal AF, structural heart disease, antiplatelet therapy, larger left atrium, higher brain natriuretic peptide (BNP), reduced LAA flow, and higher CHA2DS2-VASc score were all associated with LAA thrombi. On multivariate analysis, BNP ≥173 pg/mL remained the only independent predictor of LAA thrombi.Conclusions:LAA thrombi were found in 2.7% of Japanese NVAF patients scheduled for procedures despite ongoing oral anticoagulation therapy. Incidence of thrombi was similar for patients on DOAC and on warfarin.
Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted ...accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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