Cardiovascular disease constitutes a major and increasing health burden in developed countries. Although treatments have progressed, the development of novel treatments for patients with ...cardiovascular diseases remains a major research goal. The endoplasmic reticulum (ER) is the cellular organelle in which protein folding, calcium homeostasis, and lipid biosynthesis occur. Stimuli such as oxidative stress, ischemic insult, disturbances in calcium homeostasis, and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins, a condition referred to as ER stress. ER stress triggers the unfolded protein response (UPR) to maintain ER homeostasis. The UPR involves a group of signal transduction pathways that ameliorate the accumulation of unfolded protein by increasing ER-resident chaperones, inhibiting protein translation and accelerating the degradation of unfolded proteins. The UPR is initially an adaptive response but, if unresolved, can lead to apoptotic cell death. Thus, the ER is now recognized as an important organelle in deciding cell life and death. There is compelling evidence that the adaptive and proapoptotic pathways of UPR play fundamental roles in the development and progression of cardiovascular diseases, including heart failure, ischemic heart diseases, and atherosclerosis. Thus, therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat cardiovascular diseases. In this review, we summarize the recent progress in understanding UPR signaling in cardiovascular disease and its related therapeutic potential. Future studies may clarify the most promising molecules to be investigated as targets for cardiovascular diseases.
Heart diseases due to myocardial ischemia, such as myocardial infarction or ischemic heart failure, are major causes of death in developed countries, and their number is unfortunately still growing. ...Preliminary exploration into the pathophysiology of ischemia-reperfusion injury, together with the accumulation of clinical evidence, led to the discovery of ischemic preconditioning, which has been the main hypothesis for over three decades for how ischemia-reperfusion injury can be attenuated. The subcellular pathophysiological mechanism of ischemia-reperfusion injury and preconditioning-induced cardioprotection is not well understood, but extensive research into components, including autacoids, ion channels, receptors, subcellular signaling cascades, and mitochondrial modulators, as well as strategies for modulating these components, has made evolutional progress. Owing to the accumulation of both basic and clinical evidence, the idea of ischemic postconditioning with a cardioprotective potential has been discovered and established, making it possible to apply this knowledge in the clinical setting after ischemia-reperfusion insult. Another a great outcome has been the launch of translational studies that apply basic findings for manipulating ischemia-reperfusion injury into practical clinical treatments against ischemic heart diseases. In this review, we discuss the current findings regarding the fundamental pathophysiological mechanisms of ischemia-reperfusion injury, the associated protective mechanisms of ischemic pre- and postconditioning, and the potential seeds for molecular, pharmacological, or mechanical treatments against ischemia-reperfusion injury, as well as subsequent adverse outcomes by modulation of subcellular signaling mechanisms (especially mitochondrial function). We also review emerging translational clinical trials and the subsistent clinical comorbidities that need to be overcome to make these trials applicable in clinical medicine.
•Syndromic hereditary aortopathies are caused by mutations in the transforming growth factor-β-related genes.•Patients with Marfan syndrome exhibiting a FBN1 truncating variant carry an increased ...risk of aortic events.•There is a limitation to identify the underlying causative genes of non-syndromic juvenile aortopathies.•Genetic testing for hereditary thoracic aortic aneurysms and dissections should be performed with appropriate counseling.
Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, and COL3A1). On the other hand, approximately 20% of the non-syndromic hereditary TAADs result from altered components of the contractile apparatus of vascular smooth muscle cells, which are encoded by ACTA2, MYH11, MYLK, and PRKG1 genes; however, the remaining 80% cannot be explained by previously reported candidate genes. Moreover, the relationship between the genotype and phenotype of TAADs has extensively been reported to investigate better methods for risk stratification and further personalized treatment strategies. With regard to MFS-causing FBN1, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant exhibiting a haploinsufficient-type effect, typically comprising nonsense or small insertions/deletions resulting in out-of-frame effects, compared to those carrying a variant with dominant negative-type effect, typically comprising missense variants. Therefore, cardiologists are required to have sufficient knowledge regarding the genetics of hereditary TAADs for providing the best clinical management, with an appropriate genetic counseling. In the current review, we present current advances in the genetics of hereditary TAADs and discuss the benefits and limitations with respect to the use of this genetic understanding in clinical settings.
Cardiac hypertrophy is characterized by complex multicellular alterations, such as cardiomyocyte growth, angiogenesis, fibrosis, and inflammation. The heart consists of myocytes and nonmyocytes, such ...as fibroblasts, vascular cells, and blood cells, and these cells communicate with each other directly or indirectly via a variety of autocrine or paracrine mediators. Accumulating evidence has suggested that nonmyocytes actively participate in the development of cardiac hypertrophy. In this review, recent progress in our understanding of the importance of nonmyocytes as a hub for induction of cardiac hypertrophy is summarized with an emphasis of the contribution of noncontact communication mediated by diffusible factors between cardiomyocytes and nonmyocytes in the heart.
Background:Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure ...Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records’ data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range IQR, 76.9–88.0%), there were wide variations in the proportions of patients prescribed β-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6–55.7%; ACEI/ARB, 52.0%, IQR 40.3–62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8–47.6%; ACEI/ARB, 41.0%, IQR 31.7–49.1%).Conclusions:A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327–2335)
Heart failure is a leading cause of death, and the number of patients with heart failure continues to increase worldwide. To realize precision medicine for heart failure, its underlying molecular ...mechanisms must be elucidated. In this review summarizing the “The Research Achievement Award Lecture” of the 2019 XXIII ISHR World Congress held in Beijing, China, we would like to introduce our approaches for investigating the molecular mechanisms of cardiac hypertrophy, development, and failure, as well as discuss future perspectives.
•Mechanical stress-induced molecular mechanisms in cardiomyocytes are essential for cardiac hypertrophy.•Wnt/β-catenin signaling and Csx/Nkx2.5 are critical for cardiomyocyte differentiation and heart development.•DNA damage and subsequent p53 signaling in cardiomyocytes are crucial for the induction of heart failure.•Integration of clinical and basic research is very important for the advancement of precision medicine.
Background:His-bundle pacing is an emerging routine technique that avoids pacing-dependent side effects. However, the success rate of His-bundle pacing is not 100%.Methods and Results:Left bundle ...pacing or peri-left bundle pacing (LBP/peri-LBP) are recently developed techniques that directly capture the left bundle or ventricular tissue near the left bundle. We evaluated the success rate of LBP/peri-LBP in patients whose treatment with His-bundle pacing failed. In addition, we evaluated left ventricular contraction and desynchrony after LBP/peri-LBP.Conclusions:LBP/peri-LBP is an alternative ventricular pacing method in atrioventricular block in patients with failure of His-bundle pacing.
Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we ...conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (n
= 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
The new Imperial era, Reiwa, started in May, 2019. After World War II, Reiwa is the third Imperial era following Showa and Heisei. In each era, we had specific healthcare problems in cardiovascular ...medicine and implemented preventive strategies against them. Furthermore, nationwide healthcare policies such as a universal healthcare insurance system (kaihoken) and health check-up system largely contribute to overcoming these problems. Here, we summarize the specific issues in cardiovascular medicine and nationwide strategies policies against them in each era. We also describe what we should do in the new Imperial era from the cardiovascular viewpoint.
Improvements in the long-term survival of cancer patients have led to growing awareness of the clinical importance of cancer therapeutics-related cardiac dysfunction (CTRCD), which can have a ...considerable effect on the prognosis and quality of life of cancer patients and survivors. Under such circumstances, onco-cardiology/cardio-oncology has emerged as a new discipline, with the aim of best managing cardiovascular complications, including CTRCD. Despite the recent accumulation of epidemiological and clinical information regarding CTRCD, the molecular mechanisms underlying the pathogenesis of CTRCD by individual drugs remain to be determined. To achieve the goal of preventing cardiovascular complications in cancer patients and survivors, it is important to elucidate the pathogenic mechanisms and to establish diagnostic strategies with risk prediction and mechanism- and evidence-based therapies against CTRCD.
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