•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.
Intestinal epithelial stem cell identity and location have been the subject of substantial research. Cells in the +4 niche are slow-cycling and label-retaining, whereas a different stem cell niche ...located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a specific marker of +4 cells. Hopx-expressing cells give rise to CBCs and all mature intestinal epithelial lineages. Conversely, CBCs can give rise to +4 Hopx-positive cells. These findings demonstrate a bidirectional lineage relationship between active and quiescent stem cells in their niches.
Background: The cost-effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors for chronic kidney disease (CKD) has not been evaluated in Japan, so we analyzed the cost-effectiveness of ...dapagliflozin, an SGLT2 inhibitor, for CKD stages 3a and 3b.Methods and Results: We used the Markov model for CKD to assess the costs and benefits associated with and without dapagliflozin from a health system perspective. We estimated the incremental cost-effectiveness ratio (ICER), expressed as per quality-adjusted life-years (QALYs). An ICER <5 million Japanese yen (JPY)/QALY was judged to be cost-effective. The effect of dapagliflozin on renal and cardiovascular events was based on published clinical trials. In patients with CKD stage 3a, the ICER of dapagliflozin over standard treatment was 4.03 million JPY/QALY gained. With a cost-effectiveness threshold of 5 million JPY/QALY gained, the cost-effectiveness probability of dapagliflozin over standard treatment was 52.6%. In patients with CKD stage 3b, the ICER of dapagliflozin over standard treatment was 0.12 million JPY/QALY gained. The cost-effectiveness probability of dapagliflozin over standard treatment was 75.2%.Conclusions: The results seemed to show acceptable cost-effectiveness when dapagliflozin was used for CKD stage 3b. On the other hand, cost-effectiveness of dapagliflozin for CKD stage 3a was ambiguous, and further validation is needed.
Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling ...pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (
and
) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders.
Background:Obesity and metabolic disorders frequently coexist, and both are established risk factors for cardiovascular disease (CVD). Although the phenotype of obesity without metabolic disorders, ...referred to as metabolically healthy obesity (MHO), is attracting clinical interest, the pathophysiological impact of MHO remains unclear.Methods and Results:Using the Japan Medical Data Center database, we studied 802,288 subjects aged ≥20 years without any metabolic disorders or a prior history of CVD. MHO, defined as obesity (body mass index ≥25 kg/m2) with no metabolic disorders, was observed in 9.8% of the study population. The subjects’ mean (±SD) age was 42.8±9.4 years and 44.7% were men. The mean follow-up period was 1,126±849 days. Multivariable Cox regression analysis showed that MHO alone did not significantly increase the risk of any CVD. However, abdominal obesity alone increased the risk of heart failure and atrial fibrillation. Moreover, the coexistence of MHO and abdominal obesity increased the risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation. The incidence of stroke was not associated with the presence of MHO and abdominal obesity.Conclusions:Among individuals with no metabolic disorders, MHO alone did not significantly increase the subsequent CVD risk. However, individuals with comorbid MHO and abdominal obesity had a higher risk of myocardial infarction, angina pectoris, heart failure, and atrial fibrillation, suggesting the prognostic importance of abdominal obesity in subjects with MHO.
Background:Because the early diagnosis of subclinical cardiac sarcoidosis (CS) remains difficult, we developed a deep learning algorithm to distinguish CS patients from healthy subjects using ...echocardiographic movies.Methods and Results:Among the patients who underwent echocardiography from January 2015 to December 2019, we chose 151 echocardiographic movies from 50 CS patients and 151 from 149 healthy subjects. We trained two 3D convolutional neural networks (3D-CNN) to identify CS patients using a dataset of 212 echocardiographic movies with and without a transfer learning method (Pretrained algorithm and Non-pretrained algorithm). On an independent set of 41 echocardiographic movies, the area under the receiver-operating characteristic curve (AUC) of the Pretrained algorithm was greater than that of Non-pretrained algorithm (0.842, 95% confidence interval (CI): 0.722–0.962 vs. 0.724, 95% CI: 0.566–0.882, P=0.253). The AUC from the interpretation of the same set of 41 echocardiographic movies by 5 cardiologists was not significantly different from that of the Pretrained algorithm (0.855, 95% CI: 0.735–0.975 vs. 0.842, 95% CI: 0.722–0.962, P=0.885). A sensitivity map demonstrated that the Pretrained algorithm focused on the area of the mitral valve.Conclusions:A 3D-CNN with a transfer learning method may be a promising tool for detecting CS using an echocardiographic movie.
Emerging evidence has suggested a potential impact of gut microbiota on the pathophysiology of heart failure (HF). However, it is still unknown whether HF is associated with dysbiosis in gut ...microbiota. We investigated the composition of gut microbiota in patients with HF to elucidate whether gut microbial dysbiosis is associated with HF. We performed 16S ribosomal RNA gene sequencing of fecal samples obtained from 12 HF patients and 12 age-matched healthy control (HC) subjects, and analyzed the differences in gut microbiota. We further compared the composition of gut microbiota of 12 HF patients younger than 60 years of age with that of 10 HF patients 60 years of age or older. The composition of gut microbial communities of HF patients was distinct from that of HC subjects in both unweighted and weighted UniFrac analyses. Eubacterium rectale and Dorea longicatena were less abundant in the gut microbiota of HF patients than in that of HC subjects. Compared to younger HF patients, older HF patients had diminished proportions of Bacteroidetes and larger quantities of Proteobacteria. The genus Faecalibacterium was depleted, while Lactobacillus was enriched in the gut microbiota of older HF patients. These results suggest that patients with HF harbor significantly altered gut microbiota, which varies further according to age. New concept of heart-gut axis has a great potential for breakthroughs in the development of novel diagnostic and therapeutic approach for HF.
Background: The applicability of the Stages of Change model for cardiovascular disease-related behaviors, such as smoking, exercise, diet, and sleep quality, is unclear.Methods and Results: Using a ...large-scale epidemiological dataset, we found that baseline behavior change intention, as per the transtheoretical model, was associated with modifications of unhealthy lifestyles including cigarette smoking, physical inactivity, skipping breakfast, and poor sleep quality.Conclusions: Our results suggest that an individual’s motivation to change assessed by a general questionnaire may contribute to lifestyle modification and potentially prevent subsequent cardiovascular disease.
Background: Data regarding the relationship between benign prostatic hyperplasia (BPH) and incident cardiovascular disease (CVD) are scarce. We aimed to clarify the association of BPH with the risk ...of developing CVD using a nationwide epidemiological database.Methods and Results: This retrospective observational cohort study analyzed data from the JMDC Claims Database between 2005 and 2022, including 2,370,986 men (median age 44 years). The primary endpoints were myocardial infarction (MI), angina pectoris (AP), stroke, heart failure (HF), and atrial fibrillation (AF), which were assessed separately. BPH was observed in 48,651 (2.1%) men. During a mean (±SD) follow-up of 1,359±1,020 days, 7,638 MI, 52,167 AP, 25,355 stroke, 58,183 HF, and 16,693 AF events were detected. Hazard ratios of BPH for MI, AP, stroke, HF, and AF were 1.04 (95% confidence interval CI 0.92–1.18), 1.31 (95% CI 1.25–1.37), 1.26 (95% CI 1.18–1.33), 1.21 (95% CI 1.16–1.27), and 1.15 (95% CI 1.07–1.24), respectively. We confirmed the robustness of our primary findings through a multitude of sensitivity analyses. In particular, a history of BPH was associated with a higher risk of developing CVD, even in participants without obesity, hypertension, diabetes, or dyslipidemia.Conclusions: Our analysis of a nationwide epidemiological dataset demonstrated that BPH was associated with a greater risk of developing CVD in middle-aged men.
Aim: Using a nationwide epidemiological database, we sought to examine whether there was a sex difference in the association between lipid profiles and subsequent cardiovascular disease (CVD) in ...young adults.Methods: Medical records of 1,909,362 young adults (20–49 years old) without a prior history of CVD and not taking lipid-lowering medications were extracted. We conducted multivariable Cox regression analyses to identify the association between the number of abnormal lipid profiles and incident CVD.Results: After a mean follow-up of 3.4±2.6 years, myocardial infarction (MI), angina pectoris (AP), stroke, and heart failure (HF) developed in 2,575 (0.1%), 26,006 (1.4%), 10,748 (0.6%), and 24,875 (1.3%) subjects, respectively. The incidence of MI, AP, and HF increased with the number of abnormal lipid profiles in both men and women, whereas the incidence of stroke increased with the number of abnormal lipid profiles only in men but not in women. Multivariable adjusted hazard ratios (HRs) for MI per 1-point higher abnormal lipid profile were 1.57 (95% confidence interval CI 1.49–1.65) in men and 1.25 (95% CI 1.07–1.47) in women. HRs for AP, stroke, and HF per 1-point higher abnormal lipid profile were 1.14 (95% CI 1.12–1.16), 1.06 (95% CI 1.02–1.09), and 1.10 (95% CI 1.08–1.12) in men and 1.18 (95% CI 1.13–1.23), 1.09 (95% CI 1.03–1.16), and 1.10 (95% CI 1.05–1.14) in women.Conclusion: Our analysis demonstrated an association between the number of abnormal lipid profiles and incident CVD in both men and women. The association between the number of abnormal lipid profiles and incident MI was pronounced in men.
PDF
