Yoshiro Onoue

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway.

Background— Sirt7, 1 of the 7 members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process. Methods and Results— In wild-type mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7−/−) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7−/− mice. In vitro, Sirt7−/− mouse–derived or Sirt7 siRNA–treated cardiac fibroblasts showed reduced transforming growth factor-&bgr; signal activation and low expression levels of fibrosis-related genes compared with wild-type mice–derived or control siRNA–treated cells. These changes were accompanied by reduction in transforming growth factor receptor I protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. Transforming growth factor-&bgr; receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-C&agr; was involved in this process. Conclusion— Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining TGF-β Signaling Pathway

Background— Sirt7, 1 of the 7 members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process. Methods and Results— In wild-type mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7−/−) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7−/− mice. In vitro, Sirt7−/− mouse–derived or Sirt7 siRNA–treated cardiac fibroblasts showed reduced transforming growth factor-&bgr; signal activation and low expression levels of fibrosis-related genes compared with wild-type mice–derived or control siRNA–treated cells. These changes were accompanied by reduction in transforming growth factor receptor I protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. Transforming growth factor-&bgr; receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-C&agr; was involved in this process. Conclusion— Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.

Fragmented QRS complex is a diagnostic tool in patients with left ventricular diastolic dysfunction

Fragmented QRS complex (fQRS) on 12-lead ECG is associated with myocardial fibrosis and ischemic scar. Interstitial fibrosis is one of the histological characteristics of left ventricular diastolic dysfunction (LVDD). However, the clinical importance of fQRS in patients with LVDD remains unclear. Here, we assessed the hypothesis that the presence of fQRS is associated with disease severity in patients with LVDD, and could be used as an additional parameter to differentiate patients with heart failure with preserved ejection fraction (HFpEF) from LVDD. We analyzed 12-lead ECG of 239 patients with LVDD. The patients were divided into two groups according to the presence or absence of fQRS; 88 patients had fQRS (fQRS group) and 151 patients did not have fQRS (non-fQRS group). The percentage of patients with heart failure in the fQRS group was significantly higher than that in the non-fQRS group. The levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T were significantly higher in the fQRS group than those in the non-fQRS group. In univariate logistic regression analysis, fQRS was associated with the presence of heart failure in patients with LVDD. Multivariate logistic regression analysis identified fQRS and BNP as independent indicators for HFpEF. In conclusion, the presence of fQRS on the ECG could be used as an additional tool to differentiate HFpEF from LVDD.

Percutaneous coronary intervention strategy for acute coronary syndrome caused by spontaneous coronary artery dissection for relieving ongoing ischemia—Case series and literature review

Although spontaneous coronary artery dissection (SCAD) is one of the causes of acute coronary syndrome (ACS) or sudden cardiac death, its standard management, especially primary percutaneous coronary intervention (PCI) in ACS patients with ongoing ischemia, has not been established. We experienced three ACS patients with SCAD who were treated with a different strategy of primary PCI. Each PCI strategy led to different clinical and procedural results. We describe here such PCI strategies and results, and also discuss the literature regarding primary PCI strategies for SCAD-induced ACS patients with ongoing ischemia. <Learning objective: SCAD is a cause of ACS. However, the treatment strategy of primary PCI for SCAD has not been fully investigated. We used different PCI strategies for three SCAD patients with ongoing ischemia. Our case series suggested that plain old balloon angioplasty is an acceptable option to avoid coronary stenting because the majority of patients were young menstruating women. Coronary vasospasm might be associated with SCAD. Treatment with vasodilators could be a potential pharmacological option for avoiding recurrence of SCAD.>.

Expression of Let-7 family microRNAs in skin correlates negatively with severity of pulmonary hypertension in patients with systemic scleroderma

Background Pulmonary hypertension (PH) is a serious complication in patients with systemic scleroderma (SSc), therefore it is important to identify the factors that could predict the presence and progression of PH. Skin biopsy is performed in patients with SSc to examine the type and severity of the disease. MicroRNAs (miRNAs) are potential biomarkers for various cardiovascular diseases including PH. Methods and results We determined the skin miRNA expression profile in 15 SSc patients with (n = 6) and without PH (n = 9). A mixture of equal amounts of miRNAs from PH and non-PH patients were prepared and used for miRNA PCR array analysis. The analysis identified 591 upregulated miRNAs and 57 downregulated miRNAs in the PH group. Of these, only miRNAs with a Ct value of less than 35 were subjected to further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated and 14 miRNAs were downregulated in the PH group. Interestingly, 5 out of 14 downregulated miRNAs belonged to the let-7 family. The results were validated by quantitative real-time PCR with specific primer for each miRNA, which showed significant downregulation of five let-7 family members (let-7a, -7d, -7e, -7f, -7g) in 6 PH compared with 9 non-PH skin samples. The expression levels of let-7d and 7b correlated negatively with pulmonary arterial pressure measured by echocardiography. Conclusions The results suggest that skin miRNA is a potentially useful marker for the presence and severity of PH in patients with SSc.

Serial intravascular ultrasound assessment of very late stent thrombosis after sirolimus-eluting stent placement

PURPOSE In-stent restenosis has been decreasing through the introduction of drug-eluting stents (DES). On the other hand, adverse events such as very late stent thrombosis (VLST) and late catch-up phenomenon can occur especially with sirolimus-eluting stents (SES, first-generation DES) in long-term follow-up. However, the precise mechanisms underlying VLST have not been well investigated in vivo. METHODS AND RESULTS From 2004 to 2010, 2034 SES were implanted in 1656 patients and caused eight VLST (0.48% per patient) at Fukuoka Tokushukai Medical Center. Of these, serial intravascular ultrasound (IVUS) images (post-stent implantation and at the time of VLST onset) were obtained from three patients with VLST. Comparing them with eight control patients with SES implanted, the vascular reactivity of VLST patients was analyzed. Eight VLST happened 50 ± 15 months after stent implantation and three of the eight patients with VLST had not taken aspirin daily. There were no differences in minimum stent area, maximum external elastic membrane (EEM) area, and stent edge (distal and proximal) EEM area in post-procedural IVUS images. Compared with the control group patients, ΔEEM area (10.6 ± 3.4mm(2) vs. 1.7 ± 1.9 mm(2), p=0.01) and vessel expansion ratio (185.6 ± 40.3% vs. 112.0 ± 12.1%, p=0.01) were significantly greater in the VLST group based on the greater peri-stent plaque expansion (262.1 ± 72.8% vs. 118.7 ± 21.2%, p=0.01). CONCLUSION Our serial IVUS study showed that the vascular positive remodeling after SES implantation is one of the most probable morphological mechanisms for VLST development.

Cardioprotective Effects of LCZ696 (Sacubitril/Valsartan) After Experimental Acute Myocardial Infarction

Visual Abstract

Expression of Let-7 Family microRNAs in Skin Correlates Negatively with Severity of Pulmonary Hypertension in Patients with Systemic Scleroderma

article i nfo Background:Pulmonaryhypertension (PH)isaseriouscomplicationinpatients withsystemic scleroderma (SSc), therefore it isimportant to identify the factors that could predict the presenceand progression of PH.Skinbiopsy is performed in patients with SSc to examine the type and severity of the disease. MicroRNAs (miRNAs) are po- tential biomarkers for various cardiovascular diseases including PH. Methods and results: We determined the skin miRNA expression profile in 15 SSc patients with (n = 6) and without PH (n = 9). A mixture of equal amounts of miRNAs from PH and non-PH patients were prepared and used for miRNA PCR array analysis. The analysis identified 591 upregulated miRNAs and 57 downregulated miRNAs in thePH group.Of these, onlymiRNAs with a Ct value of less than 35 weresubjected to further analysis. When a 1.5-fold difference was considered meaningful, 32 miRNAs were upregulated and 14 miRNAs were downregulated in the PH group. Interestingly, 5 out of 14 downregulated miRNAs belonged to the let-7 family. The resultswerevalidatedbyquantitative real-timePCRwith specificprimerforeachmiRNA,which showedsig- nificant downregulation of five let-7 family members (let-7a, -7d, -7e, -7f, -7g) in 6 PH compared with 9 non-PH skinsamples. The expression levels of let-7dand7bcorrelated negatively with pulmonary arterial pressuremea- sured by echocardiography. Conclusions:TheresultssuggestthatskinmiRNAisapotentiallyusefulmarkerforthepresenceandseverityofPH in patients with SSc.

In vivo intravascular ultrasound imaging of fibromuscular dysplastic region and intravascular pressure gradient-guided percutaneous transluminal renal angioplasty

Fibromuscular dysplasia (FMD) is one of the etiologies of renal artery stenosis (RAS) and secondary hypertension. Balloon angioplasty has emerged as the mainstay of treatment because patients with FMD usually show substantial clinical and anatomic response to renal angioplasty without stenting. We report a 21-year-old male case of FMD-induced RAS treated with intravascular ultrasound- and pressure gradient-guided renal angioplasty. Ultrasonic imaging of the stenotic renal artery clearly visualized adventitial fibrotic band surrounding the negative remodeled renal artery and the accompanying atherosclerotic plaque. The findings suggest that atherosclerotic change can occur in young patients with renal FMD that is basically considered to be nonatherosclerotic. Pressure gradient measurement is also useful in confirming hemodynamic improvement during angioplasty.

Non-invasive testing for sarcopenia predicts future cardiovascular events in patients with chronic kidney disease

BACKGROUND Sarcopenia is frequently observed and associated with poor outcomes in patients with chronic kidney disease (CKD). A simple screening test for sarcopenia using age, grip strength, and calf circumference was recently developed. However, the clinical utility of this sarcopenia score in patients with CKD remains unclear. METHODS AND RESULTS We calculated the sarcopenia score of 265 patients with CKD and followed the patients for cardiovascular events. The endpoint of this study was the composite of cardiovascular hospitalization and total mortality. We divided all participants into high (n = 166) and low (n = 99) sarcopenia score groups using a simple scoring system. Patients in the high sarcopenia score group showed significantly higher plasma B-type natriuretic peptide (BNP) levels than those in the low sarcopenia score group (median: 103.1, interquartile range: 46.3-310.0 vs. 46.7, 18.0-91.8 pg/mL; p < 0.0001). The Kaplan-Meier curve revealed that the risk of cardiovascular events was significantly greater in the high sarcopenia score group (log-rank test: p < 0.0001), even after potential confounding factors were corrected using propensity score matching. Multivariate Cox hazard analysis identified a high sarcopenia score (hazard ratio: 3.04, 95% confidence interval: 1.45-6.38, p = 0.003) as an independent predictor of the primary endpoints. Furthermore, the combination of a high sarcopenia score and high BNP level identified patients with a significantly higher probability of future events (p < 0.0001). CONCLUSIONS This study demonstrates that this simple screening score for sarcopenia could be a useful tool for estimating the future adverse event risk in patients with CKD.