Sirt7 Deficiency Attenuates Neointimal Formation Following Vascular Injury by Modulating Vascular Smooth Muscle Cell Proliferation.

BACKGROUND: Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.Methods and Results:Systemic (Sirt7-/-) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7-/-mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7-/-mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7-/-compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7-/-mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice. CONCLUSIONS: Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.

Cardiomyocyte Sirt (Sirtuin) 7 Ameliorates Stress-Induced Cardiac Hypertrophy by Interacting With and Deacetylating GATA4.

Sirt (Sirtuin) 7, the most recently identified mammalian sirtuin, has been shown to contribute to appropriate wound healing processes after acute cardiovascular insult. However, its role in the development of cardiac remodeling after pressure overload is unclear. Cardiomyocyte-specific Sirt7-knockout and control mice were subjected to pressure overload induced by transverse aortic constriction. Cardiac hypertrophy and functions were then examined in these mice. Sirt7 protein expression was increased in myocardial tissue after pressure overload. Transverse aortic constriction-induced increases in heart weight/tibial length were significantly augmented in cardiomyocyte-specific Sirt7-knockout mice compared with those of control mice. Histological analysis showed that the cardiomyocyte cross-sectional area and fibrosis area were significantly larger in cardiomyocyte-specific Sirt7-deficient mice. Cardiac contractile functions were markedly decreased in cardiomyocyte-specific Sirt7-deficient mice. Mechanistically, we found that Sirt7 interacted directly with GATA4 and that the exacerbation of phenylephrine-induced cardiac hypertrophy by Sirt7 knockdown was decreased by GATA4 knockdown. Sirt7 deacetylated GATA4 in cardiomyocytes and regulated its transcriptional activity. Interestingly, we demonstrated that treatment with nicotinamide mononucleotide, a known key NAD+ intermediate, ameliorated agonist-induced cardiac hypertrophies in a Sirt7-dependent manner in vitro. Sirt7 deficiency in cardiomyocytes promotes cardiomyocyte hypertrophy in response to pressure overload. Sirt7 exerts its antihypertrophic effect by interacting with and promoting deacetylation of GATA4.

Grip strength predicts cardiac adverse events in patients with cardiac disorders: an individual patient pooled meta-analysis.

OBJECTIVE: Grip strength is a well-characterised measure of weakness and of poor muscle performance, but there is a lack of consensus on its prognostic implications in terms of cardiac adverse events in patients with cardiac disorders. METHODS: Articles were searched in PubMed, Cochrane Library, BioMed Central and EMBASE. The main inclusion criteria were patients with cardiac disorders (ischaemic heart disease, heart failure (HF), cardiomyopathies, valvulopathies, arrhythmias); evaluation of grip strength by handheld dynamometer; and relation between grip strength and outcomes. The endpoints of the study were cardiac death, all-cause mortality, hospital admission for HF, cerebrovascular accident (CVA) and myocardial infarction (MI). Data of interest were retrieved from the articles and after contact with authors, and then pooled in an individual patient meta-analysis. Univariate and multivariate logistic regression was performed to define predictors of outcomes. RESULTS: Overall, 23 480 patients were included from 7 studies. The mean age was 62.3±6.9 years and 70% were male. The mean follow-up was 2.82±1.7 years. After multivariate analysis grip strength (difference of 5 kg, 5× kg) emerged as an independent predictor of cardiac death (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001), all-cause death (OR 0.87, 95% CI 0.85 to 0.89, p<0.0001) and hospital admission for HF (OR 0.88, 95% CI 0.84 to 0.92, p<0.0001). On the contrary, we did not find any relationship between grip strength and occurrence of MI or CVA. CONCLUSION: In patients with cardiac disorders, grip strength predicted cardiac death, all-cause death and hospital admission for HF. TRIAL REGISTRATION NUMBER: CRD42015025280.

Akt1-Mediated Muscle Growth Promotes Blood Flow Recovery After Hindlimb Ischemia by Enhancing Heme Oxygenase-1 in Neighboring Cells.

BACKGROUND: Resistance exercise has beneficial effects for patients with peripheral arterial diseases. The hypothesis that muscle growth promotes angiogenesis by interacting with neighboring cells in ischemic lesions was assessed. Methods and Results: Skeletal muscle-specific inducible Akt1 transgenic (Akt1-TG) mice that induce growth of functional skeletal muscles as a model of resistance training were used. Proteomics analysis identified significant upregulation of heme oxigenase-1 (HO-1) in muscle tissue in Akt1-TG mice compared with control mice. Blood flow recovery after hindlimb ischemia was significantly increased in Akt1-TG mice compared with control mice. Enhanced blood flow and capillary density in Akt1-TG mice were completely abolished by the HO-1 inhibitor, Tin-mesoporphyrin. Immunohistochemistry showed that HO-1 expression was not increased in muscle cells, but it was increased in macrophages and endothelial cells. Consistent with these findings, blood flow recovery after hindlimb ischemia was similar between control mice and skeletal muscle-specific HO-1-knockout mice. Adenoviral-mediated overexpression of Akt1 did not increase HO-1 protein expression in C2C12 myotubes; however, the conditioned medium from Akt1-overexpressing C2C12 myotubes increased HO-1 expression in endothelial cells. Cytokine array demonstrated that a panel of cytokine secretion was upregulated in Akt1-overexpressing C2C12 cells, suggesting paracrine interaction between muscle cells and endothelial cells and macrophages. CONCLUSIONS: Akt1-mediated muscle growth improves blood flow recovery after hindlimb ischemia by enhancing HO-1 expression in neighboring cells.

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.

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

LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.

Reduced trans-mitral A-wave velocity predicts the presence of wild-type transthyretin amyloidosis in elderly patients with left ventricular hypertrophy.

Wild-type transthyretin amyloidosis (ATTRwt) is often overlooked in elderly patients with left ventricular hypertrophy (LVH). Impaired atrial function, in addition to ventricular diastolic dysfunction, is one of the hallmarks of cardiac amyloidosis. Here, we assessed the hypothesis that atrial function evaluated by A-velocity in pulse Doppler echocardiography is useful to differentiate ATTRwt in elderly patients with LVH. We analyzed 133 consecutive patients who underwent tissue biopsy to rule out infiltrative cardiomyopathy in our institute. We excluded patients younger than 50 years, without LVH (LV thickness was less than 12 mm), with other types of cardiac amyloidosis and patients with chronic atrial fibrillation, and analyzed remaining 51 patients (ATTRwt: 16, non-ATTRwt: 35). ATTRwt patients were significantly older and had advanced heart failure compared with non-ATTRwt group. In echocardiography, E/A, E/e', and relative wall thickness was significantly higher in ATTRwt group than non-ATTRwt group. A-velocity was significantly decreased in ATTRWT group compared with non-ATTRwt group (40.8 ± 20.8 vs. 78.7 ± 28.2 cm/s, p = 0.0001). Multivariate logistic analysis using eight forced inclusion models identified trans-mitral Doppler A-wave velocity was more significant factor of cardiac amyloidosis in ATTRwt. In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) for A-wave velocity in discrimination between ATTRwt and non-ATTRwt were 0.86 (CI 0.76-0.96, p < 0.001). The cut-off value was 62.5 cm/s, and it yielded the best combination of sensitivity (69.7%) and specificity (87.5%) for prediction of amyloidosis. We concluded that reduced A-velocity predicts the presence of ATTRwt in elderly patients with LVH in sinus rhythm.

A simple sarcopenia screening test predicts future adverse events in patients with heart failure.

BACKGROUND: Progressive loss of skeletal muscle termed "sarcopenia" is an independent risk factor for mortality in patients with cardiovascular diseases. A simple screening test that can identify sarcopenia using three variables (age, grip strength and calf circumference) was recently developed. We evaluated the clinical utility of this screening test in patients with heart failure (HF). METHODS AND RESULTS: HF patients were divided into the sarcopenia (n=82) and non-sarcopenia (n=37) groups based on the sarcopenia score. Circulating BNP and high-sensitive cardiac troponin T levels were significantly higher, and left ventricular ejection fraction was lower in the sarcopenia group than non-sarcopenia group. Kaplan-Meier curve showed that HF event-free survival rate was significantly lower in the sarcopenia group. Multivariate Cox proportional hazards analysis identified BNP (ln[BNP]) (hazard ratio [HR]: 1.58; 95% CI: 1.09-2.29, p=0.02), hs-CRP (ln[CRP]) (HR: 1.82; 95% CI: 1.23-2.68; p<0.01) and sarcopenia score (HR: 1.03; 95% CI: 1.01-1.05, p<0.01) as independent predictors of HF events. In receiver operating characteristic analysis, adding the sarcopenia score to BNP levels increased an area under the curve for future HF events (sarcopenia score alone, 0.77; BNP alone, 0.82; combination, 0.89). CONCLUSIONS: The sarcopenia screening test can be used to predict future adverse events in patients with HF.

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.

Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-ß 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-ß 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-ß receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-Cα was involved in this process. CONCLUSION: Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.

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.

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. .

Multidisciplinary mechanical supports improve outcome in a shock patient with cardiac amyloidosis: a case report.

Shock patients with restrictive cardiomyopathy due to cardiac amyloidosis are refractory to medical treatment. Here, we report a case of early initiation of intra-aortic balloon pumping (IABP) in a patient with cardiac amyloidosis who developed postoperative shock. Continuous hemodiafiltration was also applied to control circulating fluid volume. The mechanical treatments allowed reduction of the doses of catecholamine and diuretics and resulted in full recovery. It is reasonable to initiate IABP and hemofiltration dialysis during the early stages for the appropriate control of hemodynamics and fluid in shock patients with cardiac amyloidosis.

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.