Hirotaka Yamamoto

Effects of telmisartan therapy on interleukin-6 and tumor necrosis factor-alpha levels: a meta-analysis of randomized controlled trials

A recent meta-analysis of randomized head-to-head trials suggests that therapy with telmisartan, an angiotensin II receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor-gamma, may increase adiponectin levels more strongly than other ARB therapies. Therefore, telmisartan would be expected to reduce interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-α). To determine whether telmisartan reduces IL-6 or TNF-α, we performed the first meta-analysis of randomized controlled trials of telmisartan therapy. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched through November 2011. Eligible studies were prospective randomized controlled trials of telmisartan vs. unrestricted control therapy reporting IL-6 or TNF-α levels as an outcome. For each study, data regarding percent changes from baseline to final IL-6 or TNF-α levels in both the telmisartan and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Nine reports of randomized trials enrolling a total of 645 patients were identified. Pooled analysis of seven and five trials demonstrated a statistically significant reduction in percent changes of IL-6 (fixed-effects SMD, –0.385; 95% CI, –0.581 to –0.189; P<0.001; P for heterogeneity=0.073) and TNF-α levels (random-effects SMD, –0.627; 95% CI, –0.945 to –0.308; P<0.001; P for heterogeneity=0.029) with telmisartan relative to control therapy, respectively. In conclusion, based on a meta-analysis of nine randomized controlled trials, telmisartan therapy is likely effective in reducing IL-6 and TNF-α levels.

A meta-analysis of effects of prosthesis–patient mismatch after aortic valve replacement on late mortality

Prosthesis–patient mismatch (PPM) describes a state in which the effective orifice area (EOA) of a normally functioning heart valve prosthesis is too small in relation to thepatients bodysize,which results in high transvalvular pressure gradients [1]. For aortic valve prostheses, PPM is considered to be severe when the indexed EOA (IEOA) is b0.65 cm/m and moderate when this value is 0.65–0.85 cm/m; and PPMis classedasnot clinically significantwhen the IEOA isN0.85 cm/m [2]. Patients with PPM have worse functional class and exercise capacity, reduced regression of left ventricular hypertrophy, inferior recovery of coronary flow reserve, impaired blood coagulation status, andmore adverse cardiac events after aortic valve replacement (AVR) compared with patients without PPM [3,4]. Further, PPMmay be also associated with an increased risk of both perioperative and late mortalities. Although a lot of studies investigated whether PPM impaired late survival, there have been no formal attempts to conduct any meta-analysis of such studies to date. We performed the first metaanalysis of studies comparing late mortality in patients with and without PPM after AVR. Public domain databases including MEDLINE and EMBASE were searched through January 2012 using Web-based search engines (PubMed, OVID).

Perioperative results of robotic lung lobectomy: summary of the literature.

We read with great interest the excellent results of a study by Augustin et al. [1] on robotic lung lobectomy. A number of studies on robotic lung lobectomy have been published to date. To summarize the perioperative results of robotic lobectomy for lung cancer, we performed a systematic literature search and metaanalysis of identified studies. The MEDLINE database was searched through April 2011 using PubMed exploding keywords including ‘‘robot,’’ ‘‘robotic,’’ and ‘‘lung cancer.’’ Data regarding the baseline characteristics of enrolled patients and the perioperative results were abstracted from each individual study. Most of the studies reported the median and range of continuous data (operative time, number of removed lymph nodes, and hospital length of stay). To combine the data, we used the median as representative of the mean because the median is very similar to the mean when the distribution of the data is symmetric. The standard deviation (SD) was estimated to be one-fourth of the typical range of data values because 95 % of values lie within two SDs on either side of the mean when data are normally distributed. Study-specific means with SDs and event rates were combined using a random-effects model. All analyses were conducted using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, NJ, USA). Our comprehensive search identified 17 studies, but we excluded 10 studies because of their small number of patients (\10). As Gharagozloo et al. [3] reported the results for 61 patients in 2008 [2] and for 100 patients (including the 61 patients) in 2009 [3], we included the latter in the current metaanalysis. Our metaanalysis included data on 326 patients with lung cancer undergoing robotic lobectomy from six studies [1, 3–7] (Table 1). Only one study [6] compared robotic lobectomy with open lobectomy. The other studies were single-arm studies. Half of patients were men, and the mean age was 65.9 years. The clinical stages of lung cancer were 1A [7], 1 [1], and 1 and 2 [3–6], with 78.2 % of the patients representing stage 1, 15.4 % representing stage 2, and 5.6 % representing stage 3. The pooled operative time was 215 min (95 % CI, 183–247 min), the number of removed lymph nodes 12 (95 % CI, 7.5–16.5), the conversion rate 9.4 % (95 % CI, 4.7–17.6 %), the morbidity rate 18.3 % (95 % CI, 14.1–23.3 %), the mortality rate 2.1 % (95 % CI, 1.0–4.6 %), and the hospital length of stay 6 days (95 % CI, 4.3–7.6 days) (Table 2). Our summarized operative time for robotic lobectomy (215 min) compares with that for video-assisted lobectomy (median of mean/median, 222 min) and open lobectomy (median of mean/median, 216 min) demonstrated in a metaanalysis by Yan et al. [8]. The conversion rate for robotic lobectomy (9.4 %) also approximated that for video-assisted lobectomy (median of mean/median, 8.1 %). The hospital length of stay for robotic lobectomy (6 days), however, is likely to be about half of that for video-assisted lobectomy (median of mean/median, 12.0 days) and open lobectomy (median of mean/median, 12.2 days). On the other hand, only one comparative study by Veronesi et al. [6] using propensity score matching indicated similar conversion rates between robotic lobectomy and open lobectomy, with a longer operative time and H. Takagi (&) H. Yamamoto S. Goto M. Matsui T. Umemoto Department of Cardiothoracic Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan e-mail: kfgth973@ybb.ne.jp

Effects of telmisartan on proteinuria or albuminuria: A meta-analysis of randomized trials

BACKGROUND Although telmisartan is suggested to improve proteinuria/albuminuria (or prevents progression of proteinuria/albuminuria), conclusive evidence is still lacking. We perform the first meta-analysis of randomized controlled trials of telmisartan therapy on proteinuria/albuminuria. METHODS MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through February 2012. Eligible studies were prospective randomized controlled trials of telmisartan therapy versus other angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), other anti-hypertensive drug therapy, placebo, or no medication and reporting urinary protein/albumin excretion (UPE/UAE) or urinary protein/albumin to creatinine ratio (UPCR/UACR) levels as an outcome. For each study, data regarding percent changes from baseline to final UPE/UAE/UPCR/UACR levels in both the telmisartan and control groups were used to generate mean differences (MDs) and 95% confidence intervals (CIs). RESULTS Of 49 potentially relevant articles screened initially, 20 reports of randomized trials enrolling a total of 25,425 patients were included. Pooled analysis suggested a significant reduction in percent changes of UPE/UAE/UPCR/UACR in the 7 ARB-control (MD, -19.99%; 95% CI, -28.68% to -11.30%; p<0.00001), 7 ACEI-control (MD, -14.08%; 95% CI, -25.36% to -2.80%; p=0.01), 6 non-ARB/ACEI-control (MD, -39.82%; 95% CI, -55.96% to -23.69%; p<0.00001), and all the 20 trials (MD, -24.36%; 95% CI, -32.85% to -15.87%; p<0.00001). CONCLUSION We found that, based on a meta-analysis of 20 randomized controlled trials including >25,000 patients, telmisartan therapy is likely effective in the improvement of proteinuria/albuminuria or in the prevention of progression in proteinuria/albuminuria.

Effects of rosuvastatin versus atorvastatin on small dense low-density lipoprotein: a meta-analysis of randomized trials

In addition to their high-intensity effects on the reduction in low-density lipoprotein (LDL) levels, rosuvastatin and atorvastatin would be expected to also reduce small dense LDL (sdLDL) levels. To determine which reduces sdLDL levels more, we performed the first meta-analysis and meta-regression of randomized head-to-head trials of rosuvastatin versus atorvastatin therapy. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through April 2012. Eligible studies were prospective, randomized controlled trials of rosuvastatin versus atorvastatin therapy reporting final sdLDL (directly measured or calculated) levels as an outcome. For each study, data regarding final sdLDL levels in both the rosuvastatin and atorvastatin groups were used to generate mean differences (MD) and 95 % confidence intervals (CI). Meta-regression analysis was performed to determine whether the effects of rosuvastatin therapy were modulated by the prespecified factors. Of 159 potentially relevant articles screened initially, 28 reports of randomized trials enrolling a total of 7802 patients were included. Pooled analysis suggested a significant reduction in final sdLDL levels among patients randomized to rosuvastatin versus atorvastatin therapy (MD, −1.56 mg/dl; 95 % CI, −2.30 to −0.83 mg/dl; P < 0.0001). The meta-regression coefficients were statistically significant for the baseline LDL/sdLDL level and the difference in LDL changes between the two groups. In conclusion, rosuvastatin rather than atorvastatin therapy is likely more effective in reduction of sdLDL levels. It should be further investigated whether the reduction in sdLDL levels implies overt clinical benefits of rosuvastatin over atorvastatin.

A meta-analysis comparing observed 30-day all-cause mortality with the Society of Thoracic Surgeons Predicted Risk of Mortality in contemporary studies using Valve Academic Research Consortium definitions

processes that contributed to this, the current study provides a ‘proof of concept’ that MRI can be used to delineate mechanisms in heart failure. When incorporated into clinical practice, these findings could enable theuse of CMRI for the characterisation of longitudinalfibre dysfunction, or alternatively, circumferential fibre compensation, as a tool for a more sensitive and specific approach to the diagnosis of HFPEF. More specifically, these techniques may be of use in differentiating pathologic from adaptive forms of ventricular hypertrophy, for example HCM or hypertensive hypertrophy versus the physiologic hypertrophy of the athlete heart, and thus warrants further investigation. In addition, this type of specific myocardial fibre function characterisation may assist in more targeted surveillance for specific types of heart failure, in addition to the more traditional approach with 2-D echocardiography.

Less invasiveness may not always result in less mortality: A meta-analysis of transcatheter versus surgical aortic valve replacement for aortic stenosis

population was patients with AS; patients were assigned toTAVI versus AVR; and main outcomes included 30-day all-cause mortality. Data regarding30-daymortality(adjustedoddsratios[ORs]formortalityand their confidence intervals [CIs] in case of OCSs) were abstracted from each individual study. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic ORs in both fixedand random-effects models. Between-study heterogeneity was analyzed by means of standard χ 2 tests. Where no significant statistical

Propensity score-matching analysis of hybrid video-assisted thoracoscopic surgery and thoracoscopic lobectomy for clinical stage I lung cancer

OBJECTIVES Video-assisted thoracoscopic surgery (VATS) lobectomy is classified into hybrid VATS (direct and video vision) and thoracoscopic VATS (video vision only). In this study, the outcomes of hybrid VATS and thoracoscopic VATS for clinical stage I lung cancer were compared using a propensity score-matching analysis. METHODS Hybrid and thoracoscopic VATS were performed in 178 and 76 patients, respectively. Propensity scores were calculated using logistic regression analysis and matched within a score of ±0.03 for age, sex, size of tumour, Charlson comorbidity index, preoperative therapy, percent vital capacity, forced expiratory volume in 1 s, clinical stage, pathological stage and histology. RESULTS In the non-matched analysis, the results for hybrid and thoracoscopic VATS, respectively, were as follows: mean age, 69 ± 9 and 66 ± 10 years (P = 0.04); tumour size, 24 ± 10 and 20 ± 7 mm (P < 0.01); 2-deoxy-2 [F-18]fluorodeoxyglucose positron emission tomography SUV, 5.6 ± 4.4 and 3.6 ± 3.2 (P < 0.01); clinical stage (IA/IB), 130/48 and 69/7 (P < 0.01); pathological stage (IA/IB/IIA and IIB/IIIA and IIIB), 89/56/15/18 and 57/14/2/3 (P < 0.01); postoperative complications, 66 (37.1%) and 16 (21.1%; P = 0.01); respiratory complications, 32 (18.0%) and 6 (7.9%; P = 0.04); 5-year overall survival (OS), 77.0 and 88.8% (log-rank P = 0.045); and 5-year disease-free survival (DFS), 67.2 and 81.1% (log-rank P = 0.02). In 66 matched cases, the results for hybrid and thoracoscopic VATS, respectively, were as follows: mean operative time, 245 ± 96 and 285 ± 85 min (P = 0.01); blood loss, 95 ± 100 and 86 ± 123 ml (P = 0.67); mean duration of drainage, 3.6 ± 2.7 and 3.2 ± 2.2 days (P = 0.37); postoperative complications, 21 (31.8%) and 14 (21.2%; P = 0.17); respiratory complications, 11 (16.7%) and 5 (7.6%; P = 0.11); 5-year OS, 72.5 and 86.0% (log-rank P = 0.25); and 5-year DFS, 68.4 and 77.2% (log-rank P = 0.17). CONCLUSIONS In this single-institution, propensity score-matched study, hybrid VATS showed a shorter operative time and similar outcomes compared with thoracoscopic lobectomy for clinical stage IA lung cancer.

Drug-eluting stents increase late mortality compared with coronary artery bypass grafting in triple-vessel disease: A meta-analysis of randomized controlled and risk-adjusted observational studies

A recent meta-analysis [1] of 11 observational studies including 17,333 patients with multivessel coronary artery disease (MVD) (not only triple-vessel [3VD] but also double-vessel disease [2VD]), drugeluting stent (DES) placement was associated with a similar risk of death compared to coronary artery bypass grafting (CABG) (5.6% versus 5.9%, respectively; risk ratio [RR], 1.18; 95% confidence interval [CI], 0.80 to 1.75; p=0.39). Despite not randomized but observational studies, however, the authors abstracted and combined not adjusted but unadjusted data from them. In the Asan-Multivessel Registry [2], the adjusted risk of 5-year mortality was significantly lower in the DES group than in the CABG group in patients with 2VD (hazard ratio [HR], 0.60; 95% CI, 0.38 to 0.95; p=0.03). There were, however, no significant differences of treatment effect in the rates of death among patients with 3VD (HR, 1.18; 95% CI, 0.85 to 1.63; p=0.32). Further, in a subgroup analysis of the SYNTAX (SYNergy between PCI [percutaneous coronary intervention] with TAXUS and Cardiac Surgery) randomized trial (enrolling patients with 3VD or left main coronary artery disease) [3], 3-year overall mortality was significantly increased in 3VD patients treated with DES (9.5% versus 5.7%, p=0.02). Herein, we performed a meta-analysis of randomized International Journal of Cardiology 159 (2012) 230–248

An evidence-based hypothesis for beneficial effects of telmisartan on Marfan syndrome

Telmisartan is a unique angiotensin II type 1 receptor (AT1) blocker (ARB) with strong binding affinity to AT1 [1] and peroxisome proliferation-activated receptor-gamma (PPAR-γ)-modulating activity [2]. In the present paper, we endeavor to advocate an evidence-based hypothesis that telmisartan as well as or over losartan [3] could play a role in promising therapeutic intervention for vascular therapy in Marfan syndrome. Mutations in the gene, FBN1, that encodes the extracellular matrix protein, fibrillin-1, cause classic Marfan syndrome [4]. Other families or sporadic patients, in which some of the features of Marfan syndrome occur but typicallywithout ectopia lentis, havemutations in 1 of 2 genes (TGFBR1 and TGFBR2) that encode receptors for the cytokine transforming growth factor-beta (TGF-β) [5]. TGF-β is secreted as a large latent complex, TGF-β plus latency-associated peptide plus latent TGF-β binding protein (LTBP),which is sequestered by the extracellularmatrix [6]. Fibrillin-1 shares homology with LTBPs, and the TGF-β latent complex specifically binds to fibrillin-1 domains [7]. Matrix sequestration is critical to the regulated activation of TGF-β, and perturbation of this fibrillin-1 function contributes to the pathogenesis of Marfan syndrome [8]. Excess TGF-β activation in tissues correlates with failure of lung septation, developmentof amyxomatousmitral valve, and aortic root dilatation inmice, intowhich ahumanmutation that causesMarfan syndrome was introduced [9]. Angiotensin II binds two G-protein-coupled receptors, AT1 and angiotensin II type 2 receptor, with opposing effects [10]. AT1 activation by angiotensin II, autoantibodies, or mechanical stress can stimulate cell growth andmigration, as well as inflammation and vasoconstriction [11]. Activation of AT1 signaling is the result of a mechanically induced conformational change of the receptor and can be inhibited by ARBs [12]. Experimentally induced renal and cardiac fibrosis in murine models has linked angiotensin II activation to TGF-β signaling through up-regulation of thrombospondin-1, an activator of latent TGF-β, in addition to documenting the therapeutic efficacy of angiotensin-converting enzyme inhibitors or ARBs in fibrotic disorders [13–17]. Based on these correlative lines of evidence, the ARBs emerged as a promising therapeutic intervention for vascular therapy in Marfan syndrome [17]. Indeed, Habashi et al. [3] showed that aortic aneurysm in a mouse model of Marfan syndrome was associated with increased TGF-β signaling and could be prevented by TGF-β antagonists such as TGF-β-neutralizing antibodyor theARB, losartan. Currently there aremultipleongoing clinical randomized trials designed to assess the efficacy of losartan versus atenolol [18], nebivolol [19], no additional treatment [20], and placebo [21,22] in Marfan syndrome individuals. Beneficial effects of PPAR-γ ligand troglitazone on ameliorating the progression of glomerulosclerosis are independent of insulin/glucose effects and associatedwith decreased TGF-β expression [23]. Thus, via the decrease in the effects of TGF-β by activation of PPAR-γ, telmisartanwith selective PPAR-γ-modulating activity [2] could make a contribution to a therapeutic strategy for Marfan syndrome. Takahashi et al. [24] investigatedwhether treatmentwith telmisartan canprevent renal tissue injury in relation to the renal tissuemRNA levels of PPAR-γ and TGF-β1 in spontaneously hypertensive rats given N(G)-nitro-L-arginine methyl ester. The perivascular cell infiltration and fibrosis area were significantly reduced together with the PPAR-γ mRNA increase and TGF-β1 mRNA decrease. Yao et al. [25] examined whether and how telmisartan (ARB with PPAR-γ-modulating activity) inhibited TGF-β-induced glomerulosclerosis in rat glomerular mesangial cells. In a dose-dependent manner, telmisartan, but not valsartan (another ARB) up-regulated PPAR-γprotein levels, and activation of PPAR-γ response elementwas also increasedwith higher concentration of telmisartan. Furthermore, telmisartan inhibited TGF-β-induced alpha-smooth muscle actin expression and collagen IV secretion inmesangial cells. An inhibitor of PPAR-γ blocked the inhibitory effects of telmisartan on TGF-β-induced glomerulosclerosis in mesangial cells. These findings indicate a benefit of telmisartan as a PPAR-γ agonist against TGF-β-inducedmesangial cells activation in renal glomerulus. Zou et al. [26] studied theprobablemechanismsof the anti-glomerulosclerosis International Journal of Cardiology 158 (2012) 101–179