Sho Torii

Clinical Effectiveness of Tolvaptan in Patients With Acute Heart Failure and Renal Dysfunction

BACKGROUND More efficacious and/or safer decongestive therapy is clearly needed in acute heart failure (AHF) patients complicated by renal dysfunction. We tested the hypothesis that adding tolvaptan, an oral vasopressin-2 receptor antagonist, to conventional therapy with loop diuretics would be more effective treatment in this population. METHODS AND RESULTS A multicenter, open-label, randomized control trial was performed, and 217 AHF patients with renal dysfunction (estimated glomerular filtration rate 15-60 mL • min(-1) • 1.73 m(-2)) were randomized 1:1 to treatment with tolvaptan (n=108) or conventional treatment (n=109). The primary end point was 48-hour urine volume. The tolvaptan group showed more diuresis than the conventional treatment group (6464.4 vs 4999.2 mL; P <.001) despite significantly lower amounts of loop diuretic use (80 mg vs 120 mg; P <.001). Dyspnea relief was achieved significantly more frequently in the tolvaptan group at all time points within 48 hours except 6 hours after enrollment. The rate of worsening of renal function (≥0.3 mg/dL increase from baseline) was similar between the tolvaptan and conventional treatment groups (24.1% vs 27.8%, respectively; P =.642). CONCLUSIONS Adding tolvaptan to conventional treatment achieved more diuresis and relieved dyspnea symptoms in AHF patients with renal dysfunction. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index/htm/ Unique identifier: UMIN000007109.

Comparison of vascular response between durable and biodegradable polymer-based drug-eluting stents in a porcine coronary artery model.

AIMS Biodegradable polymer-based drug-eluting stents are thought to be safer than durable polymer-based stents. However, the long-term vascular response remains unclear. The aim of this study was to compare the biocompatibility of durable polymer-based sirolimus-eluting (SES) and everolimus-eluting (EES) stents with biodegradable polymer-based biolimus-eluting (BES) stents in a porcine coronary model. Stents were implanted in porcine coronaries. Acetylcholine challenge tests and optical coherence tomography (OCT) examination were performed at one month. Animals were sacrificed at three and six months (n=6 each), and the stents were analysed histologically. At one month, acetylcholine challenge tests revealed a trend towards greatest vasoconstriction in SES, less in BES, and least in EES, but the differences were not significant. OCT analysis demonstrated the highest incidence of uncovered struts in SES, followed by BES, while EES showed almost complete strut coverage (41.7±27.0%, 24.5±23.8%, 0.4±0.8%, respectively; p=0.004). Upon histological analysis at three months, SES showed a significantly higher inflammatory score than BES and EES (2.9±1.4, 0.8±0.9, 0.5±0.4, respectively; p=0.001), and this was maintained at six months (1.6±1.5, 0.3±0.3, 0.4±0.6, respectively; p=0.049). While SES showed an increased inflammatory reaction, EES and BES showed minimal inflammation. These results indicate that the late inflammatory reaction does not necessarily depend on degradability of the polymer, if the combination of the drug, metal, and polymer is biocompatible.

Coronary Angiographic Characteristics That Influence Fractional Flow Reserve

BACKGROUND Percutaneous coronary intervention (PCI) guided with fractional flow reserve (FFR) has been shown to improve clinical outcome. Although coronary angiography is the standard method for PCI guidance, the visual severity of stenosis is not always correlated with functional severity, suggesting that there are additional angiographic factors that affect functional ischemia. METHODS AND RESULTS To evaluate angiographic predictors of positive FFR in stenotic lesions, angiographic characteristics of 260 consecutive patients (362 lesions) who underwent FFR testing from April 2009 to September 2012 were analyzed. A scoring system (STABLED score) using these predictors was developed and compared with quantitative coronary angiography (QCA). %Diameter stenosis >50% (OR, 8.43; P<0.0001), tandem lesion (OR, 4.00; P<0.0001), true bifurcation (OR, 2.42; P=0.028), lesion length >20 mm (OR, 5.40; P=0.0002), and distance from ostium <20 mm (OR, 1.94; P=0.028) were determined as independent predictors of positive FFR. Area under the ROC curve for probability of positive FFR using the STABLED score (Stenosis 2 points, TAndem lesion 1 point, Bifurcation 1 point, LEsion length 1 point, Distance from ostium 1 point) was 0.85, higher than that for QCA stenosis alone (0.76). STABLED score ≥3 had 72.3% sensitivity and 83.6% specificity for predicting positive FFR, and PPV was 76.7%. CONCLUSIONS Specific angiographic features are applicable for predicting functional ischemia. STABLED score correlates well with FFR.

Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds: Magmaris Versus Absorb in a Porcine Arteriovenous Shunt Model

Background— A comparison in acute thrombogenicity between the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold has not been performed. This study assessed acute thrombogenicity of Magmaris compared with Absorb and the Orsiro hybrid drug-eluting stent in a porcine arteriovenous shunt model. Methods and Results— An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to SYLGARD tubing containing the Magmaris, Absorb, and Orsiro scaffolds/stents and allowed to run in the shunt for a maximum of 1 hour. Twelve shunts (2 shunt runs per pig) were run comparing the 3 scaffolds in alternating order. Nested generalized linear mixed models were used to compare variables between scaffold groups while adjusting for variability between shunt runs. Confocal fluorescent microscopy costaining CD61/CD42b demonstrated that both Magmaris (3.0%) and Orsiro (4.6%) had less platelet coverage of the total scaffold compared with Absorb (21.8%). Scanning electron microscopy demonstrated significantly less thrombus deposition to Magmaris as a percentage of the total scaffold compared with Absorb (5.0% versus 16.1%, P=0.02). Magmaris had significantly less PM-1–positive neutrophil and CD14-positive monocyte adherence compared with both Orsiro and Absorb. Orsiro had significantly less monocyte deposition compared with Absorb. Conclusions— Despite a similar scaffold strut thickness, the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold was significantly less thrombogenic compared with the Absorb bioresorbable vascular scaffold in an ex vivo porcine arteriovenous shunt model. Further studies are needed to determine whether the reduced thrombogenicity of Magmaris will result in reductions in major cardiovascular events.

Prognostic impact of early treatment with tolvaptan in patients with acute heart failure and renal dysfunction.

BACKGROUND Renal dysfunction is a common comorbidity in acute heart failure (AHF) patients. The prognostic significance of early treatment with tolvaptan in AHF patients complicated with renal dysfunction has not been elucidated. METHODS Post hoc analysis was performed on a randomized clinical study for prespecified prognostic endpoints and prespecified subgroups. 217 AHF patients with renal dysfunction (eGFR 15 to 60mL/min/1.73m(2)) were randomized within 6h from hospitalization to either tolvaptan treatment for 2days or conventional treatment. The primary outcome was the combined endpoint of all-cause death and HF readmission. RESULTS During follow-up (636days, median) 99 patients experienced combined endpoint and 53 patients died. There was no significant difference in event-free survival rate for either the combined events (Log-rank: P=0.197) or all-cause death (Log-rank: P=0.894) between tolvaptan and conventional groups. In prespecified subgroup analysis, in patients whose BUN/creatinine ratio was above the median (>20), tolvaptan significantly reduced the risk of combined events (HR: 0.52, 95% CI: 0.30-0.91, P=0.021) with a significant interaction (P value for interaction=0.045). Likewise, in patients whose eGFR was 30mL/min/1.73m(2) or above, tolvaptan reduced the risk of combined events (HR: 0.54, 95% CI: 0.32-0.90, P=0.017) with a significant interaction (P value for interaction=0.015). CONCLUSION Short-term use of tolvaptan in acute-phase in AHF with renal dysfunction showed a neutral effect on prognosis. Patients with relatively preserved renal function and relatively high BUN/creatinine ratios are potentially favorable subgroups for treatment with tolvaptan.

CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis

Intake of hemoglobin by the hemoglobin-haptoglobin receptor CD163 leads to a distinct alternative non–foam cell antiinflammatory macrophage phenotype that was previously considered atheroprotective. Here, we reveal an unexpected but important pathogenic role for these macrophages in atherosclerosis. Using human atherosclerotic samples, cultured cells, and a mouse model of advanced atherosclerosis, we investigated the role of intraplaque hemorrhage on macrophage function with respect to angiogenesis, vascular permeability, inflammation, and plaque progression. In human atherosclerotic lesions, CD163+ macrophages were associated with plaque progression, microvascularity, and a high level of HIF1&agr; and VEGF-A expression. We observed irregular vascular endothelial cadherin in intraplaque microvessels surrounded by CD163+ macrophages. Within these cells, activation of HIF1&agr; via inhibition of prolyl hydroxylases promoted VEGF-mediated increases in intraplaque angiogenesis, vascular permeability, and inflammatory cell recruitment. CD163+ macrophages increased intraplaque endothelial VCAM expression and plaque inflammation. Subjects with homozygous minor alleles of the SNP rs7136716 had elevated microvessel density, increased expression of CD163 in ruptured coronary plaques, and a higher risk of myocardial infarction and coronary heart disease in population cohorts. Thus, our findings highlight a nonlipid-driven mechanism by which alternative macrophages promote plaque angiogenesis, leakiness, inflammation, and progression via the CD163/HIF1&agr;/VEGF-A pathway.

Very Late Pathological Responses to Cobalt–Chromium Everolimus‐Eluting, Stainless Steel Sirolimus‐Eluting, and Cobalt–Chromium Bare Metal Stents in Humans

Background The “very late” clinical outcomes for durable polymer drug‐eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long‐term vascular compatibility of BMSs is still regarded to be superior to drug‐eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug‐eluting stents (cobalt–chromium [CoCr] everolimus‐eluting stents [EESs] and stainless steel sirolimus‐eluting stents [SS‐SESs]) versus BMSs (CoCr‐BMSs). Methods and Results From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr‐EESs, 44 SS‐SESs, 35 CoCr‐BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr‐EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr‐BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS‐SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS‐SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr‐EESs (50%) was significantly less than with SS‐SESs (77%, P=0.02) but significantly greater than with CoCr‐BMSs (20%, P<0.01). Conclusions CoCr‐EESs, SS‐SESs, and BMSs each demonstrated distinct vascular responses. CoCr‐EESs demonstrated the least inflammation, near‐equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug‐eluting stents and may have implications for future stent design.

Tissue characterization with depth-resolved attenuation coefficient and backscatter term in intravascular optical coherence tomography images

Abstract. An important application of intravascular optical coherence tomography (IVOCT) for atherosclerotic tissue analysis is using it to estimate attenuation and backscatter coefficients. This work aims at exploring the potential of the attenuation coefficient, a proposed backscatter term, and image intensities in distinguishing different atherosclerotic tissue types with a robust implementation of depth-resolved (DR) approach. Therefore, the DR model is introduced to estimate the attenuation coefficient and further extended to estimate the backscatter-related term in IVOCT images, such that values can be estimated per pixel without predefining any delineation for the estimation. In order to exclude noisy regions with a weak signal, an automated algorithm is implemented to determine the cut-off border in IVOCT images. The attenuation coefficient, backscatter term, and the image intensity are further analyzed in regions of interest, which have been delineated referring to their pathology counterparts. Local statistical values were reported and their distributions were further compared with a two-sample t-test to evaluate the potential for distinguishing six types of tissues. Results show that the IVOCT intensity, DR attenuation coefficient, and backscatter term extracted with the reported implementation are complementary to each other on characterizing six tissue types: mixed, calcification, fibrous, lipid-rich, macrophages, and necrotic core.

Coronary Artery Calcification and its Progression: What Does it Really Mean?

Coronary artery calcification is concomitant with the development of advanced atherosclerosis. Coronary artery calcification pathologically begins as microcalcifications (0.5 to 15.0 μm) and grows into larger calcium fragments, which eventually result in sheet-like deposits (>3 mm). This evolution is observed to occur concurrently with the progression of plaque. These fragments and sheets of calcification can be easily identified by radiography as well as by computed tomography and intravascular imaging. Many imaging modalities have proposed spotty calcification to be a predictor of unstable plaque and have suggested more extensive calcification to be associated with stable plaques and perhaps the use of statin therapy. We will review the pathology of coronary calcification in humans with a focus on risk factors, relationship with plaque progression, correlation with plaque (in)stability, and effect of pharmacologic interventions.

Evaluation of coronary arterial calcification – Ex-vivo assessment by optical frequency domain imaging

AIMS The purpose of this study was to determine the diagnostic ability of optical frequency domain imaging (OFDI) to carry out quantitative and qualitative evaluation of coronary calcification in comparing with ex vivo human autopsy heart specimens. METHODS Analysis was carried out in 25 coronary artery specimen obtained from 16 cadavers that were imaged ex-vivo imaging by OFDI and intravascular ultrasound (IVUS). Of 235 cross-sections obtained for histologic evaluation, 149 were classified as showing calcified plaques, and in this group a comparison between histology versus co-registered images by OFDI and IVUS was performed. RESULTS Maximum thickness of calcification measured by OFDI was well correlated with histology (rs = 0.70, p < 0.0001) whereas IVUS was not useful for quantitative analysis because of the presence of acoustic shadows occurring behind calcifications. Furthermore qualitative evaluation could be carried out using OFDI, for calcifications with vague or invisible outer borders by OFDI had lipid contents (lipid pool or histologic necrotic core) more frequently as compared to those with a clear outer border (79% vs. 24%, p < 0.0001). We also found that calcified nodules, a well-recognized thrombogenic substrate, demonstrated atypical appearance in OFDI, showing irregular surfaces with high attenuation. CONCLUSION OFDI demonstrated a greater ability than IVUS to provide quantitative and qualitative evaluation of coronary arterial calcification. Precise recognition of calcified plaque morphology by OFDI may serve to determine the treatment strategy of patients having atherosclerotic coronary disease.