Histological analysis of nucleus pulposus tissue from patients with lumbar disc herniation after condoliase administration.

Background: Condoliase is an enzyme used as a treatment for lumbar disc herniation (LDH). This enzyme degrades chondroitin sulfate (CS) in the nucleus pulposus of the intervertebral disc (IVD). However, there are cases in which symptoms do not improve, despite condoliase administration. This study reports histological analysis of lumbar disc tissue of LDH patients who underwent surgery because condoliase had no therapeutic effect. Methods: Between March 2019 and August 2019, 12 LDH patients who underwent full endoscopic spine surgery (FESS) discectomy at the Dezawa Akira PED Clinic were the subjects of the study. There are two study groups: six cases underwent FESS after condoliase administration, while six underwent FESS without condoliase administration. The average duration from drug administration to surgery was 152 days. Herniated disc removed at surgery was evaluated by histological staining including immunohistochemistry by anti-CS antibodies. Results: Multiple large clusters (40-120 µm in diameter) were observed in the nucleus pulposus of those who received condoliase, but no clusters were observed in those who did not. The lumbar disc tissues, including the nucleus pulposus of recipients, were stained with anti-CS antibodies that recognize the CS unsaturated disaccharide, but non-administration tissue was not stained. These findings suggest that the enzyme acted on the nucleus pulposus, even in cases where symptoms were not improved by condoliase administration. Furthermore, there was no histological difference between stained images of the extracellular matrix in those who did or did not receive condoliase, suggesting that condoliase acted specifically on CS in the nucleus pulposus. Conclusions: We demonstrated that CS in the nucleus pulposus was degraded in patients in whom condoliase did not have a therapeutic effect. Moreover, condoliase acts in human IVD without causing necrosis of chondrocytes and surrounding tissues.

Injectable in situ cross-linking hyaluronan hydrogel for easier removal of posterior vitreous cortex in vitrectomy.

PURPOSE: Removing transparent vitreous tissues, such as a residual vitreous cortex (VC) or proliferative membrane, without damaging the retina is often problematic in vitrectomy. We examined the feasibility of an injectable in situ cross-linking hyaluronan hydrogel (XL-HA) for vitrectomy. STUDY DESIGN: Experiments using ex vivo and in vivo animal models. METHODS: HA-dibenzocyclooctyne and HA-azidoethylamine solutions were mixed to form XL-HA, which then gradually formed a hydrogel. We tested the function of XL-HA in ex vivo porcine eyes. We then examined the performance of XL-HA in in vivo rabbit models of posterior vitreous detachment, posterior VC removal, and proliferative vitreoretinopathy. RESULTS: The ex vivo study showed that XL-HA rapidly embedded triamcinolone acetonide, mimicking VC attached to the retina, and became hard enough to be pinched with tweezers within 3 minutes, allowing us to remove only the triamcinolone acetonide without impairing the internal limiting membrane. In the in vivo rabbit models, XL-HA injection improved posterior vitreous detachment, and the thin and fragile posterior VC or fibrous proliferative membrane was readily peeled off without any damage to the underlying retina as compared with untreated controls. A short-term intraocular biocompatibility test demonstrated that the intraocular pressure remained normal with XL-HA injected into the eye. In addition, transmission electron microscopy showed no obvious abnormalities in the cornea or in the inner and outer retina. CONCLUSION: The results indicate that XL-HA is a potential adjunctive device to help make vitrectomy safe, effective, and successful.

Development of in situ crosslinked hyaluronan as an adjunct to vitrectomy surgery.

Ophthalmologists have used hyaluronan (HA) products as adjuncts to ocular surgery since the 1970s. However, HA products are not always functional in surgeries of the posterior eye segment due to their lack of biomechanical strength. In this study, we developed an in situ crosslinked HA (XL-HA) and evaluated its potential as an adjunct to vitrectomy surgery in an in vitro model with a triamcinolone acetonide (TA) layer used as a pseudo residual vitreous cortex (RVC). Within a few minutes at concentrations over 0.9%, XL-HA, generated by the click chemistry of HA-dibenzocyclooctyne and HA-azidoethylamine, formed a hydrogel with the appropriate hardness for tweezers peeling. XL-HA (concentration, 0.76-1.73%) without dispersion successfully entered the TA layer and removed more than 45% of the total TA. Dynamic viscoelasticity helps to explain the rheological behavior of hydrogels, and the assessment results for XL-HA indicated that suitable concentrations were between 0.97% and 1.30%. For example, 1.30% XL-HA hydrogel reached sufficient hardness at 3 min for tweezers peeling, and the TA removal ability exceeded 70%. These results demonstrated that XL-HA was a potential adjunct to successful vitrectomy.

Diagnostic and Therapeutic Strategies for Stable Coronary Artery Disease Following the ISCHEMIA Trial.

Until recently, coronary revascularization with coronary artery bypass grafting or percutaneous coronary intervention has been regarded as the standard choice for stable coronary artery disease (CAD), particularly for patients with a significant burden of ischemia. However, in conjunction with remarkable advances in adjunctive medical therapy and a deeper understanding of its long-term prognosis from recent large-scale clinical trials, including ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), the approach to stable CAD has changed drastically. Although the updated evidence from recent randomized clinical trials will likely modify the recommendations for future clinical practice guidelines, there are still unresolved and unmet issues in Asia, where prevalence and practice patterns are markedly different from those in Western countries. Herein, the authors discuss perspectives on: 1) assessing the diagnostic probability of patients with stable CAD; 2) application of noninvasive imaging tests; 3) initiation and titration of medical therapy; and 4) evolution of revascularization procedures in the modern era.

Biochemical and crystallographic assessments of the effect of 4,6-O-disulfated disaccharide moieties in chondroitin sulfate E on chondroitinase ABC I activity.

O-sulfated N-acetyl-d-galactosamine (GalNAc) residues in chondroitin sulfate (CS) play a crucial role in chondroitinase ABC I (cABC-I) activity. CSA containing mainly 4-O-monosulfated GalNAc was a good substrate for the enzyme, but not CSE containing mainly 4,6-O-disulfated GalNAc [GalNAc(4S,6S)]. Each CS isomer exhibits structural heterogeneity; CSE has di-sulfated disaccharide units and mono-sulfated disaccharide units. Disaccharide composition analysis of digested products revealed that mono-sulfated disaccharide units in CSE contributed to the enzyme reactivity. Although enough substrate (CSA) was present in mixtures of CSA and CSE for reaction, the reactivity was reduced depending on the amount of CSE in the mixture. These results suggested that CSE is not only resistant to enzyme digestion but also attenuates enzyme activity. To understand the mechanism of action, crystallography of cABC-I in complex with unsaturated CSE-disaccharide, ΔDi-(4,6)S, was performed. Both 4-O- and 6-O-sulfate groups in ΔDi-(4,6)S interact with Arg500, suggesting that there was a greater interaction between ΔDi-(4,6)S and Arg500 than between mono-sulfated disaccharides and Arg500. Besides, this interaction attenuated enzyme activity by interfering with a function of Arg500, which is the charge neutralization of the carboxy group of D-glucuronic acid (GlcA) residues in CS. When interacting with the CSE-disaccharide unit [GlcAß1-3GalNAc(4S,6S)] in CS, cABC-I cannot interact with other CS-disaccharide units until it has digested the CSE-disaccharide unit. The low reactivity of cABC-I with CSE is attributable to two suggested factors: (a) resistance of E-units in CSE molecules to digestion by cABC-I, and (b) tendency of E-units in CSE molecules to attenuate cABC-I activity.

Effect of contrast media on the enzyme activity of condoliase: In vitro assessment.

Background: Condoliase has been used in Japan to treat patients with lumbar disc herniation by its injection into the nucleus pulposus. The injection of condoliase together with contrast media is prohibited; because there are no data whether contrast media have any effect on condoliase activity. This study aimed to elucidate the effects of contrast media on condoliase activity. Methods: Condoliase with chondroitin sulfate (CS) and without CS were mixed with various contrast media (nonionic [iohexol or iotrolan]; ionic [amidotrizoic acid]). (i) The mixtures with CS were incubated at 37°C; (ii) the mixtures without CS were stored at 24°C for 60 min, followed by addition of CS to assess condoliase activity by measuring the amount of N-acetylhexosamines enzymatically cleaved from CS using Morgan-Elson method. Results: (i) In the presence of CS, the ionic contrast media reduced condoliase activity within 10 min in a dose-dependent manner, and the nonionic contrast media had no effect on condoliase activity for at least 120 min. (ii) In the absence of CS, the ionic contrast media almost completely inactivated condoliase within 15 min, and the nonionic contrast media also reduced condoliase activity; the residual activity was 65% with iotrolan and 35% with iohexol at 60 min. Conclusions: The ionic contrast media significantly reduced condoliase activity regardless of presence or absence of CS. Although the nonionic contrast media did not affect condoliase activity in the presence of CS, it reduced activity in the absence of CS. Mixing condoliase with contrast media, especially ionic type contrast media, should be avoided.

[Clinical Functionality of Dispersive OVDs: Improvement of One of the Properties of 3% Hyaluronic Acid and 4% Chondroitin Sulfate Combination].

Ophthalmic viscosurgical devices (OVDs) are mainly divided into two general categories: cohesive and dispersive. Dispersive OVDs such as the 3% hyaluronic acid and 4% chondroitin sulfate (HA/CS) combination have excellent adhesion to ocular tissues and protect the corneal endothelium to a greater extent than cohesive OVDs. Herein, we summarize our recent findings regarding one of the properties of the HA/CS combination related to clinical performance. (i) The room temperature stability of OVDs and needle clogging by OVDs remain clinical issues. We demonstrated that adding d-sorbitol to the HA/CS combination preserved its viscosity, which was equivalent after 2 year-storage at room temperature to the viscosity of HA/CS combination stored under refrigeration for 2 years without d-sorbitol. Besides, the HA/CS combination with d-sorbitol could be used repeatedly without cleaning or replacing the needle, suggesting that the addition of d-sorbitol prevents drying and solidification of the OVD on the needle. (ii) Although it can be inferred from numerous studies that the tissue adhesion of OVDs influences their retention by the eye, little is known about the physical properties of OVDs that contribute to intraocular retention. To address this issue, we compared two types of adhesive forces, detachment force and repulsive force, for each OVD. Compared with other dispersive OVDs, the HA/CS combination showed higher values for both adhesive forces. These results suggest that adhesive forces may be used as an index of dispersive OVD retention in the eye.

Cardiac macrophages regulate isoproterenol-induced Takotsubo-like cardiomyopathy.

Takotsubo syndrome (TTS) is an acute, stress-induced cardiomyopathy that occurs predominantly in women after extreme physical and/or emotional stress. To date, our understanding of the molecular basis for TTS remains unknown and, consequently, specific therapies are lacking. Myocardial infiltration of monocytes and macrophages in TTS has been documented in clinical studies. However, the functional importance of these findings remains poorly understood. Here, we show that a single high dose of isoproterenol (ISO) in mice induced a TTS-like cardiomyopathy phenotype characterized by female predominance, severe cardiac dysfunction, and robust myocardial infiltration of macrophages. Single-cell RNA-Seq studies of myocardial immune cells revealed that TTS-like cardiomyopathy is associated with complex activation of innate and adaptive immune cells in the heart, and macrophages were identified as the dominant immune cells. Global macrophage depletion (via clodronate liposome administration) or blockade of macrophage infiltration (via a CCR2 antagonist or in CCR2-KO mice) resulted in recovery of cardiac dysfunction in ISO-challenged mice. In addition, damping myeloid cell activation by HIF1α deficiency or exposure to the immunomodulatory agent bortezomib ameliorated ISO-induced cardiac dysfunction. Collectively, our findings identify macrophages as a critical regulator of TTS pathogenesis that can be targeted for therapeutic gain.

KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II-induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

Association between coronary artery calcium score on non-contrast chest computed tomography and all-cause mortality among patients with congestive heart failure.

Coronary artery calcium (CAC) score is a robust prognostic tool to predict cardiac events. Although patients with congestive heart failure (CHF) occasionally undergo non-contrast computed tomography (NCCT), the prognostic utility of CAC by NCCT is not widely known. We aimed to determine if CAC measured on NCCT is associated with all-cause mortality (ACM) among patients with CHF. We identified 550 patients admitted due to CHF who underwent NCCT. Patients were categorized into three groups according to CAC scores 0, 1-999, and ≥ 1000. The multivariate Cox proportional hazards model was used to assess if CAC by NCCT was associated with ACM after adjusting for traditional coronary artery disease (CAD) risk factors, brain natriuretic peptide and left ventricular ejection fraction (LVEF). In a subset of 245 patients with invasive coronary angiography (ICA), the associations between CAC scores and ACM were assessed in the multivariate Cox proportional hazards model. Further, we assessed if CAC increased statin use at discharge. During a mean follow-up of 3.3 ± 3.1 years, ACM occurred in 168 patients (30.55%). Compared with patients with CAC 0, those with CAC ≥ 1000 (HR 1.564, 95% CI 0.969-2.524, P = 0.067) were more likely to experience ACM, while those with CAC score 1-999 (HR 0.971, 95% CI 0.673-1.399, P = 0.873) were not. Similarly, a trend toward significance was observed in patients with LVEF < 40% (HR 2.124, 95% CI 0.929-4.856, P = 0.074). In the sub-analysis, patients with CAC ≥ 1000 had increased ACM compared to those with CAC 0, only if ICA ≥ 50% (HR 3.668, 95% CI 1.141-11.797, P = 0.029). Multivariate logistic regression revealed that statin use at discharge was increased with ICA ≥ 50%, but not CAC. The CAC score measured by NCCT tended to be associated with ACM among CHF patients. Statin use was not increased by CAC on NCCT.

Substrate specificity of Chondroitinase ABC I based on analyses of biochemical reactions and crystal structures in complex with disaccharides.

Chondroitinase ABC I (cABC-I) is the enzyme which cleaves the ß-1,4 glycosidic linkage of chondroitin sulfate (CS) by ß-elimination. To elucidate more accurately the substrate specificity of cABC-I, we evaluated the kinetic parameters of cABC-I and its reactivity with CS isomers displaying less structural heterogeneity as substrates, e.g., approximately 90 percent of disaccharide units in Chondroitin sulfate A (CSA) or Chondroitin sulfate C (CSC) is D-glucuronic acid and 4-O-sulfated N-acetyl galactosamine (GalNAc) (A-unit) or D-glucuronic acid and 6-O-sulfated GalNAc (C-unit), respectively. cABC-I showed the highest reactivity to CSA and CSC among all CS isomers, and the kcat/Km of cABC-I was higher for CSA than for CSC. Next, we determined the crystal structures of cABC-I in complex with CS disaccharides, and analyzed the crystallographic data in combination with molecular docking data. Arg500 interacts with 4-O-sulfated and 6-O-sulfated GalNAc residues. The distance between Arg500 and the 4-O-sulfate group was 0.8 Å shorter than that between Arg500 and the 6-O-sulfated group. Moreover, it is likely that the 6-O-sulfated group is electrostatically repulsed by the nearby Asp490. Thus, we demonstrated that cABC-I has the highest affinity for the CSA richest in 4-O-sulfated GalNAc residues among all CS isomers. Recently, cABC-I was used to treat lumbar disc herniation. The results provide useful information to understand the mechanism of the pharmacological action of cABC-I.

Contemporary Management of Stable Coronary Artery Disease　- Implications of the ISCHEMIA Trial.

Coronary artery disease (CAD) remains a leading cause of mortality and morbidity in developed countries. Although urgent revascularization is the cornerstone of management of acute coronary syndrome (ACS), for patients with stable CAD recent large-scale clinical trials indicate that a mechanical 'fix' of a narrowed artery is not obviously beneficial; ACS and stable CAD are increasingly recognized as different clinical entities. We review the perspectives on (1) modifying the diagnostic pathway of stable CAD with the incorporation of modern estimates of pretest probability, (2) non-imaging evaluations based on their availability, (3) the optimal timing of invasive coronary angiography and revascularization, and (4) the implementation of medical therapy during the work-up.

Advances in Understanding the Mechanism of Ophthalmic Viscosurgical Device Retention in the Anterior Chamber or on the Corneal Surface during Ocular Surgery.

Retention durability, especially in the eye, is one of the most important properties of ophthalmic viscosurgical devices (OVDs) during ocular surgery. However, the information on the physical properties of OVDs is insufficient to explain their retention durability. The purpose of this study is to clarify the mechanism of OVD retention to improve understanding of the behavior of OVDs during ocular surgery. To elucidate the mechanism of OVD retention, we have developed a new test method for measuring repulsive force. As a result, the maximum repulsive force of OVDs was positively and well correlated with the retention durability of investigated OVDs. Consequently, we demonstrated that the repulsive force could be used as an index of retention durability on the ocular surface and in the eye. We directly compared the intraocular retention durability of three OVDs (Shellgan, Viscoat, and Opegan-Hi) in ex vivo porcine eyes. Opegan-Hi was immediately removed from the anterior chamber, but Shellgan and Viscoat remained largely in the anterior chamber as determined by fluorescence imaging. These results showed that the intraocular retention behavior of OVDs was similar to their ocular surface behavior in our previous report, suggesting that retention durability is dependent on the OVD itself. The retention durability of Shellgan seemed to be higher than that of Viscoat, and the maximum repulsive force of Shellgan was 1.35-fold higher than that of Viscoat. Therefore, the repulsive force might be a useful index for assessing the difference in the retention durability between OVDs such as Shellgan and Viscoat.

Quantitative Assessment of Ophthalmic Viscosurgical Devices on Visibility, Spreadability, and Durability as Corneal Wetting Agents for the Wet Shell Technique.

PURPOSE: To evaluate ophthalmic viscosurgical devices (OVDs) as corneal wetting agents for the wet shell technique, a common procedure in Japan to maintain the wettability of corneal surfaces. METHODS: We surveyed Japanese ophthalmologists to determine the current state of the wet shell technique. After developing three ex vivo testing methods, we evaluated the corneal wetting properties of OVDs including 3% hyaluronic acid (HA) solution and OVD products, Opegan, Opelead, Viscoat, Shellgan, Discovisc, and Opegan-Hi. RESULTS: Overall, 214 ophthalmologists (70%) had performed the wet shell technique, and 91% of ophthalmologists who performed vitreous surgery had performed this technique. Using a questionnaire, we evaluated the performance of OVD as corneal wetting agents as follows: (i) visibility, smoothness of OVD surface; (ii) spreadability, coverage of the cornea; and (iii) retention durability, residual ratio of OVD on the corneal surface. The smoothness and spreadability of Opegan, Opelead, and 3% HA were superior to other OVDs. Adding an appropriate amount of balanced salt solution to the other OVDs improved smoothness and spreadability similar to that of Opelead or 3% HA. Shellgan and Viscoat, combination OVDs consisting of 3% HA and 4% chondroitin sulfate, showed high retention durability, resulting in remaining longer on the cornea compared with other OVDs. CONCLUSIONS: Physical properties of OVDs tested in this study may provide useful information for ophthalmologists to select a suitable OVD when performing the wet shell technique.

A Clinical Association between an Increasing Renal Resistive Index and the Atherosclerotic Burden in Patients with a Preserved Renal Function.

Objective A positive correlation is observed between the progression of renal impairment and the increasing risk of cardiovascular disease. Our aim was to examine the relationship between the renal resistive index (RRI) assessed by duplex sonography and the extent of atherosclerosis in patients without renal impairment undergoing vascular imaging studies. Methods The RRI was evaluated pre-procedurally among 106 outpatients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 undergoing clinically-driven coronary computed tomography angiography (CCTA). In those subjects, a carotid artery ultrasound scan was also performed to evaluate carotid artery disease. We investigated the association between the RRI and the atherosclerotic extent, defined by the presence of coronary artery calcium (CAC) >0 and carotid intima-media thickness (cIMT) ≥1.0 mm. Results Multi-site atherosclerosis (CAC>0 and cIMT≥1.0 mm) was found in 31 patients. The RRI was significantly increased with an increasing number of atherosclerotic vessels (absence of atherosclerosis: 0.65±0.04 vs. single-site atherosclerosis: 0.67±0.06 vs. multi-site atherosclerosis: 0.71±0.05, p<0.001). A multivariate logistic regression analysis showed that RRI>0.70 [odds ratio (OR): 4.05, 95% confidence interval (CI), 1.37-12.0, p=0.01], cardio ankle vascular index (CAVI) ≥9.0 (OR: 8.18, 95% CI: 2.47-27.1, p<0.01), diabetes (OR: 4.34, 95% CI: 1.37-13.7, p=0.01) and an eGFR>90 mL/min/1.73 m2 (OR: 5.89, 95% CI: 1.39-25.1, p=0.01) were associated with multi-site atherosclerosis. Conclusion The RRI, a sub-clinical renal parameter is an atherosclerotic marker in patients without renal impairment.

Heart Rate After Resuscitation From Out-of-Hospital Cardiac Arrest due to Acute Coronary Syndrome Is an Independent Predictor of Clinical Outcome.

BACKGROUND: Heart rate (HR) is a useful predictor of cardiovascular disease, especially in acute coronary syndrome (ACS). However, it is unclear whether there is an association between HR and clinical outcomes after resuscitation from out-of-hospital cardiac arrest (OHCA) due to ACS. The aim of this study was to investigate the impact of HR on clinical outcome in individuals resuscitated from OHCA due to ACS.Methods and Results:Data from 3,687 OHCA patients between October 2002 and October 2014 were retrospectively analyzed. We divided 154 patients diagnosed with ACS into 2 groups: those with tachycardia (HR >100 beats/min, n=71) and those without tachycardia (HR ≤100 beats/min, n=83) after resuscitation. The primary endpoint was 1-year mortality and the secondary endpoint was neurological injury at discharge according to cerebral performance category score. Overall, mean HR was 95.6 beats/min. There were several significant differences in patient characteristics, indicating poor general condition of patients with tachycardia. Mortality at 1-year was 41.6%, and neurological injury at discharge was observed in 44.1% of individuals. In the multivariate analysis, tachycardia after resuscitation was an independent predictor of both 1-year mortality (hazard ratio, 2.66; 95% CI: 1.20-5.85; P=0.03) and neurological injury at discharge (odds ratio, 2.65; 95% CI: 1.27-5.55; P=0.04). CONCLUSIONS: In patients who recovered from OHCA due to ACS, tachycardia after resuscitation predicted poor clinical outcome.

The Difference in the Changes of Indoxyl Sulfate after Catheter Ablation among Atrial Fibrillation Patients with and without Kidney Dysfunction.

Indoxyl sulfate (IS), a protein-bound uremic toxin, induces chronic kidney disease (CKD) and atrial fibrillation (AF). Catheter ablation (CA) of AF improves the renal function. However, the transition of uremic toxins is unclear. This study aimed to investigate the transition of the serum IS level in AF patients with and without CKD after CA. A total of 138 consecutive AF patients who underwent CA and maintained sinus rhythm were prospectively enrolled (paroxysmal AF 67.4%). The patients were divided into 4 groups (non-CKD/low-IS:68, non-CKD/high-IS:28, CKD/low-IS:13, and CKD/high-IS:29). The plasma IS levels and estimated glomerular filtration rate (eGFR) were determined before and 1-year after CA. CKD was defined as CKD stage III and a high-IS according to the mean IS (IS ≥ 1.1 µg/ml). CA significantly improved the eGFR in CKD patients (p < 0.001). The serum IS level in the non-CKD/high-IS group was significantly decreased (from 1.7 ± 0.7 to 1.1 ± 0.6 µg/ml, p < 0.001). However, the serum IS level in the CKD/high-IS group did not improve (from 1.9 ± 0.9 to 1.7 ± 0.7 µg/ml, p = 0.22). The change in the IS in the CKD patients significantly differed from that in those without CKD. In the CKD patients, CA did not significantly decrease the IS, a risk factor of CKD, regardless of an improved eGFR.

Frailty and coronary plaque characteristics on optical coherence tomography.

The relationship between frailty and plaque characteristics is unclear and was investigated by optical coherence tomography (OCT) in this study. One hundred and four patients undergoing OCT before percutaneous coronary intervention were evaluated. Frailty was defined as a clinical frailty scale score of ≧6. Frailty was found in 16% of the patients (17/104). Compared with the nonfrail patients, frail patients showed significantly lower body mass index (BMI; 20.8 ± 4.0 kg/m2 vs. 25.0 ± 3.9 kg/m2, P < 0.001), less dyslipidemia [47% (8/17) vs. 75% (65/87), P = 0.023], lower triglycerides levels (95 ± 42 mg/dL vs. 147 ± 81 mg/dL, P < 0.001), less use of statin [29% (5/17) vs. 60% (52/87), P = 0.021], more lipid-rich plaque [82% (14/17) vs. 46% (40/87), P = 0.006] on OCT, more thin-cap fibroatheromas [TCFAs; 71% (12/17) vs. 26% (23/87), P < 0.001], more plaque rupture [53% (9/17) vs. 25% (22/87), P = 0.023], and significantly higher adverse clinical outcomes (death, acute myocardial infarction, acute heart failure, acute coronary syndrome, or target lesion revascularization) [24% (4/17) vs. 6% (5/87), P = 0.007]. The multivariable analysis showed that frailty was one of the independent predictors of TCFAs (odds ratio 8.95, 95% CI 2.40-33.32, P = 0.001). In conclusion, frailty was associated with high plaque vulnerability due to more lipid-rich plaque, TCFAs and plaque rupture on OCT regardless of low BMI, less dyslipidemia and low triglycerides levels, and frail patients had higher adverse clinical outcomes.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.