TIFAB regulates the TIFA-TRAF6 signaling pathway involved in innate immunity by forming a heterodimer complex with TIFA.

Nuclear factor κB (NF-κB) is activated by various inflammatory and infectious molecules and is involved in immune responses. It has been elucidated that ADP-ß-D-manno-heptose (ADP-Hep), a metabolite in gram-negative bacteria, activates NF-κB through alpha-kinase 1 (ALPK1)-TIFA-TRAF6 signaling. ADP-Hep stimulates the kinase activity of ALPK1 for TIFA phosphorylation. Complex formation between phosphorylation-dependent TIFA oligomer and TRAF6 promotes the polyubiquitination of TRAF6 for NF-κB activation. TIFAB, a TIFA homolog lacking a phosphorylation site and a TRAF6 binding motif, is a negative regulator of TIFA-TRAF6 signaling and is implicated in myeloid diseases. TIFAB is indicated to regulate TIFA-TRAF6 signaling through interactions with TIFA and TRAF6; however, little is known about its biological function. We demonstrated that TIFAB forms a complex not with the TIFA dimer, an intrinsic form of TIFA involved in NF-κB activation, but with monomeric TIFA. The structural analysis of the TIFA/TIFAB complex and the biochemical and cell-based analyses showed that TIFAB forms a stable heterodimer with TIFA, inhibits TIFA dimer formation, and suppresses TIFA-TRAF6 signaling. The resultant TIFA/TIFAB complex is a "pseudo-TIFA dimer" lacking the phosphorylation site and TRAF6 binding motif in TIFAB and cannot form the orderly structure as proposed for the phosphorylated TIFA oligomer involved in NF-κB activation. This study elucidated the molecular and structural basis for the regulation of TIFA-TRAF6 signaling by TIFAB.

Visualization of mutagenic nucleotide processing by Escherichia coli MutT, a Nudix hydrolase.

Escherichia coli MutT prevents mutations by hydrolyzing mutagenic 8-oxo-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) in the presence of Mg2+ or Mn2+ ions. MutT is one of the most studied enzymes in the nucleoside diphosphate-linked moiety X (Nudix) hydrolase superfamily, which is widely distributed in living organisms. However, the catalytic mechanisms of most Nudix hydrolases, including two- or three-metal-ion mechanisms, are still unclear because these mechanisms are proposed using the structures mimicking the reaction states, such as substrate analog complexes. Here, we visualized the hydrolytic reaction process of MutT by time-resolved X-ray crystallography using a biological substrate, 8-oxo-dGTP, and an active metal ion, Mn2+. The reaction was initiated by soaking MutT crystals in a MnCl2 solution and stopped by freezing the crystals at various time points. In total, five types of intermediate structures were refined by investigating the time course of the electron densities in the active site as well as the anomalous signal intensities of Mn2+ ions. The structures and electron densities show that three Mn2+ ions bind to the Nudix motif of MutT and align the substrate 8-oxo-dGTP for catalysis. Accompanied by the coordination of the three Mn2+ ions, a water molecule, bound to a catalytic base, forms a binuclear Mn2+ center for nucleophilic substitution at the ß-phosphorus of 8-oxo-dGTP. The reaction condition using Mg2+ also captured a structure in complex with three Mg2+ ions. This study provides the structural details essential for understanding the three-metal-ion mechanism of Nudix hydrolases and proposes that some of the Nudix hydrolases share this mechanism.

Contribution of Phe112, Ser114, and Tyr115 to Drug-Binding Selectivity in the A Variant of α1-Acid Glycoprotein.

The plasma protein α1-acid glycoprotein (AGP) primarily affects the pharmacokinetics of basic drugs. There are two AGP variants in humans, A and F1*S, exhibiting distinct drug-binding selectivity. Elucidation of the drug-binding selectivity of human AGP variants is essential for drug development and personalized drug therapy. Herein, we aimed to establish the contribution of amino acids 112 and 114 of human AGP to drug-binding selectively. Both amino acids are located in the drug-binding region and differ between the variants. Phe112/Ser114 of the A variant and its equivalent residues in the F1*S variant (Leu112/Phe114) were swapped with each other. Binding experiments were then conducted using the antiarrhythmic drug disopyramide, which selectively binds to the A variant. A significant decrease in the bound fraction was observed in each singly mutated A protein (Phe112Leu or Ser114Phe). Moreover, the bound fraction of the double A mutant (Phe112Leu/Ser114Phe) was decreased to that of wild-type F1*S. Intriguingly, the double F1*S mutant (Leu112Phe/Phe114Ser), in which residues were swapped with those of the A variant, showed only partial restoration in binding. The triple F1*S mutant (Leu112Phe/Phe114Ser/Asp115Tyr), where position 115 is thought to contribute to the difference in pocket size between variants, showed a further recovery in binding to 70% of that of wild-type A. These results were supported by thermodynamic analysis and acridine orange binding, which selectively binds the A variant. Together, these data indicate that, in addition to direct interaction with Phe112 and Ser114, the binding pocket size contributed by Tyr115 is important for the drug-binding selectivity of the A variant.

Structure of the mammalian adenine DNA glycosylase MUTYH: insights into the base excision repair pathway and cancer.

Mammalian MutY homologue (MUTYH) is an adenine DNA glycosylase that excises adenine inserted opposite 8-oxoguanine (8-oxoG). The inherited variations in human MUTYH gene are known to cause MUTYH-associated polyposis (MAP), which is associated with colorectal cancer. MUTYH is involved in base excision repair (BER) with proliferating cell nuclear antigen (PCNA) in DNA replication, which is unique and critical for effective mutation-avoidance. It is also reported that MUTYH has a Zn-binding motif in a unique interdomain connector (IDC) region, which interacts with Rad9-Rad1-Hus1 complex (9-1-1) in DNA damage response, and with apurinic/apyrimidinic endonuclease 1 (APE1) in BER. However, the structural basis for the BER pathway by MUTYH and its interacting proteins is unclear. Here, we determined the crystal structures of complexes between mouse MUTYH and DNA, and between the C-terminal domain of mouse MUTYH and human PCNA. The structures elucidated the repair mechanism for the A:8-oxoG mispair including DNA replication-coupled repair process involving MUTYH and PCNA. The Zn-binding motif was revealed to comprise one histidine and three cysteine residues. The IDC, including the Zn-binding motif, is exposed on the MUTYH surface, suggesting its interaction modes with 9-1-1 and APE1, respectively. The structure of MUTYH explains how MAP mutations perturb MUTYH function.

A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.

HIV-1 often acquires drug-resistant mutations in spite of the benefits of antiretroviral therapy (ART). HIV-1 integrase (IN) is essential for the concerted integration of HIV-1 DNA into the host genome. IN further contributes to HIV-1 RNA binding, which is required for HIV-1 maturation. Non-catalytic-site integrase inhibitors (NCINIs) have been developed as allosteric IN inhibitors, which perform anti-HIV-1 activity by a multimodal mode of action such as inhibition of the IN-lens epithelium-derived growth factor (LEDGF)/p75 interaction in the early stage and disruption of functional IN multimerization in the late stage of HIV-1 replication. Here, we show that IN undergoes an adaptable conformational change to escape from NCINIs. We observed that NCINI-resistant HIV-1 variants have accumulated 4 amino acid mutations by passage 26 (P26) in the IN-encoding region. We employed high-performance liquid chromatography (HPLC), thermal stability assays, and X-ray crystallographic analysis to show that some amino acid mutations affect the stability and/or dimerization interface of the IN catalytic core domains (CCDs), potentially resulting in the severely decreased multimerization of full-length IN proteins (IN undermultimerization). This undermultimerized IN via NCINI-related mutations was stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1 in viral particles. Recombinant HIV-1 clones with IN undermultimerization propagated similarly to wild-type HIV-1. Our study revealed that HIV-1 can eventually counteract NCINI-induced IN overmultimerization by IN undermultimerization as one of the escape mechanisms. Our findings provide information on the understanding of IN multimerization with or without HIV-1 RNA and may influence the development of anti-HIV-1 strategies.IMPORTANCE Understanding the mechanism of HIV-1 resistance to anti-HIV-1 drugs could lead to the development of novel drugs with increased efficiency, resulting in more effective ART. ART composed of more potent and long-acting anti-HIV-1 drugs can greatly improve drug adherence and also provide HIV-1 prevention such as preexposure prophylaxis. NCINIs with a multimodal mode of action exert potent anti-HIV-1 effects through IN overmultimerization during HIV-1 maturation. However, HIV-1 can acquire some mutations that cause IN undermultimerization to alleviate NCINI-induced IN overmultimerization. This undermultimerized IN was efficiently stabilized by HIV-1 RNA and restored to the same level as that of wild-type HIV-1. Our findings revealed that HIV-1 eventually acquires such a conformational escape reaction to overcome the unique NCINI actions. The investigation into drug-resistant mutations associated with HIV-1 protein multimerization may facilitate the elucidation of its molecular mechanism and functional multimerization, allowing us to develop more potent anti-HIV-1 drugs and unique treatment strategies.

Rescuing Patients With Severe Biventricular Failure in the Era of Continuous-Flow Left Ventricular Assist Device.

BACKGROUND: We evaluated clinical outcomes of left ventricular assist device (LVAD) support in patients with or without severe right heart failure, in order to determine what kind of organ allocation system could help severe biventricular failure patients to be safely bridged to heart transplantation (HTx), even in Japan where the waiting time for HTx is extremely long. Methods and Results: One hundred and seventy consecutive patients who were implanted with continuous-flow LVAD at the present institution were included in this study. The patients were divided into 2 groups: 158 patients with isolated LVAD (group-LVF) and 12 patients who required long-term mechanical or inotropic right heart support (group-BVF). Post-LVAD survival in group-BVF was significantly worse than in group-LVF (P<0.0001). Given that many patients in group-BVF died between 1 and 2 years after LVAD implantation, Kaplan-Meier survival curve simulation was carried out under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received HTx at 365 days after LVAD implantation and survived thereafter. In this simulation, no significant difference in survival was seen between the groups (P=0.2424). CONCLUSIONS: A new allocation system that allows severe right heart failure patients to receive HTx at around 1 year would enable rescue of the patients with severe right heart failure.

Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity.

The human MutT homolog 1 (hMTH1, human NUDT1) hydrolyzes oxidatively damaged nucleoside triphosphates and is the main enzyme responsible for nucleotide sanitization. hMTH1 recently has received attention as an anticancer target because hMTH1 blockade leads to accumulation of oxidized nucleotides in the cell, resulting in mutations and death of cancer cells. Unlike Escherichia coli MutT, which shows high substrate specificity for 8-oxoguanine nucleotides, hMTH1 has broad substrate specificity for oxidized nucleotides, including 8-oxo-dGTP and 2-oxo-dATP. However, the reason for this broad substrate specificity remains unclear. Here, we determined crystal structures of hMTH1 in complex with 8-oxo-dGTP or 2-oxo-dATP at neutral pH. These structures based on high quality data showed that the base moieties of two substrates are located on the similar but not the same position in the substrate binding pocket and adopt a different hydrogen-bonding pattern, and both triphosphate moieties bind to the hMTH1 Nudix motif (i.e. the hydrolase motif) similarly and align for the hydrolysis reaction. We also performed kinetic assays on the substrate-binding Asp-120 mutants (D120N and D120A), and determined their crystal structures in complex with the substrates. Analyses of bond lengths with high-resolution X-ray data and the relationship between the structure and enzymatic activity revealed that hMTH1 recognizes the different oxidized nucleotides via an exchange of the protonation state at two neighboring aspartate residues (Asp-119 and Asp-120) in its substrate binding pocket. To our knowledge, this mechanism of broad substrate recognition by enzymes has not been reported previously and may have relevance for anticancer drug development strategies targeting hMTH1.

Watching DNA polymerase η make a phosphodiester bond.

DNA synthesis has been extensively studied, but the chemical reaction itself has not been visualized. Here we follow the course of phosphodiester bond formation using time-resolved X-ray crystallography. Native human DNA polymerase η, DNA and dATP were co-crystallized at pH 6.0 without Mg(2+). The polymerization reaction was initiated by exposing crystals to 1 mM Mg(2+) at pH 7.0, and stopped by freezing at desired time points for structural analysis. The substrates and two Mg(2+) ions are aligned within 40 s, but the bond formation is not evident until 80 s. From 80 to 300 s structures show a mixture of decreasing substrate and increasing product of the nucleotidyl-transfer reaction. Transient electron densities indicate that deprotonation and an accompanying C2'-endo to C3'-endo conversion of the nucleophile 3'-OH are rate limiting. A third Mg(2+) ion, which arrives with the new bond and stabilizes the intermediate state, may be an unappreciated feature of the two-metal-ion mechanism.

Mitral Valve Structure in Addition to Myocardial Viability Determines the Outcome of Functional Mitral Regurgitation After Coronary Artery Bypass Grafting.

BACKGROUND: Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical analysis, the addition of estimated coaptation length and jet direction to the reported predictors (ejection fraction, left ventricular end-diastolic dimension, and tenting height) more accurately predicted changes in post-CABG MR than the reported 3 factors alone. CONCLUSIONS: Residual MR was associated with the emergence of congestive heart failure in the long term after CABG. A specific mitral valve structure, such as large mitral leaflet size or predominant tethering of the posterior leaflet, was a predictive factor for the reversibility of post-CABG functional MR.

Restrictive Mitral Annuloplasty With or Without Papillary Muscle Approximation for Functional Mitral Regurgitation.

BACKGROUND AND AIM OF THE STUDY: The impact of adding papillary muscle approximation (PMA) to restrictive mitral annuloplasty (RMA) on postoperative left ventricular (LV) function is unknown. Changes in LV function parameters and clinical outcome were evaluated following RMA with and without PMA in patients with clinically relevant functional mitral regurgitation (FMR). METHODS: A total of 176 patients with advanced cardiomyopathy underwent RMA either with (n = 59) or without (n = 117) PMA. Propensity score analysis was used to adjust for group differences in several baseline characteristics, such as age, gender and LV ejection fraction (LVEF) (C-statistic = 0.80, goodness-of-fit value = 0.58). RESULTS: Serial echocardiography in 30 propensity score-matched pairs demonstrated decreases in LV end-systolic dimension (RMA alone: 57 ± 9 mm at baseline versus 54 ±11 mm at one month versus 56 ± 13 mm at latest examination; RMA + PMA: 56 ± 8 mm versus 53 ± 9 mm versus 48 ± 11 mm, respectively) and improvement in LVEF (RMA alone: 28 ± 8% versus 28 ± 11% versus 29 ± 10%; RMA + PMA: 30 ± 8% versus 30 ± 9% versus 36 ± 13%, respectively) in both groups. Greater degrees of changes in value were noted for patients receiving RMA + PMA (group effect p <0.05 for both). The two-year survival of both groups was similar (73 ± 8% versus 77 ± 23%, p = 0.7), but the RMA + PMA group showed a trend towards a greater freedom from composite events, defined as mortality and/or unscheduled heart failure re-admission (48 ± 9% versus 63 ± 9%, p = 0.1). CONCLUSIONS: RMA + PMA induced greater long-term effects on unloading of the left ventricle and improvements in LV systolic function than did RMA alone. PMA may be a useful adjunct repair in combination with RMA, although its clinical benefits remain to be determined.

Curative surgery for gastric cancer in a patient with an implantable left ventricular assist device.

The number of patients with end-stage heart failure treated by a left ventricular assist device (LVAD) is dramatically increasing, because the LVAD has been widely accepted for its clinical results. According to the initiation of destination therapy, the prevalence of malignancy in patients with an LVAD is estimated to increase. In patients with LVADs, abdominal surgery for visceral malignancy is associated with technical difficulties because of the presence of an LVAD pump or the driveline which is located transversely in the preperitoneal space. Herein, we describe the technical management for complete resection of gastric cancer in a patient with an LVAD.

The impact of age on the postoperative response of the diastolic function and left ventricular mass regression after surgical or transcatheter aortic valve replacement for severe aortic stenosis.

PURPOSE: We examined the impact of advanced age on left ventricular mass regression and the change in the diastolic function after aortic valve replacement in patients with aortic stenosis. METHODS: The present study included 129 patients who underwent either surgical or transcatheter aortic valve replacement and 1-year postoperative echocardiography. The patient characteristics and echocardiographic findings were compared between patients who were <80 years of age (group Y: n = 69) and those who were ≥80 years of age (group O: n = 60). RESULTS: Preoperative echocardiography revealed that although the left ventricular mass was similar between the groups, the patients in group O had more severe diastolic dysfunction in comparison to those in group Y. Postoperatively, left ventricular mass regression was significantly greater (p = 0.02) and diastolic dysfunction was less prevalent in group Y (p = 0.02) in comparison to group O. The change in E/e' was significantly correlated with the left ventricular mass regression in group Y (p = 0.02), but not in Group O (p = 0.21). CONCLUSIONS: The patients in group O were less susceptible to improvements in myocardial remodeling and the diastolic function in comparison to those in group Y. The altered physiological response to aortic valve replacement might help to determine the appropriate timing of surgery in elderly patients.

Reinforced mitral valve replacement using a xenopericardium collared prosthetic valve for a heavily calcified or disrupted mitral annulus: a simple "Dumpling technique".

Heavy mitral annular calcification or severe destruction of the mitral annulus in the setting of mitral valve replacement may result in fatal complications, such as atrioventricular disruption, ventricular rupture, valve dehiscence, and perivalvular leakage. Collar-reinforced mitral valve replacements with xenopericardium have been reported to prevent perivalvular leakage and valve detachment. We herein describe our experience with an easy method of handling the modified collar-reinforced prosthetic valve, which we call the "Dumpling technique", in six patients.

C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir.

UNLABELLED: We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1(WT)), with 50% effective concentrations (EC50s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC50) for GRL-015, -085, and -097 of 80, >100, and >100 µM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIVMDR). Importantly, darunavir (DRV) was >1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1DRV(R) P51); the three compounds remained active against HIV-1DRV(R) P51 with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and/or HIVMDR. IMPORTANCE: Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIVDRV(R) ) has recently been observed in vivo and in vitro. Here, we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C-5 hydroxyl (GRL-015, -085, and -097) which potently suppress the replication of HIVDRV(R) . Moreover, the emergence of HIV-1 strains resistant to the three compounds was considerably delayed compared to the case of DRV. The C-5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased activity against HIVDRV(R) . The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIVDRV(R) .

Building a bridge to recovery: the pathophysiology of LVAD-induced reverse modeling in heart failure.

Heart failure mainly caused by ischemic or dilated cardiomyopathy is a life-threatening disorder worldwide. The previous work in cardiac surgery has led to many excellent surgical techniques for treating cardiac diseases, and these procedures are now able to prolong the human lifespan. However, surgical treatment for end-stage heart failure has been under-explored, although left ventricular assist device (LVAD) implantation and heart transplantation are options to treat the condition. LVAD can provide powerful circulatory support for end-stage heart failure patients and improve the survival and quality of life after implantation compared with the existing medical counterparts. Moreover, LVADs play a crucial role in the "bridge to transplantation", "bridge to recovery" and recently have served as "destination therapy". The structural and molecular changes that improve the cardiac function after LVAD implantation are called "reverse remodeling", which means that patients who have received a LVAD can be weaned from the LVAD with restoration of their cardiac function. This strategy is a desirable alternative to heart transplantation in terms of both the patient quality of life and due to the organ shortage. The mechanism of this bridge to recovery is interesting, and is different from other treatments for heart failure. Bridge to recovery therapy is one of the options in regenerative therapy which only a surgeon can provide. In this review, we pathophysiologically analyze the reverse remodeling phenomenon induced by LVAD and comment about the clinical evidence with regard to its impact on the bridge to recovery.

Symptomatic peripheral artery disease is associated with decreased long-term survival after coronary artery bypass: a contemporary retrospective analysis.

PURPOSE: Little has been documented about whether the severity of peripheral artery disease (PAD) affects the postoperative outcomes of coronary artery bypass grafting (CABG). METHODS: We performed a retrospective analysis of 683 patients who underwent isolated CABG, comparing preoperative profiles and postoperative outcomes between patients with PAD (n = 116) and those without PAD (n = 567). Kaplan-Meier analysis was done to examine the long-term survival and the Cox proportional hazard model was used to establish the preoperative risk factors associated with survival. RESULTS: The PAD patients were older and had more preoperative comorbidities than those without PAD. There were three operative deaths in each group (p = 0.07). The patients with PAD had more postoperative complications related to transfusion requirement (p = 0.004), the need for re-exploration for bleeding (p = 0.04), longer ventilation time (p < 0.001), and longer ICU stay (p = 0.001), than those without PAD. The 10-year survival rate of the PAD patients was lower than that of the non-PAD patients (p < 0.001). Univariate and multivariate analyses revealed that symptomatic PAD (p = 0.008) was associated with decreased long-term survival. CONCLUSION: Symptomatic PAD was found to be an independent factor for poor long-term survival after CABG. Thus, aggressive screening measures for coronary disease, early surgical revascularization, and secondary prevention may improve the early and long-term outcomes of these patients.

Diabetes Mellitus Impairs Left Ventricular Mass Regression after Surgical or Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis.

BACKGROUND: It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is related to suboptimal postoperative outcomes after aortic valve replacement. Although diabetes is known to potentially exacerbate myocardial hypertrophy, it has yet to be examined if it affects postoperative left ventricular mass regression (LVMR). METHODS: A single-centre, retrospective analysis was performed on 183 consecutive patients who underwent either surgical or transcatheter aortic valve replacement between 2010 and May 2013. Patient demographics, postoperative outcomes and echocardiographic data were obtained preoperatively and a year after surgery. RESULTS: There were 42 diabetic and 141 non-diabetic patients. Preoperative characteristics of diabetic patients were statistically similar to those of non-diabetic patients, except for higher prevalence of hyperlipidaemia (p <0.001) and history of cerebrovascular disorder (p=0.046) in diabetic patients. Median value of postoperative LVMR of all patients was -36.5 g/m(2), and was significantly greater in the non-diabetics compared to the diabetics (-39.1 vs. -22.2 g/m(2), p=0.008). Univariate and multivariate analyses were performed on preoperative variables, and stepwise multiple regression analysis demonstrated that diabetes (standardised partial regression coefficient (SPRC)=-0.187, p=0.018), female gender (SPRC=0.245, p=0.026) and age (SPRC=0.203, p=0.018) were associated with poor postoperative LVMR. CONCLUSIONS: Patients with diabetes showed suboptimal postoperative LVMR, and the disease was a prognostic factor that was associated with poor LVMR. These findings suggest that diabetes may predispose the particular group of patients to worse postoperative outcomes.

Procedural selection strategy and clinical outcomes in mitral valve surgery with concomitant aortic valve replacement in elderly patients.

Introduction: In the context of double-valve surgery for elderly high-risk patients involving both the aortic and mitral valves, a clinically significant problem has been that no clear criteria or surgical strategies have been reported for the selection of mitral valve plasty (MVP) or mitral valve replacement (MVR) for mitral valve disease management during surgical aortic valve replacement (SAVR) to achieve better clinical outcomes. This study investigated valve durability and survival using our surgical strategy for mitral valve disease with concomitant SAVR in elderly patients. Methods: Eighty-six patients aged > 65 years (mean 75 years) who underwent a double-valve procedure for mitral valve surgery with concomitant SAVR from 2010 to 2022 were reviewed. Our surgical strategy for mitral valve disease with concomitant SAVR for the elderly patients was as follows: MVP was selected for patients in whom mitral valve disease was expected to be controlled with simple surgical procedures (n = 47), otherwise MVR was selected (n = 39). Results: The hospital mortality rate was 8% (n = 7). The mean follow-up was 4.9 (0-12.3) years. And the 10-year survival rate was 62%. The 10-year freedom from aortic valve reoperation rate was 95%. No mitral valve reintervention was performed during follow-up. Echocardiographic follow-up demonstrated freedom from at least moderate mitral regurgitation in 86% of cases at 10 years. Conclusion: In double-valve surgery for elderly high-risk patients, appropriate selection of the mitral valve procedure with concomitant SAVR provided better early and long-term survival and valve durability. This surgical strategy may be beneficial in elderly patients with combined aortic and mitral valve disease.

The Association of the Cholesterol Efflux Capacity with the Paraoxonase 1 Q192R Genotype and the Paraoxonase Activity.

AIMS: Paraoxonase 1 (PON1) binds to high-density lipoprotein (HDL) and protects against atherosclerosis. However, the relationship between functional PON1 Q192R polymorphism, which is associated with the hydrolysis of paraoxon (POXase activity) and atherosclerotic cardiovascular disease (ASCVD), remains controversial. As the effect of PON1 Q192R polymorphism on the HDL function is unclear, we investigated the relationship between this polymorphism and the cholesterol efflux capacity (CEC), one of the biological functions of HDL, in association with the PON1 activity. METHODS: The relationship between PON1 Q192R polymorphisms and CEC was investigated retrospectively in 150 subjects without ASCVD (50 with the PON1 Q/Q genotype, 50 with the Q/R genotype, and 50 with the R/R genotype) who participated in a health screening program. The POXase and arylesterase (AREase: hydrolysis of aromatic esters) activities were used as measures of the PON1 activity. RESULTS: The AREase activity was positively correlated with CEC independent of the HDL cholesterol levels. When stratified by the PON1 Q192R genotype, the POXase activity was also positively correlated with CEC independent of HDL cholesterol. PON1 Q192R R/R genotype carriers had a lower CEC than Q/Q or Q/R genotype carriers, despite having a higher POXase activity. Moreover, in a multiple regression analysis, the PON1 Q192R genotype was associated with the degree of CEC, independent of the HDL cholesterol and POXase activity. CONCLUSIONS: The PON1 Q192R R allele is associated with reduced CEC in Japanese people without ASCVD. Further studies on the impact of this association on the severity of atherosclerosis and ASCVD development are thus called for.

Long-Term Outcomes of Endovascular Aneurysm Repair in Patients Aged ≤70 Years.

Objectives: The efficacy of endovascular aneurysm repair (EVAR) against abdominal aortic aneurysm (AAA) in younger patients remains unknown. Hence, the current study aimed to investigate whether the aneurysm-related mortality rate of EVAR is acceptable among patients aged ≤70 years. Methods: Among 644 patients, 148 underwent EVAR (EVAR group), and 496 received open surgical repair (OSR group). The cumulative incidence rates of aneurysm-related death, any intervention, and serious aneurysm-related events after AAA repair were evaluated using the cumulative incidence function in the presence of competing risks. Results: The EVAR group had higher prevalences of several comorbidities, and overall survival for the EVAR group was significantly inferior to that of the OSR group. The cumulative incidence rates of aneurysm-related death, any intervention, and serious aneurysm-related events at 5 years were 1.5%, 11.7%, and 6.4% in the EVAR group and 1.3%, 5.3%, and 5.9% in the OSR group, respectively. EVAR was not a significant prognostic factor of aneurysm-related mortality and serious aneurysm-related events. However, it was an independent poor prognostic factor of any intervention. Conclusion: EVAR was not a significant prognostic factor of aneurysm-related mortality and serious aneurysm-related events. Therefore, it demonstrated acceptable procedure-related long-term outcomes, at least in high-risk young patients.