Feasibility, Safety, and Long-Term Outcomes of Zero-Contrast Percutaneous Coronary Intervention in Patients With Chronic Kidney Disease.

BACKGROUND: The long-term safety and utility of intravascular ultrasound (IVUS)-guided zero-contrast percutaneous coronary intervention (PCI) in patients with chronic kidney disease (CKD) are unknown.Methods and Results: A total of 698 consecutive patients treated with PCI (1,061 procedures) in our center were studied. Patients with acute coronary syndrome, who are on maintenance hemodialysis, and who had a planned rotational atherectomy were excluded. Finally, they were divided into 2 groups: zero-contrast PCI (n=55, 78 procedures) and conventional PCI (n=462, 670 procedures). After propensity score matching, 50 patients were matched for each group to evaluate long-term outcomes. Primary endpoints were major adverse cardiovascular events (MACE), including all-cause death, non-fatal myocardial infarction (MI), and clinically driven target lesion revascularization. All patients in the zero-contrast PCI group had stage 3-5 CKD with an estimated glomerular filtration rate of 38.3±14.8 mL/min/1.73 m2. Zero-contrast PCI was successful in all 78 procedures without renal events such as acute kidney injury or emergent hemodialysis and procedural complications such as coronary perforation or periprocedural MI. During a follow-up period of 32 months, 7 patients died (1 cardiac, 6 non-cardiovascular), and 4 patients were introduced to renal replacement therapy. The incidence of MACE was similar between the zero-contrast and conventional PCI groups (log-rank, P=0.95). CONCLUSIONS: IVUS-guided zero-contrast PCI might be safe and feasible in patients with CKD with satisfactory acute and long-term renal and cardiovascular outcomes.

The Prognostic Value of Left Atrial Reservoir Functional Indices Measured by Three-Dimensional Speckle-Tracking Echocardiography for Major Cardiovascular Events.

BACKGROUND: Left atrial (LA) volume and left ventricular longitudinal strain (LVLS) have significant prognostic values for major cardiovascular events (MACEs). Prognostic values of LA reservoir functional indices measured by 3-dimensional (3D) speckle-tracking echocardiography (STE) were evaluated.Methods and Results:A total of 264 patients, who underwent 2-dimensional (2D) echocardiography and 3DSTE for various underlying heart diseases, were followed up to record MACE. After a mean follow up of 547±435 days, 30 patients developed MACE: 7 cardiac deaths, 6 strokes, 1 non-fatal myocardial infarction, and 22 admissions for heart failure (5 of these had cardiac death after discharge, whereas 1 sustained stroke after discharge). Receiver operating characteristic curve analysis was performed to determine the optimal cut-off levels of 4 LA functional indices: LA emptying fraction (LAEmpF), LA longitudinal strain (LALS), LA circumferential strain (LACS), and LA area change ratio (LAAC), using 3DSTE. Among these factors, 2DLVLS, 3DLAEmpF, and 3DLALS demonstrated a higher hazard ratio (>5.0) than other variables. The 3DLAEmpF and 3DLALS had a higher average treatment effect (ATE) and ATE on the treated (ATT), respectively, than the other indices after propensity score matching. Addition of 3DLAEmpF to the base model using clinical variables and LV ejection fraction or 2DLVLS demonstrated higher prognostic power. CONCLUSIONS: LAEmpF calculated using 3DSTE possessed additive prognostic values for the prediction of MACE.

Extended Posterior Leaflet Augmentation for Ischemic Mitral Regurgitation　- Augmented Posterior Leaflet Snuggling up to Anterior Leaflet.

BACKGROUND: The ideal surgical technique for ischemic mitral regurgitation (MR) is controversial. We introduced an extended posterior mitral leaflet (PML) augmentation technique for functional MR with severe tethering, which detached the PML from the annulus almost completely and augmented it with a large 3×6-cm oval pericardial patch. Methods and Results: A total of 17 mitral repairs using the new technique were performed for ischemic MR with no 30-day mortality and 2 hospital deaths. The NYHA class was III in 47% and IV in 13%. The EuroSCORE II was 9.7±4.9. The ring size was 32±1.4 mm. Concomitant coronary bypass was performed in 67% and left ventricular repair in 28%. The mechanism of leaflet closure was evaluated using transthoracic echocardiography in 15 survivors. MR decreased to none or trivial with a significant increase in coaptation length (Pre: 4.6±0.8 mm vs. Post: 9.8±2.5 mm; P<0.001). The PML flexibly moved forward and tightly contacted as if "snuggling up" to the anterior leaflet. There were no late deaths, heart failure readmissions or MR recurrences during follow-up (850±181 days). All patients remained in NYHA I or II. CONCLUSIONS: Extended PML augmentation for ischemic MR showed excellent early results with deep leaflet coaptation through a "snuggling up" phenomenon, which would help prevent late MR recurrence.

Prognostic Value of Left Atrial Size and Functional Indices Measured by 3-Dimensional Speckle-Tracking Analysis.

BACKGROUND: The prognostic value of indices for left atrial volumes (LAV) and reservoir function measured by 3D speckle-tracking analysis (3DSTA) has not been determined. Methods and Results: LA maximal and minimal volume indices (LAVImax, LAVImin), and LA emptying fraction (LAEmpF) were measured via 2D echocardiography (2DE) and 3DSTA in 514 patients (62% male, mean age: 66±15 years) with various cardiovascular diseases. Two cutoff values using normal±2SD (cutoff criterion 1) and receiver-operating characteristic analysis (cutoff criterion 2) were evaluated. During a mean follow-up of 720±383 days, MACE (cardiac death, nonfatal myocardial infarction, stroke and admission for heart failure) occurred in 98 patients. Kaplan-Meier survival analysis showed both cutoff criteria measured by 2DE and 3DSTA had significant predictive power for MACE (P<0.001). For cutoff criterion 1, 3DSTA measurements yielded higher hazard ratios than 2DE by Cox proportional hazard model. Cutoff criterion 2 using 3DSTA had higher average treatment effect values than 2DE by matching propensity scores on the outcome. Further, a regression model that included clinical variables, left ventricular ejection fraction and cutoff criterion 2 using 3DSTA-derived LAEmpF had significantly higher prognostic power than 2DE. CONCLUSIONS: LA indices measured by 3DSTA had greater prognostic power for future MACE than 2DE. In particular, 3DSTA-derived LAEmpF has the potential to be a valuable prognostic tool in clinical settings.

Urinary extracellular vesicular release of aquaporins in patients with renal transplantation.

BACKGROUND: Diuresis has been observed within a week following renal transplantation, suggesting that the procedure causes acute disturbance of renal water homeostasis. Aquaporin (AQP) 1 and AQP2, important proteins for renal water reabsorption, have been identified in urinary extracellular vesicles (uEV-AQP1 and -AQP2), and experimental studies have shown that the presence of uEV-AQP1 and -AQP2 may be an indicator of their levels of expression in the kidney. However, the release patterns of uEV-AQP1 and -AQP2 during the acute phase following renal transplantation are largely unknown. METHODS: In this study, we examined the release of uEV-AQP1 and -AQP2 in recipients until 6 days (day 6) after renal transplantation. At Miyazaki prefectural Miyazaki Hospital, Japan, uEVs were obtained from 7 recipients, all of whom had received renal allografts from living donors. uEVs were isolated by differential centrifugation. RESULTS: Immunoblotting analysis showed that the release of uEV-AQP2 was significantly decreased on day 1 in comparison with a control sample (from 3 healthy volunteers), accompanied by high urine output and low urine osmolality. Thereafter, the level increased gradually to the control level by day 6. The release pattern of uEV-AQP1 was similar to that of uEV-AQP2, but the levels did not reach statistical significance in comparison with the control level at any of the time points examined. Evaluation of the relationship between urinary osmolality and uEV-AQPs revealed a significant correlation for uEV-AQP2, but not for uEV-AQP1. CONCLUSION: These results indicate that acute diuresis after renal transplantation might be due to a decrease in the renal expression of AQP2, whose level can be estimated from the amount released in uEVs.

Long-Term Effects of Enzyme Replacement Therapy for Anderson-Fabry Disease.

Anderson-Fabry disease is a rare X-linked lysosomal storage disease caused by α-galactosidase A (α-GalA) gene variants and characterized by a large genotypic and phenotypic spectrum. Enzyme replacement therapy (ERT) using recombinant α-GalA has been approved for > 10 years as a specific therapy for the disease. However, the long-term clinical efficacy for cardiac manifestations has been equivocal because it depends on several factors such as genotype, sex, age, and disease severity at the initiation of ERT. We report the differences in the clinical effects of ERT continued for > 10 years in three patients with the same genotype. Left ventricular hypertrophy and myocardial dysfunction progressed in the heterozygote proband even under ERT, although disease progression was prevented in two sons of Case 1.

Characterization of urinary exosomal release of aquaporin-1 and -2 after renal ischemia-reperfusion in rats.

Acute kidney injury (AKI) is an important risk factor for the development of chronic kidney disease (CKD), and an alteration in renal water handling has been observed during the transition of AKI to CKD. Urinary exosomal release of aquaporin-1 (AQP1) and AQP2, important proteins for renal water handling, has recently been reported to predict their levels of renal expression. Therefore, we examined the patterns of urinary exosomal release of AQP1 and AQP2, and the exosomal marker proteins tumor susceptibility 101 protein (TSG101) and ALG-2 interacting protein X (Alix), in the acute and chronic phases following induction of AKI by renal bilateral ischemia/reperfusion (I/R) in rats. Blood tests and histological examinations indicated that AKI occurred before at 7 days after renal I/R ( day 7) and that renal fibrosis developed progressively thereafter. Immunoblotting demonstrated significant decreases in the urinary exosomal release of AQP1 and AQP2 during severe AKI. Urinary exosomal release of Alix and TSG101 was significantly increased on day 7. These data were also confirmed in rats with unilateral renal I/R causing more serious AKI. Urinary exosomal release of either the Ser-256- or Ser-269-phosphorylated form of AQP2, both of which are involved in apical trafficking of AQP2, was positively correlated with that of total AQP2. These results suggest that urinary exosomal release of AQP1 and AQP2 is reduced in I/R-induced AKI, whereas that of Alix and TSG101 is increased in the initial phase of renal fibrosis. Furthermore, apical trafficking of AQP2 appears to be related to urinary exosomal release of AQP2.

Minimally invasive recipient procedure in kidney transplantation.

Background: There are several procedural variations for kidney transplant donors, including open, laparoscopic, hand-assisted, and robotic methods, with either an intra- abdominal or retroperitoneal approach. Conversely, fewer options are available for the recipient procedure. We introduce a method that involves a small incision, with the goal of being less invasive for recipients. Methods: Our current method was introduced in April 2022. As of July 2023, we have completed 27 cases. We analyzed several factors in these 27 cases, including the size of the incision, rewarming time, anastomosis time, graft function, analgesic use, and complications. Results: The average incision size was 73 mm. The time taken for anastomosis was 24. 1 minutes, while the rewarming time averaged 43.1 minutes. There were no instances of primary nonfunction. One case necessitated postoperative dialysis three times due to heart failure. Following stent removal, one patient developed grade 1 hydronephrosis. There was one instance of bleeding from the drain insertion site. Another case involved a clamp injury to the external iliac artery, which necessitated stent insertion on the fourth postoperative day. Compared to procedures performed using conventional methods, the use of analgesics was less in these cases. Conclusions: Our minimally invasive technique, which involves a small incision, is a feasible alternative that could potentially be less invasive than traditional methods.

Chronic kidney disease is a key predictive factor for potential myocardial ischaemia and poor prognosis in asymptomatic patients with diabetes mellitus.

Some asymptomatic patients with diabetes mellitus (DM) have critical coronary artery disease (CAD), although the guidelines do not recommend aggressive screening for CAD in asymptomatic patients. Chronic kidney disease (CKD) is among the serious co-morbidities of severe systemic atherosclerosis. Thus, CKD may be associated with potential myocardial ischaemia. Therefore, the present study aimed to determine the impact of CKD on the incidence of silent myocardial ischaemia (SMI) and the long-term outcomes in asymptomatic patients with DM. This study investigated 461 consecutive patients with DM. All patients who were asymptomatic and self-sufficient in daily life underwent the ergometer exercise (ERG) test. Coronary angiography was performed if the stress test was positive, or if the patient did not achieve 90% of the target heart rate. The primary end point included major adverse cardiac and cerebrovascular events (MACCE) including death, non-fatal myocardial infarction and stroke. The median follow-up duration after study enrolment was 35 months for the entire cohort of 461 patients. Eighty-one patients were diagnosed with SMI. The estimated glomerular filtration rate was significantly lower in the SMI group (70.5 ± 23.8 vs. 81.8 ± 30.0 mL/min/1.73 m2, P < 0.001). SMI occurred more frequently in patients with advanced CKD [27/103, (26.2%) in stages 3-5], whereas only 5/68 (7.3%) patients without CKD, 13/81 (16.0%) patients with stage 1 CKD and 36/209, (17.2%) in stage 2, had SMI. The Kaplan-Meier curves revealed that, patients with SMI had poor clinical outcomes (log-rank: P = 0.016). The incidence of MACCE (log-rank: P = 0.009) was higher in patients with severe CKD > stage 3a in the SMI subgroup. Urinary albumin (mg/gCr) was associated with MACCE in the SMI subgroup [HR 3.37, 95%CI (1.170-9.521), P = 0.025] after adjusting for age, sex, and conventional risk factors. SMI was more prevalent in patients with CKD and the incidence was proportional to the CKD stage in asymptomatic patients with DM. Those Patients with CKD and SMI exhibited poor clinical outcomes. CKD may be a key factor for the identification and management of SMI in asymptomatic patients with DM in routine clinical practice.Trial Registration: UMIN000038340.

Reduced urinary release of AQP1- and AQP2-bearing extracellular vesicles in patients with advanced chronic kidney disease.

Although several studies have shown that release of water channel proteins, aquaporin 1 (AQP1) and AQP2 in urinary extracellular vesicles (uEV-AQP1 and -AQP2), were altered in experimental kidney injury models, their release in human chronic kidney disease (CKD) has been largely unexplored. The aim of the present study was to clarify whether the release of uEV-AQP1 and -AQP2 is altered in patients with CKD. Urine samples were collected from 15 healthy volunteers (normal group) and 62 CKD patients who were categorized into six glomerular filtration rate (GFR) categories (G1, G2, G3a, G3b, G4, and G5) in between 2005 and 2016 at Miyazaki Prefectural Miyazaki Hospital, Japan. uEV-proteins were evaluated by immunoblot analysis. The release of AQP1 and AQP2 were significantly decreased in patients with both CKD G4 and G5, in comparison with the normal group. The area under the receiver operating characteristic (ROC) curve (AUC) values for AQP1 and AQP2 in patients with CKD G4 and G5 were 0.926 and 0.881, respectively. On the other hand, the AUC values in patients with CKD G1-G3 were 0.512 for AQP1 and 0.680 for AQP2. Multiple logistic regression analysis showed that AQP1 and AQP2 in combination were useful for detecting CKD G4 and G5, with a higher AUC value of 0.945. These results suggest that the release of uEV-AQP1 and -AQP2 was decreased in patients with CKD G4 and G5, and these proteins might be helpful to detect advanced CKD.

The protective effect of radicicol against renal ischemia--reperfusion injury in mice.

Overexpression of heat shock protein 70 kDa (HSP70) is known to confer cellular protection against ischemia-reperfusion (I/R) injury. Radicicol, a HSP90 inhibitor, has been reported to induce the expression of HSP70 protein. Here we studied whether radicicol attenuated renal I/R injury in vivo. Treatment of mice with radicicol ameliorated renal I/R injury and increased renal HSP70 mRNA and protein. Administration of radicicol with quercetin, an inhibitor of HSP70 induction, eliminated the renoprotective effect of radicicol. Our results suggest that the up-regulation of renal HSP70 protein by radicicol leads to a novel drug therapy against renal I/R injury.

Factors affecting outcome of intracerebral hemorrhage in patients undergoing chronic hemodialysis.

To date, despite a markedly high incidence of intracerebral hemorrhage (ICH) in patients with end-stage renal disease, only few studies have focused on factors that affect patient's prognosis. To elucidate these factors, we retrospectively investigated 22 consecutive patients who had chronic renal failure, were maintained by hemodialysis (HD), had suffered from ICH, and were hospitalized and treated in our institute from 2006 to 2008. Hematoma volume, blood pressure on admission, blood pressure 3 days after ICH onset, and neurological deterioration significantly affected patient mortality. Progression of neurological symptoms during HD was observed often in patients with hematoma of more than 60 mL or in patients with pontine hemorrhages. Age, gender, duration of HD, anti-platelet or anticoagulant therapies, or maximal dose of nicardipine did not affect patient's prognosis. Based on this study we conclude that controlling blood pressure on admission and within 3 days after onset of ICH may be the most important factor that would improve patient's prognosis. Further, special care might be required for patients with large hematomas (more than 60 mL) or those with brainstem hemorrhages, because progression of neurological symptoms occurs often in such patients.

Influence of sex on the incidence of potential coronary artery disease and long-term outcomes in asymptomatic patients with diabetes mellitus.

BACKGROUND: Diabetic patients often have coronary artery disease (CAD) without symptoms. It is known that females tend to have silent or less chest pain and worse prognoses when they develop acute coronary syndrome. Thus, sex differences may impact long-term outcomes in diabetes mellitus (DM) patients with silent myocardial ischemia (SMI). The present study aimed to assess the influence of sex on long-term outcomes in DM patients with SMI. METHODS: A total of 461 consecutive asymptomatic and self-sufficient DM patients seen at our hospital from 2011 to 2017 were prospectively reviewed. Patients underwent an ergometer exercise test. When the exercise test was positive or the patient could not achieve 90% of their target heart rate, coronary angiography was performed. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCEs), including death, non-fatal myocardial infarction, and stroke. RESULTS: SMI was diagnosed in 81 patients. The median follow-up duration from diagnosis was 35 (15-57) months. The incidence of SMI was similar in females and males [34/170 (20%) vs. 47/291 (16.2%), p = 0.36]. Enrolled patients were divided into four groups according to sex and the presence/absence of SMI. Female patients with SMI showed worse clinical outcomes. After adjustment for age and coronary risk factors, female SMI was independently associated with MACCEs [hazard ratio 2.59, 95% confidence interval 1.07-5.68, p = 0.024], while male SMI was not. CONCLUSIONS: Female SMI was associated with worse long-term outcomes in DM patients. Early diagnosis of potential SMI and appropriate care are required in female DM patients. (UMIN000038340).

Risk Factors for Atrial Fibrillation Recurrence After Cox Maze IV Performed Without Pre-exclusion.

BACKGROUND: New guidelines from The Society of Thoracic Surgeons recommend adding surgical ablation as a concomitant procedure for class I indications. We performed the maze procedure for all patients who experienced atrial fibrillation (AF) before cardiac surgery, without surgeon pre-exclusion. METHODS: We retrospectively analyzed 83 patients, aged 71 ± 11 years (22% >80 years), who underwent Cox maze IV for persistent AF between 2014 and 2017. The mean AF duration (AFD) was 6.9 ± 8.6 years and European System for Cardiac Operative Risk Evaluation II was 7.2 ± 6.8. RESULTS: The 30-day mortality was 2.4%. During follow-up (mean, 675 days), the 1-, 2-, and 3-year survival rates were 92%, 86%, and 82%, respectively. No strokes were observed despite a mean CHA2DS2-VASC (Congestive heart failure, Hypertension, Age [≥65 = 1 point, ≥75 = 2 points], Diabetes, and Stroke/transient ischemic attack [2 points], vascular disease, Sex [female = 1 point]) score of 4.1 (expected stroke rate, 4%/y). Twelve patients required a new pacemaker; 56 of 73 survivors (77%) remained AF free. Multivariate logistic regression identified preoperative AFD, f wave size, and mean heart rate per Holter as important risk factors for AF recurrence, with AFD as the most important: 98% of patients with AFD less than 5 years remained AF free. Although the AF-free rate with the AFD of 5 or more years was only 55%, their symptoms improved without heart failure readmission. Concomitant atrial plication was performed more frequently in the group with AFD for 5 or more years, with greater atrial volume reduction and appreciable increases in stroke volume. CONCLUSIONS: The Cox maze IV procedure performed without pre-exclusion showed reasonable survival rates. Although AF recurred in patients with longer AFD, they fared well with substantial increases in stroke volume. Concomitant atrial volume reduction may have contributed to these additional benefits.

Decreased abundance of urinary exosomal aquaporin-1 in renal ischemia-reperfusion injury.

Urinary exosomes, secreted into urine from renal epithelial cells, are known to contain many types of renal functional membrane proteins. Here, we studied whether renal ischemia-reperfusion (I/R) affects urinary exosomal aquaporin-1 (AQP1) excretion in rats subjected to renal I/R and patients who underwent renal transplantation. Immunoblotting studies demonstrated reduction of the urinary exosomal AQP1 level even at 6 h after renal I/R, and the level continued to be low over 96 h after I/R. Renal AQP1 mRNA and protein analyses revealed that the decreased excretion of urinary exosomal AQP1 is associated with renal AQP1 protein retention in the early phase and with a decreased expression level of renal AQP1 in the later phase of renal I/R injury. Decreased abundance of urinary exosomal AQP1 in a recipient patient was also observed at 48 h after renal allograft transplantation. No significant decrease in urinary exosomal AQP1 was observed in a rat model of nephropathy or in patients with proteinuria. Our studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exosomal AQP1 is a novel urinary biomarker for renal I/R injury.

Acid-catalyzed chirality-transferring intramolecular Friedel-Crafts cyclization of α-hydroxy-α-alkenylsilanes.

Acid-catalyzed intramolecular Friedel-Crafts cyclization of optically active α-hydroxy-α-alkenylsilanes possessing a benzene ring (>99% ee) with TMSOTf as a Lewis acid gave enantio-enriched tetrahydronaphthalenes (up to 98% ee). The silyl group attached to the chiral carbon played a crucial role in the chirality transfer.

Post-cardiotomy venovenous extracorporeal membrane oxygenation without heparinization.

We present the cases of eight patients (mean age 75 years; EuroSCORE II 17.0 ± 22.0) who underwent post-cardiotomy venovenous extracorporeal membrane oxygenation (ECMO) without heparinization due to serious bleeding. Three liver cirrhosis, two chronic hemodialysis, three redo sternotomy, and two urgent surgery cases were included. Respiratory ECMO Survival Prediction score was - 5.1 ± 4.2 (estimated survival rate: approximately 30%). Mean ECMO duration was 14 days with 9 circuit exchanges. Five patients were weaned from ECMO and three were discharged alive at 90 days (survival 37.5%). There was a case of pump-head thrombosis requiring urgent circuit exchange. All experienced bleeding complications without clinically apparent pulmonary thromboembolism. Disseminated Intravascular Coagulation scores (Pre 1.3 ± 0.8 vs. Post 3.8 ± 1.7; p < 0.05) significantly increased (N = 6). Post-cardiotomy ECMO without heparinization facilitated patient rescue at a reasonable survival rate. However, bleeding complications were still observed. More sophisticated management protocols are warranted.