Prognostic study of cardiac events in Japanese patients with chronic kidney disease using ECG-gated myocardial Perfusion imaging: Final 3-year report of the J-ACCESS 3 study.

BACKGROUND: Myocardial perfusion imaging (MPI) is considered useful for risk stratification among patients with chronic kidney disease (CKD), without renal deterioration by contrast media. METHODS AND RESULTS: The Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS 3) is a multicenter, prospective cohort study investigating the ability of MPI to predict cardiac events in 529 CKD patients without a definitive coronary artery disease. All patients were assessed by stress and rest MPI with 99mTc-tetrofosmin and data were analyzed using a defect scoring method and QGS software. Major cardiac events were analyzed for 3 years after registration. The mean eGFR was 29.0 ± 12.8 (mL/minute/1.73 m2). The mean summed stress/rest/difference (SSS, SRS, SDS) scores were 1.9 ± 3.8, 1.1 ± 3.0, and 0.8 ± 1.8, respectively. A total of 60 cardiac events (three cardiac deaths, six sudden deaths, five nonfatal myocardial infarctions, 46 hospitalization cases for heart failure) occurred. The event-free survival rate was lower among patients with kidney dysfunction, higher SSS, and higher CRP values. Multivariate Cox regression analysis independently associated SSS ≥8, eGFR <15 (mL/minute/1.73 m2), and CRP ≥0.3 (mg/dL) with cardiac events. CONCLUSIONS: Together with eGFR and CRP, MPI can predict cardiac events in patients with CKD.

Incidence and predictors of bleeding complications after percutaneous coronary intervention.

BACKGROUND: Bleeding complications remain one of the most important challenges in percutaneous coronary intervention (PCI), particularly in Asians who are known to be vulnerable to the use of antiplatelets or anticoagulants. However, the incidence and predictors of bleeding complications after PCI have not been thoroughly investigated in Japan. METHODS: We studied 13,075 consecutive patients in a Japanese multicenter PCI registry (Japan Cardiovascular Database - Keio interhospital Cardiovascular Study: JCD-KiCS) from September 2008 to March 2014. Multivariate logistic regression analysis was performed to investigate independent predictors of bleeding complications, and to create three risk prediction models for bleeding events. Model 1 included patients' characteristics alone. In model 2, we added patients' clinical presentation. Model 3 included covariates in model 2 along with angiographic and technical factors. Model discrimination was assessed using the area under the receiver operating curve (AUC). RESULTS: Overall, bleeding complications, according to the pre-specified US National Cardiovascular Data Registry criteria, were observed in 402 patients (3.1%). Independent predictors of bleeding complications included age, female gender, previous PCI, previous heart failure, hemodialysis (variables included in model 1), ST-elevation and non-ST-elevation myocardial infarction, cardiogenic shock (added in model 2), transradial intervention, use of intra-aortic balloon pumping or a rotablator, and PCI for chronic total occlusion (added in model 3). Above all, previous PCI and transradial intervention were inverse predictors of bleeding. The predictability of the risk models improved as the number of variables increased, with AUC of 0.667, 0.747, and 0.791 for models 1, 2, and 3, respectively. CONCLUSIONS: The incidence of bleeding complications among Japanese PCI patients was approximately 3% in standard nomenclature, which is equivalent to that of other international registries. Patients' characteristics, clinical presentation, and angiographic and technical factors all independently contributed to its prediction.

Recovery of endocochlear potential after severe damage to lateral wall fibrocytes following acute cochlear energy failure.

Reduction of endocochlear potential (EP) is one of the main causes of sensorineural hearing loss. In this study, we investigated changes in the EP using a mouse model of acute cochlear energy failure, which comprised severe cochlear lateral wall damage induced by the local administration of 3-nitropropionic acid to the inner ear. We also analyzed the correlation between EP changes and histological findings in the cochlear lateral wall. We detected the recovery of the EP and hearing function at lower frequencies after severe damage of the cochlear lateral wall fibrocytes at the corresponding region. Remodeling of the cochlear lateral wall was associated with EP recovery, including the re-expression of ion transporters or gap junctions (i.e. Na/K/ATPase-ß1 and connexin 26). These results indicate a mechanism for late-phase hearing recovery after severe deafness, which is frequently observed in clinical settings.

Angiographic Lesion Complexity Score and In-Hospital Outcomes after Percutaneous Coronary Intervention.

OBJECTIVE: We devised a percutaneous coronary intervention (PCI) scoring system based on angiographic lesion complexity and assessed its association with in-hospital complications. BACKGROUND: Although PCI is finding increasing application in patients with coronary artery disease, lesion complexity can lead to in-hospital complications. METHODS: Data from 3692 PCI patients were scored based on lesion complexity, defined by bifurcation, chronic total occlusion, type C, and left main lesion, along with acute thrombus in the presence of ST-segment elevation myocardial infarction (1 point assigned for each variable). RESULTS: The patients' mean age was 67.5 +/- 10.8 years; 79.8% were male. About half of the patients (50.3%) presented with an acute coronary syndrome, and 2218 (60.1%) underwent PCI for at least one complex lesion. The patients in the higher-risk score groups were older (p < 0.001) and had present or previous heart failure (p = 0.02 and p = 0.01, respectively). Higher-risk score groups had significantly higher in-hospital event rates for death, heart failure, and cardiogenic shock (from 0 to 4 risk score; 1.7%, 4.5%, 6.3%, 7.1%, 40%, p < 0.001); bleeding with a hemoglobin decrease of >3.0 g/dL (3.1%, 11.0%, 13.1%, 10.3%, 28.6%, p < 0.001); and postoperative myocardial infarction (1.5%, 3.1%, 3.8%, 3.8%, 10%, p = 0.004), respectively. The association with adverse outcomes persisted after adjustment for known clinical predictors (odds ratio 1.72, p < 0.001). CONCLUSION: The complexity score was cumulatively associated with in-hospital mortality and complication rate and could be used for event prediction in PCI patients.

Impact of body mass index on in-hospital complications in patients undergoing percutaneous coronary intervention in a Japanese real-world multicenter registry.

BACKGROUND: Obesity is associated with advanced cardiovascular disease. However, some studies have reported the "obesity paradox" after percutaneous coronary intervention (PCI). The relationship between body mass index (BMI) and clinical outcomes after PCI has not been thoroughly investigated, especially in Asian populations. METHODS: We studied 10,142 patients who underwent PCI at 15 Japanese hospitals participating in the JCD-KICS registry from September 2008 to April 2013. Patients were divided into four groups according to BMI: underweight, BMI <18.5 (n=462); normal, BMI ≥ 18.5 and <25.0 (n=5,945); overweight, BMI ≥ 25.0 and <30.0 (n=3,100); and obese, BMI ≥ 30.0 (n=635). RESULTS: Patients with a high BMI were significantly younger (p<0.001) and had a higher incidence of coronary risk factors such as hypertension (p<0.001), hyperlipidemia (p<0.001), diabetes mellitus (p<0.001), and current smoking (p<0.001), than those with a low BMI. Importantly, patients in the underweight group had the worst in-hospital outcomes, including overall complications (underweight, normal, overweight, and obese groups: 20.4%, 11.5%, 8.4%, and 10.2%, p<0.001), in-hospital mortality (5.8%, 2.1%, 1.2%, and 2.7%, p<0.001), cardiogenic shock (3.5%, 2.0%, 1.5%, and 1.6%, p=0.018), bleeding complications (10.0%, 4.5%, 2.6%, and 2.8%, p<0.001), and receiving blood transfusion (7.6%, 2.7%, 1.6%, and 1.7%, p<0.001). BMI was inversely associated with bleeding complications after adjustment by multivariate logistic regression analysis (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; p=0.002). In subgroup multivariate analysis of patients without cardiogenic shock, BMI was inversely associated with overall complications (OR, 0.98; 95% CI, 0.95-0.99; p=0.033) and bleeding complications (OR, 0.95; 95% CI, 0.91-0.98; p=0.006). Furthermore, there was a trend that BMI was moderately associated with in-hospital mortality (OR, 0.94; 95% CI, 0.88-1.01; p=0.091). CONCLUSIONS: Lean patients, rather than obese patients are at greater risk for in-hospital complications during and after PCI, particularly for bleeding complications.

Impact of acute kidney injury on in-hospital outcomes in patients with DeBakey type III acute aortic dissection.

The relation between the incidence and severity of acute kidney injury (AKI) and clinical outcomes remains unclear in patients with DeBakey type III acute aortic dissection (AAD). We retrospectively assessed 56 patients admitted to our hospital for type III AAD within 48 hours of the onset of symptoms. The presence of AKI was identified, and its severity was staged on the basis of changes in serum creatinine (SCr) levels within 7 days after admission. We investigated the relations between AKI and clinical presentations, in-hospital complications, and predischarge renal function; AKI was observed in 20 patients (36%). After adjusting for age, gender, and body mass index, the incidence of AKI was associated with a history of hypertension, electrocardiographic ST-T changes, DeBakey type IIIb, and SCr level on admission. Maximum white blood cell count and serum C-reactive protein level were higher in patients with AKI than in those without AKI. AKI was associated with a greater incidence of in-hospital complications (70% vs 39%, p = 0.03) and higher SCr levels at discharge (1.1 [range 1.0 to 2.0] vs 0.9 [range 0.7 to 1.0] mg/dl, p = 0.0001). These associations were more pronounced in patients with relatively severe AKI. Multivariate analysis revealed that SCr level on admission and DeBakey type IIIb with renal artery involvement were major predictors of AKI. In conclusion, renal function on admission and renal artery involvement were significant risk factors for AKI, which was associated with poor outcomes and enhanced inflammatory response during hospitalization in patients with type III AAD.

Myocardial perfusion imaging for predicting cardiac events in Japanese patients with advanced chronic kidney disease: 1-year interim report of the J-ACCESS 3 investigation.

PURPOSE: Whether myocardial perfusion imaging (MPI) can predict cardiac events in patients with advanced conservative chronic kidney disease (CKD) remains unclear. METHODS: The present multicenter prospective cohort study aimed to clarify the ability of MPI to predict cardiac events in 529 patients with CKD and estimated glomerular filtration rates (eGFR) < 50 ml/min per 1.73(2) without a definitive diagnosis of coronary artery disease. All patients were assessed by stress-rest MPI with (99m)Tc-tetrofosmin and analyzed using summed defect scores and QGS software. Cardiac events were analyzed 1 year after registration. RESULTS: Myocardial perfusion abnormalities defined as summed stress score (SSS) ≥4 and ≥8 were identified in 19 and 7 % of patients, respectively. At the end of the 1-year follow-up, 33 (6.2 %) cardiac events had occurred that included cardiac death, sudden death, nonfatal myocardial infarction, and hospitalization due to heart failure. The event-free rates at that time were 0.95, 0.90, and 0.81 for groups with SSS 0-3, 4-7, and ≥8, respectively (p = 0.0009). Thus, patients with abnormal SSS had a higher incidence of cardiac events. Multivariate Cox regression analysis showed that SSS significantly impacts the prediction of cardiac events independently of eGFR and left ventricular ejection fraction. CONCLUSION: MPI would be useful to stratify patients with advanced conservative CKD who are at high risk of cardiac events without adversely affecting damaged kidneys.

J waves in accidental hypothermia.

BACKGROUND: The J wave is an ECG marker of ventricular fibrillation. However, the prevalence and clinical implications of J waves in hypothermic patients remain unclear. METHODS AND RESULTS: We evaluated the clinical characteristics and ECGs of patients who were admitted for accidental hypothermia (<35.0°C). J waves were defined as notches or slurs in the terminal part of the QRS complex with an amplitude ≥0.1mV. We analyzed the prevalence of J waves and the relationship between body temperature (BT) and J wave amplitude. We also examined the augmentation of J waves following variable R-R intervals in patients with atrial fibrillation. Furthermore, we assessed the incidence of ventricular arrhythmias. A total of 60 hypothermic patients were recruited (mean age, 64±9 years; 97% male). The mean BT was 31.3°C (range, 29.4-33.5°C). J waves, which disappeared after rewarming, were observed in 30 patients (50%), with a higher frequency in patients with lower BT. Higher amplitude of J waves was associated with lower BT (P<0.001). Of the 8 patients with J waves and atrial fibrillation, 4 exhibited an augmentation of J waves following a short R-R interval. Only 1 patient with J waves developed ventricular tachycardia during rewarming. CONCLUSIONS: The prevalence of J waves and their amplitude increased with the severity of hypothermia. The temporal development of J waves might not be associated with fatal arrhythmic events.

Disparity in the application of guideline-based medical therapy after percutaneous coronary intervention: analysis from the Japanese prospective multicenter registry.

BACKGROUND: Despite the known benefits of evidence-based medical care in patients with coronary artery disease, disparities exist in the application of guideline-based medical therapy (GBMT) after percutaneous coronary intervention (PCI), particularly in patients who have undergone revascularization procedures. Underestimation of risk, overestimation of side effects, and preference of the treating physician to prioritize invasive procedures may all affect the prescription pattern. OBJECTIVE: We sought to describe how GBMT is prescribed after PCI in Japan. METHODS: From September 2008 to 2010, 1,612 patients underwent PCI with stenting at 14 Japanese hospitals participating in the Japanese Cardiovascular Database Registry. GBMT was defined as treatment including dual antiplatelet therapy, beta-adrenoceptor antagonists (beta-blockers) and/or calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, and statins. RESULTS: Overall, 749 patients (46.5%) were discharged on GBMT. Notably, the prescription rate of GBMT became lower with age (e.g. from 50.3% [age 50-59 years] to 35.9% [age over 80 years]). In addition, patients presenting with acute coronary syndrome (ACS) tended to receive GBMT more frequently (ST-segment elevation myocardial infarction [STEMI] 33.8 vs. 18.3%; p<0.001; non-ST-segment elevation myocardial infarction [NSTEMI] 8.5 vs. 5.9%; p=0.042), whereas patients presenting with cardiogenic shock (CS) had lower prescription rates of GBMT (2.1 vs. 4.1%; p=0.032). Overall age (odds ratio [OR] 0.647; p=0.020), as well as the acute and emergent presentation (OR 3.229; p<0.001 for STEMI; OR 2.122; p<0.001 for NSTEMI; OR 0.35; p=0.002 for CS) were also associated with prescription of GBMT. CONCLUSION: Only about half of the post-PCI patients were discharged on ideal GBMT. Elderly patients and those presenting with non-ACS status or hemodynamic compromise tended not to receive GBMT, and required more attention for optimization of their care.

Use of thrombolysis in myocardial infarction risk score to predict bleeding complications in patients with unstable angina and non-ST elevation myocardial infarction undergoing percutaneous coronary intervention.

Thrombolysis in myocardial infarction (TIMI) is a prognostic score developed for managing the high risk of cardiac events immediately after unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI). In Asian populations that have a higher rate of bleeding complications, data about TIMI score are lacking. Using a Japanese multicenter registry, we investigated the impact of utilizing TIMI score in UA/NSTEMI patients, focusing on bleeding complications. The TIMI score was calculated for 587 patients who underwent percutaneous coronary intervention (PCI) for UA/NSTEMI (2008-2010). They were classified into low-risk (TIMI score 0-2, N = 268, 45.6 %), intermediate-risk (TIMI score 3-4, N = 264, 45.0 %) and high-risk (TIMI score 5-7, N = 55, 9.4 %) groups; patient characteristics for each group were statistically analyzed. The patients in the higher TIMI score group were older (p < 0.001), had lower GFR (p = 0.021) and hemoglobin level after PCI (p < 0.001), and severe coronary disease pattern (p = 0.014 and p = 0.023, respectively, for left main and three-vessel disease). The TIMI score was significantly associated with requirement of blood transfusion (low-risk, moderate-risk, and high-risk groups: 1.1, 4.2, and 7.3 %, respectively; p = 0.021), and the incidence of access site bleeding (1.1, 2.7, and 5.5 %, p = 0.112). The TIMI score might aid in subjectively quantifying the risk of in-hospital complication rates such as access site bleeding.

Safety of transradial approach for percutaneous coronary intervention in relation to body mass index: a report from a Japanese multicenter registry.

Transradial coronary intervention (TRI) is commonly performed in Japan, but its efficacy may differ from that in Western countries, particularly given the smaller body habitus of Japanese patients. We compared the clinical outcomes of TRI with those of transfemoral coronary intervention (TFI) and evaluated their relationship with body mass index in a multicenter registry. We analyzed data from 1230 patients who underwent percutaneous coronary intervention (TRI 306, TFI 924) at 14 Japanese hospitals from September 2008 to August 2010. Multivariate logistic regression analysis was performed to evaluate the odds ratio regarding complications between TRI and TFI. Propensity scores were used to adjust for differences in TRI and TFI, extracting 274 matched patients from each group for comparisons. The overall complication rate was significantly lower (10.8 vs. 18.0%, p = 0.003) and the bleeding complication rate trended lower (4.6 vs. 7.6%, p = 0.088) in TRI than in TFI. TRI was moderately associated with a smaller bleeding risk after multivariable adjustment (OR 0.54; p = 0.072). After propensity score matching, TRI was associated with significantly lower complication rates compared with TFI (9.5 vs. 18.2%, p = 0.003), especially bleeding complications (3.3 vs. 9.9%, p = 0.002) and puncture site bleeding (1.1 vs. 5.5%, p = 0.004). Notably, bleeding rate was inversely related to body mass index in both groups. TRI appeared to be a safe alternative to TFI in this Japanese real-world multicenter registry, which includes high numbers of TRI.

A novel animal model of hearing loss caused by acute endoplasmic reticulum stress in the cochlea.

Many stimuli such as ischemia, hypoxia, heat shock, amino acid starvation, and gene mutation, exhibit a cellular response called endoplasmic reticulum (ER) stress. ER stress induces expression of a series of genes, leading to cell survival or apoptosis. Previously, we found that in an animal model of hearing loss caused by acute mitochondrial dysfunction, several ER stress markers including C/EBP homologous protein were induced in the cochlear lateral wall. To elucidate the mechanism of hearing loss caused by ER stress, we established a novel animal model of hearing loss by perilymphatic perfusion of tunicamycin, an ER stress activator that inhibits N-acetylglucosamine transferases. Subacute and progressive hearing loss was observed at all sound frequencies studied, and stimulation of ER stress marker genes was noted in the cochlea. The outer hair cells were the most sensitive to ER stress in the cochlea. Electron microscopic analysis demonstrated degeneration of the subcellular organelles of the inner hair cells and nerve endings of the spiral ganglion cells. This newly established animal model of hearing loss from ER stress will provide additional insight into the mechanism of sensorineural hearing loss.

Late-phase recovery in the cochlear lateral wall following severe degeneration by acute energy failure.

We previously reported a model of acute cochlear energy failure using a mitochondrial toxin, 3-nitropropionic acid (3-NP), to study mechanisms of inner ear disorders such as inner ear ischemia. In this model, the main cause of hearing loss is apoptosis of fibrocytes in the cochlear lateral wall. Here, we analyzed the time course of structural and hearing level changes in the cochlea from the acute phase to the chronic phase up to 2 months after surgery. Hearing levels as determined by auditory brainstem response (ABR) thresholds exceeded the maximum acoustic output (>87 dBSPL) of the system at all frequencies 1 day after 3-NP treatment. Histology showed nearly complete loss of fibrocytes 2 weeks after 3-NP treatment. However, after 2 months, ABR showed significant recovery at low frequency (8 kHz) in four of five rats treated with 3-NP. ABR thresholds at 20 kHz occasionally showed some recovery. At 40 kHz, recovery of ABR thresholds was not observed. Histology of 3-NP-treated rats revealed partial recovery of the lateral wall and the regenerated fibrocytes in the spiral ligament expressed Na/K-ATPase in the cochlear basal turn 2 months after 3-NP treatment. These results indicate that ABR recovery is caused by regeneration of the cochlear lateral wall. Our findings demonstrate the recoverable capacity of the cochlear lateral wall that leads to functional recovery after severe damage.

Prognostic study of cardiac and renal events in Japanese patients with chronic kidney disease and cardiovascular risk using myocardial perfusion SPECT: J-ACCESS 3 study design.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease. Recent studies have indicated that the incidence of cardiovascular disease increases inversely with estimated glomerular filtration rate. Although coronary angiography is considered the gold standard for detecting coronary artery disease, contrast-induced nephropathy or cholesterol microembolization remain serious problems; therefore, a method of detecting coronary artery disease without renal deterioration is desirable. From this viewpoint, stress myocardial perfusion single photon emission computed tomography (SPECT) might be useful for patients with chronic kidney disease. We recently performed the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS) investigating patients with suspected or extant coronary artery disease and the J-ACCESS 2 study of patients with diabetes. The findings from these studies showed that SPECT can detect coronary artery disease and help to predict future cardiac events. Thus, we proposed a multicenter, prospective cohort study called "J-ACCESS 3" in patients with chronic kidney disease and cardiovascular risk. The study aimed at predicting cardiovascular and renal events based on myocardial perfusion imaging and clinical backgrounds. We began enrolling patients in J-ACCESS 3 at 74 facilities from April 2009 and will continue to do so until 31 March 2010, with the aim of having a cohort of 800 patients. These will be followed up for three years. The primary endpoints will be cardiac death and sudden death. The secondary endpoints will comprise any cardiovascular or renal events. This study will be completed in 2013. Here, we describe the design of the J-ACCESS 3 study.

Balance dysfunction resulting from acute inner ear energy failure is caused primarily by vestibular hair cell damage.

Inner ear energy failure is associated with disorders such as inner ear ischemia. Recently, we used the mitochondrial toxin 3-nitropropionic acid (3-NP) to establish an animal model of inner ear energy failure that presents with auditory dysfunction. Here we investigated the mechanisms underlying balance disorders in the 3-NP animal model. Spontaneous nystagmus peaked 6 hr after treatment with either 300 mM or 500 mM 3-NP. The nystagmus attenuated gradually and disappeared 3 days after 3-NP treatment. A caloric test using ice water was performed to evaluate residual vestibular function 7 days after 3-NP treatment. The response to caloric stimulation was reduced to approximately 40% of the response of the untreated ear following 300 mM 3-NP and was undetectable following 500 mM 3-NP. Structural changes in the peripheral vestibular organs were analyzed by light and electron microscopy. Severe loss of stereocilia was observed following 500 mM 3-NP, whereas disorganized and mildly reduced stereocilia were observed following 300 mM 3-NP. There was severe loss and degeneration of vestibular hair cells following 500 mM 3-NP but only slight loss and degeneration of hair cells following 300 mM 3-NP. These results indicate that acute inner ear energy failure causes balance dysfunction mainly by damaging hair cells in the vestibule, which is distinct from the mechanism underlying auditory disorders.

Mesenchymal stem cell transplantation accelerates hearing recovery through the repair of injured cochlear fibrocytes.

Cochlear fibrocytes play important roles in normal hearing as well as in several types of sensorineural hearing loss attributable to inner ear homeostasis disorders. Recently, we developed a novel rat model of acute sensorineural hearing loss attributable to fibrocyte dysfunction induced by a mitochondrial toxin. In this model, we demonstrate active regeneration of the cochlear fibrocytes after severe focal apoptosis without any changes in the organ of Corti. To rescue the residual hearing loss, we transplanted mesenchymal stem cells into the lateral semicircular canal; a number of these stem cells were then detected in the injured area in the lateral wall. Rats with transplanted mesenchymal stem cells in the lateral wall demonstrated a significantly higher hearing recovery ratio than controls. The mesenchymal stem cells in the lateral wall also showed connexin 26 and connexin 30 immunostaining reminiscent of gap junctions between neighboring cells. These results indicate that reorganization of the cochlear fibrocytes leads to hearing recovery after acute sensorineural hearing loss in this model and suggest that mesenchymal stem cell transplantation into the inner ear may be a promising therapy for patients with sensorineural hearing loss attributable to degeneration of cochlear fibrocytes.