Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).

BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up. CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.

Feasibility of simultaneous 99mTc-tetrofosmin and 123I-BMIPP dual-tracer imaging with cadmium-zinc-telluride detectors in patients undergoing primary coronary intervention for acute myocardial infarction.

BACKGROUND: Simultaneous dual-tracer imaging using isotopes with close photo-peaks may benefit from improved properties of cadmium-zinc-telluride (CZT)-based scanners. METHODS: Thirty patients having undergone primary percutaneous coronary intervention for acute myocardial infarction underwent single-(99mTc-tetrofosmin (TF) or 123I-BMIPP first) followed by simultaneous 99mTc-TF /123I-BMIPP dual-tracer imaging using a Discovery NM/CT 670 CZT. The values for the quantitative gated-SPECT (QGS) and the quantitative perfusion SPECT (QPS) were assessed. RESULTS: The intra-class correlation (ICC) coefficients between the single- and dual-tracer imaging were high in all the QGS and QPS data (Summed motion score: 0.95, summed thickening score: 0.94, ejection fraction: 0.98, SRS for 99mTc-TF: 0.97/ for 123I-BMIPP: 0.95). Wall motion, wall thickening and rest scores per coronary-territory-based regions were also comparable between the single- and dual imaging (ICC coefficient > 0.91). The interrater concordance in the visual analysis for the infarction and perfusion-metabolism mismatch was significant for the global and regional left ventricle (P < 0.001). CONCLUSION: The quantitative/semi-quantitative values for global and regional left-ventricular function, perfusion, and fatty acid metabolism were closely comparable between the dual-tracer imaging and the single-tracer mode. These data suggests the feasibility of the novel CZT-based scanner for the simultaneous 99mTc-TF /123I-BMIPP dual-tracer acquisitions in clinical settings.

The Predictive Value of Changes in Body Mass Index for the Incidence of Device-Specific Infections in Patients With Implantable Left Ventricular Assist Devices.

BACKGROUND: Implantable left ventricular assist devices (LVAD) have improved quality of life and survival in patients with advanced heart failure. However, LVAD-specific infections and predicting which patients will develop infections remain challenging. This study investigated whether changes in body mass index (BMI) during hospitalization following LVAD implantation are associated with LVAD-specific infections within 1 year of implantation.Methods and Results:Patients (n=135) undergoing LVAD implantation were retrospectively divided into 2 groups based on changes in BMI from LVAD implantation to discharge: those with and without decreases in BMI. Each group was further subdivided according to baseline albumin concentrations (high [>3.7 g/dL] and low [≤3.7 g/dL]). Twenty patients developed LVAD-specific infections within 1 year. Receiver operating characteristic curve analysis resulted in a ∆BMI cut-off of less than -0.128 kg/m2. In multivariate analysis, younger patients and those with decreases in BMI had significantly higher rates of LVAD-specific infection (P=0.010 and P=0.035, respectively). LVAD-specific infection rates were significantly higher for patients with low albumin and decreases in BMI than for patients with low albumin but no decrease in BMI. CONCLUSIONS: Decreases in BMI during hospitalization after LVAD implantation and younger age were independently associated with LVAD-specific infection within 1 year. Strict patient management may be needed to avoid decreases in BMI during hospitalization after LVAD implantation, particularly in patients with low baseline albumin concentrations.

Risk stratification based on J-ACCESS risk models with myocardial perfusion imaging: Risk versus outcomes of patients with chronic kidney disease.

BACKGROUND: This study aimed to validate the accuracy of major-event risk models created in the multicenter J-ACCESS prognostic study in a new cohort of patients with chronic kidney disease (CKD). METHODS AND RESULTS: Three multivariable J-ACCESS risk models were created to predict major cardiac events (cardiac death, non-fatal acute coronary syndrome, and severe heart failure requiring hospitalization): Model 1, four variables of age, summed stress score, left ventricular ejection fraction and diabetes; Model 2 with five variables including estimated glomerular filtration rate (eGFR, continuous); and Model 3 with categorical eGFR. The validation data used three-year (3y) cohort of patients with CKD (n = 526, major events 11.2%). Survival analysis of low (< 3%/3y), intermediate (3% to 9%/3y), and high (> 9%/3y)-risk groups showed good stratification by all three models (actual event rates: 3.1%, 9.9%, and 15.9% in the three groups with eGFR ≥ 15 mL/min/1.73 m2, P = .0087 (Model 2). However, actual event rates were equally high across all risk groups of patients with eGFR < 15 mL/min/1.73 m2. CONCLUSION: The J-ACCESS risk models can stratify patients with CKD and eGFR ≥ 15 mL/min/1.73 m2, but patients with eGFR < 15 mL/min/1.73 m2 are potentially at high risk regardless of estimated risk values.

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.

Analysis of the heart rate variability during cryoballoon ablation of atrial fibrillation.

Aims: Vagal responses such as marked bradycardia or a rapid blood pressure decrease are often observed during pulmonary vein (PV) isolation of atrial fibrillation (AF) using a cryoballoon (CB). However, the relationship between the marked vagal response and change in the heart rate variability (HRV) as a marker of the autonomic tone is not well understood. Methods and results: Fifty-four paroxysmal AF patients underwent CB ablation. The CB ablation was started from the right sided PVs in 25 patients (R group) and left sided PVs in 29 (L group). The HRV and haemodynamic status during the procedure were analysed. A vagal response was observed in 16 L group patients (61.5%) during the ablation of the different PVs (RSPV:1, RIPV:5, LSPV:15, LIPV:5), while it was observed in only 2 R group patients (9.5%) (RSPV:0, RIPV:0, LSPV:1, LIPV:1) (P = 0.0002). The HRV in the L group was significantly higher than that in the R group just after the CB ablation especially for the left sided PVs (L group vs. R group, total power of the HRV, median; RSPV, 11184.7 vs. 4360.0, P = 0.21; RIPV, 9044.3 vs. 2115.1, P = 0.01; LSPV, 21186.0 vs. 1314.2, P = 0.0002; LIPV 10265.9 vs. 1236.2, P = 0.0007). Conclusion: A marked increase in the HRV parameters was observed just after the CB ablation. An initial CB ablation of the right PVs decreased the change in the autonomic tone during the right PV ablation and subsequent left PV ablation. It prevented an excessive vagal response during the CB ablation and might be a safe procedure.

Demeanor of rivaroxaban in activated/inactivated FXa.

Activated factor X (FXa) plays an important role in thrombin generation and inflammation. Factor X is not converted constitutively to FXa, but only after intrinsic clotting factors are activated and/or cellular injury occurs. Although rivaroxaban is one of direct FXa inhibitors, its function in the inactivated coagulation cascade is unclear. In human umbilical vein endothelial cells that natively express protease-activated receptor-1 and -2, high dose rivaroxaban did not alter gene transcripts including pro-inflammatory genes in DNA microarray. Upon FXa stimulation, the expressions of pro-inflammatory genes such as monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1, and interleukin-8 were maximally increased at 4 h after stimulation, and were suppressed by rivaroxaban. To confirm these results, quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) for MCP-1 were performed. FXa evoked the expression of MCP-1 maximally at 4 h after stimulation, whereas MCP-1 displayed a different temporal activation in ELISA. Interestingly, rivaroxaban inhibited both time courses of MCP-1 expression. These results suggest that rivaroxaban may not influence gene modulation in the inactivated coagulation state, but can attenuate the endothelial damage evoked by FXa and pro-inflammatory cytokine genes.

Left atrial appendage wall-motion velocity associates with recurrence of nonparoxysmal atrial fibrillation after catheter ablation.

Catheter ablation (CA) for nonparoxysmal atrial fibrillation (AF) is controversial due to its high recurrence rate. The aim of this study was to assess retrospectively the diagnostic value of preprocedural left atrial appendage (LAA) wall-motion velocity in predicting recurrence of AF within 1 year after CA. We hypothesized that tissue Doppler-derived measurement of LAA wall-motion velocity associate with recurrence of AF within 1 year after CA. We retrospectively reviewed 47 consecutive patients with nonparoxysmal AF (defined as AF lasting for 1 week or longer) who underwent both transthoracic and transesophageal echocardiography before their first treatment by CA in a single center. Forty-one patients aged 58 ± 10 years were included, and variables predicting the recurrence of AF within 1 year after CA were evaluated. Seventeen patients (41%) developed recurrence of AF within 1 year after CA. Univariate analyses showed that preprocedural LAA upward wall-motion velocity at the apex assessed by transesophageal echocardiography was significantly lower in patients with recurrence of AF than those without recurrence (OR = 1.45, 95% CI: 1.13-2.01, P = 0.009). Multivariate logistic analyses including other potential predictors (duration of AF, left ventricular ejection fraction, E-wave deceleration time, and left atrial wall-motion velocity) identified LAA upward wall-motion velocity at the apex as an independent predictor of outcome. These data suggest in patients with nonparoxysmal AF, preprocedural LAA upward wall-motion velocity at the apex, as determined by tissue Doppler imaging during transesophageal echocardiography, may be a useful indicator for predicting recurrence of AF within 1 year after CA.

Percutaneous Coronary Intervention for Septic Emboli in the Left Main Trunk as a Complication of Infective Endocarditis.

Infective endocarditis (IE) complicated by acute myocardial infarction (AMI) is frequently fatal and may require emergent interventions. However, the optimal treatment of this rare condition remains controversial as it lacks established guidelines. We successfully treated a patient with IE complicated by AMI during the acute phase using percutaneous coronary intervention (PCI) followed by surgery. A 73-year-old man was diagnosed with IE of the mitral and aortic valves caused by Streptococcus oralis. Four weeks after the initiation of antibiotics sensitive to the causative bacteria, he suddenly developed AMI manifested by chest pain and dyspnoea with cardiovascular collapse. Emergent coronary angiography revealed that the myocardial infarction was secondary to septic emboli in the left main trunk. Emergent PCI comprising aspiration and stent deployment, was successfully performed, and his vital signs were immediately stabilised. He subsequently underwent mitral and aortic valve replacement and debridement without major post-operative complications. Although the optimal treatment strategy for haemodynamically unstable AMI secondary to IE requires further discussion, the present case indicates the importance of early diagnosis and the potential effectiveness of aggressive PCI as a bridge to the following surgery.

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.

Cardiac event risk in Japanese subjects estimated using gated myocardial perfusion imaging, in conjunction with diabetes mellitus and chronic kidney disease.

BACKGROUND: Cardiac event risk is estimated using quantitative gated myocardial perfusion imaging (MPI) and clinical background in patients with ischemic heart disease. The aim of the present study was to calculate major cardiac event risk and tabulate it in the Heart Risk Table for clinical use of risk stratification. METHODS AND RESULTS: Multivariate logistic regression was performed based on a multicenter prognostic database (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated Single-photon emission computed tomography [J-ACCESS investigation]) using MPI (n=2,395). The risk of major cardiac events (cardiac death, non-fatal myocardial infarction and heart failure requiring hospitalization) was estimated using age, ejection fraction (EF), estimated glomerular filtration rate (eGFR) and presence of diabetes mellitus (DM). Age-matched standard eGFR was determined in 77 subjects. Major cardiac event risk was calculated using the equation: risk (%/3 years)=1/(1+Exp(-(-4.699-0.0151×eGFR+0.7998×DM+0.0582×age+0.697×SSS-0.0359×EF))×100, where SSS refers to summed stress scores. Risk was determined without eGFR (the initial version) and using the present formula with eGFR (revised version), with consistent results. DM and chronic kidney disease were major determinants of cardiac events. CONCLUSIONS: Cardiac event risk was estimated using MPI defect score and left ventricular EF in conjunction with eGFR and the presence of DM. The risk table might be used for risk evaluation in Japanese patients undergoing MPI.

Predictive value of electrocardiography-gated myocardial perfusion imaging to new-onset heart failure in patients with chronic kidney disease: findings from the J-ACCESS 3 study.

The incidence of heart failure (HF) increases in patients with chronic kidney disease (CKD). Factors that could predict patients with CKD who are at high risk for developing HF should be identified. We analysed clinical parameters and stress/rest myocardial perfusion imaging (MPI) findings derived from 499 patients with CKD by the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT 3 (J-ACCESS 3) to clarify predictors of new-onset HF. Forty-one patients with congestive HF in the J-ACCESS 3 database were followed up for three years. Multivariable Cox hazards models selected haemoglobin (hazard ratio [HR] 0.809; 95% confidence interval [CI] 0.679-0.964), summed stress score (HR 1.082; 95% CI 1.016-1.151) and left ventricular ejection fraction (HR 0.970; 95% CI 0.949-0.992) as independent predictors of new-onset HF. Haemoglobin combined with summed stress scores and ejection fraction had the greatest incremental prognostic value over any one or more combined factors (global χ2, 29.9). Anaemia, stress-induced myocardial ischaemia, and left ventricular contraction are independent predictors of risk of new-onset HF in patients with CKD. Stress/rest MPI provides additional information with which to identify patients with CKD at greater risk of new-onset HF.

Mid-term predictive value of calciprotein particles in maintenance hemodialysis patients based on a gel-filtration assay.

BACKGROUND AND AIMS: Calciprotein particles (CPPs), nano-aggregates containing fetuin-A-bound calcium-phosphate, are associated with aortic stiffness and coronary calcification in maintenance hemodialysis patients. A novel gel-filtration assay can detect low-density small CPPs, which are actually a major form of circulating CPPs in vivo. We sought to investigate whether circulating CPP levels measured by gel-filtration method would accurately predict hard endpoints in maintenance hemodialysis patients. METHODS: This study used a prospective, multicenter, longitudinal, and observational design. One-hundred eight patients enrolled in this study were followed-up for about 2 years. We reported all-cause death and cardiovascular events, which included major adverse cardiac, cerebrovascular, and limb events. RESULTS: Kaplan-Meier analysis showed no significant difference between patients with the higher (>median) and lower (

Prognostic risk stratification of myocardial ischaemia evaluated by gated myocardial perfusion SPECT in patients with chronic kidney disease.

PURPOSE: The aim of this study was to identify useful predictors of cardiac events in patients with chronic kidney disease (CKD). METHODS: Among 4,031 patients identified from the Japanese Assessment of Cardiac Events and Survival Study (J-ACCESS) database with suspected or known ischaemic heart disease, we selected 820 with an estimated glomerular filtration rate (eGFR) of < 60 ml/min per 1.73 m(2). RESULTS: A total of 75 cardiac events developed among these 820 patients. The incidence of cardiac events was higher in the group with a lower eGFR. Multivariate Cox analysis indicated that age, diabetes mellitus, end-systolic volume, summed stress score (SSS) and eGFR were predictors of cardiac events. Event rates of patients with SSS >or= 9 were significantly higher in groups with lower eGFR values (< 40 and 40-49 ml/min). CONCLUSION: The SSS value (>or= 9) is a reliable predictor of cardiac events and myocardial single photon emission computed tomography has incremental value for predicting cardiac events and survival in CKD.

Prognostic value of myocardial perfusion and ventricular function in a Japanese multicenter cohort study (J-ACCESS): the first-year total events and hard events.

OBJECTIVE: To determine the prognostic value of myocardial ischemia, function and coronary risk factors on total and hard cardiac events using myocardial perfusion imaging in a Japanese population. METHODS: A prospective cohort study was performed in 117 Japanese hospitals, each with a nuclear cardiology facility. A total of 4,031 patients with suspected or confirmed ischemic heart disease were registered. The patients were followed up for a year to investigate total and hard events, and those who had any events were followed up for 3 years to evaluate subsequent hard events. A stress-rest gated myocardial perfusion study was performed with (99m)Tc-tetrofosmin using gated single-photon emission computed tomography (SPECT) and analyzed by semi-quantitative scores. RESULTS: During the 1-year follow-up period, 263 (6.5%) patients had total events comprising all-cause death, non-fatal myocardial infarction (MI), heart failure, unstable angina, angina pectoris and coronary revascularization. Cardiac death occurred in 23 patients (0.6%) and non-fatal MI in 11 (0.3%). Among patients with ejection fraction (EF) of <45% and a summed difference score (SDS) of >/=2, 18.7% (2.4% for cardiac death and 0.6% for non-fatal MI) experienced total events compared with 3.9% (0.3% for cardiac death and 0.2% for non-fatal MI; P < 0.0001) of those with EF >/= 45% and SDS < 2. Multivariate analysis identified EF, SDS, age, history of revascularization and diabetes as significant predictors of all events, while the significant predictors were age and EF for hard events. When the patients who had heart failure in the first year were followed up, 9 of 41 (22.0%) experienced cardiac death in the subsequent 3-year follow-up period. CONCLUSIONS: Myocardial ischemia defined by SDS and ventricular function were the main predictors of total events despite the relatively low incidence of hard events in this Japanese population. In patients with cardiac events in a year, closer attention should be paid to subsequent hard events particularly in patients with heart failure.

Shortened acquisition time in simultaneous 99mTc-tetrofosmin and 123I-ß-methyl-p-iodophenyl pentadecanoic acid dual-tracer imaging with cadmium-zinc-telluride detectors in patients undergoing primary coronary intervention for acute myocardial infarction.

OBJECTIVE: The use of cadmium-zinc-telluride-based scanners may increase the clinical feasibility of simultaneous dual-isotope imaging. In the current study, we sought to investigate a potential acquisition time in simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-isotope imaging using a Discovery NM/CT 670 cadmium-zinc-telluride. METHODS: Simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-isotope imaging was performed in 29 patients who had undergone primary percutaneous coronary intervention for acute myocardial infarction. Referenced images with an acquisition time of 65 s/view (16.25 min) were reframed to produce images with acquisition times of 33, 16, and 8 s/view. The values for the quantitative-gated single-photon emission computed tomography (SPECT) and the quantitative perfusion SPECT were compared. RESULTS: The quantitative-gated SPECT values for images with 33, 16, and 8 s/views showed good consistency with those for 65 s/view (the lower 95% confidence intervals for the intraclass correlation were ≥0.80). The quantitative perfusion SPECT values for Tc-tetrofosmin images with 33, 16, and 8 s/views also showed good consistency with those for 65 s/view; however, the quantitative perfusion SPECT values for I-ß-methyl-p-iodophenyl pentadecanoic acid images with an acquisition time of 8 s/view were not consistent with the reference acquisition time of 65 s/view. CONCLUSIONS: The quantitative-gated SPECT and quantitative perfusion SPECT values obtained from images with shorter acquisition times correlated with the values obtained from images with a reference acquisition time of 65 s/view; however, tracer-specific predisposition should be considered. These findings suggest that it is possible to reduce acquisition time when performing simultaneous Tc-tetrofosmin/I-ß-methyl-p-iodophenyl pentadecanoic acid dual-tracer imaging with the novel cadmium-zinc-telluride scanner.