The first percutaneous coronary intervention (PCI) was performed in September 1977, and after 1980 this minimally invasive treatment was established in Japan. To deliver this treatment to a larger population, a number of cardiovascular clinics emerged across the country in the 2000s, and the number of PCI cases performed has been steadily increasing, to >250,000 cases per year. In the early 2000s, a single catheterization unit was profitable, if it performed a certain number of treatments and was adequately staffed without excessive capital investment. In the late 1990s, the price of a balloon catheter medical device used for PCI was approximately JPY300,000, although the price was reduced to JPY32,000, almost one-tenth in price, in the April 2022 revision of the National Health Insurance. The reimbursement of the mainstream drug-eluting stent has also decreased from JPY421,000, when it was first introduced, to JPY136,000 currently. In addition, the consumption tax and reforms in working hours will have a major impact on clinic management. We present a history of cardiovascular clinics in Japan and their present and future positions under the variable external environment.

Background: Dialysis patients have strong intracoronary calcification, accelerated by secondary hyperparathyroidism as well as atherosclerosis. We evaluated the association of intact parathyroid hormone (iPTH) level with intracoronary calcification evaluated by intravascular ultrasound (IVUS), and its impact on both stent expansion after percutaneous coronary intervention (PCI) and long-term clinical outcomes, in dialysis patients with coronary artery disease (CAD).

Methods and Results: A total of 116 patients on dialysis, who underwent PCI with IVUS guidance between March 2012 and December 2020, were enrolled. Patients were divided into 2 groups based on their median iPTH level. The degree of intracoronary calcification was evaluated by calcification score using grayscale IVUS in the target lesions. Preprocedural calcification scores were significantly higher in the high iPTH group compared with the low iPTH group (2.9±1.1 vs. 2.1±0.7, P<0.001). After PCI, the high iPTH group had a significantly lower stent expansion index (0.6±0.2 vs. 0.7±0.1, P<0.001) and stent symmetry index (0.5±0.1 vs. 0.7±0.1, P<0.001) compared with the low iPTH group. The incidence of major adverse cardiac or cerebrovascular events within 3 years was significantly higher in the high iPTH group (log-rank P<0.05).

Conclusions: High iPTH level is likely to increase intracoronary calcification, and cause inadequate stent expansion, which may be associated with increased risk of future adverse events in dialysis patients with CAD requiring PCI.

Background: Contrast-induced nephropathy (CIN) is a frequent complication in patients undergoing percutaneous coronary intervention (PCI). The degree of recovery of renal function from CIN may affect long-term prognosis. N-terminal pro B-type natriuretic peptide (NT-proBNP) is a simple but useful biomarker for predicting CIN. However, the predictive value of preprocedural NT-proBNP for CIN non-recovery and long-term outcomes in patients undergoing PCI remains unclear.

Methods and Results: This study prospectively enrolled 550 patients with CIN after PCI between January 2012 and December 2018. CIN non-recovery was defined as persistent serum creatinine >25% or 0.5 mg/dL over baseline from 1 week to 12 months after PCI in patients who developed CIN. CIN non-recovery was observed in 40 (7.3%) patients. Receiver operating characteristic analysis indicated that the best NT-proBNP cut-off value for detecting CIN non-recovery was 876.1 pg/mL (area under the curve 0.768; 95% confidence interval [CI] 0.731–0.803). After adjusting for potential confounders, multivariable analysis indicated that NT-proBNP >876.1 pg/mL was an independent predictor of CIN non-recovery (odds ratio 1.94; 95% CI 1.03–3.75; P=0.0042). Kaplan-Meier curves showed higher rates of long-term mortality among patients with CIN non-recovery than those with CIN recovery (Chi-squared=14.183, log-rank P=0.0002).

Conclusions: Preprocedural NT-proBNP was associated with CIN non-recovery among patients undergoing PCI. The optimal cut-off value for NT-proBNP to predict CIN non-recovery was 876.1 pg/mL.

Background: This study evaluated the association of body mass index (BMI) with adverse clinical outcomes during chronic maintenance antiplatelet monotherapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES).

Methods and Results: Overall, 5,112 patients were stratified (in kg/m²) into underweight (BMI ≤18.4), normal weight (18.5–22.9), overweight (23.0–24.9), obesity (25.0–29.9) and severe obesity (≥30.0) categories with randomized antiplatelet monotherapy of aspirin 100 mg or clopidogrel 75 mg once daily for 24 months. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome and major bleeding of Bleeding Academic Research Consortium type ≥3. Compared with normal weight, the risk of primary composite outcomes was higher in the underweight (hazard ratio [HR] 2.183 [1.199–3.974]), but lower in the obesity (HR 0.730 [0.558–0.954]) and severe obesity (HR 0.518 [0.278–0.966]) categories, which is partly driven by the difference in all-cause death. The risk of major bleeding was significantly higher in the underweight (HR 4.140 [1.704–10.059]) than in the normal weight category. A decrease in categorical BMI was independently associated with the increased risk of primary composite outcomes.

Conclusions: Lower BMI is associated with a higher risk of primary composite outcomes, which is primarily related to the events of all-cause death or major bleeding during chronic maintenance antiplatelet monotherapy after PCI with DES.

Background: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD).

Methods and Results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69–0.82, P<0.001, and HR: 0.92, 95% CI: 0.84–1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002).

Conclusions: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.

Background: Drug-coated balloons (DCB) have shown promising results for the treatment of in-stent restenosis (ISR) and small vessel disease (SVD). However, data comparing the treatment efficacy of different DCBs are limited.

Methods and Results: AGENT Japan is a prospective randomized controlled trial that compares the Agent balloon coated with a low-dose formulation of paclitaxel (2 μg/mm²) to the SeQuent Please paclitaxel-coated balloon (3 μg/mm²) for the treatment of SVD. Patients with target lesion length ≤28 mm and reference diameter between ≥2.00 and <3.00 mm were randomized 2 : 1 for treatment with Agent (n=101) or SeQuent Please (n=49). This trial also includes a separate single-arm substudy evaluating the clinical safety and effectiveness of Agent in patients with ISR. The primary endpoint of 6-month target lesion failure (TLF) was observed in 3.0% of Agent and 0.0% of SeQuent Please patients (difference=3.0%; 97.5% upper confidence bound [UCB]=9.57%, which is less than the prespecified margin of 13.2%; P_{non-inferiority}=0.0012). There were no deaths or thrombosis, and angiographic and quality-of-life outcomes were comparable between groups. The AGENT Japan ISR substudy (n=30) primary endpoint was met because the one-sided 97.5% UCB for 6-month TLF (3.3%) was significantly less than the study success criterion of 15.1% (97.5% UCB=9.8%; P<0.0001).

Conclusions: Data from this study demonstrate good clinical outcomes with the Agent DCB when used to treat patients with SVD or ISR.

Background: The predictive value of both atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) is well known. This study evaluated the prognostic value of a novel natriuretic peptide index (NPI) combining ANP and BNP.

Methods and Results: This study included 849 consecutive patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). Patients were followed up clinically for up to 3 years or until the occurrence of major adverse cardiac events (MACE). The primary endpoint was a composite of all-cause death and non-fatal myocardial infarction. The NPI (pg/mL) was defined as . MACE occurred in 73 patients (8.6%) during the follow-up period. Receiver operating characteristic curve analysis showed the highest area under the curve for NPI (0.779) compared with ANP and BNP (0.773 and 0.755, respectively). A risk analysis of MACE occurrence adjusted for the multivariable model showed the highest hazard ratio (HR) for NPI (1.33; 95% confidence interval [CI] 1.18–1.51; P<0.001) compared with ANP and BNP (HR 1.25 [95% CI 1.13–1.39] and 1.30 [95% CI 1.13–1.49], respectively; P<0.001). The NPI was a significant independent predictor of MACE, among other clinical parameters, in the multivariable analysis.

Conclusions: Compared with ANP and BNP, the NPI was more effective in predicting future adverse events after PCI.

Background: The effect of delayed ambulation on the outcome of coronary artery bypass grafting (CABG) remains to be clarified.

Methods and Results: The long-term and in-hospital outcomes of 887 patients who underwent isolated CABG (455 off-pump cases, 135 urgent cases) were evaluated, with a focus on the timing of first ambulation. In-hospital mortality cases were excluded. Early ambulation (first ambulation within 3 days after operation) was achieved in 339 (38%) patients. In the multivariable logistic regression analysis, longer operation time and urgent case, EuroSCORE II, re-thoracotomy, and respiratory time were associated with delayed (≥4 days) ambulation. Delayed ambulation was associated with a high incidence of postoperative complications, such as pneumonia, and stroke (P<0.01). Following discharge, 22.2% of patients experienced major cardiac events and 13.8% died during the follow-up period (median follow-up 60 months). Cox hazards analysis revealed that delayed ambulation was associated with long-term adverse events (hazard ratio 1.04 per day, P<0.001). With adjustment for preoperative factors, the estimated future risk of adverse events was found to be increased day-by-day during the delay until initial ambulation.

Conclusions: In isolated CABG patients, delayed ambulation was associated with poor outcomes, even in the long-term period. The results support the current guideline recommending early ambulation protocol after cardiac surgery.

Background: We compared postoperative outcomes in octogenarians who underwent off-pump isolated coronary artery bypass grafting for multivessel disease using either skeletonized bilateral or single internal thoracic artery (ITA).

Methods and Results: Among 1,532 patients who underwent isolated coronary artery bypass grafting between 2002 and 2021, 173 octogenarians were analyzed retrospectively. After inverse probability of treatment weighting, we found no statistically significant difference regarding patients’ preoperative characteristics. No patient experienced deep sternal wound infection. More patients in the single than bilateral ITA group died within 30 days after surgery (5.0% vs. 0%, respectively; P=0.003). The mean follow-up duration was 4.2 years. At 5 years, the freedom from overall death following bilateral versus single ITA grafting was 78.2% and 53.7%, respectively (log-rank test, P=0.003), and freedom from major adverse cardiac and cerebrovascular events (MACCE) was 67.9% and 44.8% respectively (log-rank test, P=0.002). In multivariable Cox models, bilateral ITA grafting was significantly associated with a lower risk of overall death (hazard ratio [HR] 0.555; 95% confidence interval [CI] 0.342–0.903; P=0.018) and MACCE (HR 0.586; 95% CI 0.376–0.913; P=0.018).

Conclusions: Compared with single ITA grafting, off-pump skeletonized bilateral ITA grafting is associated with lower rates of overall death and MACCE in octogenarians undergoing CABG and does not increase the risk of deep sternal wound infection.

Background: Data regarding the performance of computational fractional flow reserve in patients with diabetes mellitus (DM) remain scarce. This study sought to explore the impact of DM on quantitative flow ratio (QFR) and its association with intravascular ultrasound (IVUS)-derived anatomical references.

Methods and Results: IVUS and QFR were retrospectively analyzed in 237 non-diabetic and 93 diabetic patients with 250 and 102 intermediate lesions, respectively. Diabetics were further categorized based on adequate (HbA1c <7.0%: 47 patients with 53 lesions) or poor (HbA1c ≥7.0%: 46 patients with 49 lesions) glycemic control. Lesions with QFR ≤0.8 or minimum lumen area (MLA) ≤4.0 mm²and plaque burden (PB, %) ≥70 were considered functionally or anatomically significant, respectively. PB increased, and MLA decreased stepwise across non-diabetics, diabetics with adequate glycemic control and those with poor glycemic control. In contrast, QFR was similar among the 3 groups. PB correlated significantly with the QFR for lesions in non-diabetics, but not for lesions in diabetics. DM was independently correlated with the functionally non-significant lesions (QFR >0.8) with high-risk IVUS features (MLA ≤4.0 mm²and PB ≥70; OR 2.053, 95% CI: 1.137–3.707, P=0.017). When considering the effect of glycemic control, HbA1c was an independent predictor of anatomical-functional discordance (OR 1.347, 95% CI: 1.089–1.667, P=0.006).

Conclusions: Anatomical-functional discordance of intermediate coronary lesions assessed by IVUS and QFR is exacerbated in patients with diabetes, especially when glycemia is poorly controlled.

Background: Coronary intraplaque microluminal structures (MS) are associated with plaque vulnerability, and the inward progression of vascular inflammation from the adventitia towards the media and intima has also been demonstrated. Therefore, in the present study we investigated the relationships among MS, local inflammation in adjacent epicardial adipose tissue (EAT), and coronary plaque characteristics.

Methods and Results: Optical coherence tomography (OCT) revealed MS in the left anterior descending coronary artery in 10 fresh cadaveric hearts. We sampled 30 lesions and subdivided them based on the presence of MS: MS (+) group (n=19) and MS (−) group (n=11). We measured inflammatory molecule levels in the adjacent EAT and percentage lipid volume assessed by integrated backscatter intravascular ultrasound in each lesion. The expression levels of vascular endothelial growth factor B and C-C motif chemokine ligand 2 were significantly higher in the MS (+) group than in the MS (−) group (0.9±0.7 vs. 0.2±0.2 arbitrary units (AU), P=0.04 and 1.5±0.5 vs. 0.6±0.7 AU, P=0.02, respectively). Percentage lipid volume was significantly higher in the MS (+) group than in the MS (−) group (38.7±16.5 vs. 23.7±10.9%, P=0.03).

Conclusions: Intraplaque MS observed on OCT were associated with lipid-rich plaques and local inflammation in the adjacent EAT. Collectively, these results suggest that local inflammation in the EAT is associated with coronary plaque vulnerability via MS.

Background: The optimal heart rate (HR) and optimal dose of β-blockers (BBs) in patients with coronary artery disease (CAD) have been unclear. We sought to clarify the relationships among HR, BB dose, and prognosis in patients with CAD using a multimodal data acquisition system.

Methods and Results: We evaluated the data for 8,744 CAD patients who underwent cardiac catheterization from 6 university hospitals and the National Cerebral and Cardiovascular Center and who were registered using the Clinical Deep Data Accumulation System. Patients were divided into quartile groups based on their HR at discharge: Q1 (HR <60 beats/min), Q2 (HR 60–66 beats/min), Q3 (HR 67–74 beats/min), and Q4 (HR ≥75 beats/min). Among patients with acute coronary syndrome (ACS) and patients with chronic coronary syndrome (CCS), those in Q4 (HR ≥75 beats/min) had a significantly greater incidence of major adverse cardiac and cerebral events (MACCE) compared with those in Q1 (ACS patients: hazard ratio 1.65, P=0.001; CCS patients: hazard ratio 1.45, P=0.019). Regarding the use of BBs (n=4,964), low-dose administration was significantly associated with MACCE in the ACS group (hazard ratio 1.41, P=0.012), but not in patients with CCS after adjustment for covariates.

Conclusions: HR ≥75 beats/min was associated with worse outcomes in patients with CCS or ACS.

Background: Low-dose aspirin (LDA) is used to prevent recurrent cardiovascular (CV) events, but is associated with upper gastrointestinal (GI) bleeding; concomitant use of a proton pump inhibitor (PPI) reduces this risk. This study aimed to assess the cost-effectiveness of vonoprazan compared with PPIs (lansoprazole and esomeprazole) in patients taking LDA for secondary prevention of CV events.

Methods and Results: A Markov simulation model was developed to predict the number of GI bleeding and acute CV events using 3 strategies (vonoprazan+LDA, esomeprazole+LDA, and lansoprazole+LDA), which were translated into quality-adjusted life-years (QALYs) and costs. Transition probabilities and utilities were derived from the results of published literature, and medical costs were based on the Japanese National Health Insurance fee table and claims databases in 2020. Outcomes were projected over 30 years starting at age 65 years and discounted at 2% annually. Expected costs with esomeprazole 20 mg, lansoprazole 15 mg and vonoprazan 10 mg were JPY 1,225,657, JPY 943,930, and JPY 1,059,510, respectively. The QALY gain for vonoprazan vs. esomeprazole was 0.35, thus vonoprazan was dominant against esomeprazole. The QALY gain for vonoprazan vs. lansoprazole was 0.29 and the incremental cost-effectiveness ratio (ICER) was JPY 398,551, thus, vonoprazan was more cost-effective than lansoprazole.

Conclusions: Vonoprazan is dominant or cost-effective compared with esomeprazole and lansoprazole in patients taking LDA for secondary prevention of CV events.

Background: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins.

Methods and Results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70–100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70–100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58–1.18, P=0.32, and HR 1.25, 95% CI 0.88–1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60–1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08–5.17, P<0.001).

Conclusions: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70–100 mg/dL) in patients receiving the same doses of statins.

Background: The exercise stress test is a widely used noninvasive test for diagnosing ischemic heart disease. Patients with a “positive” result have a higher risk than those with a “negative” result. However, the outcomes of patients with an “inconclusive” result remain uncertain.

Methods and Results: We retrospectively collected the data of patients who underwent an ECG-based treadmill stress test between August 2009 and March 2020. Propensity score matching (PSM) was performed to adjust for confounders. Clinical outcomes were compared in terms of all-cause death and cardiovascular (CV) death. Subgroup analysis evaluated treatment interactions, including medication and examinations. In total, 25,475 patients were recruited, and after exclusion and PSM, 4,847 (1,621 with a positive result, 1,606 with a negative result, and 1,621 with an inconclusive result) remained. Compared with the negative group, the inconclusive group, but not the positive group, had a significantly worse outcome in terms of all-cause death (hazard ratio [HR]: 1.834, 95% confidence interval [CI]: 1.34–2.511 and HR: 1.327, 95% CI: 0.949–1.857, respectively); however, CV death was not significantly different in the inconclusive and positive groups (HR: 1.728, 95% CI: 0.413–7.232 and HR: 2.067, 95% CI: 0.517–8.264, respectively).

Conclusions: Clinicians must not underestimate the potential for worse outcomes in patients with an inconclusive stress test result.