Ischemic heart disease (IHD) is commonly recognized as the consequence of coronary atherosclerosis and obstructive coronary artery disease (CAD). However, a significant number of patients may present angina or myocardial infarction even in the absence of any significant coronary artery stenosis and impairment of the coronary microcirculation has been increasingly implicated as a relevant cause of IHD. The term “coronary microvascular dysfunction” (CMD) encompasses several pathogenic mechanisms resulting in functional and/or structural changes in the coronary microcirculation and determining angina and myocardial ischemia in patients with angina without obstructive CAD (“primary” microvascular angina), as well as in several other conditions, including obstructive CAD, cardiomyopathies, Takotsubo syndrome and heart failure, especially the phenotype with preserved ejection fraction. The pathogenesis of CMD is complex and involves the combination of functional and structural alterations leading to impaired coronary blood flow and resulting in myocardial ischemia. In the absence of therapies specifically targeting CMD, attention has been focused on the role of modifiable risk factors. Here, we provide updated evidence regarding the pathophysiological mechanisms underlying CMD, with a particular focus on the role of cardiovascular risk factors and comorbidities. Moreover, we discuss the specific pathogenic mechanisms of CMD across the different cardiovascular diseases, aiming to pave the way for further research and the development of novel strategies for a precision medicine approach.

Background: Little evidence is available regarding the long-term outcome in elderly patients after deferral of revascularization based on fractional flow reserve (FFR).

Methods and Results: From the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicenter registry), 1,262 patients were divided into 2 groups according to age: elderly and younger patients (aged ≥75 or <75 years, respectively). The primary endpoint was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel-related myocardial infarction (TVMI), and clinically driven target vessel revascularization (CDTVR). Cumulative 5-year incidence of TVF was not significantly different between elderly and younger patients (14.3% vs. 10.8%, P=0.12). Cardiac death occurred more frequently in elderly patients than younger patients (4.4% vs. 0.8%, P<0.001), whereas TVMI and CDTVR did not differ between groups (1.3% vs. 0.9%, P=0.80; 10.7% vs. 10.1%, P=0.80, respectively). FFR values in lesions with diameter stenosis <50% were significantly higher in elderly patients than in younger patients (0.88±0.07 vs. 0.85±0.07, P=0.01), whereas this relationship was not observed in those with diameter stenosis ≥50%.

Conclusions: Elderly patients had no excess risk of ischemic events related to the deferred coronary lesions by FFR, although FFR values in mild coronary artery stenosis were modestly different between elderly and younger patients.

Background: The 12-month results of the PENDULUM registry showed that after implantation of second-generation drug-eluting stents (DES), high P2Y₁₂reaction unit (HPR) were independently associated with ischemic but not bleeding events.

Methods and Results: This study analyzed cumulative incidences of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding (Bleeding Academic Research Consortium type 3 and 5) at 30 months after index percutaneous coronary intervention (PCI) (primary endpoints). Of 6,422 patients undergoing PCI with DES, 5,796 completed the 30-month follow up. The continuation rate of dual antiplatelet therapy decreased to 59.3% at 12 months and 26.4% at 30 months. At 30 months, the cumulative incidence of MACCE increased linearly and reached 9.5% (95% confidence interval 8.8–10.2) and that of major bleeding had the inflection point at 12 months and was 4.4% (3.9–5.0). MACCE and bleeding events were higher in HPR patients (unadjusted P value). After covariate adjustment, P2Y₁₂reactivity units measured immediately after index PCI was not an independent risk factor for MACCE or major bleeding at 30 months.

Conclusions: MACCE consistently increased after 12 months post-PCI, whereas the increase in major bleeding events slowed down after 12 months in Japanese PCI patients in a real-world clinical setting. HPR patients had increased MACCE and bleeding complications, but HPR was not an independent risk factor of events at 30 months.

Background: In PENDULUM mono, Japanese patients with high bleeding risk (HBR) received short-term dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with prasugrel after percutaneous coronary intervention (PCI). One-year data from PENDULUM mono showed better outcomes with prasugrel monotherapy after short-term DAPT compared with matched patients in the PENDULUM registry with longer DAPT durations according to guidelines at that time. This study presents 2-year results.

Methods and Results: We compared 24-month data from PENDULUM mono (n=1,107; de-escalation strategy group) and the PENDULUM registry (n=2,273; conventional strategy group); both were multicenter, non-interventional, prospective registry studies, using the inverse probability of treatment weighting (IPTW) method. In the PENDULUM mono group, the cumulative incidence of clinically relevant bleeding (CRB) at 24 months post-PCI (primary endpoint) was 6.8%, and that of major adverse cardiac and cerebrovascular events (MACCE) was 8.9%. After IPTW adjustment, the cumulative incidence of CRB was 5.8% and 7.2% in PENDULUM mono and the PENDULUM registry, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.57–1.04; P=0.086), and that of MACCE was 8.0% and 9.5%, respectively (HR 0.77; 95% CI 0.59–1.01; P=0.061).

Conclusions: Japanese PCI patients with HBR prescribed prasugrel SAPT after short-term DAPT had a lower ischemic event risk than those prescribed long-term DAPT, and this was particularly relevant for ischemic events after 1 year.

Background: Differences in the impact of the 1- or 2-stent strategy in similar coronary bifurcation lesion conditions are not well understood. This study investigated the clinical outcomes and its predictors between 1 or 2 stents in propensity score-matched (PSM) complex bifurcation lesions.

Methods and Results: We analyzed the data of patients with bifurcation lesions, obtained from a multicenter registry of 2,648 patients (median follow up, 53 months). The patients were treated by second generation drug-eluting stents (DESs). The primary outcome was target lesion failure (TLF), composite of cardiac death, target vessel myocardial infarction (TVMI), and ischemia-driven target lesion revascularization (TLR). PSM was performed to balance baseline clinical and angiographic discrepancies between 1 and 2 stents. After PSM (N=333 from each group), the 2-stent group had more TLRs (hazard ratio [HR] 3.14, 95% confidence interval [CI] 1.42–6.97, P=0.005) and fewer hard endpoints (composite of cardiac death and TVMI; HR 0.44, 95% CI 0.19–1.01, P=0.054), which resulted in a similar TLF rate (HR 1.40, 95% CI 0.83–2.37, P=0.209) compared to the 1-stent group. Compared with 1-stent, the 2-stent technique was more frequently associated with less TLF in the presence of main vessel (p_interaction=0.008) and side branch calcification (p_interaction=0.010).

Conclusions: The 2-stent strategy should be considered to reduce hard clinical endpoints in complex bifurcation lesions, particularly those with calcifications.

Background: The Academic Research Consortium for High Bleeding Risk (ARC-HBR) defined a consensus clinical criterion for patients at HBR undergoing percutaneous coronary intervention (PCI). This study aimed to validate and compare the ARC-HBR criteria and the contemporary risk score for long-term bleeding outcomes using a cohort of patients undergoing PCI.

Methods and Results: This study analyzed 3,410 patients who underwent PCI between 2010 and 2013. The endpoint was defined as incidence of The Bleeding Academic Research Consortium 3 or 5 bleeding events. In addition to ARC-HBR, this study validated the predictability of the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score, Patterns of non-adherence to Anti-platelet Regimens In Stented patients (PARIS) bleeding score, and Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) bleeding scores for bleeding events. There was a trend toward an increase in bleeding events, as the risk score increased for all bleeding risk scores used in this study. The ARC-HBR criteria had higher diagnostic sensitivity for bleeding events than other bleeding risk scores.

Conclusions: Patients with a higher number of risk factors in each of the four bleeding risk scores had a higher risk of long-term bleeding events. In comparison to other contemporary risk scores, the ARC-HBR criteria were more sensitive in the identification of patients with bleeding events in the long-term.

Background: Patients with acute myocardial infarction (AMI) caused by calcified nodules (CN) have worse clinical outcomes following primary percutaneous coronary intervention (PCI). This study investigated the late vascular response after everolimus-eluting stent (EES) implantation assessed by optical coherence tomography (OCT) in patients with AMI caused by CN, by comparing with plaque rupture (PR) and plaque erosion (PE).

Methods and Results: Based on the OCT findings in AMI culprit lesions before PCI, a total of 141 patients were categorized into 3 groups (PR, PE, or CN), and the OCT findings immediately and 10 months after PCI were compared. The frequency of PR, PE, and CN was 85 (60%), 45 (32%), and 11 patients (8%), respectively. In the 10-month follow-up OCT, the frequency of lesions with uncovered struts and lesions with malapposed struts were highest in the CN group, followed by the PR and PE groups (82% vs. 52% vs. 40%, P=0.042 and 73% vs. 26% vs. 16%, P<0.001, respectively). The incidence of intra-stent thrombus, re-appearance of CN within the stent, and target lesion revascularization were higher in the CN group compared with the PR and PE groups (36% vs. 9% vs. 7%, P=0.028; 27% vs. 0% vs. 0%, P<0.001; and 18% vs. 2% vs. 2%, P=0.024, respectively).

Conclusions: Late arterial healing response at 10 months after EES implantation in the CN was worse compared with PR and PE in patients with AMI.

Background: A polymer-free biolimus A9-coated stent (PF-BCS) may achieve better arterial healing than a durable polymer drug-eluting stent owing to its polymer-free feature.

Methods and Results: This multicenter, prospective, observational study enrolled 105 patients (132 lesions) who underwent PF-BCS (51 patients, 71 lesions) or durable polymer everolimus-eluting stent (DP-EES, 54 patients, 61 lesions) implantation. Serial coronary angioscopy (CAS) and optical coherence tomography (OCT) examinations were performed at 1 and 12 months, and the serial vessel responses were compared between PF-BCS and DP-EES. The primary outcome measure was the incidence of subclinical intrastent thrombus on CAS. The secondary outcome measures were: adequate strut coverage (≥40 μm) on OCT and maximum yellow color grade on CAS. The incidence of thrombus was high at 1 month (100% vs. 93%, P=0.091), but decreased at 12 months (18% vs. 25%, P=0.56), without a significant difference between PF-BCS and DP-EES. The adequate strut coverage rate was significantly higher (84±14% vs. 69±22%, P<0.001) and yellow color was significantly less intense (P=0.012) at 12 months in PF-BCS than in DP-EES; however, they were not significantly different at 1 month (adequate strut coverage: 47±21% vs. 50±17%, P=0.40; yellow color: P=0.99).

Conclusions: Although the thrombogenicity of PF-BCS was similar to that of DP-EES, the adequate coverage and plaque stabilization rates of PF-BCS were superior to those of DP-EES at 12 months.

Background: The diagnostic accuracy of stress myocardial perfusion single-photon emission computed tomography (SPECT) to detect coronary artery disease (CAD) is reduced by the balanced reduction of myocardial perfusion in patients with multi-vessel or left main trunk CAD (multi-vessel group). This study investigated the diagnostic performance of a simultaneous acquisition rest ^{99 m}Tc/stress ²⁰¹Tl dual-isotope protocol for myocardial perfusion SPECT (MPS) in a multi-vessel group by examining the assessment of a slow ²⁰¹Tl washout rate (WR) finding in comparison to the accuracy of perfusion assessments.

Methods and Results: This study enrolled 91 patients who had undergone angiography within 3 months after MPS. The diagnostic performances of perfusion assessments and a slow ²⁰¹Tl WR parameter were compared using the area under the curve (AUC) in a multi-vessel group of patients with mild ischemia (2≤summed difference score [SDS]≤7). The AUC of a slow WR parameter was significantly larger compared with that for perfusion assessments, in patients with mild ischemia, (AUC, 0.736 vs. 0.504–0.558, P value: <0.01–0.05).

Conclusions: Among patients with mild ischemia, a slow ²⁰¹Tl WR parameter improved the detection of CAD in a multi-vessel group.

Background: It is unknown whether beneficial effects of higher-dose statins on cardiovascular events are different according to the thrombotic risk in patients with chronic coronary syndrome (CCS).

Methods and Results: The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study is a randomized trial comparing 4 mg and 1 mg pitavastatin in patients with CCS. This study categorized 12,413 patients into 3 strata according to the CREDO-Kyoto thrombotic risk score: low-risk (N=9,434; 4 mg: N=4,742, and 1 mg: N=4,692), intermediate-risk (N=2,415; 4 mg: N=1,188, and 1 mg: N=1,227); and high-risk (N=564; 4 mg: N=269, and 1 mg: N=295). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. Cumulative 4-year incidence of the primary endpoint was significantly higher in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001). In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the 4 mg than in the 1 mg group (4.0% and 4.9%, P=0.02), whereas in the intermediate- and high-risk strata, it was numerically lower in the 4 mg than in the 1 mg group. There was no significant treatment-by-subgroup interaction for the primary endpoint (P-interaction=0.77).

Conclusions: High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events irrespective of the thrombotic risk in patients with CCS.

Background: After the publication of the Japanese Circulation Society guideline of sleep-disordered breathing (SDB) in 2010, with new evidence and changes to the health insurance system, trends in the practice pattern for SDB in patients with cardiovascular disease (CVD) might have changed.

Methods and Results: This study evaluated the temporal changes in the practice pattern for SDB by using a nationwide claim database, the Japanese Registry of All Cardiac and Vascular Diseases – Diagnosis Procedure Combination (JROAD-DPC), from 2012 to 2019. The main findings were: (1) the number of CVD patients diagnosed with SDB increased (especially those with atrial fibrillation [AF] and heart failure [HF]); (2) the number of diagnostic tests for SDB performed during hospitalization increased for AF patients (from 1.3% in 2012 to 1.8% in 2019), whereas it decreased for other CVD patients; (3) the number of patients diagnosed with SDB increased in each type of CVD, except for patients with acute myocardial infarction (AMI); (4) continuous positive airway pressure (CPAP) treatment increased for AF patients (from 15.2% to 17.5%); (5) CPAP treatment decreased for patients with angina pectoris (AP) and AMI, and any treatment decreased for HF patients (from 46.1% to 39.7%); and (6) SDB was treated more often in HF patients than in AF, AP, and AMI patients (41.7% vs. 17.2%, 19.1% and 20.4%, respectively).

Conclusions: The practice pattern for SDB in CVD patients has changed from 2012 to 2019.

Background: The disease burden of ischemic heart disease (IHD) continues to increase. This study aimed to assess the age, period, and cohort effects on the long-term trends of IHD incidence and mortality in China from 1990 to 2019.

Methods and Results: The data were obtained from the Global Burden of Disease Study (GBD) 2019, and the age-standardized incidence/mortality rate (ASIR/ASMR) was calculated. The age-period-cohort (APC) model, which is a generalized linear model revealing the correlation of disease rate and attained age, period, and cohort, was applied to estimate the net drift (estimated annual percentage change [EAPC]s), the local drifts (age-specific EAPCs), the age, period, and cohort effects. The analyses elucidated that the ASIR and ASMR of IHD declined after 2013. The net drift of incidence was 0.212% in females, and the net drift of mortality was 0.371% in males. The local drifts of mortality were above 0 in males aged 20–84 years and in females aged 65–84 years. The age effects showed elevated trends during the study period. The period effects declined after 2013. The cohort effects of mortality in males were higher than that in females.

Conclusions: The decrease of ASIR and ASMR indicated that measures to prevent IHD have been effective in China. However, the cardiovascular health of the elderly and males should be considered in future policy decisions.

Background: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.

Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE.

Conclusions: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.

Background: Previous studies have reported that high-dose strong statin therapy reduces the incidence of contrast-induced nephropathy (CIN) in statin naïve patients; however, the efficacy of high-dose strong statins for preventing CIN in real-world clinical practice remains unclear. The aim of this study was to evaluate the efficacy of strong statin therapy in addition to fluid hydration for preventing CIN after cardiovascular catheterization.

Methods and Results: This prospective, multicenter, randomized controlled trial included 420 patients with chronic kidney disease who underwent cardiovascular catheterization. They were assigned to receive high-dose pitavastatin (4 mg/day × 4 days) on the day before and of the procedure and 2 days after the procedure (Statin group, n=213) or no pitavastatin (Control group, n=207). Isotonic saline hydration combined with a single bolus of sodium bicarbonate (20 mEq) was scheduled for administration to all patients. In the control group, statin therapy was continued at the same dose as that before randomization. CIN was defined as a ≥0.5 mg/dL increase in serum creatinine or ≥25% above baseline at 48 h after contrast exposure. Before randomization, 83% of study participants were receiving statin treatment. The statin group had a higher incidence of CIN than the control group (3.0% vs. 0%, P=0.01). The 12-month rate of major adverse cardiovascular events was similar between the 2 groups.

Conclusions: High-dose pitavastatin increases the incidence of CIN in this study population.

Background: This study aimed to establish a clinically useful nomogram to evaluate the probability of hypertension onset in the Chinese population.

Methods and Results: A prospective cohort study was conducted in 2012–2013 and followed up in 2015 to identify new-onset hypertension in 4,123 participants. The dataset was divided into development (n=2,748) and verification (n=1,375) cohorts. After screening risk factors by lasso regression, a multivariate Cox regression risk model and nomogram were established. Among the 4,123 participants, 818 (19.8%) developed hypertension. The model identified 10 risk factors: age, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, high pulse rate, history of diabetes, family history of hypertension and stroke, intake frequency of bean products, and intensity of physical labor. The C-indices of the model in the development and validation cohorts were 0.744 and 0.768, respectively. After the inclusion of serum calcium and magnesium concentrations, the C-indices in the development and validation cohorts were 0.764 and 0.791, respectively, with areas under the curve for the updated model of 0.907 and 0.917, respectively. The calibration curve showed that the nomogram accurately predicted the probability of hypertension. The updated nomogram was clinically beneficial across thresholds of 10–60%.

Conclusions: The newly developed nomogram has good predictive ability and may effectively assess hypertension risk in high-risk rural areas in China.