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Background: The left internal mammary artery (LIMA) is protected from developing atherosclerosis. Perivascular inflammation, which is closely associated with atherosclerosis, can be measured by perivascular adipose tissue attenuation on computed tomography angiography. Whether the absence of atherosclerosis in LIMA is related to the lower level of perivascular inflammation is unknown. This study was performed to compare the level of perivascular inflammation between LIMA in situ and native coronary arteries in patients with coronary artery disease., Methods and Results: A total of 573 patients who underwent both computed tomography angiography and optical coherence tomography imaging were included. The level of perivascular adipose tissue attenuation between LIMA in situ and coronary arteries was compared. Perivascular adipose tissue attenuation around LIMA in situ was significantly lower around the 3 coronary arteries (-82.9 [-87.3 to -78.0] versus -70.8 [-75.9 to -65.9]; P <0.001), irrespective of the level of pericoronary inflammation or the number of vulnerable features on optical coherence tomography. When patients were divided into high and low pericoronary inflammation groups, those in the high inflammation group had more target vessel failure (hazard ratio, 2.97 [95% CI, 1.16-7.59]; P =0.017)., Conclusions: The current study demonstrated that perivascular adipose tissue attenuation was significantly lower around LIMA in situ than around native coronary arteries. The lower level of perivascular inflammation may be related to the low prevalence of atherosclerosis in LIMA., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04523194.

Background: It was recently reported that thin-cap fibroatheroma (TCFA) detected by optical coherence tomography was an independent predictor of future cardiac events in patients with diabetes. However, the clinical usefulness of this finding is limited by the invasive nature of optical coherence tomography. Computed tomography angiography (CTA) characteristics of TCFA have not been systematically studied. The aim of this study was to investigate CTA characteristics of TCFA in patients with diabetes., Methods and Results: Patients with diabetes who underwent preintervention CTA and optical coherence tomography were included. Qualitative and quantitative analyses were performed for plaques on CTA. TCFA was assessed by optical coherence tomography. Among 366 plaques in 145 patients with diabetes, 111 plaques had TCFA. The prevalence of positive remodeling (74.8% versus 50.6%, P <0.001), low attenuation plaque (63.1% versus 33.7%, P <0.001), napkin-ring sign (32.4% versus 11.0%, P <0.001), and spotty calcification (55.0% versus 34.9%, P <0.001) was significantly higher in TCFA than in non-TCFA. Low-density noncalcified plaque volume (25.4 versus 15.7 mm 3 , P <0.001) and remodeling index (1.30 versus 1.20, P =0.002) were higher in TCFA than in non-TCFA. The presence of napkin-ring sign, spotty calcification, high low-density noncalcified plaque volume, and high remodeling index were independent predictors of TCFA. When all 4 predictors were present, the probability of TCFA increased to 82.4%., Conclusions: The combined qualitative and quantitative plaque analysis of CTA may be helpful in identifying TCFA in patients with diabetes., Registration Information: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194.

Background: Recent studies have indicated high rates of future major adverse cardiovascular events in patients with Takotsubo cardiomyopathy (TC), but there is no well-established tool for risk stratification. This study sought to evaluate the prognostic value of several artificial intelligence-augmented ECG (AI-ECG) algorithms in patients with TC., Methods and Results: This study examined consecutive patients in the prospective and observational Mayo Clinic Takotsubo syndrome registry. Several previously validated AI-ECG algorithms were used for the estimation of ECG- age, probability of low ejection fraction, and probability of atrial fibrillation. Multivariable models were constructed to evaluate the association of AI-ECG and other clinical characteristics with major adverse cardiac events, defined as cardiovascular death, recurrence of TC, nonfatal myocardial infarction, hospitalization for congestive heart failure, and stroke. In the final analysis, 305 patients with TC were studied over a median follow-up of 4.8 years. Patients with future major adverse cardiac events were more likely to be older, have a history of hypertension, congestive heart failure, worse renal function, as well as high-risk AI-ECG findings compared with those without. Multivariable Cox proportional hazards analysis indicated that the presence of 2 or 3 high-risk findings detected by AI-ECG remained a significant predictor of major adverse cardiac events in patients with TC after adjustment by conventional risk factors (hazard ratio, 4.419 [95% CI, 1.833-10.66], P =0.001)., Conclusions: The combined use of AI-ECG algorithms derived from a single 12-lead ECG might detect subtle underlying patterns associated with worse outcomes in patients with TC. This approach might be beneficial for stratifying high-risk patients with TC.

Background: Protruding aortic plaque is known to be associated with an increased risk for future cardiac and cerebrovascular events. However, the relationship between protruding aortic plaque and coronary plaque characteristics has not been systematically investigated., Methods and Results: A total of 615 patients who underwent computed tomography angiography, and preintervention optical coherence tomography imaging were included. Coronary plaque characteristics were compared to evaluate coronary plaque vulnerability in patients with protruding aortic plaque on computed tomography angiography. 615 patients, the 186 (30.2%) patients with protruding aortic plaque were older and had more comorbidities such as hypertension, chronic kidney disease, and a prior myocardial infarction than those without. They also had a higher prevalence of coronary plaques with vulnerable features such as thin-cap fibroatheroma (85 [45.7%] versus 120 [28.0%], P <0.001), lipid-rich plaque (165 [88.7%] versus 346 [80.7%], P =0.014), macrophages (147 [79.0%] versus 294 [68.5%], P =0.008), layered plaque (117 [62.9%] versus 213 [49.7%], P =0.002), and plaque rupture (96 [51.6%] versus 111 [25.9%], P <0.001). Patients with protruding aortic plaque experienced more major adverse cardiac and cerebrovascular events, including all-cause mortality, nonfatal acute coronary syndromes, and stroke (27 [14.7%] versus 21 [4.9%], P <0.001; 8 [4.3%] versus 1 [0.2%], P <0.001; 5 [2.7%] versus 3 [0.7%], P =0.030; and 5 [2.7%] versus 2 [0.5%], P =0.013, respectively)., Conclusions: The current study demonstrates that patients with protruding aortic plaque have more features of coronary plaque vulnerability and are at increased risk of future adverse events.

Background: High cardiovascular mortality has been reported in young patients with diabetes. However, the underlying pathology in different age groups of patients with diabetes has not been studied., Methods and Results: The aim of this study was to investigate the plaque characteristics and underlying pathology of acute coronary syndrome in different age groups of patients with or without diabetes in a large cohort. Patients who presented with acute coronary syndrome and underwent preintervention optical coherence tomography imaging were included. Culprit plaque was classified as plaque rupture, plaque erosion, or calcified plaque and stratified into 5 age groups. Plaque characteristics including features of vulnerability were examined by optical coherence tomography. Among 1394 patients, 482 (34.6%) had diabetes. Patients with diabetes, compared with patients without diabetes, had a higher prevalence of lipid-rich plaque (71.2% versus 64.8%, P =0.016), macrophage (72.0% versus 62.6%, P <0.001), and cholesterol crystal (27.6% versus 19.7%, P <0.001). Both diabetes and nondiabetes groups showed a decreasing trend in plaque erosion with age (patients with diabetes, P =0.020; patients without diabetes, P <0.001). Patients without diabetes showed an increasing trend with age in plaque rupture ( P =0.004) and lipid-rich plaque ( P =0.018), whereas patients with diabetes had a high prevalence of these vulnerable features at an early age that remained high across age groups., Conclusions: Patients without diabetes showed an increasing trend with age in plaque rupture and lipid-rich plaque, whereas patients with diabetes had a high prevalence of these vulnerable features at an early age. These results suggest that atherosclerotic vascular changes with increased vulnerability start at a younger age in patients with diabetes., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT04523194, NCT03479723. URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000041692.

Background The prognostic impact of optical coherence tomography-diagnosed culprit lesion morphology in acute coronary syndrome (ACS) has not been systematically examined in real-world settings. Methods and Results This investigator-initiated, prospective, multicenter, observational study was conducted at 22 Japanese hospitals to identify the prevalence of underlying ACS causes (plaque rupture [PR], plaque erosion [PE], and calcified nodules [CN]) and their impact on clinical outcomes. Patients with ACS diagnosed within 24 hours of symptom onset undergoing emergency percutaneous coronary intervention were enrolled. Optical coherence tomography-guided percutaneous coronary intervention recipients were assessed for underlying ACS causes and followed up for major adverse cardiac events (cardiovascular death, myocardial infarction, heart failure, or ischemia-driven revascularization) at 1 year. Of 1702 patients with ACS, 702 (40.7%) underwent optical coherence tomography-guided percutaneous coronary intervention for analysis. PR, PE, and CN prevalence was 59.1%, 25.6%, and 4.0%, respectively. One-year major adverse cardiac events occurred most frequently in patients with CN (32.1%), followed by PR (12.4%) and PE (6.2%) (log-rank P <0.0001), primarily driven by increased cardiovascular death (CN, 25.0%; PR, 0.7%; PE, 1.1%; log-rank P <0.0001) and heart failure trend (CN, 7.1%; PR, 6.8%; PE, 2.2%; log-rank P <0.075). On multivariate Cox regression analysis, the underlying ACS cause was associated with 1-year major adverse cardiac events (CN [hazard ratio (HR), 4.49 [95% CI, 1.35-14.89], P =0.014]; PR (HR, 2.18 [95% CI, 1.05-4.53], P =0.036]; PE as reference). Conclusions Despite being the least common, CN was a clinically significant underlying ACS cause, associated with the highest future major adverse cardiac events risk, followed by PR and PE. Future studies should evaluate the possibility of ACS underlying cause-based optical coherence tomography-guided optimization.

Background Cardiac death or myocardial infarction still occurs in patients undergoing contemporary percutaneous coronary intervention (PCI). We aimed to identify adverse clinical and vessel characteristics related to hard outcomes after PCI and to investigate their individual and combined prognostic implications. Methods and Results From an individual patient data meta-analysis of 17 cohorts of patients who underwent post-PCI fractional flow reserve measurement after drug-eluting stent implantation, 2081 patients with available clinical and vessel characteristics were analyzed. The primary outcome was cardiac death or target-vessel myocardial infarction at 2 years. The mean age of patients was 64.2±10.2 years, and the mean angiographic percent diameter stenosis was 63.9%±14.3%. Among 11 clinical and 8 vessel features, 4 adverse clinical characteristics (age ≥65 years, diabetes, chronic kidney disease, and left ventricular ejection fraction <50%) and 2 adverse vessel characteristics (post-PCI fractional flow reserve ≤0.80 and total stent length ≥54 mm) were identified to independently predict the primary outcome (all P <0.05). The number of adverse vessel characteristics had additive predictability for the primary end point to that of adverse clinical characteristics (area under the curve 0.72 versus 0.78; P =0.03) and vice versa (area under the curve 0.68 versus 0.78; P =0.03). The cumulative event rate increased in the order of none, either, and both of adverse clinical characteristics ≥2 and adverse vessel characteristics ≥1 (0.3%, 2.4%, and 5.3%; P for trend <0.01). Conclusions In patients undergoing drug-eluting stent implantation, adverse clinical and vessel characteristics were associated with the risk of cardiac death or target-vessel myocardial infarction. Because these characteristics showed independent and additive prognostic value, their integrative assessment can optimize post-PCI risk stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04684043. www.crd.york.ac.uk/prospero/. Unique Identifier: CRD42021234748.

Background This study assessed risk factors for mitral regurgitation (MR) recurrence or functional mitral stenosis during long-term follow-up in patients undergoing mitral valve repair for isolated posterior mitral leaflet prolapse. Methods and Results We assessed a consecutive series of 511 patients who underwent primary mitral valve repair for isolated posterior leaflet prolapse between 2001 and 2021. Annuloplasty using a partial band was selected in 86.3%. The leaflet resection technique was used in 83.0%, whereas the chordal replacement without resection was used in 14.5%. Risk factors were analyzed for MR recurrence ≥grade 2 or functional mitral stenosis with mean transmitral pressure gradient ≥5 mm Hg using a multivariable Fine-Gray regression model. The 1-, 5-, and 10-year cumulative incidence of MR ≥grade 2 was 7.8%, 22.7%, and 30.1%, respectively, whereas that of mean transmitral pressure gradient ≥5 mm Hg was 8.1%, 20.6%, and 29.3%, respectively. Risk factors for MR ≥grade 2 included chordal replacement without resection (hazard ratio [HR], 2.50, P <0.001) and larger prosthesis size (HR, 1.13, P =0.023), whereas factors for functional mitral stenosis were use of a full ring (partial band versus full ring, HR, 0.53, P =0.013), smaller prosthesis size (HR, 0.74, P <0.001), and larger body surface area (HR, 3.03, P =0.045). Both MR ≥grade 2 and mean transmitral pressure gradient ≥5 mm Hg at 1 year post surgery were significantly associated with the long-term incidence of reoperation. Conclusions Leaflet resection with a large partial band may be an optimal strategy for isolated posterior mitral valve prolapse.

Background A previous coronary computed tomography (CT) angiographic study failed to discriminate optical coherence tomography-defined intact fibrous cap culprit lesions (IFC group) from those with ruptured fibrous caps (RFC group) in patients with coronary artery disease. This study aimed to evaluate the diagnostic efficacy of preprocedural coronary CT imaging in identifying subsequently performed optical coherence tomography-defined plaque rupture or erosion at culprit lesions in patients with non-ST-segment-elevation acute myocardial infarction. Methods and Results This study used data from 2 recently published studies that tested the hypothesis that coronary CT angiography (CCTA) before percutaneous coronary intervention may provide diagnostic information on the high-risk atherosclerotic burden in patients with non-ST-segment-elevation acute myocardial infarction. In the analysis of 186 patients, optical coherence tomography identified 106 RFC plaques and 80 IFC plaques as the culprit lesions. On CT, the prevalence of low-attenuation plaque, positive remodeling, napkin-ring sign, and spotty calcification were all significantly lower in the IFC group. The culprit vessel pericoronary adipose tissue inflammation and coronary artery calcium scores were significantly lower in the IFC group than in the RFC group. The absence of low-attenuation plaque, napkin-ring sign, zero coronary artery calcium, and low pericoronary adipose tissue inflammation were independent predictors of IFC. When stratified into 5 subgroups according to the number of these 4 CT factors, the prevalence of IFC was 8.3%, 20.8%, 44.6%, 75.6%, and 100% ( P <0.001), respectively. Conclusions Preprocedural comprehensive coronary CT imaging, including coronary artery calcium and pericoronary adipose tissue inflammation assessment, can accurately and noninvasively identify optical coherence tomography-defined IFC or RFC culprit lesions.

Background Mechanisms underlying bioprosthetic valve deterioration are multifactorial and incompletely elucidated. Reparative circulating progenitor cells, and conversely calcification-associated osteocalcin expressing circulating progenitor cells, have been linked to native aortic valve deterioration. However, their role in bioprosthetic valve deterioration remains elusive. This study sought to evaluate the contribution of different subpopulations of circulating progenitor cells in bioprosthetic valve deterioration. Methods and Results This single-center prospective study enrolled 121 patients who had peripheral blood mononuclear cells isolated before bioprosthetic aortic valve replacement and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh peripheral blood mononuclear cells were analyzed for the surface markers CD34, CD133, and osteocalcin. Bioprosthetic valve deterioration was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30 mm Hg or at least moderate intraprosthetic regurgitation. Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of osteocalcin-positive cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] versus 270 [130, 420], P =0.002; osteocalcin-positive cells: 3060 [523, 5528] versus 670 [180, 1930], P =0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD (hazard ratio, 0.995 [95% CI, 0.990%-0.999%]). Conclusions Circulating levels of CD34 + CD133 + cells and osteocalcin-positive cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. Circulating progenitor cells might play a vital role in the mechanism, risk stratification, and a potential therapeutic target for patients with bioprosthetic valve deterioration.

Background Intracoronary physiologic indexes such as coronary flow reserve (CFR) and left ventricular ejection fraction (LVEF) have been regarded as prognostic indicators in patients with coronary artery disease. The current study evaluated the association between intracoronary physiologic indexes and LVEF and their differential prognostic implications in patients with coronary artery disease. Methods and Results A total of 1889 patients with 2492 vessels with available CFR and LVEF were selected from an international multicenter prospective registry. Baseline physiologic indexes were measured by thermodilution or Doppler methods and LVEF was recorded at the index procedure. The primary outcome was target vessel failure, which was a composite of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization over 5 years of follow-up. Patients with reduced LVEF <50% (162 patients [8.6%], 202 vessels [8.1%]) showed a similar degree of epicardial coronary artery disease but lower CFR values than those with preserved LVEF (2.4±1.2 versus 2.7±1.2, P <0.001), mainly driven by the increased resting coronary flow. Conversely, hyperemic coronary flow, fractional flow reserve, and the degree of microvascular dysfunction were similar between the 2 groups. Reduced CFR (≤2.0) was seen in 613 patients (32.5%) with 771 vessels (30.9%). Reduced CFR was an independent predictor for target vessel failure (hazard ratio, 2.081 [95% CI, 1.385-3.126], P <0.001), regardless of LVEF. Conclusions CFR was lower in patients with reduced LVEF because of increased resting coronary flow. Patients with reduced CFR showed a significantly higher risk of target vessel failure than did those with preserved CFR, regardless of LVEF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Background In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests (NIT) in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA). The differential prognosis of INOCA according to the presence of coronary microvascular dysfunction (CMD) and incremental prognostic value of CMD with intracoronary physiologic assessment on top of NIT information remains unknown. Methods and Results From the international multicenter registry of intracoronary physiologic assessment (ILIAS [Inclusive Invasive Physiological Assessment in Angina Syndromes] registry, N=2322), stable patients with NIT and nonobstructive coronary stenoses with fractional flow reserve >0.80 were selected. INOCA was diagnosed when patients showed positive NIT results. CMD was defined as coronary flow reserve ≤2.5. According to the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA nor CMD, n=116); group 2 (only CMD, n=90); group 3 (only INOCA, n=41); and group 4 (both INOCA and CMD, n=40). The primary outcome was major adverse cardiovascular events, a composite of all-cause death, target vessel myocardial infarction, or clinically driven target vessel revascularization at 5 years. Among 287 patients with nonobstructive coronary stenoses (fractional flow reserve=0.91±0.06), 81 patients (38.2%) were diagnosed with INOCA based on positive NIT. By intracoronary physiologic assessment, 130 patients (45.3%) had CMD. Regardless of the presence of INOCA, patients with CMD showed a significantly lower coronary flow reserve and higher hyperemic microvascular resistance compared with patients without CMD ( P <0.001 for all). The cumulative incidence of major adverse cardiovascular events at 5 years were 7.4%, 21.3%, 7.7%, and 34.4% in groups 1 to 4. By documenting CMD (groups 2 and 4), intracoronary physiologic assessment identified patients at a significantly higher risk of major adverse cardiovascular events at 5 years compared with group 1 (group 2: adjusted hazard ratio [HR adjusted ], 2.88; 95% CI, 1.52-7.19; P =0.024; group 4: HR adjusted , 4.00; 95% CI, 1.41-11.35; P =0.009). Conclusions In stable patients with nonobstructive coronary stenoses, a diagnosis of INOCA based only on abnormal NIT did not identify patients with higher risk of long-term cardiovascular events. Incorporating intracoronary physiologic assessment to NIT information in patients with nonobstructive disease allowed identification of patient subgroups with up to 4-fold difference in long-term cardiovascular events. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04485234.

Background This study aimed to evaluate the prognostic value of hyperemic coronary sinus flow (h-CSF) and global coronary flow reserve (g-CFR) obtained by phase-contrast cine-magnetic resonance imaging in patients with acute myocardial infarction (MI). Methods and Results This retrospective study analyzed patients with acute MI (n=523) who underwent primary (ST-segment-elevation MI) or urgent (non-ST-segment-elevation MI) percutaneous coronary intervention. Absolute coronary sinus blood flow (CSF) at rest and during vasodilator stress hyperemia was quantified at 30 days (24-36 days) after the index infarct-related lesion percutaneous coronary intervention and revascularization of functionally significant non-infarct-related lesions. We used Cox proportional hazards regression modeling to examine the association between h-CSF, g-CFR, and major adverse cardiac events defined as all-cause death, nonfatal MI, hospitalization for congestive heart failure, and stroke. Finally, 325 patients with ST-segment-elevation MI (62.1%) and 198 patients with non-ST-segment-elevation MI (37.9%) were studied over a median follow-up of 2.5 years. The rest CSF, h-CSF, and g-CFR were 0.94 (0.68-1.26) mL/min per g, 2.05 (1.42-2.73) mL/min per g, and 2.17 (1.54-3.03), respectively. Major adverse cardiac events occurred in 62 patients, and Cox proportional hazards analysis showed that h-CSF and g-CFR were independent predictors of major adverse cardiac events (h-CSF: hazard ratio [HR], 0.64; 95% CI, 0.47-0.88; P =0.005; g-CFR: HR, 0.62; 95% CI, 0.47-0.82; P =0.001). When stratified by h-CSF and g-CFR, cardiac event-free survival was the worst in patients with concordantly impaired h-CSF (<1.6 mL/min per g) and g-CFR (<1.7) ( P <0.001). Conclusions Global coronary sinus flow quantification using phase-contrast cine-magnetic resonance imaging provided significant prognostic information independent of infarction size and conventional risk factors in patients with acute MI undergoing revascularization.

Background A recent study reported that the outcome of patients with plaque erosion treated with stenting is poor when the underlying plaque is lipid rich. However, the detailed phenotype of patients with plaque erosion, particularly as related to different age groups, has not been systematically studied. Methods and Results Patients with acute coronary syndromes caused by plaque erosion were selected from 2 data sets. Demographic, clinical, angiographic, and optical coherence tomography findings of the culprit lesion were compared between 5 age groups. Among 579 erosion patients, male sex and current smoking were less frequent, and hypertension, diabetes, and chronic kidney disease were more frequent in older patients. ST-segment-elevation myocardial infarction was more frequent in younger patients. Percentage of diameter stenosis on angiogram was greater in older patients. The prevalence of lipid-rich plaque (27.3% in age <45 years and 49.4% in age ≥75 years, P <0.001), cholesterol crystal (3.9% in age <45 years and 21.8% in age ≥75 years, P =0.027), and calcification (5.5% in age <45 years and 54.0% in age ≥75 years, P <0.001) increased with age. After adjusting risk factors, younger patients were associated with the presence of thrombus, and older patients were associated with greater percentage of diameter stenosis and the presence of lipid-rich plaque and calcification. Conclusions The demographic, clinical, angiographic, and plaque phenotypes of patients with plaque erosion distinctly vary depending on age. This may affect the clinical outcome in these patients. Registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03479723, NCT02041650.

Background In tandem stenoses, nonhyperemic pressure ratio pullback is the preferred method to fractional flow reserve (FFR), based on the assumption of stable resting coronary flow. This study aimed to evaluate temporal changes of coronary circulatory indexes in tandem stenoses before and after angioplasty for proximal stenosis. Methods and Results Coronary tandem stenoses were created by porcine restenosis model with 2 bare metal stents in the left anterior descending artery. Four weeks later, changes in distal coronary pressure (Pd), averaged peak velocity, microvascular resistance, transstenotic pressure gradient across distal stenosis, resting Pd/aortic pressure, and FFR were measured before and 1, 5, 10, 15, and 20 minutes after balloon angioplasty for proximal stenosis. After angioplasty, there were significant changes in both resting and hyperemic Pd, averaged peak velocity, microvascular resistance, and transstenotic pressure gradient across distal stenosis (all P values <0.01). After initial acute changes, hyperemic averaged peak velocity and microvascular resistance did not show significant difference from the baseline values ( P =0.712 and 0.972, respectively). Conversely, resting averaged peak velocity remained increased (10.1±0.7 to 17.8±0.7; P <0.001) and resting microvascular resistance decreased (6.0±0.1 to 2.2±0.7; P <0.001). Transstenotic pressure gradient across distal stenosis was significantly increased in both resting (13.1±7.6 to 25.3±4.2; P =0.040) and hyperemic conditions (11.0±3.0 to 27.4±3.3 mm Hg; P <0.001). Actual post-percutaneous coronary intervention Pd/aortic pressure and FFR were significantly lower than predicted values (Pd/aortic pressure, 0.68±0.22 versus 0.85±0.14; P <0.001; FFR, 0.63±0.08 versus 0.81±0.08; P <0.001). Conclusions After angioplasty for proximal stenosis, transstenotic pressure gradient across distal stenosis showed similar changes between resting and hyperemic conditions. Both actual post-percutaneous coronary intervention resting Pd/aortic pressure and FFR were significantly lower than predicted values.

Background The role of coronary calcification in cardiovascular events and plaque stabilization is still being debated, and factors involved in the progression of coronary calcification are not fully understood. This study aimed to identify the predictors for rapid progression of coronary calcification. Methods and Results Patients with serial optical coherence tomography imaging at baseline and at 6 months were selected. Changes in the calcification index and predictors for progression of calcification were studied. Calcification index was defined as the product of the mean calcification arc and calcification length. Rapid progression of calcification was defined as an increase in the calcification index above the median value. Among 187 patients who had serial optical coherence tomography imaging, 235 calcified plaques were identified in 105 patients (56.1%) at baseline. After 6 months, the calcification index increased in 95.3% of calcified plaques from 132.0 to 178.2 ( P <0.001). In multivariable analysis, diabetes mellitus (odds ratio [OR], 3.911; P <0.001), chronic kidney disease (OR, 2.432; P =0.037), lipid-rich plaque (OR, 2.698; P =0.034), and macrophages (OR, 6.782; P <0.001) were found to be independent predictors for rapid progression of coronary calcification. Interestingly, rapid progression of calcification was associated with a significant reduction of inflammatory features (thin-cap fibroatheroma; from 21.2% to 11.9%, P =0.003; macrophages; from 74.6% to 61.0%, P =0.001). Conclusions Diabetes mellitus, chronic kidney disease, lipid-rich plaque, and macrophages were independent predictors for rapid progression of coronary calcification. Baseline vascular inflammation and subsequent stabilization may be related to rapid progression of calcification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01110538.

Background Impaired global coronary flow reserve (g-CFR) is related to worse outcomes. Inflammation has been postulated to play a role in atherosclerosis. This study aimed to evaluate the relationship between pre-procedural pericoronary adipose tissue inflammation and g-CFR after the urgent percutaneous coronary intervention in patients with first non-ST-segment-elevation acute coronary syndrome. Methods and Results Phase-contrast cine-magnetic resonance imaging was performed to obtain g-CFR by quantifying coronary sinus flow at 1 month after percutaneous coronary intervention in a total of 116 first non-ST-segment-elevation acute coronary syndrome patients who underwent pre-percutaneous coronary intervention computed tomography angiography. On proximal 40-mm segments of 3 major coronary vessels on computed tomography angiography, pericoronary adipose tissue attenuation was assessed by the crude analysis of mean computed tomography attenuation value. The patients were divided into 2 groups with and without impaired g-CFR divided by the g-CFR value of 1.8. There were significant differences in age, culprit lesion location, N-terminal pro-B-type natriuretic peptide levels, high-sensitivity C-reactive protein (hs-CRP) levels, mean pericoronary adipose tissue attenuation between patients with impaired g-CFR and those without (g-CFR, 1.47 [1.16, 1.68] versus 2.66 [2.22, 3.28]; P <0.001). Multivariable logistic regression analysis revealed that age (odds ratio [OR], 1.060; 95% CI, 1.012-1.111, P =0.015) and mean pericoronary adipose tissue attenuation (OR, 1.108; 95% CI, 1.026-1.197, P =0.009) were independent predictors of impaired g-CFR (g-CFR <1.8). Conclusions Mean pericoronary adipose tissue attenuation, a marker of perivascular inflammation, obtained by computed tomography angiography performed before urgent percutaneous coronary intervention, but not hs-CRP, a marker of systemic inflammation was significantly associated with g-CFR at 1-month after revascularization. Our results may suggest the pathophysiological mechanisms linking perivascular inflammation and g-CFR in patients with non-ST-segment-elevation acute coronary syndrome.

Background Recent studies have reported the association between pericoronary inflammation assessed by pericoronary adipose tissue attenuation (PCATA) on computed tomography angiography and worse outcomes in patients with coronary artery disease. We investigated the determinants predicting increased PCATA in patients with known or suspected coronary artery disease. Methods and Results A total of 540 patients who underwent computed tomography angiography and invasive coronary angiography were studied. Mean computed tomography attenuation values of PCAT (-190 to -30 Hounsfield units) (PCATA) were assessed at the proximal 40-mm segments of all 3 major coronary arteries by crude analysis. Univariable and multivariable analyses were performed to determine the predictors of increased PCATA surrounding the proximal right coronary artery. Mean right coronary artery-PCATA was -72.22±8.47 Hounsfield units and the average of 3-vessel PCATA was -70.24±6.60 Hounsfield units. Multivariable linear regression analysis revealed that the independent determinants of right coronary artery-PCATA were male (β coefficient=4.965, P <0.001), left ventricular mass index (β coefficient=0.040, P =0.025), and angiographically significant stenosis (diameter stenosis >50%) (β coefficient=2.418, P =0.008). Sex-related determinants were NT-proBNP level (N-terminal pro-B-type natriuretic peptide; β coefficient <0.001, P =0.026), Agatston score (β coefficient=-0.002, P =0.010), left ventricular mass index (β coefficient=0.041, P =0.028), and significant stenosis (β coefficient=4.006, P <0.001) in male patients and left ventricular ejection fraction (β coefficient=-0.217, P =0.010) and significant stenosis (β coefficient=3.835, P =0.023) in female patients. Conclusions Right coronary artery-PCATA was associated with multiple clinical characteristics, established risk factors, and the presence of significant stenosis. Our results suggest that clinically significant factors such as sex, left ventricular hypertrophy, ejection fraction, calcification, and epicardial stenosis should be taken into account in the assessment of pericoronary inflammation using computed tomography angiography.

Background Coronary flow capacity (CFC), which is a categorical assessment based on the combination of hyperemic coronary flow and coronary flow reserve (CFR), has been introduced as a comprehensive assessment of the coronary circulation to overcome the limitations of CFR alone. The aim of this study was to quantify coronary flow changes after percutaneous coronary intervention in relation to the classification of CFC and the current physiological cutoff values of fractional flow reserve, instantaneous wave-free ratio, and CFR. Methods and Results Using the combined data set from DEFINE FLOW (Distal Evaluation of Functional Performance With Intravascular Sensors to Assess the Narrowing Effect -Combined Pressure and Doppler FLOW Velocity Measurements) and IDEAL (Iberian-Dutch-English), a total of 133 vessels that underwent intracoronary Doppler flow measurement before and after percutaneous coronary intervention were analyzed. CFC classified prerevascularization lesions as normal (14), mildly reduced (40), moderately reduced (31), and severely reduced (48). Lesions with larger impairment of CFC showed greater increase in coronary flow and vice versa (median percent increase in coronary flow by revascularization: 4.2%, 25.9%, 50.1%, and 145.5%, respectively; P <0.001). Compared with the conventional cutoff values of fractional flow reserve, instantaneous wave-free ratio, and CFR, an ischemic CFC defined as moderately to severely reduced CFC showed higher diagnostic accuracy with higher specificity to predict a >50% increase in coronary flow after percutaneous coronary intervention. Receiver operating characteristic curve analysis demonstrated that only CFC has a superior predictive efficacy to CFR ( P <0.05). Multivariate analysis revealed lesions with ischemic CFC to be the independent predictor of a significant coronary flow increase after percutaneous coronary intervention (odds ratio, 10.7; 95% CI, 4.6-24.8; P <0.001). Conclusions CFC showed significant improvement of identification of lesions that benefit from revascularization compared with CFR with respect to coronary flow increase. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02328820.

Background Seasonal variations in acute coronary syndromes (ACS) have been reported, with incidence and mortality peaking in the winter. However, the underlying pathophysiology for these variations remain speculative. Methods and Results Patients with ACS who underwent optical coherence tomography were recruited from 6 countries. The prevalence of the 3 most common pathologies (plaque rupture, plaque erosion, and calcified plaque) were compared between the 4 seasons. In 1113 patients with ACS (885 male; mean age, 65.8±11.6 years), the rates of plaque rupture, plaque erosion, and calcified plaque were 50%, 39%, and 11% in spring; 44%, 43%, and 13% in summer; 49%, 39%, and 12% in autumn; and 57%, 30%, and 13% in winter ( P =0.039). After adjusting for age, sex, and other coronary risk factors, winter was significantly associated with increased risk of plaque rupture (odds ratio [OR], 1.652; 95% CI, 1.157-2.359; P =0.006) and decreased risk of plaque erosion (OR, 0.623; 95% CI, 0.429-0.905; P =0.013), compared with summer as a reference. Among patients with rupture, the prevalence of hypertension was significantly higher in winter ( P =0.010), whereas no significant difference was observed in the other 2 groups. Conclusions Seasonal variations in the incidence of ACS reflect differences in the underlying pathobiology. The proportion of plaque rupture is highest in winter, whereas that of plaque erosion is highest in summer. A different approach may be needed for the prevention and treatment of ACS depending on the season of its occurrence. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03479723.

Background Resistive reserve ratio is a thermodilution-based index which integrates both coronary flow and pressure. Resistive reserve ratio represents the vasodilatory capacity of interrogated vessels including both epicardial coronary artery and microvascular circulation. We evaluated the prognostic potential of resistive reserve ratio compared with pressure-derived index (fractional flow reserve [FFR]) or flow-derived index (coronary flow reserve [CFR]). Methods and Results A total of 1245 patients underwent coronary pressure and flow measurement using pressure-temperature wire. Resistive reserve ratio was calculated by CFR adjusted using the ratio between resting and hyperemic distal coronary pressure ([resting mean transit time/hyperemic mean transit time]×[resting distal coronary pressure/hyperemic distal coronary pressure]). Clinical outcome was assessed by patient-oriented composite outcome (POCO), a composite of any death, myocardial infarction, and revascularization at 5 years. At 5 years, the cumulative incidence of POCO was significantly different according to quartiles of resistive reserve ratio (9.9%, 11.3%, 17.2%, and 22.7% in quartiles 1 to 4, respectively, log rank P <0.001). Among patients with deferred revascularization, those with depressed resistive reserve ratio (<3.5) showed a significantly higher risk of POCO than those with preserved resistive reserve ratio (≥3.5) in patients with FFR>0.80 or patients with CFR>2.0. (FFR>0.80 group: 14.8% versus 6.0%; log rank P =0.001; CFR>2.0 group: 13.5% versus 7.1%; log rank P =0.045). Adding resistive reserve ratio into the model for 5-year POCO showed significantly higher global Chi square value than FFR or CFR ( P <0.001, respectively, for FFR and CFR). Resistive reserve ratio <3.5 was significantly associated with the risk of POCO at 5 years in multivariable model (adjusted hazard ratio 1.597, 95% CI, 1.098-2.271, P =0.014). Conclusions Resistive reserve ratio, which integrated both coronary flow and pressure, showed incremental prognostic implications in patients with coronary artery disease undergoing elective percutaneous coronary intervention guided by invasive physiologic evaluation. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03690713.

Background Sex difference in fractional flow reserve (FFR) and resting index has not been fully clarified. We sought to investigate the impact of sex on the discordance of revascularization decision making between FFR and diastolic pressure ratio during the diastolic wave-free period (dPR WFP ). Methods and Results A total of 759 angiographically intermediate lesions with 30% to 80% diameter stenosis by quantitative coronary angiography in 577 patients in whom FFR and dPR WFP were measured were investigated. dPR WFP was measured during the wave-free window of 5 heart cycles at an independent core laboratory. FFR ≤0.80 and dPR WFP ≤0.89 were considered positive studies. A total of 164 vessels in 126 women (21.6%) and 595 vessels in 451 men (78.4%) were included. In lesions with negative dPR WFP , positive FFR was less frequently observed in women (13 of 73; 17.8%) than in men (97 of 286; 33.9%) ( P =0.009). In lesions with positive dPR WFP , the frequency of negative FFR was observed in 22 of 91 vessels (24.2%) in women and 51 of 309 vessels (16.5%) in men, which did not reach statistical significance ( P =0.098). In multivariable analyses, female sex was independently associated with FFR-dPR WFP discordance both in negative dPR WFP cohort (odds ratio, 0.44; 95% CI, 0.21-0.98; P =0.036) and in positive dPR WFP cohort (odds ratio, 2.41; 95% CI, 1.17-4.96; P =0.017) after adjustment for age, weight, quantitative coronary angiography data, and baseline physiological indexes. Conclusions The frequency of FFR-dPR WFP discordance was significantly associated with sex, which may indicate potential shift of optimal threshold of either FFR or dPR WFP , or both of them, according to sex.

Background Sex-specific differences may influence prognosis after deferred revascularization following fractional flow reserve (FFR) measurement. This study sought to investigate the sex differences in long-term prognosis of patients with deferred revascularization following FFR assessment. Methods and Results A total of 879 patients (879 vessels) with deferred revascularization with FFR >0.75 who underwent FFR and coronary flow reserve measurements were enrolled from 3 countries (Korea, Japan, and Spain). Long-term outcomes were assessed in 649 men and 230 women by the patient-oriented composite outcome (POCO, a composite of any death, any myocardial infarction, and any revascularization). We applied inverse-probability weighting based on propensity scores to account for differences at baseline between women and men (age, hyperlipidemia, diabetes mellitus, diameter stenosis, lesion length, multivessel disease, FFR, coronary flow reserve. The median follow-up duration was 1855 days (745-1855 days). Median FFR values were 0.88 (0.83-0.93) in men and 0.89 (0.85-0.94) in women, respectively. The occurrences of POCO were significantly high in men compared with that in women (10.5% versus 4.2%, P =0.007). Kaplan-Meier analysis revealed that women had a significantly lower risk of POCO (χ 2 =7.2, P =0.007). Multivariate COX proportional hazards regression analysis revealed that age, male, diabetes mellitus, diameter stenosis, lesion length, and coronary flow reserve were independent predictors of POCO. After applying IPW, the hazard ratio of males for POCO was 2.07 (95% CI, 1.07-4.04, P =0.032). Conclusions This large multinational study reveals that long-term outcome differs between women and men in favor of women after FFR-guided revascularization deferral. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT02186093.

Background Plaque erosion is responsible for 25% to 40% of patients with acute coronary syndromes (ACS). Recent studies suggest that anti-thrombotic therapy without stenting may be an option for this subset of patients. Currently, however, an invasive procedure is required to make a diagnosis of plaque erosion. The aim of this study was to identify clinical or laboratory predictors of plaque erosion in patients with ACS to enable a diagnosis of erosion without additional invasive procedures. Methods and Results Patients with ACS who underwent optical coherence tomography imaging were selected from 11 institutions in 6 countries. The patients were classified into plaque rupture, plaque erosion, or calcified plaque, and predictors were identified using multivariable logistic modeling. Among 1241 patients with ACS, 477 (38.4%) patients were found to have plaque erosion. Plaque erosion was more frequent in non-ST-segment elevation-ACS than in ST-segment-elevation myocardial infarction (47.9% versus 29.8%, P =0.0002). Multivariable logistic regression models showed 5 independent parameters associated with plaque erosion: age <68 years, anterior ischemia, no diabetes mellitus, hemoglobin >15.0 g/dL, and normal renal function. When all 5 parameters are present in a patient with non-ST-segment elevation-ACS, the probability of plaque erosion increased to 73.1%. Conclusions Clinical and laboratory parameters associated with plaque erosion are explored in this retrospective registry study. These parameters may be useful to identify the subset of ACS patients with plaque erosion and guide them to conservative management without invasive procedures. The results of this exploratory analysis need to be confirmed in large scale prospective clinical studies. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03479723.

Background Although most coronary thromboses occur on the surface of lipid-rich plaque ( LRP ) with plaque rupture ( PR ), previous pathological and optical coherence tomography studies demonstrated diversity in the morphological characteristics of culprit plaque underlying the thrombus, including lesions with intact fibrous cap ( IFC ). We investigated the clinical significance of IFC in relation to the presence or absence of LRP observed via optical coherence tomography in culprit lesions of acute coronary syndrome. Methods and Results We investigated 510 patients with acute coronary syndrome who underwent optical coherence tomography for the culprit lesion. Optical coherence tomography analysis included the presence or absence of PR , which were categorized into the PR group and the IFC group, respectively. The IFC group was further categorized on the basis of the presence of LRP . Incidence of major adverse cardiac events ( MACEs ), including cardiac death, myocardial infarction, and clinically driven remote revascularizations, was compared. Culprit lesions were categorized into 328 PR s and 182 IFC s. MACEs occurred in 85 patients (16.7%) during the median follow-up duration of 621 days. LRP was detected in 325 lesions (99%) with PR , whereas 60 (33.0%) of the lesions with IFC did not show LRP . Kaplan-Meier analysis revealed significantly lower MACEs in the IFC group compared with the PR group. Furthermore, the IFC group without LRP showed significantly lower MACEs compared with the IFC group with LRP . Multivariate Cox proportional hazards analysis demonstrated that IFC without LRP was an independent predictor of better prognosis. Conclusions Exclusion of LRP underneath IFC culprit lesions in acute coronary syndrome may predict a lower risk of future MACEs .

Background: Despite a moderate correlation between angiographical stenosis and physiological significance, the mechanism of discordance has not been fully elucidated, particularly regarding the significance of microvascular function. This study sought to clarify whether microvascular function affects visual-functional mismatch between quantitative coronary angiography (QCA) and fractional flow reserve (FFR)., Methods and Results: We assessed QCA, FFR, coronary flow reserve, and the index of microcirculatory resistance in 849 non-left-main coronary lesions with visually estimated intermediate stenoses from 532 patients. Clinical and lesion-specific characteristics and physiological parameters associated with mismatch and reverse mismatch were studied. Coronary flow reserve and index of microcirculatory resistance showed a weak, but significant, correlation with FFR (R=0.306, P <0.001 and R=0.158, P <0.001, respectively). Four hundred twenty-two lesions were visually nonsignificant (diameter stenosis assessed by QCA [QCA-DS] ≤50%) and 427 lesions were visually significant (QCA-DS >50%). Among visually nonsignificant lesions, FFR ≤0.80 (reverse mismatch) was observed in 129 lesions (30.6%). Among visually significant lesions, FFR >0.80 (mismatch) were observed in 179 lesions (41.9%). The significant predictors of reverse mismatch were male sex, nonculprit lesions of acute coronary syndrome, left anterior descending artery location, smaller QCA reference diameter, greater QCA-DS, lower coronary flow reserve, and lower index of microcirculatory resistance. Mismatch was associated with right coronary artery location, greater QCA reference diameter, smaller QCA-DS, lesion length, higher coronary flow reserve, and higher index of microcirculatory resistance., Conclusions: There was a high prevalence of visual-functional mismatches between QCA and FFR. The discrepancy was related to clinical characteristics, lesion-specific factors, and microvascular resistance that was undistinguishable by coronary angiography, thus suggesting the importance of physiological lesion assessment., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Fractional flow reserve (FFR) and coronary flow reserve (CFR) are well-validated physiological indices; however, changes in FFR and CFR after percutaneous coronary intervention (PCI) remain elusive. We sought to evaluate these changes and to investigate whether physiological indices predict cardiac event-free survival after PCI., Methods and Results: Physiological assessment of 220 stenoses from 220 patients was performed before and after PCI. The changes in FFR and CFR were studied, and factors associated with CFR change were investigated. Follow-up data were collected to determine the predictor of cardiac events. CFR increase was found in 158 (71.8%) territories, and 62 (28.2%) presented a decrease, whereas FFR increased in all 220 (100%) territories. Pre- and post-PCI percentage diameter stenoses were 57.7±11.2% and 7.48±4.79%, respectively. Post-PCI CFR increase was associated with pre-PCI indices including low FFR, low CFR and high microvascular resistance, and post-PCI hyperemic coronary flow increase. Post-PCI CFR decrease was not associated with significant post-PCI hyperemic coronary flow increase. At a median follow-up of 24.3 months, adverse event-free survival was significantly worse in patients with lower pre-PCI CFR (log-rank test λ 2 =7.26; P=0.007). Cox proportional hazards analysis showed that lower pre-PCI CFR (hazard ratio 0.73; 95% CI 0.55-0.97; P=0.028) was an independent predictor of adverse cardiovascular events after PCI., Conclusions: CFR decrease after PCI was not uncommon, and discordant change in FFR and CFR was associated with high pre-PCI CFR, low pre-PCI microvascular resistance, and no significant post-PCI hyperemic coronary flow increase. Pre-PCI CFR, not post-PCI physiological indices, may help identify patients who require adjunctive management strategy after successful PCI., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)