Pathophysiology and diagnostic pathway of myocardial infarction with non-obstructive coronary arteries.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous and diverse disease entity, which accounts for about 6 % of all acute myocardial infarction (AMI) cases. In patients with chest pain and acute myocardial injury detected by a highly sensitive troponin assay, the absence of epicardial coronary stenosis of 50 % or greater on angiography leads to the working diagnosis of MINOCA. The updated JCS/CVIT/JCC 2023 Guideline described MINOCA as a new disease concept and recommended a multimodality approach to uncovering the underlying causes of MINOCA. Cardiac magnetic resonance (CMR) is useful in not only making a definite diagnosis of MINOCA, but also excluding non-ischemic causes that mimic AMI such as takotsubo cardiomyopathy and myocarditis. Meanwhile, intracoronary imaging, particularly optical coherence tomography (OCT), enables us to evaluate precisely intracoronary morphological alterations including plaque disruption and spontaneous coronary artery dissection which are not revealed by angiographic findings alone. Recent studies have shown that an initial workup with the combination of CMR and OCT could provide a definite diagnosis in a significant percentage of patients suspected of MINOCA. Consecutively, patients with inconclusive results of a series of CMR and OCT implementation are eligible for assessing the potential for coronary functional abnormalities or blood coagulopathy as another factor involved in the development of MINOCA. Although uncovering the pathogenesis of MINOCA might be essential for establishing an individualized treatment approach, significant knowledge gaps in terms of secondary prevention strategies for MINOCA focusing on the improvement of long-term prognosis remain to be overcome. In this review, we summarize our current understanding of MINOCA and highlight contemporary diagnostic approaches for patients with suspected MINOCA.

Disparity of Performance Measure by Door-to-Balloon Time Between a Rural and Urban Area for Management of Patients With ST-Segment Elevation Myocardial Infarction　- Insights From the Nationwide Japan Acute Myocardial Infarction Registry.

BACKGROUND: Although a door-to-balloon (D2B) time ≤90 min is recognized as a key indicator of timely reperfusion for patients with ST-segment elevation myocardial infarction (STEMI), it is unclear whether regional disparities in the prognostic value of D2B remain in contemporary Japan.Methods and Results: We retrospectively analyzed 17,167 STEMI patients (mean [±SD] age 68±13 years, 77.6% male) undergoing primary percutaneous coronary intervention. With reference to the Japanese median population density of 1,147 people/km2, patients were divided into 2 groups: rural (n=6,908) and urban (n=10,259). Compared with the urban group, median D2B time was longer (70 vs. 62 min; P<0.001) and the rate of achieving a D2B time ≤90 min was lower (70.7% vs. 75.4%; P<0.001) in the rural group. In-hospital mortality was lower for patients with a D2B time ≤90 min than >90 min, regardless of residential area, whereas multivariable analysis identified prolonged D2B time as a predictor of in-hospital death only in the rural group (adjusted odds ratio 1.57; 95% confidence interval 1.18-2.09; P=0.002). Importantly, the rural-urban disparity in in-hospital mortality emerged most distinctively among patients with Killip Class IV and a D2B time >90 min. CONCLUSIONS: These data suggest that there is a substantial rural-urban gap in the prognostic significance of D2B time among STEMI patients, especially those with cardiogenic shock and a prolonged D2B time.

Prediction of the development of delirium after transcatheter aortic valve implantation using preoperative brain perfusion SPECT.

OBJECTIVES: Delirium is an important prognostic factor in postoperative patients undergoing cardiovascular surgery and intervention, including transcatheter aortic valve implantation (TAVI). However, delirium after transcatheter aortic valve implantation (DAT) is difficult to predict and its pathophysiology is still unclear. We aimed to investigate whether preoperative cerebral blood flow (CBF) is associated with DAT and, if so, whether CBF measurement is useful for predicting DAT. METHODS: We evaluated CBF in 50 consecutive patients before TAVI (84.7±4.5 yrs., 36 females) using 99mTc ethyl cysteinate dimer single-photon emission computed tomography. Preoperative CBF of the DAT group (N = 12) was compared with that of the non-DAT group (N = 38) using whole brain voxel-wise analysis with SPM12 and region of interest-based analysis with the easy-Z score imaging system. Multivariable logistic regression analysis with the presence of DAT was used to create its prediction model. RESULTS: The whole brain analysis showed that preoperative CBF in the insula was lower in the DAT than in the non-DAT group (P<0.05, family-wise error correction). Decrease extent ratio in the insula of the DAT group (17.6±11.5%) was also greater relative to that of the non-DAT group (7.0±11.3%) in the region of interest-based analysis (P = 0.007). A model that included preoperative CBF in the insula and conventional indicators (frailty index, short physical performance battery and mini-mental state examination) showed the best predictive power for DAT (AUC 0.882). CONCLUSIONS: These results suggest that preoperative CBF in the insula is associated with DAT and may be useful for its prediction.

The influence of COVID-19 pandemic on management of acute myocardial infarction in Japan; Insight from the Miyagi AMI Registry Study.

Due to the coronavirus disease 2019 (COVID-19) pandemic, the first state of emergency had been declared from April 7 to May 25, 2020, in Japan. This pandemic might affect the management for patients with acute myocardial infarction (AMI). Method and Results: To evaluate the critical care and outcomes of AMI patients during the COVID-19 outbreak, we examined the patients with AMI hospitalized in 2020 (n = 1186) and those in 2017-2019 (n = 4877) using a database of the Miyagi AMI Registry Study. The door-to-device time under the emergency declaration became longer as compared with that of the same period in 2017-2019 [83(65-111) vs 74(54-108) min, p = 0.04]. Importantly, the time delay was noted in only patients with Killip class I on arrival, but not in those with Killip class II-IV. Meanwhile, there were no significant changes in the duration from the symptom onset to hospital arrival, the use rate of ambulance and the performance rate of primary percutaneous coronary intervention before and after the COVID-19 outbreak. Eventually, in-hospital mortality had not deteriorated under the state of emergency (6.7 vs 7.8 %, P = 0.69). Conclusion: The emergence of the COVID-19 outbreak seemed to affect AMI management and highlight understanding the barriers to cardiovascular critical care.

Prognostic Links Between OCT-Delineated Coronary Morphologies and Coronary Functional Abnormalities in Patients With INOCA.

OBJECTIVES: Whether there are prognostic links between coronary morphologies and coronary functional abnormalities was examined in ischemia and nonobstructive coronary artery disease (INOCA) patients. BACKGROUND: Although INOCA has attracted much attention, little is known about the prognostic impact of coronary morphologies in this disorder. METHODS: A total of 329 consecutive INOCA patients were enrolled and underwent spasm provocation testing combined with lactate sampling for diagnosis of epicardial and microvascular spasm (MVS). On the basis of the functional tests, the patients were classified into 4 groups: a control group without epicardial spasm or MVS (n = 32), MVS alone (n = 51), diffuse spasm in ≥2 coronary segments (n = 204), and focal spasm in 1 segment (n = 42). In this population, optical coherence tomography imaging of the left anterior descending coronary artery was performed for evaluation of adventitial vasa vasorum (AVV) and intraplaque neovessels (IPN). Index of microcirculatory resistance was also measured. RESULTS: MVS frequently coexisted with diffuse (70%) and focal spasm (68%) with a good correlation between AVV and index of microcirculatory resistance (R = 0.353; p = 0.022). For a median follow-up of 1,043 days, focal spasm showed the worst prognosis (log rank p = 0.005), for which IPN was a significant prognostic factor. By contrast, diffuse spasm showed the greatest AVV with an intermediate prognosis. The prognostic value of INOCA was significantly enhanced by adding AVV and IPN to the physiological indices (area under the curve = 0.88 vs. 0.76; p = 0.048). CONCLUSIONS: These results provide the first evidence that there are important prognostic links between coronary morphologies (evaluated by optical coherence tomography) and coronary functional abnormalities in patients with INOCA, indicating the importance of both evaluations in this population.

Prognostic Impacts of Comorbid Significant Coronary Stenosis and Coronary Artery Spasm in Patients With Stable Coronary Artery Disease.

BACKGROUND Stable coronary artery disease is caused by a variable combination of organic coronary stenosis and functional coronary abnormalities, such as coronary artery spasm. Thus, we examined the clinical importance of comorbid significant coronary stenosis and coronary spasm. METHODS AND RESULTS We enrolled 236 consecutive patients with suspected angina who underwent acetylcholine provocation testing for coronary spasm and fractional flow reserve (FFR) measurement. Among them, 175 patients were diagnosed as having vasospastic angina (VSA), whereas the remaining 61 had no VSA (non-VSA group). The patients with VSA were further divided into the following 3 groups based on angiography and FFR: no organic stenosis (≤50% luminal stenosis; VSA-alone group, n=110), insignificant stenosis of FFR>0.80 (high-FFR group, n=36), and significant stenosis of FFR≤0.80 (low-FFR group, n=29). The incidence of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, urgent percutaneous coronary intervention, and hospitalization attributed to unstable angina was evaluated. All patients with VSA received calcium channel blockers, and 28 patients (95%) in the low-FFR group underwent a planned percutaneous coronary intervention. During a median follow-up period of 656 days, although the incidence of major adverse cardiovascular events was low and comparable among non-VSA, VSA-alone, and high-FFR groups, the low-FFR group had an extremely poor prognosis (non-VSA group, 1.6%; VSA-alone group, 3.6%; high-FFR group, 5.6%; low-FFR group, 27.6%) (P<0.001). Importantly, all 8 patients with major adverse cardiovascular events in the low-FFR group were appropriately treated with percutaneous coronary intervention and calcium channel blockers. CONCLUSIONS These results indicate that patients with VSA with significant coronary stenosis represent a high-risk population despite current guideline-recommended therapies, suggesting the importance of routine coronary functional testing in this population.

Beneficial effects of exercise training on physical performance in patients with vasospastic angina.

AIMS: In vasospastic angina (VSA), coronary vasomotion abnormalities could develop not only in epicardial coronary arteries but also in coronary microvessels, where calcium channel blockers (CCBs) have limited efficacy. However, efficacy of exercise training for VSA remains to be elucidated. We thus aimed to examine whether vasodilator capacity of coronary microvessels is impaired in VSA patients, and if so, whether exercise exerts beneficial effects on the top of CCBs. METHODS: We performed 2 clinical protocols. In the protocol 1, we measured myocardial blood flow (MBF) using adenosine-stress dynamic computed tomography perfusion (CTP) in 38 consecutive VSA patients and 17 non-VSA controls. In the protocol 2, we conducted randomized controlled trial, where 20 VSA patients were randomly assigned to either 3-month exercise training group (Exercise group) or Non-Exercise group (n= 10 each). RESULTS: In the protocol 1, MBF on CTP was significantly decreased in the VSA group compared with the Non-VSA group (138 ± 6 vs 166 ± 10 ml/100 g/min, P = 0.02). In the protocol 2, exercise capacity was significantly increased in the Exercise group than in the Non-Exercise group (11.5 ± 0.5 to 15.4 ± 1.8 vs 12.6 ± 0.7 to 14.0 ± 0.8 ml/min/kg, P < 0.01). MBF was also significantly improved after 3 months only in the Exercise group (Exercise group, 145 ± 12 to 172 ± 8 ml/100 g/min, P < 0.04; Non-Exercise group, 143 ± 14 to 167 ± 8 ml/100 g/min, P = 0.11), although there were no significant between-group differences. CONCLUSIONS: These results provide the first evidence that, in VSA patients, exercise training on the top of CCBs treatment may be useful to improve physical performance, although its effect on MBF may be minimal.

Assessment of coronary vasomotor responses to acetylcholine in German and Japanese patients with epicardial coronary spasm-more similarities than differences?

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11 years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.

Marked Impairment of Endothelium-Dependent Digital Vasodilatations in Patients With Microvascular Angina: Evidence for Systemic Small Artery Disease.

OBJECTIVE: It remains to be elucidated whether and how endothelial functions are impaired in peripheral circulation of patients with coronary functional disorders, such as vasospastic angina (VSA) and microvascular angina (MVA). We simultaneously examined endothelial functions of peripheral conduit and resistance arteries in patients with coronary functional disorders, with a special reference to NO and endothelium-dependent hyperpolarization factors. Approach and Results: Based on the results of invasive coronary acetylcholine testing and coronary physiological measurements, we divided 43 patients into 3 groups; VSA, MVA, and VSA+MVA. Endothelium-dependent vasodilatations of the brachial artery and fingertip arterioles to intra-arterial infusion of bradykinin were simultaneously evaluated by ultrasonography and peripheral arterial tonometry, respectively. To assess NO and endothelium-dependent hyperpolarization factors, measurements were repeated after oral aspirin and intra-arterial infusion of NG-monomethyl-L-arginine. Additionally, endothelium-independent vasodilatations to sublingual nitroglycerin and plasma levels of biomarkers for endothelial functions were measured. Surprisingly, digital vasodilatations to bradykinin were almost absent in patients with MVA alone and those with VSA+MVA compared with those with VSA alone. Mechanistically, both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations were markedly impaired in patients with MVA alone. In contrast, endothelium-independent vasodilatations to nitroglycerin were comparable among the 3 groups. Plasma levels of soluble VCAM (vascular cell adhesion molecule)-1 were significantly higher in patients with MVA alone compared with those with VSA alone. CONCLUSIONS: These results provide the first evidence that both NO- and endothelium-dependent hyperpolarization-mediated digital vasodilatations are markedly impaired in MVA patients, suggesting that MVA is a cardiac manifestation of the systemic small artery disease.

Disappearance of Angiodysplasia Following Transcatheter Aortic Valve Implantation in a Patient with Heyde's Syndrome: A Case Report and Review of the Literature.

An 83-year-old woman with severe aortic stenosis was admitted to our hospital due to heart failure with refractory anemia requiring blood transfusions. She had repetitive bleeding episodes from endoscopically proven angiodysplasia in the stomach. Moreover, she repeatedly underwent endoscopic argon plasma coagulation for hemostasis. Importantly, she had a deficiency of the high-molecular-weight (HMW) multimers of von Willebrand factor (VWF), and she was diagnosed with Heyde's syndrome.After she underwent transcatheter aortic valve implantation (TAVI), aortic valve area and mean left ventricular aorta pressure gradient improved. Notably, endoscopy showed cessation of bleeding at 10 days after TAVI and the disappearance of angiodysplasia at 4 months after TAVI. Even at 2 years after TAVI, follow-up endoscopy showed remaining free of angiodysplasia in the stomach. She experienced no episodes of anemia since TAVI procedure. Additionally, analysis of HMW multimers demonstrated immediate and lasting recovery after TAVI.Recovery of HMW multimers of VWF with cessation of gastrointestinal bleeding following aortic valve replacement has been previously reported in a patient diagnosed with Heyde's syndrome. To the best our knowledge, this is the first case to demonstrate that angiodysplasia disappears after TAVI for a long term with endoscopic images in a patient with Heyde's syndrome. Here, we summarized case reports of patients with Heyde's syndrome that required aortic valve intervention. Cessation of gastrointestinal bleeding and anemia after aortic valve intervention for severe aortic stenosis may be attributed not only to recovery of HMW multimers of VWF but also to the disappearance of angiodysplasia.

Temporal trends in the prevalence and outcomes of geriatric patients with acute myocardial infarction in Japan-A report from the Miyagi AMI Registry Study.

BACKGROUND: Along with the global aging, the number of geriatric patients with acute myocardial infarction (AMI) has been increasing. However, temporal trends in the prevalence and outcomes of geriatric patients with AMI, with a special reference to heart failure (HF) on admission, remain to be elucidated. METHODS: The Miyagi AMI Registry is a prospective, multicenter, and observational study. This registry was established in 1979 and has been continued for 40 years. We examined a total of 6,596 AMI patients aged ≥70 years (male/female 4,141/2,455) registered in this registry from 2005 to 2016 and divided them into 3 groups according to age [70-79 (n = 3,485), 80-89 (n = 2,601), and ≥90 years (n = 510)]. RESULTS: Of those, 17.6% had HF (Killip class ≥ II) on admission, for which age, female sex, diabetes, and previous MI were identified as independent predictors. Importantly, the prevalence of HF on admission significantly increased in all ages during the study period (all p for trend <0.01). Despite the presence of HF on admission, primary percutaneous coronary intervention (PCI) was performed in about 70% of patients aged in their 80 s and about half of those aged ≥90 years. In each group, performance rate of primary PCI also progressively increased (all p < 0.05) irrespective of concomitant HF. However, in-hospital mortality remained unchanged. Multivariable analysis demonstrated that, even for patients with HF on admission, primary PCI was associated with improved in-hospital mortality in the younger 2 groups [adjusted odds ratios (ORs), 95% confidence intervals (CI) 0.58 (0.36-0.93) for 70s, 0.64 (0.43-0.95) for 80s, and 0.99 (0.44-2.21) for ≥90s], whereas PCI was ineffective to reduce long-term hospitalization ≥30 days in all groups [adjusted ORs (95%CI) 0.90 (0.52-1.54), 0.66 (0.38-1.14), and 0.38 (0.07-2.10)]. CONCLUSIONS: These results demonstrate that increasing prevalence of HF on admission and increasing performance of primary PCI counteract each other with resultant unchanged in-hospital outcomes in geriatric AMI patients in Japan.

Coronary Functional Abnormalities in Patients With Angina and Nonobstructive Coronary Artery Disease.

BACKGROUND: Approximately one-half of patients undergoing diagnostic coronary angiography for angina have no significant coronary stenosis, in whom coronary functional abnormalities could be involved. OBJECTIVES: This study examined the significance of coronary functional abnormalities in a comprehensive manner for both epicardial and microvascular coronary arteries in patients with angina and nonobstructive coronary artery disease (CAD). METHODS: This study prospectively enrolled 187 consecutive patients (male/female 113/74, 63.2 ± 12.3 years), who underwent acetylcholine provocation test for coronary spasm and measurement of index of microcirculatory resistance (IMR) to evaluate coronary microvascular function, and followed them for a median of 893 days. RESULTS: Of all subjects, acetylcholine test identified 128 patients with vasospastic angina (VSA) (68%), and cardiac events occurred in 10 patients (5.3%) during the follow-up. Multivariable analysis revealed that IMR correlated with the incidence of cardiac events (hazard ratio: 1.05; 95% confidence interval: 1.02 to 1.09; p = 0.002) and receiver-operating characteristics (ROC) curve analysis identified IMR of 18.0 as the optimal cut-off value. Among the 4 groups based on the cut-off value of IMR and the presence of VSA, the Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with high IMR (≥18.0) and VSA compared with other groups (log rank, p = 0.002). Importantly, intracoronary administration of fasudil, a Rho-kinase inhibitor, significantly ameliorated IMR in the VSA patients with increased IMR (p < 0.0001). CONCLUSIONS: These results indicate that in patients with angina and nonobstructive CAD, coexistence of epicardial coronary spasm and increased microvascular resistance is associated with worse prognosis, for which Rho-kinase activation may be involved.

Usefulness of intracoronary administration of fasudil, a selective Rho-kinase inhibitor, for PCI-related refractory myocardial ischemia.

BACKGROUND: Intra-procedural myocardial ischemia as an iatrogenic complication still remains a critical issue in contemporary interventional cardiology. The aim of this study was to examine the usefulness of fasudil, a selective Rho-kinase inhibitor, for percutaneous coronary intervention (PCI)-related myocardial ischemia. METHODS: Among 448 PCI sessions performed between October 2015 and December 2017, we retrospectively examined 36 patients (69.0 ±â€¯9.1 [SD] yrs., M/F 26/10) who underwent intracoronary administration of fasudil during a procedure to resolve myocardial ischemia that was resistant to intracoronary nitrate administration. RESULTS: The refractory myocardial ischemia was caused by distal embolization (69%), enhanced vasoconstriction at distal site of chronic total occlusion (11%), coronary spasm (11%), and coronary dissection (8%), most of which occurred immediately after balloon or stent dilatation. Intracoronary fasudil significantly improved corrected TIMI frame count (from 37 [30-56] to 24 [12-36]) and TIMI flow grade (from 2 [1-2.5] to 3 [2-3]) (both P < 0.001). Finally, 86% of all subjects successfully obtained TIMI flow grade 3 at the end of the procedure. Intracoronary fasudil tended to be more effective in patients with an attenuated plaque detected by intravascular ultrasound. Importantly, among the 19 elective cases, fasudil successfully prevented 17 patients from developing post-procedure myocardial infarction. Although fasudil-induced transient hypotension requiring a vasopressor was noted in 22% of the subjects, no other adverse effects were noted. CONCLUSIONS: These results indicate that fasudil is a useful and safe therapeutic option for PCI-related myocardial ischemia refractory intracoronary nitrate.

A multicenter trial of extracorporeal cardiac shock wave therapy for refractory angina pectoris: report of the highly advanced medical treatment in Japan.

We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia through coronary neovascularization both in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris (AP). In this study, we further addressed the efficacy and safety of CSWT in a single-arm multicenter study approved as a highly advanced medical treatment by the Japanese Ministry of Health, Labour and Welfare. Fifty patients with refractory AP [mean age 70.9 ± 12.6 (SD) years, M/F 38/12] without the indications of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were enrolled in 4 institutes in Japan. Ischemic myocardial regions in the left ventricle (LV) were identified by drug-induced stress myocardial perfusion imaging (MPI). Shock waves (200 shots/spot at 0.09 mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3 months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3 months. CSWT markedly improved weekly nitroglycerin use [from 3.5 (IQR 2 to 6) to 0 (IQR 0 to 1)] and the symptoms [Canadian Cardiovascular Society functional class score, from 2 (IQR 2 to 3) to 1 (IQR 1 to 2)] (both P < 0.001). CSWT also significantly improved 6-min walking distance (from 384 ± 91 to 435 ± 122 m, P < 0.05). There were no significant changes in LV ejection fraction evaluated by echocardiography and LV stroke volume evaluated by cardiac magnetic resonance imaging (from 56.3 ± 14.7 to 58.8 ± 12.8%, P = 0.10, and from 52.3 ± 17.4 to 55.6 ± 15.7 mL, P = 0.15, respectively). Percent myocardium ischemia assessed by drug-induced stress MPI tended to be improved only in the treated segments (from 16.0 ± 11.1 to 12.1 ± 16.2%, P = 0.06), although no change was noted in the whole LV. No procedural complications or adverse effects related to the CSWT were noted. These results of the multicenter trial further indicate that CSWT is a useful and safe non-invasive strategy for patients with refractory AP with no options of PCI or CABG.

Prognostic impact of residual stenosis after percutaneous coronary intervention in patients with ischemic heart failure - A report from the CHART-2 study.

BACKGROUND: Complete revascularization with PCI is not always achieved in patients with ischemic HF. Therefore, this study aimed to elucidate the prognostic impact of residual coronary stenosis (RS) after percutaneous coronary intervention (PCI) in patients with ischemic heart failure (HF). METHODS: We analyzed a total of 1307 patients with symptomatic HF and a history of PCI registered in our Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study. RS that was defined as the presence of ≥70% luminal stenosis in major coronary arteries at the last coronary angiography. RESULTS: Among the study population, 851 patients (65.1%) had RS. During a median follow-up period of 3.2 years, patients with RS had higher all-cause mortality than those without it even after propensity score matching (21.9 vs. 11.6%, log-rank P = 0.027). Multivariable Cox hazard analysis also showed the negative impact of RS on all-cause death in ischemic HF patients [hazard ratio (HR):1.62, 95% confidence interval (CI): 1.07-2.46, P = 0.024]. Importantly, when divided all subjects into three subgroups by left ventricular ejection fraction (LVEF) [LVEF < 40% (HFrEF), LVEF 40-49% (HFmrEF), and LVEF ≥ 50% (HFpEF)], inverse probability of treatment weighted method provided a similar result that RS after PCI was an independent risk factor for death in the HFpEF [HR(95%CI); 1.94(1.22-3.09), P < 0.01] and HFmrEF [4.47(1.13-14.98), P < 0.01] groups, but not in the HFrEF group [1.20(0.59-2.43), P = 0.62]. CONCLUSIONS: These results indicate that RS after PCI could aggravate long-term prognosis of ischemic HF patients with moderate- to well-preserved EF, but not those with reduced EF.

Coronary Adventitial and Perivascular Adipose Tissue Inflammation in Patients With Vasospastic Angina.

BACKGROUND: Recent studies suggested that perivascular components, such as perivascular adipose tissue (PVAT) and adventitial vasa vasorum (VV), play an important role as a source of various inflammatory mediators in cardiovascular disease. OBJECTIVES: The authors tested their hypothesis that coronary artery spasm is associated with perivascular inflammation in patients with vasospastic angina (VSA) using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). METHODS: This study prospectively examined 27 consecutive VSA patients with acetylcholine-induced diffuse spasm in the left anterior descending artery (LAD) and 13 subjects with suspected angina but without organic coronary lesions or coronary spasm. Using CT coronary angiography and electrocardiogram-gated 18F-FDG PET/CT, coronary PVAT volume and coronary perivascular FDG uptake in the LAD were examined. In addition, adventitial VV formation in the LAD was examined with optical coherence tomography, and Rho-kinase activity was measured in circulating leukocytes. RESULTS: Patient characteristics were comparable between the 2 groups. CT coronary angiography and ECG-gated 18F-FDG PET/CT showed that coronary PVAT volume and coronary perivascular FDG uptake significantly increased in the VSA group compared with the non-VSA group. Furthermore, optical coherence tomography showed that adventitial VV formation significantly increased in the VSA group compared with the non-VSA group, as did Rho-kinase activity. Importantly, during the follow-up period with medical treatment, both coronary perivascular FDG uptake and Rho-kinase activity significantly decreased in the VSA group. CONCLUSIONS: These results provide the first evidence that coronary spasm is associated with inflammation of coronary adventitia and PVAT, where 18F-FDG PET/CT could be useful for disease activity assessment. (Morphological and Functional Change of Coronary Perivascular Adipose Tissue in Vasospastic Angina [ADIPO-VSA Trial]; UMIN000016675).

Low-energy cardiac shockwave therapy to suppress left ventricular remodeling in patients with acute myocardial infarction: a first-in-human study.

OBJECTIVE: Although primary percutaneous coronary intervention (PCI) substantially reduces the mortality of patients with acute myocardial infarction (AMI), left ventricular (LV) remodeling after AMI still remains an important issue in cardiovascular medicine. We have previously demonstrated that low-energy cardiac shockwave (SW) therapy ameliorates LV remodeling after AMI in pigs. In this first-in-human study, we examined the feasibility and the effects of the SW therapy on LV remodeling after AMI in humans. PATIENTS AND METHODS: Seventeen patients with AMI who successfully underwent primary PCI (peak-creatine kinase<4000 U/l) were treated with the SW therapy. Low-energy shock waves were applied to the ischemic border zone around the infarcted area at 2, 4, and 6 days since AMI. Next, we compared these patients with historical AMI controls by propensity score matching (N=25). RESULTS: There were no procedure-related complications or adverse effects. At 6 and 12 months after AMI, LV function as assessed by MRI showed no signs of deleterious LV remodeling. When we compared the SW-treated group with the historical AMI controls at 6 months after AMI, LV ejection fraction was significantly higher in the SW-treated group (N=7) than in the historical control group (N=25) by echocardiography (66±7 vs. 58±12%, P<0.05). LV end-diastolic dimension also tended to be smaller in the SW than in the control group (47.5±4.6 vs. 50.0±5.9 mm, P=0.29). CONCLUSION: These results suggest that low-energy extracorporeal cardiac SW therapy is feasible and may ameliorate postmyocardial infarction LV remodeling in patients with AMI as an adjunctive therapy to primary PCI.

Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina.

Aims: Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results: We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone. Conclusion: Rho-kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients.

Absence of adventitial vasa vasorum formation at the coronary segment with myocardial bridge - An optical coherence tomography study.

BACKGROUND: Myocardial bridge (MB) is a myocardial bundle through which coronary segment tunnels and could compress coronary arteries causing myocardial ischemia. However, the characteristic structural findings of MB remain to be fully elucidated. Recently, we demonstrated that optical coherence tomography (OCT) enables us to visualize adventitial vasa vasorum (VV) formation in humans. In this study, we examined adventitial VV formation at the coronary segment with MB in humans using OCT. METHODS: We examined 15 consecutive patients with suspected angina pectoris and MB in the left anterior descending (LAD) coronary arteries but no angiographic coronary stenosis. MB was detected on coronary angiography as a segment with milking effect. We performed intracoronary OCT imaging along the entire LAD. Morphometric analysis was performed at MB and proximal/distal segments at every 1mm. RESULTS: OCT examination showed the absence of adventitial VV formation at MB in the LAD, while VV was clearly noted at both the proximal and distal reference segments. Adventitial VV area was significantly less at MB compared with the proximal or distal references. CONCLUSIONS: These results with OCT imaging indicate that coronary segments with MB lack adventitial VV formation in humans, suggesting that MB could influence morphological and functional changes of the coronary artery.