Corrigendum to "Oncostatin M mediates cardioprotection via angiogenesis in ischemic heart disease" [Am. Heart J. Plus Cardiol. Res. Pract. vol. 35, 2023, 100331].

[This corrects the article DOI: 10.1016/j.ahjo.2023.100331.].

Takotsubo syndrome associated with coronary microvascular dysfunction: A case study.

The patient, a 68-year-old man, presented to our emergency room with chest pain, prompting an emergency cardiac catheterization due to elevated cardiac troponin-I levels. While no obvious coronary artery stenosis was found, there was evidence of apical ballooning wall motion in the left ventricle, leading to a diagnosis of takotsubo syndrome. Three months later, he occasionally experienced chest pain at rest, prompting us to conduct another cardiac catheterization. Left ventriculography showed normal contraction. Suddenly, he experienced chest pain accompanied by ST elevation, which occurred spontaneously. Subsequently, slow-flow phenomenon was observed in the intermediate part of left anterior descending artery (LAD). We promptly administered nitroglycerin to alleviate the symptoms. Following the diagnosis of coronary microvascular dysfunction (CMD), he started calcium-channel blocker therapy and remained asymptomatic. One year later, we re-performed cardiac catheterization to further explore his condition. Acetylcholine provocation test was performed, which showed no epicardial coronary spasm. However, lactic acid elevation was observed in the coronary sinus blood sample. Additionally, a coronary physiological measurement in the LAD revealed a high index of microcirculatory resistance and low coronary flow reserve. Based on this series of clinical events, we inferred a significant contribution of CMD to the patient's condition. Learning objective: Coronary microvascular dysfunction (CMD) is increasingly recognized as an important cardiovascular disease, leading to myocardial ischemia, which is occasionally associated with takotsubo syndrome (TTS). In this report, we present a case of spontaneous CMD associated with TTS. This case emphasizes the significance of accurate diagnosis and appropriate treatment, highlighting the importance of recognizing CMD in patients with TTS.

Oncostatin M mediates cardioprotection via angiogenesis in ischemic heart disease.

Objective: Oncostatin M (OSM) is an inflammatory cytokine belonging to the interleukin-6 family member, which plays an important role in various cardiovascular diseases. We recently reported increased serum OSM levels in patients with coronary artery disease. However, the specific role in HF with ischemic heart disease (IHD) remains unclear. Methods and results: A total of 120 patients with HF and 48 control subjects were enrolled in this study. Serum OSM levels were measured using a sandwich technique immunoassay during the compensated state. The results revealed significantly higher serum OSM levels in HF patients compared to controls. Importantly, HF patients with IHD had higher OSM levels, and those with collateral flow showed the even higher levels, indicating a potential involvement in angiogenesis. Furthermore, a positive correlation was found between serum OSM levels and levels of vascular endothelial growth factor (VEGF). In vitro experiments demonstrated that recombinant OSM upregulated VEGF production in cultured human coronary artery endothelial cells. We additionally observed that endogenous OSM levels were enhanced through exercise. Lastly, we identified the potential of SGLT2 inhibitors to enhance OSM production. Conclusions: Serum OSM levels were elevated in HF patients, particularly in those with IHD Our data indicated that endogenous OSM induces VEGF production in the heart, suggesting the activation of angiogenesis, which can be further enhanced by exercise or SGLT2 inhibitors.

Different characteristics of postoperative atrial tachyarrhythmias between congenital and non-congenital heart disease.

PURPOSE: The chance of encountering tachyarrhythmias has been increasing in adult congenital heart disease (CHD) patients with previous open-heart surgery, along with the improvement of their longevity. However, the characteristics of these arrhythmias remain to be elucidated. METHODS: We examined the characteristics of atrial tachyarrhythmias (ATs) in 26 consecutive CHD patients (M/F 17/9) referred for catheter ablation and compared them with 16 non-CHD patients with cardiac surgery (M/F 11/5). RESULTS: The CHD group was younger and had a longer period from cardiac surgery until the occurrence of ATs compared with the non-CHD group (44.8 ± 19.5 vs. 67.6 ± 12.5 years old, and 23.3 ± 13.2 vs. 6.3 ± 4.9 years, respectively, both P < 0.05). Multiple ATs were equally induced in both groups, 12 in CHD (46.1%) and 5 in non-CHD (31.3%). Although the prevalence of macro-reentrant ATs (cavo-tricuspid isthmus-dependent atrial flutter (AFL) or intra-atrial reentrant tachycardia (IART)) was comparable, the mechanisms were different between the 2 groups (AFL and IART), 34% and 27% in CHD and 71% and 24% in non-CHD, respectively. Furthermore, focal AT (FAT) was noted in 9 patients (34.6%) in CHD but none in non-CHD (P < 0.05). Electroanatomical mapping showed that the surface area and low-voltage area (LVA) of the right atrium were significantly larger in CHD than in non-CHD (197.1 ± 56.4 vs. 132.4 ± 41.2 cm2, and 40.8 ± 33.3 vs. 13.6 ± 9.0 cm2, respectively, both P < 0.05). Ten out of 14 FATs (71.4%) were highly associated with LVA, especially near the crista terminalis. CONCLUSIONS: The development of ATs in CHD patients could be associated with large atrial remodeling, resulting in complicated ATs.

Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs In Vivo.

Objective- We have previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary vasomotion abnormalities, including drug-eluting stent (DES)-induced coronary hyperconstricting responses. Importantly, the adventitia also harbors lymphatic vessels, which may prevent inflammation by transporting extravasated fluid and inflammatory cells. We thus aimed to examine the roles of coronary adventitial lymphatic vessels in the pathogenesis of DES-induced coronary hyperconstricting responses in a porcine model in vivo. Approach and Results- We performed 2 experimental studies. In protocol 1, 15 pigs were divided into 3 groups with or without DES and with bare metal stent. Nonstented sites 20 mm apart from stent implantation also were examined. In the protocol 2, 12 pigs were divided into 2 groups with or without lymphatic vessels ligation followed by DES implantation at 2 weeks later (n=6 each). We performed coronary angiography 4 weeks after DES implantation, followed by immunohistological analysis. In protocol 1, the number and the caliber of lymphatic vessels were greater at only the DES edges after 4 more weeks. In protocol 2, coronary hyperconstricting responses were further enhanced in the lymphatic vessels ligation group associated with adventitial inflammation, Rho-kinase activation, and less adventitial lymphatic vessels formation. Importantly, there were significant correlations among these inflammation-related changes and enhanced coronary vasoconstricting responses. Conclusions- These results provide evidence that cardiac lymphatic vessel dysfunction plays important roles in the pathogenesis of coronary vasoconstrictive responses in pigs in vivo.

Development of a Shock-Wave Catheter Ablation System for Ventricular Tachyarrhythmias: Validation Study in Pigs In Vivo.

Background Although radiofrequency catheter ablation is the current state-of-the-art treatment for ventricular tachyarrhythmias, it has limited success for several reasons, including insufficient lesion depth, prolonged inflammation with subsequent recurrence, and thromboembolisms due to myoendocardial thermal injury. Because shock waves can be applied to deep lesions without heat, we have been developing a shock-wave catheter ablation ( SWCA ) system to overcome these fundamental limitations of radiofrequency catheter ablation. In this study, we evaluated the efficacy and safety of our SWCA system for clinical application to treat ventricular tachyarrhythmia. Methods and Results In 33 pigs, we examined SWCA in vivo for the following 4 protocols. First, in an epicardial substrate model (n=8), endocardial SWCA significantly decreased the sensing threshold (pre- versus postablation: 11.4±3.8 versus 6.8±3.6 mV ; P<0.05) and increased the pacing threshold (pre- versus postablation: 1.6±0.8 versus 2.0±1.1 V; P<0.05), whereas endocardial radiofrequency catheter ablation failed to do so. Second, in a myocardial infarction model (n=3), epicardial SWCA of the border zone of the infarcted lesion was as effective as ablation of the normal myocardium. Third, in a coronary artery application model (n=10), direct application of shock waves to the epicardial coronary arteries caused no adverse effects in either the acute or chronic phase. Fourth, with an epicardial approach (n=8), we found that 90 shots per site provided an ideal therapeutic condition to create deep lesions with less superficial damage. Conclusions These results indicate that our new SWCA system is effective and safe for treatment of ventricular tachyarrhythmias with deep arrhythmogenic substrates.

Development of a novel shock wave catheter ablation system-A validation study in pigs in vivo.

Aims: Although the radiofrequency catheter ablation (RFCA) is widely used for the treatment of tachyarrhythmias, it has three fundamental weaknesses as a thermal ablation system, including a limited lesion depth, myoendocardial injury linking to thromboembolism, and prolonged inflammation followed by subsequent recurrences. In order to overcome these limitations, we have been developing a shock wave (SW) catheter ablation (SWCA) system as a novel non-thermal therapy. In the present study, we validated our new SWCA system with increased SW intensity. Methods and results: In a total of 36 pigs, we applied our new SWCA to ventricular muscle in vivo for the following protocols. (i) Epicardial approach (n = 17): The lesion depth achieved by the SWCA from the epicardium was examined. High intensity SW achieved 5.2 ± 0.9 mm lesions (35 applications), where there was a strong correlation between SW intensity and lesion depth (R = 0.80, P < 0.001, 54 applications). (ii) Endocardial approach (n = 6): The extent of endocardial injury with the two energy sources was examined by electron microscopy (8 applications each). Shock wave catheter ablation markedly reduced myoendothelial injury compared with RFCA (4.3 ± 1.2 vs. 79.6 ± 4.8%, P < 0.01). The electrophysiological effects on the SW lesions were also confirmed using three-dimensional mapping system. (iii) Time-course study (n = 6 each): The healing process after ablation therapy was examined. We found transient inflammatory responses and accelerated reparative process with preserved blood flow in the SWCA group. Conclusion: These results indicate that our SWCA system is characterized, as compared with RFCA, by deeper lesion depth, markedly less myoendocardial injury and accelerated tissue repair process.

Renal Denervation Suppresses Coronary Hyperconstricting Responses After Drug-Eluting Stent Implantation in Pigs In Vivo Through the Kidney-Brain-Heart Axis.

OBJECTIVE: Drug-eluting stent-induced coronary hyperconstricting responses remain an important issue. The adventitia harbors a variety of components that potently modulate vascular tone, including sympathetic nerve fibers (SNF) and vasa vasorum. Catheter-based renal denervation (RDN) inhibits sympathetic nerve activity. We, thus, examined whether RDN suppresses drug-eluting stent-induced coronary hyperconstricting responses, and if so, what mechanisms are involved. APPROACH AND RESULTS: Protocol 1: pigs implanted with everolimus-eluting stents into the left coronary arteries underwent coronary angiography at 1 month after implantation for assessment of coronary vasomotion and adventitial SNF formation. Drug-eluting stent-induced coronary hyperconstricting responses were significantly enhanced associated with enhanced coronary adventitial SNF and vasa vasorum formation. Protocol 2: pigs implanted with everolimus-eluting stents were randomly assigned to the RDN or sham group. The RDN group underwent renal ablation. At 1 month, RDN significantly caused marked damage of the SNF at the renal arteries without any stenosis, thrombus, or dissections. Notably, RDN significantly upregulated the expression of α2-adrenergic receptor-binding sites in the nucleus tractus solitarius, attenuated muscle sympathetic nerve activity, and decreased systolic blood pressure and plasma renin activity. In addition, RDN attenuated coronary hyperconstricting responses to intracoronary serotonin at the proximal and distal stent edges associated with decreases in SNF and vasa vasorum formation, inflammatory cell infiltration, and Rho-kinase expression/activation. Furthermore, there were significant positive correlations between SNF and vasa vasorum and between SNF and coronary vasoconstricting responses. CONCLUSIONS: These results provide the first evidence that RDN ameliorates drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo through the kidney-brain-heart axis.

Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs: 18F-Fluorodeoxyglucose Positron Emission Tomography Imaging Study.

OBJECTIVE: Although coronary perivascular adipose tissue (PVAT) may play important roles as a source of inflammation, the association of coronary PVAT inflammation and coronary hyperconstricting responses remains to be examined. We addressed this important issue in a porcine model of coronary hyperconstricting responses after drug-eluting stent implantation with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomographic imaging. APPROACH AND RESULTS: An everolimus-eluting stent (EES) was randomly implanted in pigs into the left anterior descending or the left circumflex coronary artery while nonstented coronary artery was used as a control. After 1 month, coronary vasoconstricting responses to intracoronary serotonin (10 and 100 µg/kg) were examined by coronary angiography in vivo, followed by in vivo and ex vivo 18F-FDG positron emission tomographic/computed tomographic imaging. Coronary vasoconstricting responses to serotonin were significantly enhanced at the EES edges compared with the control site (P<0.01; n=40). Notably, in vivo and ex vivo 18F-FDG positron emission tomographic/computed tomographic imaging and autoradiography showed enhanced 18F-FDG uptake and its accumulation in PVAT at the EES edges compared with the control site, respectively (both P<0.05). Furthermore, histological and reverse transcription polymerase chain reaction analysis showed that inflammatory changes of coronary PVAT were significantly enhanced at the EES edges compared with the control site (all P<0.01). Importantly, Rho-kinase expressions (ROCK1/ROCK2) and Rho-kinase activity (phosphorylated myosin phosphatase target subunit-1) at the EES edges were significantly enhanced compared with the control site. CONCLUSIONS: These results indicate for the first time that inflammatory changes of coronary PVAT are associated with drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo and that 18F-FDG positron emission tomographic imaging is useful for assessment of coronary PVAT inflammation.

Prognostic Significance of Late Potentials in Outpatients with Type 2 Brugada Electrocardiogram.

Brugada syndrome is characterized by distinguishing electrocardiogram (ECG) patterns (coved and saddle-back types with day-to-day variation) and occurrence of lethal tachy-arrhythmias. The appearance of coved type ECG (type 1) is required for the diagnosis of Brugada syndrome, whereas the significance of saddle-back type ECG (type 2), which is inadequate for the diagnosis, has not been fully established. We enrolled 34 consecutive patients with type 2 ECG on outpatient-clinic. Among them, 7 patients were ventricular fibrillation (VF) survivors who were diagnosed as Brugada syndrome with transient appearance of type 1 ECG, and showed type 2 ECG on their first outpatient-clinic visit after the VF event (VF group). The remaining 27 were asymptomatic and never showed type 1 ECG on repeated ECG examinations (control group). The VF group showed significantly longer RJ intervals in leads V1 and V2 and QTc intervals in lead V2 compared with the control group (P < 0.030, P < 0.017, and P < 0.030, respectively). Late potentials, detected on the signal-averaged ECG (SA-ECG), reflect conduction abnormalities and are known as one of the risk markers of arrhythmic events. Among the 34 patients, late potentials were negative in 12 patients belonging to the control group. In conclusion, the SA-ECG could be helpful to identify high-risk patients for its high negative predictive value as the first step, and ECG parameters, including RJ intervals in leads V1 and V2 and QTc interval in lead V2, could be useful for further risk stratification in patients with type 2 Brugada ECG.

Time Course and Factors Correlating With Ventricular Tachyarrhythmias After Introduction of Steroid Therapy in Cardiac Sarcoidosis.

BACKGROUND: The time course and factors correlating with ventricular tachyarrhythmias (VTs) after introduction of corticosteroid therapy in patients with cardiac sarcoidosis remain to be elucidated. METHODS AND RESULTS: We examined 68 consecutive patients with cardiac sarcoidosis in the Tohoku University Hospital from October 1998 to September 2014 (age: 57±11 years old; male:female 18:50) and evaluated VTs after initiation of steroid therapy. VTs were defined as documented ventricular tachycardia or ventricular fibrillation lasting for more than 30 seconds or resulting in cardiovascular collapse, or appropriate implantable cardioverter defibrillator therapy. During a mean follow-up of 5.5 years, 20 out of 68 patients (29%) experienced VTs after initiation of corticosteroid therapy, especially in the first 12 months in 14 patients (70%). A multivariable analysis revealed that positive gallium scintigraphy had a significant correlation with VTs (hazard ratio, 11.33; 95% confidence interval, 3.22-39.92; P<0.001), in addition to reduced left ventricular ejection fraction (hazard ratio, 0.94; 95% confidence interval, 0.90-0.97; P=0.001). Furthermore, electrical storm was noted in 10 patients (14.7%), 8 within the first 12 months of treatment, whereas the recurrence of electric storm was relatively less. CONCLUSIONS: These results indicate that VTs and electric storm frequently occur in the first 12 months after initiation of corticosteroid therapy, presumably because of inflammatory conditions, and that the positive gallium scintigraphy is a significant and independent predictor of VTs. The present findings may be useful to further improve the management of VTs in patients with cardiac sarcoidosis.

Beneficial Effects of a Novel Bioabsorbable Polymer Coating on Enhanced Coronary Vasoconstricting Responses After Drug-Eluting Stent Implantation in Pigs in Vivo.

OBJECTIVES: The aim of this study was to examine which component of drug-eluting stents (DES) plays a major role in enhanced coronary vasoconstricting responses after DES implantation in pigs. BACKGROUND: Recent studies have reported unremitting angina due to vasomotion abnormalities even after successful DES implantation. However, it remains to be elucidated which component of DES (metal stent, polymer coating, or antiproliferative drug) is responsible for DES-induced coronary hyperconstricting responses. METHODS: We developed poly-dl-lactic acid and polycaprolactone (PDLLA-PCL) copolymer technology with higher biocompatibility that is resorbed within 3 months. Four types of coronary stents were made: 1) a stent with polylactic acid (PLA) polymer coating containing antiproliferative drug (P1+D+); 2) a stent with PLA polymer coating alone without any drug (P1+D-); 3) a stent with novel PDLLA-PCL polymer coating alone (P2+D-); and 4) a bare metal stent (P-D-). The 4 stents were randomly deployed in the left anterior descending and left circumflex coronary arteries in 12 pigs. RESULTS: After 1 month, coronary vasoconstriction by intracoronary serotonin was enhanced at P1+D+ and P1+D- stent edges compared with P2+D- and P-D- stent edges and was prevented by a specific Rho-kinase (a central molecule of coronary spasm) inhibitor, hydroxyfasudil. Immunostainings showed that inflammatory changes and Rho-kinase activation were significantly enhanced at P1+D+ and P1+D- sites compared with P2+D- and P-D- sites. There were significant positive correlations between the extent of inflammation or Rho-kinase expression/activation and that of coronary vasoconstriction. CONCLUSIONS: These results indicate the important roles of PLA polymer coating in DES-induced coronary vasoconstricting responses through inflammatory changes and Rho-kinase activation in pigs in vivo, which are ameliorated by PDLLA-PCL copolymers.

Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans - a validation study - .

BACKGROUND: Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS: In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS: These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.