Unique left pulmonary vein isolation in straight common trunk based on longitudinal conduction of left lateral ridge.

BACKGROUND: A left common pulmonary vein (LCPV) is the most common anatomical variation in the pulmonary vein (PV) and often influences strategies of PV isolation for atrial fibrillation (AF). Our objective was to elucidate the electrical properties of the specific shape of LCPV and to apply it to an ablation procedure. METHODS AND RESULTS: We investigated consecutive 12 out of 204 paroxysmal AF patients who had the shape of a straight common trunk in LCPV defined by the formation of a single conduit with parallel cranial and caudal walls after the coalescence of superior and inferior PVs on the distal side. The distance between the top of the bifurcation of LPVs and the level coinciding with the middle of the anterior wall of LCPV (left lateral ridge: LLR) was more than 10 mm in all the patients. The activation pattern of the LLR showed longitudinal conduction without outside connections. All the LCPV except one were successfully isolated without ablating the LLR (C-shape ablation). Only one patient had AF recurrence during the follow-up period. CONCLUSION: The LLR in LCPV with a straight common trunk has longitudinal conduction without outside connections, which permits the isolation of LCPV without ablating LLR.

Non-invasive recanalization of first-generation sirolimus-eluting stent thrombosis due to stent fracture and coronary artery aneurysm after clopidogrel treatment 15 years after implantation.

In 2020, a 48-year-old male patient was admitted to our hospital due to unstable angina. In 2005, three first-generation sirolimus-eluting stents (1st-SESs) had been deployed to his right coronary artery (RCA). Over the past 10 years or so, the patient has been treated with single antiplatelet therapy using aspirin. Coronary angiography (CAG) revealed severe stenosis in the left circumflex artery (LCx) and total occlusion at the proximal portion of the stented RCA. Furthermore, fluoroscopy showed multiple 1st-SES fractures. After ad hoc percutaneous coronary intervention of the LCx, dual antiplatelet therapy (DAPT) was resumed by adding the P2Y12 inhibitor clopidogrel to aspirin. Two months later, CAG revealed complete recanalization and multiple peri-stent coronary artery aneurysms (CAAs) in the RCA. Intravascular ultrasound revealed late-acquired stent malapposition (LSM) and formation of true aneurysms. Coronary angioscopy showed the uncovered struts of the 1st-SES and mural red thrombus. DAPT was continued thereafter, and 8 months later, follow-up CAG showed no significant RCA restenosis. To date, the patient remains free from cardiovascular events. This report documents a rare case of thrombotic occlusion of a 1st-SES with LSM, CAA, and stent fractures followed by non-invasive recanalization after clopidogrel treatment 15 years after 1st-SES implantation. Learning objective: Stent thrombosis due to stent fracture and coronary aneurysm can occur even years after first-generation sirolimus-eluting stent (1st-SES) implantation. Risk assessment using coronary imaging should be made and long-term dual antiplatelet therapy (DAPT) should be recommended in patients with a high risk of stent thrombosis after 1st-SES implantation. In cases of stent thrombosis of the 1st-SES, resuming DAPT, including P2Y12 receptor inhibitors, may be a useful non-invasive treatment option.

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.

Plasma cyclophilin A is a novel biomarker for coronary artery disease.

BACKGROUND: Oxidative stress induces secretion of cyclophilin A (CyPA) from vascular smooth muscle cells and it plays a crucial role in the pathogenesis of atherosclerosis in mice. Therefore, we tested our hypothesis that plasma CyPA levels are increased in patients with coronary artery diseases (CAD). METHODS AND RESULTS: In 320 consecutive patients undergoing coronary angiography, we examined the relationship between plasma CyPA levels and the severity of CAD. We measured plasma CyPA by an immunoassay based on the sandwich technique. Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it (P<0.001). A positive correlation was noted between plasma CyPA levels and significant coronary stenosis. The average number of stenotic coronary arteries and the need for coronary intervention were significantly increased in the quartiles of higher CyPA levels (both P<0.001). Indeed, the plasma CyPA level significantly correlated with the presence of CAD (adjusted odds ratio for CAD, 6.20; 95% confidence interval, 3.14-12.27; P<0.001). Interestingly, plasma levels of CyPA increased according to the number of atherosclerotic risk factors, all of which induce oxidative stress. Furthermore, plasma levels of CyPA significantly reduced after medical treatment of risk factors. Finally, CyPA was strongly expressed in coronary atherosclerotic plaque in patients with myocardial infarction. CONCLUSIONS: Plasma CyPA level is a novel biomarker for oxidative stress and CAD in humans.

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.

Involvement of rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease.

BACKGROUND: Activation of Rho-kinase plays a central role in the pathogenesis of drug-eluting stents (DES)-induced coronary hyperconstricting responses in pigs in vivo has been previously demonstrated. In the present study, Rho-kinase activation involved in those responses in patients with coronary artery disease (CAD) is examined. METHODS AND RESULTS: In 24 patients with CAD who underwent coronary intervention with either DES or bare-metal stents (BMS), coronary vasomotor responses to intracoronary acetylcholine (ACh) before and after intracoronary pre-treatment with a Rho-kinase inhibitor, fasudil was examined. Coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT) was evaluated. QCA showed that the coronary vasoconstricting responses to ACh were significantly enhanced in the DES group compared with the BMS group both at the proximal and the distal segments adjacent to the stents (proximal: BMS -13.0±10.7% vs. DES -25.4±14.3%, P=0.036; distal: BMS -24.4±12.2% vs. DES -43.8±14.7%, P=0.003). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal 10.2±11.7%, distal 14.4±10.5% vs. before fasudil, both P<0.01). In the OCT imaging analysis, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. CONCLUSIONS: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD, suggesting the therapeutic importance of Rho-kinase pathway.

Current perspectives on protective roles of erythropoietin in cardiovascular system: erythropoietin receptor as a novel therapeutic target.

Erythropoietin (EPO) is a principal regulator that promotes proliferation and terminal differentiation of erythroid progenitor cells. EPO receptors are expressed not only in hematopoietic lineage cells but also in the cardiovascular system. We performed animal experiments using transgene-rescued EPO receptor null mutant mice (EpoR-/- rescued) that express the EPO receptor exclusively in the hematopoietic cells. The results of these experiments suggest that endogenous EPO/EPO receptor system in the heart exerts cardioprotective effects against myocardial injury induced by ischemia followed by reperfusion and pressure-overload induced left ventricular dysfunction. Many animal experiments have shown that the administration of recombinant human EPO also elicits cardioprotective effects against myocardial injury induced by ischemia and reperfusion. In contrast to the promising results of these animal experiments, recent clinical trials failed to demonstrate the reduction in infarct size or improvement of cardiac function by the administration of recombinant human EPO in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention. It should be tested in future clinical studies whether a relatively low dose of recombinant human EPO or its derivatives that have no erythropoietic action reduces infarct size and ameliorates cardiac dysfunction in patients with acute myocardial infarction. In this article, we review implications of anemia associated with chronic heart failure, roles of the endogenous EPO/EPO receptor system, and the effects of the administration of erythropoiesis-stimulating agents in pathologic conditions of the heart by focusing on the EPO receptor as a potential candidate of novel therapeutic targets in cardiovascular diseases.

A case of ventricular fibrillation without left ventricular systolic dysfunction induced by trastuzumab emtansine for breast cancer.

Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment. However, cardiac complications of trastuzumab without left ventricular systolic dysfunction have been rarely reported. These include left bundle branch block, sinus node dysfunction, and ventricular tachycardia. We herein report a case of a 47-year-old female with human epidermal growth factor receptor 2-positive, stage IV breast cancer without a history of cardiovascular disease. During treatment with trastuzumab emtansine (T-DM1), she presented with out-of-hospital cardiac arrest and was resuscitated by automated cardioverter defibrillator (AED). Emergent cardiac catheterization revealed no organic obstruction and coronary vasospasm in her coronary arteries, and no left ventricular systolic dysfunction. Ventricular fibrillation (VF) was documented by an event memory of AED. T-DM1 was withdrawn and implantable cardioverter defibrillator was implanted. Thereafter, VF or life-threatening arrhythmia were not documented for 36 months until her death by breast cancer. We concluded that the etiology of her VF event was T-DM1-induced cardiotoxicity. We believe this is the first report of life-threatening VF event without cardiomyopathy induced by T-DM1. .

Diagnosed corrected transposition of great arteries after cesarean section: A case report.

BACKGROUND: Corrected transposition of the great arteries (cTGA) is a cardiac malformation in which the ventricular and arterial-ventricular positions in the heart are doubly reversed. In general, this defect puts a load on the systemic circulation and causes heart failure, resulting in a poor prognosis. This article reports a case of cTGA detected in a patient with post-caesarean pregnancy who had undergone elective caesarean section and was experiencing an episode of acute heart failure. CASE SUMMARY: This was the case of a 36-year-old gravida 3 para 1 woman. No problems were noted in the puerperal course following the previous pregnancy. The current pregnancy was also uneventful. An elective caesarean section was performed and the patient was discharged from the hospital 7 d after the operation. On postoperative day 18, the patient became aware of breathing difficulty and presented at a nearby clinic, where she was referred to our institution after bilateral pleural effusions were detected. She was then diagnosed with acute heart failure after noting the presence of a prominent pedal oedema and SpO2 91% (supine position and room air); the patient was promptly hospitalised for close examination and treatment. Although chest computed tomography revealed the presence of cTGA, no other cardiac malformations were observed. Owing to improvements in both the pedal oedema and pleural effusions, the patient was discharged on day 9. CONCLUSION: Close examination should be performed on the premise of congenital cardiac malformation when heart failure symptoms are noted during perinatal control.

Protective effects of recombinant human erythropoietin against pressure overload-induced left ventricular remodeling and premature death in mice.

Chronic left ventricular (LV) pressure overload induced by hypertension is one of the most common causes of heart failure. Earlier reports have shown the cardioprotective effects of erythropoietin (EPO). In the present study, we tested the hypothesis that recombinant human EPO exerts a protective effect against pressure-overload induced LV remodeling. Mice subjected to transverse aortic constriction (TAC) (n = 70) were randomly assigned to the treatment with phosphate buffer solution (PBS) (TAC-PBS) or EPO (2,000 U/kg twice a week) (TAC-EPO). At 8 weeks after TAC, LV weight was comparably increased in both TAC groups compared with sham-operated mice (Sham) (both P < 0.001). The treatment with EPO improved the survival of TAC mice as compared with treatment with PBS (80 vs. 47%, P < 0.01), which was associated with reductions in the extent of myocardial fibrosis and the number of TUNEL positive cardiomyocytes (both P < 0.05). Echocardiography revealed that TAC increased LV chamber diameter and decreased LV fractional shortening compared with Sham (P < 0.05), which was ameliorated by the treatment with EPO (P < 0.05). In TAC-EPO as compared to TAC-PBS, phosphorylation of STAT3, Akt and eNOS was all increased, while phosphorylation of p38 was decreased (all P < 0.05). Importantly, the expression level of VEGF and the capillary density in LV myocardium were similar among the 3 groups. These results suggest that recombinant human EPO ameliorates the cardiac remodeling and the premature death associated with chronic LV pressure overload through the mechanisms independent of angiogenesis.

A case of vasospastic angina with exertional sign.

We herein report a case of a 56-year-old woman with angina pectoris. She visited our emergency room because of chest pain. She finally underwent emergency percutaneous coronary intervention in right coronary artery due to acute coronary syndrome. Several months later, she complained of exertional chest pain again. Exercise-stress electrocardiogram showed ST-segment depression in V2-V6. However, coronary angiography showed no organic stenosis and we conducted acetylcholine provocation test. We finally detected severe coronary artery spasm and diagnosed exercise-induced vasospastic angina (VSA). This case highlights the importance of the recognition of exercise-induced VSA. Exercise-induced VSA needs the definite diagnosis and appropriate treatment. Learning objective Many patients felt chest pain even if they have undergone percutaneous coronary intervention (PCI). This case highlights the importance of the recognition of exercise-induced vasospastic angina (VSA). Exercise-induced VSA needs definite diagnosis and appropriate treatment. This case report describes the importance of precise diagnosis and highlights the recognition of exercise-induced VSA. We recommend the acetylcholine provocation test after PCI in order to determine the diagnosis of exercise-induced VSA.

Oncostatin M is a novel biomarker for coronary artery disease - A possibility as a screening tool of silent myocardial ischemia for diabetes mellitus.

OBJECTIVE: Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family which plays a crucial role in the pathogenesis of atherosclerosis. Therefore, we tested our hypothesis that serum OSM levels are increased in patients with coronary artery diseases (CAD). METHODS AND RESULTS: Serum OSM level was measured by sandwich technique immunoassay in 315 consecutive patients and who underwent coronary angiography at the International University of Health and Welfare Hospital from April 2019 to March 2021. A diagnosis of CAD was made in 169 patients. Serum OSM levels were significantly higher in patients with significant coronary stenosis compared to those without it. [123.0 ± 46.7 pg/mL (n = 169) vs. 98.3 ± 47.9 pg/mL (n = 146), p < 0.001]. A positive correlation was noted between serum OSM levels and severity and complexity of coronary stenosis. Importantly, the coronary revascularization significantly decreased the serum OSM levels. We furthermore detected a positive correlation between serum OSM levels and HbA1c levels. Finally, our data suggested that 120 pg/mL of serum OSM was the potential cutoff value for screening of silent myocardial ischemia related with diabetic mellitus (DM). CONCLUSION: Serum OSM can be a novel biomarker for CAD and may be useful for the screening of asymptomatic CAD in patients with DM.

Identification of cardiac-specific myosin light chain kinase.

Two myosin light chain (MLC) kinase (MLCK) proteins, smooth muscle (encoded by mylk1 gene) and skeletal (encoded by mylk2 gene) MLCK, have been shown to be expressed in mammals. Even though phosphorylation of its putative substrate, MLC2, is recognized as a key regulator of cardiac contraction, a MLCK that is preferentially expressed in cardiac muscle has not yet been identified. In this study, we characterized a new kinase encoded by a gene homologous to mylk1 and -2, named cardiac MLCK, which is specifically expressed in the heart in both atrium and ventricle. In fact, expression of cardiac MLCK is highly regulated by the cardiac homeobox protein Nkx2-5 in neonatal cardiomyocytes. The overall structure of cardiac MLCK protein is conserved with skeletal and smooth muscle MLCK; however, the amino terminus is quite unique, without significant homology to other known proteins, and its catalytic activity does not appear to be regulated by Ca(2+)/calmodulin in vitro. Cardiac MLCK is phosphorylated and the level of phosphorylation is increased by phenylephrine stimulation accompanied by increased level of MLC2v phosphorylation. Both overexpression and knockdown of cardiac MLCK in cultured cardiomyocytes revealed that cardiac MLCK is likely a new regulator of MLC2 phosphorylation, sarcomere organization, and cardiomyocyte contraction.

Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects.

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit (Na(v)1.5-alpha), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.

Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris.

BACKGROUND: Low-energy shock wave (SW) therapy has improved myocardial ischemia in both a porcine model and in patients with severe angina pectoris. METHODS AND RESULTS: To further confirm the effectiveness and safety of SW therapy, 8 patients with severe angina pectoris were treated with SW therapy in a double-blind, placebo-controlled and cross-over manner. SW therapy, but not placebo, significantly improved chest pain symptoms and cardiac function without any complications or adverse effects. CONCLUSIONS: Extracorporeal cardiac SW therapy is an effective, safe and non-invasive therapeutic option for severe angina pectoris.

Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation.

Mutations in homeoprotein NKX2-5 are linked to human congenital heart disease, resulting in various cardiac anomalies, as well as in postnatal progressive conduction defects and occasional left ventricular dysfunction; yet the function of Nkx2-5 in the postnatal period is largely unexplored. In the heart, the majority of cardiomyocytes are believed to complete cell-cycle withdrawal shortly after birth, which is generally accompanied by a re-organization of chromatin structure shown in other tissues. We reasoned that the effects of the loss of Nkx2-5 in mice may be different after cell-cycle withdrawal compared with those of the perinatal loss of Nkx2-5, which results in rapid conduction and contraction defects within 4 days after the deletion of Nkx2-5 alleles (Circ Res. 2008;103:580). In this study, floxed-Nkx2-5 alleles were deleted using tamoxifen-inducible Cre transgene (Cre-ER) beginning at 2 weeks of age. The loss of Nkx2-5 beginning at 2 weeks of age resulted in conduction and contraction defects similar to the perinatal loss of Nkx2-5, however, with a substantially slower disease progression shown by 1 degrees atrioventricular block at 6 weeks of age (4 weeks after tamoxifen injections) and heart enlargement after 12 weeks of age (10 weeks after tamoxifen injections). The phenotypes were accompanied by a slower and smaller degree of reduction of several critical Nkx2-5 downstream targets that were observed in mice with a perinatal loss of Nkx2-5. These results suggest that Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age, but with a substantially distinct level of necessity at 2 weeks of age compared with that in the perinatal period.

Protective role of endogenous erythropoietin system in nonhematopoietic cells against pressure overload-induced left ventricular dysfunction in mice.

BACKGROUND: Erythropoietin (Epo) receptors (EpoRs) are expressed in the heart. We have recently demonstrated that the endogenous Epo-EpoR system plays an important protective role in myocardial ischemia in mice and humans. In the present study, we tested our hypothesis that the endogenous Epo-EpoR system in nonhematopoietic cells also plays a protective role against pressure overload-induced cardiac dysfunction in vivo. METHODS AND RESULTS: Transgene-rescued EpoR-null mutant mice (EpoR-/-(rescued)) that express EpoR exclusively in the hematopoietic cells were subjected to transverse aortic constriction (TAC). At 1 week after TAC, left ventricular weight and lung weight were significantly increased in EpoR-/-(rescued) mice compared with wild-type mice, although the fibrotic area was comparably increased after TAC in the 2 genotypes. In the EpoR-/-(rescued) mice with TAC, left ventricular end-diastolic diameter was significantly increased, left ventricular fractional shortening was significantly decreased, and survival rate was significantly decreased compared with wild-type mice with TAC. Phosphorylation of STAT3 at 5 hours and 1 week after TAC and that of p38 at 5 hours after TAC were significantly increased in wild-type mice but not in EpoR-/-(rescued) mice. Vascular endothelial growth factor protein expression and capillary density in left ventricular myocardium were significantly decreased in EpoR-/-(rescued) mice with TAC compared with wild-type mice with TAC. CONCLUSIONS: These results suggest that the endogenous Epo-EpoR system in the nonhematopoietic cells plays an important protective role against pressure overload-induced cardiac dysfunction in vivo.

Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion.

OBJECTIVE: Recent studies suggested that erythropoietin (Epo) receptors (EpoR) are expressed not only in the hematopoietic lineage cells but also in the heart and that the administration of recombinant human Epo elicits protective effects in myocardial ischemia and reperfusion (I/R). We tested our hypothesis that endogenous Epo signals mediated by EpoR expressed in the non-hematopoietic lineage cells play a protective role against myocardial I/R injury. METHODS: Transgene-rescued EpoR null mutant mice (RES), which express EpoR exclusively in the hematopoietic lineage cells, were subjected to 30 min left coronary artery occlusion followed by reperfusion. RESULTS: Hematocrit, heart rate, blood pressure, heart weight, and echocardiographic parameters were comparable between wild-type mice (WT) and RES under the baseline condition. After 24 h of reperfusion, the infarct size in RES with I/R (RES/MI) was larger than that in WT/MI. Caspase-3 activity and number of TUNEL-positive cardiomyocytes in the ischemic area were increased in RES/MI compared with WT/MI. The extents of p38 and JNK phosphorylations in the ischemic area were significantly increased in WT/MI, but not in RES/MI as compared with corresponding sham-operated mice. Plasma Epo concentration in RES/MI did not differ from that in sham-operated RES, while that in WT/MI was peaked at 24 h post I/R. Additionally, left ventricular (LV) end-diastolic diameter was increased and LV fractional shortening tended to be reduced in the RES/MI compared with WT/MI at 21 days after I/R. CONCLUSIONS: These results suggest that the endogenous Epo-EpoR system in the non-hematopoietic lineage cells plays an important protective role against myocardial I/R injury.