Consecutive electrocardiographic changes during percutaneous coronary intervention for acute coronary syndrome with high-grade atrioventricular block: a case report.

BACKGROUND: Acute coronary syndrome (ACS) with high-grade atrioventricular block (HAVB) still has a poor mortality risk, even in the current percutaneous coronary intervention (PCI) era. However, early PCI for ACS with HAVB is associated with improved in-hospital survival and a 6-month survival similar to that of ACS without HAVB. CASE PRESENTATION: A 70-year-old man was admitted to our hospital for ACS with HAVB. ECG showed complete AV block, complete right bundle branch block (CRBBB), and left axis deviation. Cardiac enzymes were elevated. He underwent temporary pacemaker insertion and coronary angiography, which showed severe stenosis of the proximal right coronary artery (RCA), 99% stenosis of the distal RCA with Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow, and total occlusion of the proximal left anterior descending artery (LAD). We performed primary PCI in both the RCA and LAD, which resulted in TIMI grade 3 flow in both. After PCI, the HAVB recovered to normal sinus rhythm with CRBBB; a normal QRS interval returned within three days. The patient was discharged from the hospital without complications. CONCLUSION: In this case of ACS with HAVB, early intensive coronary artery reperfusion resulted in long-term patient survival. The blood supply to the AV node and bilateral bundle branches is complex. Multivessel ischemia may compromise both primary and collateral blood flows to the AV node and septum, resulting in severe conduction impairment. Clinicians performing PCI should be aware of this anatomy and physiology.

The potential hazard of a non-slip element balloon causing distal longitudinal stent deformation: the first clinical experience and in vitro assessment.

BACKGROUND: A new complication, longitudinal stent deformation (LSD), is increasingly reported with recent intracoronary stent designs. There have been experiences of unusual cases of distal LSD caused by entrapment of a Lacrosse® non-slip element (NSE) balloon (Goodman Co., Ltd., Nagoya, Japan), which has three flexible nylon elements to prevent slippage. Accordingly, the aim of this study is to report the clinical experience of distal LSD caused by the NSE in the documented center and to investigate the incidence and mechanisms involved. METHODS: Coronary intervention cases were retrospectively reviewed using the NSE balloon in hospital between May 2014 and June 2017. In bench testing, distal LSD was reproduced in a silicon tube model to identify its mechanism. RESULTS: A total of 95 patients with 107 lesions underwent coronary interventions with NSE. Of these, 72 lesions (12 de-novo lesions and 60 in-stent restenosis) were treated using in-stent dilatation. Two distal LSD cases occurred, representing an incidence of 2.78% (2/72) among all procedures; 16.7% (2/12) of the de-novo lesions developed LSD. In vitro experimentation allowed indentification of the mechanisms involved and bailout strategies. CONCLUSIONS: This is the first study to evaluate NSE balloon catheter entrapment complicated by distal LSD in which reconstruction of the deformed stent and retrieval of the NSE could be achieved successfully. There is a potential hazard for distal LSD during post-dilatation using the NSE balloon due to its structural characteristics. Careful assessment is needed to prevent this complication.

The effectiveness of super-selective injection with anchor balloon technique for collateral channel assessment.

The careful assessment of collateral channels is important for a retrograde approach for a chronic total coronary occlusion (CTO). This case report describes a percutaneous coronary intervention for CTO of the distal right coronary artery with good collateral circulation. All visible collateral channels failed by the retrograde approach; however, the procedure was successful using the distal atrial circumflex (AC) channel. Although this distal channel was poorly visualized on standard coronary angiography, it was clearly contrasted retrogradely from the CTO exit using a super-selective injection through the proximal AC channel as the antegrade flow was obstructed by the anchor balloon. This case highlights a unique super-selective injection with anchor balloon technique for collateral channel assessment.

The potential hazard of drug-eluting stent-induced coronary vasospasm causing subacute stent thrombosis: a case report.

BACKGROUND: Drug-eluting stent (DES) -induced coronary vasospasm is a well known phenomenon after stent implantation; however, the extent of this risk is still unknown. We report a case in which DES-induced severe coronary vasospasm was clinically suspected as a cause of subacute stent thrombosis (ST). CASE PRESENTATION: A 67-year-old man came to our hospital due to chest pain with mild exercise. He was diagnosed with effort angina by coronary angiography and underwent DES implantation in the mid-left ascending artery (LAD) after the administration of dual anti-platelet therapy. The procedure was uneventful, but his symptoms changed from effort angina to rest angina after stenting. Five days after the procedure, subacute ST occurred, requiring aspiration thrombectomy and balloon angioplasty. Thereafter, he continued to report early morning chest discomfort. We performed a spasm provocation test to evaluate the coronary vasomotor response; it revealed severe stent-edge spasm in the left main trunk to the LAD, except for the stented lesion, and total occlusion of the left circumflex artery. CONCLUSIONS: To our knowledge, the present case is the first report describing in-stent thrombosis secondary to stent-edge spasm. This case describes the potential hazard of DES-induced coronary vasospasm. Although there are several overlapping risk factors for ST development, we consider that stent-edge spasm also plays an important role in ST development. Therefore, we should monitor new-onset rest angina after stent implantation and carefully assess DES-induced coronary vasospasm.

Acute myocardial infarction with "wrap around" right coronary artery mimicking Takotsubo cardiomyopathy: a case report.

BACKGROUND: Takotsubo cardiomyopathy (TC) is a cardiomyopathy that shows distinctive clinical conditions first described more than 20 years ago. Because clinical features of TC mimic those of anterior acute myocardial infarction (AMI), the differential diagnosis is important in selecting the appropriate treatment strategy in the acute phase. But it was difficult to differentiate those two diseases because the TC-like findings; such as the electrocardiogram (ECG) changes and left ventricular wall motion abnormality can occur in AMI especially with the anatomical variance of the coronary artery. CASE PRESENTATION: A 63-year-old man was admitted due to sudden onset of chest pain and was in a cardiogenic shock state. His ECG showed ST-segment elevation in precordial (V2-6) and inferior leads (II, III, and aVF) and ST-segment depression in lead aVR. Blood biochemistry showed that cardiac enzymes were not elevated. Ultrasonic cardiography showed that the left ventricular apical level was akinetic, papillary muscle level was severely hypokinetic, and basal level was hyperkinetic, mimicking TC. However, coronary angiogram showed total occlusion of his right coronary artery wrapping around the cardiac apex. Successful percutaneous coronary intervention reversed his critical status. CONCLUSION: To our knowledge, the present case is the first report described AMI with wrap-around RCA, mimicking TC. Although TC is increasingly recognized as a true but relatively infrequent clinical entity, it is still important to carefully rule out obstructive coronary artery disease.

Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction.

Oxidative stress plays a critical role in the pathophysiology of cardiac failure, including the modulation of neovascularization following myocardial infarction (MI). Redox molecules thioredoxin (Trx) and glutaredoxin (Grx) superfamilies actively maintain intracellular thiol-redox homeostasis by scavenging reactive oxygen species. Among these two superfamilies, the pro-angiogenic function of Trx-1 has been reported in chronic MI model whereas similar role of Grx-1 remains uncertain. The present study attempts to establish the role of Grx-1 in neovascularization and ventricular remodeling following MI. Wild-type (WT) and Grx-1 transgenic (Grx-1(Tg/+)) mice were randomized into wild-type sham (WTS), Grx-1(Tg/+) Sham (Grx-1(Tg/+)S), WTMI, Grx-1(Tg/+)MI. MI was induced by permanent occlusion of the LAD coronary artery. Sham groups underwent identical time-matched surgical procedures without LAD ligation. Significant increase in arteriolar density was observed 7 days (d) after surgical intervention in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Further, improvement in myocardial functional parameters 30 d after MI was observed including decreased LVIDs, LVIDd, increased ejection fraction and, fractional shortening was also observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Moreover, attenuation of oxidative stress and apoptotic cardiomyocytes was observed in the Grx-1(Tg/+)MI group as compared to the WTMI animals. Increased expression of p-Akt, VEGF, Ang-1, Bcl-2, survivin and DNA binding activity of NF-κB were observed in the Grx-1(Tg/+)MI group when compared to WTMI animals as revealed by Western blot analysis and Gel-shift analysis, respectively. These results are the first to demonstrate that Grx-1 induces angiogenesis and diminishes ventricular remodeling apparently through neovascularization mediated by Akt, VEGF, Ang-1 and NF-κB as well as Bcl-2 and survivin-mediated anti-apoptotic pathway in the infarcted myocardium.

Thioredoxin 1 enhances neovascularization and reduces ventricular remodeling during chronic myocardial infarction: a study using thioredoxin 1 transgenic mice.

Oxidative stress plays a crucial role in disruption of neovascularization by alterations in thioredoxin 1 (Trx1) expression and its interaction with other proteins after myocardial infarction (MI). We previously showed that Trx1 has angiogenic properties, but the possible therapeutic significance of overexpressing Trx1 in chronic MI has not been elucidated. Therefore, we explored the angiogenic and cardioprotective potential of Trx1 in an in vivo MI model using transgenic mice overexpressing Trx1. Wild-type (W) and Trx1 transgenic (Trx1(Tg/+)) mice were randomized into W sham (WS), Trx1(Tg/+) sham (TS), WMI, and TMI. MI was induced by permanent occlusion of LAD coronary artery. Hearts from mice overexpressing Trx1 exhibited reduced fibrosis and oxidative stress and attenuated cardiomyocyte apoptosis along with increased vessel formation compared to WMI. We found significant inhibition of Trx1 regulating proteins, TXNIP and AKAP 12, and increased p-Akt, p-eNOS, p-GSK-3ß, HIF-1α, ß-catenin, VEGF, Bcl-2, and survivin expression in TMI compared to WMI. Echocardiography performed 30days after MI revealed significant improvement in myocardial functions in TMI compared to WMI. Our study identifies a potential role for Trx1 overexpression and its association with its regulatory proteins TXNIP, AKAP12, and subsequent activation of Akt/GSK-3ß/ß-catenin/HIF-1α-mediated VEGF and eNOS expression in inducing angiogenesis and reduced ventricular remodeling. Hence, Trx1 and other proteins identified in our study may prove to be potential therapeutic targets in the treatment of ischemic heart disease.

Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats.

OBJECTIVE: Hyperglycemia impairs angiogenesis in response to ischemia, leading to ventricular remodeling. Although the effects of overexpressing angiogenic growth factors have been studied in inducing angiogenesis, the formation of functional vessels remains a challenge. The present study evaluates the reversal of diabetes-mediated impairment of angiogenesis in the infarcted diabetic rat myocardium by proangiogenic gene therapy. RESEARCH DESIGN AND METHODS: Ad*VEGF and Ad*Ang1 were intramyocardially administered in combination immediately after myocardial infarction to nondiabetic and diabetic rats. Ad*LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. The myocardial function was measured by echocardiography 30 days after the intervention. RESULTS: We observed reduced fibrosis and increased capillary/arteriolar density along with reduced ventricular remodeling, as assessed by echocardiography in the treated diabetic animals compared with the nontreated diabetic controls. We also observed increased phosphorylated mitogen-activated protein kinase-activated protein kinase-2, 2 days after the treatment and increased expression of vascular endothelial growth factor (VEGF), Flk-1, angiopoietin-1 (Ang-1), Tie-2, and survivin, 4 days after treatment in the diabetic animals. Gel shift analysis revealed that the combination gene therapy stimulated the DNA binding activity of nuclear factor-kappaB in the diabetic animals. CONCLUSIONS: Our preclinical data demonstrate the efficacy of coadministration of adenoviral VEGF and Ang-1 in increasing angiogenesis and reducing ventricular remodeling in the infarcted diabetic myocardium. These unique results call for the initiation of a clinical trial to assess the efficacy of this therapeutic strategy in the treatment of diabetes-related human heart failure.

N-acetylcysteine abolishes the protective effect of losartan against left ventricular remodeling in cardiomyopathy hamster.

Oxidative stress mediated by activation of angiotensin II type-1 receptor (AT(1)R) plays a crucial role in the progression of heart failure. We investigated the effect of N-acetylcysteine (NAC) and an AT(1)R blocker on oxidative stress and left ventricular (LV) remodeling in BIO14.6 cardiomyopathy hamsters. The cardiomyopathy hamsters were treated with NAC or the AT(1)R blocker losartan for 20 weeks. Although NAC and losartan inhibited oxidative stress and upregulation of iNOS in the cardiomyopathy hamster heart, only losartan inhibited LV chamber dilation, myocardial fibrosis, and LV dysfunction in the cardiomyopathy hamster. Co-treatment with NAC abolished the protective effect of losartan against LV remodeling associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt and eNOS activation. An iNOS inhibitor 1400W or a nonselective NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) exacerbated LV remodeling in the cardiomyopathy hamster. However, L-NAME but not 1400W abrogated losartan-mediated inhibition of LV remodeling. These results suggest that redox-sensitive upregulation of iNOS plays a crucial role in preventing LV remodeling in the BIO14.6 cardiomyopathy hamster. Losartan inhibits LV remodeling by switching the cardioprotective mechanism from iNOS- to eNOS-dependence, but NAC abolishes the protective effect of losartan by inhibiting redox-sensitive activation of PI3K/Akt and eNOS in the cardiomyopathy hamster.

White wine induced cardioprotection against ischemia-reperfusion injury is mediated by life extending Akt/FOXO3a/NFkappaB survival pathway.

Recent studies on the protection afforded by moderate wine consumption against cardiovascular diseases have focused mainly on the activity of red wine in view of its high content of antioxidants, especially polyphenols. White wine lacks polyphenols, but it contains other compounds such as hydroxycinnamic acids (caffeic acid) and monophenols (tyrosol), which are known to have antioxidant properties. Therefore, this study was designed to examine the effect of white wine in myocardial ischemic-reperfusion injury. The experimental rats were gavaged with white wine (Soave Suavia "Le Rive" 2004) at a dosage of 6.5 mL/(kg.rat.day) for 30 days. Rats were divided into four groups: control sham (CS), wine-treated sham (WS), control ischemia (I)/reperfusion (R) (CIR), and wine + IR (WIR). All the rats in both IR groups underwent 30 min occlusion of the left anterior descending coronary artery followed by 8, 24 h, and 30 days of reperfusion (R). Significant reduction in infarct size (21 vs 39%, n = 6), cardiomyocyte (274 vs 384 counts/100 HPF, n = 6), and endothelial cell apoptosis (387 vs 587 counts/100 HPF) was observed in WIR as compared with CIR after 24 h of reperfusion. Echocardiography demonstrated significant increased fractional shortening (32 vs 22%) and ejection fraction (60 vs 44%) following 30 days of reperfusion in WIR rats compared to CIR ( n = 6). In addition, increased phosphorylation of AKT, Foxo3a, and eNOS were found in WS and WIR, as compared to their respective controls. The gel-shift analysis demonstrated significant upregulation of DNA binding activity of NF-kappaB in the white wine-treated groups. This report demonstrated for the first time that the white wine mediated cardioprotection in ischemic reperfused myocardium is through the PI-3kinase/Akt/FOXO3a/e-NOS/NF-kappaB survival pathway.

Angiotensin II type 1 receptor blocker preserves tolerance to ischemia-reperfusion injury in Dahl salt-sensitive rat heart.

Oxidative stress is involved in the tolerance to ischemia-reperfusion (I/R) injury. Because angiotensin II type 1 receptor blockers (ARBs) inhibit oxidative stress, there is concern that ARBs abolish the tolerance to I/R injury. Dahl salt-sensitive (DS) hypertensive and salt-resistant (DR) normotensive rats received an antioxidant, 2-mercaptopropionylglycine (MPG), or an ARB, losartan, for 7 days. Losartan and MPG significantly inhibited oxidative stress as determined by tissue malondialdehyde + 4-hydroxynoneal and increased expression of inducible nitric oxide synthase (iNOS) in the DS rat heart. However, losartan but not MPG activated endothelial nitric oxide synthase (eNOS) as assessed by phosphorylation of eNOS on Ser1177. Infarct size after 30-min left coronary artery occlusion followed by 2-h reperfusion was comparable between DS and DR rat hearts. Although MPG and losartan had no effect on infarct size in the DR rat heart, MPG but not losartan significantly increased infarct size in the DS rat heart. A selective iNOS inhibitor, 1400W, increased infarct size in the DS rat heart, but it had no effect on infarct size in the losartan-treated DS rat heart. However, a nonselective NOS inhibitor, Nomega-nitro-l-arginine methyl ester, increased infarct size in the losartan-treated DS rat heart. These results suggest that losartan preserves the tolerance to I/R injury by activating eNOS despite elimination of redox-sensitive upregulation of iNOS and iNOS-dependent cardioprotection in the DS rat heart.

Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS.

We investigated the mechanism of exercise-induced late cardioprotection against ischemia-reperfusion (I/R) injury. C57BL/6 mice received treadmill exercise (60 min/day) for 7 days at a work rate of 60-70% maximal oxygen uptake. Exercise transiently increased oxidative stress and activated endothelial isoform of nitric oxide synthase (eNOS) during exercise and increased expression of inducible isoform of NOS (iNOS) in the heart after 7 days of exercise. The mice were subjected to regional ischemia by 30 min of occlusion of the left coronary artery, followed by 2 h of reperfusion. Infarct size was significantly smaller in the exercised mice. Ablation of cardiac sympathetic nerve by topical application of phenol abolished oxidative stress, activation of eNOS, upregulation of iNOS, and cardioprotection mediated by exercise. Treatment with the antioxidant N-(2-mercaptopropionyl)-glycine during exercise also inhibited activation of eNOS, upregulation of iNOS, and cardioprotection. In eNOS(-/-) mice, exercise-induced oxidative stress was conserved, but upregulation of iNOS and cardioprotection was lost. Exercise did not confer cardioprotection when the iNOS selective inhibitor 1400W was administered just before coronary artery occlusion or when iNOS(-/-) mice were employed. These results suggest that exercise stimulates cardiac sympathetic nerves that provoke redox-sensitive activation of eNOS, leading to upregulation of iNOS, which acts as a mediator of late cardioprotection against I/R injury.

Role of mechanical stress in the form of cardiomyocyte death during the early phase of reperfusion.

BACKGROUND: The hypothesis that mechanical stress during reperfusion produces myocyte oncosis and inhibits apoptosis was tested in the present study. METHODS AND RESULTS: Isolated and perfused rat hearts were subjected to 30 min ischemia followed by 150 min reperfusion. In the control-reperfusion heart, the form of myocyte death was a mixture of apoptosis only, oncosis only, and both apoptosis and oncosis. Apoptotic myocytes contained mitochondria that maintained membrane potential (Deltapsim), whereas oncotic myocytes contained only Deltapsim-collapsed mitochondria. Treatment with the contractile blocker 2,3-butanedione monoxime (BDM) during reperfusion increased caspase-3 activity and produced predominantly apoptosis. However, withdrawal of BDM provoked oncosis in terminal deoxynucleotide nick-end labeling (TUNEL)-positive myocytes. Myocardial stretch by inflating an intraventricular balloon at the time of reperfusion with BDM increased only oncotic myocytes, whereas the same mechanical stress 120 min after reperfusion increased oncotic myocytes positive for TUNEL. Increased mechanical stress at the time of reperfusion by treatment with isoproterenol or hyposmotic buffer inhibited caspase-3 activity and increased only oncotic myocytes. Co-treatment with the caspase-3 inhibitor, Ac-DEVD-CHO, and BDM during reperfusion inhibited myocyte apoptosis and oncosis but did not inhibit oncosis after withdrawal of BDM. CONCLUSIONS: These results suggest that mechanical stress is a critical determinant of the form of myocyte death during the early phase of reperfusion.

Role of oxidative/nitrosative stress in the tolerance to ischemia/reperfusion injury in cardiomyopathic hamster heart.

We investigated the role of oxidative/nitrosative stress in the tolerance to ischemia/reperfusion (I/R) injury in BIO14.6 cardiomyopathy hamster hearts at 6 weeks of age. These hearts showed no significant morphologic change and left ventricular (LV) dysfunction. However, expression and activity of iNOS, nitrotyrosine (NT) formation, and protein kinase C (PKC)-epsilon activity were increased in these hearts. When the BIO14.6 hamster hearts were isolated and subjected to 40 min of global ischemia, they showed smaller myocardial necrosis and greater recovery of LV function during reperfusion compared with the control hamster heart. All of these effects were abrogated by prolonged treatment with the antioxidant, 2-mercaptopropionylglycine (MPG). Brief preischemic treatment with MPG or the iNOS inhibitor 1400W also abrogated NT formation and activation of PKC-epsilon and inhibited the tolerance to I/R injury in the BIO14.6 hamster heart. Brief preischemic treatment with the PKC inhibitor chelerythrine or the K(ATP) channel blockers, 5-hydroxydecanoate (5-HD) and glibenclamide, had no effect on iNOS activation and NT formation but inhibited the tolerance to I/R injury in the cardiomyopathic heart. These results suggest that oxidative/nitrosative stress plays a role in the tolerance to I/R injury in the cardiomyopathic heart through activation of PKC and the downstream effectors, K(ATP) channels.

Effects of intravenous administration of tissue plasminogen activator before thrombectomy in patients with acute myocardial infarction.

BACKGROUND: Myocardial salvage after acute myocardial infarction (AMI) largely depends on the removal of infarct-related thrombus. Although both thrombolysis and thrombectomy are effective strategies to remove thrombus, there is a paucity of reports regarding the benefit of the combination therapy. Therefore, the efficacy of intravenous administration with mutant tissue plasminogen activator (Mt-PA) before thrombectomy and ordinary percutaneous coronary intervention (PCI) was evaluated. METHODS AND RESULTS: Consecutive 44 AMI patients without contraindication of Mt-PA were enrolled in the study and randomly assigned to thrombectomy with Mt-PA pre-administration (group T) or thrombectomy alone (group N). Although Thrombolysis in Myocardial Infarction (TIMI) grade before PCI and TIMI myocardial perfusion grade immediately after PCI were significantly greater in group T (p<0.05), there was no improvement of left ventricular ejection fraction immediately and 6 months after PCI. CONCLUSIONS: These results suggest that intravenous administration with Mt-PA before thrombectomy had no significant benefit in the salvage of infracted myocardium over thrombectomy alone, despite improvement of coronary microcirculation immediately after PCI.

Dystrophin is a possible end-target of ischemic preconditioning against cardiomyocyte oncosis during the early phase of reperfusion.

OBJECTIVE: Dystrophin is a sarcolemmal membrane protein that prevents the myocyte from oncosis induced by physical stress. Because ischemic preconditioning (IPC) protects mitochondria and prevents oncosis during reperfusion, we hypothesized that dystrophin is an end-target of IPC distal to mitochondrial protection. METHODS AND RESULTS: Isolated rat hearts were subjected to 30 min ischemia followed by reperfusion. IPC was introduced by 3 cycles of 5 min ischemia and 5 min reperfusion. The loss of sarcolemmal dystrophin and myocardial ATP during ischemia was comparable between the control and the IPC heart. Similar changes in sarcolemmal dystrophin and myocardial ATP were observed when the heart was treated with 2,4-dinitrophenol (DNP), an uncoupler of mitochondrial respiration, or oligomycin, an inhibitor of mitochondrial F1F0-ATPase. However, the IPC heart increased sarcolemmal dystrophin during reperfusion associated with an increase in tetramethylrhodamine ethylester (TMRE) uptake, an indicator of mitochondrial membrane potential (DeltaPsim), and myocardial ATP and inhibited myocyte oncosis. The increase in myocardial ATP and relocalization of dystrophin to the sarcolemma mediated by IPC was inhibited by treatment with DNP or oligomycin during reperfusion. In vitro experiments demonstrated that mitochondria isolated from the ischemic IPC heart increased ATP generation and facilitated relocalization of dystrophin from the insoluble to the soluble fractions in a manner sensitive to DNP and oligomycin. CONCLUSIONS: These results suggest that enhanced relocalization of dystrophin to the sarcolemma during reperfusion may be a mechanistic link between IPC-mediated improvement of mitochondrial function and its protection against oncosis during the early phase of reperfusion.

Opposing effect of p38 MAP kinase and JNK inhibitors on the development of heart failure in the cardiomyopathic hamster.

OBJECTIVE: p38 MAP kinase (p38 MAPK) and c-Jun NH2-terminal kinase (JNK) have been implicated in the pathophysiology of heart failure. We investigated the effects of chronic treatment with p38 MAPK and JNK inhibitors on the development of heart failure in dilated cardiomyopathy (DCM) hamster heart. METHODS AND RESULTS: BIO14.6 hamster hearts showed markedly increased p38 MAPK and JNK activities at 6 weeks of age when there was no significant increase in the area of fibrosis, heart weight/body weight, left ventricular (LV) chamber dilation and LV dysfunction. p38 MAPK and JNK activities were attenuated at 26 weeks of age and abolished at 40 weeks of age in BIO14.6 hamster hearts. BIO14.6 hamsters and the control BIOF1B hamsters were chronically treated (i.p.) with the p38 MAPK inhibitors, SB203580 (1 mg/kg/day) and FR167653 (3 mg/kg/day), or the JNK inhibitor, SP600125 (1 mg/kg/day) or vehicle for 20 weeks starting from 6 weeks of age. Treatment of BIO14.6 hamster hearts with SB203580 and FR167653 reduced the number of TUNEL-positive myocytes, the area of fibrosis and heart weight/body weight associated with a significant decrease of LV dimension and an increase in LV ejection fraction and LV contractility compared to the vehicle-treated counterpart. In contrast, treatment with SP600125 increased the number of TUNEL-positive myocytes and the area of interstitial fibrosis associated with aggravation of LV chamber dilation and LV dysfunction. CONCLUSIONS: These results suggest that chronic treatment with p38 MAPK and JNK inhibitors produces opposing effects on the development of heart failure in the DCM hamster heart.