Prognosis in myocardial infarction of young patients: Results of a prospective registry.

BACKGROUND: Myocardial infarction (MI) in young patients is rare. To address the gap in published all comers German studies concerning the clinical course and outcome of young patients aged ≤40 years with acute MI, the aim of this study was to identify differences between young and older, consecutive patients with MI and to compare these findings with previously published data. METHODS: This analysis used data of the prospective Dresden Myocardial Infarction Registry (1/2005-9/2014), an all comers, prospective registry in the department of Internal Medicine and Cardiology at the Heart Center Dresden, University Hospital Dresden. RESULTS: In total, data from 119 patients ≤40 years and 5754 patients >40 years were included in the analysis. In contrast to the older patients, younger patients were more often male (79.0% vs. 70.5%), smokers, had a positive family history for MI, lower educational qualifications, and lived alone. Young patients experienced more frequently STEMI than NSTEMI (70% vs. 30%), while the older patient group showed an equal distribution of infarction types (50% vs. 50%). The in-hospital mortality of young patients (2.5% vs. 7.6%) was lower. The survival rate of young patients in the 2-year follow-up was significantly higher (95% vs. 82.7%). Lifestyle modifications as part of secondary prevention were only moderately implemented. CONCLUSIONS: Compared to older patients, the outcome of young patients is significantly better and the acute event resolved without serious sequelae in most cases. Despite good cardiologic follow-up, implementation of secondary prevention was only moderate, indicating a need for more efficient patient education.

Correction to: Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients.

Because of a technical error, the code corresponding to the outcome for the Basir et al. cohort was mis-implemented in the original version of our article. Characteristics of the cohort are in fact the followings.

Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients.

OBJECTIVE: Catecholamines have been the mainstay of pharmacological treatment of cardiogenic shock (CS). Recently, use of epinephrine has been associated with detrimental outcomes. In the present study we aimed to evaluate the association between epinephrine use and short-term mortality in all-cause CS patients. DESIGN: We performed a meta-analysis of individual data with prespecified inclusion criteria: (1) patients in non-surgical CS treated with inotropes and/or vasopressors and (2) at least 15% of patients treated with epinephrine administrated alone or in association with other inotropes/vasopressors. The primary outcome was short-term mortality. MEASUREMENTS AND RESULTS: Fourteen published cohorts and two unpublished data sets were included. We studied 2583 patients. Across all cohorts of patients, the incidence of epinephrine use was 37% (17-76%) and short-term mortality rate was 49% (21-69%). A positive correlation was found between percentages of epinephrine use and short-term mortality in the CS cohort. The risk of death was higher in epinephrine-treated CS patients (OR [CI] = 3.3 [2.8-3.9]) compared to patients treated with other drug regimens. Adjusted mortality risk remained striking in epinephrine-treated patients (n = 1227) (adjusted OR = 4.7 [3.4-6.4]). After propensity score matching, two sets of 338 matched patients were identified and epinephrine use remained associated with a strong detrimental impact on short-term mortality (OR = 4.2 [3.0-6.0]). CONCLUSIONS: In this very large cohort, epinephrine use for hemodynamic management of CS patients is associated with a threefold increase of risk of death.

The endothelial nitric oxide synthase cofactor tetrahydrobiopterin shields the remote myocardium from apoptosis after experimental myocardial infarction in vivo.

BACKGROUND: Following myocardial infarction (MI), apoptosis occurs early in the remote myocardium and contributes to the processes of myocardial remodelling. Increased nitrosative stress is a well-known and potent inductor of myocardial apopto¬sis. Excess activation of endothelial nitric oxide synthase (eNOS) increases its uncoupling potential and results in nitrosative stress via formation of peroxynitrite. However, the pathophysiological role of eNOS signalling in the remote myocardium after MI is as yet undefined. AIM: The impact of eNOS activation on pro- and anti-apoptotic signalling in the remote myocardium and the influence of pretreatment with the eNOS cofactor tetrahydrobiopterin (BH4) on eNOS activation, nitrosative stress level, and apoptosis induction and execution were studied in a rat MI model in vivo. RESULTS: Twenty-four hours after anterior MI, eNOS activity in animals treated with left anterior descending coronary artery ligation (LIG) significantly increased in the posterior left ventricular (LV) myocardium as did protein nitrosylation when com¬pared to sham treatment. This was paralleled by induction of apoptosis via the extrinsic and intrinsic pathways. Moreover, anti-apoptotic signalling via protein kinase B/Akt and glycogen synthase-kinase 3 beta was suppressed. Notably, pretreatment with the eNOS cofactor BH4 reduced eNOS activation, prevented excess protein nitrosylation, blunted apoptosis induction, facilitated anti-apoptotic signalling, and eventually prevented apoptosis execution. CONCLUSIONS: Here we showed that 24 h after experimental MI in rats in vivo, apoptosis was induced in the posterior non-in¬farcted LV wall. Evidence is presented that pretreatment with the eNOS cofactor BH4 resulted in less nitrosative stress and weakened apoptotic processes, although the stabilisers contained did participate in this phenomenon. Because apoptosis is a crucial component of myocardial remodelling, influencing eNOS signalling might be an interesting pharmacological target for the development of novel anti-remodelling therapies.

[Treatment of acute heart failure]. / Therapie der akuten Herzinsuffizienz.

Acute heart failure is a symptom complex of heterogeneous etiology. Clinically, it comprises a broad spectrum ranging from hypertensive pulmonary edema in patients with preserved left ventricular systolic function up to cardiogenic shock in patients with severely depressed left ventricular function. The pathophysiology of acute heart failure is based on a mismatch between myocardial pump function and afterload. Besides causal measures, vasodilators and diuretics are the mainstay of therapy. Catecholamines are indicated only when other drugs are unsuccessful. Opioids are often used in clinical practice but should be used cautiously as they are associated with a negative prognosis. Further adjunctive treatment consists of thromboembolism prophylaxis, non-invasive ventilation and in some cases mechanical circulatory support and renal replacement therapy. This article discusses the differential use of these treatment modalities.

Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study.

BACKGROUND: Currently available antiarrhythmic agents for the treatment of atrial fibrillation (AF) have important limitations, leaving an unmet need for safe and effective therapy. Ranolazine is an approved antianginal agent with a favorable safety profile and electrophysiologic properties suggesting a potential role in the treatment of AF. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of ranolazine in the prevention of AF recurrence after successful electrical cardioversion and to ascertain the most appropriate dose of this agent. METHODS: This prospective, multicenter, randomized, double-blind, placebo-control parallel group phase II dose-ranging trial randomized patients with persistent AF (7 days to 6 months) 2 hours after successful electrical cardioversion to placebo, or ranolazine 375 mg, 500 mg, or 750 mg bid. Patients were monitored daily by transtelephonic ECG. The primary end-point was the time to first AF recurrence. RESULTS: Of 241 patients randomized, 238 took at least 1 drug dose. Ranolazine proved to be safe and tolerable. No dose of the drug significantly prolonged time to AF recurrence. AF recurred in 56.4%, 56.9%, 41.7%, and 39.7% of patients in the placebo, ranolazine 375 mg, ranolazine 500 mg, and ranolazine 750 mg groups, respectively. The reduction in overall AF recurrence in the combined 500-mg and 750-mg groups was of borderline significance compared to the placebo group (P = .053) and significant compared to 375-mg group (P = .035). CONCLUSION: No dose of ranolazine significantly prolonged time to AF recurrence. However, the 500-mg and 750 mg-groups combined reduced AF recurrences, suggesting a possible role for this agent in the treatment of AF.

Local inhibition of hypoxia-inducible factor reduces neointima formation after arterial injury in ApoE-/- mice.

OBJECTIVE: Hypoxia plays a pivotal role in development and progression of restenosis after vascular injury. Under hypoxic conditions the hypoxia-inducible factors (HIFs) are the most important transcription factors for the adaption to reduced oxygen supply. Therefore the aim of the study was to investigate the effect of a local HIF-inhibition and overexpression on atherosclerotic plaque development in a murine vascular injury model. METHODS AND RESULTS: After wire-induced vascular injury in ApoE-/- mice a transient, local inhibition of HIF as well as an overexpression approach of the different HIF-subunits (HIF-1α, HIF-2α) by adenoviral infection was performed. The local inhibition of the HIF-pathway using a dominant-negative mutant dramatically reduced the extent of neointima formation. The diminished plaque size was associated with decreased expression of the well-known HIF-target genes vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and Flk-1. In contrast, the local overexpression of HIF-1α and HIF-2α further increased the plaque size after wire-induced vascular injury. CONCLUSIONS: Local HIF-inhibition decreases and HIF-α overexpression increases the injury induced neointima formation. These findings provide new insight into the pathogenesis of atherosclerosis and may lead to new therapeutic options for the treatment of in stent restenosis.

Transapical endovascular stenting of penetrating atherosclerotic ulcer of ascending aorta.

A 71-year-old woman presented with acute chest pain and was admitted at our institution. Computed tomography revealed a penetrating atherosclerotic ulcer in the ascending aorta with extensive intramural hematoma. A transapical endovascular stenting was successfully performed. Computed tomography at a 6-month follow-up visit revealed a type I endoleak, which was restented through the same approach. Despite initial satisfactory results, follow-up revealed a persistent endoleak, so that a high-risk open surgical repair was required. Surgical replacement of the ascending aorta was successfully performed without postoperative neurologic deficit.

Transapical transcatheter aortic valve implantation vs conventional aortic valve replacement in high-risk patients with previous cardiac surgery: a propensity-score analysis.

OBJECTIVES: The present analysis compared clinical and mid-term outcomes of patients with previous cardiac surgery undergoing transapical transcatheter aortic valve implantation (TAVI) with propensity-matched patients undergoing conventional redo aortic valve replacement (cAVR). METHODS: Since 2008, 508 patients were treated with TAVI. Fifty-three of these patients presented with a history of cardiac surgery and underwent transapical TAVI using the Edwards SAPIEN bioprosthesis. A propensity-matched control group of 53 patients receiving cAVR was generated out of the hospital's database. The mean age for all the patients was 77.8 ± 4.5 years. The logistic EuroSCORE was 28.4 ± 13.6% in mean, and mean EuroSCORE II was 8.56 ± 3.93%. The mean follow-up time was 245 ± 323 days, which equated to a total of 700 patient-months. RESULTS: The observed hospital mortality did not differ significantly between TAVI and cAVR (TAVI: 9.4% and cAVR: 5.7%; P = 0.695). Six-month survival was 83.0% for the TAVI and 86.8% for the cAVR patients (P = 0.768). Postoperative bleedings (TAVI: 725 ± 1770 ml and cAVR: 1884 ± 6387; P = 0.022), the need for transfusion (TAVI: 1.7 ± 5.3 vs cAVR: 6.2 ± 13.7 units packed red blood cells (PRBC); P = 0.030), consecutive rethoracotomy (TAVI: 1.9% vs cAVR: 16.9%; P = 0.002) and postoperative delirium (TAVI: 11.5% vs cAVR: 28.3%; P = 0.046) were more common in the cAVR patients. The TAVI patients suffered more frequently from respiratory failure (TAVI: 11.3% vs cAVR: 0.0%; P = 0.017) and mean grade of paravalvular regurgitation (TAVI: 0.8 ± 0.2 vs cAVR: 0.0; P = 0.047). Although primary ventilation time (P = 0.020) and intensive care unit stay (P = 0.022) were shorter in the TAVI patients, mean hospital stay did not differ significantly (P = 0.108). CONCLUSIONS: Transapical TAVI as well as surgical aortic valve replacement provided good clinical results. The pattern of postoperative morbidity and mortality was different for both entities, but the final clinical outcome did not differ significantly. Both techniques can be seen as complementary approaches by means of developing a tailor-made and patient-orientated surgery.

Transcatheter valve-in-valve therapies: patient selection, prosthesis assessment and selection, results, and future directions.

The development of transcatheter valve implantations (TAVI) has induced profound changes in the treatment of valvular heart disease over the past decade. At the same time, due to excellent clinical results, bioprostheses continuously outperformed mechanical prostheses. The increasing number of elderly patients has led to numerous patients presenting with deteriorated bioprostheses needing reoperation. In selected high-risk patients or patients with unreasonable surgical risk, valve-in-valve TAVI has advanced to a viable alternative to conventional redo surgery. High procedural success, good hemodynamics and acceptable clinical results were reported up until now. Valve-in-valve TAVI seems to be safe and effective in treatment of deteriorated valve prostheses in high-risk patients. The valve-in-valve concept presents the next step toward an individual treatment strategy for patients at prohibitive risk for conventional surgery. Present studies were reviewed with special concern to patient selection, prosthesis assessment, device selection, clinical outcome and technical challenging aspects as well.

Uncoupled eNOS annihilates neuregulin-1ß-induced cardioprotection: a novel mechanism in pharmacological postconditioning in myocardial infarction.

Myocardial infarct size can be limited by pharmacological postconditioning (pPC) with cardioprotective agents. Cardioprotective effects of neuregulin-1ß (NRG) via activation of protein kinase B (Akt) and downstream pathways like endothelial nitric oxide synthase (eNOS) have been postulated based on results from cell culture experiments. The purpose of this study was to investigate if eNOS may be involved in pPC with NRG. NRG application in an ex vivo mouse model (C57Bl6) of ischemia-reperfusion injury was analyzed. Unexpectedly, the infarct size increased when NRG was infused starting 5 min prior to reperfusion, even though protective Akt and GSK3ß phosphorylation were enhanced. In eNOS deficient mice, however, NRG significantly reduced the infarct size. Co-infusion of NRG and L-arginine (Arg) lead to a reduction in infarct size in wild type animals. Electron paramagnetic resonance measurements revealed that NRG treatment prior to reperfusion leads to an enhanced release of reactive oxygen species compared to controls and this effect is blunted by co-infusion of Arg. This study documents the cardioprotective mechanisms of NRG signaling to be mediated by GSK3ß inactivation. This is the first study to show that this protection fails in situations with dysfunctional eNOS. In eNOS deficient mice NRG exerts its protective effect via the GSK3ß pathway, suggesting that the eNOS can limit cardioprotection. As dysfunctional eNOS has been described in cardiovascular risk factors like diabetes, hypertension, and hypercholesterolemia these findings can help to explain lack of postconditioning performance in models of cardiovascular co-morbidities.

Transapical transcatheter valve-in-valve implantation for deteriorated mitral valve bioprostheses.

BACKGROUND: The transcatheter valve-in-valve concept has been described for patients requiring redo valve surgery. We report our experience with transapical mitral valve-in-valve implantation. METHODS: Since 2008, 301 patients were treated with transapical transcatheter valve implantation. Seven of these patients presented with a deteriorated mitral valve bioprosthesis and underwent transapical mitral valve-in-valve implantation. Median age was 79 years. Preoperatively, all patients presented in New York Heart Association functional class III. For risk estimation, The Society of Thoracic Surgeons and European System for Cardiac Operative Risk scores were used and predicted high mortality (mean ± standard error of mean: Society of Thoracic Surgeons mortality, 12.3% ± 2.1%; European System for Cardiac Operative Risk mortality, 58.0% ± 7.0%). Mean follow-up time was 93 ± 29 days, with a total of 21.6 patient-months. RESULTS: Preoperatively, all patients who had deteriorated bioprostheses presented with severe regurgitation and increased transvalvular pressure gradients (maximal pressure gradient, 23.9 ± 0.9 mm Hg; mean pressure gradient, 11.3 ± 1.0 mm Hg). One patient was identified with mitral valve stenosis (effective orifice area, 0.25 cm(2)). All patients underwent successful transapical mitral valve-in-valve implantation. Sizes of previously implanted bioprostheses were 27, 29, and 31 mm; Edwards SAPIEN valves at sizes 26 and 29 mm were implanted. Postoperatively, echocardiography revealed excellent hemodynamics with no remaining mitral regurgitation in 5 patients and minimal regurgitation in 2 patients. Transvalvular pressure gradients decreased significantly (maximal pressure gradient, 13.8 ± 2.1 mm Hg; mean pressure gradient 5.7 ± 0.8 mm Hg, p < 0.05). One patient had fatal pneumonia on postoperative day 34. No patient died during further follow-up, and all patients remained in New York Heart Association class I or II. CONCLUSIONS: Our results demonstrate the feasibility of transapical mitral valve-in-valve implantation for treatment of a degenerated bioprosthesis (size range, 27 to 31 mm) using the Edwards SAPIEN valve in sizes 26 and 29 mm.

Inhibition of anti-apoptotic signals by Wortmannin induces apoptosis in the remote myocardium after LAD ligation: evidence for a protein kinase C-δ-dependent pathway.

It has been shown that, in the remote myocardium after infarction (MI), protein kinase C (PKC) inhibition reduces apoptosis both by blocking proapoptotic pathways and by activating antiapoptotic signals including the Akt pathway. However, it was open if vice versa, blockade of antiapoptotic pathways may influence proapoptotic signals. To clarify this, the present study tested the effects of the PI3-kinase blocker Wortmannin on proapoptotic signals and on apoptosis execution in the remote myocardium after infarction. Rats were subjected to MI by LAD ligation in situ. Some were pre-treated with Wortmannin alone or in combination with the PKC inhibitor Chelerythrine. After 24 h, pro- and anti-apoptotic signals (caspase-3, PKC isoforms, p38-MAPK, p42/44-MAPK, Akt, Bad), and marker of apoptosis execution (TUNEL) were quantified in the myocardium remote from the infarction. Wortmannin treatment increased apoptosis in the remote myocardium both at baseline and after MI, together with an activation of the PKC-δ/p38-MAPK-pathway. PKC-ε and p42/44-MAPK were unaffected. Combined treatment with Wortmannin and Chelerythrine fully reversed the pro-apoptotic effects of Wortmannin both at baseline and after MI. The PKC-δ-p38-MAPK-pathway as a strong signal for apoptosis in the non-infarcted myocardium can be influenced by targeting the anti-apoptotic PI3-kinase pathway. This gives evidence of a bi-directional crosstalk of pro- and anti-apoptotic signals after infarction.

A prospective, randomized trial of continuous lateral rotation ("kinetic therapy") in patients with cardiogenic shock.

BACKGROUND: Continuous lateral rotation ["Kinetic therapy" (KT)] has been shown to reduce complications and to shorten hospital stay in trauma patients. Data in non-surgical patients is inconclusive. Retrospective data suggest a beneficial effect of KT in patients with cardiogenic shock (CS) requiring ventilator therapy. KT, however, has not been tested prospectively in those patients. METHODS: A prospective, randomized, open-label trial was performed to compare KT using oscillating beds (TryaDyne Proventa, KCI) with standard care (SC). Patients with cardiogenic shock requiring ventilator therapy for more than 24 h were included. Primary endpoint was the occurrence of hospital-acquired pneumonia. Secondary endpoints were the occurrence of pressure ulcers during the hospital stay and 1-year all-cause mortality. RESULTS: Forty-five patients were randomized to KT, and 44 to SC. All patients required at least one inotropic agent and one vasopressor for circulatory assistance. The groups were comparable in the etiology of heart disease, in the use of revascularization procedures, the use of balloon counterpulsation, and APACHE-II score (33 ± 5 vs. 33 ± 4) and SOFA score (11 ± 1 vs. 11 ± 1) at inclusion; however, more patients in SC were subject to resuscitation before inclusion. Hospital-acquired pneumonia occurred in 10 patients in KT and 28 patients in SC (p < 0.001); pressure ulcers were seen in 10 versus 2 patients (p < 0.001). Hospital mortality tended to be lower in KT, and 1-year all-cause mortality was 41 % in KT and 66 % in SC (p = 0.028). CONCLUSION: The use of KT reduces rates of pneumonia and pressure ulcers as compared to SC. Moreover, in this study, patients with KT had a better outcome. The study suggests that KT should be used in patients with cardiogenic shock requiring ventilator therapy for a prolonged time.

Transapical endovascular deployment of a stent-graft in the thoracic descending aorta.

We report the case of a 74-year-old man with a large aneurysm (60 mm) of the descending thoracic aorta. Because of severe calcification and kinking of the iliac vessels, the expected access-related complication during the endovascular repair urged us to search for an alternative strategy. Having good experience with transcatheter aortic valve implantation, we thought that the transapical approach may be the best option in this case. The stent-graft was successfully deployed through the heart apex without any complications. The postoperative imaging showed an excellent result.

Transcatheter valve-in-valve implantation for deteriorated aortic bioprosthesis: initial clinical results and follow-up in a series of high-risk patients.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become a viable alternative in maximum risk patients. For those patients requiring aortic valve re-replacement, the "valve-in-valve" concept has been described. We report our experience with transapical valve-in-valve implantation in 7 patients with deteriorated aortic bioprosthesis at 1-year follow up. METHODS: Since November 2008, 210 patients received transapical TAVI due to severe aortic stenosis. Seven patients presented with deteriorated aortic valve bioprosthesis and received transapical valve-in-valve implantation. Mean age was 78.7±0.8 years. Preoperatively, all patients were at New York Heart Association (NYHA) functional class III. For risk estimation, the Society of Thoracic Surgeons (STS) and European System for Cardiac Operative Risk Evaluation (ES) risk scores were used and predicted high mortality (means±standard error of the mean: STSMortality 21.6±2.8%, ESadd 14.9±1.1, ESlog 52.6±9.0%). Mean follow-up time was 517±65 days (range, 280 to 799 days). RESULTS: Six patients showed a severely deteriorated bioprosthesis in terms of a stenotic valve (aortic valve area: 0.64±0.04 cm2, maximum/mean developed transvalvular pressure gradient: dPmax 63.3±10.9 mm Hg, dPmean 40.4±5.6 mm Hg). One patient's deteriorated prosthesis was highly insufficient. Procedural success rate was 100%, mean procedure time was 46.7±12.3 minutes. Echocardiography revealed excellent hemodynamics of implanted prosthesis (dPmax 31.1±5.5 mm Hg; dPmean 19.4±4.3 mm Hg). Overall, postoperative course was uneventful. No patient died during follow-up, which ranged up to 26 months. All patients, except 1, remained in NYHA class I or II. CONCLUSIONS: Our results demonstrate feasibility and safety of the transapical valve-in-valve approach with excellent hemodynamic and clinical results. Decision making in a multidisciplinary setting is mandatory. Further studies with more patients and longer follow-up are needed to identify candidates benefiting from transapical transcatheter valve-in-valve implantation.

Continuous mechanical chest compression during in-hospital cardiopulmonary resuscitation of patients with pulseless electrical activity.

UNLABELLED: Survival after in-hospital pulseless electrical activity (PEA) cardiac arrest is poor and has not changed during the last 10 years. Effective chest compressions may improve survival after PEA. We investigated whether a mechanical device (LUCAS™-CPR) can ensure chest compressions during cardiac arrest according to guidelines and without interruption during transport, diagnostic procedures and in the catheter laboratory. METHODS: We studied mechanical chest compression in 28 patients with PEA (pulmonary embolism (PE) n=14; cardiogenic shock/acute myocardial infarction; n=9; severe hyperkalemia; n=2; sustained ventricular arrhythmias/electrical storm; n=3) in a university hospital setting. RESULTS: During or immediately after CPR, 21 patients underwent coronary angiography and or pulmonary angiography. Successful return of a spontaneous circulation (ROSC) was achieved in 27 out of the 28 patients. Ten patients died within the first hour and three patients died within 24h after CPR. A total of 14 patients survived and were discharged from hospital (13 without significant neurological deficit). Interestingly, six patients with PE did not have thrombolytic therapy due to contraindications. CT-angiography findings in these patients showed fragmentation of the thrombus suggesting thrombus breakdown as an additional effect of mechanical chest compressions. No patients exhibited any life-threatening device-related complications. CONCLUSION: Continuous chest compression with an automatic mechanical device is feasible, safe, and might improve outcomes after in-hospital-resuscitation of PEA. Patients with PE may benefit from effective continuous chest compression, probably due to thrombus fragmentation and increased pulmonary artery blood flow.

The iron-regulatory peptide hepcidin is upregulated in the ischemic and in the remote myocardium after myocardial infarction.

Recent evidence suggests that iron metabolism contributes to the ischemic damage after myocardial infarction. Hepcidin, a recently discovered peptide hormone, regulates iron uptake and metabolism, protecting the body from iron overload. In this study we analyzed the regulation of hepcidin in the heart and blood of rats after myocardial infarction. To induce a myocardial infarction in the rats, left anterior descending coronary artery ligation was performed. After 1-24h, biopsies from the ischemic and the non-ischemic myocardium were taken. In these biopsies, the mRNA levels and the protein expression of hepcidin were analyzed by quantitative RT-PCR and immunoblot analysis, respectively. In parallel, the serum levels of prohepcidin were measured by ELISA. Six hours after myocardial infarction, the hepcidin mRNA expression was temporally upregulated in the ischemic and in the non-ischemic myocardium. The upregulation was specific for hepcidin, since other iron-related genes (hemojuvelin, IREG-1) remained unchanged. Furthermore, the alteration of the hepcidin protein expression in the ischemic area was connected to the level of hepcidin in the serum of the infarcted rats, where hepcidin also raised up. Angiotensin receptor blockade with candesartan did not influence the mRNA regulation of hepcidin. Together, these data show a particular upregulation of the iron-regulatory peptide hepcidin in the ischemic and the non-ischemic myocardium after myocardial infarction. It is speculated that upregulation of hepcidin may reduce iron toxicity and thus infarct size expansion in an infarcted heart.

Ischemic post-conditioning reduces infarct size of the in vivo rat heart: role of PI3-K, mTOR, GSK-3beta, and apoptosis.

Post-conditioning by repetitive cycles of reperfusion/ischemia after prolonged ischemia protects the heart from infarction. The objectives of this study were: Are kinases (PI3-kinase, mTOR, and GSK-3beta) involved in the signaling pathway of post-conditioning? Does post-conditioning result in a diminished necrosis or apoptosis? In open chest rats the infarct size was determined after 30 min of regional ischemia and 30 min of reperfusion using propidium iodide and microspheres. Post-conditioning was performed by three cycles of 30 s reperfusion and reocclusion each, immediately upon reperfusion. PI3-kinase and mTOR were blocked using wortmannin (0.6 mg/kg) or rapamycin (0.25 mg/kg), respectively. The phosphorylation of GSK-3beta and p70S6K was determined with phospho-specific antibodies. TUNEL staining and detection of apoptosis-inducing factor (AIF) were used for the determination of apoptosis. Control hearts had an infarct size of 49 +/- 3%, while post-conditioning significantly reduced it to 29 +/- 3% (P < 0.01). Wortmannin as well as rapamycin completely blocked the infarct size reduction of post-conditioning (51 +/- 2% and 54 +/- 5%, respectively). Western blot analysis revealed that post-conditioning increased the phosphorylation of GSK-3beta by 2.3 times (P < 0.01), and this increase could be blocked by wortmannin, a PI3-kinase inhibitor. Although rapamycin blocked the infarct size reduction, phosphorylation of p70S6K was not increased in post-conditioned hearts. After 2 h of reperfusion, the post-conditioned hearts had significantly fewer TUNEL-positive nuclei (35 %) compared to control hearts (53%; P < 0.001). AIF was equally reduced in post-conditioned rat hearts (P < 0.05 vs. control). Infarct size reduction by ischemic post-conditioning of the in vivo rat heart is PI3-kinase dependent and involves mTOR. Furthermore, GSK-3beta, which is thought to be a regulator of the mPTP, is part of the signaling pathway of post-conditioning. Finally, apoptosis was inhibited by post-conditioning, which was shown by two independent methods. The role of apoptosis and/or autophagy in post-conditioning has to be further elucidated to find therapeutic targets to protect the heart from the consequences of acute myocardial infarction.