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Background: The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. Methods: Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. Results: AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). Conclusions: In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart. Keywords: Ischemia-reperfusion injury, Myocardial infarction, Arrhythmias, Mitochondrial Na+/Ca2+ exchanger, CGP-37157

Background The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. In the present study we investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion. Methods Acute myocardial infarction was induced in 38 Wistar rats and 29 farm pigs by ligation of the left anterior descending coronary artery, followed by reperfusion. Animals were randomized to undergo intracoronary infusion of 2μM 4-CLD or vehicle just prior (pigs) or immediately after (rats) reperfusion. Infarcted rats were euthanized either after 1h of reperfusion (for histological assessment of the "no reflow" area) or after 60days (for serial evaluation of cardiac function and structure by echocardiography and assessment of infarct size). Infarcted pigs were euthanized after 2h of reperfusion for histological assessment of infarct size and "no reflow" area. Results In infarcted rats, intracoronary infusion of 4-CLD resulted in acute reduction of the "no reflow" area and conferred durable long-term structural and functional benefits (reduction in infarct size, attenuation of adverse remodeling, improvement in global systolic function). In infarcted pigs, intracoronary infusion of 4-CLD was well-tolerated from a hemodynamic standpoint and resulted in acute reduction in infarct size, reduction in "no reflow" area and more rapid resolution of ST-segment elevation. Conclusions In a rat model of myocardial infarction, intracoronary administration of 4-CLD attenuated the "no reflow" phenomenon and produced long-term structural and functional benefits. In a porcine model of myocardial infarction intracoronary administration of 4-CLD did not raise safety concerns and conferred acute cardioprotective effects.

ΕΙΣΑΓΩΓΗ :Ο ρόλος της μιτοχονδριακής αντλίας Na+/Ca2+ (mNCX) έχει αναγνωριστεί πλέον στην παθογένεση της αρρυθμιογένεσης και της βλάβης από ισχαιμία-επαναιμάτωση, καθιστώντας την αναστολή της έναν πιθανό θεραπευτικό στόχο. Σκοπός της παρούσας τυχαιοποιημένης μελέτης ήταν να διερευνηθεί η αποτελεσματικότητα του CGP-37157, ενός εκλεκτικού αναστολέα της μιτοχονδριακής αντλίας Na+/Ca22+, στην πρόληψη αρρυθμιών,στον περιορισμό της έκτασης του εμφράγματος και του φαινομένου μη επαναρροής σε χοίρειο μοντέλο ισχαιμίας-επαναιμάτωσης. ΜΕΘΟΔΟΣ: Για τη μελέτη χρησιμοποιήθηκαν 34 χοίροι (30-35 κιλά) στους οποίους προκλήθηκε ισχαιμία, με απολίνωση της ΠΚΣΑ, διάρκειας 60 λεπτών και στη συνέχεια επαναιμάτωση της ισχαιμούσας περιοχής, με λύση της απολίνωσης, διάρκειας 120 λεπτών. Τα πειραματόζωα τυχαιοποιήθηκαν στην ενδοστεφανιαία χορήγηση 0.02 mg/kg CGP-37157 ή φυσιολογικού ορού είτε κοντά στην έναρξη της ισχαιμίας είτε πέντε λεπτά πριν την επαναιμάτωση. Κατά τη διάρκεια του πειράματος υπήρχε συνεχής ηλεκτροκαρδιογραφική παρακολούθηση για καταγραφή αρρυθμιών. Μετά την ολοκλήρωση του πειράματος ακολούθησε προσδιορισμός της υπό κινδύνου περιοχής, του μεγέθους του εμφράκτου(ως ποσοστό της υπό κινδύνου περιοχής) και του no reflow (ως ποσοστό της υπό κινδύνου περιοχής). ΑΠΟΤΕΛΕΣΜΑΤΑ: Η υπό κίνδυνος περιοχή, το μέγεθος του εμφράκτου και η έκταση του no reflow ήταν παρόμοια και για τις δύο ομάδες. Η χορήγηση του CGP-37157 προ της ισχαιμίας είχε ως αποτέλεσμα: 1) καταστολή των κοιλιακών ταχυαρρυθμιών (επεισόδια κοιλιακής μαρμαρυγής ανά πειραματόζωο 1.5±1.1 vs 3.5±1.9, p=0.014), 2) ευκολότερη καρδιοανάταξη των κοιλιακών ταχυαρρυθμιών (απινιδώσεις που απαιτήθηκων για καρδιοανάταξη κάθε επεισοδίου κοιλιακής μαρμαρυγής 2.6±2.3 vs 6.2±2.1, p=0.006) και γ) μικρότερο μέγιστο βάθος των κατασπάσεων του σημείου J (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007) συγκριτικά με την ομάδα ελέγχου. Η χορήγηση του CGP-37157 πριν την επαναιμάτωση οδήγησε σε γρηγορότερη επάνοδο των κατασπάσεων (πλήρης επάνοδος στα 30 λεπτά της επαναιμάτωσης σε 7/8 πειραματόζωα που έλαβαν CGP-37157 έναντι 1/9 στην ομάδα ελέγχου (p=0.003). ΣΥΜΠΕΡΑΣΜΑΤΑ: Σε παρακλινικό χοίρειο μοντέλο οξέως στεφανιαίου συνδρόμου η ενδοστεφανιαία χορήγηση CGP-37157 δεν προσέφερε καμία καρδιοπροστατευτική επίδραση στη έκταση του εμφράγματος και του no reflow. Ωστόσω, οδήγησε σε σημαντική κταστολή των κοιλιακών αρρυθμιών, μείωσε το μέγεθος των κατασπάσεων του σημείου J στην διάρκεια της ισχαιμία και οδήγησε σε ταχεία επάνοδο των κατασπάσεων μετά την επαναιμάτωση. Τα ευρήματα αυτά αποτελούν πλέον ένα κίνητρο για την περαιτέρω διερεύνηση της φαρμακολογικής αναστολής της μιτοχονδριακής αντλίας Νa/ Ca ως δυνητικά θεραπευτική στρατηγική στην καταστολή των αρρυθμιών στην ισχαιμoύσα καρδιά. Background: The activity of the mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmiogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrythmogenesis, infarct size (IS) and area of no reflow (NRA) in a porcine model of ischemia-reperfusion. Methods: Thirty-four farm pigs underwent acute myocardial infarction by ligation of the left anterior descending coronary artery for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle either prior to the onset of ischemia (study 1, n=17) or 5 minutes before reperfusion (study 2, n=17). Following 2 hours of reperfusion, animals were euthanized to measure area at risk (AR), infarct size, and area of no reflow. Animals were continuously monitored for arrhythmias. Results: Area at risk, area of no reflow and infarct size were comparable between groups in both studies. Administration of CGP-37157 before the onset of ischemia resulted in: a) suppression of ventricular tachyarrhythmias (ventricular fibrillation events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each ventricular fibrillation episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 prior to reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). Conclusion: In a porcine model of acute myocardial infarction, intracoronary administration of CGP-37157 did not confer a cardioprotective effect in terms of IS and NRA reduction. However it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart.

New Findings What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia–reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction. The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload-induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia.

The mitochondrial NaForty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology.AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003).In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart.

SummaryIndependent of the size of the dog and the type of injury, serious infections may follow a dog bite and these may result in the abrupt onset of multiorgan failure. Early recognition of the warning signs with regard to the underlying severity of the infection is of the utmost importance. Reticulate skin eruptions constitute a precursory phenomenon.

What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia-reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction. The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload-induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia.

To the Editor: The prevalence of anemia in patients with New York Heart Association (NYHA) functional class IV heart failure (HF) approaches 80% ([1][1]). Iron deficiency (ID) has been reported as the cause of anemia in more than 70% of advanced HF patients ([2][2]). The underlying mechanisms of ID

Diuretics relieve congestion in HF patients but activate the renin-angiotensin-aldosterone system (RAAS). High furosemide doses have been correlated with higher mortality; it is not clear whether higher diuretic doses represent a marker of disease severity or an independent prognostic factor. We

Inhibition of mitochondrial Na+/Ca2+ exchanger has been recently recognized as a novel therapeutic target for the prevention of arrhythmias in heart failure. We examined the effects of CGP-37157, an inhibitor of the mitochondrial Na+/Ca2+ exchanger, administered at the onset of reperfusion, on