Abstract: Resuscitated cardiac arrest (CA), leading to harmful cardiovascular dysfunction and multiple organ failure, includes a whole-body hypoxia-reoxygenation phenomenon. Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in ischaemia-reperfusion injury. We hypothesized that pharmacological inhibition of mPTP opening may prevent the post-CA syndrome.
Abstract: Abstract Reperfusion therapy is the indispensable treatment of acute myocardial infarction (AMI) and must be applied as soon as possible to attenuate the ischemic insult. Evidence indicates that reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore. Ischemic postconditioning is a new way to dramatically reduce the lethal reperfusion injury. Several clinical studies using angioplasty postconditioning now support its protective effects in patients with an AMI. An interesting alternative is pharmacological postconditioning, which could be applied to a much larger number of patients. The mitochondrial permeability transition pore inhibitor cyclosporine A has been shown to generate a comparable protection in AMI patients. Future large-scale trials are needed to determine whether postconditioning may improve clinical outcome in ST-segment elevation MI patients. Antioxid. Redox Signal. 14, 811-820.
Abstract: ABSTRACT: BACKGROUND: Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. METHODS: DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. RESULTS: The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. CONCLUSIONS: These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00627783.
Abstract: Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg). Treatments were administered intravenously 5 min before BD induction. Echocardiography (ATL-5000, 8 MHz) was performed to measure left ventricular (LV) dimensions and fractional shortening at baseline, during BD induction and 5 min and 15 min after BD. In controls, BD was immediately associated with an increase in wall thickness and a decrease in LV cavity dimension. This myocardial wall hypertrophy was completely prevented by β-blockers, but not with calcium- and alpha-blockers. Extensive myocardial interstitial edema was found in all groups, except in the β-blocker group. Myocardial wall hypertrophy was also prevented during a longer follow-up of 180 min after BD in β-blocker group as opposed to controls. In conclusion, BD is associated with an immediate and severe myocardial damage related to an important interstitial edema which is prevented by β-blockers.
Abstract: Previous studies have suggested that implantation of mesenchymal stem cells (MSC) or their conditioned media (MSC CM) improves heart function after myocardial infarction. We sought to determine whether MSC and MSC CM added at the onset of reperfusion attenuates myocardial reperfusion injury.
Abstract: Ischaemic postconditioning (brief periods of ischaemia alternating with brief periods of reflow applied at the onset of reperfusion following sustained ischaemia) effectively reduces myocardial infarct size in all species tested so far, including humans. Ischaemic postconditioning is a simple and safe manoeuvre, but because reperfusion injury is initiated within minutes of reflow, postconditioning must be applied at the onset of reperfusion. The mechanisms of protection by postconditioning include: formation and release of several autacoids and cytokines; maintained acidosis during early reperfusion; activation of protein kinases; preservation of mitochondrial function, most strikingly the attenuation of opening of the mitochondrial permeability transition pore (MPTP). Exogenous recruitment of some of the identified signalling steps can induce cardioprotection when applied at the time of reperfusion in animal experiments, but more recently cardioprotection was also observed in a proof-of-concept clinical trial. Indeed, studies in patients with an acute myocardial infarction showed a reduction of infarct size and improved left ventricular function when they underwent ischaemic postconditioning or pharmacological inhibition of MPTP opening during interventional reperfusion. Further animal studies and large-scale human studies are needed to determine whether patients with different co-morbidities and co-medications respond equally to protection by postconditioning. Also, our understanding of the underlying mechanisms must be improved to develop new therapeutic strategies to be applied at reperfusion with the ultimate aim of limiting the burden of ischaemic heart disease and potentially providing protection for other organs at risk of reperfusion injury, such as brain and kidney.
Abstract: This study examined the effect of a single dose of cyclosporine administered at the time of reperfusion on left ventricular (LV) remodeling and function by cardiac magnetic resonance 5 days and 6 months after myocardial infarction.
Abstract: The therapeutic strategies for acute myocardial infarction in the last decade have, among other therapeutic targets, focused on myocardial reperfusion injury, which accounts for a significant part of the final infarct size. Although several experiments in the last 20 years have reported that pharmacological interventions at reperfusion might reduce myocardial reperfusion injury, this could not be consistently confirmed in animal models or human studies. An alternative to chemical modifiers, postconditioning (brief repeated periods of ischemia applied at the onset of reperfusion) is the first method proven to be efficient in different animal models and to be confirmed in a recent human study. This simple method, applied in the first minute of reperfusion, reduces the final infarct size by 30-50%. This review will focus on the postconditioning technique and show how the data from different animal models and experimental settings have advanced our understanding of both the mechanisms and the definition of an accurate protocol that is easily applicable in human patients in the setting of acute myocardial infarction.
Abstract: Reperfusion therapy is the primary treatment of acute myocardial infarction and must be applied as soon as possible to limit the ischemic insult. Unfortunately, reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore. Ischemic postconditioning is a powerful intervention that dramatically reduces lethal reperfusion injury. Several clinical studies using angioplasty postconditioning now support its protective effects in patients with an acute myocardial infarction. Alternatively, pharmacological postconditioning could afford comparable protection and be applied to a much larger number of patients. Indeed, the mitochondrial permeability transition pore inhibitor cyclosporine A has been shown to generate a similar protection in acute myocardial infarction patients. Future large-scale trials are needed to determine whether angioplasty or pharmacological postconditioning may improve clinical outcome in STEMI patients.
Abstract: Infarct size is determined not only by the severity of ischemia but also by pathological processes initiated at reperfusion. Accumulating experimental evidence indicates that lethal reperfusion injury might account for up to half of the final size of the myocardial infarct. Ischemic postconditioning (brief repeated periods of ischemia-reperfusion applied at the onset of coronary reflow) has been recently described as a powerful cardioprotection mechanism that prevents lethal reperfusion injury. This is the first method proven to reduce the final infarct size by about 50% in several in vivo models and to be confirmed in recent preliminary human studies. The molecular pathways are incompletely mapped but they probably converge to a mitochondrial key target: the mitochondrial permeability transition pore (PTP) which opening during early reperfusion is an event that promotes myocardial cell death. In different animal models and experimental settings, pharmacological PTP inhibition at the onset of reperfusion reproduces all the cardioprotective effects of ischemic postconditioning. In a recent proof-of-concept trial, the administration (just before percutaneous coronary intervention) of cyclosporine A, a potent PTP inhibitor, was associated with smaller infarct size. This review will focus on the physiological preclinical data on both ischemic and pharmacological postconditioning that are relevant to their translation to clinical therapeutics.
Abstract: Diabetic cardiomyopathy has been characterized by an early impairment of left ventricular (LV) longitudinal function as opposed to preserved LV radial function.
Abstract: The effects of ischemia-reperfusion on opening of the mitochondrial permeability transition pore (mPTP) and its blockade in the immature brain are not fully understood. Presently, we evaluated the effect of cyclosporine A (CsA) on cell death and mPTP opening in a model of transient focal ischemia induced by permanent left middle cerebral artery, and homolateral transient common carotid artery occlusion (50min) in P7 rats. CsA (10mg/kg) was administered 14h before induction of ischemia and effects were analyzed at 30-40min and 48h after reperfusion. CsA administration reduced infarct size, DNA fragmentation and apoptotic bodies, and inflammatory responses in mild but not severe injury. CsA increased the Ca(2+) load required to open the mPTP (78.4+/-19.2 vs. 50.2+/-19.9nmol.mg(-)(1) protein, p<0.05) in limiting the decoupling of the respiratory chain by unchanged state 3 but reduced state 4, and attenuated early calpain-mediated alpha-spectrin proteolysis. In conclusion, CsA mediates inhibition of mPTP opening and has a tendency to protect immature rat brain against mild ischemic injury.
Abstract: Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia-reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the "Hatter Workshop Recommendations". These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit.
Abstract: A large body of experimental evidence indicates that during an acute myocardial infarction (AMI), tissue injury occurring after reperfusion represents a significant amount of the whole, irreversible damage. It is now recognized that mitochondrial permeability transition pore opening plays a crucial role in this specific component of myocardial infarction. Ischaemic postconditioning and cyclosporine A (CsA) have been shown to dramatically reduce infarct size in many animal species. Recent proof-of-concept clinical trials support the idea that lethal myocardial reperfusion injury is also of significant importance in patients with ongoing AMI, and that targeting mitochondrial permeability transition by either percutaneous coronary intervention postconditioning or CsA can reduce infarct size and improve the recovery of contractile function after reperfusion. Large-scale trials are ongoing to address whether these new treatments may improve clinical outcome in reperfused AMI patients.
Abstract: Mitochondrial permeability transition pore (mPTP) inhibition plays a relevant role in postconditioning (PostC). Ischemia damages the electron transport chain, and the potential contribution of additional modifications in mitochondrial function caused by PostC remains unknown. We sought to determine which mitochondrial functions are involved in the inhibition of mPTP opening during the first minutes of reperfusion. Anesthetized New Zealand White rabbits underwent 30-min ischemia followed by 10-min reperfusion. At reperfusion, they received either no intervention (Control, C), PostC with 4 cycles of 1-min ischemia followed by 1-min reperfusion, or an IV injection of 5 mg/kg cyclosporine A (CsA: a powerful inhibitor of mPTP opening). Sham rabbits underwent no ischemia throughout the 40-min experiment. At the end of the 10-min reperfusion, mitochondria were isolated from the area at risk by differential centrifugations. Calcium retention capacity (CRC) and mitochondrial membrane potential (DeltaPsi(m)) were assessed by fluorimetry in subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Oxidative phosphorylation was assessed using a Clark-type electrode, and oxidative stress via protein carbonylation by Western blotting. PostC and CsA treatments improved CRC when compared to the C group. Control, PostC and CsA mitochondria exhibited a comparable significant dissipation of DeltaPsi(m), together with a comparable significant decrease in state 3 and an increase in state 4 respiration, in both SSM and IFM. However, PostC but not CsA treatment reduced total heart oxidative stress. These data suggest that during the early minutes of reperfusion, PostC reduces oxidative stress and inhibits mPTP opening, independent of alteration of oxidative phosphorylation or of DeltaPsi(m).
Abstract: Microvascular obstruction (MO) is a factor of adverse outcome in patients with ST-elevated myocardial infarction (STEMI). We assessed the presence and extent of MO and its relationship with infarct size and left ventricular (LV) functional parameters after acute non-ST-elevated myocardial infarction (NSTEMI).
Abstract: Recent work has demonstrated the benefit of low pressure (LP) reperfusion to protect the heart undergoing an ischemic insult. The goal of the present study was to determine the optimal pressure for the application of LP reperfusion. Isolated rats hearts (n = 30) were exposed to 40 minutes of global warm ischemia followed by 70 minutes of reperfusion with a pressure fixed at 100 cm H(2)O (normal pressure [NP] = control group), 85 cm (group LP [low pressure]-85), 70 cm (group LP-70), or 55 cm (group LP-55). Cardiac function was assessed during reperfusion using the Langendorff model. Myocardial necrosis was assessed by measuring lactate dehydrogenase (LDH) and creatine kinase (CK) leakage in the coronary effluents. Functional recovery was progressively and significantly improved with decreased perfusion pressure. Rate-pressure product (RPP) averaged 3765 +/- 408, 6824 +/- 439, and 12,036 +/- 664 mm Hg/min, respectively, among the control, LP-85, and LP-70 groups (P < .001, LP-70 vs other groups). However, RPP collapsed in the LP-55 group. Similarly, necrosis as measured by LDH and CK leakage progressively reduced between LP-100 and LP-70 hearts (P < .01), with a drastic increase in enzyme in the LP-55 group. In conclusion, this study demonstrated that 70 cm H(2)O is an optimal LP to improve postischemic contractile dysfunction and attenuate necrosis during reperfusion.
Abstract: New therapeutic strategies aim to reduce the extent of myocardial infarction (MI) to decrease long-term left ventricular (LV) remodeling. These innovations are often developed on murine models of MI and have led to the need for a sensitive tool allowing follow-up. The aim of this study was to investigate by strain rate (SR) imaging early and long-term alteration in regional LV function occurring after MI in mice.
Abstract: Openers of K+(ATP) channels protect the myocardium from I/R injury. Sulfonylureas are known as potent blockers of K(ATP) channels. We investigated whether 1) mitochondrial permeability transition pore may be involved in the protection afforded by the mitoK+(ATP) opener nicorandil and 2) whether sulfonylureas may prevent this beneficial effect. Anesthetized New Zealand White rabbits underwent 30 min of coronary artery occlusion, followed by 60 (isolated mitochondria) or 240 min (infarct size) of reperfusion. They received an administration of either saline (control) or nicorandil (0.5 mg kg(-1), i.v.) 15 min before ischemia. Each control and nicorandil group was divided in four subgroups pretreated by either saline, glibenclamide (Glib; 1 mg kg(-1)), gliclazide (Glic; 1 mg kg(-1)), or glimepiride (Glim; 5 microg kg(-1)) 10 min before this. Infarct size was assessed by triphenyltetrazolium chloride staining. Mitochondria were isolated from the area at risk for further assessment of the calcium retention capacity. Glibenclamide (35 +/- 8), but neither Glic (61 +/- 9) nor Glim (48 +/- 7), reversed the improvement in calcium retention capacity due to nicorandil (58 +/- 10 vs. 27 +/- 8 nmoles CaCl2 mg(-1) proteins in control). Infarct size reduction by nicorandil (32% +/- 6% vs. 65% +/- 6% of area at risk) was abolished by Glib (55 +/- 5) but not by Glic (37 +/- 3) or Glim (31 +/- 5). These data suggest that 1) the protective effect of nicorandil involves the inhibition of the mitochondrial permeability transition pore and 2) that unlike Glib, second-generation sulfonylureas preserve this cardioprotection.
Abstract: Both myocardial blush grade (MBG) and cardiac magnetic resonance (CMR) are imaging tools that can assess myocardial reperfusion after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI).
Abstract: PURPOSE: Although delayed enhanced CMR has become a reference method for infarct size quantification, there is no ideal method to quantify total infarct size in a routine clinical practice. In a prospective study we compared the performance and post-processing time of a global visual scoring method to standard quantitative planimetry and we compared both methods to the peak values of myocardial biomarkers. MATERIALS AND METHODS: This study had local ethics committee approval; all patients gave written informed consent. One hundred and three patients admitted with reperfused AMI to our intensive care unit had a complete CMR study with gadolinium-contrast injection 4+/-2 days after admission. A global visual score was defined on a 17-segment model and compared with the quantitative planimetric evaluation of hyperenhancement. The peak values of serum Troponin I (TnI) and creatine kinase (CK) release were measured in each patient. RESULTS: The mean percentage of total left ventricular myocardium with hyperenhancement determined by the quantitative planimetry method was (20.1+/-14.6) with a range of 1-68%. There was an excellent correlation between quantitative planimetry and visual global scoring for the hyperenhancement extent's measurement (r=0.94; y=1.093x+0.87; SEE=1.2; P<0.001) The Bland-Altman plot showed a good concordance between the two approaches (mean of the differences=1.9% with a standard deviation of 4.7). Mean post-processing time for quantitative planimetry was significantly longer than visual scoring post-processing time (23.7+/-5.7min vs 5.0+/-1.1min respectively, P<0.001). Correlation between peak CK and quantitative planimetry was r=0.82 (P<0.001) and r=0.83 (P<0.001) with visual global scoring. Correlation between peak Troponin I and quantitative planimetry was r=0.86 (P<0.001) and r=0.85 (P<0.001) with visual global scoring. CONCLUSION: A visual approach based on a 17-segment model allows a rapid and accurate assessment of the myocardial global delayed enhancement. This scoring method could be used on a daily practice and useful for the management strategy of post-MI patients.
Abstract: There is not general agreement concerning the optimal time of reperfusion necessary to assess myocardial function and necrosis on isolated perfused heart model. Nevertheless, the study of cardioprotection (especially, pre- and postconditioning) requires a reliable and standardized assessment of myocardial necrosis.
Abstract: Infusion of saline attenuates the decrease in renal function induced by radiographic contrast agents among patients with chronic renal insufficiency.
Abstract: This study aimed to assess the influence of afterload alteration on radial (R) and longitudinal (L) left ventricular (LV) systolic regional functions.
Abstract: Ca(2+) is the main trigger for mitochondrial permeability transition pore opening, which plays a key role in cardiomyocyte death after ischemia-reperfusion. We investigated whether a reduced accumulation of mitochondrial Ca(2+) might explain the attenuation of lethal reperfusion injury by postconditioning. Anesthetized New Zealand White rabbits underwent 30 min of ischemia, followed by either 240 (infarct size protocol) or 60 (mitochondria protocol) min of reperfusion. They received either no intervention (control), preconditioning by 5-min ischemia and 5-min reperfusion, postconditioning by four cycles of 1-min reperfusion and 1-min ischemia at the onset of reflow, or pharmacological inhibition of the transition pore opening by N-methyl-4-isoleucine-cyclosporin (NIM811; 5 mg/kg iv) given at reperfusion. Area at risk and infarct size were assessed by blue dye injection and triphenyltetrazolium chloride staining. Mitochondria were isolated from the risk region for measurement of 1) Ca(2+) retention capacity (CRC), and 2) mitochondrial content of total (atomic absorption spectrometry) and ionized (potentiometric technique) calcium concentration. CRC averaged 0.73 +/- 0.16 in control vs. 4.23 +/- 0.17 mug Ca(2+)/mg proteins in shams (P < 0.05). Postconditioning, preconditioning, or NIM811 significantly increased CRC (P < 0.05 vs. control). In the control group, total and free mitochondrial calcium significantly increased to 2.39 +/- 0.43 and 0.61 +/- 0.10, respectively, vs. 1.42 +/- 0.09 and 0.16 +/- 0.01 mug Ca(2+)/mg in sham (P < 0.05). Surprisingly, whereas total and ionized mitochondrial Ca(2+) decreased in preconditioning, it significantly increased in postconditioning and NIM811 groups. These data suggest that retention of calcium within mitochondria may explain the decreased reperfusion injury in postconditioned (but not preconditioned) hearts.
Abstract: We previously demonstrated that ischemic postconditioning decreases creatine kinase release, a surrogate marker for infarct size, in patients with acute myocardial infarction. Our objective was to determine whether ischemic postconditioning could afford (1) a persistent infarct size limitation and (2) an improved recovery of myocardial contractile function several months after infarction.
Abstract: Mitochondrial permeability transition pore (mPTP) opening is a crucial event in cardiomyocyte death after I/R. We questioned whether preconditioning (PC) may inhibit mPTP opening during ischemia and/or during reperfusion and whether this effect would persist as reperfusion evolves. Anesthetized New Zealand white rabbits underwent a test ischemia followed by reperfusion. Ischemia lasted either 10 or 30 min, whereas reperfusion duration varied from 5 to 20, 60 and up to 240 min. For each duration of ischemia and reperfusion, animals were randomized as either control or PC. Preconditioning was induced by 5 min of ischemia followed by 5 min of reperfusion. Mitochondria were isolated from myocardium at risk for assessment of the calcium retention capacity (CRC) (potentiometric technique) used here as an index of sensitivity of the mPTP to Ca2+ loading. In controls, the CRC was moderately reduced after ischemia alone, but reperfusion severely and time-dependently accelerated further CRC reduction. Preconditioning failed to modify mPTP opening during ischemia alone, but significantly improved CRC during reperfusion. This protective effect persisted as reperfusion evolved. These data suggest that (a) reperfusion strikingly increases the susceptibility to Ca2+-induced mPTP opening, and that (b) PC inhibits mPTP opening at reflow and throughout the first hours of reperfusion.
Abstract: Experimental evidence suggests that cyclosporine, which inhibits the opening of mitochondrial permeability-transition pores, attenuates lethal myocardial injury that occurs at the time of reperfusion. In this pilot trial, we sought to determine whether the administration of cyclosporine at the time of percutaneous coronary intervention (PCI) would limit the size of the infarct during acute myocardial infarction.
Abstract: Cardiac resynchronization therapy (CRT) produces an early improvement in left ventricular (LV) function in patients with congestive heart failure (CHF), but little is known about its effects on right ventricular (RV) function.
Abstract: Opening of the mitochondrial permeability transition pore (mPTP) is a crucial event in lethal reperfusion injury. Phosphorylation (inhibition) of glycogen synthase kinase-3beta (GSK3beta) has been involved in cardioprotection. We investigated whether phosphorylated GSK3beta may protect the heart via the inhibition of mPTP opening during postconditioning.
Abstract: In vivo evaluation of the transmural extension of myocardial infarction (TEI) is crucial to prediction of viability and prognosis. With the rise of transgenic technology, murine myocardial infarction (MI) models are increasingly used. Our study aimed to evaluate systolic strain rate (SR), a new parameter of regional function, to quantify TEI in a murine model of acute MI induced by various durations of ischemia followed by 24 h of reperfusion. Global and regional left ventricular (LV) function were assessed by echocardiography (13 MHz, Vivid 7, GE) in 4 groups of wild-type mice (C57BL/6, 2 mo old): a sham-treated group (n = 10) and three MI groups [30 (n = 11), 60 (n = 10), and 90 (n = 9) min of left coronary artery occlusion]. Conventional LV dimensions, anterior wall (AW) thickening, and peak systolic SR were measured before and 24 h after reperfusion. Area at risk (AR) was measured by blue dye and infarct size (area of necrosis, AN) and TEI by triphenyltetrazolium chloride staining. AN increased with ischemia duration (25 +/- 2%, 56 +/- 5%, 71 +/- 6% of AR for 30, 60, and 90 min, respectively; P < 0.05). LV end-diastolic volume significantly increased with ischemia duration (30 +/- 5, 34 +/- 5, 43 +/- 5 microl; P < 0.05), whereas LV ejection fraction decreased (63 +/- 5%, 58 +/- 6%, 46 +/- 5%; P < 0.05). AW thickening decrease was not influenced by ischemia duration. Conversely, systolic SR decreased with ischemia duration (13 +/- 5, 4 +/- 3, -2 +/- 6 s(-1); P < 0.05) and was significantly correlated with TEI (r = 0.89, P < 0.01). Receiver operating characteristic (ROC) curves identified systolic SR as the most accurate parameter to predict TEI. In conclusion, in a murine model of MI, SR imaging is superior to conventional echocardiography to predict TEI early after MI.
Abstract: Acute myocardial infarction is the leading cause of morbidity and mortality in industrialized countries. Ischemic postconditioning, that consists of repeated brief episodes of ischemia-reperfusion performed just after reflow following a prolonged ischemic insult, dramatically reduces infarct size in animal models. Recent data indicate that it might involve the activation of the PI3-kinase-Akt-eNOS as well as PKC signalling pathways and inhibition of the opening of the permeability transition pore. A recent clinical study demonstrated that postconditioning protects the human heart. Repeated brief episodes of inflation-deflation of the angioplasty balloon performed immediately after re-opening of the culprit coronary artery reduced infarct size by 36%. Additional studies are required to determine whether infarct size limitation by postconditioning would improve functional recovery as well as patient's outcome. Further research is needed to find new pharmacological agents that would mimick postconditioning in order to treat all patients with ongoing acute myocardial infarction.
Abstract: The aim of this study was to evaluate the role of the mitochondrial permeability transition pore (MPTP) in the protection achieved by post-conditioning of hearts submitted to hypothermic cardioplegia and ischemia.
Abstract: Inhibition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricular (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice. Anesthetized mice underwent 25 min of ischemia and 24 h (protocol 1) or 30 days (protocol 2) of reperfusion. At reperfusion, they received no intervention (control), postconditioning (3 cycles of 1 min ischemia-1 min reperfusion), or intravenous injection of the mPTP inhibitor Debio-025 (10 mg/kg). At 24 h of reperfusion, mitochondria were isolated from the region at risk for assessment of the Ca(2+) retention capacity (CRC). Infarct size was measured by triphenyltetrazolium chloride staining. At 30 days of reperfusion, mortality and LV contractile function (echocardiography) were evaluated. Postconditioning and Debio-025 significantly improved Ca(2+) retention capacity (132 +/- 13 and 153 +/- 31 vs. 53 +/- 16 nmol Ca(2+)/mg protein in control) and reduced infarct size to 35 +/- 4 and 32 +/- 7% of area at risk vs. 61 +/- 6% in control (P < 0.05). At 30 days, ejection fraction averaged 74 +/- 6 and 77 +/- 6% in postconditioned and Debio-025 groups, respectively, vs. 62 +/- 12% in the control group (P < 0.05). At 30 days, survival was improved from 58% in the control group to 92 and 89% in postconditioned and Debio-025 groups, respectively. Inhibition of mitochondrial permeability transition at reperfusion improves functional recovery and mortality in mice.
Abstract: Previous studies have shown the capacity of low-pressure (LP) reperfusion to protect the ischemic heart. The present study sought to determine the optimal time for the application of LP reperfusion. Isolated rat hearts (n = 30) were exposed to 40 minutes of global warm ischemia followed by 70 minutes of reperfusion. Reperfusion was performed under LP (LP = 70 cm H(2)O) for 0 (control group), 5 (group LP-5), 10 (group LP-10), 30 (group LP-30), or 60 (group LP-60) minutes. Following the LP period the hearts were reperfused with normal pressure (100 cm H(2)O) until the end of reperfusion. Cardiac function was assessed during reperfusion using the Langendorff model. Myocardial necrosis was assessed by measuring LDH leakage in the coronary effluents. Functional recovery was reduced among the control and LP-5 groups with rate-pressure products (RPP) averaging 3788 +/- 499 and 5333 +/- 892 mm Hg/min, respectively. RPP was significantly improved in other groups with RPP averaging 7363 +/- 1159, 7441 +/- 863, and 7269 +/- 692 mm Hg/min in LP-10, LP-30, and LP-60 (P < .01). Similarly, necrosis measured by LDH leakage was significantly reduced in LP-10, LP-30, and LP-60 hearts (P < .01). This study demonstrated that LP reperfusion improves postischemic contractile dysfunction and attenuates necrosis when applied for at least 10 minutes.
Abstract: Postconditioning has recently been described as a powerful cardioprotection that prevents lethal reperfusion injury. Growing evidence suggests that mitochondrial permeability transition may be a key event in postconditioning. This proposition arises from the complementary observations that: (1) conditions for the mitochondrial permeability transition pore (mPTP) opening are built up during early reperfusion, (2) mPTP opens at the time of reperfusion, (3) transgenic structural alteration of mPTP modifies its opening probability following ischemia-reperfusion, (4) mPTP plays a role in preconditioning, and (5) postconditioning attenuates lethal reperfusion injury. We review in this article current evidence for an important role of the mitochondrial transition pore in postconditioning.
Abstract: We investigated whether phosphatidylinositol 3-kinase (PI3K) might regulate mitochondrial permeability transition pore (mPTP) opening in hearts reperfused with either low pressure or postconditioning.
Abstract: HL-1, the first cell line with a cardiac phenotype for biological experiments, displays spontaneous electrophysiological and mechanical regular activity, and cyclic calcium movements. We isolated a derived line, devoid of transient movements, for confocal microscopy experiments. These cells do express cardiac proteins: connexin 43, the cardiac isoform of dihydropyridine receptors, desmin, and developmental myosin but have no sarcomeric arrangement. They still possess the electrophysiological characteristics and ionic currents of cardiac cells, among them the cardiac potassium current IKr. We also found diazoxide and glibenclamide sensitive potassium channels with properties similar to IK(ATP) in adult cardiac myocytes. The pacemaker current I(f) was not observed, in agreement with the cells showing excitability but lacking in pacemaker activity. The absence of movement is an advantage for studies which include changes of media in order to follow morphological changes under continuous perfusion. We observed however a basal spontaneous movement of mitochondria and we developed a method to quantify its amplitude using confocal microscopy. No mitochondrial depolarization could be detected when the membrane potential was measured by using very low light photomultiplier and confocal fluorescence imaging under the K(ATP) channel opener diazoxide. Thus cardiac pharmacological preconditioning by K(ATP) channel openers might involve other routes than mitochondrial K channels targeting.
Abstract: Acute myocardial infarction is the leading cause of morbidity and mortality in western countries. Ischemic postconditioning, that consists of repeated brief episodes of ischemia-reperfusion performed just after reflow following a prolonged ischemic insult, dramatically reduces infarct size. Recent data indicate that it might involve the activation of the PI3-kinase-Akt-eNOS signalling pathway and inhibition of the opening of the permeability transition pore. A recent clinical study demonstrated that postconditioning protects the human heart. Further research is needed to find new pharmacological agents that would mimick postconditioning in order to treat all patients with ongoing acute myocardial infarction.
Abstract: Acute cardiac graft rejection (ACGR) is associated with cardiomyocyte apoptosis. We investigated the respective role of the Fas/FasL and mitochondrial permeability transition pore (mPTP) pathways in cardiomyocyte apoptosis accompanying ACGR. Heterotopic cardiac transplantations were performed in 7-9-week old C57BL6 or C3H mice. Wild type or Fas-deficient (lpr) mice underwent syngeneic (GS) or allogeneic (GA) transplantation, and received either saline or NIM811, a specific inhibitor of the mPTP. At day 5, we assessed ACGR by histology, cardiomyocyte apoptosis by caspase-3 activity and cytochrome c release, Ca(2+)-induced mPTP opening by a potentiometric approach, and expression of Fas, FasL, TNFalpha, perforin, granzyme using RT-PCR. Myocardial infiltration of CD8(+) T lymphocytes was performed by immunohistochemistry. Allogenic transplantation increased infiltration of inflammatory cells, upregulated FasL, perforin, granzyme, and TNFalpha, favored Ca(2+)-induced mPTP opening and increased caspase-3 activity and cytochrome c release in WT grafts. NIM811, but not Fas-deficiency, significantly reduced all these effects. NIM811 also limited infiltration of CD8(+) into WT and lpr transplants. These data suggest that the mPTP pathway plays a major role in cardiomyocyte apoptosis associated with ACGR. Inhibition of mPTP opening may attenuate cardiomyocyte apoptosis either directly or indirectly via a limitation of CD8(+) T-cell activation.
Abstract: We investigated whether low-pressure reperfusion may attenuate postischemic contractile dysfunction, limits necrosis and apoptosis after a prolonged hypothermic ischemia, and inhibits mitochondrial permeability transition-pore (MPTP) opening. Isolated rats hearts (n = 72) were exposed to 8 h of cold ischemia and assigned to the following groups: 1) reperfusion with low pressure (LP = 70 cmH(2)O) and 2) reperfusion with normal pressure (NP = 100 cmH(2)O). Cardiac function was assessed during reperfusion using the Langendorff model. Mitochondria were isolated, and the Ca(2+) resistance capacity (CRC) of the MPTP was determined. Malondialdehyde (MDA) production, caspase-3 activity, and cytochrome c were also assessed. We found that functional recovery was significantly improved in LP hearts with rate-pressure product averaging 30,380 +/- 1,757 vs. 18,000 +/- 1,599 mmHg/min in NP hearts (P < 0.01). Necrosis, measured by triphenyltetrazolium chloride staining and creatine kinase leakage, was significantly reduced in LP hearts (P < 0.01). The CRC was increased in LP heart mitochondria (P < 0.01). Caspase-3 activity, cytochrome c release, and MDA production were reduced in LP hearts (P < 0.001 and P < 0.01). This study demonstrated that low-pressure reperfusion after hypothermic heart ischemia improves postischemic contractile dysfunction and attenuates necrosis and apoptosis. This protection could be related to an inhibition of mitochondrial permeability transition.
Abstract: The aim of this study was to examine the effect of sudden brain death (BD) on myocardial function and high energy phosphate (HEP) stores. BD was induced by cerebral vessel ligation in six swine (BD group) that were compared to six control swine. At the end of the BD period (3 hours), harvested hearts were stored at 4 degrees C. Myocardial tissue HEP were assessed by: (i) (31)P-NMR spectroscopy of left ventricle for phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi) and intracellular pH (pHi), and by (ii) HPLC for ATP, ADP, and AMP levels in left ventricle biopsies. Brain death resulted in a instantaneous major increase in catecholamines (>50-fold, P < .001) and paradoxically a significant progressive decrease in the regional contractility of the left ventricle. After cardioplegia, no significant differences on HEP compounds (ATP/Pi, PCr/Pi, ATP, energetic index) or in pHi were observed between BD and control groups. These data suggest that early heart injury occurring during BD does not seem to be an ischemic phenomenon.
Abstract: Hearts from brain dead pigs (n = 18) were submitted to 0 (group I), 10 (group II), or 20 (group III) minutes of in situ warm ischemia (animal exsanguination). After harvesting, cold cardioplegia solution was perfused in retrograde fashion and initial coronary flow (ICF) measured. After left ventricular energetic indices were measured using NMR spectroscopy, the hearts were transplanted orthotopically. Follow-up was performed over 120 minutes after cardiopulmonary bypass. We observed a progressive decrease in ICF with increased warm ischemia times: 50 +/- 3.4 mL/min per 100 g of tissue in the group I, 36 +/- 7 and 30 +/- 3.5 in groups II and III, respectively (P < .05 and P < .01 versus group I). The ICF strongly correlated with the energetic index (r = 0.76, P < .001) and with posttransplant function of the transplanted heart. These data showed that measurement of initial coronary flow after cardioplegia was a reliable test to evaluate cardiac graft viability before transplantation.
Abstract: Several testing options are available to detect asymptomatic coronary artery disease (CAD). Dobutamine stress echocardiography (DSE) has been reported to increase the sensitivity and specificity of stress testing to detect CAD. Most studies concerned patients with known or suspected CAD who have a high pretest probability of disease. We aimed to perform a preliminary evaluation of DSE in atherothrombotic stroke.
Abstract: It is debated whether brain death (BD) causes transient functional ischemia. In this investigation we used monophasic action potential (AP) recording during BD as a sensitive means to assess: (i) whether ischemia was present; and (ii) the effect of BD on a subsequent ischemia-reperfusion challenge.
Abstract: We hypothesized that low-pressure reperfusion may limit myocardial necrosis and attenuate postischemic contractile dysfunction by inhibiting mitochondrial permeability transition pore (mPTP) opening. Male Wistar rat hearts (n = 36) were perfused according to the Langendorff technique, exposed to 40 min of ischemia, and assigned to one of the following groups: 1) reperfusion with normal pressure (NP = 100 cmH(2)O) or 2) reperfusion with low pressure (LP = 70 cmH(2)O). Creatine kinase release and tetraphenyltetrazolium chloride staining were used to evaluate infarct size. Modifications of cardiac function were assessed by changes in coronary flow, heart rate (HR), left ventricular developed pressure (LVDP), the first derivate of the pressure curve (dP/dt), and the rate-pressure product (RPP = LVDP x HR). Mitochondria were isolated from the reperfused myocardium, and the Ca(2+)-induced mPTP opening was measured using a potentiometric approach. Lipid peroxidation was assessed by measuring malondialdehyde production. Infarct size was significantly reduced in the LP group, averaging 17 +/- 3 vs. 33 +/- 3% of the left ventricular weight in NP hearts. At the end of reperfusion, functional recovery was significantly improved in LP hearts, with RPP averaging 10,392 +/- 876 vs. 3,969 +/- 534 mmHg/min in NP hearts (P < 0.001). The Ca(2+) load required to induce mPTP opening averaged 232 +/- 10 and 128 +/- 16 microM in LP and NP hearts, respectively (P < 0.001). Myocardial malondialdehyde was significantly lower in LP than in NP hearts (P < 0.05). These results suggest that the protection afforded by low-pressure reperfusion involves an inhibition of the opening of the mPTP, possibly via reduction of reactive oxygen species production.
Abstract: Brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called "postconditioning." After reflow, opening of the mitochondrial permeability transition pore (mPTP) has been involved in lethal reperfusion injury. We hypothesized that postconditioning may modulate mPTP opening.
Abstract: The aim of the present study was to determine whether specific inhibition of mitochondrial permeability transition (MPT) by NIM811 at the time of reperfusion following acute myocardial infarction may protect the heart. MPT pore opening appears to be a pivotal event in cell death following acute myocardial infarction. Recently, MPT pore opening has been involved in ischemic preconditioning. In protocol 1, NZW rabbits underwent either no intervention (sham) or 10 min of ischemia followed by 5 min of reperfusion, preceded (preconditioned, PC) or not (control, C) by 5 min of ischemia and 5 min of reperfusion. Additional rabbits were treated by cyclosporin A (CsA) or its non-immunosuppressive and more specific derivative (NIM811) (10 mg kg(-1), IV bolus), either 10 min before ischemia or 1 min before reperfusion. Hearts were excised and mitochondria isolated for further assessment of Ca(2+)-induced MPT. In protocol 2, animals were randomly assigned into similar experimental groups and underwent 30 min of ischemia and 4 h of reperfusion. Infarct size was assessed by TTC staining, and apoptosis by TUNEL assay. The Ca2+ overload required to induce MPT pore opening was significantly higher in NIM811, CsA and PC groups than in controls. Both necrotic and apoptotic cardiomyocyte death were significantly reduced by NIM811, CsA and PC. In both protocols, administration of NIM811 at reperfusion provided full protection. These data indicate that specific inhibition of MPT pore opening at reperfusion following acute myocardial infarction provides a powerful antinecrotic and antiapoptotic protection.
Abstract: The feasibility of gene transfer to myocardial tissue using viral vectors was investigated over the last few years. In this study we report gene transfer using a recently described improved of Herpes simplex virus (HSV-1)-derived amplicon vectors and demonstrate that these vectors are a powerful and potentially very interesting tool for gene transfer into neonatal primary as well as in adult cardiac myocytes.
Abstract: The origin of cardiac impairment during brain death (BD) is controversial. Using a pig experimental model we sought to assess hormonal changes during the first stage of brain death and how these changes contribute to hemodynamic alteration and myocardial dysfunction.
Abstract: The aim of this study was to evaluate the effects of major components of cardioplegic solutions on myocardial tissue submitted to prolonged cold ischemia.
Abstract: In animal models, brief periods of ischemia performed just at the time of reperfusion can reduce infarct size, a phenomenon called postconditioning. In this prospective, randomized, controlled, multicenter study, we investigated whether postconditioning may protect the human heart during coronary angioplasty for acute myocardial infarction.
Abstract: Trimetazidine (TMZ) affects mitochondrial function during ischemia. Mitochondrial permeability transition is a pivotal event in cardiomyocyte death following acute ischemia. The aim of the present study was to determine whether the anti-ischemic agent TMZ might modulate mitochondrial permeability transition pore (mPTP) opening and limit lethal ischemia-reperfusion injury. Anesthetized NZW rabbits underwent 30 min of coronary artery occlusion followed by 4 hours of reperfusion. Prior to this, they underwent either no intervention (control, C), ischemic preconditioning (PC), or an IV injection of 5 mg kg(-1) TMZ 10 min before ischemia (TMZ). Additional rabbits (Sham group) underwent no ischemia/reperfusion throughout the experiment. Infarct size was assessed by triphenyltetrazolium staining, and apoptosis via measurement of caspase 3 activity. Ca(2+)-induced mPTP opening was assessed in mitochondria isolated from ischemic myocardium. TMZ and PC significantly reduced infarct size that averaged 34 +/- 4% and 21 +/- 4% of the risk region respectively, versus 63 +/- 6% in controls (P<0.005). Caspase 3 activity was reduced in both TMZ and PC groups: 37 +/- 11 and 29 +/- 7 respectively, versus 68 +/- 9 nmol min(-1) mg(-1) mitochondrial protein in controls (P=0.01 versus TMZ and PC). In controls, Ca(2+) load required for mPTP opening averaged 11 +/- 4 microM mg(-1) mitochondrial protein versus 116 +/- 6 in shams (P<0.0001). Pre-treatment by TMZ or PC attenuated this, with Ca(2+) loads averaging 45 +/- 4 and 46 +/- 4 microM mg(-1) mitochondrial proteins, respectively (P<0.005 versus C). These data suggest that TMZ inhibits mPTP opening and protects the rabbit heart from prolonged ischemia-reperfusion injury.
Abstract: The Fas/Fas ligand and mitochondria pathways have been involved in cell death in several cell types. We combined the genetic inactivation of the Fas receptor (lpr mice), on the one hand, to the pharmacological inhibition of the mitochondrial permeability transition pore (mPTP), on the other hand, to investigate which of these pathways is predominantly activated during prolonged ischemia-reperfusion. Anesthetized C57BL/6JICO (control) and C57BL/6-lpr mice were pretreated with either saline or cyclosporin A (CsA; 40 mg/kg, 3 times a day), an inhibitor of the mPTP, and underwent 25 min of ischemia and 24 h of reperfusion. After 24 h of reperfusion, hearts were harvested: infarct size was assessed by 2,3,5-triphenyltetrazolium chloride staining, myocardial apoptosis by caspase 3 activity, and mitochondrial permeability transition by Ca2+-induced mPTP opening using a potentiometric approach. Infarct size was comparable in untreated control and lpr mice, ranging from 77 +/- 5% to 83 +/- 3% of the area at risk. CsA significantly reduced infarct size in control and lpr hearts. Control and lpr hearts exhibited comparable increase in caspase 3 activity that averaged 57 +/- 18 and 49 +/- 5 pmol x min(-1) x mg(-1), respectively. CsA treatment significantly reduced caspase 3 activity in control and lpr hearts. The Ca2+ overload required to open the mPTP was decreased to a similar extent in lpr and controls. CsA significantly attenuated Ca2+-induced mPTP opening in both groups. Our results suggest that the Fas pathway likely plays a minor role, whereas mitochondria are preferentially involved in mice cardiomyocyte death after a lethal ischemia-reperfusion injury.
Abstract: Recent investigations have focused on the pivotal role of the mitochondria in the underlying mechanisms volatile anesthetic-induced myocardial preconditioning. This study aimed at examining the effect of anesthetic preconditioning on mitochondrial permeability transition (MPT) pore opening.
Abstract: Although the mechanism by which ischemic preconditioning (PC) inhibits myocardial apoptosis during ischemia-reperfusion is unclear, evidence indicates a role for the secondary messenger ceramide. We investigated in vivo whether PC may affect ceramide and sn-1,2-diacylglycerol (DAG) production, and attenuate apoptosis during ischemia. Rabbits underwent 30 min of ischemia, followed by 4 h of reperfusion. Before this, they received either no intervention (control group) or one episode of 5 min of ischemia, followed by 5 min of reperfusion (PC group), or an intravenous administration of the sphingomyelinase inhibitor D609. Myocardial content of ceramide and DAG was measured using the DAG kinase assay at different time points of the experiment. Apoptosis was detected and quantified by a sandwich enzyme immunoassay. Both AR and infarct size were measured using blue dye injection and triphenyltetrazolium chloride staining. Control hearts exhibited a peak of ceramide production at 5 min of the prolonged ischemia, with a mean value averaging 64 +/- 5 ng/mg tissue (P < 0.05 vs. 48 +/- 4 ng/mg at baseline). In contrast, ischemic PC and D609 prevented ceramide increase during the prolonged ischemia. Myocardial DAG content was increased only in PC hearts at 30 min of ischemia. Preconditioned and D609 groups developed less apoptosis, as well as a limited infarct size, compared with the control group. These results suggest that the antiapoptotic effect of PC may be due to a reduced ceramide production during sustained ischemia in the rabbit heart.
Abstract: It is unclear whether the protection observed in human heart following repetition of brief episodes of ischaemia is due to opening of coronary collaterals or to ischaemic preconditioning. We investigated whether the improvement in ST segment change following repeated episodes of brief ischaemia during coronary angioplasty is due to preconditioning when the size of the area at risk and the collateral flow are taken into account.
Abstract: Ischemic preconditioning affords the most powerful protection to a heart submitted to a prolonged ischemia-reperfusion. During the past decade, a huge amount of work allowed to better understand the features of this protective effect as well as the molecular mechanisms. Ischemic preconditioning reduces infarct size and improves functional recovery; its effects on arrhythmias remain debated. Triggering of the protection involves cell surface receptors that activate pro-survival pathways including protein kinase C, PI3-kinase, possibly Akt and ERK1/2, whose downstream targets remain to be determined. Much attention has been recently focused on the role of mitochondrial K(+)ATP channels and the permeability transition pore that seem to play a major role in the progression toward irreversible cellular injury. Based on these experimental studies attempts have been made to transfer preconditioning from bench to bedside. Human experimental models of ischemic preconditioning have been set up, including cardiac surgery, coronary angioplasty or treadmill exercise, to perform pathophysiological studies. Yet, protecting the heart of CAD (coronary artery disease) patients requires a pharmacological approach. The IONA trial has been an example of the clinical utility of preconditioning. It helped to demonstrate that chronic administration of nicorandil, a K(+)ATP opener that mimics ischemic preconditioning in experimental preparations, improves the cardiovascular prognosis in CAD patients. Recent experimental studies appear further encouraging. It appears that "postconditioning" the heart (i.e. performing brief episodes of ischemia-reperfusion at the time of reperfusion) is as protective as preconditioning. In other words, a therapeutic intervention performed as late as at the time of reflow can still significantly limit infarct size. Further work is needed to determine whether this may be transferred to the clinical practice.
Abstract: A possible role of palmitic acid/Ca2+ (PA/Ca2+) complexes in the cyclosporin-insensitive permeability transition in mitochondria has been studied. It has been shown that in the presence of Ca2+, PA induces a swelling of mitochondria, which is not inhibited by cyclosporin A. The swelling is accompanied by a drop in membrane potential, which cannot be explained only by a work of the Ca2+ uniporter. With time, the potential is restored. Evidence has been obtained indicating that the specific content of mitochondrial lipids would favor the PA/Ca2+ -induced permeabilization of the membrane. In experiments with liposomes, the PA/Ca2+ -induced membrane permeabilization was larger for liposomes formed from the mitochondrial lipids, as compared to the azolectin liposomes. Additionally, it has been found that in mitochondria of the TNF (tumor necrosis factor)-sensitive cells (WEHI-164 line), the content of PA is larger than in mitochondria of the TNF-insensitive cells (C6 line), with this difference being mainly provided by PA incorporated in phosphatidylethanolamine and especially, cardiolipin. The PA/Ca2+ -dependent mechanism of permeability transition in mitochondria might be related to some pathologies, e.g. myocardial ischemia. The heaviness of myocardial infarction of ischemic patients has been demonstrated to correlate directly with the content of PA in the human blood serum.
Abstract: Evidence indicates that acute cardiac graft rejection is associated with cardiomyocyte apoptosis. Mitochondrial permeability transition (MPT) induces apoptotic cell death. We sought to determine whether MPT might play a role in cardiomyocyte apoptosis in the rat model of heterotopic cardiac transplantation. Syngenic and allogenic transplantations were performed, and both native and grafted hearts were harvested 3 or 5 d after transplantation for detection of acute rejection, assessment of Ca(2+)-induced MPT, and myocardial apoptosis by TUNEL staining and caspase 3 activity. Allogenic grafts developed severe acute rejection at day 5 with concomitant cardiomyocyte apoptosis (apoptotic index: 7.1 +/- 1.0% vs. 1.0 +/- 0.2% in syngenic hearts, and caspase 3 activity: 38 +/- 25 vs. 5 +/- 9 nmol/mg, in allogenic vs. syngenic grafts, respectively). At day 5, Ca(2+)-induced MPT was dramatically altered in allogenic when compared with syngenic grafts (mean Ca(2+) overload averaged 0 +/- 20 vs. 280 +/- 30 microM in allogenic and syngenic grafts, respectively). NIM811, a nonimmunosuppressive derivative of cyclosporin A (CsA), that specifically inhibits the MPT pore, did not alter acute rejection, but significantly delayed Ca(2+)-induced MPT pore opening, attenuated caspase 3 activity and cardiomyocyte apoptosis in allogenic grafts. This suggests that mitochondrial permeability transition pore opening may play an important role in cardiomyocyte apoptosis associated with acute cardiac graft rejection.
Abstract: Myocardial stunning, a transient contractile dysfunction that appears following a brief period of ischemia, is at least partly due to the production of oxygen-derived free radicals. The objective of the present study was to determine whether the Ginkgo biloba extract EGb761, which has antioxidant properties in vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open-chest farm pigs underwent 10 min of occlusion of the left anterior descending coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3 mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed by sonomicrometry. Both doses of EGb 761 significantly improved recovery of contractile function in the reperfused myocardium with segment shortening averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus 81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p < 0.05 vs control in both cases). In contrast, neither dose of GkB improved functional recovery during reperfusion. ESR experiments revealed that EGb761 resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05 vs control group) was also obtained in GkB-treated animals. These results indicate that EGb 761 can attenuate myocardial stunning following a brief ischemic insult in the in situ pig heart by an effect that involves a decrease in the formation of free radicals. As the effect of EGb 761 on functional recovery cannot be explained by the presence of GkB, the beneficial action of the extract on myocardial stunning likely involves complementary effects of both its non-ginkgolide and ginkgolide constituents.
Abstract: The assessment of contractile function of the right ventricle (RV) is an important clinical issue, but this remains difficult because of its complex anatomy and structure. We thought to investigate whether new Doppler-derived myocardial deformation indexes may quantify regional contractile RV function during varying loading conditions. In nine pigs, ultrasonic crystals were inserted longitudinally in the RV inflow and outflow tracts to assess regional contractile function. The same RV segments and the interventricular septum were imaged using apical echocardiographic views. Regional function was assessed using two parameters: 1) systolic strain (SS), representing the relative magnitude of segmental systolic shortening; and 2) its temporal derivative, peak systolic strain rate (SR), i.e., the maximal velocity of segmental shortening. Data were acquired at baseline and during partial pulmonary artery constriction (PAC) and inferior vena cava occlusion (IVCO). SS decreased significantly after PAC and IVCO in both the inflow and outflow tracts but only during IVCO in the septum. SR was less sensitive to loading variations in all segments. A significant correlation was found between SS values derived from sonomicrometry and myocardial Doppler in RV segments (r = 0.84, P < 0.001). Thus regional strain and SR provide complementary information on the heterogeneous RV contractile function and can be accurately and noninvasively quantified using Doppler myocardial imaging.
Abstract: Strain rate imaging (SRI), a recently developed Doppler-derived process, allows quantification of myocardial systolic function. We investigate whether SRI quantifies the contractile reserve during dobutamine stress tests in heart transplant patients (HT), when compared with normal individuals.
Abstract: To evaluate coronary artery disease (CAD) patients regarding to their perfusion-glucose uptake relationship at rest for all myocardial regions and to determine whether this evaluation could typify patients with different positron emission tomography (PET)-pattern proportions and pathophysiological characteristics.
Abstract: We sought to determine whether brain death-induced catecholamine release preconditions the heart, and if not, whether it precludes further protection by repetitive ischemia or isoflurane. Anesthetized rabbits underwent 30 min of coronary occlusion and 4 h of reperfusion. The effect on infarct size of either no intervention (controls), ischemic preconditioning (IPC), or isoflurane inhalation (Iso) was evaluated with or without previous brain death (BD) induced by subdural balloon inflation. Plasma catecholamine levels were measured at several time points. Although it dramatically increase plasma catecholamine levels, BD failed to reduce infarct size that averaged 0.49 +/- 0.34 without BD versus 0.45 +/- 0.27 g with BD. IPC and Iso, alone as well as after BD, significantly reduced infarct size that averaged 0.11 +/- 0.04, 0.21 +/- 0.15, 0.10 +/- 0.09, and 0.22 +/- 0.10 g in IPC, Iso, BD + IPC, and BD + Iso groups, respectively (means +/- SD, P < 0.05 vs. controls). BD-induced catecholamines "storm" does not precondition the rabbit heart that however retains the ability to be protected by repetition of brief ischemia or isoflurane inhalation.
Abstract: Recent investigations showed that isoflurane can induce pharmacological preconditioning. The present study aimed to compare the potency of four different halogenated anaesthetics to induce preconditioning.
Abstract: We aimed to characterise the alterations of left ventricular twist during ischaemia-reperfusion and to study their relationship to global left ventricular function. Systolic left ventricular twist was measured at the mid-papillary muscle level by colour tissue Doppler echocardiography in 7 anaesthetised open-chest dogs at baseline, 90 min-occlusion of the left anterior descending, and 180 min after reflow. Tissue Doppler was also performed in 34 patients after anterior infarct and in 20 controls. In controls, rotation occurred counterclockwise when viewed from the base. In a random subset of subjects, the assessment of ventricular twist by tissue Doppler was validated against magnetic resonance myocardial tagging. Myocardial ischaemia led to a decrease in ventricular twist in dogs and infarct patients (p < 0.01). This decrease was correlated with the extent of the asynergic area and global left ventricular function (p < 0.001). In dogs, cardiac twist was higher after reflow relative to ischaemia (p < 0.01). Thus, acute myocardial ischaemia is responsible for a decrease in left ventricular twist that is related to global ventricular function. Colour tissue Doppler echocardiography provides straightforward assessment of left ventricular twist in humans.
Abstract: The evaluation of transmural extent of necrosis after acute myocardial infarction remains a major problem in clinical practice. We sought to determine whether color M-mode tissue Doppler imaging (TDI) could differentiate transmural from nontransmural myocardial infarction.
Abstract: Nicorandil is a K(ATP) channel opener used to treat angina. It is cardioprotective and a vasodilator. We conducted a prospective, randomized, double-blind, placebo-controlled study to assess oral nicorandil in patients undergoing coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). Twenty-two patients received nicorandil (10 mg twice a day) and 23 patients received placebo. Haemodynamic data were recorded before induction of anaesthesia (T0), 5 and 20 min after starting mechanical ventilation (T1, T2), before aortic cannulation (T3), after 30 min of CPB (T4), 10 min after CPB (T5) and after 3, 8 and 18 h in the intensive care unit (T6, T7, T8). Serum proteins (creatine kinase metabolite and cardiac troponin I) were measured before and 8 and 18 h after surgery. Haemodynamic values did not differ between the two groups. There was no tachycardia during the study, no significant difference in hypotensive episodes, ST segment changes and no changes in cardiac enzymes. Myocardial infarction after surgery was similar in the two groups. Vasoactive therapy was similar in the two groups. Nicorandil can be continued safely up to premedication without deleterious haemodynamic consequences, but a myocardial protective effect of nicorandil in CABG surgery was not found.
Abstract: The beta-adrenergic pathway may have a role in the pathophysiology of ischemic syndromes characterised by reversible left ventricular dysfunction, such as myocardial stunning and other clinical conditions of unstable angina or coronary spasms, or chronic reversible left ventricular dysfunction, which might be a consequence of repeated events of short-term ischemia ("repetitive stunning"). A partial-to-total occlusion of the left anterior descending coronary artery in pigs was used to induce short periods of ischemia (total ischemic time 12 +/- 2 min). Hypokinesis and dyskinesis of the myocardium were considered signs of myocardial dysfunction. We found a maintained function of the beta-adrenergic signalling system. Density and affinity of beta-adrenergic receptors were not different in stunned and non-ischemic regions, nor were cyclic AMP and cyclic GMP intracellular contents and ratio, nor well as the ratio of stimulatory/inhibitory G protein a subunits. Our findings are in agreement with a maintained beta-adrenergic signalling system in the pathophysiology of chronic reversible left ventricular dysfunction.
Abstract: A peripheral perfusion tracer injection at the time of coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA) may delineate the myocardial 'area at risk' related to a given artery. To evaluate the location, size and severity of the corresponding scintigraphic defects, we conducted a prospective study of 36 patients who received a 99Tcm-sestamibi injection during single-vessel coronary angioplasty (PTCA = 18 LAD, 16 RCA and 2 LCX) followed by SPET. For comparison, a reference group of 36 successive patients examined during the early phase of myocardial infarction (MI), matched for the same vascular territories (18 anterior, 16 inferior and 2 lateral), were analysed in the same way after standard stress/reinjection 201Tl SPET. The imaging characteristics of both groups showed excellent agreement as well degree of uptake defects, in terms of topography and extent. A defect index, taking into account both size and severity, was in the same range for PTCA and MI patients (mean +/- standard deviation): for LAD vs anterior = 28.4 +/- 13.5% (PTCA), 27.1 +/- 12.2% (MI-stress) and 24.2 +/- 10.0% (MI-reinjection); for RCA vs inferior = 15.5 +/- 10.2% (PTCA), 14.7 +/- 9.7% (MI-stress) and 13.2 +/- 8.2% (MI-reinjection). Sectoral correlations between PTCA and MI groups were also highly significant.
Abstract: Transmural myocardial contractile performance is nonuniform across the different layers of the left ventricular wall. We evaluated the accuracy of color M-mode tissue Doppler imaging (TDI) to assess the transmural distribution of myocardial velocities and to quantify the severity of dysfunction induced by acute ischemia and reperfusion in the inner and outer myocardial layers.
Abstract: The physiopathology of hemodynamic instability that occurs after brain death remains unknown. The aim of this study was to examine the initial response to brain death induction.
Abstract: Both mitochondrial adenosine triphosphate-sensitive potassium (MKATP) channels (selectively blocked by 5-hydroxydecanoate) and stretch-activated channels (blocked by gadolinium) have been involved in the mechanism of ischemic preconditioning. Isoflurane can reproduce the protection afforded by ischemic preconditioning. We sought to determine whether isoflurane-induced preconditioning may involve MKATP and stretch-activated channels.
Abstract: Normal cardiac function requires adequate oxygen and substrate (fatty acids, glucose lactate) supply for the energetic requirements of the myocardium. Ischaemia induces abnormalities in the production and excretion of products of myocardial metabolism. During ischaemia, the equilibrium which exists during aerobic respiration between the beta-oxidation of fatty acids and carbohydrates and which generates ATP is disturbed. Pyruvate oxidation and beta-oxidation of fatty acids decrease, and ATP is mainly produced by anaerobic glycolysis. Under these conditions, intracellular glycogen is mobilised, the lactate and protons accumulate in the cardiomyocyte. If reperfusion occurs before irreversible lesions are produced, then functional recovery is possible and is mostly dependant on the type of energetic substrate available. Circulating fatty acids are produced in large quantities after ischaemia: their beta-oxidation, which is then the principal source of ATP, may contribute to the aggravation of contractile dysfunction during reperfusion and accentuate or generate arrhythmias. The decoupling between acceleration of anaerobic glycolysis and the defect of pyruvirate oxidation (inhibition of pyruvirate dehydrogenase) participate in a significant fashion to the accumulation of protons. Rapid correction of intracellular acidosis during reperfusion by activation of the Na+/H+ exchanger, coupled with the accumulation of intracellular Na+ induces a deleterious calcium overload via the Na+/Ca++ exchanger. These different aspects of intracellular metabolism constitute pharmacological targets for the development of future cardio-protective agents.
Abstract: The patients who have only single vessel disease of the right coronary artery have an excellent prognosis, unaffected by surgery. The object of this study was to evaluate the long-term prognosis of these patients after transluminal coronary angioplasty. The criteria of analysis were survival, anginal symptoms, quality of life and ergometric parameters. Two hundred and forty eight patients with an isolated lesion of the right coronary artery who underwent angioplasty were reassessed 39.6 +/- 22 months after angioplasty. The primary success rate was 89.9% with 5.2% of severe complications during the hospital period (myocardial infarction, bypass surgery, coronary angiography +/- angioplasty). The actuarial global and cardiac survival rates at 7 years were 88.4 and 96.2% respectively with no difference between the success and failure groups. The eight cardiovascular deaths and thirteen myocardial infarctions which were observed in the long-term were all in the successful angioplasty group. From the symptomatic viewpoint, 76% of the population became asymptomatic. The same results were observed in terms of quality of life with 58% of patients estimating it to be good in correlation with anginal status. The comparison of ergometric tests showed a significant gain in performance in 67% of patients. The authors conclude that the results suggest that angioplasty in single vessel disease of the right coronary artery provides a significant symptomatic and ergometric benefit but that it is impossible to assess the eventual benefits in terms of survival which would have needed a group of similar patients assessed under anti-ischaemic treatment and taking into consideration the recent innovations (stents, statins).
Abstract: In order to give further insight into the potential role of PKC in the beneficial effects of ischemic preconditioning, we have characterized the production of diacylglycerol, the endogenous activator of PKC, and its molecular species composition in ischemic control and preconditioned hearts. Preconditioning was induced by 1 cycle of 5 min of ischemia followed by 5 min of reperfusion. In control and preconditioned groups, hearts were harvested under deep anesthesia at baseline (preischemia) and at 2, 5 and 10 min into the sustained coronary artery occlusion, i.e., preceding myocyte death. Diacylglycerol content and fatty acid composition were analyzed by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC), respectively. Myocardial diacylglycerol content was increased at 2 min into the sustained ischemia in the control group (481 +/- 34 vs 292 +/- 64 ng x mg(-1) at baseline; p < 0.05), but was comparable to the baseline value at 5 and 10 min. In the preconditioned group, diacylglycerol production remained unchanged throughout the 10-min test ischemia (317 +/- 17 at 2 min vs 312 +/- 38 ng x mg(-1) at baseline; p = NS). A detailed analysis of the molecular species composition at the time of 2 min revealed a reduced contribution of phosphatidylinositol to diacylglycerol production in preconditioned myocardium (global correlation coefficient 0.57 vs 0.66 in control myocardium) with a trend toward an enrichment of diacylglycerol composition with some species originating from phosphatidylcholine. Thus, our study revealed that brief preconditioning ischemia: (1) prevents the increase of diacylglycerol content in the early minutes of the sustained ischemia, and (2) emphasizes the contribution of phosphatidylcholine in diacylglycerol formation to the detriment of that of phosphatidylinositol.
Abstract: We sought to determine whether stretch-induced preconditioning may be related to activation of adenosine receptors, ATP-sensitive K+ (K+ATP) channels, and/or protein kinase C (PKC) in the rabbit heart. Anesthetized rabbits underwent 30 min of coronary artery occlusion followed by 3 h of reperfusion. Ischemic preconditioning was induced by one episode of 5 min of ischemia followed by 5 min of reperfusion, and stretch preconditioning was induced by a transient volume overload. The abilities of gadolinium (Gd3+), a blocker of stretch-activated channels, glibenclamide (Glib), a blocker of K+ATP channels, 8-(p-sulfophenyl)-theophylline (8-SPT), a blocker of adenosine receptors, and polymyxin B (PMXB), an antagonist of PKC, to prevent the infarct size-limiting effect of stretch-induced preconditioning were evaluated. Because the infarct size-reducing effect of stretch occurred in the absence of ischemia and was prevented by previous administration of Gd3+, Glib, 8-SPT, and PMXB, we propose that activation of mechanosensitive ion channels protects the rabbit heart from subsequent sustained ischemic insult, likely through a mechanism that involves downstream activation of PKC, adenosine receptors, and/or K+ATP channels.
Abstract: Quantification of regional myocardial function is a major unresolved issue in cardiology. We evaluated the accuracy of pulsed Doppler tissue imaging (DTI), a new echocardiographic technique, to quantify regional myocardial dysfunction induced by acute ischemia and reperfusion.
Abstract: Intravascular ultrasound enables detection of the components of atherosclerotic plaques. The diagnostic value was assessed by ROC (receiver operating characteristic) curves on images acquired in vitro and correlated with the histological findings in 61 arteries. Five questions were asked of each operator; the reply was represented by a continuous variable in order to express all nuances of judgement. The area under the ROC curve, Az, was the criterion of performance (0.5 : chance response : 1.0 : all replies were accurate). Detection of plaque was satisfactory (Az = 0.89). The three layer appearance of muscular arteries was well recognised (Az = 0.94). The fibrous composition of a plaque was only just satisfactory (Az = 0.88) with 38.7% interindividual variability. The lipid composition of the plaque was poorly recognised (Az = 0.76) with large interindividual variability (52.8%) : hypoechogenicity was too ambiguous a sign from the acoustic point of view. A hypoechogenic zone must not be synonymous with a lipid plaque but a cellular zone. Calcium can almost always be detected (Az = 0.98) with a very low interindividual variability (10.7%), fibrohyaline progression of some plaques can be confusing. The authors present a more objective description of endovascular ultrasonographic images. They conclude that the diagnostic performance of 30 MHz intravascular ultrasound is satisfactory but several limitations are apparent in the interpretation of images, especially hypoechogenic zone and hyper-reflective zones with high attenuation.
Abstract: ATP-dependent potassium (K+ATP) channels play a role in the infarct size-limiting effect of preconditioning in pigs. We previously demonstrated that preconditioning shortens monophasic action potential duration (MAPD) and accelerates the time to ventricular fibrillation (VF) during a prolonged ischemia in pigs. We sought to determine whether the mechanism of the reduced time to VF in preconditioned pigs is a consequence of K+ATP, channel activation. Pigs underwent 40 min of coronary occlusion and 2 h of reperfusion. Before this, animals received either no intervention (control), 10 min of ischemia and 10 min of reperfusion (preconditioned), or an intravenous infusion of nicorandil, a K+ATP channel opener. Additional control, preconditioned, and nicorandil-treated pigs were pretreated by glibenclamide, an antagonist of K+ATP channels. Because 1) the K+ATP channel activator nicorandil did not produce shorter time to VF, 2) the K+ATP channel inhibitor glibenclamide did not block the acceleration of VF by preconditioning, and 3) there was no relationship between time to VF and infarct size or MAPD, the major conclusion is that reduced time to VF in preconditioned animals is not a consequence of K+ATP channel activation.
Abstract: Preconditioning is commonly induced by a brief ischemic insult; myocardial stretch can trigger this protection by an unknown mechanism. Myocardial stretch preconditions the in vivo canine heart; however, the existence of a stretch-induced protection in the rat heart remains unknown. The purpose of this study was to test this myocardial protection induced, in isolated working rat heart, by global ischemia and stretch initiated by a transient increase in the left ventricle (LV). Isolated rat hearts underwent 30 min of global ischemia followed by 30 min of reperfusion. Before this, hearts received a 15-min period of either no intervention (control; C), 5 min of global ischemia + 10 min of reperfusion (preconditioning; PC) or 5 min of stretch + 10 min with no intervention (stretch; S). Stretch was induced by a transient increase in LV preload from 5 to 20 cm H2O. LV work started under a afterload of 80 cm H2O. Control, PC, and S hearts received either no drug (untreated) or staurosporine (50 nM), a protein kinase C inhibitor, before the "preconditioning" period. Creatine kinase (CK) release, ventricular fibrillation during reperfusion, and postischemic recovery of contractile function (aortic flow) were the end points of the study. In the S group, the abrupt increase in preload resulted in a significant increase of aortic flow (42 +/- 2 to 47 +/- 2 ml/min; p < 0.05). During the 30-min reperfusion period, control hearts displayed a poor recovery of contractile functions (8 +/- 3 ml/min, 30 min after reflow, versus 40 +/- 2 ml/min at baseline; p < 0.05). Both untreated PC and S groups exhibited a significant reduction in CK release, incidence of ventricular fibrillation (55% of control hearts developed persistent VF vs. 6% in both the PC and S groups), and postischemic dysfunction during reperfusion (p < 0.05 vs. control). Staurosporine prevented these beneficial effects in PC and S groups. Our study suggests that myocardial protection can be induced by stretch in the isolated working rat heart, likely through activation of protein kinase C. In conclusion, our results show that ischemic preconditioning and stretch had comparable favorable effect on functional recovery after a sustained ischemic insult in the isolated rat heart.
Abstract: Preservation of myocardial viability is a major objective of modern cardiology. Many patients develop large infarcts with major functional consequences in the short and long term. Too many still develop progressive left ventricular dysfunction for which cardiac transplantation, with all its limitations, is the only therapeutic possibility. It is therefore essential to prevent or delay the extension of necrosis. Preconditioning is a natural form of protection which delays the development of myocardial necrosis. A great deal of research is under way to understand this complex process of cardiac protection with the objective to develop pharmacological agents able of simulate or to reproduce its effects in the clinical setting.
Abstract: Preconditioning is a temporary tolerance to ischaemia acquired by the myocardium after a short period of ischaemia. It results in the limitation of the infarct size induced by prolonged coronary occlusion. The mechanism of this cytoprotection remains poorly understood. The A1 adenosine receptors, the ATP-sensitive potassium channels and protein-kinase C seem to play prominent roles. The effects of preconditioning on the complications of ischaemia/reperfusion such as myocardial stunning, ventricular arrhythmias or decreased coronary reserve are not well known. Several studies suggest that the cytoprotection resulting from preconditioning could be applied to human myocardium and constitute a preventive anti-ischaemic therapy during coronary angioplasty, cardiac surgery or the conservation of transplant grafts.
Abstract: Preconditioning protects the rat heart from ventricular arrhythmias. However, the mechanism of this beneficial effect and its existence in large animal models remain unknown. We submitted 49 pigs to 40 min of left anterior descending coronary occlusion and 2 h of reperfusion and assessed the incidence of ventricular fibrillation (VF) and time to VF. Monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were measured throughout the experiment. Preconditioning significantly reduced infarct size but failed to reduce the incidence of VF either during the 40-min ischemic insult or the following reperfusion. Moreover, preconditioning accelerated the onset of VF during the prolonged ischemia; time to VF averaged 8 +/- 2 min in the preconditioned group vs. 18 +/- 2 min in the control group (P < 0.05). This premature peak of VF in preconditioned hearts was associated with a significant decrease of VFT and shortening of MAPD. This suggests that preconditioning does not limit the incidence of VF in the pig model. Rather, preconditioning decreases the time to VF in this species, likely through lowering of the VFT and shortening of the action potential duration.
Abstract: Mechanisms responsible for the well-documented "protection" against myocardial ischemia and infarction in young women and subsequent loss of protection after menopause remain speculative. One possibility is that gender-related variables (such as endogenous hormone levels or regular loss of stored iron) alter the susceptibility of the heart to ischemia: if so, then premenopausal women when compared with men may manifest endogenous protection against acute myocardial ischemic injury. Using the canine model we therefore sought to determine whether gender influences acute myocardial ischemia and infarction. Retrospective analysis was performed on data compiled from 60 mature adult dogs subjected to 1 hour of coronary artery occlusion and > or = 4 hours of reperfusion. We first compared the incidence of lethal ventricular fibrillation in the male and female cohorts and then for survivors compared collateral blood flow during coronary occlusion (by injection of radioactive microspheres), infarct size (assessed by tetrazolium staining and expressed as a percentage of the myocardium at risk), and regional wall motion (by somomicrometry) in the infarct-related area. The incidence of lethal ventricular fibrillation was 23% in the male dogs and 19% in the female dogs (p = 0.70, difference not significant). For survivors, the area at risk of infarction was comparable in males and females (23 +/- 2% and 22% +/- 1% of the total left ventricular weight), and the groups were equally ischemic during coronary occlusion, with collateral blood flow to the ischemic subendocardium averaging 0.05 +/- 0.02 and 0.07 +/- 0.01 ml/min/g tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Preconditioning is believed to be directly triggered by brief ischemia-reperfusion. However, brief ischemia results in transient dilation (or stretching) of the heart. We therefore sought to determine whether stretch per se, induced by rapid volume overload instead of brief coronary occlusion, could precondition the heart via stretch-activated ion channels. Forty-two anesthetized dogs underwent 1 h of coronary artery occlusion followed by 4.5 h of reperfusion. Before this, each dog underwent either no intervention (control) or acute volume overload. In three additional groups, Gd3+, a potent blocker of stretch-activated channels was injected as a bolus into the left atrium of each dog at the onset of the treatment period. Then the dogs underwent either acute volume overload, a 5-min episode of coronary occlusion followed by 10 min of reperfusion, or no intervention. Myocardial stretch significantly reduced infarct size after a subsequent 60-min ischemic insult. Protection afforded by stretch was completely prevented by Gd3+. Reduction in infarct size afforded by ischemic preconditioning was partially reversed by Gd3+. Gd3+ per se did not, however, alter the extent of necrosis. The present study suggests that myocardial stretch per se can precondition the canine heart, probably by activation of stretch-activated ion channels.
Abstract: The main advantage of pulsatile flow compared with steady flow during cardiopulmonary bypass is to prevent a rise in systemic vascular resistances. We hypothesized that pulsatile flow could overcome the progressive rise in peripheral and placental vascular resistances observed during fetal bypass and leading to progressive irreversible hypoxemia.
Abstract: One or more brief episodes of coronary artery occlusion protect or "precondition" the myocardium perfused by that artery from a subsequent episode of sustained ischemia. We sought to determine whether ischemic preconditioning protects only those myocytes subjected to brief coronary occlusion or whether brief occlusions in one vascular bed also limit infarct size and/or attenuate contractile dysfunction in remote virgin myocardium subjected to subsequent sustained coronary occlusion.
Abstract: This study investigated the effects of ischemic preconditioning on myocardial carnitine-linked metabolism and high-energy phosphates in the canine model of ischemia and reperfusion.
Abstract: The biological diagnosis is usually late with respect to clinical and electrocardiographic signs of acute myocardial infarction. Recent laboratory methods have stimulated renewed interest in very early marker of infarction: myoglobin and CPK isoforms. The authors undertook a prospective study of the diagnostic sensitivity of myoglobin (MG), CPK and CPK-MM isoforms in 30 consecutive patients undergoing intravenous thrombolytic therapy in the acute phase of myocardial infarction. Blood samples were obtained on admission and every 30 minutes for 1 h 30. The Mb contributed to diagnosis of infarction on admission in 89% of patients. This percentage fell to 44% for the ratio MM3/MM1 > 0.5 to 27% for the CPK and to 24% for the ratio MM3/MM1 > 1. The sensitivity of all tests increased in the later blood samples but it remained low in the CPK and MM3/MM1 > 1 criteria. The diagnostic sensitivity of the first sample was also better in patients admitted after the 3rd hour (Mb = 100%; MM3/MM1 > 0.5: 58%; CPK: 41%) compared with those admitted before the 3rd hour (Mb = 82%; MM3/MM1 > 0.5: 35%; CPK: 17%). These results show that the diagnostic sensitivity of biological markers of myocardial infarction is very different. The serum myoglobin is an earlier and more sensitive marker than the CPK or CPK-MM isoforms.
Abstract: Previous results on the effects of angiotensin-converting enzyme (ACE) inhibition in myocardial ischemia are conflicting. To determine whether acute ACE inhibition may influence myocardial perfusion deficit during ischemia and reduce ischemia-reperfusion injury, anesthetized open-chest dogs underwent 2-h left anterior descending coronary artery (LAD) occlusion followed by 6-h reperfusion. After 1-h coronary occlusion, each dog was randomized to receive either captopril [5 mg/kg intravenous (i.v.) bolus and 0.25/kg/h infusion for 7 h] or saline. Whereas arterial pressure was reduced (p = 0.001), captopril did not influence myocardial perfusion deficit: Blood flow in the central ischemic zone represented 17.1 +/- 2.8% of the flow in the nonischemic zone versus 20.5 +/- 3.8% before treatment (NS). The values of the control group were 17.8 +/- 2.5 and 16.7 +/- 2.4%, respectively. In addition, there was no difference in infarct size: 35.9 +/- 3.3% of the area at risk in captopril-treated dogs versus 40.0 +/- 3.6% in controls. Analysis of subgroups based on the level of the collateral flow indicated, however, that ACE inhibition had an adverse effect on infarct size in dogs with high collateral flow: 31.9 +/- 4.6% in captopril dogs versus 17.6 +/- 4.7 (p = 0.048). This effect was related to a decrease in collateral flow because animals exhibiting the highest increase in perfusion deficit presented the greatest increase in infarct size (r = -0.92, p = 0.003). Although in dogs with low collateral flow, ACE inhibition appeared to exert a slight beneficial effect on infarct size, we conclude that at least in this dog model, acute ACE inhibition could exacerbate myocardial injury.
Abstract: Repeated brief episodes of myocardial ischemia performed by mechanical clamping of a coronary artery "precondition" the heart and reduce infarct size after a subsequent sustained ischemia. It is not known, however, whether spontaneous episodes of transient ischemia caused by formation of platelet thrombi, which may occur in unstable angina, have a similar cardioprotective effect.
Abstract: Despite numerous reports that one or more episodes of brief coronary artery occlusion preconditions the myocardium and dramatically reduces myocardial infarct size produced by a subsequent prolonged ischemia, we recently demonstrated that preconditioning does not attenuate contractile dysfunction in the peri-infarct tissue. However, the specific effects of preconditioning on myocardium in which wall motion has not been compromised by the preconditioning regimen per se and is further submitted to a short ischemic insult (that is, not confounded by necrosis) remain unknown.
Abstract: Calcium channel blocking agents prevent calcium entering cardiac and smooth muscle cells. With reduction of the blood pressure, heart rate and myocardial contractility, they reduce myocardial oxygen demand. By relieving spasm and coronary constriction, and dilating the collateral coronary vessels, they improve perfusion of the ischemic zones. The results in experimental infarction are contradictory: the reduction in the infarct size and ischaemia is not constant. In the Myocardial Infarction Study, a trial of lidoflazine in 1792 subjects followed up for an average of 5 years, there was no significant difference between the mortality rates of the two groups. In the Danish Verapamil Infarction Trial I, which included 436 subjects receiving 360 mg/day of verapamil or placebo, the 6 months mortality was less (NS) in the verapamil group (12.8%) than in the placebo group (13.9%) as was the reinfarction rate (7.8% versus 9.2%; NS). In the DAVIT II trial of 1775 subjects, treatment was introduced 9 +/- 2.7 days after admission. Mortality was lower (NS) in the verapamil group (11.1%) than in the placebo group (13.8%) and the recurrences were less common (p = 0.04) in the treatment group (11.0%) than with placebo (13.2%). The Secondary Prevention Reinfarction Israeli Nifedipine Trial is a comparison of Nifedipine 30 mg/day and placebo introduced 7-21 days after infarction in 2276 subjects. After 10 months, the mortality and reinfarction rate were similar in both groups, as in the SPRINT II trial (60 mg/day of nifedipine or placebo) at 6 months. In the Multicenter Diltiazem Postinfarction Trial of 2466 patients, Diltiazem 240 mg/day or placebo was administered 3 to 15 days after infarction.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Repeated brief episodes of total coronary artery occlusion (i.e., severe ischemia), each separated by brief periods of reperfusion, reduce infarct size after a subsequent sustained ischemia. The importance of the intensity of ischemia during these coronary artery occlusions and the role of the following transient reflow are poorly understood. Therefore, our objective was to determine whether moderate preconditioning ischemia induced by partial coronary artery stenosis (reducing coronary flow to approximately 50% of its baseline values), with or without a brief period of total reperfusion, could precondition the canine myocardium. Dogs were randomized to receive one of three preconditioning "treatments": the R(-) group underwent 15 minutes of partial coronary stenosis without subsequent brief reperfusion (n = 8); the R(+) group underwent 15 minutes of partial coronary stenosis followed by 10 minutes of full reflow (n = 8); and the control group underwent no intervention (n = 8). All dogs then underwent 1 hour of total coronary artery occlusion and 4.5 hours of reperfusion. Both treated groups were equally and moderately ischemic during partial stenosis: myocardial blood flow in the inner two thirds of the left ventricular wall averaged 0.25 +/- 0.05 and 0.31 +/- 0.07 ml/min per gram in the R(-) and R(+) groups, respectively (p = NS). Furthermore, all three groups were equally and severely ischemic during sustained total occlusion: myocardial blood flow in the inner two thirds of the left ventricular wall averaged 0.06 +/- 0.05, 0.05 +/- 0.03, and 0.07 +/- 0.03 ml/min/g in control, R(-), and R(+) groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: Accelerated graft coronary artery disease remains the most dramatic complication in long-term survivors of heart transplantation. The main purpose of this study was to evaluate ex vivo platelet function of heart transplant recipients as compared with that of healthy subjects and nontransplant coronary patients. The influence of aspirin, the chief antiplatelet agent, was also evaluated. The heart transplant recipients exhibited a marked platelet hyperaggregation to adenosine diphosphate as compared with the two control groups. In addition, platelets of the heart transplant recipients appeared to be resistant to the inhibitory effect of aspirin. These results could, at least partly, explain the failure of antiplatelet agents to prevent myocardial infarction in these patients.
Abstract: Peroxidation of membrane lipids has been suggested to play a role in the pathogenesis of myocardial ischemia/reperfusion injury. We therefore assessed the efficacy of U74006F, a potent in vitro vitamin E-like inhibitor of lipid peroxidation, in limiting infarct size in a canine model of transient coronary artery occlusion. Twenty dogs underwent 2 hours of occlusion of the left anterior descending coronary artery and 6 hours of reperfusion. U74006F or saline solution was administered continuously from 1 hour of occlusion to the end of the experiment. U74006F blunted any increase in production of conjugated dienes (an index of lipid peroxidation) at both 30 minutes (1.73 +/- 0.16 mol/L x 10(-4) vs 2.62 +/- 0.22 in control dogs, p less than 0.05) and 6 hours (1.39 +/- 0.22 vs 2.06 +/- 0.18 in control dogs, p less than 0.05) after reperfusion. Furthermore, 6 hours after reflow vitamin E levels tended to be lower than baseline values in control dogs and higher than baseline values in dogs treated with U74006F. However, analysis of infarct size indicated no statistically significant difference between the two groups when expressed either as a percentage of the left ventricle (10.4 +/- 1.8% in U74006F vs 15.2 +/- 2.4% in control dogs) or as a percentage of the area at risk (33.0 +/- 5.5% in U74006F vs 37.8 +/- 4.5% in control dogs). Although U74006F appeared to be a potent in vivo inhibitor of lipid peroxidation, it failed to limit infarct size after 2 hours of occlusion and 6 hours of reperfusion in this canine model.
Abstract: Because there is evidence that myocardial infarct size is modified by coronary artery reperfusion, an ex vivo experimental model of myocardial infarction was developed to determine the influence of the timing of gadolinium-tetraazacyclododecane tetraacetic acid (Gd-DOTA)-enhanced magnetic resonance imaging (MRI) on the accuracy of infarct size quantitation. Eighteen dogs underwent a 2-hour coronary occlusion followed by 1 (n = 6), 6 (n = 6), or 48 (n = 6) hours of reperfusion. Gd-DOTA was injected 10 minutes before the dogs were killed. T1 (SE 250/26) and T2 (SE 1500/78) weighted images were performed on excised hearts. Gd-DOTA concentration was measured in myocardium by atomic emission spectrometry, and correlated with myocardial blood flow evaluated by radioactive microspheres. All dogs presented with myocardial infarction (mean size 20.4% +/- 3.1% of the left ventricle), and a corresponding area of increased signal intensity on T1-weighted MR images. In none of the three groups did the area of high signal intensity correlate with the ischemic area. By contrast, after 6 and 48 hours of reperfusion, the high signal intensity area (17.9% +/- 2.4%) closely matched the area of nonreversible jeopardized tissue (16.4% +/- 2.5%), as determined on tetrazolium-stained heart slices. Although a noreflow phenomenon was observed in the jeopardized tissue, Gd-DOTA concentration was higher in the subendocardial central ischemic zone than in normally perfused myocardium. Gd-DOTA imaging enhancement seems to be the consequence of a delayed clearance of the agent from the injured tissue. Gd-DOTA-enhanced MRI accurately quantitates the size of reperfused myocardial infarction on the ex vivo heart for more than 6 hours after the beginning of reperfusion. It remains to be determined whether the in vitro results obtained here can be applied to assess the myocardial infarct size in vivo.
Abstract: The natural history of the complications of coronary heart disease has been defined by anatomicopathological and epidemiological studies, particularly the Framingham study. At the same time, research is being carried out on risk factors which play a role in the progressive development of atheromatous plaque (atherogenic factors: hypertension: hypercholesterolaemia) and those factors which lead to complications in the atheromatous plaque (aggravating or precipitating factors: smoking, thrombosis, etc.). This schematic perspective may lead to the redefinition of the strategy to adopt in fighting atherosclerotic arterial disease; a better aim will thus the taken in the fight against hypercholesterolaemia.
Abstract: Molsidomine and its metabolite, SIN-1, a donor of nitric oxide, are potent coronary vasodilator and anti-ischemic agents. Recently, SIN-1 and nitric oxide have also been shown to inhibit platelet adhesion and aggregation in vitro. The present study in dogs was designed to evaluate the in vivo antithrombotic properties of SIN-1. Coronary intimal damage and stenosis are known to induce coronary cyclic flow variations that reflect platelet thrombus formation followed by disaggregation and embolization (Folts preparation). This model of coronary artery thrombosis appears to simulate the combination of some of the factors contributing to unstable angina and myocardial infarction in human. SIN-1 infusion (10 micrograms/kg/min) significantly reduced the frequency of cyclic flow variations: 4.9 +/- 6.2/h vs. 14 +/- 4.6/h (before treatment, p less than 0.03, n = 6). Results were similar to those obtained with aspirin (5 mg/kg, bolus i.v.: 1.5 +/- 0.6/h vs. 11.7 +/- 3/h, p less than 0.03, n = 5) whereas saline had no effect (17.8 +/- 2.2/h vs. 19.3 +/- 2.4/h, n = 5). As expected, blood pressure was decreased only in the SIN-1 group: 56.2 +/- 7.8 vs. 87.3 +/- 9.3 mm Hg (p less than 0.02) (mean arterial blood pressure). The present results suggest that the well-documented anti-ischemic properties of SIN-1 could be partly due to its antithrombotic activity, clearly demonstrated with the model of coronary thrombosis used here in the dog.
