Effect of COMBinAtion therapy with remote ischemic conditioning and exenatide on the Myocardial Infarct size: a two-by-two factorial randomized trial (COMBAT-MI).

Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3-7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI.

Previously Undetected Obstructive Sleep Apnea in Patients With New-Onset Atrial Fibrillation.

Obstructive sleep apnea-hypopnea syndrome (OSA) compromises the efficacy of atrial fibrillation (AF) control strategies. Continuous positive airway pressure (CPAP) may ameliorate arrhythmia control especially in early AF stages (new-onset AF). We investigated a practical screening strategy to determine the likelihood of CPAP indication in new-onset AF patients. Seventy-seven consecutive patients with new-onset (<1 month) AF were prospectively evaluated. Of them, 4 were excluded due to previously diagnosed OSA. The remaining 73 (68% persistent AF) fulfilled the Epworth, Berlin and STOP-BANG questionnaires, an ambulatory polysomnography being performed thereafter in all them in order to determine the apnea-hipopnea index (AHI). CPAP was indicated following conventional criteria. The variables associated with the diagnosis of OSA, with the AHI value and with CPAP indication were investigated by means of descriptive, univariate and multivariate analysis. The prevalence of OSA of any degree and CPAP indication was 82% and 37%, respectively. The variables associated (p < 0.05) with a higher AHI were male gender, body mass index, obesity, hypertension, and high-risk scoring at the Berlin and STOP-BANG questionnaires. In the multivariate analysis, the STOP-BANG scoring proved superior to conventional risk factors and became the only variable predicting CPAP indication (odds ratio 4.5 [1.9 to 10.6]; p = 0.01), an optimized cutoff value of ≥4 being newly established (sensitivity/specificity 76/65%). In conclusion, in patients referred with new-onset AF we documented a high risk of OSA and of need for CPAP. A STOP-BANG scoring of ≥4 in our population was a practical screening alternative to direct polysomnography in this setting.

Anticoagulación del paciente anciano pluripatológico con fibrilación auricular no valvular: papel del rivaroxabán / Anticoagulation in elderly patients with multiple comorbidities and nonvalvular atrial fibrillation: the role of rivaroxaban

La fibrilación auricular es muy frecuente en el paciente anciano. Aunque existe una amplia experiencia con los antagonistas de la vitamina K, el empleo de estos fármacos en el paciente anciano presenta numerosas limitaciones, con una mayor susceptibilidad a las hemorragias y un peor control de la anticoagulación que en la población general. Los anticoagulantes orales de acción directa han demostrado ser una mejor alternativa terapéutica para los pacientes ancianos, no solo por su mayor simplicidad de uso, sino por sus mayores eficacia y seguridad en comparación con los antagonistas de la vitamina K, con datos que en general concuerdan con los ensayos clínicos fundamentales. Sin embargo, en el paciente anciano hay una tendencia al uso de dosis inadecuadas, generalmente por infradosificación, sobre todo con algunos de ellos, lo que conlleva una menor protección contra los ictus, sin una clara ventaja antihemorrágica. El rivaroxabán se ha estudiado ampliamente en la población anciana y no solo en ensayos clínicos, sino también en multitud de estudios en la práctica clínica real, con datos muy consistentes. En estos estudios, en comparación con los antagonistas de la vitamina K, se ha demostrado que el rivaroxabán reduce el riesgo de ictus sin un incremento de las hemorragias mortales, con lo que tiene un beneficio clínico neto favorable en la población con fibrilación auricular no valvular con mayor riesgo tromboembólico

Atrial fibrillation is common in elderly patients. Although vitamin K antagonists have been widely used for many years, they have a number of limitations in elderly patients, who are particularly susceptible to bleeding and in whom anticoagulation control is poorer than in the general population. Direct oral anticoagulants have been shown to be a better therapeutic option for these patients, not only because they are simpler to use, but also because they are more effective and safer than vitamin K antagonists. Moreover, their performance in practice is generally consistent with that in pivotal clinical trials. Nevertheless, there is a tendency to administer inappropriate doses to elderly patients, generally underdosing, particularly in certain subgroups. This can result in less protection against stroke without any clear reduction in bleeding risk. Rivaroxaban has been widely studied in the elderly population, not only in clinical trials, but also in a range of studies in routine clinical practice - findings have been highly consistent. According to these studies, and compared to vitamin K antagonists, rivaroxaban reduces the risk of stroke without increasing the rate of fatal bleeding, with a net clinical benefit in patients with nonvalvular atrial fibrillation and a high thromboembolic risk

Contemporary Yield of 24-hour Holter Monitoring: Role of Inter-Atrial Block Recognition.

BACKGROUND: The diagnostic yield of 24-hour ECG Holter monitoring (24H) is currently overcome by alternative ECG monitoring techniquesand it needs to be optimized. The recognition of inter-atrial block (IAB) has emerged as a reliable indicator of patients at risk of atrial fibrillation relapses, and its role enhancing the yield of 24H is yet to be determined. We hypothesized that a presumably low yield of 24H may be ameliorated by means of incorporating the assessment for IAB. METHODS: We retrospectively analyzed 1017 consecutive 24H registers performed in a Multidisciplinary Integrated Health Care Institution, in which a restrictive definition of diagnostic 24H findings was used. A univariate and multivariate regression analysis served to determine the variables associated with a higher 24H's yield, including the requesting medical specialty, type of indication and a number of clinical, echocardiographic and ECG variables, including IAB. RESULTS: The mean age of our population was 62 ± 17 years (55% males). The majority of 24H were indicated from the Cardiology department (48%). The overall yield was 12.8%, higher for the assessment of the integrity of the electrical conduction system (26.1%) and poorer for the assessment of syncope (3.2%) and cryptogenic stroke (4.6%). The variables associated with higher diagnostic performance were indication from Cardiology (p < 0.001), IAB (p = 0.004), structural heart disease (p = 0.008) and chronic renal failure (p = 0.009). Patients ≤ 50 years old only retrieved a 7% yield. In the multivariate analysis, indication from Cardiology and IAB remained significant predictors of higher 24H's yield. In a secondary analysis including echocardiographic data, only identification of IAB remained statistically significant. CONCLUSIONS: The recognition of IAB and the type of indication are major determinants of a higher 24H's diagnostic yield and may help to optimize the selection of candidates.

Underdiagnosis and prognosis of chronic obstructive pulmonary disease after percutaneous coronary intervention: a prospective study.

BACKGROUND: Retrospective studies based on clinical data and without spirometric confirmation suggest a poorer prognosis of patients with ischemic heart disease (IHD) and chronic obstructive pulmonary disease (COPD) following percutaneous coronary intervention (PCI). The impact of undiagnosed COPD in these patients is unknown. We aimed to evaluate the prognostic impact of COPD - previously or newly diagnosed - in patients with IHD treated with PCI. METHODS: Patients with IHD confirmed by PCI were consecutively included. After PCI they underwent forced spirometry and evaluation for cardiovascular risk factors. All-cause mortality, new cardiovascular events, and their combined endpoint were analyzed. RESULTS: A total of 133 patients (78%) male, with a mean (SD) age of 63 (10.12) years were included. Of these, 33 (24.8%) met the spirometric criteria for COPD, of whom 81.8% were undiagnosed. IHD patients with COPD were older, had more coronary vessels affected, and a greater history of previous myocardial infarction. Median follow-up was 934 days (interquartile range [25%-75%]: 546-1,160). COPD patients had greater mortality (P=0.008; hazard ratio [HR]: 8.85; 95% confidence interval [CI]: 1.76-44.47) and number of cardiovascular events (P=0.024; HR: 1.87; 95% CI: 1.04-3.33), even those without a previous diagnosis of COPD (P=0.01; HR: 1.78; 95% CI: 1.12-2.83). These differences remained after adjustment for sex, age, number of coronary vessels affected, and previous myocardial infarction (P=0.025; HR: 1.83; 95% CI: 1.08-3.1). CONCLUSION: Prevalence and underdiagnosis of COPD in patients with IHD who undergo PCI are both high. These patients have an independent greater mortality and a higher number of cardiovascular events during follow-up.

Activation of polymorphonuclear leukocytes and increased plasma vasoconstrictors in vasospastic and nonvasospastic angina.

BACKGROUND: The cause of coronary vasoconstriction in patients with angina at rest, nonsignificant coronary stenosis, and endothelial dysfunction remains unknown. Our objective was to investigate the association between enhanced coronary vasoconstriction and increased circulating levels of vasoconstrictor agents. METHODS: Plasma levels of big endothelin-1, serotonin, and superoxide produced by polymorphonuclear leukocytes were measured in 38 patients with stable angina at rest without significant coronary artery stenosis-23 with nonvasospastic angina and 15 with vasospastic angina-and were compared with 10 patients with stable coronary disease and 20 age-matched controls. RESULTS: Patients with angina at rest showed higher big endothelin-1 (1.28 vs 0.72 fmol/mL, P < 0.001), serotonin (18.0 vs 9.1 ng/mL, P = 0.002), and superoxide produced by polymorphonuclear leukocytes (177 vs 67 nmol/10 × E8 × minutes, P = 0.001) than did controls. Serotonin and superoxide produced by polymorphonuclear leukocytes were also higher than in coronary disease patients (5.4 ng/mL, P = 0.001, and 97 nmol/10 x E8 x minutes, P = 0.005), and big endothelin-1 levels tended to be higher (0.99 fmol/mL, P = 0.073). Moreover, there were no significant differences in these 3 parameters between patients with vasospastic and nonvasospastic angina, and among the latter, between patients with a positive and those with a negative exercise stress test. CONCLUSION: Systemic plasma levels of agents with the potential to produce coronary vasoconstriction are increased in patients with stable vasospastic or nonvasospastic angina and, hence, may contribute to their angina, increased coronary tone, and impaired vasodilatory capacity. Furthermore, they may establish a mechanistic link between the 2 conditions.

Spanish Acute Aortic Syndrome Study (RESA). Better diagnosis is not reflected in reduced mortality.

INTRODUCTION AND OBJECTIVES: Because acute aortic syndrome (AAS) is associated with high mortality, early diagnosis and treatment are vital. The aim of the Spanish Acute Aortic Syndrome Study (RESA) was to investigate the effectiveness of current treatment of AAS in a broad range of tertiary care hospitals in Spain. METHODS: Between January 2005 and December 2007, 24 tertiary care hospitals reported data on 519 patients with AAS (78% male, mean age 61 +/- 13 years, range 20-92 years): 357 had type-A AAS and 162 had type B. RESULTS: The time delay between symptom onset and diagnosis was <24 hours in 67% of cases and >72 hours in 11%. Some 80% of patients with type-A AAS were treated surgically. The interval between diagnosis and surgery was <24 hours in 90% of cases. In patients with type-B AAS, 34% received invasive treatment: 11% had surgery and 23% underwent endovascular procedures. Mortality during hospitalization in patients with type-A disease was 33% in those treated surgically and 71% in those treated medically. Mortality in patients with type-B disease was 17% with medical treatment, 27% with endovascular treatment and 50% with surgical treatment. CONCLUSIONS: Despite significant advances in the diagnosis of AAS, in-hospital mortality remains high. The findings of this study are representative of a broad range of unselected patients undergoing treatment for the disease and support the need for continuing improvements in therapeutic approaches to AAS.

Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine.

Increased mechanical tension in the ischemic region during acute coronary occlusion might favor the occurrence of phase Ib ventricular arrhythmias. We aimed to investigate whether intracoronary administration of Gd(3+), a stretch-activated channel blocker, into the ischemic zone reduces the incidence of these arrhythmias. In thiopental-anesthetized, open-chest pigs, the left anterior descending coronary artery (LAD) was ligated for 45 or 48 min. Phosphate-free, HEPES-buffered saline bubbled with 100% N(2) was infused into the ischemic region for 4 min, starting 5 min (series A; n = 16) or 20 min (series B; n = 16) after coronary occlusion, at a rate doubling the baseline blood flow. Animals were blindly allocated to receive 40 muM Gd(3+) or only the buffer during the final 2 min of the infusion. There were no differences between groups with respect to hemodynamic variables, plasma K(+) levels, or size of the ischemic region. In neither series was the number of phase Ib premature ventricular beats reduced by Gd(3+) (46 +/- 20 in untreated vs. 91 +/- 37 in Gd(3+)-treated animals in series A and 19 +/- 7 vs. 22 +/- 13, respectively, in series B; both P = not significant). The occurrence of ventricular tachycardia or fibrillation was significantly associated with the magnitude of early ischemic expansion of the LAD region, as measured by ultrasonic crystals, but was also not prevented by Gd(3+). These results argue against a major role of stretch-activated channels inside the area at risk in the genesis of phase Ib ischemic ventricular arrhythmias.

Comparison of plasma serotonin levels in patients with variant angina pectoris versus healed myocardial infarction.

Patients with variant angina pectoris showed greater serotonin plasma levels than did control subjects and patients with healed myocardial infarction. The levels also tended to be greater in those with >1 episode/month than in those with fewer episodes. Moreover, patients with variant angina pectoris also had greater levels of nitrite and nitrate plasma levels than did control subjects or patients with healed myocardial infarction, partly, perhaps, as a compensatory mechanism.

Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia.

OBJECTIVES: The goal of this study was to assess whether selectin blockade reduces myocardial platelet deposition and platelet-mediated injury after transient ischemia. BACKGROUND: Selectins participate in platelet adhesion to reperfused endothelium. METHODS: Thiopental-anesthetized, open-chest pigs were subjected to mechanical injury of the left anterior descending coronary artery followed by a 48-min occlusion and 2 (n = 20) or 4 (n = 16) h of reperfusion. Fifteen minutes before occlusion, animals were blindly allocated to receive a continuous intravenous infusion of the selectin blocker fucoidan (30 microg/kg/min, plus a 1-mg/kg bolus in the latter group) or saline. In isolated rat hearts infused with thrombin-activated platelets, the effects of fucoidan (30 microg/ml) administered during reperfusion after 40 min of global ischemia were also analyzed. RESULTS: Fucoidan did not prevent the development of cyclic reductions in coronary flow, but reduced the content of (99m)Tc-labeled platelets in reperfused myocardium after 2 h of reperfusion (23.4 +/- 3.3 vs. 42.1 +/- 8.3 x 10(6) platelets/g in treated and untreated animals, p = 0.03) and attenuated the impairment in the coronary flow reserve and reduced infarct size after 4 h (53 +/- 2% vs. 73 +/- 5% of the ischemic region, respectively, p = 0.003). Treated animals showed a trend toward less neutrophil infiltration early after reperfusion, but not after 4 h. In isolated hearts, fucoidan improved functional recovery and reduced coronary resistance and lactate dehydrogenase release, lacking any beneficial effects if given in the absence of platelets. CONCLUSIONS: The results suggest that selectin-dependent adhesion is a prominent mechanism of platelet deposition in reperfused cardiac microvessels and highlight its potential as a therapeutic target in patients with acute myocardial infarction.

Protection afforded by ischemic preconditioning is not mediated by effects on cell-to-cell electrical coupling during myocardial ischemia-reperfusion.

The end-effectors of ischemic preconditioning (IPC) are not well known. It has been recently shown that transgenic mice underexpressing the gap junction protein connexin43 (Cx43) cannot be preconditioned. Because gap junctions allow spreading of cell death during ischemia-reperfusion in different tissues, including myocardium, we hypothesized that the protection afforded by IPC is mediated by effects on gap junction-mediated intercellular communication. To test this hypothesis, we analyzed the effect of IPC (5 min ischemia-5 min reperfusion x 2) on the changes in electrical impedance (four electrode probe) and impulse propagation velocity (transmembrane action potential) induced by ischemia (60 min) and reperfusion (60 min) in isolated rat hearts. IPC (n = 8) reduced reperfusion-induced lactate dehydrogenase release by 65.8% with respect to control hearts (n = 9) (P = 0.04) but had no effect on the time of onset of rigor contracture (increase in diastolic tension), electrical uncoupling (sharp changes in tissue resistivity and phase angle in impedance recordings), or block of impulse propagation during ischemia. Normalization of electrical impedance during reperfusion was also unaffected by IPC. The lack of effect of IPC on ischemic rigor contracture and on changes in tissue impedance during ischemia-reperfusion were validated under in vivo conditions in pigs submitted to 48 min of coronary occlusion and 120 min of reperfusion. IPC (n = 12) reduced infarct size (triphenyltetrazolium) by 64.9% (P = 0.01) with respect to controls (n = 17). We conclude that the protection afforded by IPC is not mediated by effects on electrical coupling. This result is consistent with recent findings suggesting that Cx43 could have effects on cell survival independent on changes in cell-to-cell communication.

Pre-treatment with the Na+/H+ exchange inhibitor cariporide delays cell-to-cell electrical uncoupling during myocardial ischemia.

OBJECTIVE: Inhibition of Na(+)-H(+) exchange (NHE) delays the onset of myocardial rigor contracture during ischemia. The aim of this study was to analyse the effects of NHE inhibition on cell-to-cell electrical uncoupling during myocardial ischemia/reperfusion. METHODS: Twenty-six isolated rat hearts and 23 in situ porcine hearts were submitted to no-flow ischemia followed by reperfusion, with or without pre-treatment with cariporide (7 microM in rats and 3 mg/kg in pigs). Ischemic rigor and hypercontracture, conduction velocity and myocardial electrical impedance were monitored. RESULTS: Pre-treatment with cariporide delayed ATP depletion (luminescence assay in rat myocardium) and onset of rigor contracture (tension recordings or ultrasonic crystals) during ischemia both in rat and pig hearts (P<0.05). In addition, cariporide delayed the onset of sharp changes in tissue resistivity and phase angle in impedance recordings (four-electrode probes) from 10+/-1 to 13+/-1 min (P<0.001) in rat hearts, and from 22+/-1 to 38+/-2 min (P<0.001) in pigs. Blockade of impulse propagation (transmembrane action potentials in rat hearts) was also markedly delayed by cariporide (from 14+/-1 to 20+/-1 min, P<0.001). Reperfusion-induced LDH release in rat hearts and infarct size in pigs were markedly reduced by pre-treatment with cariporide. CONCLUSIONS: Inhibition of NHE with cariporide slows the progression of ischemic injury during myocardial ischemia, and delays the onset of cell-to-cell electrical uncoupling.

Ventricular fibrillation during acute coronary occlusion is related to the dilation of the ischemic region.

Myocardial stretch induces several electrophysiological changes and arrhythmias, but little is known on its possible role in triggering ventricular fibrillation (VF) during acute coronary occlusion. In thiopental-anesthetized, open-chest pigs submitted to a 40-min ligation of the left anterior descending coronary artery, the association between the early increase in end-diastolic length (measured by means of ultrasonic crystals) in the ischemic region and subsequent VF was analyzed. Animals received no treatment (n = 35) or intravenous nitroglycerin (2.5 microg/kg/min for 20 min, starting 10 min after coronary occlusion, n = 8) or Gd(3+) (80 microM/kg for 35 min, starting 5 min before occlusion, n = 15). Twenty-four animals (41 %) had VF, 16 to 39 min after coronary occlusion. The magnitude of ischemic dilation and the incidence of VF were similar among groups. End-diastolic length in the ischemic region 15 min after coronary occlusion was 115.7 +/- 1.2 % of baseline in animals with VF and 111.4 +/- 0.9 % in those without (P = 0.007), and was the strongest predictor of this arrhythmia (P = 0.003) after adjusting for treatment and other possible confounding variables. Thus, the dilation of the ischemic region is closely and independently associated with VF following coronary occlusion. Although the interventions tested in the present study failed to protect against this arrhythmia, the results strongly suggest an influence of ischemic dilation on VF.

Platelets activated by transient coronary occlusion exacerbate ischemia-reperfusion injury in rat hearts.

Platelets (Plt) accumulate in reperfused myocardium but their effect on myocardial necrosis has not been established. We tested the hypothesis that the effect of Plt depends on their activation status. Pig Plt were obtained before 48 min of coronary occlusion (pre-CO-Plt), 10 min after reperfusion (R-Plt), or after a 60-min sham operation (sham-Plt). Plt were infused into isolated rat hearts (n = 124) and subsequently submitted to 60 min of ischemia and 60 min of reperfusion. P-selectin expression was higher (P = 0.02) in R-Plt than in pre-CO-Plt or sham-Plt. Lactate dehydrogenase (LDH) release during reperfusion was similar in hearts receiving pre-CO-Plt, sham-Plt, or no Plt, but R-Plt increased LDH release by 60% (P = 0.004). Activation of pre-CO-Plt with thrombin increased P-selectin expression and LDH release (P < 0.001), and these results were unaffected by tirofiban. There was a close correlation between P-selectin expression and LDH release (r = 0.84; P < 0.001), and myocardial Plt accumulation (r = 0.85; P < 0.001). We conclude that the deleterious effect of Plt on reperfused myocardium depends on their activation status as represented by P-selectin expression, which is enhanced by ischemia-reperfusion.

Gap junction-mediated intercellular communication in ischemic preconditioning.

Gap junction-mediated communication can modulate cell death in different tissues. In myocardium, gap junction communication is altered during ischemia, which contributes to the development of arrhythmias, but still allows synchronization of the onset of rigor contracture in the progression of injury. During reperfusion, gap junction communication allows cell-to-cell spread of hypercontracture and cell death. Since the intracellular signal transduction systems involved in modulation of gap junction-mediated communication are activated during ischemic preconditioning, the hypothesis can be raised that gap junctions are end-effectors of preconditioning contributing to its protective effect on cell death. This paper reviews the available information supporting this hypothesis. It has been shown that ischemic preconditioning may influence gap junction-mediated intercellular communication by activation of different kinases, including PKC and MAPK cascades, and by preservation of cGMP among other mechanisms. Connexin phosphorylation by PKC, p38/MAPK, and PKG, tends to reduce intercellular communication. This effect of ischemic preconditioning seems to have no relevant consequences during prolonged ischemia, and does not significantly modify the time course of either electrical uncoupling or the frequency or temporal distribution of ventricular arrhythmias during this period. However, any modification of gap junction communication during initial reperfusion could contribute to the reduced extent of hypercontracture and cell death observed in preconditioned hearts. The potential role of gap junctions as effectors of ischemic preconditioning against lethal injury secondary to ischemia-reperfusion deserves to be investigated in depth.

Effect of inhibition of Na(+)/Ca(2+) exchanger at the time of myocardial reperfusion on hypercontracture and cell death.

OBJECTIVE: There is recent evidence that Ca(2+) influx via reverse mode Na(+)/Ca(2+) exchange (NCX) at the time of reperfusion can contribute to cardiomyocyte hypercontracture. However, forward NCX is essential for normalization of [Ca(2+)](i) during reperfusion, and its inhibition may be detrimental. This study investigates the effect of NCX inhibition with KB-R7943 at the time of reperfusion on cell viability. METHODS: The effect of several concentrations of KB-R7943 added at reperfusion was studied in Fura-2 loaded quiescent cardiomyocytes submitted to 40 min of simulated ischemia (NaCN 2 mM, pH 6.4), and in rat hearts submitted to 60 min of ischemia. [Ca(2+)](i) and cell length were monitored in myocytes, and functional recovery and LDH release in isolated hearts. From these experiments an optimal concentration of KB-R7943 was identified and tested in pigs submitted to 48 min of coronary occlusion and 2 h of reperfusion. RESULTS: In myocytes, KB-R7943 at concentrations up to 15 microM reduced [Ca(2+)](i) rise and the probability of hypercontracture during re-energization (P<0.01). Nevertheless, in rat hearts, the effects of KB-R7943 applied during reperfusion after 60 min of ischemia depended on concentration and timing of administration. During the first 5 min of reperfusion, KB-R7943 (0.3-30 microM) induced a dose-dependent reduction in LDH release (half-response concentration 0.29 microM). Beyond 6 min of re-flow, KB-R7943 had no effect on LDH release, except at concentrations > or = 15 microM, which increased LDH. KB-R7943 at 5 microM given during the first 10 min of reflow reduced contractile dysfunction (P=0.011), LDH release (P=0.019) and contraction band necrosis (P=0.014) during reperfusion. Intracoronary administration of this concentration during the first 10 min of reperfusion reduced infarct size by 34% (P=0.033) in pigs submitted to 48 min of coronary occlusion. CONCLUSIONS: These results are consistent with the hypothesis that during initial reperfusion NCX activity results in net reverse mode operation contributing to Ca(2+) overload, hypercontracture and cell death, and that NCX inhibition during this phase is beneficial. Beyond this phase, NCX inhibition may impair forward mode-dependent Ca(2+) extrusion and be detrimental. These findings may help in the design of therapeutic strategies against lethal reperfusion injury, with NCX as the target.