[Short exercise-rest versus long myocardial perfusion gated SPECT protocols in patients with ischemic cardiomyopathy]. / Protocolo corto esfuerzo reposo frente a protocolo largo en la gated-SPECT de perfusión miocárdica de pacientes con miocardiopatía isquémica.

OBJECTIVE: The purpose of this study was to analyze left systolic ventricular function and myocardial perfusion characteristics between short one day exercise-rest and long two days gated SPECT (Single Photon Emission Computed Tomography) protocols in patients with ischemic cardiomyopathy (ICM). METHODS: A prospective study of 40 patients (59.6±8.9 years, 3 women) with IHD (left ventricular ejection fraction (EF) ≤40%) was performed with myocardial perfusion gated SPECT. From 5 to 10 days after a one-day exercise-rest study (gated SPECT-1), patients were called back for a second rest study (gated SPECT-2) in order to compare EF and differences in perfusion summed rest score (ΔSRS=SRS1-SRS2) and summed difference score (ΔSDS=SDS1-SDS2) between both protocols. RESULTS: Between rest-gated SPECT-1 (short protocol) and rest-gated SPECT-2 (long protocol) EF increased (34% vs 37%, P= 0.008) in 26 patients (65%), and in 11 patients (27.5%) the increase was ≥5%. There were no significant differences in clinical and coronary angiography variables between patients with and without increase of the EF ≥5%. In the multivariate analysis, ΔSRS (95% CI: -1.1 to -29.2) and ΔSDS (0.179-1.236) were predictors for this EF increase between both studies. CONCLUSIONS: Exercise-rest short protocol can underestimate EF in patients with CM. Stunning but also contamination of rest images by previous exercise images in a short protocol could explain these results.

A pragmatic approach for mortality prediction after surgery in infective endocarditis: optimizing and refining EuroSCORE.

OBJECTIVE: To simplify and optimize the ability of EuroSCORE I and II to predict early mortality after surgery for infective endocarditis (IE). METHODS: Multicentre retrospective study (n = 775). Simplified scores, eliminating irrelevant variables, and new specific scores, adding specific IE variables, were created. The performance of the original, recalibrated and specific EuroSCOREs was assessed by Brier score, C-statistic and calibration plot in bootstrap samples. The Net Reclassification Index was quantified. RESULTS: Recalibrated scores including age, previous cardiac surgery, critical preoperative state, New York Heart Association >I, and emergent surgery (EuroSCORE I and II); renal failure and pulmonary hypertension (EuroSCORE I); and urgent surgery (EuroSCORE II) performed better than the original EuroSCOREs (Brier original and recalibrated: EuroSCORE I: 0.1770 and 0.1667; EuroSCORE II: 0.2307 and 0.1680). Performance improved with the addition of fistula, staphylococci and mitral location (EuroSCORE I and II) (Brier specific: EuroSCORE I 0.1587, EuroSCORE II 0.1592). Discrimination improved in specific models (C-statistic original, recalibrated and specific: EuroSCORE I: 0.7340, 0.7471 and 0.7728; EuroSCORE II: 0.7442, 0.7423 and 0.7700). Calibration improved in both EuroSCORE I models (intercept 0.295, slope 0.829 (original); intercept -0.094, slope 0.888 (recalibrated); intercept -0.059, slope 0.925 (specific)) but only in specific EuroSCORE II model (intercept 2.554, slope 1.114 (original); intercept -0.260, slope 0.703 (recalibrated); intercept -0.053, slope 0.930 (specific)). Net Reclassification Index was 5.1% and 20.3% for the specific EuroSCORE I and II. CONCLUSIONS: The use of simplified EuroSCORE I and EuroSCORE II models in IE with the addition of specific variables may lead to simpler and more accurate models.

Cardiac index quantification by Doppler ultrasound in patients without left ventricular outflow tract abnormalities.

OBJECTIVES: We attempted to ascertain whether cardiac index can be directly estimated from Doppler mean velocity. BACKGROUND: Although diverse Doppler echocardiographic methods have been described for cardiac output quantification, they are not widely used in clinical practice. Cross-sectional area measurement has been identified as the main source of error in flow volume quantification. METHODS: A three-phase study by Doppler echocardiography was conducted in 306 patients. In phase I, the normal mean velocity ratio of the left and right ventricular outflow tracts was established in 170 normal subjects. In phase II, cardiac index, calculated as the product of aortic annular area index by mean velocity (conventional method), and mean velocity determined in the left ventricular outflow tract and ascending aorta by pulsed and continuous wave Doppler, respectively, were correlated with thermodilution cardiac index in 66 patients. In phase III, the accuracy of the regression equations obtained was prospectively assessed in an additional 70 patients. RESULTS: The normal left/right ventricular outflow tract mean velocity ratio by pulsed wave Doppler was 1.1 +/- 0.1. Cardiac index (CI) calculated by the conventional method and thermodilution (TD) showed acceptable correlation (r = 0.90, CITD = 1.20 CIPWD + 357; r = 0.86, CITD = 0.90 CICWD + 262) for pulsed (PWD) and continuous wave (CWD) Doppler, respectively, but with systematic underestimation (-28 +/- 13%, p < 0.01) by pulsed wave Doppler. Mean velocity (MV) showed excellent correlation with the thermodilution cardiac index (r = 0.97, CITD = 172 MVPWD - 172; r = 0.93, CITD = 129 MVCWD - 255). When these regression equations were prospectively applied, better agreement with the thermodilution cardiac index was obtained by pulsed wave Doppler directly from mean velocity (SD 240 ml/min per m2) than when aortic annular area was considered in the calculation (SD 428 ml/min per m2). Similar results were obtained by continuous wave Doppler (SD 433 vs. 599 ml/min per m2) but with less accuracy. CONCLUSIONS: Left ventricular outflow tract mean velocity determined by pulsed wave Doppler permits easy, accurate cardiac index quantification in the absence of left ventricular outflow abnormalities. The simplicity of this method enhances its clinical applicability in noninvasive monitoring of cardiac index.

Diltiazem and progression of myocardial ischemic damage during coronary artery occlusion and reperfusion in porcine hearts.

This study was designed to investigate whether a cardioprotective intervention could delay the completion of necrosis so that subsequent reperfusion would be more useful. Thirty-six pigs were randomly allocated to treatment with diltiazem (15 micrograms/kg per min) or saline solution and to a 60 or 120 minute coronary occlusion period followed by reperfusion. The treatment was begun 15 minutes before coronary occlusion and terminated 75 minutes after reperfusion. Twenty-four hours after the procedure, the heart was sliced and incubated in triphenyltetrazolium chloride. The infarct area and the maximal transmural area of extension of the infarct were calculated by planimetry. The total number of red blood cells in a transmural section was also counted. In the pigs with a 60 minute coronary occlusion, diltiazem (compared with saline solution) significantly reduced infarct size from 9.7 +/- 1.5% of left ventricular mass to 5.9 +/- 0.6% (p less than 0.05) and the percent transmural extension from 0.72 +/- 0.05 to 0.61 +/- 0.05% (p less than 0.05). Red blood cell extravasation in the infarcted area was reduced from 161,934 +/- 59,905 to 78,525 +/- 46,484 cells/mm3 (p less than 0.05) with diltiazem and the percent transmural extension of the hemorrhagic necrosis from 70 +/- 10 to 36 +/- 15% (p less than 0.05). No such differences were observed in the 120 minute coronary occlusion groups. Mean red blood cell counts and the extent of hemorrhagic necrosis did not correlate with either infarct size or transmural extension.(ABSTRACT TRUNCATED AT 250 WORDS)

An epidemic of pulmonary hypertension after toxic rapeseed oil ingestion in Spain.

The cardiac profile of 38 patients readmitted to the hospital with the clinical and radiologic findings of pulmonary artery hypertension and right ventricular failure 2 months after ingestion of toxic rapeseed oil was determined with M-mode and two-dimensional echocardiography, pulsed Doppler flow studies and right and left heart catheterization and ventriculography. The echocardiogram and pulsed Doppler recordings revealed right ventricular enlargement in 84% of the patients, indirect evidence of pulmonary artery hypertension in 76% and tricuspid insufficiency in 13%. At cardiac catheterization (n = 11) the mean (+/- standard deviation) pulmonary artery pressure was 40 +/- 9 mm Hg, mean pulmonary systemic vascular resistance ratio was 0.45 +/- 0.12 and mean right ventricular end-diastolic pressure was 13 +/- 4 mm Hg. Pulmonary artery hypertension was sustained after the acute administration of 100% oxygen and persisted in six patients who were restudied within 6 months. Cardiac index and left heart pressures were normal in all but one patient. The contrast ventriculographic studies revealed right ventricular dilation in all patients, tricuspid regurgitation in three patients and a normal left ventricular contraction pattern in all but one patient. The data confirm that symptomatic pulmonary artery hypertension and associated right ventricular dysfunction can complicate toxic rapeseed oil ingestion and that these findings persist for at least 6 months.

Intravenous amiodarone in treatment of recent-onset atrial fibrillation: results of a randomized, controlled study.

OBJECTIVES: This study was designed to determine the efficacy of intravenous amiodarone in the management of recent-onset atrial fibrillation. BACKGROUND: The optimal approach for acute atrial fibrillation has not been established. Amiodarone is a unique antiarrhythmic agent with activity in both supraventricular and ventricular tachyarrhythmias, but its value for the restoration of sinus rhythm in patients with recent-onset atrial fibrillation has not been demonstrated. METHODS: Sample size was calculated to detect a 25% increase in reversion rate with amiodarone with a statistical power of 80%. One hundred consecutive patients with recent-onset (<1 week) atrial fibrillation and not taking antiarrhythmic agents were randomized to receive either intravenous amiodarone, 5 mg/kg body weight in 30 min followed by 1,200 mg over 24 h, or an identical amount of saline. Both groups received intravenous digoxin, 0.5 mg initially, followed by 0.25 mg at 2 h and 0.25 mg every 6 h thereafter, to complete 24 h while the ventricular rate was >100 beats/min. Amiodarone and digoxin blood levels were determined. Both groups were homogeneous regarding underlying heart disease, time from onset to treatment, initial ventricular rate and left atrial size. RESULTS: By the end of the 24-h treatment period, 34 patients (68%, 95% confidence interval [CI] 53% to 80%) in the amiodarone group and 30 (60%, 95% CI 45% to 74%) in the control group had returned to sinus rhythm (p = 0.532). Mean times (+/-SD) of conversion were 328 +/- 335 and 332 +/- 359 min, respectively (p =0.957). Among patients who did not convert to sinus rhythm, treatment with amiodarone was associated with a slower ventricular rate (82 +/- 15 beats/min in the amiodarone group vs. 91 +/- 23 beats/min in the control group, p = 0.022). After restoration of sinus rhythm, atrial fibrillation recurred during a 15-day follow-up period in 4 (12%) of 34 patients (95% CI 3% to 27%) in the amiodarone group and in 3 (10%) of 30 (95% CI 2% to 26%) in the control group (p = 0.861). CONCLUSIONS: Intravenous amiodarone, at the doses used in this study, produces a modest but not significant benefit in converting acute atrial fibrillation to sinus rhythm.

Myocardial oedema: a preventable cause of reperfusion injury?

Myocardial ischaemia increases cellular and extracellular osmolarity, alters membrane permeability to ions and causes moderate cell swelling and interstitial oedema. Ischaemia also reduces the mechanical resistance of the sarcolemma of myocytes, probably as a result of proteolytic digestion of the connections between cell membrane and the cellular scaffold. During reperfusion, the abrupt normalisation of extracellular osmotic pressure results in marked osmotic cell swelling. In the clinical situation, the ability of mechanical stress imposed by cell swelling to disrupt the weakened sarcolemma of viable myocytes during reperfusion has not been definitively established. Observations demonstrating the important role of mechanical stress caused by contraction and cell to cell interaction in myocyte necrosis support the hypothesis that osmotic cell swelling may actually produce lethal reperfusion injury. This hypothesis has been investigated by analysing the effect of hyperosmotic reperfusion with mannitol on final infarct size after coronary occlusion. Studies using highly hyperosmotic reperfusion after relatively short periods of ischaemia have yielded positive results, while studies using intravenous mannitol at the time of reperfusion, and more closely resembling clinical situations, have failed to detect any beneficial effect. Myocardial oedema could also contribute to postischaemic functional derangements, such as reperfusion arrhythmias and stunning, and could modify the passive mechanical properties of the infarcts and alter ventricular remodelling. Interventions aimed to limit myocardial oedema will probably not play a role as a co-adjuvant therapy in patients with acute myocardial infarction receiving thrombolytic treatment. However, they should probably form part of controlled reperfusion strategies to be evaluated in patients with acute myocardial infarction in whom reperfusion is accomplished by percutaneous transcoronary angioplasty or surgery.

Urodilatin limits acute reperfusion injury in the isolated rat heart.

OBJECTIVES: Hypercontracture is an important mechanism of myocyte death during reperfusion. cGMP modulates the sensitivity of contractile myofilaments to Ca2+, and increasing cGMP concentration during the last minutes of anoxia prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes. The purpose of this study was to determine whether stimulation of particulate guanylyl cyclase with the natriuretic peptide urodilatin, given at the time of reperfusion, reduces myocardial necrosis in the rat heart submitted to transient ischemia. METHODS: Isolated rat hearts (n = 38) were submitted to either 40 or 60 min of no-flow ischemia and 2 h of reperfusion, and were allocated to receive or not receive 0.05 microM urodilatin during the first 15 min of reperfusion or non-reperfusion treatment. RESULTS: A marked reduction in myocardial cGMP concentration was observed in control hearts during reperfusion after 40 or 60 min of ischemia. Urodilatin significantly attenuated cGMP depletion during initial reperfusion, markedly improved contractile recovery after 40 min of ischemia (P < 0.0309), and reduced reperfusion-induced increase in left ventricular end-diastolic pressure (P = 0.0139), LDH release (P = 0.0263), and contraction band necrosis (P = 0.0179) after 60 min of ischemia. The beneficial effect of urodilatin was reproduced by the membrane permeable cGMP analog 8-Bromo-cGMP. CONCLUSIONS: These results indicate that reduced cGMP concentration may impair myocyte survival during reperfusion. Stimulation of particulate guanylyl cyclase may appear as a new strategy to prevent immediate lethal reperfusion injury.

Effect of osmotic stress on sarcolemmal integrity of isolated cardiomyocytes following transient metabolic inhibition.

OBJECTIVE: Exposure to hypotonic medium induces sarcolemmal rupture in metabolically inhibited cardiomyocytes. This study investigated the effect of osmotic stress applied during reoxygenation and the possible cooperation between cell swelling and hypercontracture to produce sarcolemmal disruption. METHODS: Freshly isolated adult rat myocytes were submitted to 60 min of metabolic inhibition (NaCN 2 mM). Reoxygenation was simulated by changing to one of 3 inhibitor free buffers: (1) normo-osmotic (312 mOsm); (2) hypo-osmotic (80 mOsm); (3) low Na+ normo-osmotic (312 mOsm). The contribution of hypercontracture-induced reoxygenation on sarcolemmal rupture was investigated in myocytes submitted to hypo-osmotic reoxygenation in presence of 2,3-butanedione monoxime 30 mM, a blocker of contractility. Recovery from mechanical fragility was studied by exposing cells to hypotonic buffer 20 or 40 min after restoration of metabolic activity, in either presence or absence of 2,3-butanedione monoxime. Two control groups without metabolic inhibition were used. One was exposed to osmotic stress after 60 min incubation in control conditions, the other was induced to hypercontract by exposure to hypo-osmotic, high-calcium buffer. Cell viability was assessed by the Trypan blue test. RESULTS: Before any intervention 81.9(1.2)% of cells were rod-shaped. After 60 min of metabolic inhibition most cells developed rigor contracture and only 16.4(1.8)% remained rod-shaped. Restoration of metabolic activity induced hypercontracture of most cells with rigor independently of buffer osmolality. Cell viability, however, significantly differed among groups: only 25.9(4.4)% of cells reoxygenated with hypo-osmotic buffer were viable vs. 74.1(7.6)% in the normo-osmotic reoxygenation group, and 82.9(2.9)% in the control group. Addition of 2,3-butanedione monoxime 30 mM during hypo-osmotic reoxygenation prevented hypercontracture and preserved cell viability. Delaying osmotic stress 20 or 40 min after the onset of reoxygenation did not improve viability [19.3(3.9) and 34.9(1.3)%, respectively]. Contractile blockade with 2,3-butanedione monoxime during the first 20 or 40 min of reoxygenation was associated with a reduction in the number of hypercontracted cells after the removal of the inhibitor but did not increase the proportion of hypercontracted viable cells (25% and 27%, respectively). CONCLUSIONS: (1) Osmotic stress following transient metabolic inhibition produces sarcolemmal disruption, and this effect is not related to the low Na+ concentration present in the hypo-osmotic buffer; (2) reoxygenation-induced hypercontracture cooperates with cell swelling to produce sarcolemmal disruption; and (3) osmotic fragility persists for at least 40 min after restoration of metabolic activity.

Pre-treatment with trimetazidine increases sarcolemmal mechanical resistance in reoxygenated myocytes.

OBJECTIVE: Cytoskeletal and sarcolemmal fragility secondary to anoxia may contribute to sarcolemmal rupture and cell death during reoxygenation of cardiomyocytes. This study investigated the influence of trimetazidine (TMZ), a drug with effects on lipid metabolism and cell membranes, on reoxygenation-induced sarcolemmal rupture. METHODS: Isolated adult rat myocytes were submitted to 60 min of metabolic inhibition and 5 min of hypo-osmotic reoxygenation to simulate reperfusion edema in situ. Cells were allocated to 3 groups of treatment: in one group, TMZ 100 mumol/l was added to both the metabolic inhibition and reoxygenation buffers (group TMZ); another group was submitted to the same treatment but cells had previously been incubated with TMZ 100 mumol/l for 3 h (group TMZ-Pre); a control group underwent metabolic inhibition and hypo-osmotic reoxygenation without any treatment. Cell morphology was monitored throughout the experiment and sarcolemmal integrity was assessed by quantification of LDH activity and trypan blue exclusion test. RESULTS: After 60 min of metabolic inhibition most cells (83.1 +/- 2%) presented rigor contracture without between-group differences. Reoxygenation resulted in hypercontracture of 84.2 +/- 2.3, 91.2 +/- 1.4 and 84.1 +/- 2.1% of cells in TMZ, TMZ-Pre and control groups, P = NS. The trypan blue exclusion test revealed a higher proportion of cells with sarcolemmal integrity in TMZ and TMZ-Pre groups than in controls (12.7 +/- 2.0, 10.0 +/- 1.5 and 6.3 +/- 0.8%, respectively, P = 0.002). No between-group differences in LDH activity in the extracellular medium were observed at the onset or at the end of metabolic inhibition. However, LDH release was significantly lower (P = 0.002) in the TMZ-Pre group (1.6 +/- 0.1 IU/1000 cells) than in the TMZ and control groups (1.9 +/- 0.2 and 2.2 +/- 0.1 IU/1000 cells). CONCLUSION: Preincubation of cardiomyocytes with TMZ does not prevent rigor contracture induced by metabolic inhibition or hypercontracture during subsequent reoxygenation, but does improve sarcolemmal resistance to reoxygenation-induced mechanical stress. This could help to explain the beneficial effect of TMZ on infarct size.

Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury.

OBJECTIVE: We have recently shown that spontaneous Ca2+ oscillations elicit irreversible hypercontracture of cardiomyocytes during reoxygenation. The aim of this study was to investigate whether influx of exterior Ca2+ through the reverse mode of the Na+/Ca2+ exchanger (NCE) contributes to the development of these oscillations and, therefore, to reoxygenation-induced hypercontracture. METHODS: Isolated cardiomyocytes and hearts from rats were used as models. Cardiomyocytes were exposed to 60 min simulated ischemia (pH(o) 6.4) and 10 min reoxygenation (pH(o) 7.4). During reoxygenation cardiomyocytes were superfused with medium containing 1 mmol/l Ca2+ (control), with nominally Ca2+-free medium or with medium containing 10 micromol/l KB-R 7943 (KB), a selective inhibitor of the reverse mode of the NCE. RESULTS: In reoxygenated cardiomyocytes rapid Ca2+ oscillations occurred which were reduced under Ca2+-free conditions or in presence of KB. Hypercontracture was also significantly reduced under Ca2+-free conditions or in presence of KB. After 30 min of normoxic perfusion isolated rat hearts were subjected to 60 min global ischemia and reperfusion. KB (10 micromol/l) was present during the first 10 min of reperfusion. LVEDP, LVdevP and lactate dehydrogenase (LDH) release were measured. Presence of KB reduced post-ischemic LVEDP and improved left ventricular function (LVdevP). In KB treated hearts the reperfusion induced release of LDH was markedly reduced from 81.1 +/- 9.9 (control) to 49.3 +/- 8.8 U/60 min/g dry weight. CONCLUSION: Our study shows that inhibition of the reverse mode of the NCE, during reperfusion only, protects cardiomyocytes and whole hearts against reperfusion injury.

Ischaemic preconditioning: present position and future directions.

Preconditioning the myocardium using short episodes of sublethal ischaemia will delay the onset of necrosis during a subsequent lethal ischaemic insult. This powerful protective adaptation of the myocyte has also been observed in other cell types. The potential for clinical application to benefit patients with a variety of pathological conditions has led to an expansion in our knowledge concerning the pathophysiology of ischemia-reperfusion injury and the regulatory mechanisms underlying cellular metabolism. We feel it is timely to assess the current position in this field and provide a critical appraisal to facilitate future research.

Influence of tachycardia and arterial hypertension on infarct size in the pig.

To investigate the clinically important but controversial question of how hypertension during coronary occlusion affects infarct size 24 pigs underwent 1 h occlusion of the mid left anterior descending coronary artery and 24 h reperfusion and were randomised to one of three treatment groups. In group 1 blood pressure was increased during the occlusion period by an infusion of methoxamine; in group 2 tachycardia was induced by atrial pacing; and in group 3 no intervention was performed. The area at risk and infarct size were quantified by digital planimetry of slices of myocardium previously marked with fluorescein and with triphenyl-tetrazolium. Methoxamine maintained mean aortic blood pressure at 117 (SEM8) mmHg during occlusion, whereas the values were 80(6) mmHg in group 2 and 67(9) mmHg in group 3. Pacing increased heart rate to 146(1) beats.min-1 in group 2; it was 103(5) in group 1 and 99(8) in group 3. The pressure-rate product achieved was similar in groups 1 and 2 and significantly higher than in group 3. The pathological studies showed infarct size to be moderately but significantly larger in group 1 (14[3.5]% of the left ventricle) and similar in groups 2 (10.5[3.9]%) and 3 (10.1[2.2]%). The ratio of infarct size to area at risk was also significantly higher (0.743[0.057]) in group 1 with no differences between group 2 (0.604[0.055]) and group 3 (0.613[0.027]). At similar pressure-rate product, infarct size was thus greater with hypertension but not with pacing alone, showing a deleterious effect of increasing blood pressure in this experimental model with negligible collateral blood flow.

Analysis of myocardial oedema by magnetic resonance imaging early after coronary artery occlusion with or without reperfusion.

OBJECTIVE: The aim was to analyse the relationship between magnetic resonance (MR) imaging parameters and myocardial water content early after coronary occlusion with or without reperfusion. METHODS: 21 pigs were used. After 78 min of coronary occlusion (n = 7) or 48 min of coronary occlusion and 30 min of reperfusion (n = 14) the heart was excised. In seven animals in the reperfusion protocol the area at risk was perfused for 5 min with an anoxic buffer, starting 5 min after coronary occlusion. Serial T2 weighted and density weighted images of the heart were obtained from apex to base, by using a 1.5 tesla magnetic resonance imager. Water content was measured in samples from control and at-risk myocardium and relaxation parameters were measured in corresponding areas of the magnetic resonance images. RESULTS: Water content was 399(SEM 2) ml x 100 g-1 dry tissue in control myocardium, 427(8) in ischaemic myocardium, and 511(8) in reperfused myocardium (p < 0.001). Reperfused myocardium that had received intracoronary infusion contained less water than myocardium that did not: 498(9) v 534(4) ml x 100 g-1 (p = 0.003). T2 relaxation time and T2 weighted signal intensity in the different sampling sites of magnetic resonance images correlated well with water content in the corresponding myocardial samples (r = 0.76 and r = 0.83) and with the relative volume of extracellular space, as calculated by quantitative histology (r = 0.58 and r = 0.59, p < 0.001). The increase in T2 weighted signal intensity in the area at risk with respect to control myocardium allowed differentiation between ischaemic and reperfused myocardium [9(8)% v 63(3)% respectively]. The area at risk measured by MR imaging correlated very well with that determined at pathology by the fluorescein method (r = 0.92). CONCLUSIONS: Magnetic resonance imaging allows evaluation of myocardial oedema associated with acute coronary occlusion and reperfusion, and analysis of its spatial distribution. Changes in myocardial water content occurring early during acute myocardial infarction allow quantification of the area at risk and detection of reperfusion by magnetic resonance imaging.

Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs.

OBJECTIVE: It has been shown that cGMP content is reduced in post-ischemic myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte hypercontracture and cell death in vitro. This study was aimed at determining whether administration of the natriuretic peptide urodilatin (URO) at the time of reperfusion could limit myocardial cell death secondary to transient coronary occlusion. METHODS: The relation between cGMP content in reperfused myocardium and the extent of cell death was investigated in isolated rat hearts (n=62) receiving different URO concentrations during initial reperfusion. The dose of intravenous URO necessary to obtain the targeted increase in cGMP in reperfused myocardium was investigated in ten pigs submitted to transient coronary occlusion (CO), and the effect of two selected doses of URO on infarct size was investigated in 22 pigs. RESULTS: cGMP was severely reduced in post-ischemic rat hearts. Addition of 0.01 microM URO during the first 15 min of reperfusion had no effect on myocardial cGMP content, functional recovery or LDH release in hearts submitted to 40 or 60 min of ischemia. At 0.05 microM, URO increased myocardial cGMP to 111% of values in normoxic hearts, improved functional recovery (P=0.01) and reduced peak LDH released by 40% (P=0.02). The beneficial effect of urodilatin was abolished by ANP receptor inhibition. At 1 microM, URO increased cGMP in reperfused myocardium to 363% of normoxic controls and had no beneficial effect. In pigs allocated to 47 min of CO and 5 min of reperfusion, cGMP was markedly reduced in reperfused myocardium. Intravenous URO at 10 ng/kg per min during the first 25 min of reperfusion normalized myocardial cGMP after 5 min of reflow (95% of control myocardium), and reduced infarct size by 40% (P=0.04). At 50 ng/kg per min, urodilatin increased myocardial cGMP in reperfused myocardium to 335% of control myocardium and failed to significantly reduce infarct size (46 vs. 66%, P=0.125). None of these doses had detectable hemodynamic effects. CONCLUSIONS: Intravenous low-dose URO at the time of reperfusion normalizes myocardial cGMP and limits necrosis. Large doses of URO increasing myocardial cGMP well over normal values may lack this beneficial effect.

Myocardial reperfusion in the pig heart model: infarct size and duration of coronary occlusion.

The effect of coronary artery reperfusion on infarct size was studied in a pig heart model. Forty four open chest pigs underwent occlusion of the mid-left anterior descending artery. Fifteen minutes after occlusion the animals were randomised to one of five groups: reperfusion at 30, 45, 60, or 90 min after occlusion (groups 1-4) or permanent occlusion (group 5). Twenty four hours after coronary occlusion the pigs were killed. The heart was sectioned in slices, which were incubated in triphenyl-tetrazolium. Mean(SEM) infarct sizes calculated by planimetry were 0.46(0.42), 2.85(1.14), 9.74(1.65), 8.93(1.37), and 13.17(1.17)% of left ventricular mass in the five groups. The transmural extension of the infarct was 14.6(11.4), 42.1(12.9), 87.4(6.6), 96.2(3.2), and 100(0)% and a transmurality index used as an estimate of the mean extension of the infarct relative to wall thickness was calculated to be 0.08(0.06), 0.32(0.10), 0.72(0.06), 0.79(0.04), and 0.92(0.02) respectively. Infarct size was similar in groups 3-5, but significantly smaller in groups 1 and 2 (p less than 0.05). Infarct size and the transmurality index correlated exponentially with the duration of the occlusion (r = 0.80, p less than 0.01; and r = 0.95, p less than 0.001 respectively). These results indicate that in the pig heart model submitted to an acute coronary occlusion cell viability may be less than that suggested by previous canine studies. This observation is probably related to a less well developed collateral blood flow in the pig heart and may provide an experimental model that better resembles certain clinical conditions.

L-Arginine administration prevents reperfusion-induced cardiomyocyte hypercontracture and reduces infarct size in the pig.

OBJECTIVE: Stimulation of cGMP synthesis protects cardiomyocytes against reoxygenation-induced hypercontracture. The purpose of this study was to determine whether L-arginine supplementation has a protective effect against reperfusion-induced hypercontracture and necrosis in the intact animal. METHODS: Twenty-four Large-White pigs were randomized to receive either 100 mg/kg of L-arginine i.v. or vehicle 10 min before 48 min of coronary occlusion and 2 h of reperfusion. Hemodynamic variables, coronary blood flow and myocardial segment length changes (piezoelectric crystals) were monitored. Postmortem studies included quantification of myocardium at risk (in vivo fluorescein), infarct size (triphenyltetrazolium reaction), myocardial myeloperoxidase activity and histological analysis. Systemic, coronary vein, and myocardial cGMP concentration were measured in additional animals. RESULTS: Administration of L-arginine had no significant effect in hemodynamics or coronary blood flow. During reperfusion, myocardial cGMP content was reduced in the LAD as compared to control myocardium (P=0.02). L-Arginine increased myocardial cGMP content and caused a transient increase in plasma cGMP concentration during the initial minutes of reperfusion (P=0.02). The reduction in end-diastolic segment length induced by reperfusion, reflecting hypercontracture, was less pronounced in the L-arginine group (P=0.02). Infarct size was smaller in pigs receiving L-arginine (47.9+/-7.2% of the area at risk) than in controls (62.9+/-4.9%, P=0.047). There were no differences between groups in leukocyte accumulation in reperfused myocardium (P=0.80). CONCLUSION: L-Arginine supplementation reduces myocardial necrosis secondary to in situ ischemia-reperfusion by a direct protective effect against myocyte hypercontracture.

Dynamic intracoronary thrombosis does not cause significant downstream platelet embolization.

OBJECTIVE: A mural intracoronary thrombus is a potential source of platelet emboli that may obstruct downstream microvessels, but this phenomenon has not been characterized. The present study aimed to assess the magnitude of myocardial platelet accumulation downstream of a mural intracoronary thrombus and its modification by a concomitant transient coronary occlusion (OC) or by treatment with aspirin. METHODS: The myocardial content of 99mTc-labelled platelets was analyzed in 26 pigs submitted to intimal injury of the left anterior descending coronary artery (LAD) followed by no intervention (n=6), 25-min OC (n=6), or 48-min OC preceded (n=8) or not (n=6) by intravenous administration of 250 mg aspirin. RESULTS: After 2 h, 24 animals had had 12+/-1 cyclic flow reductions (CFRs) reflecting dynamic LAD thrombosis. Myocardial platelet content in the inferior region was similar among groups. Platelet content in the LAD region was not significantly different to that in the inferior region (129+/-19%, P=NS) in the no intervention group, but was increased following OC (172+/-20 and 312+/-71% after 25- and 48-min OC, respectively, P<0.05). Pre-treatment with aspirin lessened the number of CFRs but did not reduce platelet accumulation in LAD myocardium (483+/-148%). Myocardial platelet accumulation was not associated with the magnitude of platelet deposition in the LAD nor with the number of CFRs, but was correlated with myeloperoxidase activity (r=0.91, P<0.001) and with infarct size (r=0.52, P=0.05). Histological analysis frequently showed sparse platelets or small platelet or leukoplatelet aggregates in small vessels, but arteriolar emboli were rare. In none of seven additional experiments coronary angiography showed obstructions of arterial branches during CFRs. CONCLUSION: The magnitude of platelet embolization from a mural intracoronary thrombus into downstream myocardium is small despite the presence of repetitive CFRs.

Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na(+)-H+ exchange.

OBJECTIVE: To determine the effect of Na(+)-H+ exchange blockade on ischemic rigor contracture and reperfusion-induced hypercontracture. METHODS: Thirty-six pigs were submitted to 55 min of coronary occlusion and 5 h reperfusion. Myocardial segment length analysis with ultrasonic microcrystals was used to detect ischemic rigor (reduction in passive segment length change) and hypercontracture (reduction in end-diastolic length). RESULTS: Pretreatment with the new, highly selective Na(+)-H+ exchange inhibitor HOE642 before occlusion reduced ischemic rigor (P < 0.05), attenuated segment shrinkage (P < 0.05) during subsequent reperfusion, dramatically reduced infarct size (P < 0.0001) and attenuated arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only during reperfusion by means of direct intracoronary infusion of HOE642 into the area at risk prevented reperfusion arrhythmias but had no effect on final infarct size, while treatment with intravenous HOE642 immediately before reperfusion had no detectable effects. CONCLUSION: These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.