Thermographic evaluation of myocardial temperature during infusion of cold cardioplegia

Delay in myocardial cooling during an infusion of cold cardioplegic solution may occur in patients with coronary artery disease. Forty patients with significant stenosis of the left anterior descending coronary artery (LAD) were divided into 3 groups according to the extent of the LAD stenosis. Group A consisted of 12 patients with 70% stenosis. Group B included 23 patients with 90% stenosis, and in group C there were 5 patients with LAD occlusion. Myocardial temperature was measured with a thermocamera during infusion of 2000 ml 8 to 10 degrees C cold Bretschneider's cardioplegic solution and compared to 10 other patients without coronary artery disease undergoing mitral valve replacement (group D). In group A the myocardium cooled to 15 degrees C after 4 1/2 minutes and to 12 degrees C after 10 minutes. In group B the myocardial temperature was 15 degrees C after 5 minutes and 12 degrees C after 10 minutes. In group C the temperature reached 18 degrees C after 5 minutes and 14 degrees C after 10 minutes. In group D the myocardial temperature was 12 degrees C after 3 minutes and 10 degrees C after 7 minutes. This study shows far better myocardial cooling rates in patients with unobstructed coronary arteries.     

Optimal timing of hypothermia in relation to myocardial reperfusion

Two previous clinical trials investigating hypothermia as an adjunct therapy for myocardial infarction have failed. Recently a pilot study has demonstrated a significant reduction in infarct size. The aims of this study were to elucidate the effects of hypothermia on reperfusion injury and to investigate the optimal hypothermia protocol for a future clinical trial. Pigs (40-50?kg) were anesthetized and a normal pig temperature of 38°C was established utilizing an endovascular temperature modulating catheter. The pigs were randomized to a combination hypothermia group (1,000?ml of 4°C saline solution and endovascular cooling, n?=?8), or to normothermic controls (n?=?8). A PCI balloon was then inflated in the LAD for 40?min (control) or 45?min with hypothermia induced during the last 5?min. Furthermore, hypothermia induced by cold saline alone (n?=?8), and prolonged combination hypothermia during reperfusion (n?=?7) were also examined. Infarct size and area at risk were determined ex vivo after 4?h of reperfusion using gadolinium-enhanced MRI and Tc-99-tetrofosmin SPECT, respectively. All pigs in the combination hypothermia group were cooled to <35°C within 5?min. Combination hypothermia reduced IS/AAR by 18% compared with normothermic controls despite 5?min longer ischemic time (61?±?5 vs. 74?±?4%, p?=?0.03). Cold saline did not reduce IS/AAR. Prolonging hypothermia treatment after onset of reperfusion by an additional 45?min over that used in a previous paper did not confer any additional benefit. The cardioprotective effects of hypothermia treatment are due to an attenuation of myocardial injury during both ischemia and reperfusion. The results suggest that a hypothermia protocol using a cold saline infusion and endovascular cooling enables hypothermia to be induced in a clinical setting without delaying reperfusion therapy.     

Catheter-based transcoronary myocardial hypothermia attenuates arrhythmia and myocardial necrosis in pigs with acute myocardial infarction.

OBJECTIVES: This study evaluated the efficacy of catheter-based transcoronary myocardial hypothermia (CTMH) in pigs with acute myocardial ischemia. BACKGROUND: Although it has been suggested that hypothermia therapy can attenuate myocardial necrosis, few applications have been accepted for clinical use. METHODS: This study comprises 2 substudies. In both studies, pigs underwent 60 min of coronary occlusion and 180 min of reperfusion. In study 1, after 15 min of coronary occlusion with an over-the-wire-type balloon (OTWB), pigs in the hypothermia group (H) (n = 13) were directly infused with 4 degrees C saline into the coronary artery through the OTWB wire lumen (2.5 ml/min) for 60 min. Pigs in the normothermia group (N) (n = 15) received the same amount of 36.5 degrees C saline. In study 2, pigs in the hypothermia-reperfusion group (HR) (n = 5) were infused with 4 degrees C saline through the infusion catheter (8 ml/min) for 30 min with a later start (60 min after coronary occlusion), whereas simple reperfusion was used for the reperfusion group (R) (n = 6). RESULTS: Catheter-based transcoronary myocardial hypothermia was successful in both studies. In study 1, CTMH significantly decreased ventricular arrhythmia and the ratio of necrosis to ischemic risk area (H: 9 +/- 2%; N: 36 +/- 4%; p < 0.0001) with a significant reduction of enzyme leaks. In study 2, CTMH tended to reduce the ratio of necrosis (HR: 33 +/- 2%; R: 45 +/- 5%; p = 0.08). In both studies, CTMH significantly suppressed the increase of 8-iso-prostaglandin F(2alpha) while preserving the coronary flow reserve. CONCLUSIONS: Catheter-based transcoronary myocardial hypothermia reduced myocardial necrosis while preserving coronary flow reserve, due, in part, to attenuation of oxidative stress.     

Efficacy of intracoronary or intravenous VEGF165 in a pig model of chronic myocardial ischemia

OBJECTIVES: We sought to optimize vascular endothelial growth factor (VEGF) treatment for therapeutic angiogenesis in myocardial ischemia, we explored the efficacy of five different regimens. BACKGROUND: Although VEGF165 is one of the most potent pro-angiogenic growth factors, VEGF165 treatment for myocardial ischemia has been hampered by low efficacy and dose-limiting hypotension after systemic or intracoronary delivery. METHODS: This study evaluated the effect of intravenous or intracoronary rhVEGF165 in the presence or absence of nitric oxide (NO) synthase inhibition in a porcine model of chronic myocardial ischemia. Forty-two Yorkshire pigs with chronically occluded left circumflex coronary arteries were randomly assigned to receive 10 microg/kg of VEGF165: 1) rapid (40 min) intravenous VEGF165 0.25 microg/kg/min, 2) slow (200 min) intravenous VEGF165 0.05 microg/kg/min, 3) rapid intracoronary VEGF165 0.25 microg/kg/min, 4) rapid intracoronary VEGF165 0.25 microg/kg/min + nitro-L-arginine methyl ester hydrochloride (L-NAME) or 5) rapid vehicle infusion. RESULTS: Intracoronary and intravenous VEGF165 induced hypotension. Intracoronary VEGF-induced hypotension was blocked by L-NAME. Coronary angiography three weeks after treatment showed improvement in collateral index in both intracoronary groups but not the intravenous VEGF165 groups. Likewise, myocardial blood flow and microvascular function in the ischemic territory improved in both intracoronary groups but not in the intravenous groups. Global and regional myocardial function showed no significant improvements in any groups. CONCLUSIONS: Intracoronary infusion of VEGF165 significantly improves blood flow to the ischemic myocardium. Concomitant administration of L-NAME inhibits VEGF-induced hypotension while most likely preserving VEGF-induced angiogenesis. Intravenous infusion of VEGF165 was not effective in augmenting either myocardial flow or function in this model.     

Ultrastructural and biochemical changes of human papillary heart muscle during different methods of induced cardiac arrest.

To determine the protective effects of different methods of cardioplegia, studies on ATP/lactate levels and ultrastructure were performed in human papillary muscles obtained during mitral valve replacement. In group I (n = 5), plain ischemic arrest in hypothermia (systemic venous temperature = 24 degrees C) was accomplished. In group II (n =12), the heart was arrested by injection cardioplegia using magnesium-aspartate-procaine at systemic venous and myocardial temperatures of 24 degrees C. In group III (n = 12) Bretschneider infusion cardioplegia at systemic venous and myocardial temperatures of 26 degrees C and 19 degrees C respectively was applied. With regard to ultrastructural changes there were no clearcut differences in the three methods of hypothermic cardiac arrest after 60 minutes of ischemia. Ischemic changes tended to be slightest in group III (infusion cardioplegia). ATP decay and lactate increase were significant in group I and moderate to minimal in groups II and III after the same period of time. It is concluded that for aortic cross-clamp times up to 60 minutes, body hypothermia and injection cardioplegia using magnesium-aspartate-procaine at a myocardial temperature of 24 degrees C provide adequate protection of the myocardium. For ischemia times beyond 70 minutes, profound myocardial hypothermia below 20 degrees C is preferred.     

Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia

OBJECTIVES: We sought to improve regional myocardial delivery and subsequent collateral perfusion induced by basic fibroblast growth factor-2 (FGF-2) using selective pressure-regulated retroinfusion of coronary veins for delivery. This hypothesis was tested in a newly developed pig model with percutaneous induction of chronic ischemia. BACKGROUND: Selective pressure-regulated retroinfusion of coronary veins is a catheter-based procedure that has been shown to provide effective regional delivery of drugs and gene vectors into ischemic myocardium. METHODS: A high-grade stenosis with subsequent progression to total occlusion within 28 days was induced by implanting a reduction stent graft into the left anterior descending artery (LAD). After seven days, a 30-min retroinfusion (anterior cardiac vein) was performed with (n = 7) or without (n = 7) 150 microg FGF-2 and compared with a 30-min antegrade infusion of 150 microg FGF-2 into the LAD (n = 7). Sonomicrometry to assess regional myocardial function at rest and during pacing, and microspheres to assess regional myocardial blood flow, were performed 28 days after implantation of the reduction stent. RESULTS: Retroinfusion of FGF-2 compared favorably with controls and with antegrade infusion of FGF-2 with regard to regional myocardial function at rest (18.5 +/- 4.1% vs. 5.7 +/- 2.9% vs. 7.9 +/- 1.8%, respectively, p < 0.05) and during pacing. Regional myocardial blood flow was also higher in the LAD territory after retroinfusion of FGF-2 (1.07 +/- 0.14 vs. 0.66 +/- 0.07 vs. 0.72 +/- 0.17 ml x min(-1) x g(-1), p < 0.05). CONCLUSIONS: Selective pressure-regulated retroinfusion increased tissue binding of FGF-2 and enhanced functionally relevant collateral perfusion compared with antegrade intracoronary delivery in pigs with chronic myocardial ischemia.     

Myocardial hypothermia: a potential therapeutic technique for acute regional myocardial ischemia

The importance of temperature in the development of necrosis after myocardial ischemia in the beating heart is becoming apparent. Recent studies have shown that the proportion of the ischemic risk zone that becomes necrotic is directly correlated with temperature. This fact suggests the potential therapeutic benefits of reducing myocardial temperature after coronary artery occlusion. We have shown in a number of experimental protocols in the rabbit model of myocardial infarction that topical regional hypothermia reduces infarct size even when instituted after coronary artery occlusion. The reduction in myocardial temperature required to obtain this benefit is modest ( 30 degrees C to 34 degrees C). Topical regional hypothermia allows targeted cooling of a zone of the heart. Myocardial cooling can also be achieved by perfusing the pericardial sac with a chilled fluid by using a closed-circuit catheter system that does not cause cardiac tamponade. This technique also protects myocardium during ischemia. Myocardial hypothermia might be a useful technique to limit ischemic damage during infarction or as adjunctive therapy during minimally invasive cardiac surgery.     

Percutaneous cooling of ischemic myocardium by hypothermic retroperfusion of autologous arterial blood: effects on regional myocardial temperature distribution and infarct size

The effects of synchronized coronary venous retroperfusion of cooled autologous arterial blood on regional myocardial temperature distribution and infarct size were studied in open chest dogs with 3.5 h of left anterior descending coronary artery occlusion. After 30 min of occlusion, the dogs were randomly assigned to one of three groups: 1) untreated control group (n = 5), 2) normothermic retroperfusion group (infusion temperature 32 degrees C) (n = 7), and 3) hypothermic retroperfusion group (infusion temperature 15 degrees C) (n = 7). Regional myocardial temperatures were measured by using needle-tipped thermistors stabbed in the 1) anterior wall distal to the occlusion site, 2) anterior wall proximal to the occlusion site, 3) left lateral wall, 4) posterior wall, and 5) right ventricular free wall. Rectal and pulmonary artery temperatures were also measured. In the hypothermic retroperfusion group, the anterior wall temperature decreased rapidly by 5 degrees C at 15 min of retroperfusion (p less than 0.05 vs. normothermic retroperfusion or untreated control groups), whereas the temperature at other sites decreased with a linear trend over time. Myocardial temperatures in the ischemic area (distal anterior wall) were generally lower than those in the other sites during the first 60 min of hypothermic retroperfusion and the largest intramyocardial temperature difference (3.6 degrees C) was found at 15 min after retroperfusion. Infarct size expressed as a percent of the risk area was significantly smaller in the hypothermic retroperfusion group (6.2 +/- 3.3%) than in the control (64.9 +/- 14%) or normothermic retroperfusion groups (24.1 +/- 6.7%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Creation of anastomoses between an extracardiac artery and the coronary circulation. Proof that myocardial angiogenesis occurs and can provide nutritional blood flow to the myocardium.

The purpose of this investigation was to determine whether blood vessels could develop de novo between an extracardiac artery and a collateral-dependent zone of the heart and to quantify the nutritive blood flow afforded by the new vessels. We also adapted the preparation so that angiogenically active agents could be chronically administered directly to the site of neovascularization in subsequent studies. To induce neovascularization between a systemic artery and the coronary circulation, the left internal mammary artery (IMA) was implanted in an intramyocardial tunnel in proximity to the left anterior descending coronary artery (LAD). A tube situated in the distal IMA connected to an implanted pump provided for continuous intra-arterial infusion at the site of angiogenesis. During the same procedure, an ameroid constrictor was placed on the proximal LAD, rendering its perfusion territory collateral dependent during a 2-3 week period. After 8 weeks, the functional capacity of the anastomoses established between the implanted IMA and the LAD territory was assessed by determining regional myocardial blood flow under basal conditions, during adenosine-induced vasodilatation, and during differential occlusions of the IMA and left circumflex coronary artery (LCCA). For all dogs, IMA occlusion decreased maximal LAD territory flow from 1.31 +/- 0.11 to 1.16 +/- 0.10 ml/min/g (p less than 0.005). Occlusion of the LCCA decreased LAD zone flow to 0.73 +/- 0.12 ml/min/g, whereas occlusion of the IMA in addition to the LCCA further decreased LAD zone flow to 0.42 +/- 0.11 ml/min/g (p less than 0.02). The IMA provided measurable nutritive blood flow in seven of 12 dogs, and in these dogs, the artery provided 30.0 +/- 2.5% of total LAD zone collateral conductance under conditions of maximal vasodilatation (range, 23-42%). We conclude that angiogenesis can occur between an implanted internal mammary artery and the native coronary circulation in dogs, providing modest nutritive blood flow to a collateral-dependent region. Further studies will be necessary to determine whether direct, local infusion of angiogenically active factors can enhance neovascularization and whether sufficient flow can be reliably supplied to make some variant of this approach clinically applicable.     

A new efficient method of topical cooling and rewarming of the myocardium

Profound myocardial hypothermia (below 17 degrees C, and more often around 12 degrees C) is imperative in myocardial protection while the aorta is cross-clamped. Based on our experience in more than 800 open-heart operations, profound myocardial hypothermia can be achieved by very efficient topical cooling despite mild systemic hypothermia (30 to 33 degrees C) and a small, single dose of crystaloid K + cardioplegia. Very efficient topical cooling is achieved by a high flow (1 to 1(1/2) L/min) of continuously cooled fluid (+ 0.5 to + 2 degrees C). The great temperature-reducing capacity of the cooling system is due to a 10 to 15 meter long metal coil tube that is immersed in an ice-salt cold bath. The water pump placed in the bath makes heat exchange even more efficient. The described method of myocardial protection with stable profound myocardial hypothermia safely prolongs the ischemic time during operation to more than 2 hours. By repositioning the coil into the warm bath (39 to 40 degrees C), the whole system can be used for topical rewarming of the heart.     

Intrapericardial administration of basic fibroblast growth factor: myocardial and tissue distribution and comparison with intracoronary and intravenous administration.

Growth factor-induced angiogenesis is being investigated in ischemic heart disease. Intracoronary and intravenous delivery are the most practical, but are limited by low myocardial uptake and significant systemic recirculation. The pericardial space may act as a drug delivery reservoir with increased myocardial uptake and reduced systemic toxicities. This study was designed to investigate the myocardial and tissue deposition and retention of basic fibroblast growth factor (FGF-2) after intrapericardial administration in normal and chronically ischemic animals. Twelve Yorkshire pigs were used for the study [six normal and six animals with chronic myocardial ischemia (ameroid constrictor on LCx)] with bolus intrapericardial administration of (125)I-FGF-2 (25 micro Ci) with 30 micro g of cold FGF-2 and 3 mg of heparin. Tissue and myocardial distribution was determined at 1 and 24 hr by measuring (125)I-bFGF-specific activity. In addition, regional myocardial deposition was determined using (125)I-bFGF activity and organ level autoradiography. The heart (pericardium and myocardium) accounted for the majority of (125)I-bFGF activity in ischemic animals (30.9% at 1 hr and 23.9% at 24 hr). Left anterior descending artery territory activity/gm of tissue for nonischemic and ischemic animals was 0.01% and 0.01% at 1 hr and 0.0009% and 0.12% at 24 hr, respectively. LCx territory activity for nonischemic and ischemic animals was 0.006% and 0.008% at 1 hr and 0.03% and 0.05% at 24 hr, respectively. Endocardial activity was low at all time points. Liver uptake was 0.47% (nonischemic) and 0.34% (ischemic) at 1 hr and 0.23% (nonischemic) and 0.54% (ischemic) at 24 hr. Intrapericardial delivery of FGF-2 provides markedly higher myocardial deposition and retention and lower systemic recirculation than intracoronary or intravenous delivery at the expense of poor subendocardial penetration. This limitation, however, did not affect its efficacy.     

Comparative vasodilator effects of nitroprusside, phentolamine, and nitroglycerin on hemodynamics, regional myocardial function and epicardial electrogram in dogs with acute myocardial ischemia.

The effects of nitroprusside (NP), phentolamine (PH), and nitroglycerin (NTG) were studied on systemic hemodynamics, regional contraction and epicardial ST segment in the border and non-ischemic zones of the left ventricle of anesthetized open chest dogs. The anterior descending coronary artery (LAD) was completely occluded. NP (5 microgram/Kg/min) or PH (100 microgram/Kg/min) was drip-infused, or a bolus injection of NTG (20 microgram/Kg) was administered intravenously. The 3 vasodilator agents produced somewhat similar reductions in systemic arterial pressure. However, NP caused a greater reduction in total peripheral resistance (TPR) than in left ventricular end-diastolic pressure (LVEDP), and caused a decline, in the ischemic marginal zone, in both ST segment eievation and paradoxical systolic lengthening. PH decreased TRP without reducing LVEDP and elevated the ST segment. NTG markedly reduced LVEDP and TPR slightly. NTG improved the elevated ST segment and paradoxical systolic expansion of the segmental myocardium in the border zone. Cardiac output rose with NP and PH, whereas injected NTG caused a reduction in cardiac output. These findings suggest that NP favourably affects the ischemic myocardium mainly by reducing the afterload and that the NTG-induced improvement of myocardial ischemia can be attributed mainly to preload reduction, while PH enhances cardiac function with slight or no improvement of myocardial ischemia in the border zone.     

Cell Therapy for Cardiovascular Disease: A Comparison of Methods of Delivery

The field of myocardial regeneration utilizing novel cell-based therapies, gene transfer, and growth factors may prove to play an important role in the future management of ischemic heart disease and cardiomyopathy. Phases I and II clinical trials have been published for a variety of biologics utilizing four methods of delivery: systemic infusion, intracoronary infusion, transvenous coronary sinus, and intramyocardial. This review discusses the advantages and disadvantages of the delivery approaches above.     

Coronary flow reserve is reflective of myocardial perfusion status in acute anterior myocardial infarction.

Our objective was to determine whether coronary vasodilatory reserve (CVR) correlates with the perfusion state of infarct zone in early recovery phase of acute anterior myocardial infarction (AMI). We studied 14 patients (11 males; mean age, 46 years) who had AMI and 6 control subjects who had chest pain but normal coronary angiograms. All patients underwent successful percutaneous revascularization of left anterior descending (LAD) coronary artery. Coronary flow velocity was measured using intracoronary (IC) Doppler at baseline and following IC injection of 18 microg of adenosine. Myocardial perfusion was evaluated by myocardial contrast echocardiography (MCE). CVR was higher in patients without a perfusion defect on MCE than in those with (2.48 +/- 0.21 vs. 1.66 +/- 0.13, P = 0.001). Subjects with a perfusion defect had a lower CVR than controls (1.66 +/- 0.13 vs.2.40 +/- 0.18, P < 0.05). CVR was > 2.0 in all subjects without a perfusion defect. There was a strong correlation between the magnitude of myocardial opacification in the LAD territory and CVR (r = 0.80, P < 0.01). Increase in peak diastolic flow velocity after adenosine infusion, but not systolic flow velocity, correlated with myocardial opacification index (r = 0.63, P = 0.016). CVR of infarct-related artery correlated closely with the perfusion status of the myocardium in infarct zone and those with a CVR > 2.0 had normal myocardial perfusion. These data suggest that CVR may be used to determine the perfusion state of the myocardium in the infarct zone, which is a known predictor of myocardial viability. Cathet. Cardiovasc. Intervent. 51:281-286, 2000.     

Myocardial norepinephrine and cyclic amp concentration following myocardial ischemia--relation to ventricular fibrillation and sudden death

This study was designed to investigate the relationships of myocardial concentrations of norepinephrine (NE) and cyclic AMP (c-AMP) to the development of ventricular fibrillation (VF) with reference to the effects of a premedication of dibutyryl cyclic AMP (DBC-AMP) and propranolol in dogs with experimental myocardial infarction. Myocardial specimens were obtained serially from the ischemic and the non-ischemic zones by mini-drill biopsy, and NE and c-AMP levels were determined by high-performance liquid chromatography and radioimmunoassay, respectively. Before the occurrence of VF, myocardial NE increased in both the ischemic and the non-ischemic zones, and c-AMP increased significantly in the ischemic zone but did not in the non-ischemic zone. In dogs premedicated with DBC-AMP an increase of c-AMP was observed in both the ischemic and the non-ischemic zones in association with an increased incidence of VF. On the other hand, no significant increase of myocardial c-AMP was observed in both the ischemic and the non-ischemic zones of propranolol-premedicated dogs which were free from VF. A significant increase of myocardial c-AMP in the ischemic zone was observed in dogs which suffered from VF in spite of the premedication of propranolol. The incidence of VF was significantly reduced by 26.5% in dogs pretreated with propranolol. No significant changes in myocardial norepinephrine and c-AMP were observed in dogs which were free from VF throughout the experiments.     

Evaluation of high-pressure retrograde coronary venous delivery of FGF-2 protein.

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor-2 (FGF-2) protein via high-pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF-2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere-derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF-2 protein (6 microg/kg) was delivered via high-pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF-2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 microg; P < 0.04) and in the LAD region (1.2 vs. 0.64 microg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32-1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32-1.23; P = 0.02) and the control arms (1.32-1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30-1.23; P < 0.05), but did not change significantly in the other three arms. High-pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium.     

Hypothermia during reperfusion limits 'no-reflow' injury in a rabbit model of acute myocardial infarction

OBJECTIVE: Reflow following coronary artery occlusion is an important predictor of clinical outcome. This study tests the effects of regional hypothermia, initiated late during ischemia and maintained for 2 h of reperfusion, on the no-reflow phenomenon. METHODS: Anesthetized, open-chest New Zealand White rabbits received 30 min of coronary artery occlusion and 3 h reperfusion. Regional myocardial hypothermia (H, n=14), starting 10 min before reperfusion and continuing for 2 h of reperfusion, was compared with normothermia (N, n=14). Regional myocardial blood flow (microspheres) was measured during occlusion and at the end of reperfusion. The anatomic zone of no-reflow (thioflavin S in vivo injection) and infarct size were measured in the ischemic risk region at the end of the study. RESULTS: Myocardial temperature in H rabbits was decreased by 5.0+/-0.4 degrees C from baseline (37.1+/-0.2 degrees C) and remained about 32 degrees C during the cooling phase, returning to 36.0+/-0.3 degrees C at 3 h. N hearts remained within 0.2 degrees C of baseline (37.3+/-0.1 degrees C) throughout. Both groups were equally ischemic during occlusion, but at the end of reperfusion reflow to the previously ischemic zone was significantly higher in H, 77+/-5% of normal blood flow versus 36+/-4% in N (P=0.0001). The zone of anatomic no-reflow was significantly smaller in H, 11+/-3% of the ischemic risk zone versus 37+/-3% in N (P=0.0001), and was proportionally smaller when represented as a percent of the necrotic zone 36+/-6% compared with 75+/-5% in N. Infarct size, expressed as a percent of the ischemic risk zone was significantly smaller in H vs. N hearts (27+/-4 and 51+/-5%, P=0.0000). CONCLUSION: This study shows that hypothermic therapy initiated late during ischemia and continuing for several hours of reperfusion significantly improves reflow and reduces macroscopic zones of no-reflow and necrosis in this model. The improvement in reflow was greater than would be expected in the H group compared with N, based on the extent of necrosis. As reflow is a predictor of outcome, this intervention may have clinical implications.     

Acute coronary occlusion in the pig: Effect of nitroglycerin on regional myocardial blood flow

Myocardial blood flow was studied in 10 closed chest, anesthetized pigs after an acute balloon catheter occlusion of the left anterior descending coronary artery. With use of radioactive microspheres (15 μ), myocardial blood flow was measured before and during an intravenous nitroglycerin infusion and during a combined nitroglycerin-phenylephrine infusion. A significant zone of ischemia (myocardial blood flow less than 50 percent of normal zone flow) was produced by the occlusion and involved 15 percent of the combined left ventricular and interventricular septal mass. More than 50 percent of this ischemic zone was intensely ischemic (myocardial blood flow 0 to 3 percent of normal). Nitroglycerin resulted in a 20 to 30 mm Hg decrease in systolic blood pressure. Myocardial blood flow was unchanged in intensely ischemic areas but varied directly with the product of heart rate and systolic blood pressure in the moderately ischemic area (myocardial blood flow 26 to 50 percent of normal). S-T segment elevation was significantly increased during nitroglycerin infusion and returned to control level with the added infusion of phenylephrine sufficient to restore the systemic blood pressure to prenitroglycerin values. No improvement in ischemic zone perfusion could be demonstrated during the infusion of nitroglycerin alone or with phenylephrine. The endocardial/epicardial flow ratio in moderately ischemic areas was slightly lower than the normal zone flow ratio and decreased slightly during infusion of nitroglycerin. With the addition of phenylephrine, the ratios rose slightly and no longer differed from prenitroglycerin values.

Blood flow distribution in acutely ischemic pig myocardium differs considerably from that observed in the dog. Nitroglycerin was not shown to have any beneficial effects with or without its relative hypotensive effect. More extensive study in animal models other than the dog is needed.     

Brief myocardial ischemia affects free radical generating and scavenging systems in dogs

Summary This study examined whether brief repeated myocardial ischemia altered free radical generating and scavenging activity in a dog model. In dogs preconditioned with four 5-min left anterior descending coronary artery (LAD) occlusions and reperfusions, we examined transcardiac changes in both the function of neutrophils, cells which are major free radical generators, and in myocardial antioxidant enzyme activity, as an indication of free radical scavenging. Neutrophil function was assessed by determining luminol-enhanced whole blood chemiluminescence (CL) induced by zymosan. Blood was taken simultaneously from the carotid artery and the cardiac vein running along the occluded LAD. Preconditioning with sublethal ischemia significantly reduced whole blood CL in the cardiac vein compared with the carotid artery after the first and fourth 5-min reperfusions, while there was no difference in neutrophil count between these sampling sites. Immediately after brief repeated ischemia and reperfusion, manganese-superoxide dismutase (SOD) activity was significantly enhanced, and glutathione reductase activity was markedly reduced in the ischemic, compared with the non-ischemic, myocardium. There were no differences in the myocardial activities of copper, zinc-SOD, glutathione peroxidase, and glutathione S-transferase between the ischemic and non-ischemic regions. Also, no difference was observed between the reduced myocardial glutathione levels in these regions, although the oxidized glutathione level was significantly higher in the ischemic regions of the subepicardial and subendocardial areas. We demonstrated that brief repeated ischemia affects free radical generating and scavenging systems in the ischemic myocardium.This study was supported, in part, by research grants from the Ministries of Education, Science, and Culture of Japan.