Improved perfusion and contractile reserve after transmyocardial laser revascularization in a model of hibernating myocardium

Background. Transmyocardial laser revascularization (TMR) has been demonstrated effective for relieving angina, although prior studies have yielded inconsistent results regarding postoperative myocardial perfusion and function. This study evaluated long-term changes in myocardial perfusion and contractile reserve after TMR in a model of hibernating myocardium.

Methods. Miniswine had subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, positron emission tomography and dobutamine stress echocardiography were performed to document ischemic, viable (hibernating) myocardium in the left circumflex distribution. Animals then had sham redo thoracotomy (n = 4) or TMR (n = 6). Six months later the positron emission tomography and dobutamine stress echocardiography studies were repeated.

Results. Myocardial blood flow in the left circumflex distribution as measured by positron emission tomography was significantly reduced in all animals after 2 weeks in the low-flow state. In animals that had TMR, there was significant improvement in myocardial blood flow to the lased regions 6 months postoperatively. No significant change in myocardial blood flow was seen in sham animals at 6 months. Dobutamine stress echocardiography after 2 weeks of low-flow demonstrated severe hypocontractility at rest in the left circumflex region of all animals, with a biphasic response to dobutamine consistent with hibernating myocardium. In animals that had TMR, there was a trend toward improved resting function and significantly improved regional stress function in the lased segments 6 months postoperatively, consistent with a reduction in ischemia. Global left ventricular wall motion at peak stress improved significantly as well. There was no change in wall motion 6 months postoperatively in sham-operated animals.

Conclusions. This study found improvements in myocardial perfusion and regional and global contractile reserve 6 months after TMR in a porcine model of hibernating myocardium. This improved perfusion and function likely accounts for the clinical benefits of the procedure.     

Intramyocardial and intracoronary basic fibroblast growth factor in porcine hibernating myocardium: a comparative study

OBJECTIVE: Therapeutic angiogenesis is an alternative method of revascularization for end-stage coronary artery disease. We determined the effects of intramyocardial and intracoronary basic fibroblast growth factor 2 on myocardial blood flow and function in a porcine model of hibernating myocardium. METHODS: Twenty-four mini-swine with 90% left circumflex artery stenosis and documented hibernating myocardium by positron emission tomography and dobutamine stress echocardiography were randomized to intramyocardial basic fibroblast growth factor 2 at 0.6 microg/kg (mid-dose, n = 6, 30 injections/animal), 6 microg/kg (high-dose, n = 6, 30 injections/animal), or intramyocardial vehicle control (n = 6). The intracoronary group received 6 microg/kg basic fibroblast growth factor 2 (n = 6) into the right and left circumflex artery coronary arteries. Positron emission tomography and dobutamine stress echocardiography were repeated at 1 and 3 months. RESULTS: In the vehicle group, normalized left circumflex artery myocardial blood flow was 0.74 +/- 0.04 at 1 month and 0.75 +/- 0.07 at 3 months compared with 0.68 +/- 0.03 at baseline. In the intracoronary group, myocardial blood flow was 0.71 +/- 0.03 at 1 month and 0.72 +/- 0.04 at 3 months compared with 0.67 +/- 0.04 at baseline. In the mid group, myocardial blood flow was 0.73 +/- 0.06 at 1 month and 0.85 +/- 0.05 at 3 months (P <.001) compared with 0.67 +/- 0.04 at baseline. In the high group, myocardial blood flow was 0.81 +/- 0.06 at 1 month and 0.83 +/-.04 at 3 months (P =.03) compared with 0.71 +/- 0.02 at baseline. No significant improvements in ischemia were demonstrated in any of the groups by dobutamine stress echocardiography at 1 or 3 months. CONCLUSIONS: In porcine hibernating myocardium, intramyocardial basic fibroblast growth factor 2 significantly improved regional myocardial blood flow 3 months after treatment. There was no significant change in function in any of the 4 groups. These data suggest that intramyocardial dosing of basic fibroblast growth factor 2 (0.6 microg/kg) may be an optimal dose for improving perfusion in the treatment of end-stage coronary artery disease.     

Induction of angiogenesis after TMR: a comparison of holmium: YAG, CO2, and excimer lasers

BACKGROUND: Transmyocardial laser revascularization (TMR) is an emerging treatment for end-stage coronary artery disease. A variety of lasers are currently available to perform the procedure, although their relative efficacy is unknown. The purpose of this study was to compare changes in myocardial blood flow and function 6 months after TMR with holmium:yttrium-aluminum-garnet (holmium:YAG), carbon dioxide (CO2), and xenon chloride excimer lasers in a model of chronic ischemia. METHODS: Miniswine underwent subtotal (90%) left circumflex coronary stenosis. Baseline positron emission tomography and dobutamine stress echocardiography were performed to document hibernating myocardium in the left circumflex coronary artery distribution. Animals were then randomized to sham redo-thoracotomy (n = 5) or TMR using a holmium:YAG (n = 5), CO2 (n = 5) or excimer (n = 5) laser. Six months postoperatively, the positron emission tomography and dobutamine stress echocardiography studies were repeated and the animals sacrificed. RESULTS: In animals undergoing TMR with holmium: YAG and CO2 lasers, a significant improvement in myocardial blood flow to the lased left circumflex regions was seen. No significant change in myocardial blood flow was seen in sham- or excimer-lased animals. There was a significant improvement in regional stress function of the lased segments 6 months postoperatively in animals undergoing holmium:YAG and CO2 laser TMR that was consistent with a reduction in ischemia. There was no change in wall motion in sham- or excimer-lased animals. Significantly greater neovascularization was observed in the holmium:YAG and CO2 lased regions than with either the sham procedure or excimer TMR. CONCLUSIONS: Transmyocardial laser revascularization with either holmium:YAG or CO2 laser improves myocardial blood flow and contractile reserve in lased regions 6 months postoperatively. These changes were not seen following excimer TMR or sham thoracotomy, suggesting that differences in laser energy or wavelength or both may be important in the induction of angiogenesis.     

Basic fibroblast growth factor is upregulated in hibernating myocardium

BACKGROUND: Ischemia is known to be a potent stimulus for the upregulation of angiogenic growth factors, such as basic fibroblast growth factor (bFGF). While previous investigations have shown that many angiogenic growth factors are upregulated in animal models of myocardial ischemia, the models used are limited in their ability to produce stable ischemia beyond a few weeks. Our laboratory uses a stable model of hibernating myocardium where later time points may be examined. Therefore, the goal of this study was to examine bFGF protein levels in the myocardium at baseline and 3 or 6 months following the onset of myocardial ischemia. METHODS: A total of 18 miniswine were studied. Basal endogenous levels of bFGF were measured in control animals (n = 6) immediately following sacrifice, while 12 other pigs underwent a 90% left circumflex artery occlusion with documented hibernating myocardium by positron emission tomography ((13)N-ammonia) and dobutamine stress echocardiography. These animals were studied at 3 (n = 7) and 6 months (n = 5) postoperatively. At sacrifice, six 3 x 3 mm samples were harvested from the left circumflex (hibernating) myocardium. Basic FGF levels (picograms per microgram of protein) were determined using ELISA kits. RESULTS: Basic FGF protein levels 3 months after the creation of hibernating myocardium were three times greater than in nonischemic control animals (P < 0.05), while levels at 6 months were increased sixfold compared to control animals (P < 0.05 versus both control and 3-month groups). CONCLUSIONS: Endogenous bFGF production is upregulated at 3 and 6 months in hibernating porcine myocardium. The angiogenic effects of exogenous bFGF delivered into ischemic myocardium with varying levels of endogenous growth factors must be determined.     

Neovascularization after transmyocardial laser revascularization in a model of chronic ischemia

Background. The mechanism of clinical improvement after transmyocardial laser revascularization (TMR) is unknown. One hypothesis holds that TMR causes increased myocardial perfusion through neovascularization. This study sought to determine whether angiogenesis occurs after TMR in a porcine model of chronic myocardial ischemia.

Methods. Six miniature pigs underwent subtotal left circumflex coronary artery occlusion to reduce resting blood flow to 10% of baseline. After 2 weeks in the low-flow state, dobutamine stress echocardiography and positron emission tomography were performed to document ischemic, viable myocardium. The animals then underwent TMR and were sacrificed 6 months later for histologic and immunohistochemical analysis.

Results. Histologic analysis of the lased left circumflex region demonstrated many hypocellular areas filled with connective tissue representing remnant TMR channels. Histochemical staining demonstrated a highly disorganized pattern of neovascularization consistent with angiogenesis located predominantly at the periphery of the channels. Immunohistochemical analysis confirmed the presence of endothelial cells within neovessels. Vascular density analysis revealed a mean of 29.2 ± 3.6 neovessels per high-power field in lased ischemic myocardium versus 4.0 ± 0.3 (p < 0.001) in nonlased ischemic myocardium.

Conclusions. This study provides evidence that neovascularization is present long term in regions of ischemic, viable myocardium after TMR. Angiogenesis may represent the mechanism of clinical improvement after TMR.     

Cost-effectiveness of preoperative positron emission tomography in ischemic heart disease

BACKGROUND: Revascularization of patients with ischemic heart disease and poor left ventricular function for surgical procedures is expensive and carries considerable risks, but may improve survival for patients with hibernating myocardium. Positron emission tomography can detect hibernating myocardium, and may be cost-effective if used to select patients for operation. METHODS: An economic model was developed to compare the cost-effectiveness of three management strategies: (1) coronary artery bypass grafting for all patients; (2) using positron emission tomography to select candidates for coronary artery bypass grafting, those without hibernation remaining on medical therapy; and (3) medical therapy for all patients. The model used data from our hospital and the published literature. A sensitivity analysis was also undertaken. RESULTS: Positron emission tomography was cost-effective in selecting patients for operation. In a hypothetical population of 1,000 patients, using positron emission tomography saved marginally more life-years and cost approximately Pound Sterling 3 million less. Using positron emission tomography before coronary artery bypass grafting instead of all patients receiving medical treatment saved lives but was more expensive. The incremental cost per life-year saved was Pound Sterling 77,000. The sensitivity analysis showed that the prevalence of hibernation and the survival rate of patients refused revascularization on the basis of the positron emission tomography scan were the areas most likely to influence cost-effectiveness. CONCLUSIONS: Positron emission tomography may be cost-effective to select patients with poor left ventricular function for coronary artery bypass grafting.     

Is chronically dysfunctional yet viable myocardium distal to a severe coronary stenosis hypoperfused?

BACKGROUND: Controversy exists regarding the perfusion status of chronically dysfunctional yet viable myocardium. Studies investigating the pathophysiology of this condition have reached different conclusions, with some suggesting that myocardial blood flow (MBF) in these regions is normal at rest with regional dysfunction resulting from repetitive stress-induced ischemia (stunned myocardium), whereas others have proposed that MBF is chronically reduced at rest (hibernating myocardium). However, adequately powered experimental studies investigating this question in an appropriate animal model using clinically available techniques have not been performed. Based on the mixed results of prior studies, we hypothesized that these chronically dysfunctional yet viable regions may actually represent a mixture of hibernation and stunning. Consequently, the purpose of this study was to quantitatively determine the distribution of MBF in left ventricular regions with chronically impaired resting function but preserved viability in a large population of animals with single-vessel coronary stenosis in an attempt to further elucidate the mechanism(s) responsible for chronic, reversible myocardial dysfunction. METHODS: Fifty-two adult mini-swine with 90% proximal left circumflex (LCx) stenosis underwent dynamic positron emission tomography (PET) with 13N-ammonia and 18F-fluorodeoxyglucose and dobutamine stress echocardiography (DSE) (5 to 40 microg/kg/min) 1 month after stenosis creation. Values of MBF and FDG uptake by PET and wall motion score index (WMSI) by DSE were compared using a standard 16-segment model. RESULTS: Of 312 possible LCx segments seen on PET, 303 (97.1%) were visualized by DSE. Of the 303 LCx segments, 279 (92.1%) had rest dysfunction (WMSI > or = 2) by DSE. One hundred eighty-two segments (60.1%) had decreased (< 85% reference) MBF at rest with preserved to increased (> 60% reference) FDG uptake and were classified as hibernating. Ninety-two segments (30.4%) had preserved MBF (> or = 85% reference) and were classified as stunned. Five segments (1.7%) with reduced (< or = 60% reference) FDG uptake by PET and akinesis or dyskinesis at rest (WMSI > or = 3) and no contractile reserve were considered infarcted. Hibernating segments had significantly higher FDG uptake at rest (360.7+/-48.3 vs 212.3+/-17.7% septal values; p < 0.001) than stunned segments consistent with greater resting ischemia. Likewise, mean rest WMSI was also worse in hibernating versus stunned segments (2.35+/-0.04 vs 2.13+/-0.04; p < 0.001). There was no difference in the percentage of hibernating versus stunned segments exhibiting contractile reserve during dobutamine infusion (55.5 vs 63.7%; p = 0.4), indicating similar degrees of viability. CONCLUSIONS: Myocardial hibernation and stunning appear to frequently coexist in regions served by a stenotic coronary vessel. Hibernating regions appear to have greater resting ischemia based on higher values of FDG uptake and greater resting dysfunction. Reversible left ventricular dysfunction in the setting of chronic coronary artery disease is likely due to a combination of these two mechanisms.     

Evaluation of Regional Myocardial Nutrient Perfusion Following Selective Retrograde Arterialization of the Coronary Vein

The effects of selective coronary vein occlusion (SCVO) and selective retrograde arterialization of the coronary vein (SRACV) on nutritional myocardial blood flow was evaluated in 10 dogs with radioactive microspheres. SRACV was performed with a shunt interposed between the aorta and the great cardiac vein (GCV). Following ligation of the GCV, measurements were performed before and after ligation of the middle portion of the left anterior descending coronary artery (LAD) and then after 15 and 30 minutes of SRACV. The myocardium was divided into three regions: circumflex coronary artery (served as control), high LAD (proximal to arterial occlusion; supplied by both SRACV and coronary flow), and low LAD (distal to arterial occlusion; supplied by SRACV alone).SCVO decreased mean myocardial blood flow with increased distribution to the endocardium. SRACV to normally perfused myocardium did not significantly change myocardial blood flow; however, SRACV to acutely ischemic myocardium restored less than 50% of the decrease in myocardial blood flow. SRACV does not appear to greatly enhance blood flow to ischemic areas of the myocardium and may significantly reduce flow on the basis of venous occlusion alone.     

Influence of desflurane on regional distribution of coronary blood flow in a chronically instrumented canine model of multivessel coronary artery obstruction

The influence of desflurane on myocardial perfusion measured by a microsphere technique during a total occlusion of the left anterior descending coronary artery and concomitant moderate or severe stenosis of the left circumflex coronary artery was evaluated in chronically instrumented dogs. Hemodynamics, regional contractile function, and myocardial blood flow were measured during the conscious state and after anesthesia with desflurane (8.2%-9.2% and 12.5%-12.7%) with and without control of arterial pressure. Total left anterior descending occlusion produced in combination with a left circumflex coronary artery stenosis significantly (P less than 0.05) increased heart rate and left ventricular end diastolic pressure in the absence of desflurane anesthesia. Desflurane, administered only in the presence of left anterior descending occlusion and left circumflex stenosis, significantly (P less than 0.05) decreased mean arterial pressure, left ventricular systolic pressure, and left ventricular positive dP/dt50 without change in heart rate. Blood flow to the subendocardium of normal myocardium was reduced during the high concentration of desflurane (P less than 0.05), but perfusion of the subepicardium and midmyocardium was maintained at conscious levels. When the left circumflex stenosis was of moderate severity, only blood flow to the subendocardium distal to the stenosis was reduced by desflurane (P less than 0.05). In the presence of a severe stenosis, perfusion was decreased in the subepicardium, midmyocardium, and subendocardium of the stenotic zone (P less than 0.05). During the reduction in arterial pressure produced by desflurane, collateral blood flow in the left anterior descending region was reduced in dogs with either a moderate or severe left circumflex stenosis (P less than 0.05). When arterial pressure and heart rate conditions observed in the postocclusion conscious state were restored during the high concentration of desflurane, myocardial blood flow in all regions returned to those levels present in the conscious state (P less than 0.05). Ratios of flow between occluded and normal zones were decreased when hypotension produced by desflurane was uncontrolled, but when arterial pressure and heart rate were adjusted to conscious postocclusion levels using partial thoracic aorta occlusion and atrial pacing, the ratio remained at conscious control levels regardless of the degree of left circumflex stenosis severity (P less than 0.05). Results of this investigation indicate that desflurane does not redistribute blood flow away from collateral-dependent myocardium to other regions via a "coronary steal" mechanism in a chronically instrumented canine model of multivessel coronary artery disease.     

How to discriminate between hibernating and stunned myocardium

AIM: The aim of the present study was to examine if it is possible to discriminate between hibernating and stunned myocardium in vivo by determining the ratio between diastolic and systolic coronary arterial inflow and by measuring oxygen saturation in draining coronary venous blood. METHODS: Experiments were performed in 32 open chest pigs anesthetized with sodium pentobarbital. In 11 pigs hibernation was induced in a part of the left ventricular myocardium by reducing flow in the mid-left anterior descending coronary artery (LAD) to about 60% of baseline flow. In 12 pigs stunning was induced by occluding mid-LAD twice for 10 min with a 30 min interval. In 9 pigs (control group) coronary flow was not manipulated. RESULTS: We found, at comparable degrees of regional dysfunction, that the ratio between diastolic and systolic flow in stunned myocardium remained unaltered, but fell from about 2 to 1 in hibernating myocardium. Furthermore, coronary venous oxygen saturation decreased from about 30% to 17% in blood draining hibernating myocardium, but remained statistically unaltered in blood draining stunned myocardium. CONCLUSION: We conclude that it is possible to discriminate between hibernating and stunned myocardium by measuring phasic coronary arterial blood flow and oxygen saturation in blood draining the region in question. During hibernation only, the diastolic flow component of coronary arterial inflow is reduced and the coronary venous oxygen extraction increased.     

A hibernating kidney - ischemic preconditioning in a renal transplant recipient with a proximal stenosis of the iliac artery

Ischemic preconditioning has been first described by Murry and coworkers as the protection conferred to ischemic myocardium by preceding brief periods of sublethal ischemia separated by periods of reperfusion. Another phenomenon closely associated to IPC is hibernation and stunning. The hibernating myocardium refers to resting left ventricular dysfunction due to reduced coronary blood flow that can be partially or completely reversed by myocardial revascularization and/or by reducing myocardial oxygen demand. Similarly as for the myocardium, these effects are reproducible for other solid organs. Here we report a case of a renal transplant recipient with decompensated proximal transplant artery stenosis due to ACE inhibition resulting in acute renal failure. The transplant perfusion was strictly dependent on systemic arterial blood pressure leading to intermittent episodes of renal ischemia and reperfusion. Renal function was severely decreased (glomerular filtration rate approximately 8 ml/min) with the need of hemodialysis treatment over a period of 4 weeks after transplantation. After dilatation of the stenosis, the patient's renal function improved rapidly and achieved values better than ever before. Referring to the definition of hibernating myocardium, here we postulate a case of a hibernating kidney in context of ischemic preconditioning.     

Is there a long-term predictive value of intraoperative low-dose dobutamine echocardiography in patients who have coronary artery bypass graft surgery with cardiopulmonary bypass?

In patients with coronary artery disease, chronic regional left ventricular systolic dysfunction at rest may be caused by hibernating or by infarcted myocardium. Intraoperative low-dose dobutamine (LDD) echocardiography reliably predicts the immediate recovery of regional myocardial function after coronary artery bypass graft (CABG) surgery. We sought to determine whether intraoperative LDD echocardiography would also predict recovery of regional function after 1 yr. Twenty-five patients with coronary artery disease who underwent CABG surgery with intraoperative LDD echocardiography were evaluated 1 yr later with a follow-up transthoracic echocardiogram. The covariates of left ventricular ejection fraction, old myocardial infarction, and diabetes mellitus were considered in an analysis of regional wall motion (RWM). A 16-segment model and a 1-5-point scoring system were used to evaluate 350 myocardial segments. Multiple logistic regression analysis was performed to determine whether response to intraoperative LDD echocardiography (5 microg. kg(-1). min(-1)) predicted changes in regional function at 1 yr. A segment was defined as stunned if the RWM score obtained during LDD infusion deteriorated after cardiopulmonary bypass but recovered in the 1-yr follow-up echocardiogram. A response to intraoperative LDD predicted changes in regional function at 1 yr. The overall odds of improvement in regional function were 2.22 times greater (95% confidence interval = 1.29, 3.82; P = 0.0039) with a positive response to intraoperative LDD. The positive predictive value of intraoperative LDD echocardiography for improvement in myocardial function was 0.81 and the negative predictive value was 0.34. The predictive values did not vary with the examined covariates. Of segments with unexpected deterioration of RWM immediately after cardiopulmonary bypass, 87% recovered at the time of the 1-yr follow-up echocardiogram. Contractile reserve demonstrated by intraoperative LDD echocardiography predicts regional function at 1 yr; however, the test cannot predict which segment will not recover. Most of unexpected regional ventricular systolic dysfunction immediately after CABG surgery can be attributed to myocardial stunning. IMPLICATIONS: In patients undergoing coronary artery bypass graft surgery, intraoperative low-dose dobutamine echocardiography has only limited value for the prediction of regional myocardial function at 1 yr. Small-dose dobutamine echocardiography predicts regional myocardial function at 1 yr when baseline regional wall motion abnormalities improve with dobutamine; however, the test cannot be used to predict which segment will not recover at 1 yr.     

Retrograde coronary capillary perfusion for prevention and reversal of cardiogenic shock in experimental myocardial infarction.

The coronary sinus and coronary veins offer an access route for delivery of increased oxygen to ischemic myocardium surrounding the central dead zone of heart muscle in cardiogenic shock due to myocardial infarction. This investigation was conducted to determine if transvenous retrograde coronary capillary perfusion with oxygenated blood would prevent and reverse cardiogenic shock in experimental myocardial infarction produced by acute ligation of the circumflex and anterior descending left coronary artery in dogs. Cardiac output and systemic blood pressure were maintained near control values for up to 30 minutes when total left coronary ligation was accompanied by coronary retroperfusion. Conversely, both cariac output and systemic blood pressure fell to severe cardiogenic shocks levels within 2 minutes of total left cardiogenic shock levels within 2 minutes of total left coronary artery occlusion without retrograde flow or when retrograde flow was terminated 5 to 30 minutes following simultaneous coronary ligation and institution of retrograde flow.     

Difference in the effect of halothane on regional oxygen demand-supply relationship depending on the severity of coronary artery stenosis

We examined the effect of halothane on myocardial oxygen balance and hemodynamics in three groups of canine heart. We measured regional subendocardial oxygen tension before and after 30 minute inhalation of 0.8% and 1.5% halothane in the mixture of nitrogen and oxygen (FIO2 not equal to 0.5). In moderate and severe stenosis group, left circumflex coronary artery flow was reduced to 66% and 31% respectively, at buprenorphine-anesthetized basal condition. In occlusion group, left circumflex coronary artery was ligated at its origin. Both concentrations of halothane decreased heart rate, aortic pressure and LV dp/dt max in all groups. Subendocardial oxygen tension increased in moderate stenosis group. But it was unchanged in severe stenosis group, and it rather decreased in occlusion group with 1.5% halothane inhalation. Halothane might improve endocardial oxygen demand-supply relation in the myocardium with mild to moderate coronary stenosis, while it will possibly deteriorate endocardial oxygen demand-supply balance in ischemic myocardium after coronary artery occlusion.     

Alterations in collateral blood flow produced by isoflurane in a chronically instrumented canine model of multivessel coronary artery disease

The actions of isoflurane and adenosine on left ventricular myocardial perfusion during a total occlusion of the left anterior descending coronary artery and concomitant stenosis of the left circumflex coronary artery were investigated in dogs chronically instrumented for measurement of systemic and coronary hemodynamics, regional myocardial contractile function (via ultrasonic sonomicrometers), and myocardial blood flow (via the radioactive microsphere technique). An Ameroid constrictor was implanted on the left circumflex coronary artery to produce a slowly progressive stenosis that gradually depleted the coronary reserve of the distal vascular bed. The reductions in reserve were evaluated by daily measurement of baseline left circumflex coronary blood flow velocity and the hyperemic response to injection of adenosine. At a stage of moderate or severe left circumflex stenosis development, the left anterior descending coronary artery was totally occluded via a hydraulic occluder to simulate multivessel coronary artery disease, and control measurements of hemodynamics, regional contractile function, and myocardial blood flow were completed. In separate groups of experiments, either adenosine (0.64 and 1.28 mg/min) or isoflurane (1.6-1.8 and 2.3-2.5%, end-tidal) was administered and measurements remade during steady state hemodynamic conditions. Finally, diastolic aortic pressure and heart rate were adjusted to levels present in the control state during administration of adenosine or isoflurane, and additional measurements were recorded. Isoflurane reduced mean arterial pressure, left ventricular systolic pressure, and the rate of increase of left ventricular pressure at 50 mmHg (positive dP/dt50) without change in heart rate. Administration of isoflurane decreased blood flow in normal, stenotic, and occluded regions; however, when arterial pressure and heart rate were restored to levels present in the conscious state, myocardial perfusion in all regions was maintained at control levels. Ratios of flow between occluded and normal or stenotic zones remained unchanged from the conscious state during a constant aortic pressure and heart rate. Similar results were obtained in dogs with either a moderate or severe left circumflex coronary artery stenosis. In contrast, adenosine produced a dose-related decrease in collateral flow and occluded-to-normal or occluded-to-stenotic zone flow ratio. The results of this investigation indicate that adenosine but not isoflurane redistributes blood flow away from collateral-dependent myocardium to other regions in a chronically instrumented canine model of multivessel coronary artery disease.(ABSTRACT TRUNCATED AT 400 WORDS)     

Direct CO2 laser "revascularization" of the myocardium

Evidence of regional myocardial perfusion and contractile function after direct CO2 laser myocardial revascularization (DLR) is lacking. We examined myocardial segment shortening, adenine nucleotide concentrations, and regional blood flow after DLR of the left anterior descending coronary artery (LAD) distribution before and after its proximal ligation in seven anesthetized conditioned dogs. Sonomicrometry assessed myocardial fiber shortening and radioactive microspheres were used to estimate baseline regional blood flows. Cardiopulmonary bypass was followed by cardioplegia arrest. Laser channels (1 mm diameter) were made every 3 to 5 mm in the LAD region with an 80 watt Laser-sonics CO2 unit. Bypass was terminated, the LAD occluded, and parameters reassessed. Core samples of myocardium from the lased LAD and control circumflex area were taken to assess adenine nucleotides. After occlusion, LAD distribution blood flow and myocardial shortening were reduced to pre-lasting ischemic controls. Adenine nucleotides were reduced in the LAD region relative to the control CMX area. DLR cannot be relied upon to acutely revascularize the ischemic myocardium.     

Metabolism of hibernating myocardium assessed by microdialysis during surgical revascularization: report of a case

We present an 80-year-old woman with hibernating myocardium in the left anterior descending coronary artery (LAD) territory who underwent surgical revascularization and metabolic evaluation of the dysfunctioning segments by microdialysis (microD) technique. Myocardial lactate, pyruvate, and glucose did not show obvious changes throughout the procedure. Conversely, myocardial glycerol and glutamate concentrations markedly increased early after cardioplegic arrest and subsided after weaning from cardiopulmonary bypass (CPB) and recovery of myocardial function. Intraoperative myocardial microD may add relevant pathophysiologic information on hibernating myocardium undergoing coronary flow restoration and, eventually, improve patient care.     

Regional myocardial function in the presence of coronary artery stenosis and inotropic intervention: a case for myocardial hibernation?

The aim of this study was to examine the effect of an inotropic intervention on regional myocardial function in the presence of a significant stenosis in a coronary artery. During 0.5% halothane anesthesia, intravenous dobutamine (2.5 and 5 micrograms.kg-1.min-1) was administered to eight pigs. A critical constriction was applied to the left anterior descending (LAD) coronary artery and regional myocardial function was determined with the end-systolic pressure-length relationship in the area of distribution of the LAD and left circumflex coronary artery. Infusion of dobutamine was associated with an increase in the end-systolic pressure-length relationship in the left circumflex coronary artery region from 31.81 +/- 7.87 to 81.03 +/- 21.43 mm Hg.mm-1 (X +/- SEM, P = 0.005), whereas function in the LAD coronary artery region did not change significantly (21.78 +/- 3.97 to 21.97 +/- 6.91 mm Hg.mm-1, P = 0.124). Regional stroke work in the left circumflex coronary artery distribution area increased from 124.38 +/- 24.04 to 222.00 +/- 37.83 mm Hg.mm during the administration of 5 micrograms.kg-1.min-1 dobutamine (P = 0.0125). In the LAD coronary artery area, regional stroke work remained at baseline values. Once the constriction was released, the end-systolic pressure-length relationship in the LAD artery segment increased from 21.97 +/- 2.45 to 35.36 +/- 4.55 mm Hg.mm-1 (P = 0.121). These results suggest that hibernation develops in the myocardial segment supplied by a stenotic coronary artery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor

OBJECTIVE: We investigated the efficacy of directly injecting a plasmid with complementary DNA encoding human hepatocyte growth factor into ischemic canine myocardium to induce angiogenesis. METHODS: Four weeks after ligation of the left anterior descending coronary artery, 125 microg of a complementary DNA plasmid encoding the gene for either hepatocyte growth factor (n = 8) or LacZ (transfection control group, n = 8) was injected directly into the myocardium at the border between the normal tissue and the infarction. Eight other dogs were used as a sham control group. Regional thickening fraction, which indicated contractile function, and blood flow in the normal (circumflex branch territory) and ischemic areas were evaluated under dobutamine administration just before and 4 weeks after transfection. The animals were killed, and capillary numbers in both areas were assessed. These data in the ischemic area were evaluated as the percentage of those in the normal. RESULTS: The number of myocardial capillaries in the ischemic area was successfully increased to approximately 140% of usual in the hepatocyte growth factor group, whereas no change was observed in the other groups (P =.0017 by analysis of variance). Furthermore, regional thickening fraction and blood flow in the ischemic area, which had deteriorated after coronary ligation, showed significant improvement in the hepatocyte growth factor group relative to the other groups (thickening fraction P <.0001 by analysis of variance, blood flow P =.0005 by analysis of variance). CONCLUSIONS: These results support the efficacy of the direct injection of plasmid complementary DNA encoding human hepatocyte growth factor to induce therapeutic angiogenesis in the ischemic myocardium.     

Autologous peripheral stem cell transplantation in patients with congestive heart failure due to ischemic heart disease.

OBJECTIVE: Ischemic heart disease accounts for 50% of all cardiovascular deaths and is the leading cause of congestive heart failure. Medical therapy, cardiac assist devices and surgical procedures including heart transplantation have limited efficiency and availability. Stem cell transplantation represents a new therapeutic opportunity for such patients. METHOD: Six patients with the diagnosis of ischemic cardiomyopathy were included in this study. All of the patients had clinical, radiological and echocardiographic signs of heart failure, and reduced left ventricular ejection fraction (LVEF< or =25%). They underwent coronary angiography and stress tests with dobutamine echocardiography, thallium scintigraphy and positron emission tomography to assess myocardial ischemia and viability. Peripheral stem cells were mobilized and collected by apheresis. They were transplanted into areas of injury with open-heart surgery. To increase blood flow to the engrafted areas, coronary artery by-pass surgery was also performed. RESULTS: The patients were followed at least for 4 months. Echocardiography, thallium scintigraphy and positron emission tomography were repeated after at least 6 weeks following surgery. There was a significant increase in life quality and NYHA class. Some benefit was documented on echocardiography, thallium scintigraphy, and positron emission tomography. CONCLUSION: This approach opens a new window in the treatment of 'no hope' patients with congestive heart failure.