Intravenous adenosine suppresses cardiac release of endothelin after myocardial ischaemia and reperfusion.

OBJECTIVE: Intravenous adenosine decreases infarct size in experimental models of myocardial ischaemia/reperfusion. Ischaemia/reperfusion is associated with a significant increase in cardiac release of endothelin. The effect of cardioprotective doses of adenosine on endothelin release was explored in dogs undergoing 90 min coronary occlusion and 210 min reperfusion. METHODS: Dogs were assigned to intravenous adenosine in a dose of 0.15 mg.kg-1.min-1 (n = 12) or control (n = 11) during the first 150 min reperfusion. Serial endothelin levels were obtained from the coronary sinus and aortic blood and measured by radioimmunoassay. RESULTS: Adenosine significantly reduced infarct size expressed as a percent of the risk region (28.8 6% v 14.4 2%; p = 0.03). A similar increase in aortic and coronary sinus blood endothelin was observed in both groups during temporary occlusion. A significant transcardiac increase in endothelin levels was present in the control group 60 min after reperfusion whereas no increase occurred in the adenosine treated group [control 5.6(SEM 1.9) v adenosine -0.2(1.4) pg.ml-1; p = 0.02]. Similarly, intravenous adenosine tended to prevent the increase in myocardial endothelin production seen in control animals during the early reperfusion period [control 280(146) v adenosine -57(55) pg.min-1; p = 0.05]. Endocardial blood flow in the ischaemic zone 210 min after reperfusion was significantly higher in the adenosine group, at 0.60(0.02) v 0.38(0.02) ml.min-1.g-1; p < 0.05. A significant correlation between endothelin levels, endocardial flow and infarct size was observed in the control group 3 h after reperfusion: r = 0.73, p = 0.02; r = 0.62, p = 0.03 respectively. This relationship was absent in animals treated with adenosine. CONCLUSIONS: Intravenous adenosine suppresses the release of endothelin from the previously ischaemic myocardium during the early reperfusion period. This effect may in part contribute to the improvement by adenosine in postischaemic microcirculatory flow resulting in attenuation of the "no reflow" phenomenon.

Staging recurrent metastatic colorectal carcinoma with PET.

UNLABELLED: Accurate detection of recurrent colorectal carcinoma remains a diagnostic challenge. The purposes of this study were to assess the accuracy of 18FDG-PET in patients with recurrent colorectal carcinoma in detecting liver metastases compared with computed tomography (CT) and CT portography, detecting extrahepatic metastases compared with CT and evaluating the impact on patient management. METHODS: Fifty-two patients previously treated for colorectal carcinoma presented on 61 occasions with suspected recurrence and underwent 18FDG-PET of the entire body. PET, CT and CT portography images were analyzed visually. The final diagnosis was obtained by pathology (n = 44) or clinical and radiological follow-up (n = 17). The impact on management was reviewed retrospectively. RESULTS: A total of 166 suspicious lesions were identified. Of the 127 intrahepatic lesions, 104 were malignant, and of the 39 extrahepatic lesions, 34 were malignant. Fluorine-18-fluorodeoxyglucose imaging was more accurate (92%) than CT and CT portography (78% and 80%, respectively) in detecting liver metastases and more accurate than CT for extrahepatic metastases (92% and 71%, respectively). Fluorine-18-fluorodeoxyglucose detected unsuspected metastases in 17 patients and altered surgical management in 28% of patients. CONCLUSION: These data identify that 18FDG-PET is the most accurate noninvasive method for staging patients with recurrent metastatic colorectal carcinoma and plays an important role in management decisions in this setting.

Losartan improves diastolic ventricular filling of hypertensive patients with diastolic dysfunction.

To evaluate the role of losartan on left ventricular (LV) function of hypertensive patients. Hypertensive patients (n = 19) underwent evaluation of systolic and diastolic LV function, using radionuclide ventriculography (RVG), before and at 3 mo into the treatment with the angiotensin II antagonist losartan. All patients underwent a baseline 12 lead ECG and an echocardiogram (ECHO), which was also repeated at 3 mo into treatment. Results are expressed as mean +/- SEM and statistics were performed using paired t-test. A p value < or = 0.05 was considered significant. Treatment with losartan for 3 mo had no effect on LV mass measured by echo (141+/-5 vs. 139+/-6 g/m2). The LV ejection fraction, measured by RVG, was unchanged by treatment when compared to the baseline study (58+/-2% vs. 57+/-2%, respectivelly, p = 0.49). Considering all patients involved in the study (n = 19), the LV "Peak Filling Rate" (PFR), a parameter of diastolic function measured by RVG, was also unchanged by treatment when compared to baseline (2.5+/-0.2 EDV/s vs. 2.5+/-0.3 EDV/s, respectively, p = 0.9). However the analysis of those patients with evidence of diastolic dysfunction (n = 12) on the baseline RVG (PFR < 2.5 EVD/s), demonstrated significant improvement of LV filling after therapy with losartan (PFR = 1.8+/-0.1 EDV/s vs. 2.3 +/-0.2 EDV/s, respectively, p = 0.05). This change was associated with improvement of symptoms. Our results demonstrated that hypertensive patients with diastolic dysfunction on radionuclide ventriculography have significant improvement of ventricular filling at 3 mo into treatment with losartan.

Positron emission tomography to stage suspected metastatic colorectal carcinoma to the liver.

BACKGROUND: Accurate detection of recurrent colorectal carcinoma remains a clinical challenge. Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18FDG) is an imaging technique that allows direct evaluation of cellular metabolism. 18F-fluorodeoxyglucose PET was compared to computed tomography (CT) and CT portography for staging metastatic colorectal carcinoma. PATIENTS AND METHODS: Twenty-four patients previously treated for colorectal carcinoma who had suspected recurrence to the liver underwent an 18FDG PET scan of the entire body. All patients had either a CT scan of the abdomen (n = 17), a CT portogram (n = 18), or both (n = 11). The final diagnosis was obtained by tissue pathology in 19 patients and clinical follow-up in 5 patients. RESULTS: A total of 60 suspicious lesions were identified. Of the 55 intrahepatic lesions, 39 were malignant and 16 were benign. Of the 5 extra-hepatic lesions, 4 were malignant. The 18FDG PET imaging had a higher accuracy (93%) than CT and CT portography (both 76%) in detecting metastatic disease to the liver, and detected unsuspected extrahepatic recurrence in 4 patients. Although the sensitivity of 18FDG PET (90%) was slightly lower than that of CT portography (97%), the specificity was much higher (100% versus 9%), including postsurgical sites. 18FDG PET altered surgical plans in 6 (25%) of 24 patients. CONCLUSIONS: 18FDG PET is extremely useful in staging patients with suspected metastatic colorectal carcinoma to the liver.

Occult breast carcinoma presenting as an axillary mass.

Breast carcinoma presents rarely (<5% of cases) as an axillary mass without an obvious primary tumor. The value of mammography in detecting an occult breast carcinoma is low, with a sensitivity of 29 per cent and specificity of 73 per cent. MRI and positron emission tomography (PET) are potentially more sensitive in this setting. We present a case recently seen at the Vanderbilt University Hospital, a 63-year-old woman with a 2-cm painless mass in the right axilla. Mammography was negative, and fine needle aspiration revealed atypical cells suspicious for malignancy. An excisional biopsy of the right axillary lymph node revealed metastatic adenocarcinoma, most likely breast primary. A PET showed increased uptake of 18-fluorodeoxyglucose and 99m Technetium in the right axilla and the right lateral breast. The patient underwent right modified radical mastectomy. The final pathological report revealed a 0.9-cm primary tumor in the upper inner quadrant of the breast and 1 of 41 nodes positive for tumor. This case confirms that mammography has low sensitivity in identifying the primary tumor in occult breast carcinoma and illustrates the usefulness of PET in identifying the primary tumor. We advocate an aggressive approach to evaluation of the breast in women presenting with metastatic adenocarcinoma in the axillary nodes. This evaluation should include clinical examination and mammography in all cases, and PET and MRI in selected cases. PET and MRI may be particularly useful when considering a breast-conserving surgical procedure.

Recurrent gallbladder carcinoma at laparoscopy port sites diagnosed by positron emission tomography: implications for primary and radical second operations.

Inapparent gallbladder carcinoma discovered by histologic examination following 1 per cent of cholecystectomies generates a difficult clinical problem. There is evidence that radical resection can prolong survival, especially for locally advanced (> or = PT2, according to the Union International Centre Cancer pathologic T classification) lesions. Case reports of recurrence at port sites after laparoscopic cholecystectomy add another aspect to the management difficulty. A 64-year-old woman underwent laparoscopic cholecystectomy for biliary colic. Histologic evaluation revealed an incidental adenocarcinoma, stage pT3. Radical resection with curative intent occurred 11 days later, including mesohepatectomy, skeletonization resection of the common bile duct with en bloc lymph node dissection, and bilateral Roux-en-Y hepaticojejunostomies. There was no tumor identified in the re-excision specimen (T3N0M0). At 7-month follow-up, the patient presented with nodules in the right subcostal area and in the periumbilical incision. Positron emission tomography demonstrated carcinoma at both sites. Biopsy confirmed metastatic gallbladder carcinoma. This case emphasizes the significance of tumor seeding at port sites during laparoscopy. An open technique is indicated if carcinoma is suspected. To avoid dissemination of unsuspected carcinoma during routine laparoscopic procedures, isolation techniques must be applied. The benefit of radical resection was clearly thwarted in this case, and resection of port sites at the time of reoperation is warranted. Finally, positron emission tomography scan is useful in delineating the recurrence of gallbladder carcinoma and its extent.

Positron emission tomography with F-18-fluorodeoxyglucose to evaluate the results of hepatic chemoembolization.

BACKGROUND: Positron emission tomography (PET) using F-18-flurodeoxyglucose (18FDG) is an imaging modality allowing direct evaluation of cellular glucose metabolism. The purpose of this study was to examine the role of 18FDG-PET in monitoring chemoembolization therapy of patients with liver metastases from adenocarcinoma. METHODS: Thirty-four hepatic lesions in 4 patients were evaluated with 18FDG-PET before and 2-3 months after interventional therapy. All patients underwent transcatheter arterial chemoembolization. A total of nine PET studies were performed. Semiquantitative measurement of the metabolic activity of the lesions was performed using the standard uptake value (SUV) of 18FDG. Comparison was performed between sequential PET scans using Student's t test for paired data analysis. The PET findings were also compared with tumor marker levels measured at the time of the PET scans. RESULTS: Twenty-five of 34 lesions had decreased 18FDG uptake (SUV = 8 +/- 2 vs. 3 +/- 1; P < 0.00001), as expected in successful tumor chemoembolization. These findings were associated with a significant decrease in serum tumor marker levels (86 +/- 4%; P < 0.05) after treatment. However, there were 3 new lesions, and 6 of the 34 lesions demonstrated persistent or increased 18FDG uptake after treatment (SUV = 8 +/- 2 vs. 13 +/- 3; P < 0.05), consistent with the presence of residual viable tumor. These findings led to further interventional therapy in all patients. CONCLUSIONS: 18FDG-PET allows monitoring of response to treatment with hepatic chemoembolization in patients with liver metastases from adenocarcinoma. PET is a useful diagnostic tool and has the potential to be used to guide further interventional therapy.

Sustained reduction in myocardial reperfusion injury with an adenosine receptor antagonist: possible role of the neutrophil chemoattractant response.

Recent studies have demonstrated that three membrane-permeant A(1) receptor antagonists reduced infarct size in a model of ischemia followed by brief reperfusion. However, it was not determined whether cardioprotection was mediated by nonspecific intracellular effects of these highly lipophilic drugs and whether the antagonists only delayed myocardial necrosis without affecting the ultimate infarct size. In the present study, closed-chest dogs were subjected to 90 min of left anterior descending coronary artery occlusion and 72 h of reperfusion and received either a nonmembrane-permeant adenosine receptor blocker that is devoid of direct intracellular effects and is 6-fold selective for the A(1) receptor [1, 3-dipropyl-8-p-sulfophenylxanthine (DPSPX); n = 11] or vehicle (n = 12). DPSPX was administered as three 200-mg boluses 60 min before and 30 and 120 min after reperfusion. The area of necrosis was determined histologically and expressed as a percentage of the area at risk. Baseline predictors of infarct size were similar in the two groups. The ratio of the area of necrosis to the area at risk was less in the DPSPX group (17.8 +/- 4.3% versus 35.0 +/- 1.9%; P =. 012), and DPSPX improved regional ventricular function. Under both basal and stimulated (formyl-Met-Leu-Phe) conditions, suspensions of human neutrophils generated extracellular adenosine levels (approximately 50 nM) sufficient to activate A(1) receptors. Moreover, both DPSPX and 1,3-dipropyl-8-cyclopentylxanthine, a selective A(1) receptor antagonist, significantly reduced the chemoattractant response of neutrophils to formyl-Met-Leu-Phe. We conclude that blockade of A(1) adenosine receptors attenuates myocardial ischemic/reperfusion injury, possibly in part by decreasing the chemoattractant response of neutrophils.

Reduction of myocardial infarct size in rabbits and inhibition of activation of rabbit and human neutrophils by lidocaine.

Myocardial reperfusion is associated with increased influx of activated neutrophils and intracellular accumulation of sodium in the ischemic zone. Lidocaine is a sodium channel blocker that also inhibits several neutrophil functions. We investigated the effect of lidocaine on infarct size in rabbits undergoing 30 minutes of ischemia and 48 hours of reperfusion. Animals randomly received lidocaine (10 mg/kg, n = 11) or saline (n = 11) during occlusion. The area of necrosis (AN) was measured histologically and expressed as a percentage of the area at risk (AR). Myocardial oxygen consumption and the perfusion bed at risk were similar in the two groups. Lidocaine reduced infarct size compared with control (AN/AR = 30% +/- 4% vs 61% +/- 5%, respectively; p = 0.0001). This reduction was associated with a significant decrease in neutrophil infiltration and in the degree of hemorrhage in the reperfused myocardium. Lidocaine also significantly inhibited superoxide anion production by rabbit and human neutrophils in whole blood. Therefore, lidocaine treatment results in a significant reduction in infarct size in the rabbit model, partly through reduction of neutrophil-mediated injury to viable cells, suggesting that lidocaine may be useful to enhance myocardial salvage in patients undergoing pharmacologic or mechanical reperfusion.

Role of endothelin in a rabbit model of acute myocardial infarction: effects of receptor antagonists.

The role of endothelin (ET) in acute myocardial infarction and proarrhythmic potential was investigated in a rabbit model. One group of rabbits underwent 30 min of circumflex occlusion and 3 h of reperfusion with measurements of myocardial blood flow and myocardial levels of ET-1 messenger RNA (mRNA). In a second group, the systemic and coronary effects of exogenous ET were studied in animals pretreated with either saline, FR139317, an ETA-receptor antagonist, or PD145065, an ETA-and ETB-receptor antagonist. In a third study, animals undergoing 30 min of circumflex occlusion followed by 48 h of reperfusion were treated with exogenous ET-1, FR139317, PD145065, or saline. Arrhythmias were recorded and infarct size measured at 48 h. These studies revealed that ischemia and reperfusion was followed by a progressive microcirculatory failure ("no-reflow phenomenon") in rabbits. This was associated with a 2.6-fold elevation in levels of myocardial ET-1 mRNA in the ischemic zone in comparison to the nonischemic zone (p = 0.04). Exogenous ET-1 caused elevation in coronary and systemic vascular resistance that was significantly blocked by antagonism of the ETA receptor. In rabbits subjected to myocardial ischemia and reperfusion, ET-1 infusion led to a higher incidence of ventricular arrhythmias, whereas ET-receptor antagonism with PD145065 significantly reduced ventricular arrhythmias. Exogenous ET-1 and FR139317 failed to alter infarct size (AN) of the area at risk (AR) compared with control [AN/AR(%) was 46 +/- 8, 55 +/- 9, and 47 +/- 7, respectively]. However, PD145065 significantly decreased AN/AR (22 +/- 7; p < or = 0.02). The increased production of ET-1, resulting from increased levels of mRNA after reperfusion, may contribute to the no-reflow phenomenon. Although the vasoconstrictor effects of ET-1 can be blocked by ETA-receptor antagonism alone, only blockade of both the ETA and ETB receptors significantly reduced infarct size. These data suggest that production of ET increases in the heart during ischemia and is deleterious to the reperfused myocardium.

Exercise supplementation to dipyridamole prevents hypotension, improves electrocardiogram sensitivity, and increases heart-to-liver activity ratio on Tc-99m sestamibi imaging.

BACKGROUND: Myocardial perfusion imaging with dipyridamole is an alternative with which to evaluate patients who are unable to exercise. Many patients who undergo dipyridamole testing are limited in their ability, but are not completely unable, to exercise. There are benefits from adding low workload exercise to dipyridamole testing, including a reduction of thallium 201 concentration in the liver, leading to a higher heart-to-liver activity ratio and better image quality. This prospective study was designed to evaluate a protocol of exercise supplementation during dipyridamole technetium 99m sestamibi imaging and to verify whether a higher heart-to-liver activity ratio could be obtained. We also evaluated the potential of this combined protocol to prevent hypotension and induce ischemic changes on the electrocardiogram (ECG). METHODS AND RESULTS: Ninety consecutive patients who were not completely disabled for exercise underwent dipyridamole Tc-99m sestamibi cardiac single photon emission computed tomography with a protocol of exercise supplementation (DipEx). The heart-to-liver activity ratio, hemodynamics, and electrocardiographic changes were studied. The findings were compared with those of a control group (Dip) composed of 99 patients who underwent dipyridamole infusion alone. Patients with left bundle branch block, pacemaker, and atrial fibrillation were excluded. The DipEx patients tolerated the protocol, exercising 4.2 +/- 1.3 minutes on the treadmill (Bruce protocol). Compared with Dip, patients in the DipEx group had a higher heart-to-liver activity ratio (1.3 +/- 0.4 vs 1.6 +/- 0.5, respectively; P =.00001), had no incidence of hypotension (6% vs 0%, respectively; P =.03), and had a higher sensitivity of the ECG to detect ischemia (6% vs 34%, respectively; P =.003). The increase in sensitivity seen in the DipEx group was accompanied by a significant decrease in specificity compared with the Dip group (67% vs 100%, P =.000001). CONCLUSIONS: Our data show that the addition of limited exercise to dipyridamole results in benefits during Tc-99m sestamibi imaging, increasing heart-to-liver activity ratio, preventing vasodilator-induced hypotension, and improving ECG sensitivity for the detection of ischemia. Furthermore, this protocol also provides an estimation of the patient's physical capacity and could be used as an alternative for patients undergoing dipyridamole infusion who are not completely unable to exercise.