Markus Schwaiger

Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model

Positron emission tomography allows noninvasive assessment of myocardial blood flow and metabolism, and may aid in defining the extent and severity of an ischemic injury. This hypothesis was tested by studying, in chronically instrumented dogs, regional blood flow and metabolism during and after a 3 hour balloon occlusion of the left anterior descending coronary artery. The metabolic findings after ischemia were compared with the recovery of regional function over a 4 week period. N-13 ammonia was used as a blood flow tracer, and C-11 palmitic acid and F-18 deoxyglucose as tracers of fatty acid and glucose metabolism, respectively. Regional myocardial function was monitored with ultrasonic crystals implanted subendocardially. Regional function improved most between 24 hours and 1 week after reperfusion, but was still attenuated at 4 weeks. The slow functional recovery was paralleled by sustained metabolic abnormalities, reflected by segmentally delayed clearance of C-11 activity from myocardium and increased uptake of F-18 deoxyglucose. Absence of blood flow and C-11 palmitic acid uptake at 24 hours of reperfusion correlated with extensive necrosis as evidenced by histologic examination. Conversely, uptake of C-11 palmitic acid with delayed C-11 clearance and increased F-18 deoxyglucose accumulation identified reversibly injured tissue that subsequently recovered functionally and revealed little necrosis. Thus, recovery of metabolism after 3 hours of ischemia is slow in canine myocardium and paralleled by slow recovery of function. Metabolic indexes by positron tomography early after reperfusion can identify necrotic and reversibly injured tissue. Positron tomography may therefore aid in defining the extent and prognosis of an ischemic injury in patients undergoing reperfusion during evolving myocardial infarction.

Afterload reduction with vasodilators and diuretics decreases mitral regurgitation during upright exercise in advanced heart failure

In advanced heart failure, mitral regurgitation increases the burden of the failing ventricle and decreases effective stroke volume. Although tailored afterload reduction decreases mitral regurgitation at rest, it is not known if this benefit is maintained during upright exercise. Simultaneous radionuclide ventriculography and thermodilution stroke volumes were compared to measure the forward ejection fraction in 10 patients during upright bicycle exercise before and after therapy with vasodilators and diuretics tailored to decrease pulmonary capillary wedge pressure and systemic vascular resistance. Ventricular volumes, total ejection fraction and the forward ejection fraction did not change during exercise at baseline. At rest, tailored therapy decreased average pulmonary capillary wedge pressure from 36 to 19 mm Hg (p less than 0.01), systemic vascular resistance from 1,570 to 1,210 dynes.s.cm-5 (p less than 0.05), and left ventricular volume index from 251 to 177 ml/m2 (p less than 0.01), while increasing the forward ejection fraction from 0.53 to 0.85 (p less than 0.01) without change in total ejection fraction (0.18 from 0.17). During steady state exercise at low work load, tailored therapy decreased left ventricular volume index from 279 to 213 (p less than 0.05) and increased forward ejection fraction from 0.52 to 0.79 (p less than 0.01) without change in total ejection fraction (0.20 from 0.19). The total stroke volume during exercise was not increased after therapy; the increase in forward stroke volume after therapy appeared to result instead from the decrease in mitral regurgitant flow. The benefits of tailored afterload reduction are maintained throughout upright exercise.

Regional myocardial blood flow and metabolism at rest in mildly symptomatic patients with hypertrophic cardiomyopathy

Previous observations and clinical manifestations suggest the presence of ischemia in the disproportionately thickened septum of patients with hypertrophic cardiomyopathy. Metabolic consequences of ischemia can be demonstrated with positron emission tomography. Therefore, 10 patients with hypertrophic cardiomyopathy and an echocardiographic septum to posterior wall thickness ratio of 1.8 +/- 0.4 cm (range 1.3 to 2.5) were studied with the use of nitrogen (N)-13 ammonia, carbon (C)-11 palmitate and fluoro (F)-18 2-deoxyglucose as tracers of myocardial blood flow, fatty acid metabolism and exogenous glucose utilization. The results of positron emission tomography in 9 patients with hypertrophic cardiomyopathy were compared with those in 10 normal volunteers. In the hypertrophic cardiomyopathy group, observed myocardial activity of N-13 ammonia and C-11 palmitate in the septum was similar to that in the lateral wall. Septum to lateral wall tissue activity ratios averaged 1.04 +/- 0.15 for N-13 ammonia and 1.04 +/- 0.18 for C-11 palmitate, and were similar to those in the normal volunteers (0.98 +/- 0.07 and 0.98 +/- 0.03, respectively; p = NS). Myocardial clearance half-time and residual fraction of C-11 palmitate did not differ significantly between the septum and lateral wall. However, F-18 2-deoxyglucose uptake was significantly lower in the septum than in the lateral wall (15,768 +/- 4,314 versus 19,818 +/- 5,234 counts/pixel; p less than 0.003). The mean septum to lateral wall activity ratio of 0.83 +/- 0.21 was less than that observed in normal volunteers (0.92 +/- 0.07; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Retention and clearance of C-11 palmitic acid in ischemic and reperfused canine myocardium

Free fatty acids are the major energy source for cardiac muscle. Oxidation of fatty acid decreases or even ceases during ischemia. Its recovery after transient ischemia remains largely unexplored. Using intracoronary carbon-11 palmitic acid as a tracer of myocardial fatty acid metabolism in an open chest dog model, retention and clearance of tracer in myocardium were evaluated at control, during ischemia and after reperfusion following a 20 minute occlusion of the left anterior descending coronary artery. Myocardial C-11 time-activity curves were analyzed with biexponential curve-fitting routines yielding fractional distribution and clearance half-times of C-11 palmitic acid in myocardial tissue. In animals with permanent occlusion and intracoronary injection of C-11 palmitic acid distal to the occlusion site, the relative size and half-time of the early clearance curve component differed markedly from control values and did not change with ongoing ischemia. Conversely, in animals with only 20 minutes of coronary occlusion, the relative size of the early C-11 clearance phase was still significantly depressed at 20 and 90 minutes of reperfusion but returned to control level at 180 minutes. Tissue C-11 clearance half-times remained significantly prolonged throughout the reperfusion period. Regional function in reperfused myocardium monitored with ultrasonic crystals recovered slowly and was still less than control after 3 hours of reperfusion. The data indicate that after transient ischemia, myocardial fatty acid metabolism fails to recover immediately. Because the metabolic recovery occurs in parallel with recovery of regional function, C-11 palmitic acid in conjunction with positron tomography may be useful for studying regional fatty acid metabolism noninvasively after an ischemic injury, and may be helpful in identifying reversible tissue injury.

Detection of coronary artery disease with positron emission tomography and rubidium 82

Myocardial blood flow was evaluated in 31 subjects with not only visual but also, for the first time, circumferential profile analysis of rubidium 82 (82Rb) images acquired with positron emission tomography. Fifteen were control subjects and 16 subjects had significant coronary artery disease, defined as 50% or greater diameter stenosis in a major coronary artery or a first-order branch. Simultaneous 82Rb images at three myocardial levels were obtained before and after intravenous dipyridamole plus handgrip stress. In patients with significant coronary artery disease, visual analysis correctly identified significant disease in 26 (76%) of 34 arteries and its absence in 12 (86%) of 14 normal arteries. According to circumferential profile analysis, these numbers were 91% and 86%, respectively. Thus circumferential analysis of 82Rb images, obtained before and after intravenous dipyridamole plus handgrip stress, yielded improved sensitivity and comparable specificity compared with visual analysis.

Studies of fatty acid metabolism with positron emission tomography in patients with cardiomyopathy.

Positron emission tomography (PET) permits in vivo as well as noninvasive study of fatty acid metabolism. Parameters of 11C-palmitate kinetics relate to the oxidation of fatty acids, and palmitic acid uptake is impaired in patients with coronary disease and cardiomyopathy. Normal myocardium shows homogenous fatty acid·metabolism and can resort to alternate substrates. Diseased myocardium exhibits regional heterogeneity in fatty acid uptake and utilization. In patients with cardiomyopathy, distinct patterns of fatty acid metabolism can be observed following changes of substrate availability by application of an oral glucose load. This intervention also enhances the heterogeneity of 11C-palmitic acid (CPA) uptake and clearance. Thus, PET studies with CPA permit the noninvasive demonstration of effects on substrate availability and may help to characterize patients with ventricular dysfunction on the biochemical level.

Relationship between TI-201, Tc-99m (Sn) pyrophosphate and F-18 2-deoxyglucose uptake in ischemically injured dog myocardium

We have previously demonstrated that enhanced glucose utilization in reperfused myocardium as assessed by F-18 2-deoxyglucose (FDG) and positron tomography predicts functional recovery. In this study, we compared segmental uptake of F-18 FDG with that of Tl-201 and Tc-99m (Sn) pyrophosphate (Tc-99m PPi) as conventional markers of tissue viability in seven dogs after a 3-hour intracoronary balloon occlusion and 20 hours of reperfusion. Myocardial blood flow was determined with microspheres. Regional retention fractions were calculated from tracer tissue concentrations, the arterial input function, and blood flow. Ischemic injury was assessed by triphenyltetrazolium chloride (TTC) staining and histologic analysis. At 24 hours, blood flow was 22% lower in reperfused than in control myocardium (p less than 0.05). Uptake of Tl-201 was related linearly to blood flow (r = 0.92), while glucose utilization and Tc-99m PPi were 2.9 (p less than 0.01) and 4.7 (p less than 0.05) times higher in reperfused than in control myocardium. Retention fractions of Tc-99m PPi increased with the degree of ischemic injury, while F-18 FDG uptake was highest in segments with mild cell injury. Thus, in ischemically injured myocardium, Tl-201 primarily reflects blood flow. F-18 FDG as a marker of glucose utilization identifies ischemically injured but viable tissue. The admixture of necrotic cells can be determined with Tc-99m PPi. Our results indicate that a dual tracer approach might best characterize the presence and extent of reversibly and of irreversibly injured tissue in a given myocardial region.

Assessment of mitral flow velocity with exercise by an index of stress-induced left ventricular ischemia in coronary artery disease.

Exercise-induced myocardial ischemia results in both diastolic and systolic left ventricular (LV) dysfunction. To investigate the utility of Doppler assessment of LV diastolic function with exercise, 28 consecutive patients underwent digital stress echocardiography, including measurement of mitral flow velocity by pulsed-wave Doppler and simultaneous stress thallium imaging. The mean mitral flow velocity was measured as the integrated area under the LV diastolic inflow Doppler spectral display. The change in mean mitral flow velocity from baseline to immediate postexercise was compared among 3 patient groups: (1) patients with thallium redistribution or exercise-induced wall-motion abnormalities, or both, consistent with exercise-induced ischemia (n = 18), (2) patients with no evidence of stress-induced ischemia, with or without resting wall-motion abnormalities (n = 10), and (3) 10 control subjects of similar age with normal resting 12-lead electrocardiograms, normal resting and postexercise 2-dimensional echocardiograms and normal electrocardiographic treadmill stress testing. The percent increase in mean mitral flow velocity was 101% (+/- 59) for controls and 86% (+/- 53) for patients without stress-induced ischemia versus 33% (+/- 24) in patients with stress-induced ischemia (p less than 0.005). An increase in mean mitral flow velocity with exercise of greater than 50% correctly identified 9 of 10 nonischemic control patients. An increase in mean velocity of less than 50% predicted ischemia in 15 of 18 patients with evidence of stress-induced ischemia (p less than 0.005) Thus, Doppler assessment of LV diastolic function with exercise expressed as a change in the mean velocity of mitral flow is a useful indicator of stress-induced ischemia.

Sex, smoking and striatal dopamine

Angiogenesis, the formation of new blood vessels, is one of the hallmarks of cancer and a key process in the growth of solid tumors (1). Therefore, this process could be targeted for the molecular imaging of malignancies and for the treatment of tumors through the inhibition of key processes in the formation of new blood vessels. The imaging of angiogenesis has become increasingly important with the increasing use of targeted antiangiogenic agents, such as bevacizumab (Avastin; Genentech). The latter was shown to have therapeutic efficiency when used in combination with chemotherapy for

Limitations of quantitative phase analysis of radionuclide angiograms for detecting coronary artery disease in patients with impaired left ventricular function

Phase analysis of radionuclide ventriculograms is used for identifying ischemic wall motion abnormalities. Myocardial segments with an abnormal phase, that is, delayed onset of wall motion, can be localized on a phase distribution image, and the synchronicity of left ventricular (LV) wall motion can be assessed from a histogram of LV phase distribution. The standard deviation of the LV peak on this histogram (SDP-LV) describes the width of the peak and is used as an index of the synchronicity of wall motion. We examined in this study the sensitivity of SDP-LV for identifying coronary artery disease (CAD) and its specificity in patients with normal and various degrees of LV impairment. A total of 84 patients were studied. Forty-five patients had CAD and 39 had congestive cardiomyopathy or valvular heart disease. Patients were grouped according to their LV ejection fraction (EF). In group I (37 patients) resting LVEF was equal to or greater than 50%, in group II (24 patients) it ranged from 35% to 50%, and in group III (23 patients) it was less than 25%. SDP-LV was highly specific in groups I and II for CAD with sensitivities of 48% and 89% at rest that increased with exercise to 88% and 100%. In group III patients, SDP-LV remained highly sensitive but was no longer specific for CAD. Therefore, in severe LV impairment, phase analysis does not aid in distinguishing CAD from other causes of ventricular dysfunction. By contrast, phase analysis is highly sensitive and specific for CAD in patients with normal or moderately depressed LV function.