Spatial heterogeneity in tumor perfusion measured with functional computed tomography at 0.05 microliter resolution.

High speed (200 ms temporal resolution) functional computed tomography was used to demonstrate tumor vascular heterogeneity with 0.05 microliter spatial resolution. Vascular topologies were investigated in 2 human small cell lung cancer lines implanted either s.c. or as a tissue isolated preparation in immunocompromised mice. Peripheral versus central vascular topology was identified in the s.c. and tissue-isolated preparations, respectively. Pharmacokinetic analysis demonstrated that tumor physiology was influenced by cell line (P = 0.016) and not by location (P > 0.6). This new technique has the potential to characterize individual tumors in patients with minimal invasiveness, permitting more detailed prognosis and management.

Changes in QTc interval induced with Renografin-76 and Hypaque-76 during coronary arteriography.

Renografin-76 and Hypaque-76 are both recommended for coronary arteriography. Both have the same osmolality and iodine concentration, but differ in their calcium binding properties. After selective right or left coronary arteriography in patients, Renografin-76 caused significantly more prolongation of the QTc interval than did Hypaque-76. Less calcium binding in the Hypaque formulation is probably responsible for its lesser effect on the QTc interval. This study suggests, but does not prove, that Hypaque-76 is safer than Renografin-76 for coronary arteriography.

Hemodynamic changes induced by cardiac angiography with ioxaglate: comparison with diatrizoate.

The hemodynamic and electrocardiographic changes induced by left ventriculography and coronary arteriography with ioxaglate (a new low osmolality angiographic contrast agent) were characterized and compared with the changes induced by a commercial formulation of the commonly used angiographic contrast agent, diatrizoate (Renografin-76). Left ventriculography and coronary arteriography were performed in 25 patients utilizing ioxaglate and in another 25 patients utilizing diatrizoate. Both agents increased left ventricular end-diastolic pressure and decreased arteriovenous oxygen difference after left ventriculography, but the magnitude of the increase caused by ioxaglate was significantly less than that caused by diatrizoate (changes in left ventricular end-diastolic pressure was 5.3 +/- 1.3 mm Hg with ioxaglate and 9.5 +/- 1.5 mm Hg with diatrizoate [p less than 0.02] ). Change in arteriovenous oxygen difference was -0.33 +/- 0.19 ml/100 ml with ioxaglate and -0.85 +/- 0.13 ml/100 ml with diatrizoate (p less than 0.05). Both agents were well tolerated when used for coronary arteriography with no adverse events occurring in either group. Ioxaglate is a well tolerated cardiac angiographic contrast agent that produces less hemodynamic disturbance than diatrizoate. Accordingly, it may be particularly well suited to use in patients with impaired left ventricular function.

Changes in vascularization of human breast cancer xenografts responding to antiestrogen therapy.

To elucidate the previously suggested vascular effect(s) of antiestrogen therapy, we studied the effect of estrogen withdrawal and tamoxifen on 1) vascular resistance, 2) glucose and oxygen consumption, and 3) vascular density in a perfused breast cancer line (ZR75-1). Furthermore, we examined ZR75-1 tumors by functional CT-scanning (fCT) to determine changes in parameters related to tumor capillary transfer constants and vascular volume fraction in response to antiestrogenic manipulations. The vascular resistance decreased significantly from 42.7 to 20.8 mmHg x min x g x ml(-1) (P< .03) on day 9 after estrogen withdrawal, but not after 9 days of tamoxifen treatment. The estrogen-depleted tumors were significantly smaller than controls on day 9. There was no difference in nutrient consumption or vascular density in any of the experimental groups compared to controls. fCT showed an increase (P < .03) in vascular volume fraction during tumor growth, and this parameter was significantly lower after estrogen withdrawal when compared to controls (P < .05). Vascular resistance correlated with tumor size (R = 0.7, P < .0001), indicating that vascular resistance increases during tumor growth. The changes in vascular parameters after estrogen withdrawal indicate a vascular remodeling effect. This inhibition of vascular development by hormone deprivation may have important implications for future planning of multimodal treatment regimens.

Temporal correlation analysis of penumbral dynamics in focal cerebral ischemia.

A novel temporal correlation technique was used to map the first-pass transit of iodinated contrast agents through the brain. Transit profiles after bolus injections were measured with dynamic computed tomography (CT) scanning (1 image/s over 50 s). A rabbit model of focal cerebral ischemia (n = 6) was used, and dynamic CT scans were performed at 30, 60, 90, and 120 min postocclusion. Within the ischemic core, no bolus transit was detectable, demonstrating that complete ischemia was present after arterial occlusion. In the periphery of the ischemic distribution, transit dynamics showed smaller peaks, broadened profiles, and overall delay in bolus transit. A cross-correlation method was used to generate maps of delays in ischemic transit profiles compared with normal transit profiles from the contralateral hemisphere. These maps showed that penumbral regions surrounding the ischemic core had significantly delayed bolus transit profiles. Enlargement of the ischemic core over time (from 30 to 120 min postocclusion) was primarily accomplished by the progressive deterioration of the penumbral regions. These results suggest that (a) temporal correlation methods can define regions of abnormal perfusion in focal cerebral ischemia, (b) peripheral regions of focal cerebral ischemia are characterized by delays in bolus transit profiles, and (c) these regions of bolus transit delay deteriorate over time and thus represent a hemodynamic penumbra.

MRI measurements of water diffusion and cerebral perfusion: their relationship in a rat model of focal cerebral ischemia.

The aim of this study was to examine the quantitative relationship between changes in apparent diffusion coefficient (ADC) and transverse relaxivity (delta R2*) measurements of relative perfusion deficits within the gradients of a focal ischemic insult. Sixty minutes after permanent occlusion of the middle cerebral artery, rats (n = 7) were subjected to spin echo diffusion-weighted scans followed by fast low-angle shot (FLASH) perfusion-sensitive scans. Diffusion-weighted images showed clear ischemic lesions in the affected basal ganglia and cortex. Ischemic deficits were demonstrated as a decrease in first-pass transit of injected boluses of gadodiamide. ADC maps were generated and regions of interest (ROIs) were obtained to span the range of ADC reductions from the lesion center or core to the periphery or penumbra. Corresponding ROIs from the bolus injection images were used to calculate perfusion indexes relative to contralateral levels as ratios of delta R2* integrals and ratios of delta R2* peak values. In all animals, the degree of ADC reductions was related to the degree of delta R2* perfusion deficits, ranging from severe ischemia in the core of the lesion to intermediate and moderate changes toward the lesion periphery. In the ischemic periphery, ADC reductions were linearly correlated with delta R2* peak ratios. However, no significant correlation was found between ADC reductions and delta R2* integral ratios. These data suggest that magnetic resonance measurements of ADC and delta R2* peak ratios can be used to quantitatively assess the variable gradients in focal ischemia, including potentiallyn critical areas at risk in the ischemic periphery.

Brain imaging abnormalities in mental disorders of late life.

Psychiatric inpatients with dementia (N = 61) or depression (N = 67) in late life were 2.6 times more likely to manifest magnetic resonance imaging abnormalities of the brain than were elderly controls (N = 44). Controlling for the effects of age and gender, demented patients were distinguishable from controls by an increased prevalence of cortical atrophy and infarction, while depressed patients exhibited an increased prevalence of cortical infarctions and leukoencephalopathy. Patients with dementia were distinguishable from those with major depression by an increased prevalence of cortical atrophy. These results indicate that major depression in late life, like dementia, is associated with a remarkable increase in overt pathologic changes in the brain.

Role of magnetic resonance contrast agents in cardiac imaging.

Improvements in magnetic resonance imaging (MRI) technology allow adequate spatial and temporal resolution to capture cardiac anatomy and contractile function in exceptional detail and with little risk. However, tissue characterization of the pathophysiologic state of the myocardium may require special indicators or MR contrast agents. These must be tailored for detection by the MRI process, but available agents are effective at low dose and provide a wide range of indicator properties (e.g., myocardial extracellular space, blood pool, capillary permeability and membrane transport). Each agent has a dynamic washin and washout time-intensity curve that may reflect myocardial perfusion or consequences of ischemia. The combined use of MRI and MR contrast agents may provide a single diagnostic examination that fully and quantitatively assesses all indexes of cardiac performance. Such information would be both global and regional, and would be well tolerated by patients. The cost, value and cost-effectiveness of such studies remain speculative.

Magnetic resonance imaging and the future of cardiac imaging.

Within the last 5 years, technology for cardiac imaging has improved spectacularly. The choices now include ultrasound with Doppler, single-photon emission computed tomography and positron emission tomography, cine computed tomography, biplane and digital subtraction angiography and magnetic resonance imaging (MRI). MRI is the most expensive noninvasive option, but also provides the best information on chamber size, wall motion, valvular function and great vessel blood flow. It is multiplanar and multiparametric; thus, nearly any clinical problem except detailed coronary anatomy can be addressed, but the very plethora of technical details is daunting. With contrast agents as indicators, relative tissue perfusion of any organ appears achievable, including regional perfusion of the myocardial wall. As patient acceptance is high, MRI may become a major cardiac imaging tool and occupy the central position between office ultrasound and invasive angiography.

considerations on the incidence of pancreatic cancer.

Comprehensive histopathological evaluations of the pancrease in autopsy material revealed a remarkably high (10%) incidence of neoplastic pancreatic lesions. The fact that many malignant pancreatic lesions apparently remained clinically occult may be due to attribution of the death of patients to other malignancies. The differential diagnostic difficulties encountered in primary and secondary pancreatic cancer which are reported in the literature comprise additional factors that obviously mask real incidence figures of pancreatic cancer. The multiplicity of lesions found in this, and in previous studies, may be one reason for the extremely poor prognosis associated with this disease.

Biologic and instrumentation issues in MR contrast agent research.

The interaction between magnetic resonance (MR) detectors and MR contrast agents as "dyes" or indicators is important. Indicator-dilution methods can be adapted to dynamic studies with available contrast agents, but the change in MR intensity must quantitatively reflect change in MR contrast agent concentration. Although spatial and temporal resolution may conflict in determining the MRI parameters, examples show that imaging of physiologic function in vivo is feasible. Cost effectiveness also should be studied early.

A double-blind clinical comparison of the electrophysiologic adverse effects of Hexabrix and Renografin-76.

A clinical and an animal study were performed to examine adverse effects when ratio 3 and ratio 1.5 contrast media are injected directly into the heart. In a randomized double-blind clinical trial of 50 patients undergoing cardiac angiography, the safety and efficacy of Hexabrix (ratio 3) and Renografin-76 (ratio 1.5) were compared. Cardiac output increased more significantly in the Renografin-76 group, and there was a significant difference in AV 02 indicating less vasodilatation with Hexabrix. There was dramatically less prolongation in the QT interval for the Hexabrix group. Ventricular fibrillation threshold studies of dogs examined the adverse electrophysiologic effects on the heart. One-ml doses of Hexabrix and Renografin-76 were injected in the left coronary artery and compared. Renografin-76 significantly reduced threshold, whereas Hexabrix was much less toxic. Ratio 3 agents are less hazardous in terms of total adverse effects and are particularly indicated for certain risk groups.

Adult peripheral angiography. Results from four North American randomized clinical trials of ionic media vs. iohexol.

Four, randomized, double blind comparisons of iohexol versus ionic media for peripheral angiography are summarized. Iohexol is safe, effective, and significantly less painful than ionic media for this indication.

Cardiovascular radiology. The fibrillatory propensities of contrast agents.

Ventricular fibrillation threshold (VFT), the electrical stimulus strength required to fibrillate the heart during the vulnerable period of the cardiac cycle, has been used to evaluate the properties of many arrhythmogenic and antiarrhythmic drugs, and is easily adaptable to determining ventricular vulnerability following coronary arteriography. Using this method, the authors find that there is a large decrease in VFT within seconds following intracoronary arteriography with 1 ml of sodium meglumine diatrizoate. During the first minute, the threshold decreases by an additional 10%, then returns rapidly and completely to control levels. The change in threshold persists much longer than artery-to-sinus transit time, longer than changes in contractility, and somewhat longer than repolarization changes in the surface electrocardiogram. There is a strong dose relation. Injections through impacted catheters or slow injections cause disproportionate decreases in VFT. Ionic solutions of CaCl2 progressively lower VFT, but, when added to sodium meglumine iothalamate solutions, minimize the fibrillatory potential of ionic contrast agents in a complex way. A modified model of myocardial ischemia produced by intracoronary mercury injection is described. With myocardial ischemia, the fibrillation threshold falls, and during coronary arteriography still lower thresholds are seen. The use of VFT measurements is recommended for further evaluation of the fibrillatory potential of contrast media in clinically relevant situations.

The influence of short-duration stretch on vasoconstrictor response in rabbit aortas.

Circumferential strips of rabbit aorta were subjected to 60-second graded stretches in vitro. Before and after each stretch, the vasoconstrictor dose-responses to potassium and norepinephrine were measured. For stretch between 130 to 190% of resting length, vasoconstrictor response was progressively enhanced. However, arteries stretched 190 to 220% of resting length showed a significant fall in developed tension in response to either vasoconstrictor. Since arteries in vivo operate at 150 to 180% of resting length due to physiologic distention, it is likely that effective angioplasty does induce paralysis of vascular smooth muscle.

The tissue proton T1 and T2 response to gadolinium DTPA injection in rabbits. A potential renal contrast agent for NMR imaging.

Three different doses of gadolinium (Gd) DTPA were administered intravenously to rabbits. Cardiovascular responses and changes in blood T1 and T2 were serially followed for 15 minutes when the animals were sacrificed for in vitro measures of tissue T1 and T2. Gd-DTPA was distributed and excreted like water soluble iodinated contrast agents with large changes in blood, urine, and kidney proton relaxation. An imaging experiment confirmed the efficacy as an NMR contrast agent for renal excretion. At effective doses, no adverse effects were observed and the agent appeared to be much safer than x-ray contrast agents, but with a similar potential for clinical utility.

Angioplasty-induced vasospasm in rabbit model. Mechanisms and treatment.

Angioplasty of the distal iliac and proximal femoral arteries in rabbits resulted in focal and diffuse vasospasm similar to that seen in humans. The focal vasospasm occurred in all experiments immediately distal to the site of angioplasty. Occasional diffuse vasospasm was preceded by intravascular thrombosis or extravasation. Heparin reduced the incidence of diffuse vasospasm and reduced the severity of focal vasospasm. Verapamil and Dazoxiben reversed focal vasospasm, but only Verapamil in the presence of heparin prevented vasospasm. Prazocin had no effect on vasospasm.

New angiographic agents with less fibrillatory propensity.

Coronary angiography with Renografin-76 (meglumine sodium diatrizoate, Squibb) lowers the ventricular fibrillation threshold (VFT) significantly and in a dose-dependent manner. Recently new contrast materials have been synthesized for possible angiographic use. We compared the fibrillatory propensities of Hexabrix (meglumine sodium ioxaglate, Guerbet), a monacid dimer; Exypaque (Nyegaard; U.S. iohexol, Winthrop), a new nonionic agent; and Amipaque (metrizamide, Winthrop), an older nonionic agent, to Renografin-76 in anesthetized dogs. The VFT following subselective left circumflex artery injections of 370-mg I and 740-mg I doses of each agent was compared to the control (no injection) threshold in 115 paired experiments in 25 dogs. At the low dose, the VFT for Renografin was significantly lower (61.8 +/- 2.3% of control threshold) than that of Hexabrix or Exypaque (69.3 +/- 2.1%, respectively; P less than 0.05). At the higher dose, the differences were more pronounced among Renografin, Hexabrix, and Exypaque (32.4 +/- 1.4%, 65.7 +/- 2.6%, and 59.2 +/- 2.4%, respectively; P less than 0.001). No statistical difference was detected between the latter two agents at these doses in nonischemic dogs. Amipaque was also less fibrillatory than Renografin and equivalent to the other two agents. These newer agents appear to offer enhanced safety for use in angiographic studies in the heart.

Morphometric changes in normal arteries and those undergoing transluminal angioplasty.

To understand the morphometric effects of balloon catheter angioplasty in autopsy specimens, we studied the effect of histologic preparation on the size of control arterial specimens (N) and those having angioplasty at room temperature (CD) or body temperature (WD). Diameters of external and internal iliac arteries were measured with calipers, photography, and X-rays without any distention, after 200 mm Hg in a balloon catheter, after angioplasty to 4 atmospheres, and after fixation with a balloon catheter in place was inflated to 200 mm Hg. Arterial diameters were also taken from the tissue blocks and histologic slides. Images taken from the photos, X-rays, tissue blocks, and slides were digitized, and the diameter was calculated from circumference measurements. Diameters increased approximately 30% (P less than .001) when distended from the resting state to 200 mm Hg. There was a 7.4-8.2% decrease in diameter of arteries in blocks (P less than .01) and a further decrease of 9.8-11.9% from block to slide (P less than .005). Thus, significant size changes occur during arterial preparation. The postmortem artery shrinks without any distending pressure. Paraffin embedding and slide preparation are also associated with significant decreases in arterial size. These changes may influence the understanding of the pathophysiology of angioplasty and the estimation of stenoses by histopathology.

Changes in ventricular fibrillation threshold induced by contrast agents during acute coronary artery occlusion.

In the first few hours after acute coronary thrombosis, clinical coronary angiography is associated with enhanced risk of ventricular fibrillation. In these experiments, the ventricular fibrillation threshold (VFT) was measured in anesthetized dogs before and during acute occlusion of the left circumflex coronary artery. Ischemia alone reduced the fibrillation threshold. Angiography with 1- or 2-ml does of Renografin 76 lowered VFT significantly more than did equal doses of iohexol or iopamidol. It is concluded that nonionic agents may be safer for coronary angiography in the presence of acute coronary insufficiency.