To determine the effects of dobutamine stimulation on myocardium distal to a coronary stenosis, transmural spatially localized phosphorus 31 nuclear magnetic resonance measurements of myocardial high-energy phosphate compounds (adenosine triphosphate and phosphocreatine), inorganic phosphate, and blood flow and systolic wall thickening were made in 8 open-chested dogs. Data were collected under (1) control conditions, (2) after the application of a moderate coronary stenosis, (3) during infusion of dobutamine with continuing stenosis, and (4) after the release of the stenosis with continuing dobutamine. Stenosis was associated with concordant reductions of subendocardial blood flow, wall thickening, and high-energy phosphate, and mild elevation of inorganic phosphate; subepicardial measurements were essentially unchanged. During dobutamine infusion, blood flow increased in all myocardial layers. Wall thickening returned to control values in the subendocardium and increased nonsignificantly in the subepicardium. Additional loss of high-energy phosphate occured only in the subepicardium. The data suggest that improved contractile function associated with dobutamine infusion resulted from the inotropic effects of dobutamine and was made possible by the improved blood flow it produced. The data indicate that measurements of blood flow and contractile function do not reliably predict the transmural myocardial metabolic responses to inotropic perturbations in the hypoperfused heart. Taken together, the present findings yield insights with regard to the interpretation of diagnostic dobutamine stimulation testing with single photon emission tomography, radionuclide angiography, and echocardiography.

The response of myocardial high-energy and inorganic phosphates (HEP and Pi, respectively) and associated changes in myocardial blood flow, lactate uptake, and O2 consumption (MVo2) rates were examined in an open-chest canine model during progressively increasing workloads achieved by catecholamine infusion. HEP and Pi levels (measured with transmurally localized 31P-nuclear magnetic resonance spectroscopy) were unaffected by moderate increases in the level of energy expenditure but were significantly altered by high workloads, especially in the subepicardium. The MVo2 and HEP data from three different protocols that utilized pharmacological augmentation of blood flow demonstrated that the maximal rate of myocardial energy production during inotropic stimulation was dictated by perfusion limitation. This limitation was more severe in the subepicardial layer at the high workloads despite equivalent or even higher increases in blood flow to this layer, reflecting a preferential enhancement of demand in the outer layer by catecholamines. In contrast, under basal conditions, existence of a marginal perfusion limitation was evident in the inner but not in the outer layer.

With the advent of ultrafast Magnetic Resonance Imaging (MRI), it is now possible to produce images with high temporal resolution. This gives the opportunity to record the passage of the paramagnetic contrast material Gadolinium-DTPA through the tissue of the heart muscle, yielding information on regional myocardial perfusion. We assessed the accuracy of MRI to detect and quantify reductions in coronary flow secondary to stenosis in dogs and patients. Regional blood flow was measured in dogs by left atrial injection of microspheres labeled with different radioactive isotopes. Signal intensity (SI) curves were generated in regions of interest over the myocardium and the cavum of the left ventricle. A newly developed two-compartment model based on the indicator-dilution method was used for interpretation of the SI-curves. In an optimization process the free parameters of the model equation were fitted to the measured SI-curves. The following flow parameters were determined: model parameter Q*, time to peak intensity (T), maximum signal intensity (SImax) and mean transit time (MTT) as calculated from a gamma variate fit. Absolute blood flow values were calculated for the parameters MTT and Q* assuming that the intravascular volume represents 10% of the total myocardial tissue volume. Measurements were performed on a 1.5 T Magnetom SP (Siemens AG, Erlangen) using a Turbo Flash sequence (TR = 6.5 ms, TE = 3 ms, TI = 100 ms, Flip Winkel = 9 degrees). Endsystolic images (voxel size = 1.8, 2.7, 15 mm3) were taken with an 18-cm Helmholtz surface coil in the short-axis view. A Gd-DTPA bolus (0.05 mmol/kg) was injected into the left atrium of 3 anesthetized closed-chest dogs. From the myocardial SI-curves the different parameters of myocardial perfusion were compared with flow assessed by microsphere injection over a wide range of myocardial blood flows (from 0.04 ml/min/g to 7.6 ml/min/g). A third-order polynominal fit showed a good correlation for the parameter Q* and MTT, whereas T and SImax were found to have a poor correlation. The linear regression analysis for a limited range of 2 ml/min/g was significantly underestimated by the MRT-measurements, but the parameter Q* showed the smallest amount of the divergent changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Spatially localized nuclear magnetic resonance (NMR) spectroscopy was used to examine the effect of tachycardia and inotropic stimulation on myocardial ATP, creatine phosphate (CrP), and inorganic phosphate (Pi) in animals with left ventricular hypertrophy (LVH). Studies were performed in eight normal dogs and seven dogs with moderate LVH produced by banding the ascending aorta. 31P-NMR spectra were obtained from five layers across the LV wall, while blood flow (BF) was measured with microspheres during control conditions, pacing at 200 and 240 beats/min, and during dobutamine infusion (Dob). Myocardial ATP and CrP levels were normal in the LVH hearts during control conditions. Pacing did not alter the transmural distribution of perfusion or the levels of CrP, ATP, and Pi in normal hearts. In contrast, in four of seven LVH hearts, pacing decreased the subendocardial/subepicardial (ENDO/EPI) BF ratio and caused depletion of CrP and appearance of Pi characteristic of ischemia in the subendocardium. Dob produced greater increases in the heart rate x LV systolic pressure product (RPP) and greater increases of Pi and decreases of CrP in LVH than in normal hearts; however, at comparable elevations of RPP the alterations of Pi and CrP were similar in both groups. Although Dob decreased the ENDO/EPI in LVH hearts, Dob-induced alterations in CrP and Pi were uniform across the LV wall. Increasing myocardial BF with adenosine or carbochromen did not reverse the alterations in Pi or CrP produced by Dob. We conclude that 1) ENDO perfusion abnormalities during tachycardia in LVH do produce ENDO subendocardial ischemia; 2) when the degree of augmentation of mechanical performance is considered, the metabolic changes induced by Dob were similar in normal and LVH hearts; 3) Dob-induced alterations in Pi and CrP were not related to inadequate perfusion, since increasing coronary BF did not reverse these changes; and 4) alterations of Pi and CrP during Dob infusion were not more prominent in the ENDO, indicating that the decreased ENDO/EPI flow did not cause ENDO ischemia but may reflect relatively lower O2 demands in this region during inotropic stimulation.

With the advent of ultrafast Magnetic Resonance Imaging (MRI), it is now possible to produce images with high temporal resolution. This gives the opportunity to record the passage of the paramagnetic contrast material Gadolinium-DTPA through the tissue of the heart muscle, yielding information on regional myocardial perfusion. We assessed the accuracy of MRI to detect and quantify reductions in coronary flow secondary to stenosis in dogs and patients. Regional blood flow was measured in dogs by left atrial injection of microspheres labeled with different radioactive isotopes. Signal intensity (SI) curves were generated in regions of interest over the myocardium and the cavum of the left ventricle. A newly developed two-compartment model based on the indicator-dilution method was used for interpretation of the SI-curves. In an optimization process the free parameters of the model equation were fitted to the measured SI-curves. The following flow parameters were determined: model parameter Q*, time to peak intensity (T), maximum signal intensity (SImax) and mean transit time (MPT) as calculated from a gamma variate fit. Absolute blood flow values were calculated for the parameters MTT and Q* assuming that the intravascular volume represents 10 % of the total myocardial tissue volume. Measurements were performed on a 1.5 T Magnetom SP (Siemens AG, Erlangen) using a Turbo Flash sequence (TR = 6.5 ms, TE = 3 ms, TI = 100 ms, Flip Winkel = 9 degrees). Endsystolic images (voxel size = 1.8, 2.7, 15 mm(3)) were taken with an 18-cm Helmholtz surface coil in the short-axis view. A Gd-DTPA bolus (0.05 mmol/kg) was injected into the left atrium of 3 anesthetized closed-chest dogs. From the myocardial SI-curves the different parameters of myocardial perfusion were compared with flow assessed by microsphere injection over a wide range of myocardial blood flows (from 0.04 ml/min/g to 7.6 ml/min/g). A third-order polynominal fit showed a good correlation for the parameter Q* and MTT, whereas T and SImax were found to have a poor correlation. The linear regression analysis for a limited range of < 2 ml/min/g showed a superior estimation of myocardial perfusion for the parameter Q* than MTT. Blood flow > 2 ml/min/g was significantly underestimated by the MRT-measurements, but the parameter Q* showed the smallest amount of the divergent changes. In our study of 10 healthy human subjects and 10 patients the Gd-DTPA bolus was delivered through an intravenous catheter placed in the right subclavian vein. Patients with a significant proximal coronary artery stenosis identified by selective coronary angiography were found to have significantly lower blood flow values in regional myocardium with wall motion impairment compared to the non-diseased myocardium. It is concluded that ultrafast MRI can measure myocardial blood flow over a limited but clinically relevant range of flows as defined as slightly above normal to ischemic.

The sensitivity of contrast-enhanced MR first pass perfusion imaging in detection and quantification of hypoperfused myocardium was evaluated using an instrumented, closed-chest dog model where graded regional hypoperfusion was induced by applying predetermined levels of stenosis to the left anterior descending artery (LAD). All measurements were performed at rest and under stress induced by dipyridamole (DIP). Myocardial perfusion was assessed both with MR and radiolabeled microspheres injected immediately before the administration of the MR contrast agent. Ultrafast MR imaging was performed using a Turbo FLASH sequence with a 180 degrees inversion prepulse. A Gd-DTPA bolus was injected into the left atrium and T1-weighted images were acquired with every heart beat. Signal intensity measured from the images in regions of the LAD and left circumflex (LCx) perfusion beds was plotted against time to generate signal intensity versus time curves (SI time curve). Various flow indices were derived according to the indicator dilution theory, and compared with and without volume correction due to vasodilation to the myocardial blood flow (MBF) calculated from radiolabeled microspheres. Correlation of the MR and MBF data demonstrated that different transmural and regional myocardial perfusion levels can be easily visualized in the perfusion images and accurately monitored by the SI time curves. Detection of the impairment of myocardial perfusion improved significantly after administration of DIP. The inverse mean transit time calculated from the SI time curve was found to yield a linear correlation to absolute MBF derived from the microsphere data. These results suggest that with intracardiac injections of exogenous contrast agent, myocardial perfusion can be assessed parametrically with first pass contrast enhanced ultrafast MRI.

The response of the myocardium to prolonged or chronic ischemia may differ from the well documented changes that occur acutely subsequent to the onset of hypoperfusion. Therefore, we have examined in an instrumented canine model and using spatially localized spectroscopy to achieve transmural differentiation, the myocardial HEP and P(i) levels as well as wall thickening in situ during prolonged ischemia induced by sustained coronary artery stenosis. The results demonstrate that subtotal coronary artery occlusion causes immediate and transmurally inhomogeneous decreases in the myocardial HEP content and increase in the P(i)/CP ratio; however, during prolonged mild hypoperfusion, metabolic changes occur which lead to statistically significant recovery of CP (but not ATP) and disappearance of P(i) despite the persistence of reduced blood flow and oxygen supply. Upon release of the occlusion, the previously ischemic muscle recovered blood flow, and some (but not all) of its preischemic contractile function without parallel changes in the HEP levels. It is concluded that normal HEP and P(i) levels cannot be equated with either the absence of underperfusion or insensitivity of NMR spectroscopy to ischemia. Rather, it is imperative that both functional and spectroscopic measurements are performed simultaneously to distinguish between ischemic myocardium which is adapted versus unadapted to the hypoperfusion.

By administering gadolinium-diethylenetriamine-penta-acetic acid (Gd-DTPA) in conjunction with the Turbo-Flash sequence, the authors assessed the potential of dynamic contrast-enhanced ultrafast magnetic resonance imaging (MRI) to detect and quantify reductions in myocardial perfusion secondary to stenosis and hyperemia induced by Dipyridamole. In ten subjects and three dogs signal intensity-time curves were generated in regions of interest over myocardium. A one-compartment model was introduced to describe the kinetics of Gd-DTPA. The first results indicate that measurements of Gd-DPTA kinetics seem of potential value for the non-invasive assessment of myocardial perfusion

Spatially localized phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy has been applied to the study of the normal canine myocardium to measure the relative content of high energy phosphates across the left ventricular wall. Transmural NMR data were acquired in five voxels spanning the wall of the left ventricle using the FLAX-ISIS technique. The validity of the FLAX-ISIS approach in acquiring localized spectra for transmural studies and in providing quantitative information from the localized spectra was examined rigorously by studies involving phantoms, intact rats, and the canine myocardium in vivo. The results indicated that (1) this technique yields spatially resolved spectra with partial overlap between adjacent voxels and virtually no overlap between every other voxel; (2) in the canine heart, signals from subepicardium, midwall, and subendocardium can be detected separately without cross contamination; and (3) relative metabolite contents within a voxel and among voxels can be quantitated. Transmural 31P NMR spectra were acquired with cardiac gating on 29 separate animals either at early systole or late diastole, and at three different workloads with the heart rate peak systolic pressure product (RPP) increasing from 6000 mmHg/min to 35,000 mmHg/min. The data revealed that in the normal canine myocardium, the creatine phosphate (CP) content and the CP/ATP ratio was significantly lower in the subendocardium than in the subepicardium. ATP levels were transmurally constant. Both the CP content and the CP/ATP ratio measured for each voxel remained unaltered in relation to either the phase of the cardiac cycle or approximately fourfold increase in workload. Free ADP levels calculated for each voxel showed that ADP was relatively higher in the subendocardium than the subepicardium, and in all transmural layers was higher than its apparent Km for oxidative phosphorylation. In this domain changes in ADP content with workload and MVO2 are not expected and were not observed.

Spatially localized nuclear magnetic resonance spectroscopy was used to investigate with transmural differentiation the response of myocardial high energy phosphate compounds and inorganic orthophosphate (Pi) to graded reductions in coronary blood flow caused by sustained coronary stenosis. In an open-chest model, localized 31P nuclear magnetic resonance spectra from five layers across the left ventricular wall were obtained simultaneously with transmural blood flow measurements during control conditions and during sustained graded reductions in intracoronary pressure. Both the blood flow, and high energy phosphate and Pi contents displayed transmural heterogeneity in response to decreases in intracoronary pressure. The subendocardial creatine phosphate (CP) level remained unchanged as blood flow was reduced to approximately 0.7 ml/min/g wet wt and decreased precipitously beyond this critical flow level. The relation between CP and flow in the midmyocardium and especially in the subepicardium was more complex. Subepicardial CP content did not correlate well with blood flow; however, in cases in which a coronary stenosis resulted in subendocardial hypoperfusion but subepicardial flow was near or above normal, a close correlation was present between subepicardial and subendocardial CP levels. ATP levels in all layers remained unaltered until blood flow was severely reduced. These results demonstrate that 1) the myocardial high energy phosphate and Pi levels at any transmural layer are not generally determined by O2 and blood flow limitation under basal conditions; 2) during subtotal coronary occlusion, increased oxygen extraction is able to meet myocardial needs until a critical level of stenosis is reached; 3) below a critical flow level, subendocardial CP and Pi contents are closely correlated with absolute subendocardial blood flow; and 4) in the presence of a coronary stenosis, subepicardial CP and Pi contents may change even in the absence of perfusion deficit secondary to loss of subendocardial function.

Adiabatic pulses have been employed in spectroscopic imaging and relaxation rate measurements at 4.7 T to demonstrate the feasibility of obtaining spectroscopic data from the complete sensitive volume of a surface coil using the surface coil as a transmitter and receiver. With conventional B 1 sensitive pulses, spectroscopic localization or imaging techniques, such as chemical‐shift imaging, yield resonance intensities that are distorted severely as a function of space, and maximal signal is detected from a small region within the complete sensitive volume of the coil. With adiabatic pulses, however, this problem is eliminated completely. In addition, a new method of spatial localization is introduced. This method, referred to as FLAX‐ISIS, is a derivative of longitudinally modulated Fourier series window and ISIS approaches and utilizes adiabatic inversion and excitation pulses. The method allows construction of localized spectra for multiple regions along the surface coil axis by postacquisition data manipulation of a single set of free induction decays. These techniques were applied to the study of the myocardium using an implanted surface coil in an instrumented closed‐chest canine model and in an open‐chest preparation. The results demonstrate that one‐dimensional techniques are adequate for transmural detection of metabolites provided signal origin is restricted to a column perpendicular to the left ventricle wall. © 1989 Academic Press, Inc.

Coronary stenosis results in transmurally non‐uniform blood flow with the inner layers of the left ventricular wall typically suffering a more severe hypoperfusion relative to the outer layers. Coupled with numerous other transmural non‐uniformities such as systolic tension development and oxygen needs, the heterogeneous blood flow distribution in the presence of coronary stenosis is expected to result in transmurally heterogeneous ischemia. All previous NMR spectroscopy studies of myocardial metabolism and bioenergetics under normal and ischemic conditions treated the organ as a homogeneous tissue. We have utilized spatially localized 31P NMR spectroscopy together with non‐NMR measurements of regional blood flow to study the myocardium with transmural spatial differentiation under normal and flow‐restricted conditions. 31P NMR and blood flow data obtained concurrently on each heart revealed that sustained coronary artery stenosis resulted in transmurally non‐uniform ischemia which largely paralleled the hypoperfusion pattern. The reduction in creatine phosphate content (with consequent elevation of Pi) and hypoperfusion was tightly correlated in the subendocardium for flow rates less than ∼0.7 mL/min per g wet myocardium. The high energy phosphate and Pi content of the epicardium, however, was responsive not only to the flow to this region but also to the extent of ischemia in the subendocardial layers. These results document the utility of localized NMR spectroscopy in physiologic research and suggest potential biomedical applications due to the tight correlation noted between alterations in blood flow and changes in the phosphorylated metabolite levels detected by 31P NMR.