Neutralising antibodies in Spike mediated SARS-CoV-2 adaptation.

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2, and amino acid variation in Spike is increasingly appreciated. Given both vaccines and therapeutics are designed around Wuhan-1 Spike, this raises the theoretical possibility of virus escape, particularly in immunocompromised individuals where prolonged viral replication occurs. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences by both short and long read technologies over 23 time points spanning 101 days. Although little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days, N501Y in Spike was transiently detected at day 55 and V157L in RdRp emerged. However, following convalescent plasma we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility, but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type and appeared to compensate for the reduced infectivity of D796H. Consistent with the observed mutations being outside the RBD, monoclonal antibodies targeting the RBD were not impacted by either or both mutations, but a non RBD binding monoclonal antibody was less potent against ΔH69/ΔV70 and the double mutant. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with reduced susceptibility to neutralising antibodies.

Kinetics of rubidium-82 after coronary occlusion and reperfusion. Assessment of patency and viability in open-chested dogs.

Currently available noninvasive techniques are unable to rapidly assess artery patency and tissue viability during acute myocardial infarction. In prior studies, rubidium-82 (Rb-82), a short-lived positron emitter obtained from a generator, was validated as an indicator of flow with a model that included the rate constants for transfer into and out of the cell. Accordingly, in the current study, 20 open-chested dogs with experimental infarction were studied serially at base line, after coronary occlusion, and at reperfusion. Time-activity curves acquired with beta probes on the epicardial surface were used to measure flow and net transfer of rubidium. Flow decreased to 0.41 +/- 0.08 ml/min per gram during occlusion and increased to 2.73 +/- 0.56 ml/min per gram in potentially viable ischemic tissue, whereas flows were 0.32 +/- 0.08 during occlusion (P less than 0.05 vs. viable) and 1.58 ml/min per gram (P less than 0.002 vs. viable) in irreversibly injured tissue. The transfer rate constant for Rb-82, kT, at base line was +1.22 +/- 0.60 X 10(-3) s-1 and did not change significantly during occlusion in viable vs. nonviable samples (+1.41 +/- 1.27 vs. +0.93 +/- 1.51 X 10(-3) s-1, respectively), except that 4 out of 11 nonviable tissue samples had negative kTs. At reperfusion, viable myocardial samples were all positive (+1.26 +/- 1.58 X 10(-3) s-1), whereas all irreversibly injured tissues had a negative kT, indicating leakage of tracer (-1.50 +/- 1.10 X 10(-3) s-1, P less than 0.001). This study suggests that Rb-82 time-activity curves can be useful to determine patency of an infarct related artery and potential viability after reperfusion during myocardial infarction.

Urinary excretion of elastin peptides containing desmosin after intratracheal injection of elastase in hamsters.

The intratracheal injection of pancreatic elastase results in an acute loss of elastin from the lungs of hamsters and the development of emphysema. We used measurements of the unique covalent cross linking amino acids of elastin, desmosine and isodesmosine, to quantitate elastin. Direct measurements on the lungs estimated an average loss of elastin of 57% after elastase injection. Elastin breakdown products were also quantitated in the urine and feces after injection. An average of 8.8 nmol of desmosines was recovered from the urine of each hamster. This amount represented the desmosines from 61% of the elastin lost from the lungs. Desmosine and isodesmosine existed in the urine in peptide fractions that ranged from 9 to 27,000 daltons with an average of 13,000. Only trace quantities of desmosines could be detected in feces. Desmosines injected intraperitoneally were completely recovered in the urine, and radioactive tracer studies failed to reveal in vivo catabolism of injected desmosines. These results suggest that measurement of urinary desmosines holds promise for the study of elastin turnover.

Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium.

Lysophosphoglycerides, products of membrane phospholipid catabolism known to influence membrane function in several systems, appeared in the effluents of anoxic isolated rabbit hearts perfused at low flow and accumulated in perfused hearts and myocardium rendered ischemic in situ. Comparable concentrations of lysophosphoglycerides bound to albumin markedly and reversibly altered action potentials of isolated canine Purkinje fibers in vitro. Changes induced included diminution of the maximum diastolic potential, peak dV/dt of phase zero, amplitude, and action potential duration--alterations resembling those seen in ischemic myocardium in vivo. These electrophysiological alterations are compatible with changes implicated in predisposing to dysrhythmia dependent on reentry, a phenomenon potentiated by the presence of zones of decreased conduction. Thus, accumulation of lysophosphoglycerides induced by ischemia may contribute to the genesis of malignant dysrhythmia early after its onset.

Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man.

To determine the relation between stenosis anatomy and perfusion in man, 31 patients had quantitative coronary arteriography and positron imaging (PET) with Rb-82 or N-13 ammonia at rest and after dipyridamole-handgrip stress. 10 patients were also studied after angioplasty (total stenoses = 41). Percent narrowing and absolute cross-sectional luminal area were related through a quadratic function to myocardial perfusion reserve determined with PET. Arteriographically determined coronary flow reserve was linearly related to relative myocardial perfusion reserve as expected, based on the derivation of equations for stenosis flow reserve. All of the correlations had considerable scatter, indicating that no single measurement derived by coronary arteriography was a good indicator of perfusion reserve by PET in individual patients. This study provides the relation between all anatomic dimensions of coronary artery stenoses and myocardial perfusion reserve in man, and suggests that PET indicates the functional significance of coronary artery stenoses for clinical purposes.

Comparison of technetium-99m teboroxime tomography with automated quantitative coronary arteriography and thallium-201 tomographic imaging.

Technetium-99m (Tc-99m) teboroxime is a new perfusion tracer that is highly extracted and rapidly cleared by the myocardium. To determine the feasibility of Tc-99m teboroxime imaging in the diagnosis of patients with suspected coronary artery disease, 30 patients underwent single photon emission computed tomography imaging with Tc-99m teboroxime (25.2 +/- 1 mCi) at peak exercise and again 60 min later at rest. All patients underwent either a thallium stress test (n = 26) or automated quantitative coronary arteriography (n = 25), or both, without intervening revascularization or infarction. Images were reviewed by two investigators who had no knowledge of clinical data. Coronary lesions with greater than or equal to 50% diameter narrowing by quantitative coronary arteriography were considered significant. Both thallium and Tc-99m teboroxime detected disease in all patients with two or three vessel disease. One vessel disease was detected with Tc-99m teboroxime in 9 of 10 patients and with thallium in 8 of 10 (p = NS). In patients without angiographically significant disease. Tc-99m teboroxime demonstrated normal perfusion in six of eight patients and thallium in three of five (p = NS). Overall, when presence or absence of disease detected by Tc-99m teboroxime or thallium was compared with quantitative coronary arteriography, there was no difference between Tc-99m teboroxime and thallium. These results suggest that Tc-99m teboroxime is comparable to thallium as an imaging agent. The rapid biologic half-life, 5.3 min, allows studies to be completed in 60 to 90 min.

Efficacy and safety of sustained (48 hour) intravenous infusions of milrinone in patients with severe congestive heart failure: a multicenter study.

Milrinone is a new bipyridine inotrope that has shown promise in initial clinical testing when administered intravenously or orally. The present multicenter study was designed to evaluate the clinical effectiveness and safety of sustained (48 hour) intravenous infusions of different doses of milrinone, as would be used clinically, in a controlled fashion using invasive hemodynamic monitoring. Entry was limited to adult patients with chronic heart failure of functional class III or IV, with a cardiac index less than or equal to 2.5 liters/min per m2 or a pulmonary capillary wedge pressure greater than or equal to 15 mm Hg, or both. After stable baseline hemodynamic recordings were obtained, milrinone was given as loading (microgram/kg per 10 min) and maintenance infusions (microgram/kg per min) to 189 patients in one of four loading/maintenance dosage regimens: 37.5/0.375 (low dose, n = 26), 50/0.50 (intermediate dose, n = 95), 75/0.75 (high dose, n = 15) and 50/0.25 (lowest dose, n = 53). The lowest dose was shown to be ineffective for maintenance therapy. Effective individual patient responses were defined as greater than or equal to 20% increase in cardiac index or decrease in pulmonary capillary wedge pressure, or both. During early therapy (less than or equal to 3 hour), 99% of patients showed an effective maximal response, and 90% an effective mean response. An effective mean response was observed during days 1 and 2 in 80% of patients, with a positive dose-response trend (69% response, low dose; 80%, intermediate dose; 93%, high dose; day 1). Each loading regimen was effective, with maximal mean response occurring at 15 minutes. Cardiac index initially increased by an average of 24 to 42% for all patients in the three groups, whereas pulmonary capillary wedge pressure decreased by 24 to 33%. Initial decreases in systemic vascular resistance averaged 15 to 31%. Initial changes in heart rate (+4 to +13%) and mean arterial pressure (-2 to -13%) were modest. Significant mean hemodynamic responses were maintained over the 48 hours. Increases in cardiac index for days 1 and 2 averaged 38 and 39% for those completing constant low dose drug, 34 and 37% for intermediate dose and 73 and 44% for high dose. Decreases in pulmonary capillary wedge pressure for all patients averaged 18 to 32% on days 1 and 2, with little dose response. Heart rate changes were modest and variable, averaging -9 to 9%.(ABSTRACT TRUNCATED AT 400 WORDS)

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced rubidium-82.

The purpose of this study was to determine the clinical feasibility of diagnosing significant coronary artery disease by positron imaging of myocardial perfusion without a cyclotron, using generator-produced rubidium-82 (82Rb). Fifty patients underwent positron emission tomography of the entire heart using a multislice positron camera and intravenous 82Rb or nitrogen-13 ammonia (13NH3) before and after intravenous dipyridamole combined with handgrip stress. Images were read by two observers blinded as to clinical or arteriographic data. Automated quantitative coronary arteriography was obtained for the arteriographic determination of coronary flow reserve, previously demonstrated to be a single integrated measure of stenosis severity accounting for all its geometric dimensions of length, absolute diameter, percent narrowing and asymmetry by quantitative analysis of cine films. Significant coronary artery disease was defined as an arteriographically determined coronary flow reserve of less than 3.0 based on all stenosis dimensions. Any single geometric measure of stenosis severity alone was an inadequate reference standard for comparison with perfusion images. Sensitivity of identifying patients with coronary artery disease having an arteriographically determined coronary flow reserve of less than 3.0 was 95% by positron imaging with a specificity of 100%. The single case that was missed, studied with 13NH3, had a 43% diameter narrowing of a small ramus intermedius off the left coronary artery with no significant narrowing of the major coronary arteries. Positron emission tomography of myocardial perfusion before and after intravenous dipyridamole combined with handgrip stress utilizing generator-produced 82Rb provides sensitive and specific diagnosis of reduced coronary flow reserve due to coronary artery disease in humans.

Generalized protein tertiary structure recognition using associative memory Hamiltonians.

In previous papers, a method of protein tertiary structure recognition was described based on the construction of an associative memory Hamiltonian, which encoded the amino acid sequence and the C alpha co-ordinates of a set of database proteins. Using molecular dynamics with simulated annealing, the ability of the Hamiltonian to successfully recall the structure of a protein in the memory database was successfully demonstrated, as long as the total number of database proteins did not exceed a characteristic value, called the capacity of the Hamiltonian, equal to 0.5N to 0.7N, where N is the number of amino acid residues in the protein to be recalled. In this paper, we describe the development of additional methods to increase the capacity of the Hamiltonian, including use of a more complete representation of the protein backbone and the incorporation of contextual information into the Hamiltonian through the use of secondary structure prediction. In addition, we further extend the ability of associative memory models to predict the tertiary structures of proteins not present in the protein data set, by making the Hamiltonian invariant with respect to biological symmetries that represent site mutations and insertions and deletions. The ability of the Hamiltonian to generalize from homologous proteins to an unknown protein in the presence of other unrelated proteins in the data set is demonstrated.

Predicting protein secondary structure with probabilistic schemata of evolutionarily derived information.

We demonstrate the applicability of our previously developed Bayesian probabilistic approach for predicting residue solvent accessibility to the problem of predicting secondary structure. Using only single-sequence data, this method achieves a three-state accuracy of 67% over a database of 473 non-homologous proteins. This approach is more amenable to inspection and less likely to overlearn specifics of a dataset than "black box" methods such as neural networks. It is also conceptually simpler and less computationally costly. We also introduce a novel method for representing and incorporating multiple-sequence alignment information within the prediction algorithm, achieving 72% accuracy over a dataset of 304 non-homologous proteins. This is accomplished by creating a statistical model of the evolutionarily derived correlations between patterns of amino acid substitution and local protein structure. This model consists of parameter vectors, termed "substitution schemata," which probabilistically encode the structure-based heterogeneity in the distributions of amino acid substitutions found in alignments of homologous proteins. The model is optimized for structure prediction by maximizing the mutual information between the set of schemata and the database of secondary structures. Unlike "expert heuristic" methods, this approach has been demonstrated to work well over large datasets. Unlike the opaque neural network algorithms, this approach is physicochemically intelligible. Moreover, the model optimization procedure, the formalism for predicting one-dimensional structural features and our previously developed method for tertiary structure recognition all share a common Bayesian probabilistic basis. This consistency starkly contrasts with the hybrid and ad hoc nature of methods that have dominated this field in recent years.

Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients.

Hyperlipidemia and hypertension, two major risk factors for accelerated atherosclerosis, undoubtedly contribute to the excessive cardiovascular morbidity and mortality experienced by renal transplant recipients. The present survey of posttransplant hyperlipidemia in 500 cyclosporine-treated patients documented a 37.6% incidence of hypercholesterolemia, which occurred within 6 months posttransplant in 82% of patients. An etiologic relation to corticosteroid therapy was suggested by the strong correlation between prednisone doses and cholesterol levels, by the reduced cholesterol levels in patients undergoing steroid withdrawal, and by the reduction in hypercholesterolemia to 13% by 3 years posttransplant when steroid doses were less than 10 mg daily. Hypertriglyceridemia, which was present in 14.7% of the patients, was more severe under CsA-prednisone compared with azathioprine-prednisone therapy. Hypertriglyceridemia, which occurred later in the posttransplant course than hypercholesterolemia, strongly correlated with an excessive percent relative weight and elevated serum creatinine but not with steroid or CsA doses. Increasing age, diabetes mellitus, beta-blockers and nephrotic syndrome contribute to posttransplant hyperlipidemia in the CsA-Pred era as they did in the azathioprine era of immunosuppression.

Rubidium-82 kinetics after coronary occlusion: temporal relation of net myocardial accumulation and viability in open-chested dogs.

Serial assessment of perfusion and viability during myocardial infarction has not been feasible, in part, because of the long half-lives of available tracers. Rubidium-82 (82Rb) is a generator-produced, positron-emitting potassium analog with a short half-life (75 sec) that permits repeated studies. To determine the temporal relation of net myocardial 82Rb accumulation to loss of viability during prolonged ischemia, a 2-3 mCi bolus of 82Rb was given to 46 open-chested dogs while regional myocardial time-activity curves were obtained with beta probes at baseline, and serially after coronary occlusion lasting 1-6 hr. Hearts were then stained with triphenyl tetrazolium chloride (TTC) to assess the viability of the epicardium under the probe to a depth corresponding to the range of positrons. Irreversible injury occurred in two out of 16 experiments at 1 hr and ten out of 15 experiments at 3 hr and also at 6 hr (p less than 0.05 vs. 1 hr). In viable myocardial samples, rubidium extraction increased with low flow as compared with nonischemic controls for all time periods but was unchanged (failed to increase) in nonviable tissue. Net 82Rb accumulation decreased during 1 to 6 hr of occlusion in irreversibly injured samples (0.28 +/- 0.19 to 0.16 +/- 0.07, p less than 0.05) but remained unchanged in myocardial tissue subsequently shown to be viable. For myocardial samples that were nonviable at 3 and 6 hr, changes in net accumulation of tracer became abnormal only after 6 hr of occlusion. The mechanisms primarily responsible for the decrease in net accumulation of 82Rb at 6 hr appeared to be leakage of tracer after first pass. Therefore, failure to increase extraction at low flows may be an early indicator of cell death, whereas membrane leakage occurs several hours after loss of viability.

Limited myocardial perfusion reserve in patients with left ventricular hypertrophy.

Experimental studies in animals have suggested that coronary flow reserve may be limited in patients with left ventricular hypertrophy (LVH). Accordingly, to noninvasively determine the effect of LVH on myocardial perfusion reserve, 25 patients, 9 with LVH and 16 controls, underwent positron imaging with rubidium-82 (82Rb) (30-55 mCi) or nitrogen-13 (13N) ammonia (12-19 mCi) at rest and following intravenous dipyridamole and handgrip stress. LVH was documented by echocardiographic and/or electrocardiographic measurements. LVH patients had either no chest pain (n = 8) and/or a normal coronary angiogram (n = 6). Nine simultaneous transaxial images were acquired, and the mean ratio of stress to rest activity (S:R), based on all regions for each heart, was calculated as an estimate of myocardial perfusion reserve. There were no regional differences in activity (i.e., perfusion defects) in any of the studies. S:R averaged 1.41 +/- 0.10 (s.d.) for controls and 1.06 +/- 0.09 for patients with LVH (p less than 0.0001). These data provide support for an abnormality in perfusion reserve in patients with LVH.

Detection of myocardial ischemia before infarction, based on accumulation of labeled pyruvate.

To determine whether ischemic, but not irreversibly injured myocardium, can be differentiated from normal tissue based on accumulation of labeled pyruvate, isolated hearts were perfused with buffer containing [14C]pyruvate under conditions of normal or low flow. Fifteen minutes after the hearts were exposed to labeled material, myocardial radioactivity was fourfold greater in ischemic compared to control hearts, due to accumulation of label in sequestered lactate produced from the pyruvate. Open-chest rabbits subjected to coronary occlusion exhibited a 1.73:1 ratio of radioactivity in ischemic compared with normal myocardium 15 min after systemic injection of [14C]pyruvate. The results obtained suggest that zones of myocardial ischemia should be detectable in vivo by positron tomography after systemic administration of [11C]pyruvate as well.

Economic analysis of clinical positron emission tomography of the heart with rubidium-82.

This report describes a cost analysis for clinical positron emission tomography (PET) of the heart using generator produced rubidium-82 (82Rb). Considered sequentially are the clinical problem, current noninvasive radionuclide methods, positron emission tomograph, and the cost of PET per study. Also analyzed are the costs of PET versus thallium imaging in the management of chest pain, for screening asymptomatic men at high risk for coronary artery disease and for evaluating myocardial viability after myocardial infarction or thrombolytic therapy. Noninvasive assessment of coronary artery stenosis and myocardial ischemia/viability in symptomatic or asymptomatic subjects remains a major medical problem because the sensitivity and specificity of thallium imaging are only 70-85% and 50-70%, respectively, in recent studies. Cardiac positron imaging has an accuracy for noninvasive diagnosis of coronary artery disease in symptomatic or asymptomatic patients with a sensitivity and specificity of 95-98%. It can also be used for assessing physiologic stenosis severity, for imaging myocardial infarction and viability, for assessing effects of interventions such as thrombolysis, percutaneous transluminal coronary angioplasty (PTCA) or bypass surgery on myocardial perfusion, metabolism or coronary flow reserve, for assessing collateral function noninvasively in man, and for diagnosing cardiomyopathy not due to coronary artery disease. Although the cost for cardiac PET with 82Rb may be modestly higher than for 201Tl, the greater diagnostic yield of PET results in comparable or lower overall medical management costs than no diagnostic tests/interventions and lower overall costs compared to thallium imaging for evaluating patients with chest pain, asymptomatic high risk males, and patients after acute myocardial infarction/thrombolysis for myocardial viability.

External assessment of myocardial metabolism with C-11 palmitate in vivo.

The externally detected rate of clearance of C-11 palmitate ([11C]palmitic acid) from isolated hearts varies directly with CO2 production from neutral lipids and with physiological indexes of myocardial oxygen consumption. The present study was performed to determine whether myocardial metabolism could be quantified noninvasively in vivo in a fashion analogous to that in the isolated heart. Opened chest, male rabbits were injected with C-11 palmitate (100-200 muCi) and coincidence counts were detected externally with two NaI(TI) crystals so placed that their colinear field of view encompassed the heart. The monoexponential rate of clearance of tracer--obtained from the portion of the residue-detection curve reflecting metabolism of fatty acid incorporated into neutral lipids--correlated directly with induced changes in tension-time index after injections into the left atrium (r = 0.96, n = 12), right atrium (r = 0.86, n = 14), and ear vein (r = 0.93, n = 14). Clearance of labeled palmitate from the vascular pool within the field of detection (determined with both C-14 palmitate and red blood cells labeled with C15O-hemoglobin) was rapid and did not significantly affect measurements of palmitate clearance from the heart itself.

Noninvasive assessment of coronary collaterals in man by PET perfusion imaging.

At present, coronary collateralization cannot be identified or assessed noninvasively in patients. In animal studies, coronary collaterals are associated with coronary steal, defined as a regional fall in perfusion during coronary arteriolar vasodilation. To determine the effect of coronary arteriolar vasodilation on collateral bed perfusion in man, myocardial perfusion imaging was performed before and after pharmacologic coronary vasodilation in patients with coronary artery disease (CAD). Regional myocardial activity of 82Rb or 13N ammonia was measured by positron emission tomography (PET) at rest and with intravenous dipyridamole/handgrip stress in 28 patients with angiographic collaterals and in 25 control patients with similar CAD severity by quantitative arteriography. Regional myocardial activity decreased after dipyridamole, indicating coronary steal, in 25 of 28 patients with angiographic collaterals and in only 4 of 25 control patients without angiographic collaterals. These findings suggest that developed collaterals are associated with myocardial steal in patients with CAD, allowing potential use of PET for non-invasive identification of coronary collateralization.

Positron imaging of myocardial infarction with rubidium-82.

Positron imaging provides tomographic images of regional myocardial perfusion but has required an on-site cyclotron. Rubidium-82 (82Rb) is a short-lived (T1/2 = 75 sec) positron emitter available from a generator. In order to determine the feasibility for its use to image acute myocardial infarction, 18 patients with transmural infarctions who had coronary arteriography were given 30-40 mCi of 82Rb intravenously and positron tomographic imaging was carried out within 96 hr after onset of symptoms. Nine simultaneous transaxial slices were obtained for each patient with a positron camera. Images were also reconstructed in a long-axis, short-axis, and three-dimensional display. One study could not be interpreted because of excessive lung activity. Fourteen normals were also studied. The infarct related artery determined by angiography was correctly diagnosed by positron imaging in all 17 patients as were all three prior infarcts by readers blinded to the clinical data. No defects were observed in normals or in noninfarcted myocardial regions. This study indicates that 82Rb should be useful for perfusion imaging in patients with acute myocardial infarction. The short half-life of 82Rb should make it ideal for providing serial assessment of perfusion in patients undergoing thrombolytic therapy.

Changes in myocardial perfusion reserve after PTCA: noninvasive assessment with positron tomography.

The effect of percutaneous transluminal coronary angioplasty (PTCA) on myocardial perfusion reserve has not been previously determined. Accordingly, 11 patients underwent positron imaging with [13N]ammonia or 82Rb at rest and following dipyridamole + handgrip stress before and after PTCA. The ratio of stress to rest activity (S:R) was determined for each region of interest. Relative myocardial perfusion reserve by positron tomography (RMPR) was calculated by dividing S:R of the stenotic area by a corresponding value from a normal reference area of the same patient. Automated quantitative coronary arteriography was used to objectively measure the percent diameter (%D) and the percent area narrowing (%A) of the stenoses. In nine patients with successful PTCA, %D and %A improved (68 +/- 10 to 49 +/- 15% and 92 +/- 3 to 72 +/- 5%) and RMPR increased from 0.79 +/- 0.07 to 0.96 +/- 0.05. In the two patients in whom PTCA was unsuccessful, RMPR was unchanged. Changes in RMPR correlated inversely with changes in %D (r = -0.68) and %A (r = -0.92) and directly with improved coronary flow reserve derived from all stenosis measurements (r = 0.73, p less than 0.001 for each). This study suggests that dipyridamole + handgrip stress imaging with PET can be used to assess changes in myocardial perfusion reserve before and after PTCA with the potential for determining restenosis noninvasively.

Myocardial perfusion with rubidium-82. I. Measurement of extraction fraction and flow with external detectors.

Accurate measurement of the regional extraction of a diffusible radiopharmaceutical is essential for the quantifying of regional blood flow, and may also provide an important physiologic or diagnostic indicator of the cellular viability of an organ in man through external detection by positron emission tomography. However, extraction fraction of a diffusible tracer usually decreases as flow increases, and thus noninvasive methods for measuring flow are nonlinear unless the extraction fraction can be measured independently. This report describes the theoretical basis and documents the applicability of this theory for determining, with external detectors, the first-pass regional extraction fraction of rubidium-82 by the heart, following a single intravenous bolus injection of the tracer. Measurement of extraction fraction was found to be independent of flow, thereby making it possible to determine accurately with a single intravenous bolus injection of rubidium-82, the regional blood flow in the myocardium at up to five times normal resting flow.