John W. Fanton

Radiation-Induced Endometriosis in Macaca mulatta

Female rhesus monkeys received whole-body doses of ionizing radiation in the form of single-energy protons, mixed-energy protons, X rays, and electrons. Endometriosis developed in 53% of the monkeys during a 17-year period after exposure. Incidence rates for endometriosis related to radiation type were: single-energy protons, 54%; mixed-energy protons, 73%; X rays, 71%; and electrons, 57%. The incidence of endometriosis in nonirradiated control monkeys was 26%. Monkeys exposed to single-energy protons, mixed-energy protons, and X rays developed endometriosis at a significantly higher rate than control monkeys (chi 2, P less than 0.05). Severity of endometriosis was staged as massive, moderate, and minimal. The incidence of these stages were 65, 16, and 19%, respectively. Observations of clinical disease included weight loss in 43% of the monkeys, anorexia in 35%, space-occupying masses detected by abdominal palpation in 55%, abnormal ovarian/uterine anatomy on rectal examination in 89%, and radiographic evidence of abdominal masses in 38%. Pathological lesions were endometrial cyst formation in 69% of the monkeys, adhesions of the colon in 66%, urinary bladder in 50%, ovaries in 86%, and ureters in 44%, focal nodules of endometrial tissue throughout the omentum in 59%, and metastasis in 9%. Clinical management of endometriosis consisted of debulking surgery and bilateral salpingo-oophorectomy combined in some cases with total abdominal hysterectomy. Postoperative survival rates at 1 and 5 years for monkeys recovering from surgery were 48 and 36%, respectively.

Evidence for increased cardiac compliance during exposure to simulated microgravity

We measured hemodynamic responses during 4 days of head-down tilt (HDT) and during graded lower body negative pressure (LBNP) in invasively instrumented rhesus monkeys to test the hypotheses that exposure to simulated microgravity increases cardiac compliance and that decreased stroke volume, cardiac output, and orthostatic tolerance are associated with reduced left ventricular peak dP/d t. Six monkeys underwent two 4-day (96 h) experimental conditions separated by 9 days of ambulatory activities in a crossover counterbalance design: 1) continuous exposure to 10° HDT and 2) ∼12-14 h per day of 80° head-up tilt and 10-12 h supine (control condition). Each animal underwent measurements of central venous pressure (CVP), left ventricular and aortic pressures, stroke volume, esophageal pressure (EsP), plasma volume, α1- and β1-adrenergic responsiveness, and tolerance to LBNP. HDT induced a hypovolemic and hypoadrenergic state with reduced LBNP tolerance compared with the control condition. Decreased LBNP tolerance with HDT was associated with reduced stroke volume, cardiac output, and peak dP/d t. Compared with the control condition, a 34% reduction in CVP ( P= 0.010) and no change in left ventricular end-diastolic area during HDT was associated with increased ventricular compliance ( P = 0.0053). Increased cardiac compliance could not be explained by reduced intrathoracic pressure since EsP was unaltered by HDT. Our data provide the first direct evidence that increased cardiac compliance was associated with headward fluid shifts similar to those induced by exposure to spaceflight and that reduced orthostatic tolerance was associated with lower cardiac contractility.

Evaluation of transit-time and electromagnetic flow measurement in a chronically instrumented nonhuman primate model

The Physiology Research Branch at Brooks AFB conducts both human and nonhuman primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to identify the particular mechanisms that invoke these responses. Primary investigative efforts in our nonhuman primate model require the determination of total peripheral resistance, systemic arterial compliance, and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. This study evaluated accuracy, linearity, biocompatability, and anatomical features of commercially available electromagnetic (EMF) and transit-time flow measurement techniques. Five rhesus monkeys were instrumented with either EMF (3 subjects) or transit-time (2 subjects) flow sensors encircling the proximal ascending aorta. Cardiac outputs computed from these transducers taken over ranges of 0.5 to 2.0 L/min were compared to values obtained using thermodilution. In vivo experiments demonstrated that the EMF probe produced an average error of 15% (r = .896) and 8.6% average linearity per reading, and the transit-time flow probe produced an average error of 6% (r = .955) and 5.3% average linearity per reading. Postoperative performance and biocompatability of the probes were maintained throughout the study. The transit-time sensors provided the advantages of greater accuracy, smaller size, and lighter weight than the EMF probes. In conclusion, the characteristic features and performance of the transit-time sensors were superior to those of the EMF sensors in this study.

Central hemodynamics in a baboon model during microgravity induced by parabolic flight.

We developed a chronically instrumented nonhuman primate model (baboon) to evaluate the central cardiovascular responses to transient microgravity induced by parabolic flight. Instrumentation provided simultaneous recording of high fidelity (Ao) and pulmonary artery (PA) pressures, right and left ventricular and atrial pressures, Ao and PA blood flow velocities and vessel dimensions, ECG and pleural pressures. Four daily flights in 1991 and five in 1992 were flown with forty parabola per flight. Animals flown in 1991 were not controlled for volume status. Animals flown in 1992 were studied in one of three conditions: 1) volume depleted by furosemide (DH), 2) volume expanded by saline infusion (VE), and 3) euvolemic (EU, no intervention, used for echo only). Mean right atrial pressures (RAP) during 1991 flights had a variable early microgravity response: increases in n=3 and decrease in n=3 (supine) and increases in n=5, decreases in n=2 (upright). In 1992 flights, DH, upright and supine, changed -10 +/- 4.1 mmHg, -3.2 +/- 2.2 mmHg, respectively (p < .05) compared to the pull-up phase. In contrast, VE changed (from pull-up to microgravity) +13 +/- 1.5 mmHg and +4.25 +/- 2.9 mmHg (upright and supine, respectively, p < .05). EU increased with microgravity +6.9 +/- .9 mmHg (upright only). LAP responses were similar, but more variable. Finally, heart chamber areas paralleled pressure changes. Thus, right and left heart filling pressure changes with sudden entry into microgravity conditions were dependent on initial circulatory volume status and somewhat modified by position (supine vs upright).

A Conscious Baboon Model for Evaluation of Hemodynamics in Altered Gravity

A model was developed for evaluation of cardiovascular parameters in conscious baboons exposed to altered gravitational environments. Baboons were trained to sit quietly in a confinement chair of unique design which allowed a range of normal physical activity. They were then instrumented with high-fidelity blood pressure transducers in the aorta and left ventricle, electromagnetic flow probes encircling the proximal ascending aorta, left and right atrial fluid catheters, left ventricular sonomicrometer crystals in a 3-axis configuration, and a hydraulic occluder cuff encircling the inferior vena cava. Catheters and transducer wires were exteriorized at the midscapular region of the back. Viability of percutaneous exit sites was enhanced by use of velour cuffs on the transducer wires, providing a scaffold for wound healing. Pressure transducers and flow probes were calibrated and balanced during postoperative cardiac catheterization procedures. This instrumentation allowed measurement of beat-to-beat stroke volume and cardiac output not reliant on thermodilution techniques. Postoperative longevity was from 1 to 10 months. Instrumentation failure included endocardial trapping of ventricular pressure transducers, corrosion of ventricular sonomicrometer crystals, and catheter tip thrombosis. Acquisition of high quality data was possible with this model in several different environments of altered gravitational stress, allowing characterization of aortic flow and ventricular performance.

A Method for Repeated High-Fidelity Micromanometer Measurement of Intracardiac Pressures

Dial-tipped, high-fidelity micromanometers were inserted through polyurethane catheters to acutely measure blood pressures within the chambers of the heart and the great vessels of baboons, rhesus monkeys, and goats. Repeated measurements of atrial, ventricular, aortic, and pulmonary artery pressure were possible with this method, with calibration of micromanometers accomplished immediately prior to and after pressure recordings to assure data accuracy. All attempts to pass micromanometers into the atria in all species were successful. Passage of micromanometers from the left ventricle across the aortic valve and into the aorta was successful in 97% of the attempts in baboons, 100% for rhesus monkeys, and 75% for goats; while insertions into the pulmonary artery from the right ventricle were successful in 64% of the baboons, 40% of the rhesus monkeys, and 75% of the goats. Advantages of this technique are that a permanent conduit for cardiac vascular access is available and that high-fidelity pressure signals may be acquired.

Responses to mechanical stimuli of isolated basilar and femoral arteries of the Rhesus monkey are different.

SummaryThe present study aimed to determine regional differences in diameter response to mechanical stimuli such as flow (shear stress) and transmural pressure (myogenic response) of the isolated basilar artery and femoral artery from Rhesus monkeys. Whether or not spontaneous tone developed, a transmural pressure-diameter relation was determined after the equilibration period. Vessels were then constricted with a submaximal dose of prostaglandin-F2α (PGF2α; 1.23–2µM) and a flow-diameter relation (0–2,000µl/min) and a pressure-diameter (15–125cmH2O) relation were determined. Endothelium function was tested with the calcium ionophore A-23187 (1.0 µM). The vessels were then maximally dilated (papaverine, 100µM) and a passive pressure-diameter relation was determined. The responses of the basilar and the femoral arteries were markedly different. The basilar artery developed spontaneous tone, while the femoral artery did not. The basilar artery showed flow-induced constriction (P = 0.024), while the femoral artery dilated when flow was increased (P = 0.0005). The myogenic index of the two arteries during treatment with PGF2α was not different (P = 0.49) and the strength of the myogenic response was such that the diameter of both arteries stayed constant over the pressure range studied. We conclude that the responses to mechanical stimuli of the basilar artery and the femoral artery of the Rhesus monkey are markedly different.

Chronic instrumentation for right heart cardiovascular studies in a human surrogate model

The Laboratory for Aerospace Cardiovascular Research (LACR) is a center for studying the effects of micro-and high (9Gz) gravitational forces on the cardiovascular system. Prior research efforts focused on determining pressure-volume-flow relationships of the left heart for altered G-environmcnts. This paper will describe the current right/left heart model that features less traumatic chronic implantation. This model has enabled LACR to evaluate right/left heart cardiovascular function in chronically instrumented non-human surrogate model during static rotational tilt, NASA KC-135 micro-G parabolas, and high G centrifugation.

Cardiac pacing in a chronically-instrumented non-human primate model during centrifugation

The Physiology Research Branch has developed a chronically-instrumented non-human primate model for evaluating cardiac function during exposure to altered gravitational environments. This model has been used to measure cardiovascular hemodynamics and electrical activity. The authors have expanded the model to include cardiac pacing for evaluation of responses and mechanisms in normal and dysrhythmic states. In particular, the authors have been able to produce constant heart rates by means of atrial, ventricular, and dual chamber pacing during centrifugation. Preventricular contractions, bigeminal, and trigeminal rhythms have also been invoked using this same pacing model.

Evaluation of flow biosensor technology in a chronically-instrumented non-human primate model

The Physiology Research Branch at Brooks AFB conducts both human and non-human primate experiments to determine the effects of microgravity and hypergravity on the cardiovascular system and to identify the particular mechanisms that invoke these responses. Primary investigative research efforts in a non-human primate model require the calculation of total peripheral resistance (TPR), systemic arterial compliance (SAC), and pressure-volume loop characteristics. These calculations require beat-to-beat measurement of aortic flow. We have evaluated commercially available electromagnetic (EMF) and transit-time flow measurement techniques. In vivo and in vitro experiments demonstrated that the average error of these techniques as less than 25 percent for EMF and less than 10 percent for transit-time.