John B. Gill

Prognostic Importance of Thallium Uptake by the Lungs during Exercise in Coronary Artery Disease

We studied the value of thallium imaging as compared with clinical and exercise-test variables in predicting cardiac events occurring over five years in 525 consecutive patients referred for thallium-exercise testing in 1979. Follow-up was obtained on 467 patients (89 percent). There were 105 cardiac events--25 cardiac deaths, 33 myocardial infarctions, and 47 coronary bypass procedures. A Cox survival analysis identified increased thallium uptake by the lungs, a marker of left ventricular dysfunction during exercise, as the best predictor of a cardiac event (relative risk ratio = 3.5; 95 percent confidence interval, 2.2 to 5.4). The next most powerful predictors were a history of typical angina, a previous myocardial infarction, and ST-segment depression during exercise (relative risk ratios = 2.1, 1.8, and 1.7, respectively). No combination of variables made up for the loss in prognostic power when the variable of increased thallium uptake by the lungs was removed from the model. Cardiac events occurred over five years in 10 (5 percent) of 192 patients with a normal thallium scan, 41 (25 percent) of 163 patients with an abnormal thallium scan but normal thallium activity in the lungs, and 54 (67 percent) of 81 patients with increased thallium uptake by the lungs (P less than 0.0001). We conclude that increased uptake of thallium by the lungs during exercise predicts a high risk of subsequent cardiac events.

Prognostic Importance of Myocardial Ischemia Detected by Ambulatory Monitoring Early after Acute Myocardial Infarction

BACKGROUND After an acute myocardial infarction, it is important to determine the risk of a subsequent coronary event. We studied the prognostic value of myocardial ischemia detected by ambulatory electrocardiographic (ECG) monitoring in patients who had recently had an acute myocardial infarction. METHODS Five to seven days after acute myocardial infarction, 406 patients underwent 48-hour ambulatory ECG monitoring, with submaximal exercise testing before discharge and measurement of the left ventricular ejection fraction within 28 days after infarction. Death, nonfatal myocardial infarction, and admission to the hospital because of unstable angina were the principal end points recorded during the one-year follow-up period. RESULTS The overall incidence of myocardial ischemia detected by ambulatory ECG monitoring was 23.4 percent. The mortality rates at one year were 11.6 percent among the patients with ischemia and 3.9 percent among those without ischemia (P = 0.009); 3.9 percent among the patients with a positive exercise test, 3.0 percent among those with a negative exercise test, and 16.4 percent among those in whom an exercise test was not performed (P < 0.001); and 3.6 percent among the patients with an ejection fraction greater than 50 percent, 3.5 percent among those with an ejection fraction between 35 and 50 percent, and 18.2 percent among those with an ejection fraction below 35 percent (P = 0.001). Using multiple logistic regression, we found that no diagnostic test performed after myocardial infarction provided additional prognostic information beyond that provided by the standard clinical variables used to predict the risk of death. When nonfatal myocardial infarction and admission to the hospital because of unstable angina were also included as outcome variables, ambulatory monitoring for ischemia was the only test that contributed significantly to the model. For the patients with ischemia detected by ambulatory monitoring, as compared with those who did not have evidence of ischemia, the odds ratio was 2.3 (95 percent confidence interval, 1.2 to 4.5) for death or nonfatal myocardial infarction (P = 0.009) and 2.8 (95 percent confidence interval, 1.6 to 4.8) for death, nonfatal myocardial infarction, or admission to the hospital because of unstable angina (P < 0.001). CONCLUSIONS Myocardial ischemia detected by ambulatory ECG monitoring is common early after acute myocardial infarction and provides prognostic information beyond that available from standard clinical information.

Continuous Monitoring of Left Ventricular Function by an Ambulatory Radionuclide Detector in Patients With Coronary Artery Disease

Global left ventricular function and a modified V5 electrocardiographic (ECG) lead were continuously monitored by a radionuclide recorder in 12 normal subjects and 39 patients with coronary artery disease while the subjects were performing various daily activities. The ambulatory studies revealed that walking on a level surface caused 11 of 12 normal subjects and 18 of 32 patients to increase their left ventricular ejection fraction by greater than 6% units. A transient decrease in left ventricular ejection fraction (6 to 18%) lasting greater than or equal to 1 min was observed on 36 occasions in 16 patients with coronary artery disease; 12 episodes were accompanied by chest pain or shortness of breath and 24 were asymptomatic. Electrocardiographic ST segment depression suggestive of ischemia was recorded in 6 of the 12 symptomatic and 5 of the 24 asymptomatic episodes. In 10 of the 12 symptomatic episodes, left ventricular ejection fraction began to decrease 30 to 90 s before the onset of symptoms. These studies suggest that continuous monitoring of both left ventricular function and the ECG may permit stratification of episodes of ST depression suggesting ischemia by the degree of left ventricular dysfunction they produce.

Cardiac response to daily activities and exercise in normal subjects assessed by an ambulatory ventricular function monitor.

The cardiac response to a variety of daily activities was assessed in 18 healthy adult subjects (mean age 31 years, range 21 to 39) with an ambulatory ventricular function monitor (VEST), which records serial beat-to-beat radionuclide and electrocardiographic data. The VEST was positioned and calibrated using data recorded during a multigated blood pool scan. It was worn for an average of 3.0 +/- 1.1 hours, while the subjects performed the following activities: sitting quietly (baseline); standing in place; walking; climbing stairs; bicycle or treadmill exercise; eating; sitting in a room at 4 degrees C for 20 minutes; and urinating. To calculate ejection fraction (EF), relative end-diastolic counts, relative cardiac output and heart rate, the beat-to-beat data were averaged over 15 to 30 seconds. Compared with baseline, standing increased EF by 0.03 +/- 0.04 and decreased end-diastolic volume by 10.9 +/- 4.7%. Walking and climbing stairs increased EF by 0.10 +/- 0.05 and 0.18 +/- 0.09, respectively, and increased end-diastolic volume by 7.8 +/- 5.3% and 12.8 +/- 4.3% (p less than 0.001). Eating increased EF by 0.02 +/- 0.03 and decreased end-diastolic volume by 11.3 +/- 6.1% (p less than 0.001). Cold stimuli and urinating decreased EF by 0.05 +/- 0.04 and 0.03 +/- 0.04, respectively (p less than 0.001 and less than 0.05). Serial left ventricular function monitoring during graded bicycle and treadmill exercise revealed a rapid increase in EF in the early stages of exercise, with no further change in the late stages. Heart rate and systolic blood pressure increased progressively with each successive stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproductive Hormone-Dependent and -Independent Contributions to Developmental Changes in Kisspeptin in GnRH-Deficient Hypogonadal Mice

Kisspeptin is a potent activator of GnRH-induced gonadotropin secretion and is a proposed central regulator of pubertal onset. In mice, there is a neuroanatomical separation of two discrete kisspeptin neuronal populations, which are sexually dimorphic and are believed to make distinct contributions to reproductive physiology. Within these kisspeptin neuron populations, Kiss1 expression is directly regulated by sex hormones, thereby confounding the roles of sex differences and early activational events that drive the establishment of kisspeptin neurons. In order to better understand sex steroid hormone-dependent and -independent effects on the maturation of kisspeptin neurons, hypogonadal (hpg) mice deficient in GnRH and its downstream effectors were used to determine changes in the developmental kisspeptin expression. In hpg mice, sex differences in Kiss1 mRNA levels and kisspeptin immunoreactivity, typically present at 30 days of age, were absent in the anteroventral periventricular nucleus (AVPV). Although immunoreactive kisspeptin increased from 10 to 30 days of age to levels intermediate between wild type (WT) females and males, corresponding increases in Kiss1 mRNA were not detected. In contrast, the hpg arcuate nucleus (ARC) demonstrated a 10-fold increase in Kiss1 mRNA between 10 and 30 days in both females and males, suggesting that the ARC is a significant center for sex steroid-independent pubertal kisspeptin expression. Interestingly, the normal positive feedback response of AVPV kisspeptin neurons to estrogen observed in WT mice was lost in hpg females, suggesting that exposure to reproductive hormones during development may contribute to the establishment of the ovulatory gonadotropin surge mechanism. Overall, these studies suggest that the onset of pubertal kisspeptin expression is not dependent on reproductive hormones, but that gonadal sex steroids critically shape the hypothalamic kisspeptin neuronal subpopulations to make distinct contributions to the activation and control of the reproductive hormone cascade at the time of puberty.

Myocardial uptake and clearance of thallium-201 in normal subjects: comparison of dipyridamole-induced hyperemia with exercise stress

Thallium-201 uptake and clearance after dipyridamole infusion may differ from that after exercise stress because the hemodynamic effects of these two interventions are different. In this study of normal volunteers, thallium kinetics after dipyridamole (n = 13) were determined from three serial image sets (early, intermediate and delayed) and from serial blood samples and compared with thallium kinetics after exercise (n = 15). Absolute myocardial thallium uptake was greater after dipyridamole compared with exercise (p less than 0.0001), although the relative myocardial distribution was similar. The myocardial clearance (%/h) of thallium was slower after dipyridamole than it was after exercise. Comparing dipyridamole and exercise, the differences in clearance were large from the early to the intermediate image (anterior, -11 +/- 17 versus 24 +/- 5, p = 0.0005; 50 degrees left anterior oblique, -7 +/- 11 versus 15 +/- 8, p = 0.004; 70 degrees left anterior oblique, 3 +/- 9 versus 21 +/- 6, p = 0.001). In contrast, the differences in clearance were small from the intermediate to the delayed image (anterior, 15 +/- 4 versus 20 +/- 2, p = 0.025; 50 degrees left anterior oblique, 15 +/- 4 versus 19 +/- 3, p = 0.13; 70 degrees left anterior oblique, 15 +/- 3 versus 18 +/- 2, p = 0.047). Thallium uptake and clearance in the liver, splanchnic region and spleen were greater after dipyridamole (p less than 0.001). Blood thallium levels were greater after dipyridamole (p less than 0.05) and cleared more slowly (p = 0.07). Thus, myocardial thallium-201 uptake and clearance after dipyridamole infusion differ from thallium kinetics after exercise. This difference is, in part, related to associated differences in extracardiac and blood kinetics. Diagnostic criteria for the detection of abnormal thallium-201 clearance must be specific for the type of intervention.

Gated blood pool tomography: A technology whose time has come

Tomographic gated blood pool imaging is a natural extension of the technologies of planar gated blood pool scanning and rotating Anger camera single photon emission computed tomography (SPECT). The high photon flux, optimum 140 keV energy, and volume sampling of tomography permit reconstruction of the data in any perspective. The true three-dimensional nature of this process allows the evaluation of regional wall motion of all the cardiac chambers, unencumbered by overlapping structures. The heart can be viewed from any angle, including a long axis, short axis, apical four chamber, and a true inferior view. In addition to evaluation of regional wall motion, precise determination of chamber volumes and ejection fractions is possible. Early clinical experience has demonstrated the superiority of tomographic gated blood pool imaging over planar blood pool imaging for precisely defining subtle functional abnormalities. The enormous amount of data generated by this procedure taxes the capacity of most nuclear medicine computer systems. However, the availability of 32-bit processors and large amounts of image memory in new machines should ultimately reduce this processing time to less than ten minutes. The combination of complete visualization and quantitation suggests that a renaissance for blood pool imaging is on the horizon.

New radionuclides for cardiac imaging.

T WO RADIONUCLIDES, thallium-201 and technetium-99m, have assumed preeminence in cardiovascular nuclear medicine because their photon energies, kinetics, and dosimetry are well-suited to make three major physiologic measurements: perfusion, function, and viability. The photon energies of these nuclides are well matched to the characteristics of the Anger camera, which has optimum efficiency and resolution for energies between 100 and 200 keV. The spatial resolution of the “system” for the average cardiovascular nuclear medicine study (radiopharmaceutical, collimator, camera, and computer) at the depth of the heart is approximately 1 cm full width half maximum (FWHM). Against this background, new radiopharmaceuticals suggested for the evaluation of the heart (Table 1) must offer an improvement in dosimetry and resolution, or provide data on a previously unmeasurable parameter. This review will concentrate on the new radiopharmaceuticals that have met two criteria: (1) experience with the radiopharmaceutical in human subjects, and (2) some likelihood of commercial production of the agent for widespread clinical use. Although equilibrium studies provide high quality data for evaluation of regional and global cardiac function, a high photon flux first pass approach, which could evaluate ventricular function during breathholding (to eliminate respiratory motion), would improve resolution. The ideal first pass radionuclide should have a short physical halflife, have no particulate emissions, produce photons of 100 to 200 keV, and decay to a stable daughter. Such an agent would permit multiple measurements to be performed in each view and would allow repetitive determinations of ventricular function during the action of drugs, exercise, or physiologic maneuvers (Valsalva, etc). The following agents have some of these properties and may supplant Tc-99m as the radionuclide for first pass studies.

ECHOCARDIOGRAPHY DERIVED PREDICTORS OF LONG-TERM OUTCOMES AFTER TAVR

Transaortic flow, maximum velocity (V max), mean gradient (MG), Ejection Fraction (EF), Aortic valve area (AVA) and dimensional index (DI) are important determinant of prognosis in patients with severe aortic stenosis. The specific role of these echocardiography-derived values plays in predicting

REDUCING COST OF TAVR PROGRAM THROUGH APPLYING LEAN PROCESSES

Although transcatheter aortic valve replacement TAVR provides an important alternative for patients with severe aortic stenosis, it is associated with high cost with potential economical burden on hospital performing it. Applying lean processes may help in identifying and reducing potential wastes