Regional myocardial blood flow, metabolism and function assessed noninvasively with positron emission tomography

Positron emission computed tomography is a new technique of potential value for the noninvasive measurement of myocardial blood flow, mechanical function and, in particular, metabolism. The capability of this new study method is attributable to the technologic innovations of the imaging device and the availability of radioactive tracers that are specific for blood flow and metabolism. The device permits recording of cross-sectional images of the left ventricular myocardium that quantitatively reflect regional tracer tissue concentrations. Use of tracer kinetic models with this new technique permits measurements of regional glucose and fatty acid metabolism of the heart. Positron emission tomography is already an important new tool for investigative studies of cardiac physiology and pathophysiology; its clinical utility remains to be defined.     

Hemodynamic evaluation of the Carpentier-Edwards bioprosthesis in the aortic position.

The Carpentier-Edwards bioprosthesis is a glutaraldehyde-fixed porcine xenograft with a fully flexible thin-walled stent. Cardiac catheterization studies were performed in 17 patients to evaluate use of this valve in the aortic position. Hemodynamic studies established a mean peak gradient across the prosthesis of 19 mm Hg (range 5 to 65). The mean effective orifice area was calculated to be 1.6 cm2 (range 0.8 to 3.3). All patients demonstrated an improvement in functional class after operation. Mean left ventricular ejection fraction increased from 51 +/- 16 to 68 +/- 9 percent (P less than 0.004) in eight patients operated on for aortic stenosis, but was not significantly changed in patients operated on for aortic insufficiency. Hemodynamic comparison of the Carpentier-Edwards bioprosthesis with the standard Hancock xenograft showed similar effective orifice areas for the 23 and 25 mm diameter valves. In two patients studied the 21 mm Carpentier valve demonstrated a greater effective orifice area than that previously reported for the standard Hancock xenograft. The Carpentier-Edwards bioprosthesis affords both clinical and hemodynamic improvement when used in the aortic position and may allow improved effective orifice area when used in the smaller aortic root.     

Noninvasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilation: VI. Detection of coronary artery disease in human beings with intravenous N-13 ammonia and positron computed tomography

The possibility of detecting mild coronary stenoses with positron computed tomography and nitrogen (N-13) ammonia administered during pharmacologic coronary vasodilation was previously demonstrated in chronically instrumented dogs. The feasibility of using this technique in human beings and its sensitivity in determining the degree and extent of coronary artery disease were examined in 13 young normal healthy volunteers and 32 patients with angiographically documented coronary artery disease. N-13 ammonia was administered intravenously and its distribution in the left ventricular myocardium recorded at rest and during dipyridamole-induced coronary hyperemia. In the 13 volunteers, N-13 activity was homogeneous at rest and during hyperemia, whereas 31 of the 32 patients had regional defects on the hyperemic images not present during rest. All six patients with double, all 10 with triple and 15 of 16 patients with single vessel disease (97 percent) were correctly identified with the technique. Two vessel involvement was correctly identified in five of the six patients with double vessel disease and three vessel disease in six of 10 patients. Of all 58 coronary stenoses, 52 (90 percent) were correctly identified. In a subgroup of 11 patients, the technique was compared with exercise thallium-201 planar images, which were abnormal in 10 (91 percent) whereas N-13 images were abnormal in all 11. Of the 19 stenosed coronary arteries in this subgroup, 11 (58 percent) were correctly identified with thallium-201 and 17 (89 percent) with tomography (p < 0.01). It is concluded that cross-sectional imaging of the myocardial distribution of N-13 ammonia administered during pharmacologic coronary vasodilation is a highly sensitive and accurate means for noninvasive detection of coronary stenoses in human beings and for estimating the extent of coronary artery disease.     

Effect of left ventricular size on mitral E point to ventricular septal separation in assessment of cardiac performance

Increased mitral valve E point to ventricular septal separation (EPSS) is widely used as an echocardiographic index of depressed left ventricular (LV) ejection traction (EF), yet LV size has not been examined as an independent variable potentially affecting EPSS. Accordingly, we studied the relationship between EPSS and functionally normal or depressed LV with or without increased enddiastolic dimensions (EDD). Twenty normal controls had EPSS 3.2 ± 2.2 mm (mean ± SD), EDD 47 ± 5 mm, $\text{EPSS}\text{EDD}$ (“normalized” EPSS) 0.07 ± 0.04, and fractional shortening (FS%) 38 ± 6%. Nine patients with pure chronic mitral regurgitation had dilated LV (EDD = 65 ± 7 mm) with normal LV function (FS% 41 ± 5%; angiographic EF 62 ± 9%); eight patients had dilated cardiomyopathy (EDD 69 ± 8 mm) with decreased LV function (FS% 16 ± 7%; angiographic EF 32 ± 8%); and eight patients with amyloid cardiomyopathy had nondilated LV (EDD 42 ± 5 mm) with decreased LV function (FS% 19 ± 6; angiographic EF 35 ± 7%). Mitral E point to ventricular septal separation and $\text{EPSS}\text{EDD}$ accurately separated individuals with normal and abnormal LV function irrespective of LV size (χ² = 36.7; p < 0.00001). Increased internal dimensions per se did not affect EPSS unless depressed LV function coexisted. EPSS is therefore a valid predictor of depressed ejection phase indices independent of LV size.     

Effects of tachycardia on the adequacy of subendocardial oxygen delivery in experimental aortic stenosis.

We studied the interaction of tachycardia and aortic stenosis on the adequacy of subendocardial oxygen delivery. In 18 open-chest dogs with acute supravalvular aortic stenosis, we produced subendocardial ischemia by increasing either heart rate (artrial pacing) or the severity of aortic stenosis. Ischemia was determined from ST-elevation of the intracavitary electrocardiogram. Subendocardial oxygen supply was assessed by measuring subendocardial flow (radioactive microspheres, 8 to 10 microns) and arterial oxygen content, and related to simultaneous oxygen demand [estimated from the tension time index (TTI)]. The adequacy of the supply/demand relationship in the subendocardium was estimated from the ratio DPTI times 02 content (supply)/TTI (demand). Subendocardial ischemia occurred at aortic gradients ranging from 30 to 100 mm. Hg and heart rates from 120 to 180 beats per minute. Ischemic hearts were characterized by (1) redistribution of coronary flow away from the subendocardium (endo/epi flow ratio less than 1.0), (2) reduced subendocardial oxygen delivery per unit of demand (TTI) (p less than 0.01), (3) failure to lower left ventricular end-diastolic pressure with tachycardia, and (4) supply/demand ratios (DPTI times 02 content/TTI) below 15 ( less than 0.01). These findings suggest that (1) the principal determinant of subendocardial ischemia in aortic stenosis is the unfavorable alteration of the supply/demand relationship caused by the interaction between heart rate and severity of stenosis, rather than absolute heart rate or aortic gradient and (2) the adequacy of subendocardial oxygen delivery can be assessed from readily obtained measurements of blood pressure and oxygen content.     

Measurement of regional myocardial blood flow with N-13 ammonia and positron-emission tomography in intact dogs

N-13 ammonia mimics certain properties of microspheres. It rapidly clears from blood into myocardium where it becomes fixed in proportion to myocardial blood flow. Used with positron emission tomography as a means for quantifying in vivo myocardial indicator concentrations, N-13 ammonia may be useful for noninvasive determination of myocardial blood flow with the arterial reference sampling technique. This possibility was examined in 27 experiments in 10 chronically instrumented dogs at control, high and low blood flows. Myocardial blood flow was calculated in vivo from the myocardial N-13 tissue activity concentrations derived from serial cross-sectional images of the heart, the 2 minute arterial input function and the withdrawal rate of arterial blood. These calculations were compared with blood flow determined by the standard microsphere technique. Blood flow determined in vivo with N-13 ammonia and positron emission tomography correlated with microsphere blood flow by y = -36.2 + 1.53x -0.0027x2 (r = 0.94 with a standard error of the estimate of 16 ml/min per 100 g). For flows from 44 to 200 ml/min per 100 g, the relation between in vivo and in vitro measured myocardial blood flow was nearly linear but reached a plateau at flows higher than 200 ml/min per 100 g. These results indicate that in dogs, blood flow in the physiologic range can be quantified in vivo with N-13 ammonia and positron emission tomography.     

Flail aortic valve leaflets: M-mode and two-dimensional echocardiographic manifestations

Four patients with documented flail aortic valve leaflets were studied using M-mode and two-dimensional echocardiography (2-D echo). Two had aortic valve endocarditis, one had endocarditis involving a congenital heart defect, and one had a myxomatous aortic valve. Mitral valve flutter and early mitral valve closure led to the diagnosis of severe aortic insufficiency in three patients. Diastolic aortic valve flutter, considered to be specific for a flail aortic leaflet, was present in three patients. In the fourth patient left ventricular outflow tract (LVOT) echoes were present, but did not distinguish between a flail aortic leaflet and an aortic vegetation. Two-D echo confirmed LVOT echoes in all patients. Discrimination between a flail leaflet and a vegetation(s) without leaflet disruption was accomplished by noting the hinge point of the LVOT diastolic echoes, which was the aortic wall in patients with a flail leaflet.The combination of these M-mode and 2-D echocardiographic findings permitted the diagnosis of a flail aortic leaflet to be made accurately and noninvasively. In two patients surgery was performed without prior cardiac catheterization.     

Triacetylated insulin: biologic activity and resistance to degradation.

Tritiated N-hydroxysuccinimide acetate was prepared with specific activities up to 5 Ci/mmole and utilized to prepare tritiated triacetyl insulin. Binding of triacetyl insulin to liver plasma membranes was measured by its capacity to displace 125I-monoiodoinsulin. At low concentrations, less than 10 ng/ml triacetyl insulin appears to be as effective as native insulin in reducing the binding of 125I-monoiodoinsulin to plasma membranes. At concentrations of 20 ng/ml and higher, triacetyl insulin is significantly less effective than native insulin in displacing binding of 125I-monoiodoinsulin to plasma membranes. The properties of triacetyl insulin in this system are not ascribable to deacetylation and conversion of the substituted product to native insulin. Biologic activity of triacetylated insulin was studied in two other in vitro systmes. A comparison was made of the capacity of native beef insulin and its triacetyl derivative to stimulate glucose oxidation by epididymal fat pads. At all three concentrations tested (2, 6, and 18 ng/ml), triacetyl insulin exerted considerable activity, although its potency was significantly less than that of native insulin. Similar effects were observed when biologic activity was measured by induction of tyrosine-alpha-ketoglutarate transaminase in a cultured liver cell system where significant activity of triacetyl insulin was found at concentrations of 10(-9)-10(-7) M. In all systems tested, the activity of triacetylated insulin could not be accounted for by deacetylation and conversion to native insulin. In all systems studied, triacetyl insulin was more resistant to degradation than was monoiodoinsulin.     

Effect of protein intake and dialysis on the abnormal growth hormone, glucose, and insulin homeostasis in uremia.

To evaluate the role of protein intake in the altered growth hormone (GH) secretion of chronic renal failure, GH responses to mild exercise and to an oral glucose tolerance test were measured in ten uremic patients ingesting both low and normal protein diets. To delineate the effect of uremia on any interaction between GH and protein intake, tests were performed before dialysis, after daily dialyses for 3-4 days and after withholding dialysis for 3-4 days. Results were as follows: (1) exercise-stimulated GH release was increased compared to controls; (2) protein intake did not alter GH secretion, (3) basal GH concentrations were significantly correlated with creatinine levels and were significantly lower after dialysis, (4) dialysis did not improve the oral glucose tolerance test, (5) there was no correlation between glucose tolerance and exercise-stimulated GH levels, basal GH concentrations, or the sum of GH values after glucose, and (6) dialysis significantly increased the insulin response to glucose. Conclusions: In chronic renal failure enhanced GH secretion is not affected by protein intake, does not cause glucose intolerance, and may be related to the degree of uremia. Dialysis does not improve glucose tolerance, but does increase glucose-stimulated insulin release suggesting that insulin antagonism is not ameliorated.     

The American Heart Journal: Enhanced service to the cardiovascular community

Seventeen patients presenting with unstable angina pectoris underwent percutaneous transluminal coronary angioplasty (PTCA). Despite vigorous medical therapy, all patients were disabled with 10 experiencing refractory in-hospital angina. PTCA was judged successful in 13 patients and resulted in decreased coronary diameter narrowing from 80 ± 16% to 34 ± 13% and reduced transstenotic pressure gradient from 69 ± 13 to 23 ± 12 mm Hg. Regional coronary blood flow (CBF) and myocardial metabolism were assessed at rest and during pacing tachycardia in six patients with left anterlor descending coronary stenosis. Prior to PTCA, neither regional CBF increased nor coronary vascular resistance declined during rapid pacing; myocardial lactate extraction fell, indicating a shift from aerobic to anerobic metabolism. Following PTCA, however, rapid pacing resulted in increased regional CBF, decreased coronary vascular resistance, and preservation of aerobic metabolism. Following PTCA, successfully dilated patients demonstrated marked relief of angina symptoms, increase in functional capacity, and objective exercise ECG and thallium scintigraphic evidence of relief of previously ischemic myocardium. This investigation demonstrates that PTCA, when combined with medical therapy, can be performed safely and successfully in selected patients who present with otherwise refractory unstable angina, and indicates the procedure deserves further study as a therapeutic alternative in this condition.     

Risk of infection associated with the use of Broviac and Hickman catheters

A 4-month prospective medical records review was done to investigate the occurrence of central venous catheter-related infections. Nineteen percent of the patients developed a catheter-related infection, either local infection at the insertion site (8.9%) or septicemia (10.0%). There were 7.5 catheter-related infections per 1000 catheter-use days. The infection rate was five times greater in patients with Hickman catheters than in those with Broviac catheters (p = 0.01). Analysis by the life table approach produced a linear curve of catheter-related infection over time, suggesting a constant daily risk of catheter-related infection.     

Correlation of the location of coronary arterial spasm with the lead distribution of ST segment elevation during variant angina

The lead distribution of ST segment elevation produced by severe “spasm” of major coronary arteries was correlated with the specific artery involved in a group of 110 cases of variant angina with single vessel coronary arterial spasm made up from eight cases personally observed and 102 cases abstracted from published literature.The most sensitive and specific lead for ST elevation during anterior descending (LAD) coronary arterial spasm was V₃; V₂ was almost as good. For spasm of either the right (RCA) or circumflex coronary artery (CMFX), Leads 3 and aV_F showed ST elevation most frequently; electrocardiographically it was difficult to distinguish between spasm of these two vessels. ST elevation in Leads V₅ and V₆ was not specific, occurring in some cases of spasm of each of the three major coronary arteries. ST elevation in Lead V₁ occurred in either RCA or LAD spas, but never in CMFX spasm. ST elevation in Lead 1 was never seen with isolated RCA spasm.No single lead can detect all cases of transient ST elevation. Simultaneous monitoring of Leads 3 and V₃ would have detected 98.2% of 333 cases of ST elevation reviewed, and addition of Lead aV_L would have detected most of the remainder. These findings should be considered in lead selection for monitoring to detect ST elevation, and in using the ECG to identify spastic coronary arteries.     

Retention and clearance of C-11 palmitic acid in ischemic and reperfused canine myocardium

Free fatty acids are the major energy source for cardiac muscle. Oxidation of fatty acid decreases or even ceases during ischemia. Its recovery after transient ischemia remains largely unexplored. Using intracoronary carbon-11 palmitic acid as a tracer of myocardial fatty acid metabolism in an open chest dog model, retention and clearance of tracer in myocardium were evaluated at control, during ischemia and after reperfusion following a 20 minute occlusion of the left anterior descending coronary artery. Myocardial C-11 time-activity curves were analyzed with biexponential curve-fitting routines yielding fractional distribution and clearance half-times of C-11 palmitic acid in myocardial tissue. In animals with permanent occlusion and intracoronary injection of C-11 palmitic acid distal to the occlusion site, the relative size and half-time of the early clearance curve component differed markedly from control values and did not change with ongoing ischemia. Conversely, in animals with only 20 minutes of coronary occlusion, the relative size of the early C-11 clearance phase was still significantly depressed at 20 and 90 minutes of reperfusion but returned to control level at 180 minutes. Tissue C-11 clearance half-times remained significantly prolonged throughout the reperfusion period. Regional function in reperfused myocardium monitored with ultrasonic crystals recovered slowly and was still less than control after 3 hours of reperfusion. The data indicate that after transient ischemia, myocardial fatty acid metabolism fails to recover immediately. Because the metabolic recovery occurs in parallel with recovery of regional function, C-11 palmitic acid in conjunction with positron tomography may be useful for studying regional fatty acid metabolism noninvasively after an ischemic injury, and may be helpful in identifying reversible tissue injury.     

Regional myocardial dysfunction in patients with angina at rest and response to isosorbide dinitrate assessed by phase analysis of radionuclide ventriculograms

Left and right ventricular synchrony was assessed in 15 patients with angina at rest but no previous infarction by phase analysis of equilibrium radionuclide ventriculograms. Transient thallium-201 perfusion defects were noted in all during angina at rest and coronary vasospasm was documented in nine of the patients. Radionuclide ventriculograms were performed at control, during the ischemic episodes and after intravenous isosorbide dinitrate. Left and right ventricular phase histograms were quantified by the standard deviation from the mean of the peak (SD). Left ventricular ejection fraction averaged 65 +/- 11% (mean +/- standard deviation) at control, decreased in all patients during angina at rest to 49 +/- 14% (p less than 0.01) and increased in all patients after isosorbide dinitrate to 66 +/- 12%. However, ejection fraction during ischemia was abnormal in only nine patients and changed in two by less than 5% from the control value. Regional wall motion abnormalities were noted in all patients during the ischemic episodes but resolved after isosorbide dinitrate administration. Control left ventricular SD was 14.5 +/- 4 degrees, increased in all patients to 22.8 +/- 5 degrees during angina at rest (p less than 0.01) and returned to control values after isosorbide dinitrate administration (14.2 +/- 4 degrees). In contrast, right ventricular SD did not significantly change during ischemia as compared with control and isosorbide dinitrate. It is concluded that in angina at rest, a normal left ventricular ejection fraction does not exclude severe regional dysfunction; separate left and right ventricular SD is a sensitive index in detecting transient left ventricular dysfunction, and relief of ischemia is associated with rapid normalization of regional left ventricular function.     

Insulin binding and action in isolated rat hepatocytes: Evidence for spare receptors

An in vitro assay for insulin action on hepatocytes is described. The ¹²⁵I-insulin binding and the effects of insulin on net ¹⁴C-glucose incorporation into glycogen were studied in suspensions of isolated hepatocytes from fed, 250 gram adult rats. Insulin doubled the basal value (mean ± SEM) of 9.0 ± 1.0 nmoles glucose/10⁶ cells/hr with a one-half maximal concentration of 3 ng/ml (75 μU/ml) and a maximum effect between 10 and 20 ng/ml (250 μU/ml). Insulin binding was half-maximal at 40 ng/ml and maximal between 100 and 300 ng/ml. Thus, maximal stimulation occurred at approximately 35% of maximum binding implying that hepatocytes have spare receptors for insulin action on net incorporation of ¹⁴C-glucose into glycogen. This assay was then used to investigate the time course of activation of insulin action. Isolated hepatocytes were preincubated at 37°C in the presence or absence of 40 ng/ml of insulin for 2, 15, or 30 min, washed, and then tested for action in fresh insulin-free media containing ¹⁴C-glucose. No activation was seen after 2 min, a partial activation after 15 min and maximum activation was seen only after a 30 min preincubation. Therefore, insulin activation of glucose incorporation into glycogen in liver is a time-dependent phenomenon that is reversible by early dissociation.