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.     

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.     

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.     

The effect of aging on carbohydrate metabolism: a review of the English literature and a practical approach to the diagnosis of diabetes mellitus in the elderly.

There seems little doubt that the disposal of a glucose load is progressively impaired during aging. The mechanism(s) for this alteration remains unclear. Five possibilities have been raised: (1) poor diet, (2) physical inactivity, (3) decreased lean body mass in which to store the carbohydrate load, (4) decreased insulin secretion, and (5) insulin antagonism. Although poor diet and physical inactivity may contribute to some of the abnormal glucose tolerance tests of the older population, these two factors do not provide a full explanation. Diminished lean body mass may play some role but there is almost certainly an additional effect due to aging. A few papers have suggested that glucose-induced insulin secretion may be impaired as the population ages, but the bulk of studies in this area conclude that normal or increased amounts of insulin are released by the pancreatic beta-cell during aging. If abnormalities of insulin secretion exist, either in degree or timing, they are subtle and would not seem sufficient to account for the great number of older subjects who manifest impaired glucose tolerance. The evidence for insulin antagonism seems the strongest but the data are certainly not conclusive. In actuality, the aging effect on carbohydrate metabolism may be heterogeneous in nature. Either some or all of these five factors may contribute to the aging effect to varying degrees in individual subjects. Alternatively, the glucose intolerance of aging may represent a heterogeneous group of disorders. In any event, until better methods to identify possible subgroups of these subjects and/or a marker for diabetes mellitus independent of glucose concentration become available, this problem will remain difficult to resolve. Based on the currently available data, it seems prudent to diagnose diabetes mellitus only if fasting hyperglycemia is present.     

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.     

Sustained regional abnormalities in cardiac metabolism after transient ischemia in the chronic dog model

Positron emission tomography allows noninvasive assessment of myocardial blood flow and metabolism, and may aid in defining the extent and severity of an ischemic injury. This hypothesis was tested by studying, in chronically instrumented dogs, regional blood flow and metabolism during and after a 3 hour balloon occlusion of the left anterior descending coronary artery. The metabolic findings after ischemia were compared with the recovery of regional function over a 4 week period. N-13 ammonia was used as a blood flow tracer, and C-11 palmitic acid and F-18 deoxyglucose as tracers of fatty acid and glucose metabolism, respectively. Regional myocardial function was monitored with ultrasonic crystals implanted subendocardially. Regional function improved most between 24 hours and 1 week after reperfusion, but was still attenuated at 4 weeks. The slow functional recovery was paralleled by sustained metabolic abnormalities, reflected by segmentally delayed clearance of C-11 activity from myocardium and increased uptake of F-18 deoxyglucose. Absence of blood flow and C-11 palmitic acid uptake at 24 hours of reperfusion correlated with extensive necrosis as evidenced by histologic examination. Conversely, uptake of C-11 palmitic acid with delayed C-11 clearance and increased F-18 deoxyglucose accumulation identified reversibly injured tissue that subsequently recovered functionally and revealed little necrosis. Thus, recovery of metabolism after 3 hours of ischemia is slow in canine myocardium and paralleled by slow recovery of function. Metabolic indexes by positron tomography early after reperfusion can identify necrotic and reversibly injured tissue. Positron tomography may therefore aid in defining the extent and prognosis of an ischemic injury in patients undergoing reperfusion during evolving myocardial infarction.     

Symposium on infectious complications of neoplastic disease (Part II). Immunoprophylaxis and serotherapy of bacterial infections

Immunologic approaches to the prevention and treatment of bacterial infections date back to the antecedent century. Recent interest and controversy has centered about the efficacy of gram-negative bacillary vaccines, antiserum against endotoxin, and pneumococcal vaccines. Immunization of cancer patients with Pseudomonas lipopolysaccharide vaccines has yielded inconsistent results. Factors limiting the further application of this approach are the poor immune responses in neutropenic patients and the marked pyrogenicity and pain associated with vaccine administration. Similarly, patients being treated for neoplasms of the hematopoietic system are not likely to show good antibody responses to pneumococcal antigens, even though they are not toxic. Pneumococcal immunization appears to be effective, at least as measured in terms of antibody titers, in those patients with lymphoma who have not undergone splenectomy and are not receiving chemotherapy at the time of immunization. The most reliable approach towards immunoprophylaxis may be the passive one, with antibody being produced in normal donors. The antibodies are short-lived, and this type of prophylaxis still needs to be evaluated in controlled trials. In a recently completed controlled therapeutic trial, the therapeutic application of an antiserum against core endotoxin antigens resulted in a significant reduction in deaths and increased recovery from shock complicating gram-negative sepsis. However, antiserum failed to protect cancer patients or neutropenic subjects.     

Central nervous system toxoplasmosis in homosexual men

Many opportunistic infections have been associated with an acquired immunodeficiency state in which cellular immune status has been altered. Two homosexual patients are described who presented with fever, peripheral eosinophilia, and a travel history to Haiti and were found to have central nervous system toxoplasmosis. Despite definitive diagnosis and appropriate therapy, both died. Techniques for diagnosis of central nervous system toxoplasmosis are discussed, and the importance of brain biopsy in this clinical situation is stressed. Eosinophilia may serve as an early diagnostic marker for disseminated toxoplasmosis in homosexual patients.     

M mode and cross-sectional echocardiographic features of flail posterior mitral leaflets

Seventeen patients with accepted M mode echocardiographic criteria for flail mitral leaflet were studied. M mode echocardiograms revealed characteristic disordered mitral valve motion: (1) 16 (94 percent) had chaotic diastolic mitral motion; (2) 14 (82 percent) had systolic mitral flutter; (3) 14 (82 percent) had systolic left atrial echoes; and (4) 12 (71 percent) had systolic mitral valve prolapse. In 8 patients (47 percent) all four findings were present, with three findings present in 16 (35 percent) and two findings present in 13 (18 percent); none had fewer than two findings. Cross-sectional echocardiographic studies in 10 patients revealed a systolic whipping motion of the posterior mitral leaflet into the left atrium in all, abnormal systolic mitral coaptation in all and an abnormal mass of systolic left atrial echoes in 4. None of the first three M mode criteria were observed in 230 patients with uncomplicated “mid systolic click-late systolic murmur” syndrome; cross-sectional echocardiography in 30 of 230 patients revealed normal systolic mitral coaptation and no systolic whipping of the tip of the posterior mitral leaflet into the left atrium.     

Aging changes in lymphopoietic and myelopoietic organs of the annual cyprinodont fish, Nothobranchius guentheri

The thymus of aging annual, cyprinodont fish, Nothobranchius guentheri and Cynolebias adloffi begins to undergo senescent changes at approximately four months. At this time, the histopathology reveals increased amounts of connective tissue, epithelial cysts and myoid cells, but decreased numbers of thymocytes. At 12 months, of the 50 fish observed at 10 stages from day 15 and 1, 2, 4, 6, 8, 9, 10, 11, 12 months the maximum time of senescence, there was an increased incidence of tumors in the oral cavity, connective tissue, kidney and liver in all 5 fish. At least in the kidney, the malignant transformation was classified as nodular-type histiocytic lymphoma. It is of interest that development of these tumors occurs during peak senescent changes in the thymus, supporting the view that as fish age, accompanied by atrophy of the thymus, the immune system is less vigorous and there is an increase in the incidence of cancer.     

Metabolism of 1-14C-ornithine and 1,4-14C-putrescine in chronically uremic and control rats

The metabolism of ornithine and putrescine was studied in vivo in chronically uremic and control rats. Rats were injected intraperitoneally with 1-¹⁴C-ornithine or 1,4-¹⁴C-putrescine and expired ¹⁴CO₂ was collected for 4 hr. After injection of 1-¹⁴C-ornithine, ¹⁴CO₂ expiration was decreased in uremic rats as compared to controls. Conversely, after 1,4-¹⁴C-putrescine injection, expiration of ¹⁴CO₂ was increased in uremic rats as compared to controls. Four hours after the injection of 1-¹⁴C-ornithine, there was more radioactivity in liver and muscle and less radioactivity in kidney of uremic rats as compared to the respective sources in control rats. In uremic rats, 4 hr after the 1,4-¹⁴C-putrescine injection, the radioactivity retained in the muscle and plasma was greater than in corresponding sources in control rats; whereas the radioactivity retained in uremic liver and kidney was similar to that of control rats. The greater putrescine-derived radioactivity retained in uremic tissues reflects either the retention of injected tracer compounds, or retention or decreased catabolism of putrescine metabolites. From ¹⁴CO₂ expiration data obtained, it appears that ornithine catabolism is reduced while putrescine catabolism is increased in uremia.     

Left ventricular volume characteristics in children with tricuspid atresia before and after surgery

Left ventricular volume variables (left ventricular end-diastolic volume, ejection fraction, mass and systolic output) were quantified in (1) 13 patients with tricuspid atresia preoperatively (type Ia, 3 patients; type Ib, 9 patients; type IIb, 1 patient), (2) 4 patients after a shunt procedure (Blalock-Taussig, 3; Glenn, 1), and (3) 1 patient after corrective surgery. Cardiac catheterization and angiography were performed at age 1 month to 5.8 years (mean 1.4 years). All patients had decreased pulmonary blood flow. The results were compared with data in 15 patients with no significant heart disease. Left ventricular end-diastolic volume was significantly greater than normal in 12 of the 13 patients. Left ventricular mass was significantly greater than normal, but ejection fraction was significantly less than normal. There was a positive correlation between ejection fraction and systemic oxygen saturation. Left ventricular systolic index was normal in 9 of the 13 patients preoperatively. After a shunt procedure, left ventricular end-diastolic volume and systolic index increased significantly in all four patients, and ejection fraction improved greatly in three of the four. After corrective surgery, left ventricular end-diastolic volume and left ventricular systolic index returned to the normal range and left ventricular ejection fraction improved. These findings suggest that patients with tricuspid atresia have impaired left ventricular function.     

Relation of coronary arterial spasm to sites of organic stenosis

Among 63 patients with Prinzmetal's variant angina, coronary arterial spasm responsible for attacks of variant angina was documented arteriographically in 9 patients. In each observed episode (11 attacks in nine patients), coronary spasm producing myocardial ischemia occurred at and was superimposed on a site of preexisting organic stenosis. Measurements of normal portions of "spastic" and "nonspastic" vessels suggested a generalized uniform constriction of all major coronary arteries during attacks, with "spasm" limited to the site of an organic lesion in most cases. In two cases the magnitude of constriction in all vessels was consistent with generalized coronary hypercontractility or spasm. Among 104 patients with organic coronary artery disease and documented single vessel coronary spasm (foregoing 9 patients combined with 95 others from published reports), there were 70 patients with essentially single vessel organic coronary disease in 90 percent of whom the spasm involved the diseased vessel. Of 60 cases abstracted from the literature in which the relation of coronary spasm to the site of organic disease was described, 88 percent had the spasm causing ischemia localized to the site of an organic lesion. Hypotheses attempting to describe the pathophysiologic aspects of coronary spasm in variant angina must account for the intimate association of spasm with sites of organic stenosis in the majority of cases.     

Musical murmurs: An echo-phonocardiographic study

Five patients with musical murmurs were studied noninvasively with simultaneous echocardiography and phonocardiography. Three patients had aortic regurgitation, one mitral regurgitation and one tricuspid regurgitation. The frequency of the musical murmurs ranged from 40 to 158 cycles/sec. The patient with tricuspid regurgitation manifested an inspiratory honk. Simultaneous echo-phonocardiography revealed regular valve leaflet flutter (aortic, mitral or tricuspid) at a frequency identical to that of the simultaneously recorded musical murmur. This study demonstrates that echocardiography is a useful noninvasive tool in identifying the site of origin of musical murmurs.     

Hypertension and propranolol therapy: Effect on blood pressure,plasma catecholamines and platelet aggregation

The effects of propranolol on blood pressure, plasma catecholamine concentration and platelet aggregation were examined in 16 patients with uncomplicated primary hypertension. The patients were studied at rest, during isometric handgrip stress and 48 hours after sudden discontinuation of propranolol therapy. Plasma catecholamine concentration and platelet aggregation studies were also carried out in 11 age-matched normotensive and healthy subjects at rest.Plasma catecholamine concentration and platelet aggregation were greater in the hypertensive than in the normotensive subjects, but the difference reached statistical significance for aggregation only. Exercise significantly increased catecholamines and platelet aggregability. The administration of propranolol (240 mg/day) produced a significant decrease in systolic and diastolic blood pressure and in aggregation (the percent of light transmission at 1 μM adenosine diphosphate, at rest) and a significant increase in catecholamine concentration. However, propranolol did not prevent the changes in all these variables with exercise.The abrupt discontinuation of propranolol was not associated with any subjective or objective untoward cardiovascular effect or abnormal changes in plasma catecholamines. However, in some patients the platelet aggregation studies demonstrated a hyperaggregable state, which may be due to a state of supersensitivity of platelets to circulating catecholamines.     

Ischemia in aortic stenosis: Hemodynamic prediction

The records of 12 patients with aortic stenosis previously studied by Fallen et al. ¹ in 1967 before and after infusion of isoproterenol were reviewed to assess the value of hemodynamic indexes in predicting myocardial ischemia—defined as less than 5 percent transmyocardial lactate extraction or lactate production. Potential subendocardial blood supply was estimated from a diastolic pressure-time index (DPTI), calculated from aortic and left ventricular pressure, and oxygen demand, estimated from the tension-time index (TTI). The ratio DPTI/TTI was used to estimate the supply/demand relation.

Of eight patients with aortic stenosis but without associated coronary artery disease, four (Group A) metabolized lactate normally after administration of isoproterenol, and four (Group B) had biochemical evidence of ischemia. Three of four patients (Group C) with aortic stenosis and associated coronary artery disease had abnormal glycolysis after administration of isoproterenol. Calculated aortic valve areas were comparable in all groups. In patients with aortic stenosis alone, abnormal lactate metabolism occurred whenever DPTI/TTI was less than 0.30 (P < 0.01) (Group B). Two of three patients with aortic stenosis and associated coronary artery disease (Group C) showed abnormal lactate metabolism when DPTI/TTI was greater than 0.6; this ratio was below 0.3 in the third patient.

These results suggest that the supply/demand relation calculated from these readily obtained indexes may be useful (1) in predicting in which patients with aortic stenosis ischemia will develop, (2) in distinguishing the role played by associated coronary artery disease, and (3) as an adjunct to calculation of valve area since the quantitation of associated aortic regurgitation is not necessary.     

Serologic characterization of patients with two episodes of acute viral hepatitis

Since testing for serologic markers of hepatitis B virus (HBV) became routine, we have observed in our hospital 28 patients with two distinct episodes of illnesses, each of which was compatible with acute viral hepatitis. We found no distinctions between the first and second bouts with respect to clinical characteristics, abnormalities of liver function or epidemiologic background. Testing of specimens obtained during each of the two acute episodes, the interval between the two episodes and the period subsequent to the second by sensitive procedures for hepatitis B surface antigens (HB_sAg) and their corresponding antibodies (anti-HB_s) permitted the following classification: 13 of 28 patients experienced first bouts serologically classifiable as due to HBV; 11 patients had second bouts serologically classifiable as due to HBV; 2 patients had two episodes both of which were serologically indeterminate; and 2 patients had two bouts neither of which appeared compatible with HBV infection by present criteria. No patient had a second episode for which the HB_sAg and anti-HB_s data suggested HBV recurrence or reinfection. This evidence does not favor the speculation that HBV can account for repeated episodes of acute icteric hepatitis.     

Spatial reconstruction of human femoral atheromas showing regression.

Reports of atherosclerotic changes in human subjects previously described have been based on evaluation of arteriographic edge contours. They imply unchanged roentgenographic and physiologic conditions, including identical patient positioning and vascular tone which cannot always be obtained in sequential studies. We have previously described the development of quantitative angiographic densitometry which permits measurement of vascular cross-sectional chord length distributions and areas, independent of rotational changes in vascular position. In this paper we report on application of the method to sequential femoral angiograms in two patients in whom there were significant increases in vascular cross-sectional area after a program of exercise and risk reduction. The method excludes interpretive errors due to circumferential changes in vascular tone.     

Alveolar macrophage dysfunction in human bone marrow transplant recipients

We studied the functional characteristics of alveolar macrophages obtained by segmental pulmonary lavage from allogeneic marrow transplant recipients without evidence of ongoing pulmonary infection. The macrophages were mostly of donor marrow origin as judged by Y body fluorescence and were morphologically normal, except for the intracellular accumulation of various amounts of heterogeneous foreign materials. Macrophage function of patients studied within four months after transplantation was impaired, as measured by chemotaxis, phagocytosis and killing of Candida pseudotropicalis, and killing of bacteria. In two patients studied six and 12 months after transplantation, macrophage functions returned toward normal except for a persistent defect in killing of C. pseudotropicalis. Cytomegalovirus was cultured from the lavaged cells of two patients, but the macrophage dysfunction was independent of the cytomegalovirus isolation. These results show that alveolar macrophage dysfunction occurs in marrow transplant recipients and may be associated with their increased risk for pulmonary infections.     

Increased right ventricular wall thickness on echocardiography in amyloid infiltrative cardiomyopathy

In six patients with clinically significant amyloid infiltrative cardiomyopathy, echocardiographic right ventricular anterior wall thickness was significantly increased (mean 7.5 ± 2.3 mm; range 5 to 10 mm). This finding in conjunction with the previously described abnormalities of the left ventricle (symmetric increase in wall thickness, diffuse hypokinesia, and small to normal left ventricular diastolic dimension) is consistent with the findings of a diffuse myocardial infiltrative process and should minimize confusion with constrictive pericarditis.