Preservation of myocardial ultrastructure after 24 hours of Klebsiella sepsis: histologic, functional, and biochemical correlations.

Myocardial function with ultrastructure and high energy phosphate levels in dogs was correlated after 24 hours of sepsis using live Klebsiella aerogenes. All animals developed progressive hemodynamic deterioration over a 24 hour period. Mean arterial pressure decreased from 148 +/- 7 mmHg to 85 (P less than 0.01) and cardiac output decreased from 3.43 +/- .31 to 1.6 +/- 0.5 L/min. Left ventricular stroke work decreased from 48.2 +/- 5 to 18.1 +/- 6 gm-meters (P less than 0.001). Systemic and pulmonary vascular resistances were increased at 24 hours (3,538 +/- 27 to 7,404 +/- 1,400 dyne/sec/cm-5 (P less than 0.01), and 185 +/- 20 and 619 +/- 90 dyne/sec/cm-5 (P less than 0.001), respectively. Left ventricular function curves at 24 hours showed a fixed low output. However, myocardial ultrastructure was preserved and high energy phosphate levels remained normal. These observations correlate well with the changes seen clinically in early gram negative sepsis in hypovolemic patients. Thus, this appears to be a suitable model for further investigation of the effects of gram negative sepsis on myocardial performance, ultrastructure, and maintenance of energy stores.

Aging and arteriosclerosis. Cell cycle kinetics of young and old arterial smooth muscle cells.

Intimal cell proliferation is a "hallmark" of atherosclerosis. Myointimal hyperplasia in arteries has been shown to be dependent on age after vascular endothelial denudation and injury associated with vascular transplantation. Because myointimal thickening is greater in aged rats than in younger rats, and aortic segments from old rats transplanted into young syngeneic recipients have a greater myointimal proliferative response to injury than its host environment, the authors examined the cell cycle distributions of old and young rat arterial smooth muscle cells (SMCs) by flow-cytometric analysis. They observed that there is an apparent age-dependent variation in the cell cycle distribution. Moreover, old SMCs have a greater percentage of their population in the S phase and not G2/M, compared with young SMCs; and there is a decrease in the percentage of old cells in the G0/G1 phase as compared with young SMCs. These differences may reflect the cellular changes observed during myointimal hyperplasia following vascular injury. It is concluded that our data support the hypothesis that the proliferation of SMCs is dependent, in part, on those processes related to aging as well as to the phenotypic state of the cell.

Clinical and neuropathological findings in systemic lupus erythematosus: the role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura.

We reviewed the medical records and autopsy reports of 50 patients with systemic lupus erythematosus to determine the clinical and neuropathological features of this disease. Neuropsychiatric disturbances were found in the majority (74%) of the patients, occurring as psychiatric illness only (5 patients), neurological disorders only (15 patients), and both together (17 patients). Central nervous system (CNS) lesions were present in half the patients; embolic brain infarcts (10 patients) and CNS infections (8 patients) were the most common. Cardiac sources of emboli were Libman-Sacks endocarditis (5 patients), chronic valvulitis (2 patients), and left side of heart mural thrombus (2 patients). There was no evidence of active CNS vasculitis. Clinical features of thrombotic thrombocytopenic purpura (TTP) developed during the terminal illness in 14 patients, 7 of whom also had pathological evidence of TTP. Correlation between neuropsychiatric disorders and brain lesions could be made in approximately half the patients. This study indicates that cardiac emboli from Libman-Sacks endocarditis and TTP are common pathogenetic factors of CNS disease in systemic lupus erythematosus, whereas CNS vasculitis is rare.

Ectopic insulin production by a primary ovarian carcinoid.

An insulin-containing ovarian carcinoid was found at the autopsy of a 63-year-old woman with a 12-year history of episodic hyperinsulinemic hypoglycemia. In terms of histology, the carcinoid displayed both insular and trabecular patterns and contained a small focus of mucinous cystadenoma. Beta secretory granules were demonstrated by electron microscopy, and immunoreactivity for insulin was demonstrated in tumor cell cytoplasm by immunohistochemistry. Additional autopsy findings included a solitary parathyroid adenoma and a microscopic focus of pituitary hyperplasia. This is the first recorded case of insulin production by a primary ovarian neoplasm. The patient's constellation of endocrine findings may represent a variant of the syndrome of type I multiple endocrine neoplasia.

Improved sex-specific criteria of left ventricular hypertrophy for clinical and computer interpretation of electrocardiograms: validation with autopsy findings.

In a previous study of 543 patients we developed, using echocardiographic left ventricular mass as the reference standard, two new sets of criteria that improve the electrocardiographic diagnosis of left ventricular hypertrophy (LVH). One set of criteria, which is suitable for routine clinical use, detects LVH when the sum of voltage in RaVL + SV3 (Cornell voltage) exceeds 2.8 mV in men and 2.0 mV in women. The second set of criteria, suitable for use in interpretation of the computerized electrocardiogram, uses logistic regression models based on electrocardiographic and demographic variables with independent predictive value for LVH, with separate equations for patients in sinus rhythm and atrial fibrillation. To test these criteria prospectively with use of a different reference standard, antemortem electrocardiograms were compared with left ventricular muscle mass measured at autopsy in 135 patients. Sensitivity of standard Sokolow-Lyon voltage (SLV) criteria (SV1 + RV5 or RV6 greater than 3.5 mV) for LVH was only 22%, but specificity was 100%. The Cornell voltage criteria improved sensitivity to 42%, while maintaining high specificity at 96%. Higher sensitivity (62%) was achieved by use of the new regression criteria, with a specificity of 92%. Overall test accuracy was 60% for SLV criteria, 68% for the Cornell voltage criteria, and 77% for the new regression criteria (p less than .005 vs SLV). We conclude that the Cornell voltage criteria improve the sensitivity of the electrocardiogram for detection of LVH and are easily applicable in clinical practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic detection of pressure-overload left ventricular hypertrophy: effect of criteria and patient population.

To evaluate the performance of M-mode echocardiography for detection of pressure-overload left ventricular hypertrophy (LVH), we tested the sensitivity of previously defined sex-specific upper limits of normal echo LV measurements in 31 patients with necropsy-proven pressure-overload LVH and determined the prevalence of LVH detected by each echo criterion in 316 employed patients with uncomplicated hypertension, 100 patients with hypertension evaluated in a referral center, and 38 hospital patients with moderate to severe (WHO class 2) hypertension. Echo measurements were LV mass (LVM), LVM index (LVMI), cross-sectional area (CSA), septal and posterior wall thickness (IVST and PWT), LV internal dimension (LVID), and relative wall thickness (RWT). Prevalences of echo LVH were as follows. (Table: see text). Thus, echo criteria based on LVM are more sensitive than other measurements for detection of necropsy-proven pressure-overload LVH and reveal the highest prevalence of LVH in clinical hypertension populations, and the prevalence of LVH in hypertension is highly dependent on the population studied.

Cost-effectiveness of echocardiography and electrocardiography for detection of left ventricular hypertrophy in patients with systemic hypertension.

Although echocardiography is more accurate than electrocardiography for detection of left ventricular hypertrophy, it is also more expensive, making it uncertain whether echocardiography is cost-effective for detection of this abnormality in hypertensive patients. Accordingly, the sensitivity of M-mode echocardiographic and electrocardiographic criteria for left ventricular hypertrophy was determined in necropsied patients with anatomic hypertrophy of mild (n = 26), moderate (n = 21) or severe (n = 46) degree, and the prevalence of each degree of hypertrophy was determined in 561 hypertensive adults drawn from clinical and employed population samples. The sensitivity of echocardiographic left ventricular mass index criteria was 57% in necropsied patients with mild hypertrophy and 98% in patients with moderate or severe hypertrophy. All electrocardiographic criteria exhibited lower sensitivity: 15 to 42% for mild, 10 to 38% for moderate, and 30 to 57% for severe hypertrophy. Cost estimates from three sources were $160 for M-mode echocardiography and $48 to $64 for 12-lead electrocardiography. In populations with a 12 to 40% prevalence of hypertrophy, echocardiography was calculated to cost less than electrocardiography per instance of hypertrophy detected ($390-$1013 vs $800-$1829), yielded better separation in predicted incidence of morbid events between hypertensive patients with or without hypertrophy (3.4-4.7 vs 1.5-2.1 per 100 patient-years as opposed to 3.0-4.4 vs 1.9-2.9 per 100 patient-years), and required smaller case and control samples for hypothetical research studies (n = 254-309 vs 397-3478).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging and arteriosclerosis. I. Development of myointimal hyperplasia after endothelial injury.

Old Fischer 344 rats are more susceptible to vascular lesions after arterial endothelial injury than are young animals. Thus, 20-26-mo-old Fischer 344 rats developed greater and more persistent intimal proliferative lesions than did 2-5-mo-old rats after aortic endothelial denudation. 3 d after deendothelialization, intimal thickness was increased two-fold in both old and young animals. However, 14 d after endothelial injury, intimal thickness had increased nearly five times in old animals, but had regressed to normal in young animals. Intimal thickness of young aortic grafts transplanted into young recipients did not differ significantly from adjacent host aorta or autotransplanted aortic segments 6 wk after surgery. In contrast, intimal thickness of old grafts transplanted into young recipients was eight times greater than adjacent young host aorta 6 wk after surgery. The density of cell nuclei in the intima of old grafts was also much greater than that in young grafts. Thus, in two experimental models of vascular injury, old rats have consistently had greater myointimal hyperplasia than young rats. The increased proliferative response of aortic smooth muscle cells after vascular injury of old animals may contribute to the increased prevalence of vascular disease with age.

Performance of primary and derived M-mode echocardiographic measurements for detection of left ventricular hypertrophy in necropsied subjects and in patients with systemic hypertension, mitral regurgitation and dilated cardiomyopathy.

To determine which M-mode echocardiographic (echo) measurement best detects left ventricular (LV) hypertrophy, the sensitivity and specificity of upper normal limits of echo LV anatomic measurements (previously shown to have 97% specificity in living normal subjects) were tested in 60 necropsied patients with anatomic hypertrophy and in 28 necropsied patients with normal left ventricles. The prevalence of hypertrophy by each echo criterion was determined in 165 living patients with systemic hypertension, mitral regurgitation or dilated cardiomyopathy. The best separation between patients with normal vs increased necropsy LV mass was obtained using sex-specific echo LV mass index criteria (overall accuracy = 73 of 88 patients, 83%). Lower overall accuracies for separation of patients with and without hypertrophy were observed for echo cross-sectional area (59 of 88 patients, 67%; p less than 0.05 vs LV mass index) and indexes of LV wall thickness (39 to 51%, p less than 0.001). Among 113 living patients with moderate or severe hypertension, mitral regurgitation or dilated cardiomyopathy, LV mass index was increased in 73%, cross-sectional area index in 58% (p less than 0.02 vs LV mass index), and posterior wall thickness, septal thickness and relative wall thickness in only 11 to 32% (all p less than 0.001 vs LV mass index). Thus, an M-mode echo LV mass index of more than 134 g/m2 in men and more than 110 g/m2 in women detects concentric and eccentric LV hypertrophy accurately by comparison with necropsy and clinical reference standards; cross-sectional area is slightly less useful; and other M-mode echo criteria of LV hypertrophy perform too poorly to be clinically applicable.

Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.

To determine the accuracy of echocardiographic left ventricular (LV) dimension and mass measurements for detection and quantification of LV hypertrophy, results of blindly read antemortem echocardiograms were compared with LV mass measurements made at necropsy in 55 patients. LV mass was calculated using M-mode LV measurements by Penn and American Society of Echocardiography (ASE) conventions and cube function and volume correction formulas in 52 patients. Penn-cube LV mass correlated closely with necropsy LV mass (r = 0.92, p less than 0.001) and overestimated it by only 6%; sensitivity in 18 patients with LV hypertrophy (necropsy LV mass more than 215 g) was 100% (18 of 18 patients) and specificity was 86% (29 of 34 patients). ASE-cube LV mass correlated similarly to necropsy LV mass (r = 0.90, p less than 0.001), but systematically overestimated it (by a mean of 25%); the overestimation could be corrected by the equation: LV mass = 0.80 (ASE-cube LV mass) + 0.6 g. Use of ASE measurements in the volume correction formula systematically underestimated necropsy LV mass (by a mean of 30%). In a subset of 9 patients, 3 of whom had technically inadequate M-mode echocardiograms, 2-dimensional echocardiographic (echo) LV mass by 2 methods was also significantly related to necropsy LV mass (r = 0.68, p less than 0.05 and r = 0.82, p less than 0.01). Among other indexes of LV anatomy, only measurement of myocardial cross-sectional area was acceptably accurate for quantitation of LV mass (r = 0.80, p less than 0.001) or diagnosis of LV hypertrophy (sensitivity = 72%, specificity = 94%).(ABSTRACT TRUNCATED AT 250 WORDS)

Early infarct expansion: structural or functional?

With the onset of ischemia, the length of myocardial segments increases rapidly, distorting ventricular geometry. Permanent stretching and thinning of infarcted zones have been termed infarct expansion. Although these changes are noted within minutes in vivo, infarct expansion may not be seen for days in postmortem preparations. The apparent postmortem reversal of early infarct expansion suggests that early expansion may be a functional phenomenon, reversible in the early hours of infarction. Alternatively, reversal of expansion may be a postmortem artifact, concealing the importance of underlying structural abnormalities. Myocardial infarction was produced in five dogs by occluding the left anterior descending coronary artery. Ultrasound sonomicrometers were used to measure myocardial segment end-diastolic length in the infarct and normal zones. After 3 hours of ischemia, the heart was arrested in diastole and biopsy specimens were taken from the normal and infarct zones. Sarcomere length was measured from electron photomicrographs, and myofiber width was measured from light photomicrographs. After 3 hours of ischemia, infarct zone segment length had increased significantly more than normal zone length (116 +/- 11 [SD] versus 103 +/- 4% of control length, p less than 0.05), whereas 2 minutes after cardiac arrest, both the infarct and normal zones returned to preischemic segment length, demonstrating apparent reversibility of early infarct expansion. However, histologic study revealed that the infarct zone myofibers were significantly thinner than normal zone myofibers (7.9 +/- 0.3 versus 9.4 +/- 0.3 micron, p less than 0.001) and sarcomere length in the infarct zone was significantly longer than that in the normal zone (1.9 +/- 0.2 versus 1.5 +/- 0.2 micron, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional endothelial damage by high-potassium cardioplegic solutions to saphenous vein bypass grafts.

High-potassium cardioplegic solutions (CSs) may induce endothelial cell damage in vascular grafts, promoting graft thrombosis after coronary bypass operations. We studied prostacyclin (PGI2) production by saphenous veins as a marker of endothelial cell function in a model mimicking actual operative conditions. Fresh saphenous vein segments from patients who had undergone coronary bypass were cut in half; each part was perfused and incubated sequentially with CS (with 20, 40, or 80 mEq potassium/L) or a control buffer (5 mEq potassium/L) at 4 degrees C for 30 minutes (perfusion I), buffer at 37 degrees C for 15 minutes (perfusion II), and buffer plus 25 microM sodium arachidonate at 37 degrees C for 15 minutes (perfusion III). This permitted evaluation of changes in PGI2 production during or after exposure to CS, in basal and stimulated conditions. CS with 20 mEq potassium/L did not alter PGI2 production as compared with control buffer. CS with 40 mEq potassium/L decreased PGI2 production during perfusions I and II. CS with 80 mEq potassium/L also decreased sodium arachidonate-stimulated PGI2 production. Endothelial coverage (immunoperoxidase staining for factor VIII antigen) was intact at all potassium concentrations tested. Thus potassium in CSs can depress endothelial PGI2 production without causing immediate endothelial detachment. This effect may favor thrombosis in bypass grafts.

Effects of nutrition on disease and life span. I. Immune responses, cardiovascular pathology, and life span in MRL mice.

Mice of the autoimmune, lymphoproliferative strain MRL/lpr and the congenic, nonlymphoproliferative strain MRL/n were fed one of six diets from weaning on-ward. These mice were sacrificed at 3 or 5 months of age. Low fat diets resulted in lower cholesterol and higher triglyceride levels than did cholesterol-containing high-fat diets. Caloric restriction of MRL/lpr mice was associated with an increased plaque-forming cell response to trinitrophenylated polyacrylamide beads, less lymphoproliferation, and less severe glomerulonephritis. Diet did not affect the incidence of autoimmune vasculitis in MRL/lpr mice sacrificed at 5 months. MRL/lpr mice fed a low-fat, calorically restricted diet from 5 months of age to death lived longer than mice which were fed ad libitum a cholesterol-containing, high-fat diet. At death, MRL/lpr mice fed the former diet had the autoimmune vasculitis which had been evident in mice killed at 5 months, whereas mice fed the latter diet, in addition to the vasculitis, had a high incidence of atherosclerotic lesions of intrarenal and aortic branch arteries.

Effects of nutrition of disease and life span. II. Vascular disease, serum cholesterol, serum thromboxane, and heart-produced prostacyclin in MRL mice.

Mice of the autoimmune strain MRL/1, the congenic strain MRL/n, and two control strains, Balb/c and C57BL/6 mice, were fed diets which varied in the content of lipid and cholesterol. Serum cholesterol levels were highest in mice fed diets containing cholesterol and lowest in mice fed laboratory "chow." Animals fed diets that increased serum cholesterol had decreased production of prostacyclin by vascular tissue and increased production of thromboxane A2 by platelets. Prostacyclin production by heart tissue in response to arachidonic acid showed a negative correlation (r = -0.86) with serum cholesterol. In contrast, serum thromboxane demonstrated a positive correlation (r = 0.70) with serum cholesterol. The prevalence of autoimmune vasculitis seen in MRL/lpr mice was not affected by diet. However, MRL/lpr mice fed a high-fat, cholesterol-containing diet had intimal vascular lesions containing foam cells typical of arteriosclerosis. It is suggested that diets that raise serum cholesterol may influence the nature of autoimmune-mediated vascular disease by altering the balance between thromboxane and prostacyclin.

Evaluation of a QRS scoring system for estimating myocardial infarct size. IV. Correlation with quantitative anatomic findings for posterolateral infarcts.

This study correlated the location and size of posterolateral myocardial infarcts (MIs) measured anatomically with that estimated by quantitative criteria derived from the standard 12-lead ECG. Twenty patients were studied who had autopsy-proved, single, posterolateral MIs and no confounding factors of ventricular hypertrophy or bundle branch block in their ECG. Left ventricular anatomic MI size ranged from 1 to 46%. No patient had a greater than or equal to 0.04-second Q wave in any electrocardiographic lead and only 55% had a 0.03-second Q wave. A 29-point, simplified QRS scoring system consisting of 37 weighted criteria was applied to the ECG. Points were scored by the ECG in 85% of the patients (range 1 to 8 points). MI was indicated by a wide variety of QRS criteria; 19 of the 37 criteria from 8 different electrocardiographic leads were met. The correlation coefficient between MI size measured anatomically and that estimated by the QRS score was 0.72. Each point represented approximately 4% MI of the left ventricular wall.

Coordinate induction of cytochrome P-448 mediated mixed function oxidases and histopathologic changes produced acutely in chick embryo liver by polychlorinated biphenyl congeners.

Hepatic histologic changes and induction of mixed function oxidases were examined and compared after administration to the chick embryo of four highly purified polychlorinated biphenyl (PCB) congeners: 3,4,3',4'-tetrachlorobiphenyl (TCB) and 3,4,5,3',4',5'-, 2,4,5,2',4',5'-, and 2,3,6,2',3',6'-hexachlorobiphenyls (HCBs). The major histopathologic change was hepatocyte swelling as evidenced by sinusoidal narrowing. It was observed within 24 hr after PCB administration at doses as low as 5 nmol/egg for 3,4,3',4'-TCB and 3,4,5,3',4',5'-HCB and only at doses of 5000 nmol/egg and higher for 2,4,5,2',4',5'-HCB. 2,3,6,2',3',6'-HCB was inactive. The histopathologic change was predominantly perivascular in distribution. It was accompanied by increased hepatic water content. Occasional hepatocytes showed nuclear pyknosis and cytoplasmic eosinophilia, but there was little histologic evidence of frank necrosis and no biochemical evidence, since serum glutamic-oxalic and glutamic-pyruvic transaminases and lactic dehydrogenase did not increase. Hepatic glutathione (GSH) levels were not significantly altered by 3,4,3',4'-TCB or 3,4,5,3',4',5'-HCB, indicating that GSH depletion does not have a significant role in the production of hepatotoxic changes by PCBs. Measurement of the degree of pathologic change indicated that 3,4,3',4'-TCB and 3,4,5,3',4',5'-HCB were three to four orders of magnitude more potent than 2,4,5,2',4',5'-HCB both as hepatotoxins and as inducers of the cytochrome P-448 mediated mixed function oxidases, aryl hydrocarbon hydroxylase, and 7-ethoxyresorufin deethylase. 2,3,6,2',3',6'-HCB was inactive as an inducer as well as as a hepatotoxin. The findings indicate that hepatotoxic changes are selectively produced in the chick embryo by those PCBs that also induce cytochrome P-448 mediated mixed function oxidases and in that respect resemble other manifestations of PCB toxicity (e.g., subcutaneous and pericardial edema and thymic involution) in both the chicken and other species. The results support the hypothesis that a common initial mechanism leads both to cytochrome P-448 type induction and to diverse manifestations of polyhalogenated hydrocarbon toxicity.

Glutaraldehyde-preserved pericardial allografts for pericardial closure.

Repeat cardiac surgery is significantly more difficult than the original surgery. Pericardial closure to limit adhesion formation between the heart and mediastinal structures and thus reduce the increased difficulty of reoperation has been considered. To investigate the feasibility of effecting loose pericardial closure with homologous pericardial grafts, glutaraldehyde-preserved pericardial allografts were implanted in 10 mongrel dogs. After a mean period of 6.7 months (range 6 to 8 months) the grafts were studied grossly and histologically. Adhesion formation was minimal and the adhesions were easily dissectible. The allografts evoked no significant inflammatory response. No infections resulted from graft placement. It is concluded that glutaraldehyde-preserved pericardial allografts may be useful to effect pericardial closure and deserve further investigation in this regard.