QTL and systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field.

The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53 BXD recombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20-min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significant QTL on chromosome M.m. 4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestive QTL modulating locomotion that maps to the same locus. Bioinformatic analysis indicates Disabled 1 (Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestive QTLs for a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36-37 Mb and 14 at 34-36 Mb that influences rearing frequency in males.

Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains.

Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred (RI) mouse panel using the light-dark transition model of anxiety. Strain-mean genetic mapping and a mixed-model quantitative trait loci (QTL) analysis replicated several previously published QTL for locomotor activity and identified several novel anxiety-related loci. Significant loci included a chromosome 11 saline anxiety-like QTL (Salanq1) and a chromosome 12 locus (Etanq1) influencing the anxiolytic-like response to ethanol. Etanq1 was successfully validated by studies with BXD advanced intercross strains and fine-mapped to a region comprising less than 3.5 Mb. Through integration of genome-wide mRNA expression profiles of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, we identified high priority candidate genes within Etanq1, the strongest of which was Ninein (Nin), a Gsk3ß-interacting protein that is highly expressed in the brain.

Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test.

Mechanical sensitivity is commonly affected in chronic pain and other neurological disorders. To discover mechanisms of individual differences in punctate mechanosensation, we performed quantitative trait locus (QTL) mapping of the response to von Frey monofilament stimulation in BXD recombinant inbred (BXD) mice. Significant loci were detected on mouse chromosome (Chr) 5 and 15, indicating the location of underlying polymorphisms that cause heritable variation in von Frey response. Convergent evidence from public gene expression data implicates candidate genes within the loci: von Frey thresholds were strongly correlated with baseline expression of Cacna2d1, Ift27 and Csnk1e in multiple brain regions of BXD strains. Systemic gabapentin and PF-670462, which target the protein products of Cacna2d1 and Csnk1e, respectively, significantly increased von Frey thresholds in a genotype-dependent manner in progenitors and BXD strains. Real-time polymerase chain reaction confirmed differential expression of Cacna2d1 and Csnk1e in multiple brain regions in progenitors and showed differential expression of Cacna2d1 and Csnk1e in the dorsal root ganglia of the progenitors and BXD strains grouped by QTL genotype. Thus, linkage mapping, transcript covariance and pharmacological testing suggest that genetic variation affecting Cacna2d1 and Csnk1e may contribute to individual differences in von Frey filament response. This study implicates Cacna2d1 and Ift27 in basal mechanosensation in line with their previously suspected role in mechanical hypersensitivity. Csnk1e is implicated for von Frey response for the first time. Further investigation is warranted to identify the specific polymorphisms involved and assess the relevance of these findings to clinical conditions of disturbed mechanosensation.

Heritability, correlations and in silico mapping of locomotor behavior and neurochemistry in inbred strains of mice.

The midbrain dopamine system mediates normal and pathologic behaviors related to motor activity, attention, motivation/reward and cognition. These are complex, quantitative traits whose variation among individuals is modulated by genetic, epigenetic and environmental factors. Conventional genetic methods have identified several genes important to this system, but the majority of factors contributing to the variation remain unknown. To understand these genetic and environmental factors, we initiated a study measuring 21 behavioral and neurochemical traits in 15 common inbred mouse strains. We report trait data, heritabilities and genetic and non-genetic correlations between pheno-types. In general, the behavioral traits were more heritable than neurochemical traits, and both genetic and non-genetic correlations within these trait sets were high. Surprisingly, there were few significant correlations between the behavioral and the individual neurochemical traits. However, striatal serotonin and one measure of dopamine turnover (DOPAC/DA) were highly correlated with most behavioral measures. The variable accounting for the most variation in behavior was mouse strain and not a specific neurochemical measure, suggesting that additional genetic factors remain to be determined to account for these behavioral differences. We also report the prospective use of the in silico method of quantitative trait loci (QTL) analysis and demonstrate difficulties in the use of this method, which failed to detect significant QTLs for the majority of these traits. These data serve as a framework for further studies of correlations between different midbrain dopamine traits and as a guide for experimental cross designs to identify QTLs and genes that contribute to these traits.

Angina and persistent exercise thallium defects: independent risk factors in elective vascular surgery.

OBJECTIVES: In this study, we assessed the utility of exercise thallium-201 scintigraphy and other clinical factors in predicting perioperative cardiac complications in patients undergoing elective vascular surgery. BACKGROUND: The risk of cardiac complications among such patients is very high. METHODS: The study group comprised 116 men (mean age 67 years). Fifty patients (43%) had a history of coronary artery disease, including angina pectoris in 26 (22%), myocardial infarction in 32 (28%) and coronary artery bypass surgery in 19 (16%). RESULTS: There were a total of 22 perioperative myocardial infarctions (18.9%), including 2 cardiac deaths (1.7%). A significantly greater proportion (p < 0.05) of patients with than without perioperative complications had a history of coronary artery disease (77% vs. 35%), angina (59% vs. 14%), prior myocardial infarction (50% vs. 22%), abnormal electrocardiogram (68% vs. 40%) and abnormal exercise thallium test (75% vs. 47%). The patient group with complications also had a significantly lower mean rest ejection fraction (45 +/- 3% vs. 55 +/- 2%, p < 0.005). Independent predictors of complication, as determined by straight logistic regression, were angina and fixed thallium defects after exercise. CONCLUSIONS: Our data indicate that angina and the presence of fixed thallium defects after exercise are independent predictors of cardiac risk in patients undergoing elective vascular surgery. These findings are compatible with other studies showing that nonredistribution on standard 3- to 4-h delayed studies cannot exclude viable myocardium at risk.

ZK 36-374, a stable analog of prostacyclin, prevents acute hypoxic pulmonary hypertension in the dog.

Vasodilator therapy in pulmonary hypertension is limited by the lack of an agent selective for the pulmonary circulation. The effects of intravenous prostacyclin and two stable prostaglandin analogs, ZK 36-374 and CL 115,347, were assessed on the preconstricted pulmonary vasculature of the anesthetized dog. During hypoxic vasoconstriction ZK 36-374 (0.4 micrograms/kg per min) markedly reduced pulmonary artery pressure (26 +/- 3 to 13 +/- 1 mm Hg) (p less than 0.05) and pulmonary vascular resistance (6.2 +/- 1.1 to 2.8 +/- 0.2 mm Hg/liter per min) (p less than 0.01). There was no significant effect on cardiac output, aortic pressure or arterial blood gases. Pulmonary vasoconstriction induced by prostaglandin F2 alpha was similarly affected by ZK 36-374, and in this instance the aortic pressure was also reduced (158 +/- 11 to 129 +/- 11 mm Hg) (p less than 0.01). ZK 36-374 (0.2 micrograms/kg per min) was more effective in lowering hypoxic pulmonary vascular resistance (from 6.5 +/- 0.6 to 3.0 +/- 0.3 mm Hg/liter per min) than was prostacyclin (0.75 micrograms/kg per min) (from 6.3 +/- 0.6 to 4.2 +/- 0.4 mm Hg/liter per min) (p less than 0.05) and resulted in a smaller fall in aortic pressure (p less than 0.05). CL 115,347 (1.0 micrograms/kg per min) had no effect on the pulmonary vasculature during normoxia or when preconstricted by prostaglandin F2 alpha or hypoxia, but reduced aortic pressure and total systemic resistance (p less than 0.05). It appears to be a selective systemic vasodilator with no pulmonary vascular activity.(ABSTRACT TRUNCATED AT 250 WORDS)

"Maximal" drug therapy is not necessarily optimal in chronic angina pectoris.

Beta-adrenergic blocking agents, nitrates and calcium channel antagonists are effective in treating angina pectoris, but much remains unknown about how they act in combination. Consequently, treadmill exercise was used to assess the relative efficacy of nifedipine or isosorbide dinitrate, or both, in 19 patients with stable angina receiving propranolol. Propranolol therapy was continued and either placebo, nifedipine (20 mg), isosorbide dinitrate (20 mg) or both drugs were given randomly 1 1/2 hours before exercise in a double-blind trial. In 16 patients who completed the protocol, heart rate at rest during propranolol therapy was 53.7 +/- 1.9 beats/min (mean +/- standard error of the mean); it increased 4.6 +/- 1.2 beats/min with the addition of nifedipine (p less than 0.01), but was unchanged with isosorbide dinitrate or both combined. Compared with values during treatment with propranolol alone, systolic blood pressure at rest decreased with each vasodilator individually and when combined. Rate-pressure product at maximal exercise was the same with all combinations. Exercise duration was 467 +/- 50 seconds with propranolol, increased to 556 +/- 47 seconds with isosorbide dinitrate (p less than 0.05) and to 636 +/- 50 seconds with nifedipine (p less than 0.001). Exercise duration with all three drugs was 597 +/- 47 seconds (p less than 0.01 compared with propranolol alone). The improvement with nifedipine was greater than with isosorbide dinitrate (p less than 0.05) but exercise duration was not significantly different with the combination of these drugs than when either drug was used alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype.

It has been appreciated for some time that the sexes can differ in their sensitivity to pain and its inhibition. Both the human and rodent literatures remain quite contentious, with many investigators failing to observe sex differences that others document clearly. Recent data from our laboratory have pointed to an interaction between sex and genotype in rodents, such that sex differences are observed in some strains but not others. However, these studies employed inbred mouse strains and are thus not directly relevant to existing data. We presently examined whether the observation of statistically significant sex differences in nociception and morphine antinociception might depend on the particular outbred rodent population chosen for study. Rats of both sexes and three common outbred strains were obtained from three suppliers (Long Evans, Simonsen; Sprague Dawley, Harlan; Wistar Kyoto, Taconic) and tested for nociceptive sensitivity on the 49 degrees C tail-withdrawal assay, and antinociception following morphine (1-10mg/kg, i.p.). In further studies, three outbred populations of mice (CD-1, Harlan; Swiss Webster, Harlan; Swiss Webster, Simonsen) were bred in our vivarium for several generations and tested for tail-withdrawal sensitivity and morphine antinociception (1-20male, and no significant difference. In a separate study in which the estrous cycle was tracked in female mice, we found evidence for an interaction between genotype and estrous phase relevant to morphine antinociception. However, estrous cyclicity did not explain the observed sex differences. These data are discussed with respect to the existing sex difference and pain literature, and also as they pertain to future investigations of these phenomena.

Genetic architecture of the mouse hippocampus: identification of gene loci with selective regional effects.

We recently mapped two quantitative trait loci that have widespread effects on hippocampal architecture in mouse: Hipp1a and Hipp5a. We also noted remarkable strain differences in the relative sizes of different hippocampal regions. Estimated heritable variation for these differences was 42% in hippocampus proper, 40% in dentate gyrus, 31% in granule cell layer and 18% in pyramidal cell layer. Region size varied at least 50% from largest to smallest measurement. Here we have utilized these differences to identify loci with effects on the dentate gyrus, granule cell layer, hippocampus proper and pyramidal cell layer. Our sample consists of C57BL/6J and DBA/2J and 32 BXD recombinant inbred strains. Volumetric data were corrected for shrinkage and for differences in brain weight. We identified significant loci on chromosomes (Chr) 6, 13 and 15, and a significant interaction locus on proximal Chr 11. A suggestive distal Chr 1 locus overlaps with Hipp1a. HipV13a (Chr 13, 42-78Mb) has an additive effect of 0.56 mm3 (12.1%) on dentate gyrus volume, while GrV6a (Chr 6, 29-65 Mb) has additive effects of 0.14 mm3 (16.0%) on the volume of the granule cell layer. HipV13a also interacts with DGVi11a, a locus on proximal Chr 11 that operates exclusively through its epistatic effect on HipV13a and has no independent main effect HipV15a (Chr 15, 0-51 Mb) has an additive effect of 1.76 mm3 (9.0%) on the volume of the hippocampus proper. We used WebOTL, a recently described web-based tool, to examine genetic correlation of gene expression with hippocampal volume. We identified a number of genes that map within the OTL intervals and have highly correlated expression patterns. Using WebQTL's extensive database of published BXD phenotypes, we also detected a strong and potentially biologically meaningful correlation between hippocampal volume and the acoustic startle response.

Normal catecholamine and hemodynamic responses to orthostatic tilt in subjects with mitral valve prolapse. Correlation with psychologic testing.

Various functional abnormalities of the autonomic nervous system have been reported in symptomatic patients with mitral valve prolapse. It has also been suggested that mitral valve prolapse may be a component of a neurovascular endocrine abnormality and a marker for anxiety. Eleven consecutive patients with mitral valve prolapse (six men and five women), five of whom were asymptomatic, were studied. In comparison with 11 control subjects matched for age and sex who underwent 60-degree upright tilt, there was no significant difference between plasma norepinephrine levels, heart rate, and blood pressure, before, during, and after tilting. Psychologic testing for anxiety neurosis in both groups showed no significant difference on any of these measurements. There was therefore no evidence of autonomic dysfunction or neurosis in the patients with mitral valve prolapse. This variance with the findings of other investigators is probably related to their study of patient groups skewed by a disproportionate number of symptomatic females; the patients in the study reported herein are more representative of mitral valve prolapse in the general population. The symptoms attributed to mitral valve prolapse are quite likely adrenergically mediated and precipitated by anxiety, but this probably represents a coincidence of two common conditions encountered in medical practice.

Comparative effects of nifedipine, verapamil, and diltiazem on experimental pulmonary hypertension.

The role of calcium-channel blocking agents in the treatment of pulmonary hypertension is not well defined. Consequently, the effects of diltiazem, nifedipine, and verapamil were compared in 3 groups of anesthetized dogs (n = 6 for each group). In each group, normoxic hemodynamic variables were recorded before and after increasing doses of diltiazem, nifedipine, and verapamil (5 X 10(-8) M/kg, low; 10(-7) M/kg, medium; and 10(-6) M/kg, high dose; given intravenously over 2 minutes). In addition, the effect of these doses on the pulmonary pressor responses to hypoxia (fractional inspired oxygen concentration [FIO2] 12%) and prostaglandin F2 alpha (PGF2 alpha) (5 micrograms/kg/min, intravenously for 4 minutes) was measured. During normoxia, high-dose nifedipine and verapamil decreased mean aortic pressure and systemic vascular resistance while increasing cardiac output in all dogs in both groups (p less than 0.01). Pulmonary vascular resistance, however, remained unchanged. High-dose diltiazem did not significantly alter cardiac output or pulmonary vascular resistance. During acute hypoxic pulmonary hypertension, verapamil decreased cardiac output by 30% (p less than 0.01) without appreciably altering pulmonary arterial pressure; thus pulmonary vascular resistance increased slightly (4.9 +/- 0.6 to 6.4 +/- 1.0 mm Hg/liter/min, difference not significant [NS]). Nifedipine decreased hypoxic pulmonary vascular resistance to normoxic values (p less than 0.01). Cardiac output increased 71% while pulmonary arterial pressure remained unchanged. Diltiazem administration produced no change in hypoxic pulmonary hemodynamic variables. The responses to diltiazem, nifedipine, and verapamil during acute pulmonary vasoconstriction induced by PGF2 alpha were similar to those induced by hypoxia. After verapamil, pulmonary vascular resistance tended to increase (7.3 +/- 1.3 to 8.1 +/- 1.4 mm Hg/liter/min, NS). Nifedipine, however, completely blocked pulmonary vasoconstriction by decreasing pulmonary vascular resistance to pre-PGF2 alpha levels (p less than 0.01). This was accompanied by a 157% increase in cardiac output and only a small increase in pulmonary arterial pressure (7 mm Hg). Again, diltiazem produced no change in pulmonary hemodynamic variables. In these acute studies, nifedipine appeared to be a more effective pulmonary vasodilator than verapamil or diltiazem.

Long-term efficacy of bepridil in patients with chronic stable angina pectoris: results of a multicenter, placebo-controlled study of extended bepridil use.

To evaluate whether bepridil once a day provides effective antianginal therapy during extended use, a placebo-controlled withdrawal study was conducted in 33 patients with chronic stable angina. Each patient studied had previously had a favorable response to short-term administration of bepridil and had been taking the drug once daily for greater than or equal to 9 months of continuous use. Patients were then randomly assigned to receive either continued bepridil or a placebo substitution once daily during a 4-week, double-blind, parallel-group comparison. Dosage for the bepridil group was constantly maintained for each patient at a level observed to be clinically effective. The study consisted of a comparison of angina frequency and nitroglycerin tablet consumption obtained from patient diaries and results from maximal-graded multistage treadmill tests. Patients randomized to continue receiving bepridil remained stable in terms of angina frequency and exercise performance. Discontinuation of long-term bepridil significantly increased angina frequency and nitroglycerin tablet consumption and reduced exercise capacity. Four patients (24%), all receiving placebo treatment, had increases in angina frequency and had the study terminated. Bepridil was reinstituted in these patients with resolution of symptoms and no untoward effects. The results of this placebo-controlled, double-blind, randomized study confirm that bepridil continues to provide antianginal benefit during long-term administration.

Usefulness of mean aortic valve gradient and left ventricular diastolic filling pattern for distinguishing symptomatic from asymptomatic patients.

Consecutive, symptomatic (n = 15) and asymptomatic (n = 25) men with aortic stenosis (valve area < 1.2 cm2) and no clinical evidence of myocardial ischemia underwent radionuclide angiography at rest and during supine bicycle ergometry. Ejection fraction, diastolic filling pattern and aortic valve area/gradient were measured on enrollment and when patients became symptomatic (n = 10) or underwent valve replacement (n = 22) during a 2-year follow-up period. Both groups had similar heart rate, blood pressure and ejection fractions, but mean aortic gradients were higher in symptomatic (53 +/- 4 mm Hg) than asymptomatic (37 +/- 2 mm Hg) subjects p < 0.01. Functional limitation evoked by exercise was prevalent even in the asymptomatic group but symptomatic patients exercised to lower work levels than asymptomatic subjects (184 +/- 27 and 307 +/- 32 kg.m/min, respectively, p = 0.02). Ejection fraction failed to increase with exercise in either group. Symptomatic subjects had supranormalization of early diastolic filling with shorter time to the peak filling rate than asymptomatic subjects (137 +/- 16 and 172 +/- 9 ms, respectively, p < 0.05) and a greater first 1/3 filling fraction. The 10 patients who became symptomatic during follow-up had higher first 1/3 filling fractions (53 +/- 7 and 42 +/- 5%, respectively) and mean gradients (41 +/- 4 and 33 +/- 2 mm Hg, respectively) than subjects who remained asymptomatic, p < 0.05. High mean aortic gradients, impaired exercise tolerance and enhanced early diastolic filling distinguish symptomatic from asymptomatic patients.

Bepridil for chronic stable angina pectoris: results of a prospective multicenter, placebo-controlled, dose-ranging study in 77 patients.

Bepridil, a new calcium-channel blocking agent with an extended plasma elimination half-life of greater than 50 hours, was compared to placebo in 77 patients with confirmed coronary artery disease and chronic stable angina pectoris. The effects of bepridil were compared with those of placebo on angina frequency, nitroglycerin tablet use, the resting ECG and hemodynamics at rest and maximal exercise using a study design comprising 5 sequential 2-week single-blind treatment phases. After 2 weeks of placebo (phase 1), bepridil was given for 3 phases (2, 3 and 4) at total daily dosages of 200, 300 and 400 mg, respectively; the study was completed after a final reintroduction of placebo (phase 5). Within each phase once- and twice-daily regimens of bepridil were randomly compared. Bepridil (300 mg/day) reduced anginal frequency 68%, from 8.5 +/- 1.1 (standard error of the mean) to 2.7 +/- 0.7 attacks/week and nitroglycerin tablet use 76% (p less than 0.001). Bepridil improved exercise duration 26%, from 6.9 +/- 0.4 to 8.7 +/- 0.5 minutes (p less than 0.001) and exercise work 52%, from 2.7 +/- 0.3 to 4.1 +/- 0.4 kpm X 10(-3) (p less than 0.001) on a standardized treadmill protocol. Resting and peak exercise heart rate and blood pressure were unaffected by bepridil. The antianginal effects were similar with either once- or twice-daily treatment schedules. Minor side effects of nausea, epigastric discomfort and tremor were infrequent and there were no major side effects. The results of this large but preliminary, single-blind and short-term study suggest that bepridil is an effective and well tolerated antianginal agent when administered once daily.

Congenital aneurysms adjacent to the anuli of the aortic and/or mitral valves.

The unusual occurrence of non-infected submitral and aortic aneurysms developing sequentially in an adult prompted us to review the pathogenesis of congenital aneurysms adjacent to the aortic and mitral valves. The findings support the suggestion that subvalvular aneurysms, like aortic sinus aneurysms, are a result of a congenital defect at the valve anulus. Submitral aneurysms occur only subjacent to the posterior leaflet. Whereas aortic sinus aneurysms may arise from any of the three sinuses, subaortic aneurysms occur only under the intermediate portion of the left aortic sinus. In the absence of rupture, the clinical presentation of these aneurysms results from valvular insufficiency or compression of the left coronary artery or of the conduction system.

Redox status and pulmonary vascular reactivity.

Oxygen radicals are produced during oxidative metabolism in proportion to the tissue oxygen tension. The studies reported here have shown that oxygen radicals or the sulfhydryl oxidant, diamide, caused pulmonary vasodilatation in the isolated perfused rat lung. Could oxygen radicals play a role in the physiologic control of pulmonary vascular smooth muscle tone?

Subpulmonic stenosis as a result of noncalcific constrictive pericarditis.

The clinical, electrocardiographic, and radiologic features in a patient with a pericardial band which produced an unusual form of infundibular pulmonary stenosis are presented. The findings are unique in that the band was not calcified and, therefore, not visualized roentgenographically and developed without a previous history of pericarditis or pericardial surgery. The diagnostic value of cineangiography is stressed and illustrated.

A report of Uhl's disease in identical adult twins: evaluation of right ventricular dysfunction with echocardiography and nuclear angiography.

The first example of Uhl's disease affecting identical adult twins is reported, offering support for the contention that a congenital developmental defect or hereditable tendency is the responsible cause. In one case, echocardiography and nuclear angiography proved to be valuable in making the diagnosis. Uhl's disease in the adult should be suspected among cases of isolated right ventricular enlargement and failure complicated by ventricular dysrhythmias. The diagnosis may be made using a combination of noninvasive tests, obviating the need for cardiac catheterization.

The influence of perioperative myocardial infarction on long-term prognosis following elective vascular surgery.

STUDY OBJECTIVE: The present study was performed to determine the influence of a perioperative myocardial infarction on long-term mortality in patients who have undergone elective vascular surgery. STUDY DESIGN: This was a 4-year follow-up of patients who had undergone elective vascular procedures at a Veterans Affairs Medical Center. Between January 1989 and December 1990, 115 consecutive patients underwent surgery for either an expanding abdominal aortic aneurysm (AAA) (38%) or for pain in the lower extremities (62%). RESULTS: Vital status at 4 years postsurgery was determined for all patients. Thirty-day postoperative mortality was 3%, while estimates at 1, 2, 3, and 4 years were 19%, 26%, 35%, and 39%, respectively. Of the 45 patients who died within 4 years following surgery, the major causes of death were cardiac (40%), cancer (18%), cerebrovascular (13%), and peripheral vascular disease (11%). Univariate predictors of 1-year mortality on preoperative evaluation were an abnormal ECG, moderate or greater sized exercise thallium defect and left ventricular ejection fraction < or =40%, and a perioperative myocardial infarction. Univariate predictors of 4-year mortality were non-AAA surgery and diabetes mellitus. Perioperative myocardial infarction was a marginally significant independent predictor of 1-year mortality (p=0.06), while the need for non-AAA surgery was a strong independent predictor at 4 years. CONCLUSIONS: Cardiac mortality is the major cause of late death among patients undergoing elective vascular surgery. Although preoperative indicators of symptomatic coronary artery disease and nonfatal perioperative myocardial infarction identified those individuals at increased mortality in the first postoperative year, the extent of vascular disease at presentation may be a more important determinant of long-term survival. A randomized trial in such patients is needed to assess the best strategy for treating patients with coexistent coronary artery and vascular diseases.

Clinical experience with the Lillehei-Kaster cardiac valve prosthesis.

This paper reviews our experience with the Lillehei-Kaster pivoting disc prosthesis in 155 patients with aortic and mitral valve disease. We employed 189 valves during the period 1971 to 1974. The early surgical mortality rates for isolated mitral, isolated aortic, and combined mitral and aortic valve replacements were 9 per cent, 14 per cent, and 3 per cent, respectively. Postoperatively, there was no evidence of significant hemolysis, and the gradients across the prostheses were satisfactory. Clinical evaluation of prosthetic function was made difficult by the infrequency of an opening click and the common occurrence of mid-diastolic murmurs even with minimal gradients. The most disturbing complication, which has led to our abandoning use of this valve, was thrombosis, which occurred in at least 10 per cent of the mitral and 5 per cent of the aortic valves. The cause is thought to be late prosthetic disproportion as the heart shrinks in size.