Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: a case report.

Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease following solid-organ transplantation has occurred in Latin America. This report presents the occurrence of Chagas disease despite negative serological tests in both the donor and the recipient, as well as the effectiveness of treatment. A 21-year-old woman from the state of Sao Paulo (Brazil) underwent cadaveric donor liver transplantation in November 2005, due to cirrhosis of autoimmune etiology. Ten months after liver transplantation, she developed signs and symptoms of congestive heart failure (New York Heart Association functional class IV). The echocardiogram, which was normal preoperatively, showed dilated cardiac chambers, depressed left ventricular systolic function (ejection fraction = 35%) and moderate pulmonary hypertension. Clinical investigation discarded ischemic heart disease and autoimmune and other causes for heart failure. Immuno fluorescence (immunoglobulin M and immunoglobulin G) and hemagglutination tests for T cruzi were positive, and abundant T cruzi amastigotes were readily identified in myocardial biopsy specimens. Treatment with benznidazole for 2 months yielded an excellent clinical response. At the moment of submission, the patient remains in functional class I. This case highlighted that more appropriate screening for T cruzi infection is mandatory in potential donors and recipients of solid-organ transplants in regions where Chagas disease is prevalent. Moreover, it stressed that this diagnosis should always be considered in recipients who develop cardiac complications, since negative serological tests do not completely discard the possibility of disease transmission and since good results can be achieved with prompt trypanocidal therapy.

Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients.

Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.

Minor segmental wall motion abnormalities detected in patients with Chagas' disease have adverse prognostic implications.

Recent data from our laboratory have shown that patients with the indeterminate form of Chagas' disease can have impairment of left ventricular contractility, as evaluated by the slope of the left ventricle end-systolic pressure-dimension relationship. We also showed that Chagas' disease patients with minimal baseline wall motion abnormalities detected by two-dimensional echocardiography have more intense contractility impairment when compared to patients with the indeterminate form of the disease without this abnormality. The prognostic implications of these findings have not been established. We evaluated 59 patients (37-76 years, mean = 55 years) with different clinical forms of Chagas' disease, who had normal left ventricular global systolic function at baseline (57.6 +/- 6.9%) and who had at least one additional echo during clinical follow-up (0.4-17.6; mean 4.6 years). Group 1 consisted of 14 patients with minor baseline left ventricle wall motion abnormalities and group 2 consisted of 45 patients without these abnormalities. During follow-up, global left ventricle systolic function deterioration was observed in 10 group 1 patients (71.4%) and in only 10 group 2 patients (22.2%; P < 0.005). Age and duration of follow-up were not independent determinants of left ventricular function deterioration in these patients. The present data indicate that mild segmental left ventricular wall motion abnormalities are associated with worsening of systolic function in Chagas' disease patients who have normal baseline global systolic performance.

Automated grading of left ventricular segmental wall motion by an artificial neural network using color kinesis images.

The present study describes an auxiliary tool in the diagnosis of left ventricular (LV) segmental wall motion (WM) abnormalities based on color-coded echocardiographic WM images. An artificial neural network (ANN) was developed and validated for grading LV segmental WM using data from color kinesis (CK) images, a technique developed to display the timing and magnitude of global and regional WM in real time. We evaluated 21 normal subjects and 20 patients with LVWM abnormalities revealed by two-dimensional echocardiography. CK images were obtained in two sets of viewing planes. A method was developed to analyze CK images, providing quantitation of fractional area change in each of the 16 LV segments. Two experienced observers analyzed LVWM from two-dimensional images and scored them as: 1) normal, 2) mild hypokinesia, 3) moderate hypokinesia, 4) severe hypokinesia, 5) akinesia, and 6) dyskinesia. Based on expert analysis of 10 normal subjects and 10 patients, we trained a multilayer perceptron ANN using a back-propagation algorithm to provide automated grading of LVWM, and this ANN was then tested in the remaining subjects. Excellent concordance between expert and ANN analysis was shown by ROC curve analysis, with measured area under the curve of 0.975. An excellent correlation was also obtained for global LV segmental WM index by expert and ANN analysis (R2 = 0.99). In conclusion, ANN showed high accuracy for automated semi-quantitative grading of WM based on CK images. This technique can be an important aid, improving diagnostic accuracy and reducing inter-observer variability in scoring segmental LVWM.

Clinical significance of reduced regional myocardial glucose uptake in regions with normal blood flow in patients with chronic coronary artery disease.

OBJECTIVES: The objective of this study was to assess the clinical significance of reduced regional fluorine-18 (18F) fluorodeoxyglucose uptake with normal flow in patients with chronic coronary artery disease. BACKGROUND: In patients with ischemic left ventricular dysfunction, 18F-fluorodeoxyglucose uptake may be reduced in some myocardial regions despite normal flow. The significance of this finding is unclear and has not been investigated systematically. METHODS: Twenty-three patients with coronary artery disease and impaired ventricular function (mean ejection fraction [+/- 1 SD] 28 +/- 10%) underwent positron emission tomography with 18F-fluorodeoxyglucose and oxygen-15-labeled water at rest, exercise thallium-201 tomographic imaging with rest reinjection and gated magnetic resonance imaging to measure end-diastolic wall thickness and systolic wall thickening. RESULTS: Of 168 regions with normal flow (> or = 0.7 ml/g per min), 125 (74%) had normal 18F-fluorodeoxyglucose uptake (98 +/- 10%), and the remaining 43 (26%) showed moderately reduced 18F-fluorodeoxyglucose uptake (69 +/- 8%). Systolic wall thickening was absent at rest in 14% of regions with normal 18F-fluorodeoxyglucose uptake compared with 32% of regions with reduced 18F-fluorodeoxyglucose uptake (p < 0.01). Reversible thallium abnormalities were observed in 45 (36%) of 125 regions with normal 18F-fluorodeoxyglucose uptake compared with 27 (63%) of 43 regions with reduced 18F-fluorodeoxyglucose uptake (p < 0.01). This difference was accounted for by a higher proportion of partially reversible defects in regions with reduced 18F-fluorodeoxyglucose uptake compared with regions with normal 18F-fluorodeoxyglucose uptake (42% vs. 18%, respectively, p < 0.01). CONCLUSIONS: Thus, regions with moderately reduced 18F-fluorodeoxyglucose uptake with normal flow occur commonly in patients with ischemic left ventricular dysfunction. The majority of these regions show impaired systolic function at rest and exercise-induced thallium abnormalities that are only partially reversible. These observations suggest that such regions represent an admixture of fibrotic and reversibly ischemic myocardium.

Metabolic evidence of viable myocardium in regions with reduced wall thickness and absent wall thickening in patients with chronic ischemic left ventricular dysfunction.

Reduced end-diastolic wall thickness with absent systolic wall thickening has been reported to represent nonviable myocardium in patients with chronic coronary artery disease. To assess whether reduced regional end-diastolic wall thickness and absent wall thickening accurately identify nonviable myocardium, 25 patients with ischemic left ventricular dysfunction (ejection fraction at rest 27 +/- 10%) underwent positron emission tomography with oxygen-15-labeled water and 18fluorodeoxyglucose to assess metabolic activity and spin-echo gated nuclear magnetic resonance imaging to measure regional end-diastolic wall thickness and wall thickening. The presence of metabolic activity was defined as 18fluorodeoxyglucose uptake (corrected for partial volume) greater than 50% of that in normal regions. Of 355 myocardial regions evaluated, 266 were hypokinetic or normokinetic at rest and 89 were akinetic (that is, absent wall thickening). 18Fluorodeoxyglucose uptake was observed in 97% of the hypokinetic and normokinetic regions and in 74% of the akinetic regions. End-diastolic wall thickness was greater in akinetic regions with than in those without 18fluorodeoxyglucose uptake (11 +/- 4 vs. 7 +/- 3 mm, p less than 0.01). The highest values for sensitivity and specificity of end-diastolic wall thickness in predicting the absence of metabolic activity in akinetic regions were 74% and 79%, respectively, and corresponded to an end-diastolic threshold of 8 mm. However, the positive predictive accuracy was only 55% and did not improve for other end-diastolic wall thickness values. In all myocardial regions, there was only a weak correlation between 18fluorodeoxyglucose activity and either end-diastolic wall thickness (r = 0.17) or wall thickening (r = 0.32). Thus, metabolic activity is present in many regions with reduced end-diastolic wall thickness and absent wall thickening. These data indicate that assessment of regional anatomy and function may be inaccurate in distinguishing asynergic but viable myocardium from nonviable myocardium.

Effects of heparin and protamine on left ventricular performance in the dog.

The effects of protamine on left ventricular (LV) function were measured under conditions of controlled heart rate and proximal aortic pressure in eight anaesthetized, heparinised dogs. Protamine 3 mg.kg-1 produced a 21% decrease in LV dP/dt max, a 43% decrease in cardiac output, a 47% decrease in stroke work and decreases in systolic and diastolic pressures (-16%, -19% respectively). Protamine 6 mg.kg-1 resulted in a 17% decrease in LV dP/dt max, a 26% decrease in cardiac output, a 50% decrease in LV stroke work and 25 and 30% decreases in systolic and diastolic pressures. These results show that an impairment of LV function plays an important part in the circulatory depression produced by protamine.

Mechanisms of tachycardia on standing: studies in normal individuals and in chronic Chagas' heart patients.

The reflex tachycardia induced by change from the supine position to a 70 degree head-up tilt was studied in conscious normal individuals and in patients with chronic Chagas' heart disease, known to constitute a model of parasympathetic denervation of the sinus node, in the absence of cardiac failure. Chagas' patients showed markedly decreased heart rate responses during the initial 10 s following tilt to upright posture. A similar response was obtained in normals after parasympathetic blockade with atropine. beta-Adrenergic blockade failed to produce a significant effect on the initial heart rate response of normals, but heart rate increment, at 1 and 5 min of tilt, was significantly reduced in normals and abolished in patients. These results indicate a biphasic mode of tachycardia elicited by the upright posture; initially it depends on parasympathetic withdrawal, sympathetic stimulation becoming the predominant mechanism when stabilisation is attained in the orthostatic position.

Parasympathetic contribution to bradycardia induced by endurance training in man.

Seven normal subjects of sedentary habits were submitted to a 10 week period of endurance physical training on a cycloergometer. The training programme produced a mean 15.6 +/- 1.4% (+/- SE) increase in VO2max (from 39.7 +/- 2.0 ml . kg-1 . min-1 to 45.9 +/- 2.4 ml . kg-1 . min-1) and a reduction in resting heart rate (HR) from 69 +/- 1.9 to 58 +/- 1.7 beats . min-1 in the supine position. After pharmacological blockade of the parasympathetic system with atropine sulphate, HR rose on average by 53 +/- 3.9 beats . min-1 before training and 47 +/- 3.6 beats . min-1 after training, the difference being statistically nonsignificant. The magnitude of respiratory sinus arrhythmia (RSA) was similar before and after the period of physical conditioning. The respiratory variation in HR ( Delta HR) at the 1 litre tidal volume was 20 +/- 2.4 beats . min-1 and 20 +/- 2.6 beats . min-1 before and after training, respectively. At the 2 litre tidal volume, these values were 25 +/- 3.2 and 27 +/- 4.5 beats . min-1. Similar results were obtained with the RSA test when a group of 13 sedentary individuals (VO2max = 39.4 +/- 1.3 ml . kg-1 . min-1) was compared with a group of 7 athletes who are medium distance runners (VO2max = 53.8 +/- 1.3 ml . kg-1 . min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Functional evaluation of sympathetic and parasympathetic system in Chagas' disease using dynamic exercise.

Ten normal subjects and 14 patients with chronic Chagas' disease (seven with and seven without heart disease) underwent dynamic exercise on a cycle ergometer. Heart rate (HR), pulmonary ventilation (V), oxygen consumption (VO2), carbon dioxide production (VCO2), and respiratory quotient (RQ) were measured. Increasing workloads (25, 50, 100, and 150 W) were applied for 4 min and intercalated with resting periods. The main objective of this protocol was to analyse heart rate response in relation to the other cardiorespiratory variables in order to evaluate the functional conditions of the sympathetic and parasympathetic cardiac efferents. Analysis of the results showed that (a) the group of chagasic patients with heart disease had lower heart rates (p less than 0.05) than normal subjects during the initial 10 s (delta HR 0-10 s) of effort (fast component); (b) the difference between the normal subjects and chagasic patients without heart disease was not statistically significant; (c) the abnormalities in heart rate response were due to depression of parasympathetic efferent action on the sinus node; (d) the slow heart rate response (delta HR 1-4 min), which expresses the degree of sympathetic stimulation of the sinus node, was comparable in the three groups studied, thus showing unimpaired adrenergic responses during dynamic exercise in Chagas' disease; and (e) the V, VO2, VCO2, and RQ values were normal at all workloads in each group, suggesting that vagal dysfunction does not affect oxygen transport at these submaximal levels of dynamic exercise.

Abnormal baroreflex control of heart rate in decompensated congestive heart failure and reversal after compensation.

Congestive heart failure (CHF) causes impairment of baroreflex control of heart rate (HR). To determine if this derangement is reversible, the cardiac chronotropic control was assessed in 10 patients with class IV chronic CHF of various etiologies before and after compensation achieved by bed rest, salt restriction, diuretics and vasodilators. Mean time between the 2 studies was 15 +/- 3 days. The management was modified 3 days before the second autonomic evaluation, so as to reestablish the same diet and pharmacologic conditions of the previous study. Compensation led to significant reduction in symptom-based class, body weight, and pulmonary and systemic congestion. Mean +/- standard error of the mean HR responses (beats/min) before and after compensation were, respectively: (1) to atropine (0.04 mg/kg): 10 +/- 2 and 27 +/- 2 (p less than 0.01); (2) to handgrip (30% maximum capacity, 1 minute): 9 +/- 2 and 19 +/- 3 (p less than 0.005); (3) to headup tilt (5 minutes): 4 +/- 3 and 20 +/- 4 (p less than 0.005). Mean +/- standard error of the mean baroreflex sensitivity (ms/mm Hg) of RR responses to phenylephrine and amyl nitrate-induced changes in systolic pressure was, respectively, in each condition: phenylephrine, 0.9 +/- 0.2 and 8 +/- 2.3 (p less than 0.05); amyl nitrate, 0.3 +/- 0.2 and 4.1 +/- 1.1 (p less than 0.05). A significant correlation between improvement in HR responses to atropine and tilt and changes in body weight was obtained. These findings show a reversible component of impaired baroreflex control of HR in severe CHF, possibly due to its congestive effects.

Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy.

Most patients with chronic Chagas' heart disease complain of chest pain. The pathophysiology of this symptom is unknown, although myocardial necrosis and fibrosis are frequent necropsy findings and cardiac autonomic impairment is a prominent feature of the disease. To evaluate the possibility of an ischemic cause for these abnormalities in 23 patients (18 men, aged 32 to 60 years, mean 42) with chronic Chagas' disease complaining of chest pain, thallium-201 myocardial scintigraphy was performed after maximal effort and 4-hour redistribution. Regional wall motion was assessed by radionuclide and contrast angiography. Heart rate responses to sinus respiratory arrhythmia, atropine, phenylephrine and Valsalva maneuver were evaluated in all patients and in 22 normal control subjects. Coronary angiography was performed in 16 patients. Only 1 patient had chest pain and no ischemic electrocardiographic changes occurred in any case during the effort test. Scintigraphic analysis of 7 segments per patient showed perfusion defects in at least 1 segment in all patients. Of 161 myocardial segments 16 showed fixed, 10 reversible, and 22 paradox defects (reverse redistribution). The majority (75%) of the fixed perfusion defects occurred in dyssynergic regions, whereas reverse redistribution predominated in regions with normal wall motion (82%). The reversible defects were present in normal or mildly hypokinetic regions. Markedly impaired parasympathetic cardiac control was present but no significant coronary abnormalities were seen in any of the 16 patients undergoing angiography. It is concluded that whereas fixed defects are likely to correspond to fibrotic or necrotic lesions, reversible and paradox perfusion defects may be caused by regional flow or metabolism derangements, possibly related to abnormal parasympathetic control of the coronary microcirculation.

Relation of regional sympathetic denervation and myocardial perfusion disturbance to wall motion impairment in Chagas' cardiomyopathy.

Impairment of sinus node autonomic control and myocardial perfusion disturbances have been described in patients with chronic Chagas' cardiomyopathy. However, it is not clear how these conditions contribute to myocardial damage. In this investigation, iodine-123 (I-123) meta-iodobenzylguanidine (MIBG) and thallium-201 myocardium segmental uptake were studied in correlation with the severity of left ventricular (LV) dysfunction detected in various phases of Chagas' heart disease. Group I consisted of 12 subjects (43 +/- 4 years, 7 men) with no symptoms and no cardiac involvement on electrocardiogram (ECG) or echocardiography; group II consisted of 13 patients (48 +/- 3 years, 9 men) with abnormal resting ECG and/or echocardiographic segmental abnormalities, and LV ejection fraction of > or = 0.5; group III was comprised of 12 patients (59 +/- 3 years, 10 men) with more severe heart disease, LV dilation, and LV ejection fraction of < 0.5. Eighteen control volunteers (38 +/- 3 years, 9 men) were also included in the study. I-123 MIBG single-photon emission computed tomographic (SPECT) segmental uptake defects were observed in group I (33%), group II (77%), and group III (92%). Quantitative analysis showed mean areas of reduced LV I-123-MIBG uptake: group I was 3.7 +/- 2.1%; group II was 8.3 +/- 2.3%; and group III was 19.0 +/- 3.3%. The differences between group I and both groups II and III were statistically significant (p < 0.001, analysis of variance test). Myocardial perfusion defects (reversible, fixed, and paradox) were observed in group I (83%), group II (69%), and group III (83%). A marked topographic association between perfusion, innervation, and wall motion abnormalities (assessed by gated-SPECT perfusion studies) was observed in all the groups. Defects predominated in the inferior, posterior lateral, and apical LV regions. Thus, extensive impairment of cardiac sympathetic function at the ventricular level occured early in the course of Chagas' cardiomyopathy and was related to regional myocardial perfusion disturbances, before wall motion abnormalities. Both conditions are associated with progression of ventricular dysfunction.

Thallium scintigraphy compared with 18F-fluorodeoxyglucose positron emission tomography for assessing myocardial viability in patients with moderate versus severe left ventricular dysfunction.

Thallium-201 reinjection imaging and positron emission tomography provide concordant information regarding myocardial viability in many patients with coronary artery disease and left ventricular (LV) dysfunction. It is unclear whether this concordance applies to patients with severe, as well as those with moderate, LV dysfunction. We studied 44 patients with chronic coronary artery disease and LV dysfunction, subgrouped on the basis of severity of dysfunction: 23 patients had moderate and 21 had severe dysfunction (ejection fractions 34 +/- 6% and 19 +/- 6%). Patients underwent exercise thallium single-photon emission computed tomography (SPECT) with 3- to 4-hour redistribution and reinjection imaging, as well as positron emission tomography (PET) imaging with 18fluorodeoxyglucose and 15O-water. Data were analyzed quantitatively in aligned transaxial PET and SPECT tomograms. A myocardial region was considered nonviable by PET if 18fluorodeoxyglucose activity was <50% of that in a normal region, associated with proportional reduction in blood flow. Similarly, regions were considered nonviable by thallium if activity was <50% of activity in normal regions on redistribution and reinjection studies. Thallium SPECT and PET data were concordant regarding viability in 98% and 93% of myocardial regions, respectively, in patients with moderate and with severe LV dysfunction. Lower concordance was observed only when regions with severe irreversible thallium perfusion defects on redistribution images were considered in both groups: 86% and 78%, respectively (p <0.01). Thus, thallium SPECT with reinjection yields information regarding regional myocardial viability that is similar to that provided by PET in patients with severe as well as moderate LV dysfunction. However, there is discordance in >20% of regions manifesting severe irreversible thallium defects in patients with severely reduced LV function.

Chagas' heart disease as an experimental model for studies of cardiac autonomic function in man.

Patients presented here include apparently healthy persons who had diagnostic evidence of chronic cardiac Chagas' disease in the form of a positive complement-fixation test and an abnormal electrocardiogram. They had never been in heart failure. All were examined for autonomic cardiac function. Normal persons served as controls. Patients with Chagas' disease with sole involvement of hollow viscera were also included. In patients with cardiac Chagas' disease, failure of the heart rate to increase after administration of atropine and greatly reduced reflex changes in cardiac rate are believed to be a functional disorder related to degeneration of the neuronal supply to the sinoatrial region of the heart. It is concluded that Chagas' disease is a model of spontaneous denervation of the heart which may be used for the assessment of autonomic control of cardiac function in man.

Acute myocardial infarction complicating the clinical course of dilated cardiomyopathy in childhood.

An acute myocardial infarction occurred in a 6-year-old child with dilated cardiomyopathy. This caused severe hemodynamic deterioration that led to a fatal outcome. Autopsy revealed diffuse myocardial atrophy without cell infiltrate, normal epicardial coronary arteries, and a massive healed anteroapical infarction. Coronary embolism or spasm could not be ruled out as the cause of the infarction.

Impairment of baroreflex control of the sinoatrial node after cardiac operations with extracorporeal circulation in man.

The sensitivity of the baroreceptor reflex to transient hypertension was determined in 13 patients before (control) and after (72 hours) open cardiac operations with extracorporeal circulation (ECC). In all patients early postoperative values were appreciably decreased (p less than 0.01) as compared to the preoperative values. This decrease suggested severe impairment of baroreflex control of the sinoatrial node. These changes were not correlated with concurrent alterations in heart rate or systemic arterial, left atrial, or right atrial pressures. In addition, respiratory sinus node arrhythmia was absent in all subjects. In four patients, subsequent studies 4, 8, 10, and 12 months, respectively, after the operation revealed good recovery of baroreflex sensitivity and respiratory influences on beat-to-beat variation. No similar effects were observed in two patients studied before and after cardiac operations without ECC. It is possible that direct trauma to the nervous supply of the sinoatrial node is a major factor in that reversible dysfunction; in fact, in three patients evidence was obtained that while sinoatrial node responses were impaired, the reflex control of the atrioventricular region remained unaltered. These findings point to further impairment of the fine control of heart rate imposed by the conditions of cardiac operations with ECC in patients with previously curtailed cardiac reserve.

Intraoperative measurement of the orifice area in patients with mitral valve stenosis.

This study was carried out in ten patients in order to compare results of mitral valve area evaluated by a new intraoperative technique and those provided by conventional hemodynamic methods. The results obtained correlated very well (r = 0.95) with values calculated by the Gorlin formula. Paired data checking were closer than 0.3 cm2 in all but one of patients with moderately severe mitral stenosis. It is concluded that the method for intraoperative measurement of the mitral valve area is simple, safe and reliable.

Multiple pulmonary thromboembolism diagnosed by two-dimensional echocardiography.

A 55-year-old man was admitted to our hospital because of progressive dyspnea, orthopnea and hemoptysis. Two-dimensional echocardiography multiple echo-dense images 1-4 mm in diameter were consistently seen crossing the tricuspid valve. A hypothesis of multiple pulmonary thromboembolism was raised. Clinical and postmortem evidence were later obtained to confirm this diagnosis.

Gene polymorphisms in the TNF locus and the risk of myocardial infarction.

We investigated two genetic polymorphisms in the tumor necrosis factor locus (TNF-alpha -308 G-->A and LT-alpha +252 A-->G) as risk factors for coronary atherothrombotic disease (CAD) by determining its prevalence in 148 survivors of myocardial infarction (MI) with angiographically-proven severe CAD, and in 148 age-, gender- and race-matched controls. The odds ratio (OR) for MI related to the mutant TNF-alpha and LT-alpha alleles was 0.8 (CI95: 0.4-1.3) and 1. 3 (CI95: 0.8-2.0), respectively. We also sought interaction of smoking and metabolic risk factors for MI with each mutant genotype. Smokers not carrying the LT-alpha +252 A-->G mutation had a risk of MI of 2.7 (CI95: 1.4-5.4) whereas in smoking carriers the risk was 6. 9 (CI95: 3.4-14.1). An interactive effect of the LT-alpha mutation may also exist with dyslipidemia (OR for MI in non-carriers was 12 [CI95: 3.2-41.3] and in carriers the OR was 39, [CI95: 5.1-301] and with obesity (OR for MI was 2.7, [CI95: 1-7.2] in non-carriers and in carriers the OR was 6 [CI95: 2.1-16.8]). Lastly, the OR for MI in obese non-carriers of TNF-alpha -308 G-->A was 2.8 (CI95: 1.3-6) and in obese carriers the OR was 14.5 (CI95: 1.8-113). Although significant interactive effects could not be detected, the findings suggest that interaction of polymorphisms in the TNF locus with major risk factors for CAD may exist, and should be explored in larger studies.