Showing papers in "Circulation in 1983"

Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study.

Abstract: The relationship between the degree of obesity and the incidence of cardiovascular disease (CVD) was reexamined in the 5209 men and women of the original Framingham cohort. Recent observations of disease occurrence over 26 years indicate that obesity, measured by Metropolitan Relative Weight, was a significant independent predictor of CVD, particularly among women. Multiple logistic regression analyses showed that Metropolitan Relative Weight, or percentage of desirable weight, on initial examination predicted 26-year incidence of coronary disease (both angina and coronary disease other than angina), coronary death and congestive heart failure in men independent of age, cholesterol, systolic blood pressure, cigarettes, left ventricular hypertrophy and glucose intolerance. Relative weight in women was also positively and independently associated with coronary disease, stroke, congestive failure, and coronary and CVD death. These data further show that weight gain after the young adult years conveyed an increased risk of CVD in both sexes that could not be attributed either to the initial weight or the levels of the risk factors that may have resulted from weight gain. Intervention in obesity, in addition to the well established risk factors, appears to be an advisable goal in the primary prevention of CVD.

Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog.

Abstract: Accumulation of polymorphonuclear neutrophils during the acute inflammatory response may exacerbate tissue injury through the release of activated oxygen products or proteolytic enzymes or both. To assess the role of neutrophils in acute myocardial infarction, circulating neutrophil levels in dogs were reduced by 77 +/- 2% (mean +/- SEM) by administering rabbit antiserum to dog neutrophils. Acute myocardial infarction was induced in open-chest anesthetized dogs by 90 minutes of left circumflex coronary artery occlusion followed by 6 hours of reperfusion. Dogs treated with neutrophil antiserum (n = 8) developed myocardial infarcts that were an average of 43% smaller than infarcts in dogs treated with nonimmune rabbit serum (n = 7) (27.0 +/- 4.5% vs 47.1% +/- 7.5% of the area at risk, p less than 0.05). In a saline-treated control group (n = 8), infarct size was 48.0 +/- 4.7% of the area at risk, a value not significantly different from that of the nonimmune serum group but significantly greater than that in the neutrophil antiserum dogs (p less than 0.05). There were no major hemodynamic differences between groups. Histopathologic examination revealed that infarcted myocardium from dogs given saline or treated with nonimmune serum had a substantial neutrophilic infiltrate, which was virtually absent in infarcted tissue from dogs treated with neutrophil antiserum. These observations suggest that neutrophil accumulation in response to myocardial ischemia may be responsible for a substantial portion of the irreversible myocardial injury resulting from temporary coronary artery occlusion.

Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Survival data.

Abstract: CASS includes a multicenter patient registry and a randomized controlled clinical trial. It is designed to assess the effect of coronary artery bypass surgery on mortality and selected nonfatal end points. From August 1975 to May 1979, 780 patients with stable ischemic heart disease were randomly assigned to receive surgical (n = 390) or nonsurgical (n = 390) treatment and were followed through April 15, 1983. At 5 years, the average annual mortality rate in patients assigned to surgical treatment was 1.1%. The annual mortality rate in those receiving medical therapy was 1.6%. Annual mortality rates in patients with single-, double-, and triple-vessel disease who were in the surgical group were 0.7%, 1.0%, and 1.5%; the corresponding rates in patients in the medical group were 1.4%, 1.2%, and 2.1%. The differences were not statistically significant. Nearly 75% of the patients had entry ejection fractions of at least 0.50. The annual mortality rates in patients in the surgical group in this subgroup with single-, double-, and triple-vessel disease were 0.8%, 0.8%, and 1.2% and corresponding rates in the medical group were 1.1%, 0.6%, and 1.2%. The annual rate of bypass surgery in patients who were initially assigned to receive medical treatment was 4.7%. The excellent survival rates observed both in CASS patients assigned to receive medical and those assigned to receive surgical therapy and the similarity of survival rates in the two groups of patients in this randomized trial lead to the conclusion that patients similar to those enrolled in this trial can safely defer bypass surgery until symptoms worsen to the point that surgical palliation is required.

Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community.

Abstract: Pulse wave velocity (PWV) was measured by means of transcutaneous Doppler techniques in the aorta, right arm, and right leg of 480 normal subjects of both sexes in urban Beijing, China (age range 3 to 89 years, mean age 41 +/- 20.8 SD); supine blood pressure was recorded in the brachial artery of each subject with standard sphygmomanometric procedures. Serum cholesterol was determined in a subgroup of 79 subjects (age 17 to 85 years, mean 47 +/- 26 SD). PWV (y in cm/sec) was found to vary with age (x, years) at each of the three locations according to the following regression equations: aorta, y = 9.2x + 615, r = .673 (p less than .001); right arm, y = 4.8x + 998, r = .453 (p less than .001); right leg, y = 5.6x + 791, r = .630 (p less than .001). Systolic, diastolic, mean, and pulse pressures were found to increase with age. PWV also increased with mean supine blood pressure but was not related to serum cholesterol (average 4.49 +/- 0.11 [SEM], mmol/l). Compared with that of Western populations, serum cholesterol tended to be lower at all age groups, systolic pressure higher at ages over 35 years, and PWV higher at all ages. Because change in PWV is directly related to change in arterial compliance, these results indicate that aging and not concomitant atherosclerosis (known to be rare in Asian populations) is the dominant factor associated with reduced arterial compliance and increased left ventricular load in these subjects.

Aneurysmal coronary artery disease.

Abstract: To examine the clinical and historical features and the natural history of aneurysmal coronary disease, we reviewed the registry data of the Coronary Artery Surgery Study (CASS). Nine hundred seventy-eight patients, representing 4.9% of the total registry population, were identified as having aneurysmal disease. No significant differences were noted between aneurysmal and nonaneurysmal coronary disease patients when features such as hypertension, diabetes, lipid abnormalities, family history, cigarette consumption, incidence of documented myocardial infarction, presence and severity of angina, and presence of peripheral vascular disease were examined. In addition, no difference in 5-year medical survival was noted between these two groups. These findings suggest that aneurysmal coronary disease does not represent a distinct clinical entity but is, rather, a variant of coronary atherosclerosis.

Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations.

Abstract: The arrhythmogenic role of increased dispersion of repolarization (dispersion) was studied in 23 open-chest dogs using six simultaneously recorded monophasic action potentials (MAPs) from the ventricular surface and programmed ventricular premature stimulation (VPS). Increased dispersion was induced by generalized hypothermia (29 degrees C) and regional warm blood (38-43 degrees C) perfusion through a coronary artery branch. Hypothermia and regional warm blood perfusion increased maximum dispersion from 13 +/- 10 to 111 +/- 16 msec (p less than 0.001), predominantly because of the increased MAP duration difference (10 +/- 15 vs 97 +/- 16 msec, p less than 0.001). The maximal difference between activation times was not significantly changed, but the QRS duration increased from 47 +/- 6 to 52 +/- 7 msec (p less than 0.01). Ventricular arrhythmia did not occur spontaneously but was induced by a single VPS in all 23 dogs during hypothermia and regional warm blood perfusion when dispersion reached a critical magnitude. The critical magnitude of dispersion required to induce ventricular arrhythmia was documented in 16 dogs by stepwise increments or decrements of dispersion. In four dogs, an increase in atrial pacing rate of 24 beats/min prevented induction of ventricular arrhythmia by decreasing dispersion from a critical magnitude of 103 +/- 5 msec to a nonarrhythmogenic value of 86 +/- 9 msec (p less than 0.05). In six dogs, we compared the stimulation site-dependent effects of VPS applied in the region with short and long MAPs. In all dogs, ventricular arrhythmia was inducible only by VPS from the region with a short MAP. Premature impulses from this region propagated more slowly than those from the region with a long MAP. Our results show that the large dispersion of repolarization facilitates the development of a conduction delay necessary to induce sustained arrhythmia by an early premature stimulus applied at the site with a short MAP.

Results of coronary artery surgery in patients with poor left ventricular function (CASS).

Abstract: We identified 420 medically treated and 231 surgically treated patients (coronary graft plus myocardial surgery in 30%) who had severe left ventricular dysfunction manifest by an ejection fraction below 0.36 and markedly abnormal wall motion. Compared with medically treated patients, those treated surgically had more severe angina (56.7% vs 29.0% class III or IV; p less than .001), less heart failure as predominant symptom (11.1% vs 18.8%; p less than .003), more severe coronary disease (66.7% vs 50.2% three-vessel disease; p less than .001), a greater concentration of left main coronary artery lesions greater than 70% (12.6% vs 3.8%: p less than .001), and a greater estimated extent of jeopardized myocardium (p less than .001). Multivariate regression analysis of survival, which adjusts for the above covariates, showed that surgical treatment prolonged survival (p less than .05), although it ranked below severity of heart failure symptoms, age, ejection fraction, and left main stenosis greater than 70% in determining prognosis. Surgical benefit was most apparent for patients with ejection fractions below 0.26 who had a 43% 5 year survival with medical treatment vs 63% with surgery. Surgically treated patients experienced substantial symptomatic benefit compared with medically treated patients if their presenting symptoms were predominantly angina; however, there was no relief of symptoms caused primarily by heart failure. We conclude that patients with predominantly ischemic pain symptoms, despite poor left ventricular function, benefit from surgery; however, operative mortality in this high-risk subset must equal or better the 6.9% obtained in this study.

Noninvasive evaluation of pulmonary hypertension by a pulsed Doppler technique.

Abstract: We used a pulsed Doppler technique to examine the flow velocity pattern in the right ventricular outflow tract in 33 adults. In the patients with normal pulmonary artery pressure (mean pressure less than 20 mm Hg, 16 patients), ejection flow reached a peak level at midsystole (137 +/- 24 msec, mean +/- SD), producing a domelike contour of the flow velocity pattern during systole. In contrast, the flow velocity pattern in patients with pulmonary hypertension (mean pressure greater than or equal to 20 mm Hg, 17 patients) was demonstrated to accelerate rapidly and to reach a peak level sooner (97 +/- 20 msec, p less than .01); in 10 of the pulmonary hypertensive patients a secondary slower rise in flow velocity was observed during a deceleration, resulting in the midsystolic notching. The time to peak flow (acceleration time, AcT) and right ventricular ejection time (RVET) were measured from the flow velocity pattern. Either AcT or AcT/RVET decreased with increase in mean pulmonary artery pressure, and a very high correlation (r = -.90) was found between AcT/RVET and log10 (mean pulmonary artery pressure). The use of this technique permitted the noninvasive estimation of the pulmonary artery pressure.

Left ventricular hypertrophy in patients with hypertension: importance of blood pressure response to regularly recurring stress.

Abstract: Left ventricular hypertrophy (LVH), a target organ response in essential hypertension, is only weakly related to clinical measurements of blood pressure. To determine whether blood pressure measured under basal or stress conditions more closely determines LVH, we compared echocardiographic left ventricular mass index and relative wall thickness with clinical blood pressure and with 24 hr recordings (home, work, and sleep) in 19 normal subjects and 81 patients with mild hypertension. Only a weak correlation was observed in the entire group between left ventricular mass index and clinical measurements of systolic and diastolic blood pressure (r = .24, p < .02; r = .20, p < .05, respectively), which was only slightly improved by use of systolic and diastolic blood pressure readings taken in the home (r = .31, p < .005; r = .21, p < .05, respectively). Sleep and total 24 hr blood pressure also related poorly to left ventricular mass index. In contrast, substantially higher correlations existed between left ventricular mass index and systolic and diastolic blood pressure measured by portable recorder in 60 subjects at work (r = .50, p < .001; r = .39, p < .01, respectively). Similarly, work diastolic blood pressure bore the closest relationship to relative wall thickness (r = .59, p < .001). Home blood pressure readings taken on a work day also showed a moderate relationship with indices of LVH, whereas weaker correlations were found in employed subjects whose blood pressure was recorded on a non-workday, and no relationship between blood pressure and LVH existed in subjects who were not employed. We conclude that hypertensive LVH is poorly related to clinical or home measurements of blood pressure but that a substantially closer relationship exists between LVH and blood pressure during recurring stress at work and between LVH and home blood pressure on a workday. Thus hypertensive cardiac hypertrophy appears to be more closely related to blood pressure during stressful Circulation 68, No. 3, 470-476, 1983. NUMEROUS STUDIES have demonstrated that the risk of disease and death increases as blood pressure rises.'4 However, despite the consistency of this finding and its high statistical significance in large populations, the actual correlations between blood pressure measurements and the incidence of morbid events have generally been relatively low.'4 One possible explanaFrom the Division of Cardiology, The Hypertension Center, and the Department of Neurology, The New York Hospital-Cornell Medical Center, New York, and the Department of Statistics and Data Analysis Research, Bell Laboratories, Murray Hill, NJ. Supported in part by grant HL-18323 from the NHLBI. Address for correspondence: Richard B. Devereux, M.D., Division of Cardiology, Box 222, The New York Hospital, 525 East 68th St., New York, NY 10021. Received Dec. 13, 1982; revision accepted April 28, 1983. Dr. Devereux is the recipient of a Teacher-Scientist Award from the Andrew W. Mellon Foundation. Dr. Borer is an Established Investigator of the American Heart Association. 470 situations than to basal blood pressure. tion for the lack of a closer relationship is that blood pressure itself is highly variable7-' and that clinical measurements may be unrepresentative of the longterm overload placed on the circulation.9-10 The observation by some investigators that target organ manifestations in subjects with essential hypertension are more closely related to basal,9 home, \"I or ambulatory blood pressure readings'2 has supported this hypothesis, although this finding has not been consistent.'3 Another factor that may have contributed to the poor correlations is the weak relationship between cardiac changes and their manifestations in the electrocardiogram (ECG)'4 or chest x-ray.'5 The development of methods for recording blood pressure accurately during unrestricted in-hospital or normal out-of-hospital activity\"\"lS has provided furCIRCULATION by gest on N ovem er 8, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATURAL HISTORY-HYPERTENSION ther information about blood pressure variability in normal subjects and in patients with essential hypertension. These studies have confirmed earlier reports that hypertensive patients have greater increases in blood pressure from basal levels in response to stresses such as clinic visits,'9-21 the work environment,22 isometric exercise,23 and dynamic exercise2' than do normals. However, the significance of different patterns of blood pressure reactivity and of blood pressure levels during recurring activities of daily living has not been assessed with regard to target organ manifestations of hypertension or occurrence of morbid events. The recent development of an accurate echocardiographic method for measurement of left ventricular mass24 has provided an improved \"bioassay\" for one of the most important target organ effects of hypertension. Previous studies have indicated that detectable left ventricular hypertrophy (LVH) is important not only as an indicator of the current severity of hypertension but also as a source of prognostic information independent of the level of blood pressure. 1-2, 5, 25 The present study has been designed to evaluate the relationship between blood pressure during different phases of normal activity and echocardiographic measurements of left ventricular mass. We compared clinical blood pressure readings (measured by physicians) with measurements taken by automatic portable recorder in the clinic, at work, at home, and during sleep. Methods Subjects. We studied a total of 100 subjects, 19 of whom were normal and 81 of whom had borderline26 or sustained essential hypertension. All subjects underwent quantitative echocardiographic examination and ambulatory blood pressure recording as described below. No subjects were receiving antihypertensive or other cardioactive medication at the time of study; antihypertensive drugs had been eliminated at least 3 weeks before study. No subject had evidence of coronary artery disease or other etiologic forms of heart disease by cardiovascular history, physical examination, ECG, or echocardiogram. However, three patients with mitral valve prolapse and trivial mitral regurgitation were included, since we have previously shown that this is not associated with LVH.2? Further exclusion of coronary artery disease was accomplished by performance of maximal upright treadmill exercise testing in 67 subjects and maximum supine bicycle exercise, with rest and exercise radionuclide cineangiographic studies28 in an additional nine patients; angina was not provoked in any subject, and there was no objective evidence of coronary disease. Subjects were classified by clinical blood pressure readings into normal and hypertensive groups, as described below. Normals. Nineteen normal subjects were studied in whom multiple clinical blood pressure determinations never exceeded 140 mm Hg systolic or 90 mm Hg diastolic. There were 11 men and eight women (ages 28 to 64 years, mean 40). Mean clinical blood pressure was 118 ± 15/76 ± 7 mm Hg. Twelve of the normal subjects also underwent blood pressure determinations during each stage of maximum upright treadmill exercise tests by the Bruce protocol. Patients with hypertension. Eighty-one subjects with mild essential hypertension were studied. There were 70 men and 11 women (ages 18 to 66 years, mean 43). Mean clinical blood pressure was 152 ± 15/96 + 7 mm Hg; the duration of hypertension was 5.5 ± 5.5 years. Treadmill exercise tests were performed in 55 hypertensive patients, and radionuclide cineangiograms were obtained in nine subjects. Employment status. In view of the potential importance of the blood pressure response to occupational stress in causing target organ manifestations of hypertension and of the emphasis placed by Sokolow et al. 12 on obtaining daytime blood pressure recordings on a workday, we also stratified our subjects according to employment status. A total of 60 subjects worked on the day of recording, 28 were employed but had recordings performed on a non-workday, and 12 were not employed. As seen in table 1, these groups differed only slightly with regard to age and sex, except for a higher number of women in the unemployed group, and had similar 24 hr blood pressure measurements. Echocardiographic methods. Echocardiograms were performed with standard techniques previously reported from this laboratory.29, 30 Echocardiographic tracings were coded and read blindly and in random order. End-diastolic measurements of interventricular septal thickness (IVS), left ventricular internal dimension (LVID), and posterior wall thickness (PWT) were made according to the Penn Convention protocol to measure left ventricular mass.24 This was calculated by a simple anatomically validated formula: LVM = 1.04((IVS + LVID + PWT)3 LVID)3 13.6 To minimize the impact of variation in body size on left ventricular mass, it was indexed for body surface area. End-diastolic and end-systolic measurements were also made according to the recommendations of the American Society of Echocardiography.3' End-diastolic relative wall thickness32 was calculated from these values. Blood pressure by portable recorder. The 24 hr blood pressure recordings were obtained with the Del Mar Avionics Ambulatory Blood Pressurometer II. Subjects were fitted with the recorder on the morning of the day of the recording, and a minimum of five readings were taken with the subject in the sitting position. These had to be within 5 mm Hg of simultaneous readings obtained with a stethoscope and mercury column for the recording to be considered acceptable. The recorder was then set to take readings at 15 min intervals, and subjects were TABLE 1 Employment status of subjects

Noninvasive Doppler determination of cardiac output in man. Clinical validation.

Abstract: A noninvasive technique for assessing cardiac output (CO) was evaluated by comparing it with thermodilution determinations in patients in the intensive care unit. The new method uses pulsed ultrasound to measure aortic diameter and continuous-wave Doppler ultrasound to obtain aortic blood velocity. An initial study evaluating just the velocity measurement showed that changes of the Doppler index of output (DI) correlated well with those of thermodilution cardiac output (TDCO). Linear regression analysis yielded delta DI = 0.87 delta TDCO + 0.14 (r = 0.83, n = 95). Using a university research instrument these measurements were possible in 54 of 60 patients (90%). A second study using a prototype commercial device incorporated the diameter measurement. Ultrasonic cardiac output (UCO), calculated as the time integral of velocity multiplied by the aortic area, was compared to TDCO. The data, obtained from 45 of 53 patients (85%), are described by the linear regression UCO = 0.95TDCO + 0.38 (r = 0.94, n = 110) over a range of 2-11 l/min. Patients with aortic stenosis, aortic insufficiency or a prosthetic valve have been excluded from the second study due to conditions likely to violate the assumptions upon which the calculation of absolute cardiac output is based. These results indicate that accurate CO can be measured by noninvasive ultrasound in most patients. The technique may be useful for extended CO monitoring in acute care patients and for CO assessment in many other types of patients undergoing diagnostic studies and therapeutic interventions.

Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry.

Abstract: The complications reported in the first 1500 patients enrolled in the National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry are analyzed. Data were contributed from 73 centers between September 1977 and April 1981. PTCA was successful in 63% of attempts. Five hundred forty-three in-hospital complications occurred in 314 patients (21%). The most frequent complications were prolonged angina in 121, myocardial infarction (MI) in 72, and coronary occlusion in 70. One hundred thirty-eight patients (9.2%) had major complications (MI, emergency surgery or in-hospital death). One hundred two patients (6.8%) required emergency surgery, usually for coronary dissection or coronary occlusion. Sixteen patients (1.1%) died in-hospital; the mortality rate was 0.85% in patients with one-vessel disease and 1.9% in those with multivessel disease. The mortality rate was significantly higher in patients who had had bypass surgery (p less than 0.001). Nonfatal complications were significantly influenced by the presence of unstable angina (p less than 0.001) and initial lesion severity greater than 90% diameter stenosis (p less than 0.001). This report delineates and assesses the complications encountered with PTCA during its initial 3 1/2-year clinical experience. These results support the relative safety of PTCA as a method of nonsurgical myocardial revascularization in carefully selected patients.

Prediction of cardiac events after uncomplicated myocardial infarction: a prospective study comparing predischarge exercise thallium-201 scintigraphy and coronary angiography.

Abstract: The ability of predischarge quantitative exercise thallium-201 (201T1) scintigraphy to predict future cardiac events was evaluated prospectively in 140 consecutive patients with uncomplicated acute myocardial infarction; the results were compared with those of submaximal exercise treadmill testing and coronary angiography. High risk was assigned if scintigraphy detected 201T1 defects in more than one discrete vascular region, redistribution, or increased lung uptake, if exercise testing caused ST segment depression greater than or equal to 1 mm or angina or if angiography revealed multivessel disease. Low risk was designated if scintigraphy detected a single-region defect, no redistribution, or no increase in lung uptake, if exercise testing caused no ST segment depression or angina, or if angiography revealed single-vessel disease or no disease. By 15 +/- 12 months, 50 patients had experienced a cardiac event; seven died (five suddenly), nine suffered recurrent myocardial infarction, and 34 developed severe class III or IV angina pectoris. Compared with that of patients at low risk, the cumulative probability of a cardiac event was greater in high-risk patients identified by scintigraphy (p less than .001), exercise testing (p = .011), or angiography (p = .007). Scintigraphy predicted low-risk status better than exercise testing (p = .01) or angiography (p = .05). Each predicted mortality with equal accuracy. However, scintigraphy was more sensitive in detecting patients who experienced reinfarction or who developed class III or IV angina. When all 50 patients with events were combined, scintigraphy identified 47 high-risk patients (94%), whereas exercise-induced ST segment depression or angina detected only 28 (56%) (p less than .001). The presence of multivessel disease as assessed by angiography identified nine more patients with events than exercise testing (p = .06). However, the overall sensitivity of angiography was lower than that of scintigraphy (71% vs 94%; p less than .01) because three patients who experienced reinfarction and 10 who developed class III or IV angina had single-vessel disease. Importantly, 12 (92%) of these 13 patients with single-vessel disease who had an event exhibited redistribution on scintigraphy. These results indicate that (1) submaximal exercise 201T1 scintigraphy can distinguish high- and low-risk groups after uncomplicated acute myocardial infarction before hospital discharge; (2) 201T1 defects in more than one discrete vascular region, presence of delayed redistribution, or increased lung thallium uptake are more sensitive predictors of subsequent cardiac events than ST segment depression, angina, or extent of angiographic disease; and (3) low-risk patients are best identified by a single-region 201T1 defect without redistribution and no increased lung uptake.

Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease.

Abstract: THE APPRECIATION that two oxygenated metabolites of arachidonic acid, prostacyclin (PGI2) and thromboxane A2 (TxA2), have potent and contrasting effects on vascular tone and platelet function in vitro has prompted attempts to define their importance in human vascular disease. Both compounds are formed from arachidonic acid by the enzyme cyclooxygenase via cyclic endoperoxide intermediates, PGG2 and PGH2. TxA2, the major cyclooxygenase product in the platelet, is a vasoconstrictor and potent stimulus to platelet aggregation in vitro. I PGJ2, a vasodilator and inhibitor of platelet aggregation, is the predominant product of the same enzyme in vascular endothelial cells.2 The development of techniques to study platelet function in vivo3 4 and ex vivo5 preceded the discovery of these compounds, and the application of these tests suggests that increased platelet activation may well accompany vascular occlusive events in man.4 6 Thus, it seems reasonable that PGI2 and TxA2 might play an important role in this and other syndromes of disordered platelet-vascular homeostasis in man.7 Support for this concept relies upon the development of methods to measure PGI2 and TxA2 in human biological fluids. However, both PGI2 and TxA2 have extremely short half-lives' 2 and are rapidly cleared from the bloodstream. Furthermore, arachidonic acid release from biological membranes (and thus synthesis of PGI2 and TxA2) is likely to be phasic rather than continuous. This phenomenon also renders measurement of these products highly liable to artifact when performed in media obtained by invasive sampling techniques, such as plasma. Finally, there are the technical difficulties involved in devising assays of requisite sensitivity and specificity. Three approaches have been used: bioassay, radioimmunoassay (RIA) and stable isotope dilution assays involving gas chromatography-mass spectrometry (GC/MS). Bioassays have the advantage of actually measuring biological activity and have been of critical qualitative importance in the discovery of prostaglandins,2, 8 Because of the evanescence of both PGI2 and TxA2 in the circulation, RIAs and GC/MS methods are directed toward metabolites. These methods are more sensitive and specific than bioassay and more applicable to quantitative study of prostaglandin turnover in man. Initially, the various approaches appeared

Atherosclerosis and late closure of aortocoronary saphenous vein grafts: sequential angiographic studies at 2 weeks, 1 year, 5 to 7 years, and 10 to 12 years after surgery.

Abstract: Sequential control angiographic examinations were performed at 2 weeks, 1 year, 5 to 7 years, and 10 to 12 years after aortocoronary saphenous vein bypass surgery in 82 unselected patients. Graft modifications consisting of wall irregularities and obstructive lesions of various severity and shapes that were found to develop after the first year were attributed to atherosclerosis. The incidence of these late changes increased from 16% during the interval between 1 year and 5 to 7 years to 36.4% during the subsequent interval between 7 and 12 years (p less than .01). These changes were not influenced by the severity of early diffuse or localized intimal hyperplasia. They were not related to classical risk factors except for low-density lipoprotein and low-density beta-lipoprotein cholesterol. Graft closure increased 2.5-fold from the interval between 1 year and 5 to 7 years to the following period between 7 and 12 years, 10.2% to 26.1% (p less than .02); thus the mean yearly attrition rate augmented from 2% to 5.3%. Late graft closure may result from early localized stenosis most likely related to improper surgical techniques, but the most frequent cause appears to be atherosclerosis. Graft patency at 10 to 12 years is 63.3%.

Identification and differentiation of resting myocardial ischemia and infarction in man with positron computed tomography, 18F-labeled fluorodeoxyglucose and N-13 ammonia.

Abstract: Studies have shown that the extraction of glucose per unit flow is increased in moderately ischemic myocardium primarily due to anaerobic glucose metabolism manifested as lactate production, whereas myocardial infarction is characterized by the loss of metabolically active myocardium. To determine the feasibility of demonstrating these metabolic abnormalities reflecting both ischemia and infarction, we used positron computed tomography (PCT) to evaluate relative regional myocardial exogenous glucose utilization and perfusion in 15 patients with recent myocardial infarction. The positron-emitting tracers of glucose metabolism and perfusion, 18F-2-fluoro-2-deoxyglucose (FDG) and N-13 ammonia, respectively, were used. Fourteen of 19 documented infarctions were demonstrated by PCT to have concordantly decreased glucose utilization and perfusion. However, in an additional 11 regions, glucose utilization was disproportionately increased relative to perfusion, consistent with ischemic glucose consumption. These findings correlated with the presence of postinfarction angina, the site of ischemic electrocardiographic changes during chest pain, and the presence of regional left ventricular dysfunction and severe coronary artery disease. Because three ECG infarct zones not detected by PCT demonstrated ischemic glucose utilization, only two of 19 electrocardiographically defined infarctions had no detectable metabolic abnormality. We conclude that the changes in regional FDG and N-13 ammonia concentrations detected with PCT in patients who had had a recent myocardial infarction are consistent with regional exogenous glucose utilization and perfusion in moderately ischemic and irreversibly infarcted myocardium. This approach has the potential to identify and differentiate resting myocardial ischemia from infarction and to assess tissue viability after an ischemic event.

Platelet function, thromboxane formation and blood pressure control during supplementation of the Western diet with cod liver oil.

Abstract: SUMMARY Epidemiologic andexperimental datasuggest an antiatherothrombotic potential ofc-3 polunsaturated fatty acids. Therefore, theWestern diet, whichsupplies predominantly w-6polyunsaturatedfatty acids, was supplemented with40ml/day ofcodliver oil, whichprovides about10g ofco-3 polyunsaturated fatty acids daily, for25daysineight volunteers. Thew-3polyunsaturated fatty acids were incorporated inplatelet anderythrocyte membrane phospholipids attheexpenseofw-6polyunsaturated fatty acids.Bleeding timeincreased (p< 0.01) andplatelet count(p< 0.05), platelet aggregation upon ADPandcollagen (p< 0.01-0.05), andassociated thromboxane B2 formation (p< 0.01) decreased. Blood pressure(p< 0.05) andblood pressureresponsetonorepinephrine (p< 0.01) andangiotensin II(NS)fell, without majorchanges inplasma catecholamines, renin, urinary aldosterone, kallikrein, prostaglandins E2 andF2, andredcell cation fluxes. Biochemical andfunctional changes werereversed 4weeks after codliver oilwasdiscontinued. Formation ofprostaglandins derived fromeicosapentaenoic acid andinterference of eicosapentaenoic acidwithformation andaction ofprostaglandins derived fromarachidonic acid were evident invitro. Whatever themechanism, this moderate supplement ofw-3polyunsaturated fatty acids markedly changed membranephospholipids, which wasassociated with ashift toward less reactive platelets anda blunted circulatory responsetopressurehormones. SEVERALindependent lines ofevidence suggest a protective potential ofdietary eicosapentaenoic acid (all cisC20:5cw3) against cardiovascular disease. Greenland Eskimos and, toalesser extent, someJapanese, haveahighdietary intake oflong-chain co-3 polyunsaturated fatty acids fromseafood' andalow

Coronary artery surgery study (CASS): a randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups.

Abstract: To evaluate the comparative effects of medical and surgical therapy on quality of life of patients with stable ischemic heart disease, 780 patients who had been randomly assigned to medical or surgical therapy in the CASS were systematically followed for a mean of 5.5. years. Analysis was performed according to original treatment assignment. Patients in the surgical group had significantly less chest pain, fewer activity limitations, and required less therapy with nitrates and beta-blockers. Treadmill exercise tests performed 6, 18, and 60 months after entry documented significantly longer treadmill time, less exercise-induced angina, and less ST segment depression among surgical group patients. However, employment status and recreational status did not differ significantly between medical and surgical groups. Total number of hospitalizations after randomization was higher in the surgical group owing primarily to rehospitalization during the first year of follow-up for the coronary artery bypass graft surgery. Risk factors, including high blood pressure, cigarette smoking, high cholesterol levels, overweight, and poor exercise habits remained similar between medical and surgical groups. This randomized collaborative study shows that coronary artery bypass graft surgery improves the quality of life as manifested by relief of chest pain, improvement in both subjective and objective measurements of functional status, and a diminished requirement for drug therapy. However, no significant effect on employment or recreational status was observed.

Studies of experimental coronary artery reperfusion. Effects on infarct size, myocardial function, biochemistry, ultrastructure and microvascular damage.

Abstract: The present report is a review of recent experimental studies in a canine model of acute coronary occlusion. The questions addressed were: (1) Does coronary reperfusion reduce myocardial infarct size? (2) What is the relationship between microvascular damage and hemorrhage and the development of myocardial necrosis? (3) What are the biochemical, functional and ultrastructural characteristics of reperfused tissue salvaged from necrosis? Coronary occlusion followed by reperfusion in the dog resulted in significant subepicardial salvage of myocardium if reperfusion was instituted before 6 hours of ischemia. Because ultrastructural evidence of microvascular damage was found only after irreversible damage to myocytes, and because gross hemorrhage after coronary reperfusion was confined to zones of myocardium that were already necrotic, it does not appear that hemorrhage should serve as a deterrent to reperfusing reversibly injured myocytes. Severely ischemic myocardium that had been salvaged by coronary reperfusion required several days before it returned to normal from biochemical, functional and ultrastructural standpoints.

Summary estimates of cholesterol used to predict coronary heart disease.

Abstract: The relationships of total cholesterol and the proportion of cholesterol in individual lipoprotein classes to coronary heart disease are complex. To help simplify these relationships, cholesterol values are often combined into one summary estimate to form a single risk factor with a relationship to disease that is more easily described. Although summary estimates result in convenient expressions relating cholesterols to coronary heart disease, there is the potential for sacrificing information by ignoring the joint configuration of cholesterols that make up these estimates. We investigated the extent of this possibility for the ratio of total cholesterol to high-density lipoprotein cholesterol and the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol. The findings suggest that the summary estimates are useful expressions for combining cholesterol information and are strong predictors of coronary heart disease. Clinicians who choose to use a summary estimate for screening purposes should recognize that a single ratio estimate is not always as informative as the joint configuration of the cholesterols that make up the estimate. This possibility is most clearly exhibited for the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol, and it may become more apparent in future studies as the capabilities of exploring lipoprotein cholesterol relationships improve.

Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia.

Abstract: Adenosine was administered intravenously to 17 patients undergoing intracardiac electrophysiologic studies. At a mean dose of 179 +/- 88 micrograms/kg (+/- SD), adenosine suppressed sinus node automaticity and depressed atrioventricular (AV) nodal conduction. These effects were less than 20 sec in duration and were not influenced by muscarinic blockade with atropine (0.02 to 0.03 mg/kg). Adenosine at this dose had no effect on antegrade conduction over accessory pathways in patients with Wolff-Parkinson-White syndrome. No independent hemodynamic effects were observed. In six patients, adenosine was administered intravenously during stimulation-induced paroxysmal supraventricular tachycardia. In the five patients in whom the reentry loop of their tachycardia included the AV node, adenosine at a mean dose of 83 +/- 35 micrograms/kg (+/- SD) terminated their tachycardia within 20 sec after peripheral intravenous injection. The dose of adenosine required to terminate these tachycardias did not produce manifest sinus node suppression, and sinus rhythm promptly resumed in all patients. Adenosine did not terminate either supraventricular tachycardia due to intra-atrial reentry or atrial flutter, but did produce transient AV block during these arrhythmias. Our findings demonstrate that the human sinus and AV nodes are sensitive to physiologic doses of adenosine and that adenosine may be used safely and effectively to terminate acute episodes of supraventricular tachycardia that involve the AV node in the reentry pathway.

Right ventricular tachycardia: clinical and electrophysiologic characteristics.

Abstract: This report describes the clinical and electrophysiologic characteristics of 30 patients without myocardial disease who had ventricular tachycardia with the morphologic characteristics of left bundle branch block and inferior axis. The tachycardias were nonsustained in 24 patients, sustained (greater than 30 sec) in six patients, and provocable by exercise in 14 of 23 patients undergoing a standard Bruce protocol. Ventricular tachycardia was induced during electrophysiologic study in 22 of 30 patients. Programmed stimulation induced tachycardia in 10 of 30 patients, most frequently by rapid atrial or ventricular pacing. Isoproterenol infusion facilitated tachycardia induction in 13 of 23 patients. Endocardial activation mapping, performed in 10 patients, confirmed that earliest ventricular activation during tachycardia occurred at the right ventricular outflow tract on the interventricular septum. These tachycardias were unique in their responsiveness to a wide variety of antiarrhythmic drugs, including type I drugs and propranolol. During a mean follow-up of 30 months, no patient has died or experienced cardiac arrest. Two patients appear to be in spontaneous remission, and no patient has developed additional signs of cardiac disease.

Side effects of long-term amiodarone therapy.

Abstract: Although amiodarone is an effective antiarrhythmic agent, long-term therapy may be associated with unwanted effects. We report our experience in 140 patients treated over 5 years. Important effects were seen particularly in the thyroid gland, liver, lung and skin. Some of these effects are dose-dependent and others may be related to the chemical structure and metabolism of amiodarone. Corneal microdeposits were always found when sought, but did not cause impairment of visual acuity.

Intravenous short-term infusion of streptokinase in acute myocardial infarction.

Abstract: Short-term i.v. infusion of streptokinase was performed in 93 patients within 6 hours after the onset of acute myocardial infarction. Twenty-six patients underwent angiography in the acute phase (group A) and 52 underwent angiography in the fourth week only (group B); 15 patients had no angiography. Seven patients died during the hospital stay and six suffered nonfatal reinfarctions. There were no bleeding complications. In 11 of 21 group A patients, occluded coronary arteries were opened within 1 hour after the streptokinase infusion was started. In 84% of groups A and B, the infarct-related coronary artery was patent in the fourth week. In 75% of the patent arteries, the residual luminal diameter stenosis was less than 70%. According to serial serum CK-MB curves, recanalization was achieved mostly within 1-2 hours. Myocardial salvage was indicated by improvement in local contraction disorders in the recanalized group A patients and by the significant relationship between infarct size and time from symptom onset to treatment in group B. These data suggest that a high-dose, short-term, i.v. infusion of streptokinase is a safe and efficient method of restoring coronary blood flow. Expeditious initiation of i.v. streptokinase infusion is a critical determinant for early recanalization and salvage of myocardium. Patients with thrombotically subtotal occlusion probably receive the most benefit. Evaluation of the true impact on survival and myocardial function will require controlled clinical trials.

Quantitative analysis of the high-frequency components of the terminal portion of the body surface QRS in normal subjects and in patients with ventricular tachycardia.

Abstract: Quantitative analysis of the high-frequency components of the terminal portion of the surface QRS was performed in 42 normal subjects (group 1, ages 18-67 years, mean +/- SEM 34.7 +/- 2.2 years) and in 12 patients with symptomatic, sustained ventricular tachycardia (VT) (group 2, ages 48-76 years, mean 59 +/- 2.3 years). Signal averaging and high-pass, bidirectional digital filtering were used for analysis. The total duration of the QRS, the duration of the low-amplitude signals (less than 40 microV) in the terminal portion of the QRS and the amplitude of the signals in the last 40 and 50 msec of the QRS were measured at filter settings of 25 and 40 Hz. Reproducibility of the measurements was tested in 15 normal subjects by comparing results obtained from two consecutive recordings. Significant differences were found between normal subjects and VT patients for all four indexes at both 25- and 40-Hz filters. Specific values for each of the indexes were identified at the 40-Hz filtering, which could separate normal subjects from VT patients (20 microV for the amplitude of last 40 msec; 30 microV for the amplitude of last 50 msec; 120 msec for the total duration; and 39 msec for the low-amplitude signal of the filtered QRS). Using these values for the four indexes, respectively, 90%, 98%, 100% and 90% of the normal subjects and 83%, 83%, 58% and 83% for the VT group were correctly classified. The results show that the high-frequency analysis of the signal-averaged body surface QRS is a reliable, reproducible, noninvasive method for distinguishing patients with VT from normal subjects.

The importance of the mitral apparatus in left ventricular function after correction of mitral regurgitation.

Abstract: This study evaluates the possible role of the mitral apparatus in left ventricular function after correction of chronic mitral regurgitation. Seventeen patients underwent complete preoperative and early postoperative heart catheterization. Six patients underwent conventional mitral valve replacement (group 1), six mitral valve replacement with preservation of chordae tendineae and papillary muscles (group 2), and five mitral valvuloplasty (group 3). There was no statistically significant difference among the three groups for any hemodynamic parameter as compared before surgery by analysis of variance. After correction of mitral regurgitation the increase in cardiac index was similar for all three groups. Left ventricular end-diastolic volume did not decrease significantly in group 1 (p = NS), but it did in groups 2 and 3 (p less than .005 for both). Left ventricular end-systolic volume increased in group 1 (p less than .025) and decreased in groups 2 and 3 (p less than .01 and .005, respectively). Ejection fraction decreased in group 1 (p less than .005) and did not change in groups 2 or 3 (p = NS). Left ventricular end-diastolic pressure increased in group 1 (p less than .005) and decreased in groups 2 and 3 (p less than .01 for both). These findings suggest that continuity between mitral anulus and left ventricular wall through leaflets, chordae tendineae, and papillary muscles plays a role in left ventricular function after correction of the chronic mitral regurgitation.

Bradycardia-dependent triggered activity: relevance to drug-induced multiform ventricular tachycardia.

Abstract: We used cesium chloride (CsCl) for electrophysiologic studies in canine hearts in vivo and in vitro to examine the mechanisms underlying ventricular arrhythmias that are related to prolonged repolarization. Cesium is known to depress normal ventricular automaticity and some experimental arrhythmias by blocking delayed outward currents and prolonging action potential duration. In 10 dogs in normal sinus rhythm, 1 to 1.5 mM/kg iv CsCl prolonged the QT (QU) interval and induced ventricular ectopy in all, including multiform ventricular tachycardia. In 12 dogs with atrioventricular block, 1 to 1.5 mM/kg iv CsCl produced marked suppression of idioventricular rates (from 45 +/- 6 to 8 +/- 4 beats/min). These low rates were then associated with bigeminy or bursts of multiform ventricular arrhythmia. Pacing at rates of 60 beats/min or more suppressed these arrhythmias. Low doses of tetrodotoxin (1 microgram/kg) also abolished these bradycardia-dependent arrhythmias without affecting the amplitude of ventricular electrograms. Tissue concentrations of cesium were determined by anatomic absorption spectroscopy in five dogs after injection of 1 mM/kg CsCl. Thirty minutes after the injection, cesium levels in Purkinje fibers were 5.3 +/- 1.0 mM/kg, levels in ventricular muscle were 4.6 +/- 0.9 mM/kg, and levels in atrial muscle were 4.1 +/- 0.8 mM/kg. In eight isolated endocardial preparations from canine ventricles, standard microelectrode techniques were used to study the effects of superfusion with 5 mM cesium. After 30 min, we observed early afterdepolarizations interrupting phase 3 of Purkinje fiber action potentials that already showed prolonged repolarization. Slowing the rate generated single or multiple action potentials arising from partially repolarized levels of membrane potentials (-80 to -65 mV). Pacing rates of 30 to 60 beats/min diminished the afterdepolarizations and suppressed the spontaneous beats. Tetrodotoxin at a concentration of 10(-8) g/ml, which did not affect upstroke velocity, abolished the afterpotentials. We conclude that cesium induced bradycardia-dependent ventricular arrhythmias caused by early afterdepolarizations. These data suggest that an inward current, probably carried by sodium ions, appears to be essential for the occurrence of this phenomenon. The association of delayed repolarization, afterdepolarizations, and triggered activity has similarities to the phenomenon of drug-induced prolongation of the QTU interval associated with multiform ventricular tachycardia in humans, i.e. "torsades de pointes."

Balloon dilation angioplasty of aortic coarctations in infants and children.

Abstract: Balloon dilation angioplasty (BDA) was attempted nine times in eight infants and children with aortic coarctation. In three infants (all with associated ventricular septal defect or atrioventricular canal and marked hemodynamic instability) dilation was attempted at a site of aortic narrowing that had not been operated on previously. Although the coarctation gradient fell 40% or more over the short term in two of the three, there was no angiographic or late gradient evidence of improvement. All three underwent subsequent coarctation surgery. Five dilations were performed in four infants and children who had previously undergone coarctation surgery (end-to-end anastomosis, attempted jump graft, and subclavian flap) and had residual gradients. Dilation was successful in all five cases, resulting in an increase in the diameter at the coarctation site (4.7 +/- 2.6 to 7.7 +/- 4.0 mm, p less than .05) and a decrease in the gradient measured 24 hr after dilation (42.0 +/- 15.5 to 11.8 +/- 11.2 mm Hg, p less than .05). In one child with a long area of hypoplasia of the thoracic aorta and similar lesions of the brachiocephalic vessels, a preliminary attempt to dilate a severely narrowed subclavian artery was unsuccessful. Postdilation angiography demonstrated evidence of intimal tears in three of five successful dilations. Follow-up (1 to 6 months) has demonstrated continued gradient relief in four of five children. BDA is frequently, but not always, a successful treatment for human aortic coarctation. The chief determinant of success appears to be the nature of the lesion; short-term changes in coarctation gradient are unreliable indicators of success of failure. Although BDA was not associated with mortality or significant morbidity in this group of patients, its role in the management of children with coarctation is yet to be determined.

Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure.

Abstract: We studied 30 patients with moderate-to-severe congestive heart failure in a double-blind, randomized, placebo-controlled trial to determine the acute and long-term effects of isosorbide dinitrate on clinical status and on resting and exercise hemodynamics. Seventeen patients received placebo and 13 isosorbide dinitrate. First-dose isosorbide dinitrate (40 mg orally) decreased resting and exercise pulmonary capillary wedge pressure, pulmonic and systemic arterial pressures and pulmonic and systemic vascular resistances without augmenting exercise capacity. Compared with placebo, chronic therapy with isosorbide dinitrate (40 mg orally every 6 hours for 12 weeks) significantly improved clinical status and exercise capacity. Resting and exercise systemic blood pressure and systemic vascular resistance returned to baseline values during chronic isosorbide dinitrate therapy, but pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resistance remained improved. In patients with congestive heart failure, 12 weeks of oral isosorbide dinitrate therapy improves resting and exercise hemodynamics, exercise capacity, and clinical status; tolerance develops to the systemic arterial vascular effects without attenuation of the venous and pulmonary vascular effects.

Anatomic validation of left ventricular mass estimates from clinical two-dimensional echocardiography: initial results.

Abstract: We performed a prospective anatomic validation study to determine the accuracy of left ventricular (LV) mass estimates from clinical two-dimensional echocardiographic (2-D echo) studies. In 21 subjects, antemortem 2-D echo LV mass determinations were compared with anatomic LV weight by postmortem chamber dissection. Major cardiac diagnoses included anatomic LV aneurysm in four, status post aneurysmectomy in one, transmural myocardial infarction in seven, congestive cardiomyopathy in five, rheumatic mitral disease in two, chronic severe mitral or aortic regurgitation in three, amyloid heart in two, and normal heart in three. Marked right-heart dilatation was present in 11 patients and LV thrombus in four. Regression equations derived in vitro for each 2-D echo instrument were used to correct LV mass estimates based on a short-axis, area-length method: uncorrected LV mass = 1.055 x k x 5/6 (AtLt - AcLc) + b, where At = total short-axis LV image area at the high papillary muscle level, Lc = endocardial LV length, k = an instrument-specific regression slope and b = an instrument-specific intercept. LV mass by 2-D echo correlated extremely well with actual LV weight (r = 0.93 slope = 0.85, SEE = 31 g, range 77-454 g). In contrast, M-mode echocardiographic LV mass estimates were less reliable (r = 0.86, SEE = 59 g) in these markedly distorted hearts. These 2-D echo LV mass results compare favorably with reported results from biplane angiography and M-mode echocardiography in more symmetric hearts. Thus, regression-corrected 2-D echo may be the method of choice for determining LV mass in man.

Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: the mechanism of functional mitral regurgitation.

Abstract: We sought to elucidate the mechanism of mitral regurgitation (MR) in dilated cardiomyopathy (DCM). Quantitative two-dimensional echocardiographic examinations were performed in 27 patients, 18 with DCM (nine with MR on physical examination, nine without MR) and nine without underlying heart disease. The MR and \"no MR\" patients were clinically comparable. Spatial reconstructions from multiple apical cross sections were used to estimate the mitral leaflet area needed to occlude the orifice for a given midsystolic coaptation configuration (LEAF), as well as mitral annular area index, left ventricular volume, and left atrial volume. Similarly, reconstructions from parasternal short-axis views were used to estimate central chordae tendinae length and angulation. From selective parasternal views papillary muscle (PM) length and contraction and the tethering length from the PM base to the annular plane were measured. The MR group was characterized by markedly enlarged occlusional leaflet area (LEAF 19.8 + 3.1 in MR vs 13.8 + 2.8 in no MR group vs 6.3 + 0.9 cm2 in normal group; p < .01), striking mitral annular dilatation (midsystolic annular area index 7.5 + 0.8 in MR vs 4.6 + 0.9 in no MR group vs 2.9 + 0.4 cm2/m2 in normal group; p < .01), and left atrial enlargement (end-systolic left atrial volume 129 + 39 in MR vs 73 14 in no MR group vs 29 + 5 ml in normal group; p < .01). Chordal length and angulation, PM length, contraction, and tethering length, and left ventricular volume were not significantly different in the MR vs the no MR group. Noncoaptation of the mitral leaflets at their free margins was not observed in any MR patient. With the use of stepwise linear regression LEAF was determined chiefly by annular size (R2 .868) with left ventricular size having little additional influence (R2 increment .071). Thus, DCM is associated with enlargement of the mitral anulus, which is more pronounced in those patients with MR. Based on the quantitative estimates of occlusional leaflet area, we postulate that mitral leaflet tissue can stretch somewhat to accommodate dilatation of the mitral complex, but as the requirement for occlusional leaflet area increases less tissue is available for coaptation. Thus, although coaptation continues to occur, the valvular seal becomes ineffective once a critical LEAF is reached. The chief determinant of LEAF is the mitral annular size, while left ventricular size is a less important factor. Circulation 68, No. 3, 498-508, 1983. THE PROPER FUNCTION of the mitral valve requires coordinated motion of its six components: the posterior left atrial wall, the mitral anulus and leaflets, the chordae tendinae, papillary muscles, and free left From the Department of Medicine, University of Califomia School of Medicine and Wadsworth VA Medical Center, Los Angeles. Supported in part by the Arthur Dodd Fuller Foundation for Cardiovascular Research, Los Angeles. and VA Medical Center Research Funds. Address for correspondence: Pravin M. Shah, M.D., Cardiology (691/11lE), Wadsworth VA Medical Center, Wilshire and Sawtelle Blvds., Los Angeles, CA 90073. Received Jan. 20, 1983; revision accepted May 5, 1983. Dr. Boltwood was supported as a 1981-1982 Merck Fellow of the American College of Cardiology, and as an American Heart Association Fellow. Presented in part at the American Heart Association 55th Annual Scientific Sessions, Nov. 17, 1982, Dallas. 498 ventricular wall.' Mitral insufficiency commonly occurs in the presence of left ventricular dilatation, without any primary valvular disease.2 Such functional mitral regurgitation (MR) has been attributed to dilatation of the mitral anulus and to retraction of the leaflets by chordae and papillary muscles as the left ventricle dilates.2 However, functional mitral insufficiency has not been found to correlate well with mitral annular dilatation,3-5 and data obtained at autopsy imply that the mitral leaflets have reserve surface with a ratio of valve-to-orifice area ranging from 1.5 to 2.2.6 By exclusion, therefore, MR resulting from left ventricular enlargement has been attributed to the oblique direction of papillary muscle-chordal tension that presumably accompanies ventricular dilatation.' 7NevertheCIRCULATION by gest on N ovem er 6, 2017 http://ciajournals.org/ D ow nladed from PATHOPHYSIOLOGY AND NATIJRAL HISTORY-MYOCARDIAL DISEASE less, the mitral anulus normally shortens along its posterolateral segment during atrial and early ventricular systole, thereby reducing the valvular orifice.8' 9 Annular dilatation and hypokinesis therefore may contribute to mitral insufficiency, particularly in the presence of leaflet tethering abnormalities. Indeed, the benefit of mitral annuloplasty in various forms of MR has been reported.'0 Our laboratory group has reported on an echocardiographic method of reconstructing and measuring the mitral anulus in man. \" After initial success with annular measurement, attention was turned to the mechanism of MR in dilated cardiomyopathy as an appropriate area of investigation. We hypothesized that certain clear anatomic differences might exist between patients with dilated cardiomyopathy with and without MR and that discerning these differences might yield insights into the pathophysiologic characteristics of the disease. Methods of quantitating the other features of the mitral apparatus were developed, and a comprehensive echocardiographic study was performed. The results of this study suggest a more important role for mitral annular dilatation in functional MR than has been appreciated heretofore. Materials and methods Patient selection. Patients with dilated cardiomyopathy who showed no clinical or echocardiographic evidence of coronary or primary valvular disease were enrolled in the study. The nine subjects in the \"no MR\" group had no detectable systolic murmur when examined separately by two cardiologists, while the nine in the MR group had easily detectable typical high-pitched apical holosystolic murmurs radiating to the axilla (grade 2/6 or greater) the presence of which were confirmed with phonocardiographic examination. Several patients with faint apical systolic murmurs not easily recorded on a phonocardiogram were excluded from the study. No patient was studied during an acute exacerbation of heart failure, and only one patient (in the MR group) had clinical and contrast echocardiographic evidence of associated tricuspid regurgitation. Nine age-comparable normal control subjects were enlisted from the hospital wards or from the medical staff. Subjects with technically unsatisfactory echocardiograms were excluded from the study. All subjects gave written informed consent. Echocardiographic measurements. A two-dimensional echocardiographic system (Varian 3000) was used and recordings were made on half-inch videotape (Sony). The images could be redisplayed in real time, slow motion, or as single frames. Annular and central chordal measurements were taken directly off the screen with a large protractor and/or ruler, while other measurements required tracings on transparencies. Except when specified otherwise, measurements were averaged over 4 sinus or 8 atrial fibrillation beats. The screen height relative to the observer was adjusted to minimize parallax. Vertical and horizontal screen calibrations were repeatedly measured by imaging a 30 mm in diameter wire ring in a water-filled chamber. Mitral anulus. This method has been described in detail in a prior communication from this laboratory.\"I Briefly, subjects were studied in the left lateral decubitus position. With an inclinometer'2 six separate apical recordings were obtained at 30 degree rotational intervals around the annular circumference. Each apical view was selected to maximize the annular diameter at a given rotational orientation and was recorded during held expiration. By convention, a hinge point was defined as the center of the triangular tissue supporting the base of a leaflet, as identified in cross section. At a given point in the cardiac cycle diameters between the two hinge points measured at 30 degree rotational intervals were assumed to bisect each other, and a smooth circumference was drawn to connect the outer edges of these diameters. In the original method\" the assumption of diameters bisecting other diameters was made at only one point in the cardiac cycle, namely end-isovolumetric relaxation, and a floating reference frame was used at other points in the cardiac cycle. In this study this assumption was extended to reconstruction at points of maximum and minimum annular size, i.e., use of a fixed reference frame throughout the cardiac cycle was assumed to be adequate. Also, only two points in the cardiac cycle were measured, namely maximum annular size (at the peak of the P wave, or peak of R wave in atrial fibrillation) and minimum annular size (at ventricular midsystole).\"I The area and circumference of each annular outline was obtained by computerized planimetry. This method yielded the midsystolic and middiastolic annular areas indexed to body surface area (Almin and Almax), the fractional contraction in this area from maximum to minimum (FAC), and the midsystolic and middiastolic annular circumferences (Cmin and Cmax). Leaflet coaptation. By convention, the apical views obtained with the inclinometer mentioned above were labeled 8', 9', 10', 1', 12', and 1'. Each view subtends 30 degrees of arc on two sides of the rotational center so that six views complete a 360 degree rotation. In general, the 12' view corresponds to a conventional four-chamber view, and the 9' view corresponds to a conventional two-chamber apical view. With the use of tomographic planes relatively perpendicular to the mitral closure line, the apical recordings obtained above at 10', 11', and 12' were used to study leaflet coaptation. In each recording the leaflet coaptation angle A and perpendicular distance from the annular plane D were measured at midsysto