Miguel E. Sanmarco

Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: Report of the program on the surgical control of the hyperlipidemias (posch)

BACKGROUND AND METHODS The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. RESULTS When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction. CONCLUSIONS Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.

Effects of colestipol-niacin therapy on human femoral atherosclerosis.

The 2-year therapy effect on femoral atherosclerosis was evaluated in the Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-plus-diet-controlled angiographic trial of colestipol-niacin therapy plus diet in men with previous coronary bypass surgery. Different diet compositions were prescribed to enhance the differential in blood cholesterol responses between the two groups. The annual rate of change in computer-estimated atherosclerosis (CEA), a measure of lumen abnormality, was evaluated between treatment groups. A significant per-segment therapy effect was found in segments with moderately severe atherosclerosis (p less than 0.04) and in proximal segments (p less than 0.02). When segmental CEA measures were combined into a per-patient score using an adaptation of the National Heart, Lung, and Blood Institute scoring procedure, a significant therapy effect was observed (p less than 0.02). Total variance of the annual change rate in CEA was as predicted from pilot studies, but measurement variation was larger. The therapy effect observed in femoral arteries, although significant, was less marked than the strong and consistent benefit previously reported for both native coronary arteries and aortocoronary bypass grafts.

The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results.

The Cholesterol Lowering Atherosclerosis Study (CLAS) is a prospective, placebo-controlled, angiographic trial designed to test the hypothesis that aggressive lowering of LDL cholesterol with concomitant increase in HDL cholesterol will reverse or retard the atherosclerotic process. Specifically, CLAS was designed to determine whether combined therapy with colestipol plus niacin will produce clinically significant change in coronary, carotid, and femoral artery atherosclerosis and coronary bypass graft lesions. To this purpose, 188 subjects were randomized to diet plus drug or diet plus placebo. We report on methodological aspects of planning and evaluating this study, including the choice of the study population, procedures for recruitment, the experimental design including sample size considerations, methods for evaluating outcome, and methods for evaluating compliance to treatment. Comparison of baseline data indicated no significant differences between groups at the time of randomization. Subjects were predominantly male, Caucasian, 54 years of age, 20% above ideal weight, with normal blood pressure. The average age at bypass was 50 years. The average lipids were cholesterol (243 mg/dL), HDL (45 mg/dL), and LDL (168 mg/dL). Finally, the distribution of baseline coronary stenosis was equivalent between the two groups (average number of lesions per subject = 10.6).

Abnormal blood pressure response and marked ischemic ST-segment depression as predictors of severe coronary artery disease.

The usefulness of an abnormal blood pressure response and a marked ischemic ST–segment depression during exercise testing as predictors of severe coronary artery disease was assessed in 378 consecutive patients who had a maximal symptom–limited exercise test before coronary arteriography. An abnormal blood pressure response occurred in 90 patients. The sensitivity of this response for three–vessel or left main disease was 38.6%, the specificity 87.4% and the predictive value 70%. A marked ischemic ST–segment abnormality (MIST) appeared in 85 patients. The sensitivity ofMIST for three–vessel or left main disease was 38.6%, the specificity 89.8% and the predictive value 74.1%. One hundred thirty–eight patients had either an abnormal blood pressure response or a marked ST–segment change. The sensitivity of either response for three–vessel or left main disease was 56.4%, the specificity 78.6%, and the predictive value 66.7%. Exercise duration and ejection fraction were not significantly different in patients with normal or abnormal blood pressure. We conclude that abnormal blood pressure and marked ischemic ST–segment depression during exercise testing are helpful in identifying a subset of patients with advanced coronary artery disease. The physiologic mechanism for these responses is probably exercise–induced ischemia.

Accelerated Progression of Atherosclerosis in Coronary Vessels with Minimal Lesions That Are Bypassed

Accelerated progression of atherosclerosis is known to occur in surgically bypassed coronary arteries in which the preoperative stenosis was greater than 50 per cent. To assess the effect of coronary bypass on vessels with lesser degrees of stenosis, we studied 85 men who had undergone coronary bypass surgery. In this group we identified bypass grafts placed in 37 arteries with minimal atherosclerosis, which was defined as less than 50 per cent stenosis of the vessel diameter. In the same 85 men there were 93 coronary vessels with minimal atherosclerosis for which a bypass graft had not been placed. Progression of atherosclerosis, defined as further loss of at least 25 per cent of the lumen, during an average follow-up period of 37 months was more than 10 times as frequent (38 per cent vs. 3 per cent) in bypassed arteries with minimal atherosclerosis as in comparable arteries that were not bypassed. These findings support the view that minimally diseased coronary arteries should not be bypassed.

The electrocardiogram in obesity

The electrocardiographic abnormalities ascribed to morbid obesity were analyzed in a group of 144 patients without apparent clinical cardiovascular pathology and compared with a control group of 100 normal weight patients. Fifty-eight patients in the obese group were re-analyzed after significant weight loss and the electrocardiographic findings compared with their initial changes when they entered the program. The QRS voltage for the obese group was slightly lower than the voltage of the normal population; but in a significant number of the patients restudied after weight loss, the QRS voltage decreased (37 out of 58 patients). In inferolateral leads non specific flattening of the T wave was observed in the obese group (71/144); it became normal as they lost weight. The P and QRS axes of the obese group initially were within normal limits but more to the left; they moved slightly to the right, although still within normal limits as the patients lost weight. Two conclusions can be drawn from the study: a) low voltage is not a significant feature in the ECG of the obese and, b) the most consistent finding in obese patients is a flattening of the T wave.

The ECG: QRS Change

Known and measured cardiac and torso anatomy, electrophysiology, and resistivities have been incorporated into a three-dimensional propagation model of ventricular excitation [1]. This model includes all the first-order effects known to influence the ECG in man. It has been used to generate QRS criteria for the 12-lead ECG in order to locate infarcts in 12 segments of the left ventricle and to predict the amount of infarct in each segment [2, 3]. The ability of these criteria to predict the size of infarct in each of the three main coronary artery distributions is the subject of this chapter.

Design of human atherosclerosis studies by serial angiography.

Atherosclerosis has been studied by femoral angiography in men with myocardial infarction. Smoking history recorded at entry was the strongest variable asssociated with degree of atherosclerosis at the first angiogram. This correlation was significant at the 1% level in two out of three femoral segments. Fifty-four men had two angiograms; 28 of these men had one additional angiogram. Two variables recorded in the interval between angiograms were significantly correlated with atherosclerosis change in one femoral segment; α-lipoprotein level determined by electrophoresis (a negative correlation, p < 0.01) and maximum systolic blood pressure occurring during an exercise tolerance test (a positive correlation, p < 0.01). An estimate of angiographic atherosclerosis assessment error has been obtained (S.D. = 8.28; in a scale of 1–128) and used to calculate sample size for future clinical trials which employ this endpoint. Testing the effect of therapy on lesion change with angiography requires fewer study subjects observed for a shorter period than is necessary to test a commensurate effect on atherosclerosis-related morbidity or mortality rates. For example, an angiographic study with design features comparable to those of the Coronary Drug Project could require a 1-yr observation period and 132 subjects per test group.

Evaluation of human panelists in assessing coronary atherosclerosis.

The Cholesterol Lowering Atherosclerosis Study, a randomized, angiographic clinical trial, has demonstrated the beneficial effect of niacin/colestipol therapy on coronary and femoral atherosclerosis. The primary outcome was a panel-determined consensus score evaluating global coronary changes determined angiographically at 2 years. This article presents an evaluation of interreader agreement in independently assessing the status of native coronary arteries and overall coronary condition. Parameters include 1) identification of the presence of lesions and lesion changes; 2) estimation of lesion severity (percent stenosis) and amount of change in lesion severity; and 3) global assessment of change in coronary status. Readers independently agreed on 1) presence of lesions (82%) and change in lesions (51%); 2) percent stenosis +/- 10% (76%) and change in stenosis +/- 10% (81%); and 3) global assessment of change in coronary status within one step (96%). Results of these analyses may be useful in effectively designing angiographic trials that use a panel of human evaluators as well as computerized methods for angiographic interpretation.

Spatial reconstruction of human femoral atheromas showing regression

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