Allen B. Nichols

Family history as an independent risk factor for coronary artery disease.

The risk of family history of ischemic heart disease independent of other well described risk factors has remained difficult to quantitate. Significant coronary artery disease was determined by coronary arteriography to be present in 223 patients and absent in 57 control subjects. Age, sex, blood pressure, serum cholesterol, cigarette smoking and the presence of diabetes and left ventricular hypertrophy on the electrocardiogram were tabulated for each patient and the data used to assign a risk score based on the American Heart Association multivariate model. Subjects were stratified and matched according to risk score to estimate risk of family history independent of familial aggregation of these seven other risk factors. Angina, myocardial infarction, cardiac death and any ischemic heart disease were ascertained in 1,319 first degree relatives. Odds ratios for overall, stratified and matched comparisons of these end points in relatives of patients and control subjects ranged between 2.0 and 3.9 (p less than 0.01 for all comparisons), indicating a higher frequency of all ischemic heart disease end points in relatives of patients with documented coronary artery disease. Life table comparison of patients at lowest risk with those at higher risk showed significantly greater cumulative frequency and earlier age of onset of all ischemic heart disease end points in relatives of low risk patients. These observations indicate that some of the risk associated with family history is independent of familial aggregation of other known risk factors and suggest that the independent effects of family history may be most important in individuals who otherwise are at low risk.

Quantification of relative coronary arterial stenosis by cinevideodensitometric analysis of coronary arteriograms.

A computerized method for measuring relative coronary arterial stenosis by cinevideodensitometric analysis of 35 mm coronary arteriograms was developed and validated. Video images of projected coronary arteriographic frames were digitized into a 512 X 512 matrix (256 gray levels) by computer analysis that compared integrated contrast density measured over stenotic and normal arterial segments after background subtraction. Pixel density was 70 to 80 pixels/mm2 actual area. In phantom studies performed on plexiglass cylinders, cinevideodensitometric measurements correlated linearly with concentration of contrast medium (r = .99), with cross-sectional areas (r = .99) of contrast-filled cylinders 1 to 4 mm in diameter over a wide range of contrast concentrations (25% to 100%), and with relative stenosis of eccentric lesions in the cylinders (r = .99, SEE = 3.9%). In postmortem studies of patients who died after undergoing coronary arteriography, videodensitometric measurements of relative stenosis correlated highly (r = .97, SEE = 7.0%) with percentage stenosis based on actual area measurements obtained histologically with computer-assisted microscopic planimetry. Cinevideodensitometric analysis of coronary arteriograms was reproducible (r = .92, SEE = 7.7%), and interobserver variability was low (r = .99, SEE = 4.3%). In addition, videodensitometry provided comparable values for eccentric coronary lesions filmed in right anterior oblique and left anterior oblique projections (r = .99, SEE = 1.9%). Cinevideodensitometric analysis is an accurate, rapid method for quantifying the relative stenosis of eccentric coronary lesions without manual tracing of arterial borders.

Percutaneous intraaortic balloon insertion

A new single chambered percutaneous intraaortic balloon has been constructed around a central guidewire. The balloon can be wrapped around the guidewire, enabling its insertion into the femoral artery through a 12F sheath inserted with the conventional Seldinger technique. Percutaneous intraaortic balloon insertion has been performed in 27 patients (mean age 58 years) for a variety of medical and surgical indications. Percutaneous balloons could not be advanced into the aorta in two patients (7.4 percent) with severe bilateral aortoiliac occlusive disease. In all 25 patients undergoing intraaortic balloon pumping satisfactory circulatory support was achieved, and 21 (84 percent) of the patients survived to be discharged from the hospital. The mean duration of intraaortic balloon pumping was 3.5 days. Percutaneous intraaortic balloon insertion requires less than 5 minutes and has been successfully performed in the cardiac catheterization laboratory, coronary care unit, operating room and recovery room. After direct balloon removal, external pressure was applied for 30 minutes. No patient experienced hematoma of the groin, aortic dissection, compromised distal pulses or late wound complications. Percutaneous balloon insertion permits the rapid institution of circulatory support and broadens the medical and surgical applications of intraaortic balloon pumping.

Importance of balloon size in coronary angioplasty.

The effect of balloon size on the success of coronary angioplasty was studied to develop quantitative criteria for optimal selection of balloon size. Coronary dimensions of 165 stenotic lesions were measured by computer-assisted cinevideodensitometry in 120 patients who had undergone angioplasty with a balloon selected by visual estimates. Cross-sectional areas and diameters of normal and stenotic arterial segments were measured before and after angioplasty by a previously validated cinevideodensitometric technique. The diameter of the inflated balloon compared with that of the normal arterial segment was expressed as a ratio for sizing balloons. Oversized balloons with a ratio greater than 1.3 (n = 35) caused a high (37%) incidence of dissection, with three severely compromised arterial lumens. Undersized balloons with a ratio less than 0.9 (n = 29) often resulted in significant (greater than 50% diameter stenosis) residual stenotic lesions (21%) and a significantly (p less than 0.05) higher rate of repeat angioplasty for restenosis. Selection of balloon sizes with ratios in the 0.9 to 1.3 range (n = 101) resulted in a low (4%) incidence of dissection with few patients (3%) having significant residual stenosis. Mean residual stenosis (percent diameter reduction) was most severe for undersized (35.0 +/- 18%) or oversized (23.1 +/- 19%) balloons and least severe for balloons with a ratio of 0.9 to 1.3 (18.7 +/- 14%) (p less than 0.001). Repeat angioplasty for restenosis was more frequently required (p less than 0.05) for lesions dilated with undersized balloons. Thus, selection of angioplasty balloons that approximate or slightly exceed the diameter of the normal arterial diameter yields optimal angiographic results with minimal dissections and minimal residual stenotic lesions.

Effect of left ventricular hypertrophy on myocardial blood flow and ventricular performance in systemic hypertension.

SUMMARY The effect of myocardial hypertrophy resulting from chronic pressure overload upon myocardial blood flow (MBF) and left ventricular (LV) performance was studied in 17 hypertensive patients, nine of whom had left ventricular hypertrophy (LVH), and nine normotensive controls. Mean LV MBF was measured at cardiac catheterization using the regional xenon-133 washout technique. In hypertensive patients with LVH, LV MBF was reduced at rest (35.0 ± 5.4 ml/100 g/min) compared with controls (64.8 ± 7.6 ml/100 g/min, p < 0.01) and hypertensive patients without LVH (62.6 ± 14.5 ml/ 100 g/min, p < 0.01). Coronary vascular resistance was also elevated in the hypertensive patients with LVH (37.6 ± 6.6 dyn * cm−5g−1, p < 0.01). In contrast, ejection fraction, mean velocity of circumferential fiber shortening(MVcf) and end-systolic and end-diastolic volumes were not significantly different among the three groups. Peak systolic stress was significantly lower (p < 0.01) in the hypertensive patients with LVH (225 ± 45 dyn * cm−2 X 10−8) than in the controls (385 ± 114 dyne cm−2 X 10−8) and the hypertensive patients without LVH (395 ± 39 dyn. cm−2 X 10−8). A multivariate regression equation was developed relating MBF to heart rate (HR), MVcf, and peak LV wall stress: MBF = 22.2 MVcf + 10.6 stress + 0.38 HR- 48.2 (r = 0.89, p < 0.01). When MBF was adjusted for differences in stress among patients using the regression equation, there was no significant difference in MBF between hypertensive patients with and without LVH. These results indicate that (1) resting LV myocardial blood flow is normal in hypertensive patients without LVH; (2) resting MBF Is redSuced in controlled hypertensive patients with LVH as a consequence of reduced wall stress; and (3) resting LV performance measured by ejection phase indexes is well preserved in hypertensive patients with and without LVH. These results also provide additional evidence that resting MBF in patients with normal coronary arteriograms is related to hemodynamic indexes of the major determinants of myocardial oxygen consumption.

Left ventricular mechanical efficiency in coronary artery disease

The effect of coronary artery disease and prior myocardial infarction on cardiac energetics was determined by measuring left ventricular myocardial blood flow, oxygen consumption (MVO2), efficiency and ejection phase indexes in 36 patients undergoing coronary arteriography. Eight control patients with normal coronary arteriograms and normal left ventricular function, 15 patients with coronary artery disease without prior myocardial infarction and 13 patients with coronary disease and prior myocardial infarction (greater than 6 months) were studied. Left ventricular efficiency was calculated from left ventricular work, myocardial blood flow (measured by clearance of intracoronary xenon-133), and aortic and coronary sinus oxygen content. Left ventricular volumes, mass and ejection phase indexes were measured by quantitative left ventriculography. Left ventricular myocardial blood flow per 100 g/min was reduced in patients with coronary artery disease (49.0 +/- 8; p less than 0.01) and in patients with myocardial infarction (51.6 +/- 10; p less than 0.05) compared with control subjects (62.4 +/- 16), but total left ventricular flow was not reduced because of increased left ventricular mass. As a result, MVO2 did not differ significantly for the three patient groups (control 13.3, coronary artery disease 14.0 and myocardial infarction 14.3 ml/min). In the patients with myocardial infarction, left ventricular work index was reduced (2.4 versus 4.0 kg X m/m2 per min in the control group; p less than 0.001), causing efficiency to be reduced (15.9 versus 28.8% in the control group; p less than 0.001). Decreased efficiency correlated with ejection fraction (r = 0.54), mean velocity of circumferential fiber shortening (MVcf) (r = 0.45) and mean percent chordal shortening (r = 0.43) (all p less than 0.01). These data indicate that in control patients with normal coronary arteriograms, left ventricular myocardial efficiency averages 29%; in patients with coronary disease without myocardial infarction, left ventricular MVO2 and efficiency are in the normal range; in patients with prior myocardial infarction, left ventricular efficiency is significantly reduced as a result of diminished left ventricular work and normal MVO2; and reduced efficiency after myocardial infarction correlates with reduced ejection phase indexes.

Cinevideodensitometric analysis of the effect of coronary angioplasty on coronary stenotic dimensions

The accuracy and reproducibility of caliper and cinevideodensitometric measurements of coronary stenotic dimensions were compared in radiographic phantom models and in coronary arteriograms of 28 patients undergoing coronary angioplasty. Projected, single-plane coronary cine frames were analyzed by a computer-assisted videodensitometric method, which measures stenotic cross-sectional area without assumptions about lesion geometry. The accuracy (2.4%) and precision (+/- 1.9%) of cinevideodensitometry for measuring percent area stenosis in Plexiglas models of eccentric stenotic lesions was superior to the accuracy (24.7%) and precision (+/- 5.4%) of caliper measurements. Interobserver variability was significantly (p less than 0.05) better for cinevideodensitometric (r = 0.98; SEE = 6.4%) than for caliper measurements (r = 0.87; SEE = 13.1%). After angioplasty, percent diameter stenosis measured by calipers fell from 70 +/- 12% to 30 +/- 15%. Mean percent area reduction measured by cinevideodensitometry fell from 89.1 +/- 8% to 40.1 +/- 22% and stenotic area increased five-fold, from 0.59 +/- 0.5 to 3.47 +/- 1.6 mm2. Pre and post PTCA gradients did not correlate with lesion dimensions. Cinevideodensitometric measurements of absolute stenotic dimensions were more reproducible than relative measurements expressed as a percentage, due to the tapered caliber of normal arterial segments. Thus, cinevideodensitometric measurements were more accurate and reproducible than caliper measurements. The angiographic effects of coronary angioplasty are best measured by cinevideodensitometry, because residual lesions post PTCA are often eccentric, have indistinct margins, and are better characterized by changes in area than by changes in diameter.

Effect of coronary stenotic lesions on regional myocardial blood flow at rest.

To determine the effect of atherosclerotic coronary lesions on myocardial blood flow in patients at rest, regional myocardial blood flow was measured distal to stenotic lesions in 29 patients with isolated proximal lesions of the left anterior descending artery. Severity of coronary stenosis was measured by computer-assisted cinevideodensitometric analysis of digitized coronary arteriograms. Regional myocardial blood flow was measured from the clearance rate of intracoronary 133Xe injected into the left main coronary artery and recorded with a multicrystal scintillation camera. In 21 patients with stenotic lesions ranging from 19% to 84% area reduction, distal regional myocardial blood flow was normal. In all eight patients with reduced regional myocardial blood flow distal to left anterior descending lesions, the minimum area of each stenotic lesion was less 0.80 mm2 (mean 0.34 +/- 0.2 mm2), minimum calculated diameter was less than 1 mm (mean 0.59 +/- 0.3 mm), and percent stenosis, based on the reduction in cross-sectional area, was greater than 85% (mean 94 +/- 4%). For all patients, distal flow, expressed as a fraction of normal flow, correlated with the lesion cross-sectional area (r = .84), minimum luminal diameter (r = .84), and percent area stenosis (r = -.70). Thus, resting myocardial blood flow distal to stenotic lesions of the proximal coronary arteries remains normal until the degree of narrowing is severe. The dimensions observed for critical coronary stenotic lesions correlate well with theoretical predictions based on fluid mechanics and with experimental preparations in laboratory animals.

Relationship between segmental thallium-201 uptake and regional myocardial blood flow in patients with coronary artery disease.

The relationship between the spatial distribution of thallium-201 in myocardial perfusion scintigrams and the distribution of left ventricular regional myocardial blood flow was examined in 25 patients undergoing coronary arteriography. Thallium-201 myocardial scintigrams were obtained after symptom-limited exercise and after a 4 hr delay. Regional myocardial blood flow was measured by the xenon-133 clearance method in patients at rest and during rapid atrial pacing to a double product comparable with that achieved during exercise stress testing. Patterns of regional thallium-201 activity and regional myocardial blood flow, recorded in similar left anterior oblique projections, were compared for left ventricular segments supplied by the left anterior descending (LAD) and left circumflex (CIRC) arteries. In 11 patients without significant lesions of the left coronary artery (group 1), thallium-201 was homogeneously distributed in the LAD and CIRC distributions in scintigrams taken during peak exercise; these scintigrams correspond to homogeneous regional myocardial blood flow in the LAD and CIRC regions during pacing-induced stress. In 14 patients with significant lesions of the left coronary artery (group 2), ratios of regional thallium-201 activity in the LAD and CIRC distributions of exercise scintigrams correlated well (r = .84) with ratios of regional myocardial blood flow measured during rapid pacing. Background subtraction altered the relationship between relative thallium-201 uptake and regional myocardial blood flow, causing overestimation of the magnitude of flow reduction on exercise scintigrams. These data indicate that: (1) in patients with normal left coronary arteries, thallium-201 is homogeneously distributed to the left ventricle, reflecting the homogeneous distribution of regional myocardial blood flow over a wide range of mean left ventricular flow rates and (2) in patients with significant lesions of the left coronary artery, the relative spatial distribution of thallium-201 activity in exercise perfusion scintigrams reflects the distribution of regional myocardial blood flow.

Exercise-Induced myocardial ischemia in patients with coronary artery disease: Lack of evidence for platelet activation or fibrin formation in peripheral venous blood

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.