B G Brown

Quantitative coronary arteriography: estimation of dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation.

More accurate characterization of coronary artery lesions is needed for evaluation of short and long-term interventions in coronary disease. A method of segmental artery analysis has been developed to maximize the information obtained from coronary arteriograms. Coronary lesions are traced from two projected, perpendicular, 35 mm cineangiographic views and transmitted, in digital form, to a PDP 11/45 computer. Magnification and distortion of the image are compensated for in order to determine the actual vessel profiles, using the catheter and its location as a scaling device. The two views are matched; a spatial representation of the vessel centerline is constructed mathematically; and orthogonal vessel diameters are computed at increments along this centerline. Assuming an elliptical lumen, the absolute and percentage reduction in diameter and cross-sectional area in the stenosis are computed. More complex functions (integrated atheroma mass, Poiseuille resistance, and orifice resistance) are then calculated.The accuracy and variability of the different steps involved in lesion analysis have been determined. Dimensional accuracies of ± 150 microns (SD) are feasible. Examples are given of patients with Prinzmetals angina and with progressive coronary disease.

Lumen diameter of normal human coronary arteries. Influence of age, sex, anatomic variation, and left ventricular hypertrophy or dilation.

BackgroundPrecise knowledge of the expected “normal” lumen diameter at a given coronary anatomic location is a first step toward developing a quantitative estimate of coronary disease severity that could be more useful than the traditional “percent stenosis.” Methods and ResultsEighty-three arteriograms were carefuly selected from among 9,160 consecutive studies for their smooth lumen borders indicating freedom from atherosclerotic disease. Of these, 60 men and 10 women had no abnormalities of cardiac function, seven men had idiopathic dilated cardiomyopathy, and six men had left ventricular hypertrophy associated with significant aortic stenosis. Lumen diameter was measured at 96 points in 32 defined coronary segments or major branches. Measurements were scaled to the catheter, corrected for imaging distortion, and had a mean repeat measurement error of 0.12 mm. When sex, anatomic dominance, and branch length were accounted for, normal lumen diameter at each of the standard anatomic points could usually be specified with a population variance of ±0.6 mm or less (SD) and coefficient of variation of <0.25 (SD/mean). For example, the left main artery measured 4.5±0.5 mm, the proximal left anterior descending coronary artery (LAD) 3.7±0.4 mm, and the distal LAD 1.9±0.4 mm. For the LAD, lumen diameter was not affected by anatomic dominance (right versus left), but for the right coronary artery, proximal diameter varied between 3.9±0.6 and 2.8±0.5 mm (p<0.01) and for the left circumflex, between 3.4±0.5 and 4.2±0.6 mm (p<0.01). Women had smaller epicardial arterial diameter than men (−9%; p<0.001), even after normalization for body surface area (p<0.01). Branch artery caliber was unaffected by the anatomic dominance but increased with branch length, expressed as a fraction of the origin-to-apex distance (p<0.001). Lumen diameter was not affected by age or by vessel tortuosity but was significantly increased among men with left ventricular hypertrophy (+17%; p<0.001) or dilated cardiomyopathy (+12%; p<0.001). ConclusionsThis is a reference normal data set against which to compare lumen dimensions in various pathological states. It should be of particular value in the investigation of diffuse atherosclerotic disease.

Evidence for a New Pathophysiological Mechanism for Coronary Artery Disease Regression Hepatic Lipase–Mediated Changes in LDL Density

BACKGROUND Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. METHODS AND RESULTS Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). CONCLUSIONS These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

Intimal fibromuscular hyperplasia at the venous anastomosis of PTFE grafts in hemodialysis patients. Clinical, immunocytochemical, light and electron microscopic assessment.

Failure of arteriovenous communications used for chronic hemodialysis was studied during sequential 5-year periods after placement of either endogenous Brescia-Cimino (B-C) fistulas (50 patients) or polytetrafluoroethylene (PTFE, Gore-Tex) grafts (66 patients). Venous stenosis near the anastomosis was the reason for failure in 45% of PTFE grafts compared with 16% of B-C fistulas (p less than 0.001). Failure occurred, on average, 16 months after PTFE graft placement compared with 22 for B-C fistulas (p = NS). Proximal vein segments removed from five failed and two functioning PTFE graft communications were studied using light and electron microscopy and immunocytochemical techniques. All venous segments removed during surgical shunt repair exhibited a marked intimal hyperplasia. The intimal cellular component was almost exclusively smooth muscle. Accumulation of intracellular lipid droplets was not seen. Foam cells as well as extracellular lipid deposits were absent; macrophages and lymphocytes were absent from the zone of proliferation. Ultrastructural examination revealed a large proportion of extracellular matrix surrounding smooth muscle cells in the neointima. Collagen and elastin were present in the extracellular matrix, in greatest concentration deeper in the intima. Closer to the lumen, most of the extracellular volume consisted of proteoglycan. Hemosiderin was absent from the lesions as were consistent signs of luminal and intimal fibrin. Uniform intimal gradients of actin, collagen, and proteoglycan suggest that this is a steadily progressive, rather than episodic, proliferative response. These clinical and histologic observations and an analysis of hemodynamic stresses support the postulate that upstream release of platelet-derived growth factor, and possibly, shear-induced intimal injury stimulate this response. This myointimal proliferative process provides a readily accessible model of fibromuscular hyperplasia in humans; its understanding may lead to effective methods for its prevention and may provide clues to the pathogenesis of arteriosclerosis.

Dynamic mechanisms in human coronary stenosis.

At the clinical level, coronary stenoses frequently behave as though the obstruction to flow were variable and not as rigidly fixed as previously imagined. Pressure (energy) lost in flow through a stenosis is the primary determinant of its hemodynamic impact. Ischemic episodes occur when pressure distal to the stenosis falls below that needed to perfuse the subendocardium. Three important properties of the stenosis contribute to variation in its pressure loss. First, loss is proportional to the square of stenosis flow. Thus proper distribution of perfusion is doubly vulnerable to conditions such as exercise, anemia, or pharmacologic vasodilation, which ordinarily increase myocardial blood flow. Second, pressure loss is proportional to the inverse fourth power of minimum lumen diameter. As a result, seemingly small changes in diameter are amplified to large changes in stenosis resistance. Third, a compliant arc of normal arterial wall borders part of the lumen in the majority of coronary lesions. This extremely important morphologic feature of stenoses permits transient variation in stenosis lumen diameter in response to drugs or to variation in endogenous vasomotor activity or intraluminal pressure. Although our understanding is incomplete, many of the clinical features of coronary disease and its pharmacologic responses are explained in terms of these stenosis properties and their interaction.

Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise.

To study the mechanisms of myocardial ischemia during isometric exercise, handgrip was sustained, for 4.5 min at 25% of maximum by 11 patients with at least one significant coronary stenosis each, during cardiac catheterization. After recovery, the handgrip that was repeated with simultaneous infusion of nitroglycerin (50 micrograms over 4 min) directly into the diseased vessel. The cardiovascular response was assessed by hemodynamic and by computer-assisted measurements of stenosis. During the first handgrip test pulmonary capillary wedge pressure rose 56% (15 to 23 mm Hg; p less than .001), the heart rate-systolic pressure product rose 33% (p less than .01), and the diseased epicardial arteries constricted. Luminal area in the stenotic segment was reduced by 35% (p less than .01), resulting in a 243% increase in estimated stenotic flow resistance (30 to 103 mm Hg/ml/sec; p less than .001). During handgrip with intracoronary nitroglycerin, the pressure-rate product again increased 33%, but relative to resting control, capillary wedge pressure fell 4 mm Hg in association with a 32% increase in luminal area of the stenosis and a 28% reduction in flow resistance (all significantly different from the response to handgrip alone: p less than .001, .01, and .005, respectively). Thus, coronary vasoconstriction, not increased pressure-rate product, is the dominant mechanism for ischemic left ventricular dysfunction during isometric exercise in patients with significant coronary stenoses.

Effects of intensive lipid-lowering therapy on the coronary arteries of asymptomatic subjects with elevated apolipoprotein B.

BackgroundDo the benefits of intensive lipid-lowering therapy seen in symptomatic patients extend to high-risk subjects who have never had symptoms? Methods and ResulsOf 120 men completing the FATS trial, 91 were symptomatic and 29 asymptomatic. All had apolipoprotein B 2125 mg/dL, a positive family history, and coronary atherosclerosis. All were counseled in diet and randomized to intensive therapy: colestipol 10 g TID plus either niacin 1 g QID or lovastatin 20 mg BID or to conventional therapy: placebos, or colestipol if low-density lipoprotein cholesterol was elevated. End points included quantitative arteriographic disease change and clinical events over a 2.5-year interval. At baseline, symptomatic and asymptomatic patients had comparable risk profiles, but proximal stenosis severity averaged 36% for symptomatic and 23% for asymptomatic patients (P<.001). Among the 91 symptomatic patients, those in the intensive group experienced definite (.101%S) proximal lesion progression less frequently than conventional (24% of intensive versus 48% of conventional) and definite regression more frequently (36% of intensive versus 15% of conventional) (P=.009). Similarly, among the 29 asymptomatic patients, 19% of intensive versus 38% of conventional had progression and 31% of intensive versus 0%1 of conventional, regression (P=.04). Ischemia on baseline exercise tolerance testing was associated with significantly greater proximal disease progression among the asymptomatic patients. Clinical cardiovascular events (death, infarction, or revascularization) occurred in 10 of 38 symptomatic patients originally assigned to conventional therapy, compared with 5 of 76 symptomatic patients assigned to intensive (P<.01); no asymptomatic patient had an event. ConcluionsAsymptomatic subjects with this high-risk profile have less coronary disease at baseline than comparable symptomatic patients, and they have an excellent short-term clinical prognosis. However, asymptomatic subjects are indistinguishable from symptomatic patients in terms of their arterial disease progression with conventional therapy and their regression with intensive. These findings may justify an active treatment strategy in such subjects, particularly those with provokable ischemia.

A common hepatic lipase gene promoter variant determines clinical response to intensive lipid lowering treatment

Background —The common −514 C →T polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL2 cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. Methods and Results —Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by 14C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the CC genotype had the greatest decrease in HL activity (P <0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density (P <0.005) and HDL2-C (P <0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients (P <0.001). Conclusions —In middle-aged men with established CAD and dyslipidemia, the HL gene −514 C →T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.