Angiotensin-converting enzyme inhibition as antiatherosclerotic therapy: no answer yet. QUIET Investigators. QUinapril Ischemic Event Trial.

Angiotensin-converting enzyme inhibitors have proven to be of clinical benefit in congestive heart failure. Whether they also provide benefit to patients with coronary artery disease in the absence of congestive heart failure via an antiatherosclerotic mechanism is a question the QUinapril Ischemic Event Trial quantitative coronary angiography (QCA) study attempted to answer: 1,750 patients with normal left ventricular function who were undergoing coronary angiography and angioplasty were randomized to 20 mg/day of quinapril versus placebo and followed for 3 years for cardiac end points. A randomly selected subgroup of the total cohort underwent follow-up angiography. The primary QCA end point was the categorical designation of progression versus nonprogression, defined either by QCA or by a cardiac event in patients selected for the QCA trial who had no usable follow-up x-ray film. Secondary end points in patients with 2 angiograms were: new stenosis development, change in minimum lumen diameter index, and change in percent diameter stenosis index. There were 119 progressors among 243 placebo-treated patients (49%) and 111 progressors among 234 quinapril-treated patients (47%) (p = NS). There were 44 patients with new stenosis development in the placebo group (19%) and 50 (22%) in the quinapril group (p = NS). Change in minimum lumen diameter index was -0.21+/-0.03 mm in the placebo group and -0.18+/-0.03 mm in the quinapril group (p = NS). Finally, change in percent diameter stenosis index was +5.1+/-1.0 in the placebo group and +3.5+/-1.0 in the quinapril group (p = NS). Potential confounders of this trial are presented and discussed.

Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy.

OBJECTIVES: This study sought to determine whether coronary endothelial dysfunction exists in patients with acute-onset idiopathic dilated cardiomyopathy (DCM) and to explore its relation to recovery of left ventricular systolic function in this patient population. BACKGROUND: Coronary endothelial dysfunction exists in chronic DCM, but its importance in the development and progression of ventricular dysfunction is not known. To address this issue we studied coronary endothelial function in patients with idiopathic DCM <6 months in duration and explored the relation between coronary endothelial function and subsequent changes in left ventricular ejection fraction (LVEF). METHODS: Ten patients with acute-onset idiopathic DCM (duration of heart failure symptoms 2.0 +/- 0.4 months [mean +/- SEM]) and 11 control patients with normal left ventricular function underwent assessment of coronary endothelial function during intracoronary administration of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator adenosine. Coronary cross-sectional area (CSA) was determined by quantitative coronary angiography and coronary blood flow (CBF) by the product of coronary CSA and CBF velocity measured by an intracoronary Doppler catheter. Patients with DCM underwent assessment of left ventricular function before and several months after the study. RESULTS: Acetylcholine infusion produced no change in coronary CSA in control patients but significant epicardial constriction in patients with DCM (-36 +/- 11%, p < 0.01). These changes were associated with increases in CBF in control patients (+118 +/- 49%, p < 0.01) but no change in patients with DCM. Infusion of adenosine produced increases in coronary caliber and blood flow in both groups. Follow-up assessment of left ventricular function was obtained in nine patients with DCM 7.0 +/- 1.7 months after initial study, at which time LVEF had improved by > or =0.10 in four patients. Multiple linear regression revealed a positive correlation between both the coronary CSA (r2 = 0.57, p < 0.05) and CBF (r2 = 0.68, p < 0.01) response to acetylcholine and the subsequent improvement in LVEF. CONCLUSIONS: Coronary endothelial dysfunction exists at both the microvascular and the epicardial level in patients with acute-onset idiopathic DCM. The preservation of coronary endothelial function in this population is associated with subsequent improvement in left ventricular function.

Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators. Observations in animals and humans.

BACKGROUND: Coronary thrombus is composed of platelets and fibrin, and during thrombolytic treatment, reflow may be slowed by platelet deposition. It may be possible to initiate coronary reflow without exogenous plasminogen activators by blocking platelet aggregation while fibrin generation is impeded with heparin. METHODS AND RESULTS: In 14 dogs, left anterior descending coronary artery thrombosis was produced by endothelial trauma and thrombin instillation in the presence of stenosis distally. Reflow was monitored by flow probe during treatment with (1) heparin, (2) heparin and aspirin, and (3) heparin, aspirin, and intravenous 7E3. Eighty percent of dogs treated with the third combination showed stable reflow (> or = 25% of prestenotic flow) in 50 +/- 9 minutes. In addition, 13 patients were studied during intravenous administration of c7E3 10 minutes before primary angioplasty for acute myocardial infarction and Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1 flow. Pretreatment included heparin and oral aspirin. Flow increased during a 10-minute period by at least one TIMI grade in 11 (85%) of 13 and reached TIMI grade 2 or 3 in 7 (54%) of 13 patients. Average TIMI grade flow increased from 0.31 +/- 0.5 to 1.54 +/- 0.8 (P < .001). Thrombus length 10 minutes after c7E3 was 5.1 +/- 3.5 mm. All but 1 patient then underwent angioplasty. There were no complications. CONCLUSIONS: Coronary reflow can be initiated by intravenous 7E3 administration in the presence of heparin and aspirin. In human patients, this flow can be observed in 10 minutes without exogenous thrombolytic agents.

Quantitative PET measurements of regional myocardial blood flow: observations in humans with ischemic heart disease.

This review focuses on several related issues concerning positron emission tomography measurements of regional myocardial blood flow using 13-N-ammonia in humans. The effect of partial volume correction on estimates of K1, the model parameter describing myocardial blood flow, is considered. In addition a new method for computing K1 images of myocardial flow distribution is briefly described and compared to a standard method. Potential differences between K1 and equilibrium levels of 13-N-ammonia in the myocardium for estimation of myocardial blood flow are discussed also. The issue of heterogeneity of myocardial blood flow and flow reserve in normal volunteers is considered from the clinical point of view in terms of evaluation of patients with ischemic heart disease. Finally, the use of absolute measurement of adenosine-stimulated myocardial blood flow to assess physiological significance of coronary artery stenoses is addressed.

Baseline clinical and angiographic data in the Quinapril Ischemic Event (QUIET) Trial.

The QUinapril Ischemic Event Trial (QUIET) is the first prospective, double-blind, placebo-controlled trial to investigate the long-term antiatherosclerotic effects of angiotensin-converting enzyme inhibition. Normotensive, nonhyperlipidemic subjects (1,750) with normal left ventricular systolic function were randomly assigned to treatment or placebo at percutaneous transluminal coronary angioplasty (PTCA). The primary end point is time to first cardiac ischemic event. Baseline clinical characteristics are (mean +/- SD): age 58 +/- 9 years; blood pressure 123 +/- 15/74 +/- 10 mm Hg; low density lipoprotein cholesterol 124 +/- 27 mg/dL; high density lipoprotein cholesterol 37 +/- 10 mg/dL; and triglycerides 167 +/- 91 mg/dL. In addition, 81% are men; 22% are current smokers; 49% give a history of myocardial infarction. Baseline angiographic characteristics are (mean +/- SD): left ventricular ejection fraction 59% +/- 11%; per patient diameter stenosis (excluding the PTCA segment) 49% +/- 31%; 8.9 +/- 3.5 analyzable segments per patient (excluding the PTCA segment), 3.8 +/- 2.3 of which have visible stenosis. Including the PTCA segment, 52% have single vessel disease and 48% have multivessel disease. Baseline angiographic data for non-PTCA segments will be correlated with cardiac ischemic events which occur after 6 months. Up to 500 subjects will undergo follow-up angiography with quantitative coronary angiographic analysis (QCA) of baseline and follow-up films. The primary QCA end point will be per-patient categorical designation as progressor or nonprogressor based on the presence or absence of > or = 400 microns narrowing in > or = 1 vessels that did not undergo PTCA.

Imaging myocardial fiber architecture in vivo with magnetic resonance.

Methods are presented to image the fiber architecture of the human myocardium in vitro and in vivo. NMR images are obtained of the diffusion anisotropy tensor, indicative of local myofiber orientation. Studies of cardiac necropsy specimens demonstrate classic features of ventricular myoarchitecture including the continuous endocardial to epicardial variation of fiber helix angles (angles to the ventricular circumferential direction) of approximately +1.3 to -1.3 radians. Cross-fiber anisotropy is also observed. In the beating heart, NMR diffusion data must be corrected for the effects of myocardial deformation during the cardiac cycle. This correction can be performed using an independent MRI method to map the strain-rate tensor field of the myocardium through time. Combining fiber orientation with local myocardial strain rate, local rates of myocardial fiber shortening may be computed.

Imaging and sizing of atrial septal defects by magnetic resonance.

BACKGROUND: Development of techniques for percutaneous closure of atrial septal defects (ASDs) makes accurate noninvasive sizing of ASDs important for appropriate patient selection. METHODS AND RESULTS: Magnetic resonance (MR) images of ASDs were obtained in 30 patients (mean age, 41 +/- 16 years) by both spin-echo and phase-contrast cine MR imaging. Spin-echo images were obtained in two orthogonal views (short-axis and four-chamber) perpendicular to the plane of the ASD. Spin-echo major and minor diameters were measured, and spin-echo defect area was calculated. Phase-contrast cine MR images were obtained in the plane of the ASD, and cine major diameter and defect area were measured from the region of signal enhancement or phase change due to shunt flow across the defect. MR measurements were compared with templates cut during surgery to match the defect or with ASD diameter determined by balloon sizing at catheterization. ASD size measured from cine MR images (y) agreed closely with catheterization and template standards (x). For major diameter, y = 0.78x + 5.7, r = .93, and SEE = 3.4 mm. On average, spin-echo measurements overestimated major diameter and area of secundum ASDs by 48% and 125%, respectively. CONCLUSIONS: Phase-contrast cine MR images acquired in the plane of an ASD define the defect shape by the cross section of the shunt flow stream and allow noninvasive determination of defect size with sufficient accuracy to permit stratification of patients to closure of the defect by catheter-based techniques versus surgery. Spin-echo images, on the other hand, are not adequate for defining ASD size, because septal thinning adjacent to a secundum ASD may appear to be part of the defect.

Intramural mechanics in hypertrophic cardiomyopathy: functional mapping with strain-rate MR imaging.

PURPOSE: To characterize systolic and diastolic intramural mechanics in hypertrophic cardiomyopathy (HCM) with a new metric of contractile activity. MATERIALS AND METHODS: Eleven healthy subjects and eight patients with HCM underwent velocity-encoded echo-planar magnetic resonance (MR) imaging (6-8-frame gated breath-hold movies, 3 x 3-mm resolution). A scalar strain rate (SR) parameter was compared with wall thickness and symptoms. RESULTS: The normal pattern of SR included regional uniformity, a monotonically increasing subepicardial to subendocardial gradient, and minimum transmural shear rate. In HCM, heterogeneity of SRs increased in diastole. Regional diastolic SR correlated with regional wall thickness (r = .785, P = .0001). Interobserver global SR assignment agreed in seven of eight patients. All four patients with New York Heart Association class 1 disease had a low global SR deficit score, whereas three of four patients with class 2 or 3 disease had a high SR deficit score (Spearman r = .775, P = .187). CONCLUSION: SR characterization may provide an objective measure of disease course in HCM.

A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesion progression. The initial (type 1) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

Three-dimensional intravascular ultrasound assessment of plaque volume after successful atherectomy.

The primary purpose of directional coronary atherectomy is the removal of intraluminal plaque. Angiography allows assessment of residual lumen narrowing but is limited in the assessment of residual plaque burden. Intravascular ultrasound has proven useful in assessing plaque size, but current use has been limited to a single, representative cross-sectional image rather than an evaluation of the entire plaque volume. To determine the volume of residual plaque after angiographically successful directional coronary atherectomy ( < or = 20% residual stenosis), we performed intravascular ultrasound in 19 patients before and after atherectomy. Only coronary lesions optimal for three-dimensional analysis (a single, discrete stenosis in a nontortuous, noncalcified native coronary artery) were selected. A 2.9F sheath-design intravascular ultrasound catheter with a motorized pullback device was used in all patients. The cross-sectional area of the artery (defined by the medial-adventitia border), the lumen, and the plaque were measured at 1 mm intervals over a 15 to 20 mm segment, which included the target lesion and a proximal reference segment (n = 362 cross-sections), before and after atherectomy. The volumes of the artery, vessel lumen, or plaque were calculated with a modified Simpson's equation and compared with standard area measurements at the point of maximal stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Motionless movies of myocardial strain-rates using stimulated echoes.

We present methods to acquire and analyze NMR movies of myocardial strain rates in which cardiac motion is suppressed and the histories of strain rates are accurately defined for each voxel of myocardial tissue. By means of stimulated echoes, the myocardial strain-rate tensor is phase-encoded at progressive delays in the cardiac cycle while the slice-select and spatial encoding of the image acquisition are performed at a constant cardiac delay. In these data, every image shows the identical myocardial tissue, and the anatomic configuration of the heart appears motionless. The myocardial strain-rate data, however, indicate the state of motion which existed in this slice at the time of the velocity phase-encoding, and these data evolve with the progressive delay as a movie. Using echo-planar MRI, motionless movies of myocardial strain rate of four to eight cardiac delays are obtained in a breath-hold. As an application, a quantitative characterization of cardiac mechanical synchrony is accomplished by principal component analysis (PCA) of the time series of strain rates.

Proximal jet size by Doppler color flow mapping predicts severity of mitral regurgitation. Clinical studies.

BACKGROUND: Recent studies have shown that many instrument and physiological factors limit the ability of color Doppler total jet area within the receiving chamber to predict the severity of valvular regurgitation. In contrast, the proximal or initial dimensions of the jet as it emerges from the orifice have been shown to increase directly with orifice size and to correlate well with the severity of aortic insufficiency. Only limited data, however, are available regarding the value of proximal jet size in mitral regurgitation, and it has not been examined in short-axis or transthoracic views. The purpose of the present study, therefore, was to evaluate the relation between proximal jet size and other measures of the severity of mitral regurgitation. METHODS AND RESULTS: In 49 patients, the anteroposterior height of the proximal jet as it emerges from the mitral valve was measured in the parasternal long-axis view; proximal jet width and area were measured in the short-axis view at the same level. Results were compared with regurgitant volume and fraction by pulsed Doppler subtraction of aortic and mitral flows in 47 patients without more than trace aortic insufficiency; with angiographic grade determined within 24 hours in 33 catheterized patients; and with angiographic regurgitant fraction in 13 patients who were in normal sinus rhythm and had no significant aortic and tricuspid insufficiency. Proximal jet height, width, and area correlated well with Doppler regurgitant volume and fraction (r = .86 to .95; SEE = 7.7 to 9.0 mL; 5.9% to 7.3%). Proximal jet size could also be used to distinguish angiographic grades of mitral regurgitation with minimal overlap (P < .0001) and correlated well with angiographic regurgitant fraction (r = .85 to .91; SEE = 4.1% to 5.1%). CONCLUSIONS: Proximal jet size correlates well with established measures of the severity of mitral regurgitation. It is conveniently available with transthoracic clinical scanning and should be useful in the routine evaluation of patients with mitral regurgitation.

Application of color Doppler flow mapping to calculate effective regurgitant orifice area. An in vitro study and initial clinical observations.

BACKGROUND: Analogous to stenotic valve area in the assessment of valvular stenosis, regurgitant orifice area (ROA) represents a fundamental parameter to assess valvular insufficiency. However, this parameter has not been routinely available up to now. In this study, we introduce the concept and provide the methodology to calculate regurgitant orifice area noninvasively, based on the analysis of the proximal flow convergence zone. METHODS AND RESULTS: In an in vitro study, we showed the feasibility and the accuracy of calculating effective ROA by the proximal flow convergence method throughout a range of driving pressures. The calculated and true ROA showed an excellent correlation with r = .992, delta ROA = -1.4 +/- 2.9 mm2. We then applied this concept clinically in 77 patients with mitral regurgitation and showed a very good correlation between effective ROA calculated by the proximal flow convergence method and calculated by the Doppler echocardiographic method: r = .95, delta ROA = -0.2 +/- 3.9 mm2. The ROA also correlated very well with Doppler echocardiographic-derived regurgitant stroke volume (r = .93) and regurgitant fraction (r = .82). In a subgroup of 20 patients who underwent invasive evaluation, the calculated effective ROA also correlated well with the angiographic grade of mitral regurgitation (rho = .81). CONCLUSIONS: We conclude that effective ROA represents unique information on the severity of a regurgitant lesion and can easily be calculated by the proximal flow convergence method. This new parameter should enhance our understanding and improve the serial assessment of valvular regurgitation.

The QUinapril Ischemic Event Trial (QUIET) design and methods: evaluation of chronic ACE inhibitor therapy after coronary artery intervention.

The rationale, trial design, and statistical aspects of QUIET, the QUinapril Ischemic Event Trial, are described. QUIET is a prospective, double-blind placebo-controlled study that will assess the ability of the angiotensin-converting enzyme (ACE) inhibitor quinapril to reduce the rate of cardiac ischemic events and to slow or prevent the development of coronary artery atherosclerosis as assessed by serial angiography in a normolipidemic population without left ventricular dysfunction. The study began in September 1991 and has completed recruitment with 1740 patients across 38 centers (28 U.S., 4 Canada, 6 Europe) by the end of 1992. Patients are randomized to 20 mg of quinapril or placebo once daily and continue in the study for 3 years. Study completion is projected for 1995.