Roderic I. Pettigrew

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease : Results of a Phase I open-label dose escalation study

OBJECTIVES Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.

Necrotic core thickness and positive arterial remodeling index: Emergent biomechanical factors for evaluating the risk of plaque rupture

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Core(area)) and the arterial remodeling index (Remod(index)), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Core(area) thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Core(area) and Remod(index), it remains unclear how these interact and affect peak cap stress (Cap(stress)), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Cap(stress) value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Cap(stress). It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.

Detection of high-risk atherosclerotic plaque: report of the NHLBI Working Group on current status and future directions.

The leading cause of major morbidity and mortality in most countries around the world is atherosclerotic cardiovascular disease, most commonly caused by thrombotic occlusion of a high-risk coronary plaque resulting in myocardial infarction or cardiac death, or embolization from a high-risk carotid plaque resulting in stroke. The lesions prone to result in such clinical events are termed vulnerable or high-risk plaques, and their identification may lead to the development of pharmacological and mechanical intervention strategies to prevent such events. Autopsy studies from patients dying of acute myocardial infarction or sudden death have shown that such events typically arise from specific types of atherosclerotic plaques, most commonly the thin-cap fibroatheroma. However, the search in human beings for vulnerable plaques before their becoming symptomatic has been elusive. Recently, the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study demonstrated that coronary plaques that are likely to cause future cardiac events, regardless of angiographic severity, are characterized by large plaque burden and small lumen area and/or are thin-cap fibroatheromas verified by radiofrequency intravascular ultrasound imaging. This study opened the door to identifying additional invasive and noninvasive imaging modalities that may improve detection of high-risk atherosclerotic lesions and patients. Beyond classic risk factors, novel biomarkers and genetic profiling may identify those patients in whom noninvasive imaging for vulnerable plaque screening, followed by invasive imaging for risk confirmation is warranted, and in whom future pharmacological and/or device-based focal or regional therapies may be applied to improve long-term prognosis.

B1-insensitive T2 preparation for improved coronary magnetic resonance angiography at 3 T

At 3 T, the effective wavelength of the RF field is comparable to the dimension of the human body, resulting in B1 standing wave effects and extra variations in phase. This effect is accompanied by an increase in B0 field inhomogeneity compared to 1.5 T. This combination results in nonuniform magnetization preparation by the composite MLEV weighted T2 preparation (T2 Prep) sequence used for coronary magnetic resonance angiography (MRA). A new adiabatic refocusing T2 Prep sequence is presented in which the magnetization is tipped into the transverse plane with a hard RF pulse and refocused using a pair of adiabatic fast‐passage RF pulses. The isochromats are subsequently returned to the longitudinal axis using a hard RF pulse. Numerical simulations predict an excellent suppression of artifacts originating from B1 inhomogeneity while achieving good contrast enhancement between coronary arteries and surrounding tissue. This was confirmed by an in vivo study, in which coronary MR angiograms were obtained without a T2 Prep, with an MLEV weighted T2 Prep and the proposed adiabatic T2 Prep. Improved quantitative and qualitative coronary MRA image measurement was achieved using the adiabatic T2 Prep at 3 T. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.

Incidence of aneurysm formation after Dacron patch aortoplasty repair for coarctation of the aorta: long-term results and assessment utilizing magnetic resonance angiography with three-dimensional surface rendering.

OBJECTIVES Magnetic resonance angiography with three-dimensional surface rendering was performed to determine its value in assessing anatomic detail in patients with suspected aortic aneurysms. BACKGROUND Dacron patch aortoplasty repair of coarctation of the aorta carries an inherent risk of aneurysm development. Sudden death from aortic rupture prompted discontinuing this operation and evaluating 39 patients (16 girls; mean age 6.3 years, range 10 days to 14.5 years) undergoing repair between January 1976 and October 1987. The aorta ruptured in 10 patients; 6 died at a mean interval of 8.1 years (range 0.75 to 12.4) after repair. All 33 survivors were interviewed and examined. METHODS Conventional magnetic resonance imaging was performed in 26 patients, magnetic resonance angiography in 18. Angiographic slices were used to reconstruct three-dimensional images. No catheterization or contrast angiography was performed. Surgical intervention was based on clinical findings and magnetic resonance images. RESULTS Twenty patients (11 girls) developed aneurysms, of which nine were detected in patients studied by magnetic resonance. Ruptures occurred in eight female patients, three of whom were pregnant. Surface renderings accurately defined aortic anatomy or aneurysms in all patients. On follow-up, no aneurysms have been detected in patients with negative magnetic resonance study results. Precise anatomic correlation with operative findings was reported. CONCLUSIONS Magnetic resonance angiography with three-dimensional surface rendering provides noninvasive, radiation-free and contrast agent-free high resolution images of the thoracic aorta. These images can be reviewed and have three-dimensional form and perspective. These techniques were preferred over invasive angiography by surgeons and clinicians as definitive, risk-free procedures before surgical intervention.

Effect of Gd-DTPA-BMA on blood and myocardial T1 at 1.5T and 3T in humans

To compare T1 values of blood and myocardium at 1.5T and 3T before and after administration of Gd‐DTPA‐BMA in normal volunteers, and to evaluate the distribution of contrast media between myocardium and blood during steady state.

Improved measurement of pressure gradients in aortic coarctation by magnetic resonance imaging.

OBJECTIVES This study evaluated whether magnetic resonance imaging (MRI) and magnetic resonance (MR) phase velocity mapping could provide accurate estimates of stenosis severity and pressure gradients in aortic coarctation. BACKGROUND Clinical management of aortic coarctation requires determination of lesion location and severity and quantification of the pressure gradient across the constricted area. METHODS Using a series of anatomically accurate models of aortic coarctation, the laboratory portion of this study found that the loss coefficient (K), commonly taken to be 4.0 in the simplified Bernoulli equation delta P = KV2, was a function of stenosis severity. The values of the loss coefficient ranged from 2.8 for a 50% stenosis to 4.9 for a 90% stenosis. Magnetic resonance imaging and MR phase velocity mapping were then used to determine coarctation severity and pressure gradient in 32 patients. RESULTS Application of the new severity-dependent loss coefficients found that pressure gradients deviated from 1 to 17 mm Hg compared with calculations made with the commonly used value of 4.0. Comparison of MR estimates of pressure gradient with Doppler ultrasound estimates (in 22 of 32 patients) and with catheter pressure measurements (in 6 of 32 patients) supports the conclusion that the severity-based loss coefficient provides improved estimates of pressure gradients. CONCLUSIONS This study suggests that MRI could be used as a complete diagnostic tool for accurate evaluation of aortic coarctation, by determining stenosis location and severity and by accurately estimating pressure gradients.

Three‐Dimensional, Time‐Resolved Motion of the Coronary Arteries

BACKGROUND Coronary artery motion can decrease image quality during coronary magnetic resonance angiography and computed tomography coronary angiography. PURPOSE To characterize the three-dimensional motion of the coronary arteries along the entire vessel length and to identify the temporal location and duration of periods of relatively low cardiac motion in patients with coronary artery disease. METHODS Archived digital, biplane x-ray angiography films acquired at 30 frames per second with simultaneous electrocardiogram recording were reviewed for 15 patients with coronary artery disease. The right coronary (RCA), left anterior descending (LAD), and left circumflex (LCX) arteries were divided into proximal, mid, and distal segments. The displacement and velocity of a point in each segment were calculated throughout the heart cycle. Time-dependent, three-dimensional motion of each segment on each vessel was determined. Periods of the heart cycle during which maximal displacement was less than 1 mm or 0.5 mm per frame for each artery were determined. RESULTS A period lasting an average of 187 msec was seen during mid-diastole (72+/-5% of the cardiac cycle) in which all three coronary arteries studied had relatively little motion. This period of quiescence was consistent along the length of the arteries. Although the amount of motion did vary along the length of the arteries, there was no difference in the timing of rest periods in the proximal, mid, and distal segments using a < 1 mm per frame threshold. The periods of low motion were significantly reduced in length and often altogether eliminated when the 0.5 mm per frame threshold was used.

MRI techniques for cardiovascular imaging.

Over the last several years, cardiovascular MRI has benefited from a number of technical advances which have improved routine clinical imaging techniques. As a result, MRI is now well positioned to realize its longstanding promise of becoming the comprehensive cardiac imaging test of choice in many clinical settings. This may be achieved using a combination of basic advanced techniques. In this overview, the basic cardiac MRI techniques which are clinically useful are reviewed, and the recent technical advances which are clinically promising are described. These advances include routine black blood and cine bright blood techniques that are high speed (<10s per black blood image or cine slice), multislice whole heart perfusion imaging methods, and recently emerging real‐time imaging methodologies. J Magn. Reson. Imaging 1999;10:590–601.

Coronary artery anomalies and variants: technical feasibility of assessment with coronary MR angiography at 3 T.

The purpose of this study was to prospectively use a whole-heart three-dimensional (3D) coronary magnetic resonance (MR) angiography technique specifically adapted for use at 3 T and a parallel imaging technique (sensitivity encoding) to evaluate coronary arterial anomalies and variants (CAAV). This HIPAA-compliant study was approved by the local institutional review board, and informed consent was obtained from all participants. Twenty-two participants (11 men, 11 women; age range, 18-62 years) were included. Ten participants were healthy volunteers, whereas 12 participants were patients suspected of having CAAV. Coronary MR angiography was performed with a 3-T MR imager. A 3D free-breathing navigator-gated and vector electrocardiographically-gated segmented k-space gradient-echo sequence with adiabatic T2 preparation pulse and parallel imaging (sensitivity encoding) was used. Whole-heart acquisitions (repetition time msec/echo time msec, 4/1.35; 20 degrees flip angle; 1 x 1 x 2-mm acquired voxel size) lasted 10-12 minutes. Mean examination time was 41 minutes +/- 14 (standard deviation). Findings included aneurysms, ectasia, arteriovenous fistulas, and anomalous origins. The 3D whole-heart acquisitions developed for use with 3 T are feasible for use in the assessment of CAAV.