Author + information
- Received January 14, 2014
- Revision received February 24, 2014
- Accepted March 7, 2014
- Published online August 1, 2014.
- Sharmila Dorbala, MD∗,†,‡∗ (, )
- Divya Vangala, MA†,
- John Bruyere Jr., MA†,
- Christina Quarta, MD‡,
- Jenna Kruger, BS‡,
- Robert Padera, MD§,
- Courtney Foster, MSc, CNMT†,
- Michael Hanley, MD∗,
- Marcelo F. Di Carli, MD∗,†,‡ and
- Rodney Falk, MD‡
- ∗Noninvasive Cardiovascular Imaging Program, Heart and Vascular Center, Departments of Radiology and Medicine (Cardiology), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- †Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ‡Cardiovascular Division and Cardiac Amyloidosis Program, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- §Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Sharmila Dorbala, Noninvasive Cardiovascular Imaging Program, Heart and Vascular Center, Departments of Radiology and Medicine (Cardiology), Brigham and Women's Hospital, 70 Francis Street, Shapiro 5th Floor, Room 128, Boston, Massachusetts 02115.
Objectives The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in subjects with cardiac amyloidosis.
Background Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD).
Methods Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product.
Results Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min; p = 0.004), stress MBF (0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min; p < 0.0001), and CFR (1.19 ± 0.38 vs. 2.23 ± 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator function.
Conclusions Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis.
Amyloidosis is a rare systemic disorder characterized by the extracellular deposition of misfolded protein in various organ systems, including the heart (1,2). Among the several types of amyloid fibrils, the light chain and transthyretin amyloid proteins most commonly affect the heart. Cardiac amyloid deposits result in increased ventricular wall thickness and produce a restrictive cardiomyopathy presenting primarily as biventricular congestive heart failure. Anginal symptoms and signs of ischemia have been reported in some patients with cardiac amyloidosis without obstructive epicardial coronary artery disease (CAD) (3–6). Autopsy studies have shown amyloid deposits around and between cardiac myocytes in the interstitium (7), the perivascular regions (8), and the media of intramyocardial coronary vessels (9,10). Amyloidosis is thus a prime example of a disorder with the potential to cause coronary microvascular dysfunction via 3 major mechanisms: structural (amyloid deposition in the vessel wall causing wall thickening and luminal stenosis), extravascular (extrinsic compression of the microvasculature from perivascular and interstitial amyloid deposits and decreased diastolic perfusion), and functional (autonomic and endothelial dysfunction). Accordingly, we sought to test the hypothesis that coronary flow reserve (CFR), a measure of microvascular function, is reduced in subjects with cardiac amyloidosis without evidence of epicardial CAD. Next, we sought to explore the hypothesis that reduced CFR is a function of increased myocardial mass and increased left ventricular (LV) filling pressures and is associated with subclinical abnormalities in LV systolic dysfunction (strain). Therefore, our primary aim was to study coronary microvascular function in subjects with cardiac amyloidosis compared with subjects with hypertensive left ventricular hypertrophy (LVH). Our secondary aim was to study the morphological and functional correlates of coronary microvascular dysfunction in subjects with cardiac amyloidosis.
We prospectively enrolled 31 subjects into 2 study groups. The amyloid group consisted of 21 subjects with confirmed light chain (n = 15) or transthyretin (n = 6) amyloidosis using pre-defined inclusion and exclusion criteria (Online Table 1). Ten subjects with hypertensive LVH on 2-dimensional (2D) echocardiography (LV wall thickness >11 mm) served as controls. Hypertensive subjects with LVH did not have documented kidney disease, peripheral vascular disease, cerebrovascular disease, or CAD (no history of chest pain, myocardial infarction, angiographic CAD, or coronary revascularization). Amyloidosis was diagnosed by endomyocardial biopsy (n = 10) or by a positive extracardiac biopsy specimen with typical features of cardiac involvement on 2D transthoracic echocardiography (n = 11) (e.g., wall thickness measurements >11 mm, bright echogenic myocardium, and echocardiographic evidence of diastolic dysfunction). All biopsy specimens stained positive for amyloid with either sulfated alcian blue or congo red stain, and amyloid typing was determined by a battery of stains, including immunoperoxidase stain for transthyretin and immunofluorescence stain for immunoglobulins G, M, A, kappa, lambda, protein A, and transthyretin. In equivocal cases, biopsy specimens underwent proteomics evaluation.
This study was approved by the Partners Human Research Committee. All study subjects were prospectively enrolled, provided written informed consent, and underwent evaluation of coronary microvascular function by a research test and vasodilator stress N-13 ammonia positron emission tomography/computed tomography (PET/CT) (except for 3 subjects with LVH who underwent clinical N-13 ammonia PET/CT). Obstructive epicardial CAD was carefully excluded in all subjects with amyloidosis by coronary angiography, as described in the following text. All subjects also underwent 2D transthoracic echocardiography with strain analysis to study cardiac morphology and function. Detailed characterization of the amyloid subtype was available for all subjects with amyloidosis, including staining of biopsy specimens.
Rest and vasodilator stress N-13 ammonia PET/CT was performed by using standard protocols and standard preparation (see the Online Appendix). Imaging of all subjects was performed with a whole body PET/CT scanner (Discovery Lightspeed VCT 64; GE Healthcare, Milwaukee, Wisconsin) after an overnight fast. Rest N-13 ammonia images were obtained for 20 min in 2D list mode after intravenous injection of N-13 ammonia (∼20 mCi). One hour after rest perfusion imaging, vasodilator stress was performed by using a standard infusion of adenosine (n = 9), dipyridamole (n = 18), or regadenoson (n = 4). At peak hyperemia, a second dose of N-13 ammonia (∼20 mCi) was given intravenously and stress images were recorded in the same manner. The estimated whole body effective radiation dose for the rest and stress N-13 ammonia PET/CT study was 5.4 mSv. Images were interpreted semiquantitatively and independently by 2 experienced observers (interobserver reliability kappa: 0.95) (11) by using a standard 17-segment model and a 5-point (0–4) scoring system. The global summed stress score, summed rest score, and summed difference score (the difference between the summed stress score and summed rest score) were computed. A summed stress score >0 was considered abnormal.
Global LV myocardial blood flow (MBF) (ml/g/min) was quantified at rest and during peak hyperemia by using a previously validated one-compartment model (12) and commercially available software (FlowQuant, University of Ottawa Heart Institute, Ottawa, Canada). CFR was computed as the ratio of stress MBF to rest MBF and is referred to as CFR* throughout this report. CFR was adjusted for rest rate pressure product and computed as the ratio of stress MBF to normalized rest MBF (rest MBF/rest rate pressure product) ⋅ 10,000, and is referred to as CFR throughout this report. Coronary vascular resistance, the ratio of mean arterial pressure to MBF at rest (maximal coronary vascular resistance) and peak hyperemia (minimal coronary vascular resistance) was also calculated. Reduced peak stress MBF, reduced CFR, and increased minimal coronary vascular resistance were considered to represent coronary microvascular dysfunction. Stress MBF images from one subject in the amyloid group were uninterpretable due to poor counts.
Epicardial obstructive CAD was excluded in all subjects with amyloidosis by clinical invasive coronary angiography or research CT coronary angiography. Clinically performed invasive coronary angiography (a median of 164 days before the PET study) reports were reviewed, and only subjects with <70% CAD in all coronary arteries were invited to participate in the study. All except one subject with amyloidosis underwent coronary angiography to exclude CAD within the 2-year window (1 patient underwent coronary angiography within 3 years). In 9 subjects with amyloidosis, research CT coronary angiography was performed within a median of −1 day of the PET study with standard protocols (Online Appendix).
All subjects underwent 2D transthoracic echocardiography within a median of −1 day (interquartile range: −31 to +24 days) of the PET study. Digitally acquired echocardiography images in DICOM format with acceptable image quality (n = 27) were uploaded and processed using vendor-independent offline 2D Cardiac Performance Analysis software (TomTec Imaging System, Munich, Germany) to compute peak LV longitudinal, radial, and circumferential strain values (Online Appendix). Throughout this report, we use the term “strain” to represent LV strain.
Primary outcome measures
The primary outcome measures of this study were peak stress MBF, CFR, and minimal coronary vascular resistance.
The characteristics of the subjects are described as mean ± SD compared with the Student t test. Nonparametric variables are listed as medians and compared with the Mann-Whitney U test. Discrete variables are described as proportions and compared with the chi-square test. Correlations were performed using Pearson R or nonparametric methods (Spearman rho) as indicated. Multivariable linear regression analyses were performed to study the independent contributions of various parameters on stress MBF, CFR, and minimal coronary vascular resistance. A parsimonious model with stepwise forward selection (probability of F for entry of 0.05 and for removal of 0.10) was performed to minimize model overfitting.
Baseline data on patient characteristics and hemodynamics are listed in Table 1. Notably, the amyloid group had lower body mass than the LVH group and 38% were women. Approximately one-half of the amyloid group had a history of New York Heart Association functional class ≥II heart failure. The amyloid group had ischemic symptoms of chest pain (24%), shortness of breath (62%), and jaw or buttock claudication (20%) with clinical evidence of autonomic (19%) or peripheral neuropathy (19%), proteinuria suggesting renal involvement (14%), or amyloid deposition in the liver (5%). Nine of the 15 subjects with amyloid light chain (AL) amyloidosis received specific chemotherapy for amyloidosis before this study. As expected, the mean limb lead and chest lead electrocardiographic voltage was lower in the amyloid group compared with the LVH group.
Regional myocardial perfusion
A variety of perfusion patterns (no ischemia to severe ischemia) and high-risk scan findings (transient cavity dilation and right ventricular tracer uptake) were observed in the amyloid group (Fig. 1, Online Fig. 1). In the amyloid group, despite no epicardial CAD, 57% of the subjects (12 of 21) had ischemic scans; 3 subjects had severe ischemia. High-risk scan features, such as increased right ventricular tracer uptake (62%; 13 of 21 subjects) and transient cavity dilation of the left ventricle on the post-stress images (76%; 16 of 21 subjects), were frequently seen. The mean transient cavity dilation ratio was significantly higher in the amyloid group than in the LVH group (1.18 ± 0.12 vs. 1.04 ± 0.18; p = 0.03). None of the subjects with LVH had perfusion defects on the N-13 ammonia study.
Coronary vasomotor function
The mean rest MBF, stress MBF, CFR, and CFR* were significantly lower in the amyloid group compared with the LVH group (rest MBF: 0.59 ± 0.15 ml/g/min vs. 0.88 ± 0.23 ml/g/min [p = 0.004]; stress MBF: 0.85 ± 0.29 ml/g/min vs. 1.85 ± 0.45 ml/g/min [p < 0.0001]; CFR: 1.19 ± 0.38 vs. 2.23 ± 0.88 [p < 0.0001]; CFR*: 1.44 ± 0.36 vs. 2.20 ± 0.67 [p < 0.0001]) (Table 2). Because the LVH group had significantly lower LV mass than the amyloid group, we normalized the rest MBF, stress MBF, and CFR to LV mass as follows: (MBF or CFR/LV mass) ⋅ 100. The values for rest MBF, peak stress MBF, and CFR per unit LV mass were significantly lower in the amyloid group compared with the LVH group (Fig. 2), suggesting differences independent of LV mass. The myocardial extracellular volume fraction may be expanded and the functioning myocardial mass as estimated by echocardiography may thus be lower in the amyloid group compared with control subjects (22). Hence, we performed sensitivity analysis assuming a functioning myocardial mass of 0.50 and 0.75; stress MBF was significantly lower at an LV mass of 0.75 (trend to lower stress MBF at an LV mass of 0.5), and CFR values remained significantly lower in the amyloid group. Coronary vascular resistance was significantly higher in the amyloid group compared with the LVH group at rest (147 ± 41 ml/g/min/mm Hg vs. 117 ± 28 ml/g/min/mm Hg; p = 0.05) and during maximal hyperemia (111 ± 40 ml/g/min/mm Hg vs. 70 ± 19 ml/g/min/mm Hg; p = 0.004). All except one of the subjects in the amyloid group had a significantly reduced peak stress MBF of <1.3 ml/g/min. The patterns of distribution of quantitative rest and stress MBF were significantly different with much lower stress MBF values in the amyloid group compared with the LVH group (Online Fig. 2). Finally, rest MBF, stress MBF, CFR, and minimal coronary vascular resistance did not differ in subjects with AL amyloidosis compared with subjects with transthyretin amyloidosis.
Cardiac morphological and functional parameters in the study groups
Morphologically, despite lower voltage QRS complexes on electrocardiography, the mean LV wall thickness and mass were higher in the amyloid group than in the LVH group (Table 3), consistent with amyloid deposition in the LV myocardium. We also reviewed the available myocardial biopsy specimens from 8 subjects in the amyloid group. Microscopically, while one specimen was inadequate, perivascular amyloid deposits (Fig. 1B) were found in 5 of 8 subjects; the amyloid burden ranged from 10% to 70%. Functionally, although the mean E/A ratio was similar, the e′ and a′ (early and late mitral annular tissue relaxation velocities) were significantly lower and the E/e′ ratio was significantly higher in the amyloid group, likely related to restrictive heart disease from amyloid infiltration. Also, the maximal left atrial size (4.5 ± 0.6 cm vs. 3.8 ± 0.6 cm; p = 0.003) and left atrial volume indexed to body surface area (40.5 ± 13.4 ml/m2 vs. 23.2 ± 9.6 ml/m2; p = 0.002) were significantly higher in the amyloid group than in the LVH group, suggesting greater chronic left atrial hypertension with or without amyloid atrial disease. Finally, the mean longitudinal strain (but not circumferential strain) was significantly lower in the amyloid group than in the LVH group (−11.50 ± 2.99 vs. −17.78 ± 3.41; p < 0.0001), particularly at the base and the midventricular regions (Fig. 3), consistent with previous reports of greater mid and basal contractile impairment.
Associations between LV structure and coronary vascular function
We found that parameters of coronary microvascular function were inversely correlated to increased LV mass (Fig. 4), increased diastolic filling pressures, and subclinical systolic dysfunction. Notably, in the few subjects with an LV mass of <300 g, for any given degree of LV mass, stress MBF and CFR were lower in the amyloid group than in the LVH group (Fig. 4). The mean e′, a′, and E/e′ ratio were inversely related to stress MBF, CFR, and minimal coronary vascular resistance (Table 4). Subclinical systolic dysfunction (mean LV longitudinal strain) was linearly related to rest MBF, stress MBF, CFR, minimal coronary vascular resistance, and LV mass (Table 4, Fig. 5). In stepwise forward multiple linear regression models (R = 0.87; p < 0.0001) including rest MBF, stress MBF, LV mass, and presence of amyloid, only LV mass (beta = 0.21; p < 0.0001) and amyloid (beta = 2.3; p = 0.04) were significant independent predictors of impaired longitudinal strain.
Multivariable correlates of MBF, CFR, and coronary vascular resistance
Cardiac amyloidosis was associated with worse coronary microvascular function independent of LV mass, age, and subclinical myocardial dysfunction. On separate stepwise forward multiple linear regression analyses for rest MBF, stress MBF, CFR, and minimal coronary vascular resistance, we adjusted for known confounders including age, LV mass, and mean longitudinal strain. In these models (rest MBF model: R = 0.65; p < 0.001; stress MBF model: R = 0.89; p < 0.0001; CFR model: R = 0.75; p < 0.0001 and minimal coronary vascular resistance: R = 0.50; p = 0.009), cardiac amyloidosis was independently associated with lower rest MBF (beta = −0.645; p < 0.0001), stress MBF (beta = −0.801; p < 0.0001), and CFR (beta = −0.665; p < 0.0001) and higher minimal coronary vascular resistance (beta = 0.5; p = 0.009). Older age was an independent predictor of lower CFR (beta = −0.386; p = 0.01), and higher LV mass was an independent predictor of lower stress MBF (beta = −0.001; p = 0.03).
We prospectively studied coronary microvascular function in the absence of epicardial CAD in subjects with documented cardiac amyloidosis. The findings of our study provide novel insights into the morphological correlates of coronary microvascular dysfunction and underscore the role of microvascular dysfunction as a probable mechanism for anginal symptoms in these subjects. Of note, impaired coronary microvascular flow in our subjects was almost universal and similar regardless of the underlying type of amyloid deposits (light chain or transthyretin). Minimal coronary vascular resistance was markedly increased in the amyloid group; with stress, substantial reductions in stress MBF and CFR were found when compared with the hypertensive LVH group. Coronary microvascular dysfunction was associated with several classic imaging features of cardiac amyloidosis such as increased LV mass and myocardial relaxation abnormalities such as low mitral annular relaxation velocities, high left atrial pressures (E/e′), and impaired longitudinal myocardial strain. Taken together, these findings allow us to postulate that amyloid deposits in the interstitium and perivascular regions of the heart increase coronary microvascular resistance and LV filling pressures leading to coronary microvascular dysfunction and may explain a greater vulnerability to ischemia and subclinical impairment of LV systolic function.
Longitudinal strain is often severely and disproportionately reduced in patients with cardiac amyloidosis. Because the majority of longitudinal fibers are subendocardial and this area of the myocardium is most vulnerable to ischemia, it might be postulated that disturbed microvascular function plays a role in longitudinal impairment. Support for this hypothesis comes from our finding of univariable correlation between longitudinal dysfunction and microvascular impairment. However, only the presence of amyloidosis and higher LV mass were independent determinants of lower longitudinal strain, suggesting a relation mediated via higher amyloid burden. Koyama and Falk (13) showed that reduced longitudinal strain is associated with worse survival in subjects with AL amyloidosis. Indeed, our findings combined with those of Koyama and Falk suggest that coronary microvascular dysfunction from higher amyloid mass may be the mechanistic link between impaired longitudinal strain and worse survival in subjects with AL amyloidosis.
Increased wall thickness from amyloid deposition in the heart may impede subendocardial perfusion due to vascular rarefaction and compression. Higher LV mass was related to microvascular dysfunction and to reduced rest MBF and reduced longitudinal strain. Although these findings reinforce the notion that higher LV mass contributes to coronary microvascular dysfunction, rest MBF, stress MBF, and CFR normalized to LV mass were also significantly lower in the amyloid group compared with the LVH group. This finding, along with the high frequency of vascular amyloid deposition in a small sample of subjects in our study, argues for additional mechanism(s), such as the role of vascular amyloid deposition (Fig. 1B), presumably resulting in mechanical impairment of microvascular vasodilation and angina.
Additionally, autonomic dysfunction (either covert or overt) is prevalent in transthyretin and in AL amyloidosis manifesting clinically with abnormal vascular autonomic (sympathetic) modulation and impaired baroreflex function (14). Autonomic denervation limits stress MBF and CFR, primarily via norepinephrine-mediated mechanisms and also by changes in metabolic autoregulation and endothelial dysfunction in diabetic autonomic dysfunction (15–17). Although not specifically evaluated in this study, autonomic dysfunction may also contribute to microvascular dysfunction in amyloidosis.
Coronary microvascular dysfunction has been described in hypertrophic and infiltrative heart diseases, including hypertensive heart disease, aortic stenosis, hypertrophic cardiomyopathy, and Fabry disease (18). Microvascular dysfunction in these diseases may be mechanistically related to coronary microvascular remodeling, rarefaction and interstitial fibrosis (hypertensive heart disease), small-vessel disease, relatively reduced capillary density, increased LV end-diastolic pressures and systolic compression of the septal coronary arteries (19), or increased LV mass (20). Some or all of these mechanisms may explain the coronary vasomotor dysfunction in cardiac amyloidosis. The magnitude of the microvascular dysfunction in our patients with amyloidosis is not only more severe than those seen in hypertensive disease but is also more severe than previously reported data in dilated cardiomyopathy (21) and Fabry disease (20,22).
To the best of our knowledge, this is the first prospective study to characterize coronary microvascular function noninvasively in carefully selected subjects with cardiac amyloidosis and no obstructive epicardial CAD. In this study, detailed characterization of epicardial coronary anatomy and microvascular function was performed to distinguish microvascular dysfunction from flow-limiting epicardial CAD. The study size was modest because of our stringent inclusion and exclusion criteria and the relative rarity of cardiac amyloidosis and may have limited the multivariable models. Also, the p values presented were not corrected for multiple testing. Further, because of excellent blood pressure control in the current era, hypertensive LVH without other end-organ damage is rare, limiting our enrollment of patients with hypertensive cardiomyopathy to subjects without severe LVH. Therefore, we studied CFR values normalized to LV mass (including assumed functioning LV mass of 0.5 and 0.75), and they were significantly lower in the amyloid group. Some of the subjects in the amyloid group received specific therapy for amyloidosis before study enrollment, potentially attenuating the effects of amyloid on MBF. However, significant differences in MBF were observed between the study groups, suggesting a large effect size and strengthening the study findings. Although the precise clinical implications of all our findings are not known, we believe that they may explain some of the functional limitations and poor prognosis seen in patients with cardiac amyloidosis.
Coronary vasodilation and minimal coronary vascular resistance are significantly impaired in subjects with cardiac amyloidosis even in the absence of epicardial CAD. Our findings suggest that increased myocardial amyloid burden (mass) correlates with microvascular dysfunction. Because increased amyloid mass is associated with more widespread cardiac disease, it is likely that vascular amyloid deposits also play a role. An additional role of autonomic dysfunction in coronary microvascular dysfunction remains speculative and needs to be further explored. Coronary microvascular dysfunction in amyloidosis also correlates with diastolic dysfunction and subclinical systolic dysfunction. Successful hematologic treatment of AL amyloidosis is associated with a decrease in cardiac biomarkers before a change in standard echocardiographic features. Thus, further study is required to determine if coronary microvascular function may improve after specific therapy for cardiac amyloidosis.
The authors thank the subjects who participated in this study and their colleagues at the Brigham and Women’s Hospital Cardiac Amyloidosis Program and the Boston University Amyloidosis Program.
This study was supported by the Amyloid Foundation, American Society of Nuclear Cardiology Foundation, National Institutes of Healthhttp://dx.doi.org/10.13039/100000002 (National Heart, Lung, and Blood Institute grant K23HL092299), and in part by the Demarest Lloyd, Jr. Foundation (Dr. Falk). Dr. Dorbala has received a research grant from Astellas Global Pharma Development. Dr. Di Carli has received a research grant from Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Ms. Vangala and Mr. Bruyere contributed equally to this work.
- Abbreviations and Acronyms
- amyloid light chain
- coronary artery disease
- coronary flow reserve
- computed tomography
- left ventricular
- left ventricular hypertrophy
- myocardial blood flow
- positron emission tomography
- Received January 14, 2014.
- Revision received February 24, 2014.
- Accepted March 7, 2014.
- American College of Cardiology Foundation
- Ogawa H.,
- Mizuno Y.,
- Ohkawara S.,
- et al.
- Whitaker D.C.,
- Tungekar M.F.,
- Dussek J.E.
- Modesto K.M.,
- Dispenzieri A.,
- Gertz M.,
- et al.
- Dorbala S.,
- Vangala D.,
- Sampson U.,
- Limaye A.,
- Kwong R.,
- Di Carli M.F.
- Koyama J.,
- Falk R.H.
- Bernardi L.,
- Passino C.,
- Porta C.,
- Anesi E.,
- Palladini G.,
- Merlini G.
- Vinik A.I.,
- Ziegler D.
- Di Carli M.F.,
- Bianco-Batlles D.,
- Landa M.E.,
- et al.
- Stevens M.J.,
- Dayanikli F.,
- Raffel D.M.,
- et al.
- Elliott P.M.,
- Kindler H.,
- Shah J.S.,
- et al.
- Neglia D.,
- Parodi O.,
- Gallopin M.,
- et al.