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JACC: HEART FAILURE VOL. 2, NO. 4, 2014 ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC. ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2014.03.009 CLINICAL RESEARCH Coronary Microvascular Dysfunction Is Related to Abnormalities in Myocardial Structure and Function in Cardiac Amyloidosis Sharmila Dorbala, MD,*yz Divya Vangala, MA,y John Bruyere JR, MA,y Christina Quarta, MD,z Jenna Kruger, BS,z Robert Padera, MD,x Courtney Foster, MSC, CNMT,y Michael Hanley, MD,* Marcelo F. Di Carli, MD,*yz Rodney Falk, MDz ABSTRACT 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 ¼ 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 ¼ 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. (J Am Coll Cardiol HF 2014;2:358–67) © 2014 by the American College of Cardiology Foundation. From the *Noninvasive Cardiovascular Imaging Program, Heart and Vascular Center, Departments of Radiology and Medicine (Cardiology), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; yDivision of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; zCardiovascular Division and Cardiac Amyloidosis Program, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the xDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. This study was supported by the Amyloid Foundation, American Society of Nuclear Cardiology Foundation, National Institutes of Health (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. Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 A 359 Microvascular Dysfunction in Cardiac Amyloidosis myloidosis is a rare systemic disorder charac- Table 1). Ten subjects with hypertensive ABBREVIATIONS terized by the extracellular deposition of LVH on 2-dimensional (2D) echocardiography AND ACRONYMS misfolded protein in various organ systems, (LV wall thickness >11 mm) served as con- including the heart (1,2). Among the several types of trols. Hypertensive subjects with LVH did not amyloid fibrils, the light chain and transthyretin am- have documented kidney disease, peripheral yloid proteins most commonly affect the heart. Car- vascular disease, cerebrovascular disease, or diac amyloid deposits result in increased ventricular CAD (no history of chest pain, myocardial CT = computed tomography wall thickness and produce a restrictive cardiomyop- infarction, angiographic CAD, or coronary LV = left ventricular athy presenting primarily as biventricular congestive revascularization). Amyloidosis was diag- LVH = left ventricular heart of nosed by endomyocardial biopsy (n ¼ 10) or hypertrophy ischemia have been reported in some patients with by a positive extracardiac biopsy specimen MBF = myocardial blood flow cardiac amyloidosis without obstructive epicardial with typical features of cardiac involvement PET = positron emission coronary artery disease (CAD) (3–6). Autopsy studies on 2D transthoracic echocardiography (n ¼ 11) tomography have shown amyloid deposits around and between (e.g., wall thickness measurements >11 mm, 2D = 2-dimensional failure. Anginal symptoms and signs AL = amyloid light chain CAD = coronary artery disease CFR = coronary flow reserve cardiac myocytes in the interstitium (7), the perivas- bright echogenic myocardium, and echocardiographic cular regions (8), and the media of intramyocardial evidence of diastolic dysfunction). All biopsy speci- coronary vessels (9,10). Amyloidosis is thus a prime mens stained positive for amyloid with either example of a disorder with the potential to cause cor- sulfated alcian blue or congo red stain, and amyloid onary microvascular dysfunction via 3 major mecha- typing was determined by a battery of stains, nisms: structural (amyloid deposition in the vessel including immunoperoxidase stain for transthyretin wall causing wall thickening and luminal stenosis), and immunofluorescence stain for immunoglobulins extravascular (extrinsic compression of the microvas- G, M, A, kappa, lambda, protein A, and transthyretin. culature from perivascular and interstitial amyloid In equivocal cases, biopsy specimens underwent deposits and decreased diastolic perfusion), and proteomics evaluation. functional (autonomic and endothelial dysfunction). This study was approved by the Partners Accordingly, we sought to test the hypothesis that Human Research Committee. All study subjects were coronary flow reserve (CFR), a measure of microvas- prospectively enrolled, provided written informed cular function, is reduced in subjects with cardiac consent, and underwent evaluation of coronary amyloidosis without evidence of epicardial CAD. microvascular function by a research test and vasodi- Next, we sought to explore the hypothesis that lator stress N-13 ammonia positron emission tomog- reduced CFR is a function of increased myocardial raphy/computed tomography (PET/CT) (except for 3 mass and increased left ventricular (LV) filling pres- subjects with LVH who underwent clinical N-13 sures and is associated with subclinical abnormalities ammonia PET/CT). Obstructive epicardial CAD was in LV systolic dysfunction (strain). Therefore, our pri- carefully excluded in all subjects with amyloidosis by mary aim was to study coronary microvascular func- coronary angiography, as described in the following tion in subjects with cardiac amyloidosis compared text. All subjects also underwent 2D transthoracic with subjects with hypertensive left ventricular hy- echocardiography with strain analysis to study cardiac pertrophy (LVH). Our secondary aim was to study morphology and function. Detailed characterization of the morphological and functional correlates of coro- the amyloid subtype was available for all subjects with nary microvascular dysfunction in subjects with car- amyloidosis, including staining of biopsy specimens. diac amyloidosis. PET. Rest and vasodilator stress N-13 ammonia PET/ CT was performed by using standard protocols and METHODS standard preparation (see the Online Appendix). Imaging of all subjects was performed with a whole PATIENT COHORT. We prospectively enrolled 31 body PET/CT scanner (Discovery Lightspeed VCT 64; subjects into 2 study groups. The amyloid group GE Healthcare, Milwaukee, Wisconsin) after an over- consisted of 21 subjects with confirmed light chain night fast. Rest N-13 ammonia images were obtained (n ¼ 15) or transthyretin (n ¼ 6) amyloidosis using for 20 min in 2D list mode after intravenous injection pre-defined inclusion and exclusion criteria (Online of N-13 ammonia (w20 mCi). One hour after rest 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. Manuscript received January 14, 2014; revised manuscript received February 24, 2014, accepted March 7, 2014. Dorbala et al. 360 JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis perfusion imaging, vasodilator stress was performed Global LV myocardial blood flow (MBF) (ml/g/min) by using a standard infusion of adenosine (n ¼ 9), was quantified at rest and during peak hyperemia dipyridamole (n ¼ 18), or regadenoson (n ¼ 4). At peak by using a previously validated one-compartment hyperemia, a second dose of N-13 ammonia (w20 mCi) model (12) and commercially available software was given intravenously and stress images were (FlowQuant, University of Ottawa Heart Institute, recorded in the same manner. The estimated whole Ottawa, Canada). CFR was computed as the ratio of body effective radiation dose for the rest and stress N- stress MBF to rest MBF and is referred to as CFR* 13 ammonia PET/CT study was 5.4 mSv. Images were throughout this report. CFR was adjusted for rest rate interpreted semiquantitatively and independently by pressure product and computed as the ratio of stress 2 experienced observers (interobserver reliability MBF to normalized rest MBF (rest MBF/rest rate kappa: 0.95) (11) by using a standard 17-segment model pressure product) , 10,000, and is referred to as CFR and a 5-point (0–4) scoring system. The global sum- throughout this report. Coronary vascular resistance, med stress score, summed rest score, and summed the ratio of mean arterial pressure to MBF at rest difference score (the difference between the summed (maximal coronary vascular resistance) and peak hy- stress score and summed rest score) were computed. peremia (minimal coronary vascular resistance) was A summed stress score >0 was considered abnormal. also calculated. Reduced peak stress MBF, reduced CFR, and increased minimal coronary vascular resistance were considered to represent coronary micro- T A B L E 1 Baseline Data on Patient Characteristics and Hemodynamics LVH Group (n ¼ 10) Age, yrs 62.6 12.3 Female 60 Body mass index, kg/m2 33.5 6.4 Amyloid Group (n ¼ 21) 61.7 9.5 38 25.4 3.1 vascular dysfunction. Stress MBF images from one p Value subject in the amyloid group were uninterpretable 0.8 due to poor counts. 0.3 CORONARY ANGIOGRAPHY. Epicardial obstructive <0.0001 CAD was excluded in all subjects with amyloidosis by Hypertension 100 43 0.002 Dyslipidemia 60 33 0.2 Diabetes 30 5 0.05 Chest pain 20 24 0.8 the PET study) reports were reviewed, and only sub- Dyspnea 30 62 0.09 jects with <70% CAD in all coronary arteries were Jaw claudication 0 15 0.6 invited to participate in the study. All except one Buttock claudication 0 5 0.7 NYHA functional class $II subject with amyloidosis underwent coronary angi- 0 45 40 19 coronary angiography. Clinically performed invasive coronary angiography (a median of 164 days before Symptoms <0.0001 Medications Beta-blockers clinical invasive coronary angiography or research CT 0.2 ography to exclude CAD within the 2-year window (1 patient underwent coronary angiography within ACE inhibitors 50 10 0.01 3 years). In 9 subjects with amyloidosis, research CT Diuretics 60 62 0.9 coronary angiography was performed within a me- Aspirin 90 19 <0.0001 Cholesterol medications 60 24 0.05 ECG Limb-lead voltage, mm 9.0 2.5 5.7 1.9 <0.0001 Chest-lead voltage, mm 12.6 5.0 9.4 2.9 0.03 Atrial fibrillation/flutter 14 26 69 16 72 10 Rest systolic BP, mm Hg Rest RPP, beats/min $ mm Hg Rest diastolic BP, mm Hg Stress heart rate, beats/min Stress systolic BP, mm Hg Stress RPP, beats/min $ mm Hg Stress diastolic BP, mm Hg Delta heart rate, beats/min tocols (Online Appendix). ECHOCARDIOGRAPHY. All subjects underwent 2D transthoracic echocardiography within a median of 1 day (interquartile range: 31 to þ24 days) of the PET Hemodynamics Rest heart rate, beats/min dian of 1 day of the PET study with standard pro- 0.5 149 22 114 15 <0.0001 10,298 3,173 8,169 1,358 0.01 74 15 67 9 0.1 study. Digitally acquired echocardiography images in DICOM format with acceptable image quality (n ¼ 27) were uploaded and processed using vendor-independent offline 2D Cardiac Performance Analysis software (TomTec Imaging System, Munich, 81 17 77 15 148 22 101 18 <0.0001 12,094 3,627 7,790 2,302 <0.0001 75 15 58 11 0.001 Throughout this report, we use the term “strain” to 0.06 represent LV strain. 0.04 PRIMARY OUTCOME MEASURES. The primary out- 12 12 Delta systolic BP, mm Hg 0.6 12 Delta RPP, beats/min $ mm Hg 1,795 1,761 4 9.7 13 16 379 14,840 0.5 0.001 Values are mean SD or %. ACE ¼ angiotensin-converting enzyme; BP ¼ blood pressure; ECG ¼ electrocardiography; LVH ¼ left ventricular hypertrophy; NYHA ¼ New York Heart Association; RPP ¼ rate pressure product. Germany) to compute peak LV longitudinal, radial, and circumferential strain values (Online Appendix). come measures of this study were peak stress MBF, CFR, and minimal coronary vascular resistance. STATISTICAL ANALYSIS. The characteristics of the subjects are described as mean SD compared with Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis the Student t test. Nonparametric variables are listed as medians and compared with the MannWhitney 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. RESULTS 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 F I G U R E 1 Rest and Vasodilator Stress N-13 Ammonia PET Images From a Subject With Familial Transthyretin 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) (A) Mildly abnormal N-13 ammonia myocardial perfusion images from a subject with transthyretin amyloidosis. (B) CT coronary angiogram and histopathology images. The images are shown in short axis, horizontal long axis, and vertical long axis projections and demonstrate a reversible perfusion defect in the mid and basal septum despite normal epicardial coronary arteries on CT coronary angiography. The coronary flow reserve was 1.3 (significantly impaired). The low-power photomicrograph of the myocardial biopsy spec- and high-risk scan findings (transient cavity dilation imen (H&E stain) shows near complete loss of myocytes with extensive amyloid deposition. and right ventricular tracer uptake) were observed in The second and third high-power photomicrographs (H&E and sulfated alcian blue stains, the amyloid group (Fig. 1, Online Fig. 1). In the amy- respectively) show a small vessel in which the lumen has been obliterated by vascular loid group, despite no epicardial CAD, 57% of the amyloid deposition. ANT ¼ anterior; CT ¼ computed tomography; H&E ¼ hematoxylin and 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 eosin; HLA ¼ horizontal long axis; INF ¼ inferior; LAD ¼ left anterior descending coronary artery; LAT ¼ lateral; LCX ¼ left circumflex coronary artery; OM ¼ obtuse marginal coronary artery; PET ¼ positron emission tomography; RCA ¼ right coronary artery; SA ¼ short axis; SAB ¼ sulfated Alcian Blue; SEP ¼ septum; VLA ¼ vertical long axis. 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 ¼ 0.03). None of the subjects with LVH had perfusion defects on the N-13 ammonia study. group (rest MBF: 0.59 0.15 ml/g/min vs. 0.88 0.23 ml/g/min [p ¼ 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 CORONARY VASOMOTOR FUNCTION. The mean rest mass than the amyloid group, we normalized the MBF, stress MBF, CFR, and CFR* were significantly rest MBF, stress MBF, and CFR to LV mass as fol- lower in the amyloid group compared with the LVH lows: (MBF or CFR/LV mass) , 100. The values for 361 Dorbala et al. 362 JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis extracellular volume fraction may be expanded and T A B L E 2 Results of Rest and Stress Myocardial Perfusion Imaging LVH Group (n ¼ 10) the functioning myocardial mass as estimated by Amyloid Group (n ¼ 21) p Value Myocardial perfusion imaging Summed stress score, mean rank echocardiography may thus be lower in the amyloid group compared with control subjects (22). Hence, we performed sensitivity analysis assuming a func- 11 18 0.018 Summed difference score, mean rank 12.7 17.6 0.173 tioning myocardial mass of 0.50 and 0.75; stress Summed rest score, mean rank 13.5 17.2 0.306 MBF was significantly lower at an LV mass of 0.75 (trend to lower stress MBF at an LV mass of 0.5), and 62.7 20 49 8 0.01 Rest MBF, ml/g/min 0.88 0.23 0.59 0.15 <0.0001 to 0.004 Rest MBF*, ml/g/min 0.92 0.34 0.73 0.20 0.07 Rest MBF per unit LV mass 0.47 0.19 0.22 0.16 0.001 Stress MBF, ml/g/min 1.85 0.45 0.85 0.29 <0.0001 Stress MBF per unit LV mass 1.00 0.42 0.34 0.29 <0.0001 CFR 2.23 0.88 1.19 0.38 <0.0001 maximal hyperemia (111 40 ml/g/min/mm Hg CFR* 2.20 0.67 1.44 0.36 <0.0001 vs. 70 19 ml/g/min/mm Hg; p ¼ 0.004). All except CFR per unit LV mass† 2.20 0.67 1.20 0.38 <0.0001 one of the subjects in the amyloid group had a signif- Rest LV ejection fraction, % MBF 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 ¼ 0.05) and during Maximal CVR, ml/g/min/mm Hg 117 28 147 41 0.05 70 19 111 40 icantly reduced peak stress MBF of <1.3 ml/g/min. Minimal CVR, ml/g/min/mm Hg 0.004 The patterns of distribution of quantitative rest and Values are n or mean SD. *Unadjusted for rest rate pressure product; all stress values are also unadjusted for rest rate pressure product. †CFR per unit LV mass remained the same for an assumed LV mass of 0.5 or 0.75 of functioning myocardial tissue. CFR ¼ coronary flow reserve; CVR ¼ coronary vascular resistance; LV ¼ left ventricular; MBF ¼ myocardial blood flow; other abbreviations as in Table 1. 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 trans- rest MBF, peak stress MBF, and CFR per unit LV thyretin amyloidosis. mass were significantly lower in the amyloid group compared with the LVH group (Fig. 2), suggesting CARDIAC MORPHOLOGICAL AND FUNCTIONAL PARAMETERS differences independent of LV mass. The myocardial 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 e0 and a 0 (early and late mitral annular tissue relaxation velocities) were significantly lower and the E/e0 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 ¼ 0.003) and left atrial volume indexed to body surface area (40.5 13.4 ml/m 2 vs. 23.2 9.6 ml/m 2; F I G U R E 2 Mean Rest and Stress MBF as Well as CFR per Unit LV Mass in the LVH and Amyloid Groups p ¼ 0.002) were significantly higher in the amyloid group than in the LVH group, suggesting greater chronic left atrial hypertension with or without amy- The rest MBF was higher in the LVH group. Peak stress MBF, CFR (CFR unadjusted)*, and CFR values were significantly lower in the amyloid group than in the LVH group. CFR ¼ coronary flow reserve; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy; MBF ¼ myocardial blood flow; other abbreviations as in Table 1. loid 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), Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis consistent with previous reports of greater mid and basal contractile impairment. ASSOCIATIONS BETWEEN LV STRUCTURE T A B L E 3 Cardiac Morphological Features in the Study Groups LVH Group (n ¼ 10) AND CORONARY VASCULAR FUNCTION. We found that Wall thickness, cm 1.33 0.13 parameters of coronary microvascular function were LV mass, g inversely correlated to increased LV mass (Fig. 4), LV end-diastolic diameter, cm increased diastolic filling pressures, and subclinical LV end-systolic diameter, cm Amyloid Group (n ¼ 20) p Value 1.80 0.36 <0.0001 204 64 335 123 0.004 4.1 1.0 4.1 0.7 0.89 2.8 0.9 2.9 0.6 0.48 59.5 7.0 53.9 12.3 0.19 Peak E velocity, m/s 0.9 0.4 0.8 0.2 0.52 Peak A velocity, m/s 0.9 0.4 2.8 8.2 0.46 stress MBF and CFR were lower in the amyloid group Peak E/A ratio 1.4 1.6 1.6 0.8 0.69 than in the LVH group (Fig. 4). The mean e 0 , a0 , and E/e 0 Average e0 velocity, cm/s 0.08 0.03 0.05 0.01 0.001 ratio were inversely related to stress MBF, CFR, and Average a0 velocity, cm/s 0.05 0.02 <0.0001 minimal coronary vascular resistance (Table 4). Sub- E/e0 ratio 17.98 8.06 0.045 clinical systolic dysfunction (mean LV longitudinal Left atrial size, cm systolic dysfunction. Notably, in the few subjects with an LV mass of <300 g, for any given degree of LV mass, strain) was linearly related to rest MBF, stress MBF, CFR, minimal coronary vascular resistance, and LV LV ejection fraction, % Left atrial volume index, ml/m2 Longitudinal strain, global Circumferential strain mass (Table 4, Fig. 5). In stepwise forward multiple linear regression models (R ¼ 0.87; p < 0.0001) including rest MBF, stress MBF, LV mass, and presence 0.1 0.02 11.99 5.2 3.79 0.55 4.52 0.57 0.003 23.21 9.62 40.48 13.44 0.002 17.78 3.41 23.09 0.5.66 11.50 2.99 <0.0001 25.38 7.17 0.49 Values are mean SD. Echocardiogram was unevaluable for 1 subject in the amyloid group. Abbreviations as in Tables 1 and 2. of amyloid, only LV mass (beta ¼ 0.21; p < 0.0001) and amyloid (beta ¼ 2.3; p ¼ 0.04) were significant inde- impaired coronary microvascular flow in our subjects pendent predictors of impaired longitudinal strain. was almost universal and similar regardless of the MULTIVARIABLE CORRELATES OF MBF, CFR, AND underlying type of amyloid deposits (light chain or CORONARY VASCULAR RESISTANCE. Cardiac amy- transthyretin). Minimal coronary vascular resistance loidosis was associated with worse coronary micro- was markedly increased in the amyloid group; with vascular function independent of LV mass, age, and stress, substantial reductions in stress MBF and subclinical myocardial dysfunction. On separate CFR were found when compared with the hyperten- stepwise forward multiple linear regression analyses sive LVH group. Coronary microvascular dysfunction for rest MBF, stress MBF, CFR, and minimal coronary was associated with several classic imaging features vascular resistance, we adjusted for known con- of cardiac amyloidosis such as increased LV mass founders including age, LV mass, and mean longitu- and myocardial relaxation abnormalities such as dinal strain. In these models (rest MBF model: R ¼ 0.65; p < 0.001; stress MBF model: R ¼ 0.89; p < 0.0001; CFR model: R ¼ 0.75; p < 0.0001 and minimal coronary vascular resistance: R ¼ 0.50; p ¼ 0.009), cardiac amyloidosis was independently associated with lower rest MBF (beta ¼ 0.645; p < 0.0001), stress MBF (beta ¼ 0.801; p < 0.0001), and CFR (beta ¼ 0.665; p < 0.0001) and higher minimal coronary vascular resistance (beta ¼ 0.5; p ¼ 0.009). Older age was an independent predictor of lower CFR (beta ¼ 0.386; p ¼ 0.01), and higher LV mass was an independent predictor of lower stress MBF (beta ¼ 0.001; p ¼ 0.03). DISCUSSION We prospectively studied coronary microvascular function in the absence of epicardial CAD in subjects F I G U R E 3 Longitudinal Strain at the Base, Midventricle, and Apex with documented cardiac amyloidosis. The findings of our study provide novel insights into the morphological correlates of coronary microvascular Mean longitudinal strain at the base, midventricle, and apex in the LVH group compared with the amyloid group. Mean longitudinal strain was significantly reduced in the amyloid dysfunction and underscore the role of microvas- group compared with the LVH group only in the base and cular dysfunction as a probable mechanism for midventricular regions. Abbreviations as in Figure 2. anginal symptoms in these subjects. Of note, 363 364 Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis F I G U R E 4 Relationship Between LV Mass and Rest MBF, Stress MBF, CFR, and Minimal CVR in the Study Groups The relationship between LV mass and rest MBF, stress MBF, CFR, and CVR in the LVH group (green) and the amyloid group (red) is shown. LV mass was lower in the LVH group than in the amyloid group. However, at similar degrees of LV mass, subjects in the amyloid group had lower rest MBF, stress MBF, and CFR and higher minimal CVR. Abbreviations as in Figure 2. CVR ¼ coronary vascular resistance. low mitral annular relaxation velocities, high left correlation between longitudinal dysfunction and atrial pressures (E/e 0 ), and impaired longitudinal microvascular impairment. However, only the pres- myocardial strain. Taken together, these findings ence of amyloidosis and higher LV mass were inde- allow us to postulate that amyloid deposits in the pendent determinants of lower longitudinal strain, interstitium and perivascular regions of the heart suggesting a relation mediated via higher amyloid increase coronary microvascular resistance and LV burden. Koyama and Falk (13) showed that reduced filling pressures leading to coronary microvascular longitudinal strain is associated with worse survival dysfunction and may explain a greater vulnerability in subjects with AL amyloidosis. Indeed, our findings to ischemia and subclinical impairment of LV sys- combined with those of Koyama and Falk suggest that tolic function. coronary microvascular dysfunction from higher am- Longitudinal strain is often severely and disproportionately reduced in patients with cardiac amyloidosis. Because the majority of longitudinal fi- yloid mass may be the mechanistic link between impaired longitudinal strain and worse survival in subjects with AL amyloidosis. bers are subendocardial and this area of the myocar- Increased wall thickness from amyloid deposition dium is most vulnerable to ischemia, it might be in the heart may impede subendocardial perfusion postulated that disturbed microvascular function due to vascular rarefaction and compression. Higher plays a role in longitudinal impairment. Support for LV mass was related to microvascular dysfunction and this hypothesis comes from our finding of univariable to reduced rest MBF and reduced longitudinal strain. Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis T A B L E 4 Univariable Correlations Between Cardiac Morphological Features and Myocardial Blood Flow Parameters in the Study Groups Rest MBF Variable LV mass, g LVED diameter, cm Stress MBF R Value p Value R Value 0.49 0.006 0.60 0.03 0.8 0.005 LVES diameter, cm 0.21 0.3 0.20 LV wall thickness, cm 0.59 0.001 0.66 LV ejection fraction, % 0.25 0.2 p Value 0.001 0.9 0.3 <0.0001 CFR R Value 0.41 CVR p Value 0.03 R Value 0.44 p Value 0.02 0.9 0.05 0.8 0.09 0.6 0.12 0.5 0.47 0.009 0.54 0.0004 0.22 0.3 0.06 0.8 0.05 0.003 0.8 Peak E velocity, m/s 0.23 0.2 0.07 0.7 0.09 0.6 0.007 0.9 Peak A velocity, m/s 0.07 0.8 0.031 0.9 0.03 0.9 0.19 0.4 E/A ratio 0.23 0.3 0.19 0.4 0.07 0.7 0.29 0.1 0.50 0.006 0.67 <0.0001 Mean e0 velocity, cm/s Mean a0 velocity, cm/s 0.24 0.3 0.49 0.008 0.41 0.02 0.004 0.49 0.01 0.55 E/e0 ratio 0.13 0.5 0.47 0.01 0.47 0.01 0.42 0.03 Indexed left atrial volume, ml/m2 0.32 0.11 0.48 0.01 0.31 0.13 0.36 0.07 0.67 <0.0001 0.44 0.03 0.12 0.6 0.56 0.002 Longitudinal strain, global 0.60 0.001 Circumferential strain 0.07 0.7 0.03 0.9 ECG: limb lead voltage, mm 0.43 0.02 0.48 0.009 0.51 0.004 ECG: chest lead voltage, mm 0.27 0.2 0.23 0.2 0.33 0.07 0.48 0.11 0.39 0.08 0.01 0.6 0.04 0.7 ED ¼ end diastolic; ES ¼ end systolic; other abbreviations as in Tables 1 and 2. F I G U R E 5 Relation Between Left Ventricular Longitudinal Strain and Rest, Stress Myocardial Blood Flow, Coronary Flow Reserve and Minimal Coronary Vascular Resistance in the Study Groups The relationship between mean longitudinal LV strain and rest MBF, stress MBF, CFR, minimal CVR, and LV mass in the LVH group (green) and the amyloid group (red) is shown. Abbreviations as in Figures 2 and 4. 365 366 Dorbala et al. JACC: HEART FAILURE VOL. 2, NO. 4, 2014 AUGUST 2014:358–67 Microvascular Dysfunction in Cardiac Amyloidosis Although these findings reinforce the notion that the p values presented were not corrected for multiple higher LV mass contributes to coronary microvascular testing. Further, because of excellent blood pressure dysfunction, rest MBF, stress MBF, and CFR normal- control in the current era, hypertensive LVH without ized to LV mass were also significantly lower in the other end-organ damage is rare, limiting our enroll- amyloid group compared with the LVH group. ment of patients with hypertensive cardiomyopathy This finding, along with the high frequency of vascular to subjects without severe LVH. Therefore, we studied amyloid deposition in a small sample of subjects in our CFR values normalized to LV mass (including assumed study, argues for additional mechanism(s), such as the functioning LV mass of 0.5 and 0.75), and they were role of vascular amyloid deposition (Fig. 1B), presum- significantly lower in the amyloid group. Some of the ably resulting in mechanical impairment of micro- subjects in the amyloid group received specific ther- vascular vasodilation and angina. apy for amyloidosis before study enrollment, poten- Additionally, autonomic dysfunction (either covert tially attenuating the effects of amyloid on MBF. or overt) is prevalent in transthyretin and in However, AL amyloidosis manifesting clinically with abnormal observed between the study groups, suggesting a large vascular autonomic (sympathetic) modulation and effect size and strengthening the study findings. impaired baroreflex function (14). Autonomic dener- Although the precise clinical implications of all our vation limits stress MBF and CFR, primarily via findings are not known, we believe that they may norepinephrine-mediated mechanisms and also by explain some of the functional limitations and poor changes in metabolic autoregulation and endothe- prognosis seen in patients with cardiac amyloidosis. significant differences in MBF were lial dysfunction in diabetic autonomic dysfunction (15–17). Although not specifically evaluated in this CONCLUSIONS study, autonomic dysfunction may also contribute to microvascular dysfunction in amyloidosis. Coronary vasodilation and minimal coronary vascular Coronary microvascular dysfunction has been resistance are significantly impaired in subjects with described in hypertrophic and infiltrative heart dis- cardiac amyloidosis even in the absence of epicardial eases, including hypertensive heart disease, aortic CAD. Our findings suggest that increased myocardial stenosis, hypertrophic cardiomyopathy, and Fabry amyloid burden (mass) correlates with microvascular disease (18). Microvascular dysfunction in these dis- dysfunction. Because increased amyloid mass is as- eases may be mechanistically related to coronary sociated with more widespread cardiac disease, it is microvascular remodeling, rarefaction and interstitial likely that vascular amyloid deposits also play a role. fibrosis (hypertensive heart disease), small-vessel An additional role of autonomic dysfunction in coro- disease, relatively reduced capillary density, in- nary microvascular dysfunction remains speculative creased LV end-diastolic pressures and systolic and needs to be further explored. Coronary micro- compression of the septal coronary arteries (19), or vascular dysfunction in amyloidosis also correlates increased LV mass (20). Some or all of these mecha- with diastolic dysfunction and subclinical systolic nisms may explain the coronary vasomotor dysfunc- dysfunction. Successful hematologic treatment of AL tion in cardiac amyloidosis. The magnitude of the amyloidosis is associated with a decrease in cardiac microvascular dysfunction in our patients with biomarkers before a change in standard echocardio- amyloidosis is not only more severe than those seen graphic features. Thus, further study is required to in hypertensive disease but is also more severe than determine if coronary microvascular function may im- previously reported data in dilated cardiomyopathy prove after specific therapy for cardiac amyloidosis. (21) and Fabry disease (20,22). A C K N O W L E D G M E N T S The STUDY LIMITATIONS. To the best of our knowledge, subjects who participated in this study and their this is the first prospective study to characterize colleagues at the Brigham and Women’s Hospital coronary microvascular function noninvasively in Cardiac Amyloidosis Program and the Boston Uni- carefully selected subjects with cardiac amyloidosis versity Amyloidosis Program. authors thank the and no obstructive epicardial CAD. In this study, detailed characterization of epicardial coronary anat- REPRINT REQUESTS AND CORRESPONDENCE: Dr. omy and microvascular function was performed to Sharmila Dorbala, Noninvasive Cardiovascular Imag- distinguish microvascular dysfunction from flow- ing Program, Heart and Vascular Center, Departments limiting epicardial CAD. 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