Abstract
Objectives
We sought 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 2D echocardiography. Global LV 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 to the LVH group, the amyloid group showed lower rest MBF (0.59 ± 0.15 vs. 0.88 ± 0.23 ml/g/min, P = 0.004), stress MBF (0.85 ± 0.29 vs. 1.85 ± 0.45 vs. ml/min/g, P < 0.0001), CFR (1.19 ± 0.38 vs. 2.23 ± 0.88, P < 0.0001), and higher minimal coronary vascular resistance (111 ± 40 vs. 70 ± 19 mm Hg/mL/g/min, P = 0.004). Of note, almost all amyloid subjects (> 95%) demonstrated significantly reduced peak stress MBF (< 1.3 mL/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis, increased LV 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.
Keywords: Amyloidosis, myocardial blood flow, coronary microvascular function, PET, strain
Introduction
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 individuals 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), in perivascular regions (8), and in the media of intramyocardial coronary vessels (9,10). Amyloidosis is a thus, a prime example of a disorder with the potential to cause coronary microvascular dysfunction via three major mechanisms: structural (amyloid deposition in the vessel wall causing wall thickening and luminal stenosis), extravascular mechanisms (extrinsic compression of the microvasculature from perivascular and interstitial amyloid deposits and decreased diastolic perfusion), as well as functional (autonomic and endothelial dysfunction) mechanisms. 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 would be 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 to subjects with hypertensive LV hypertrophy (LVH). Our secondary aim was to study the morphological and functional correlates of coronary microvascular dysfunction in subjects with cardiac amyloidosis.
Methods
Patient cohort
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 predefined inclusion and exclusion criteria (Supplemental Table 1). Ten subjects with hypertensive left ventricular hypertrophy (LVH) on 2D echocardiography (LV wall thickness > 11 mm) served as controls. Hypertensive LVH subjects did not have documented kidney, peripheral vascular, cerebrovascular 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 with typical features of cardiac involvement on 2D transthoracic echocardiography (N = 11) [e.g., wall thickness measurements of > 11 mm, bright echogenic myocardium and echocardiographic evidence of diastolic dysfunction]. All biopsies stained positive for amyloid with either Sulfated Alcian Blue (SAB) or Congo red stain, and amyloid typing was determined by a battery of stains including immunoperoxidase stain for transthyretin and immunofluorescence stain for immunoglobulins IgG, IgM, IgA, kappa, lambda, protein A and tranthyretin. In equivocal cases, biopsy specimens underwent proteomics evaluation.
This study was approved by the Partners Human Research Committee. All the study subjects were prospectively enrolled, provided written informed consent, and underwent evaluation of coronary microvascular function by a research rest and vasodilator stress N-13 ammonia PET/CT (except for 3 LVH subjects who underwent clinical N-13 ammonia PET/CT). Obstructive epicardial CAD was carefully excluded in all amyloid subjects by coronary angiography as described below. All subjects also underwent a 2D transthoracic echocardiogram study with strain analysis to study cardiac morphology and function. Detailed characterization of the amyloid subtype was available on all amyloid subjects including staining of biopsy specimens.
Positron Emission Tomography
Rest and vasodilator stress N-13 ammonia PET/CT was performed using standard protocols and standard preparation (see Supplemental material). All subjects were studied using a whole body PET-CT scanner (Discovery Lightspeed VCT 64, GE Healthcare, Milwaukee, Wisconsin), following an overnight fast. Rest N-13 ammonia images were obtained for 20 minutes in a 2D list mode following intravenous injection of N-13 ammonia (~20 mCi). One hour after rest perfusion imaging, vasodilator stress was performed 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 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 semi-quantitatively and independently by 2 experienced observers (interobserver reliability kappa 0.95)(11) using a standard 17 segment model and a 5-point (0–4) scoring system. Global summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS, the difference between SSS and SRS) were computed. A SSS of > 0 was considered abnormal.
Global LV myocardial blood flow (ml/g/min, MBF) was quantified at rest and during peak hyperemia using a previously validated one-compartment model (12) and commercially available software (FlowQuant ©). Coronary flow reserve (CFR) was computed as the ratio of the stress MBF to the rest MBF, referred to as CFR* throughout the paper. 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 (RPP)]* 10,000, referred to as CFR throughout this paper. 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.
Coronary Angiography
Epicardial obstructive CAD was excluded in all amyloid subjects by a clinical invasive coronary angiogram or a research CT coronary angiogram. Clinically performed invasive coronary angiogram (a median of 164 days prior to the PET study) reports were reviewed and only subjects with < 70% CAD in all coronary arteries were invited for study participation. All except one amyloid subject had undergone coronary angiography to exclude CAD within the 2 year window (one patient had a coronary angiogram within 3 years). In 9 amyloid subjects, a research CT coronary angiogram was performed within a median of −1 day of the PET study using standard protocols (Supplemental material).
Echocardiography
All subjects underwent 2D transthoracic echocardiography within a median interval −1 day (interquartile range: −31 to + 24 days) from 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 (Supplemental material). Throughout the paper we use the terms strain to represent to LV strain.
Primary outcome measures
The primary outcome measures of this study were peak stress MBF, CFR and minimal coronary vascular resistance.
Statistical analysis
Characteristics of the subjects are described as means and standard deviations and compared using a student t-test. Non parametric variables are listed as medians and compared using Mann-Whitney test. Discrete variables are described as proportions and compared using a Chi square test. Correlations were performed using a Pearsons’s R or non-parametric methods (Spearman’s rho) as indicated. Multi variable 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 step-wise forward selection (probability of F for entry 0.05 and for removal 0.10) was performed to minimize model overfitting.
Results
Baseline patient characteristics and hemodynamics are listed in Table 1. Notably, the amyloid group had a lower body mass than the LVH group and was comprised of 38% women. About half of the amyloid subjects had a history of New York Heart Association ≥ class II heart failure. The amyloid group had complaints of 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 AL amyloid subjects received specific chemotherapy for amyloidosis prior to this study. As expected, mean limb lead and chest lead ECG voltage was lower in the amyloid compared to the LVH group.
Table 1.
Baseline characteristics and hemodynamics
| Variable | LVH (N=10) | Amyloid (N=21) | P-value |
|---|---|---|---|
| Age (years, mean ± SD) | 62.6±12.3 | 61.7±9.5 | 0.8 |
| Female (%) | 60 | 38 | 0.3 |
| Body mass index (BMI, Kg/m2) | 33.5±6.4 | 25.4±3.1 | <0.0001 |
| Hypertension (%) | 100 | 43 | 0.002 |
| Dyslipidemia (%) | 60 | 33 | 0.2 |
| Diabetes (%) | 30 | 5 | 0.05 |
| Symptoms | |||
| Chest pain (%) | 20 | 24 | 0.8 |
| Dyspnea (%) | 30 | 62 | 0.09 |
| Jaw claudication (%) | 0 | 15 | 0.6 |
| Buttock claudication (%) | 0 | 5 | 0.7 |
| New York Heart Association class ≥2 (%) | 0 | 45 | <0.0001 |
| Medications | |||
| Beta-blockers (%) | 40 | 19 | 0.2 |
| ACE inhibitors (%) | 50 | 10 | 0.01 |
| Diuretics (%) | 60 | 62 | 0.9 |
| Aspirin (%) | 90 | 19 | <0.0001 |
| Cholesterol medications (%) | 60 | 24 | 0.05 |
| ECG | |||
| Limb-lead voltage (mm, mean ± SD) | 9.0±2.5 | 5.7±1.9 | <0.0001 |
| Chest-lead voltage (mm, mean ± SD) | 12.6±5.0 | 9.4±2.9 | 0.03 |
| Atrial fibrillation/Flutter (%) | 14 | 26 | |
| Hemodynamics | |||
| Rest heart rate (bpm, mean ± SD) | 69±16 | 72±10 | 0.5 |
| Rest systolic BP (mm Hg, mean ± SD) | 149±22 | 114±15 | <0.0001 |
| Rest RPP (bpm*mm Hg) | 10298±3173 | 8169±1358 | 0.01 |
| Rest diastolic BP (mm Hg, mean ± SD) | 74±15 | 67±9 | 0.1 |
| Stress heart rate (bpm, mean ± SD) | 81±17 | 77±15 | 0.5 |
| Stress systolic BP(mm Hg, mean ± SD) | 148±22 | 101±18 | <0.0001 |
| Stress RPP (bpm*mm Hg) | 12094±3627 | 7790±2302 | <0.0001 |
| Stress diastolic BP (mm Hg, mean ± SD) | 75±15 | 58±11 | 0.001 |
| Delta heart rate (bpm, mean ± SD) | 12±12 | 4±9.7 | 0.06 |
| Delta systolic. BP (mm Hg, mean ± SD) | −0.6±12 | −13±16 | 0.04 |
| Delta RPP (bpm*mm Hg) | 1795±1761 | −379±14840 | 0.001 |
LVH = left ventricular hypertrophy; ACE = angiotensin converting enzyme; BP = blood pressure; RPP = rate pressure product; SD = standard deviation; bpm = beats per minute.
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 (Figure 1 and Supplemental Figure 1). In the amyloid group, despite no epicardial CAD, 57% of the subjects (12/21) demonstrated ischemic scans with three subjects showing severe ischemia (N = 3). High-risk scan features, such as increased right ventricular tracer uptake (62%, 13/21 subjects) and transient cavity dilation of the left ventricle on the post stress images (76%, 16/21 subjects) were frequently seen. The mean transient cavity dilation ratio was significantly higher in the amyloid group compared to the LVH (1.18 ± 0.12 vs. 1.04 ± 0.18, P = 0.03). None of the LVH subjects had perfusion defects on the N-13 ammonia study.
Figure 1. A. Mildly abnormal N-13 ammonia myocardial perfusion imaging in a subject with transthyretin amyloidosis. B. CT coronary angiogram and histopathology images.
Rest and vasodilator stress N-13 ammonia PET images in a familial transthyretin amyloid subject are shown in short axis, horizontal long axis and vertical long axis projections. The images show a reversible perfusion defect in the mid and basal septum, despite normal epicardial coronary arteries on CT coronary angiography. His coronary flow reserve was 1.3 (significantly impaired). This subjects’ myocardial biopsy low power photomicrograph (H&E stain) demonstrates near complete loss of myocytes with extensive amyloid deposition. The second and third high power photomicrographs (H&E and SAB stains, respectively) show a small vessel whose lumen has been obliterated by vascular amyloid deposition.
Coronary vasomotor function
The mean rest MBF, stress MBF, CFR and CFR* were significantly lower in the amyloid compared to the LVH group (Rest MBF: 0.59 ± 0.15 vs. 0.88 ± 0.23 ml/g/min, P = 0.004, stress MBF: 0.85 ± 0.29 vs. 1.85 ± 0.45 vs. ml/min/g, 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). As the LVH group showed significantly lower LV mass than the amyloid group, we normalized the rest MBF, stress MBF and CFR to LV mass as (MBF or CFR/ LV mass)*100. Rest MBF, peak stress MBF and CFR per unit LV mass was significantly lower in the amyloid compared to the LVH group (Figure 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 compared to control subjects (22). Hence, we performed sensitivity analysis assuming a functioning myocardial mass of 0.50 and 0.75; the stress MBF was significantly lower at LV mass 0.75 (trend to lower stress MBF at LV mass 0.5) and CFR values remain significantly lower in the amyloid subjects. Coronary vascular resistance (CVR) was significantly higher in amyloid compared to the LVH group, at rest (147±41 vs. 117 ± 28 mm Hg/mL/g/min, P = 0.05) and during maximal hyperemia (111 ± 40 vs. 70 ± 19 mm Hg/mL/g/min, P = 0.004). All except one of the amyloid subjects demonstrated a significantly reduced peak stress MBF of < 1.3 mL/g/min. The patterns of distribution of the quantitative rest and stress MBF were significantly different with much lower stress MBF values in the amyloid compared to the LVH group (Supplemental Figure 2). Finally, rest MBF, stress MBF, CFR and minimal coronary vascular resistance did not differ in subjects with light chain compared to subjects with transthyretin amyloidosis.
Table 2.
Rest and stress myocardial perfusion imaging results
| Variable | LVH (N=10) | Amyloid (N=21) | P-value |
|---|---|---|---|
| Myocardial perfusion imaging | |||
| Summed stress score (mean rank) | 11 | 18 | 0.018 |
| Summed difference score (mean rank) | 12.7 | 17.6 | 0.173 |
| Summed rest score (mean rank) | 13.5 | 17.2 | 0.306 |
| Rest left ventricular ejection fraction (%) | 62.7±20 | 49±8 | .01 |
| Myocardial Blood Flow (MBF) | |||
| Rest MBF (mL/g/min) | 0.88±0.23 | 0.59±0.15 | <0.0001 |
| 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 | 2.24±0.88 | 1.20±0.38 | <0.0001 |
| CFR* | 2.20±0.67 | 1.44±0.36 | <0.0001 |
| CFR per unit LV massǂ | 2.20±0.67 | 1.20±0.38 | <0.0001 |
| Maximal CVR (mL/g/min/mm Hg) | 117±28 | 147±41 | 0.05 |
| Minimal CVR (mL/g/min/mm Hg) | 70±19 | 111±40 | 0.004 |
LVH = left ventricular hypertrophy; MBF = myocardial blood flow; CFR = coronary flow reserve; CVR = coronary vascular resistance;
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.
Figure 2. Mean rest and stress myocardial blood flow, coronary flow reserve per unit left ventricular mass in the LVH and the amyloid groups.
The rest myocardial blood flow (MBF) was higher in the left ventricular hypertrophy (LVH) group. Peak stress MBF, coronary flow reserve (CFR-unadjusted)* and CFR were significantly lower in the amyloid compared to the LVH groups.
Cardiac morphological and functional parameters in the study groups
Morphologically, despite lower voltage QRS complexes on ECG, the mean LV wall thickness and mass were higher in the amyloid compared to the LVH group (Table 3), consistent with amyloid deposition in the LV myocardium. We also reviewed the available myocardial biopsy specimens in 8 amyloid subjects. Microscopically, while, one specimen was inadequate, perivascular amyloid deposits (Figure 1B) were found in 5/8 subjects with the amyloid burden ranging 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 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 vs.3.8 ± 0.6 cm, P = 0.003) and left atrial volume indexed to body surface area (40.5 ± 13.4 vs. 23.2 ± 9.6 mL/m2, P = 0.002) were significantly higher in the amyloid compared to the LVH group, suggesting either 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 compared to the LVH group (−11.50 ± 2.99 vs. −17.78 ± 3.41, P < 0.0001), particularly at the base and the mid ventricular regions (Figure 3), consistent with previous reports of greater mid and basal contractile impairment.
Table 3.
Cardiac morphological features in the study groups
| Variable | LVH (N=10) | Amyloid (N=20) | p-Value |
|---|---|---|---|
| Wall thickness (cm, mean ± SD) | 1.33±0.13 | 1.80±0.36 | <0.0001 |
| Left ventricular mass (g, mean ± SD) | 204±64 | 335±123 | 0.004 |
| Left ventricular end-diastolic diameter (cm, mean ± SD) | 4.1±1.0 | 4.1±0.7 | 0.89 |
| Left ventricular end-systolic diameter (cm, mean ± SD) | 2.8±0.9 | 2.9±0.6 | 0.48 |
| Left ventricular ejection fraction (%) | 59.5±7.0 | 53.9±12.3 | 0.19 |
| Peak E velocity (m/sec, mean ± SD) | 0.9±0.4 | 0.8±0.2 | 0.52 |
| Peak A velocity (m/sec, mean ± SD) | 0.9±0.4 | 2.8±8.2 | 0.46 |
| Peak E/A ratio (mean ± SD) | 1.4±1.6 | 1.6±0.8 | 0.69 |
| Average e′ velocity (cm, sec, mean ± SD) | 0.08±0.03 | 0.05±0.01 | 0.001 |
| Average a′ velocity (cm, sec, mean ± SD) | 0.1±0.02 | 0.05±0.02 | <0.0001 |
| E/e′ ratio (mean ± SD) | 11.99±5.2 | 17.98±8.06 | 0.045 |
| Left atrial size (cm, mean ± SD) | 3.79±0.55 | 4.52±0.57 | 0.003 |
| Left atrial volume index (mL/m2, mean ± SD) | 23.21±9.62 | 40.48±13.44 | 0.002 |
| Longitudinal strain (global, mean ± SD) | −17.78±3.41 | −11.50±2.99 | <0.0001 |
| Circumferential strain (mean ± SD) | −23.09±0.5.66 | −25.38±7.17 | 0.49 |
LVH = left ventricular hypertrophy; SD = standard deviation. One amyloid subject echo was unevaluable.
Figure 3. Longitudinal strain at the base, mid ventricle and apex.
Mean longitudinal strain at the base, mid ventricle and the apex in the left ventricular hypertrophy (LVH) compared to the amyloid groups. Mean longitudinal strain was significantly reduced in the amyloid compared to the LVH group only in the base and mid ventricular regions.
Associations between LV structure and coronary vascular function
We found that parameters of coronary microvascular function were inversely correlated to increased LV mass (Figure 4), increased diastolic filling pressures and subclinical systolic dysfunction. Notably, in the few subjects with LV mass of < 300 g. for any given degree of LV mass, stress MBF and CFR were lower in the amyloid compared to the LVH group (Figure 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 and Figure 5). In step wise 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 (B = 0.21, P < 0.0001) and amyloid (B = 2.3, P = 0.04) were significant independent predictors of impaired longitudinal strain.
Figure 4. Relation between left ventricular mass and rest, stress myocardial blood flow, coronary flow reserve and minimal coronary vascular resistance in the study groups.
The relation between left ventricular (LV) mass and rest, stress myocardial blood flow (MBF), coronary flow reserve (CFR) and coronary vascular resistance in left ventricular hypertrophy (LVH, blue) and amyloid subjects (red). LV mass was lower in the LVH subjects compared to the amyloid subjects. But, at similar degrees of LV mass, amyloid subjects demonstrate lower rest, stress MBF and lower CFR and higher minimal coronary vascular resistance.
Table 4.
Univariable correlations between cardiac morphological features and myocardial blood flow parameters in the study groups
| Variable | Rest myocardial blood flow | Stress myocardial blood flow | Coronary flow reserve | Coronary vascular resistance | ||||
|---|---|---|---|---|---|---|---|---|
| R- value | p- value | R- value | p-value | R- value | p-value | R- value | p- value | |
| LV mass (g) | −0.49 | 0.006 | −0.60 | 0.001 | −0.41 | 0.03 | 0.44 | 0.02 |
| LVED diameter (cm) | 0.03 | 0.8 | 0.005 | 0.9 | 0.0004 | 0.9 | −0.05 | 0.8 |
| LVES diameter (cm) | −0.21 | 0.3 | −0.20 | 0.3 | −0.09 | 0.6 | 0.12 | 0.5 |
| LV wall thickness (cm) | −0.59 | 0.001 | −0.66 | <0.0001 | −0.47 | 0.009 | 0.54 | 0.003 |
| LV ejection fraction (%) | 0.25 | 0.2 | 0.22 | 0.3 | 0.06 | 0.8 | −0.05 | 0.8 |
| Peak E velocity (m/sec) | 0.23 | 0.2 | −0.07 | 0.7 | −0.09 | 0.6 | −0.007 | 0.9 |
| Peak A velocity (m/sec) | −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 | 0.24 | 0.3 |
| Mean e′ velocity (cm/sec) | 0.29 | 0.1 | 0.50 | 0.006 | 0.49 | 0.008 | −0.41 | 0.02 |
| Mean a′ velocity (cm/sec) | 0.56 | 0.002 | 0.67 | <0.0001 | 0.49 | 0.01 | −0.55 | 0.004 |
| E/e′ 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 |
| Longitudinal strain (global) | −0.60 | 0.001 | −0.67 | <0.0001 | −0.44 | 0.03 | 0.48 | 0.01 |
| Circumferential strain | −0.07 | 0.7 | 0.03 | 0.9 | 0.12 | 0.6 | −0.11 | 0.6 |
| ECG: limb lead voltage (mm) | 0.43 | 0.02 | 0.48 | 0.009 | 0.51 | 0.004 | 0.39 | 0.04 |
| ECG: chest lead voltage (mm) | 0.27 | 0.2 | 0.23 | 0.2 | 0.33 | 0.07 | −0.08 | 0.7 |
LV = LV. ED = end diastolic; ESD = end systolic; ECG = electrocardiogram;
Figure 5.
Relation between mean longitudinal left ventricular (LV) strain and rest and stress myocardial blood flow (MBF), coronary flow reserve (CFR), minimal coronary vascular resistance and LV mass in the LVH (blue) and amyloid (red) subjects.
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 step-wise 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, model R = 0.50, P = 0.009 cardiac amyloidosis was independently associated with lower rest MBF (B= −0.32, P < 0.0001), lower stress MBF (−0.67, P < 0.0001), lower CFR (B =−1.1, P <0.0001) and a higher minimal coronary vascular resistance B=41.38, P =0.009). Older age was an independent predictor of lower CFR (B =7minus;0.03, P = 0.01) and higher LV mass was an independent predictor of lower stress MBF (B =−0.001, P = 0.03).
Discussion
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 underlying type of amyloid deposits (light chain or transthyretin). The minimal coronary vascular resistance was markedly increased in the amyloid group and, with stress, substantial reductions in stress MBF and CFR were found when compared to the hypertensive LVH group. Coronary microvascular dysfunction was associated with several classic imaging features of cardiac amyloidosis such as increased LV mass and myocardial relation abnormalities such as low mitral annular relaxation velocities, high left atrial pressures (E/e′), as well as 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 cardiac amyloidosis. As the majority of longitudinal fibers are subendocardial and as 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 presence of amyloidosis and higher LV mass were independent determinant of lower longitudinal strain, suggesting a relation mediated via higher amyloid burden. Koyama et al (13) demonstrated that reduced longitudinal strain is associated with worse survival in subjects with AL amyloidosis. Indeed, our findings combined with the findings of Koyama et al 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, as well as to reduced rest MBF and reduced longitudinal strain. Although, these findings reinforce the notion that higher LV mass contributes to coronary microvascular dysfunction, rest, stress MBF and CFR normalized to LV mass were significantly lower in amyloid compared to 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 (Figure 1B), presumably resulting in mechanical impairment of microvascular vasodilation and angina.
Additionally, autonomic dysfunction (either covert or overt) is prevalent in transthyretin and in light chain 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’s 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 amyloid patients is not only more severe than those seen in hypertensive disease, but are also more severe to previously reported data in dilated cardiomyopathy (21) and in Fabry’s disease. (20,22)
Strengths and Limitations
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, due to 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, due to excellent blood pressure control in the current era, hypertensive LVH without other end organ damage is rare limiting our enrollment of 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 amyloid subjects received specific therapy for amyloidosis prior to study enrollment, potentially attenuating the effects of amyloid on MBF. Yet, significant differences in MBF were observed between the study groups, suggesting a large effect size and making the study findings stronger. While 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.
Conclusions
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. As 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 prior to change in standard echocardiographic features. Thus further study is also required to determine if coronary microvascular function may improve following specific therapy for cardiac amyloidosis.
Supplementary Material
Acknowledgments
We are indebted to the study subjects who participated in this study. We are appreciative of the research support for this study from Amyloid foundation, American Society of Nuclear Cardiology Foundation and NIH-NHLBI grant: K23HL092299. We are grateful to our colleagues at the Brigham and Women’s Hospital Cardiac Amyloidosis Program and the Boston University Amyloidosis Program.
This study was funded by the Amyloid Foundation, the American Society of Nuclear Cardiology Foundation, the National Institutes of Health (NHLBI), and in part by the Demarest Lloyd, Jr. Foundation (Falk).
Abbreviations list
- CAD
Coronary artery disease
- CFR
Coronary flow reserve
- LVH
Left ventricular hypertrophy
- PET/CT
Positron emission tomography/computed tomography
- MBF
Myocardial blood flow
- LV
Left ventricular
Footnotes
Financial Disclosures: Dorbala: Research grant Astellas Global Pharma Development; Di Carli: Research grant from Gilead Sciences.
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