European Heart Journal Advance Access published online on April 12, 2007
European Heart Journal, doi:10.1093/eurheartj/ehm066
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Vascular abnormalities in primary amyloidosis
1 Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
2 Division of Hematology, Mayo Clinic, Rochester, MN, USA
3 Division of Biostatistics, Mayo Clinic, Rochester, MN, USA
Received 31 July 2006; revised 26 February 2007; accepted 8 March 2007.
* Corresponding author: Johns Hopkins University, 600 North Wolfe Street, Carnegie 568, Baltimore, MD, USA. Tel: +1 410 955 6173; fax: +1 410 955 1509. E-mail address: Tabraha3{at}jhmi.edu
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Abstract |
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Aims: Primary amyloidosis (AL) is a systemic disease; however, there is limited information regarding the presence and character of vascular abnormalities.
Methods and results: Validated ultrasound techniques were used to prospectively determine carotid artery intimal–medial thickness (IMT) and brachial artery flow-mediated dilatation (FMD) in 59 consecutive AL patients and 17 age-similar, healthy, asymptomatic volunteers (CON). Carotid IMT was increased in AL when compared with CON (0.07 ± 0.02 vs. 0.04 ± 0.01 mm, P < 0.01). Similarly, brachial artery FMD was significantly lower in AL when compared with CON subjects (3 ± 7 vs. 12 ± 8%, P < 0.01). Multivariable analysis revealed that AL was associated with larger IMT and lower FMD after controlling for several confounding variables. However, within AL cases, there was not a significant association of cardiac vs. non-cardiac involvement with IMT or FMD (P = 0.1 and 0.2, respectively).
Conclusion: AL is associated with abnormal vascular morphology and endothelial dysfunction. Vascular abnormalities do not appear to be related to echocardiographic evidence of cardiac involvement.
Key Words: Amyloidosis • Intimal–medial thickness • Flow-mediated arterial dilatation • Endothelial function
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Introduction |
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AL (also known as primary) amyloidosis is a systemic disease that is characterized by the deposition of amyloid fibrils in various organs including the vasculature.1 Vascular deposition of amyloid may alter vascular function, which in turn may affect organ function and underlie some of the clinical manifestations of AL. Sporadic case reports and small case series studies have implicated vascular amyloid deposition in various organ systems as the potential mechanism underlying many unique manifestations of AL such as angina (in the absence of coronary artery stenosis), myopathy, neuropathy, and jaw claudication.2–8 Autopsy studies of AL patients have documented macro- and microvascular amyloid deposition in multiple organs.5,7–12 A retrospective study of bone marrow specimens of AL patients demonstrated AL deposition in blood vessel walls.13 However, a systematic clinical investigation of vascular function in AL is lacking. Clinical recognition of vascular dysfunction may provide an explanation for seemingly unrelated symptoms in AL patients.
Vascular amyloid deposition could manifest as a morphologic abnormality such as a detectable increase in vessel wall thickness or as a functional abnormality such as abnormal endothelial function. Owing to accessibility and ease of measurement, carotid artery intimal–medial thickness (IMT) is well validated and often used to determine vascular morphology.14,15 Likewise, brachial artery flow-mediated dilatation (FMD) is well validated and widely used to evaluate vascular endothelial function.16–18 Both IMT and FMD measurements are performed using high-resolution ultrasound, a well tolerated, non-invasive, and a low-risk procedure.
We prospectively studied large artery phenotype and endothelium-dependent endothelial function in AL patients.
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Methods |
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Subjects
The protocol was approved by the Institutional Review Board. From May 2002 to July 2003, we enrolled consecutive newly diagnosed biopsy-proven (fat and/or bone marrow biopsy positive for Congo red birefringence and monoclonal protein in serum/urine) AL amyloidosis patients. None of the AL patients had received therapy for the haematologic disease prior to enrolment. Cardiac involvement was defined using previously published criteria by conventional echocardiography based on morphologic and functional findings such as biventricular thickening with reduced cavity size, severe diastolic dysfunction (restrictive filling pattern), valvular thickening, and spiculated appearance of myocardium.1,19 During the period of the study, we also enrolled 17 age-similar, asymptomatic, healthy volunteers from the community recruited by a campus-wide advertisement. The control subjects (CON) had no history of hypertension, diabetes mellitus, hypercholesterolaemia, significant coronary artery or valvular heart disease, or tobacco use. All CON were submitted to an echocardiographic evaluation as well as a vascular ultrasound assessment. Only subjects who had a normal echo-Doppler examination, ejection fraction >0.55, normal regional wall motion, normal diastolic function, and normal ventricular wall thickness (<12 mm) were considered for the CON group (n = 20).
History of co-morbidities in all subjects was obtained from their electronic medical records and by personal interview. Renal failure and heart failure were considered present if noted in the diagnosis list of the patient. Renal failure was also noted if serum creatinine was >2.0 mg/dL. Dyslipidaemia was defined as serum total cholesterol or serum triglyceride >230 mg/dL. Data were excluded from six AL patients and three controls because of suboptimal image quality.
Carotid ultrasound
All B-mode ultrasound of the carotid artery were performed by an experienced observer, blinded to clinical and laboratory data, using a Vivid 7 ultrasound machine equipped with a 10 MHz linear-array transducer (GE Medical Systems, Milwaukee, WI, USA). The subject lay supine with the neck extended and the chin turned contralateral to the side being examined. The protocol12 involved scanning the right carotid artery in the transverse and longitudinal planes. The artery was imaged at a point 2 cm proximal to the bifurcation of the common carotid artery, from a longitudinal plane scan that showed the intimal–medial boundary most clearly. Using digitized magnified images, two cursors were positioned on the intimal–medial boundary of the near and far arterial wall, at three different points 
1 mm apart. The three values were averaged to yield a final value and measurements.
Brachial ultrasound
A single experienced investigator, blinded to clinical and laboratory data, performed all studies. The brachial artery was imaged using the same ultrasound equipment as that used for carotid imaging. All subjects were fasting for at least 8–12 h before the study and imaged in the morning, in a quiet, dimly lit, temperature-controlled room, in the supine position. All drugs, caffeine, and tobacco were prohibited on the morning of the study. A continuous three-lead electrocardiogram was recorded for timing diastole. A non-tortuous segment of the brachial artery, above the antecubital fossa, was identified. Baseline imaging before cuff inflation was performed by scanning the artery in the longitudinal plane.16,20 Depth and gain settings were optimized to maximize lumen–arterial wall interface, images were magnified using the zoom function of the ultrasound machine, and all machine operating parameters kept constant during the study.
When a satisfactory transducer position was found, the skin was marked and the arm remained in the same position throughout the study. A pneumatic blood pressure cuff was placed around the arm below the elbow and inflated to 50 mmHg above the systolic pressure for 5 min. Longitudinal axis scan of the artery was performed starting just prior to cuff release and continued up to 2 min after release. Endothelium-dependent FMD was assessed by calculation of the change in brachial artery diameter between baseline and hyperaemic state (1 min after cuff release). For each state (baseline and after cuff release), at least five brachial artery diameter measurements were obtained (and averaged to yield a final value) from the longitudinal image by identifying the lumen–intimal boundary with the electronic calipers on the ultrasound machine.
Statistics
Descriptive statistics are reported as mean and standard deviation or by frequency per cents. Two-group comparisons and univariate associations were assessed by using the rank sum or 
2 test or by Spearman rank correlations. Adjusted comparisons and associations were analysed using multiple linear regression, after transformations, if necessary, to achieve approximate normality. In order to synthesize the cardiac risk factors (apart from age), a score was created. This score summed up 1 point each for diagnosed hypertension or high systolic blood pressure (>140 mmHg), coronary artery disease, diabetes mellitus or high fasting glucose (110 mg/dL), dyslipidaemia or high cholesterol (>230 mg/dL), and male gender. This score was included as a candidate variable for predicting IMT and FMD in the AL cardiac and non-cardiac patients. Owing to low power, an 
= 0.10 was used. Variables significantly univariately correlated with IMT or FMD at = 0.10 were included in the multivariable model. AL status (case vs. control) and cardiac involvement status were also included in this model.
Interobserver variability was assessed by two independent, blinded observers in 10 randomly selected patients. Intra-observer variability was performed by one observer remeasuring the same 10 patients after 24 h. The interobserver variability was expressed using interclass correlation coefficient (ICC).21,22
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Results |
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We approached 97 consecutive AL patients for enrolment. Of these, 32 were excluded for logistic reasons (unable to stay for vascular study and unable to schedule vascular study before treatment regimen initiated) and analysable quality images were not obtained in six subjects. Complete data sets were, therefore, available in 59 AL and 17 CON subjects. Cardiac involvement was present in 40 patients (CAL) and absent in 19 patients (NCAL). Endomyocardial biopsy tissue was available and positive for CAL in 15 AL patients including four patients with non-diagnostic echocardiograms. The remaining 44 AL patients had clinical and histopathological evidence of AL in the kidney, liver, pancreas, and lungs. All AL patients were symptomatic. Of the 59 patients analysed, 22 presented with dyspnoea, 11 with pedal oedema, and the rest with vague symptoms such as fatigue, respiratory symptoms, and reduced urinary output. There were 33 (47%) patients with signs of heart failure (as diagnosed by a physician) in the CAL and none in the NCAL and CON groups. Electrocardiogram revealed ‘p’ waves in all and a prolonged PR interval (175 ± 42 ms) in 14 AL patients. All AL patients had ‘A’ waves on mitral inflow and pulmonary vein Doppler signal by conventional echocardiography.
Comparison of amyloidosis with controls
Clinical characteristics and medications of AL and CON are summarized in Table 1. None of the subjects had a history of peripheral vascular disease, smoking, or hormone replacement. All AL patients were recently diagnosed and, except for two patients, had not received any prior chemotherapy.
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Carotid IMT (Figure 1A) was significantly higher in AL when compared with CON subjects (0.07 ± 0.02 vs. 0.04 ± 0.01 mm, P < 0.01). Brachial artery FMD (Figure 1B) was significantly lower (3 ± 7 vs. 12 ± 8%, P < 0.01) in AL when compared with CON subjects.
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Comparisons of ‘pure’ cases with controls
As the control subjects had been specifically selected not to have hypertension, dyslipidaemia, coronary artery disease, diabetes mellitus, or renal failure, as well as not having AL, it is possible that some of the observed case–control differences could be due to these other underlying factors. To address this possibility, the group comparisons were redone, and adjustment models constructed using only those cases which were comparable to controls, specifically those 37 of 59 cases who had none of the above co-morbidities.
When group comparisons were done comparing the 37 AL cases without concurrent conditions and the 17 controls, carotid IMT was significantly higher in AL cases when compared with control subjects (0.07 ± 0.02 vs. 0.04 ± 0.01 mm, P < 0.01). Brachial artery FMD was significantly lower (3 ± 8 vs. 12 ± 8%, P < 0.01) in AL cases when compared with control subjects.
To address possible confounding with other factors, simple linear regression was first used to find the variables individually associated with carotid IMT and brachial FMD. The covariates investigated included age, gender, body surface area, systolic and diastolic blood pressures, urine albumin, heart failure symptoms (CHF), the inverse of serum creatinine, log cholesterol, log (aspartate amino transferase + 10), log serum triglyceride, and log glucose. Carotid IMT was increased in the presence of increased log serum triglyceride, in the presence of CHF, and significantly associated with AL status. A multivariable model with all three of these individually associated variables was constructed, and AL case–control status but not CHF or log serum triglyceride was associated with carotid IMT. An AL diagnosis was associated with an increase of 0.024 mm (P < 0.01) in carotid IMT, after controlling for CHF status and serum triglyceride levels. Decreased brachial FMD was associated with increased systolic and diastolic blood pressures and with AL status. A multivariable model with all three of these variables was constructed. Only AL case–control status was associated with brachial FMD, after adjusting for systolic or diastolic blood pressure or their combination. An AL diagnosis was associated with an 8% decrease in brachial FMD (P < 0.01) after controlling for blood pressure.
Comparison of amyloid with cardiac involvement (CAL) and no cardiac involvement (NCAL)
Clinical characteristics and medications were similar between NCAL and CAL subjects (Table 1). Carotid IMT was increased on average in AL patients without cardiac involvement when compared with those with cardiac involvement (0.07 ± 0.01 vs. 0.06 ± 0.02 mm, respectively, P = 0.03), but the variability of IMT was much greater among the CAL patients than among the NCAL patients. Brachial FMD was similar in the two groups (1 ± 8 vs. 4 ± 7%, P = 0.08). There was a significant inverse correlation between carotid IMT and brachial FMD within the AL cases (Figure 2; r = –0.37, P < 0.01).
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Adjusted comparison of intimal–medial thickness and flow-mediated dilatation in amyloid with cardiac involvement and cardiac involvement patients
Simple linear regression was first used to find the variables individually associated with carotid IMT and brachial FMD in the AL cases. Increased carotid IMT was associated with increased age and decreased serum creatinine (increased 1/serum creatinine level) and with NCAL. A multivariable model with all three of these variables was constructed. In this model, only age and the inverse of serum creatinine were independently associated with carotid IMT and not with cardiac involvement (P = 0.14).
Decreased brachial FMD was individually associated with increased serum creatinine (a decrease in 1/serum creatinine level). In a multivariable model of this variable plus cardiac involvement, only serum creatinine was independently associated with brachial FMD. Cardiac involvement was not independently associated with brachial FMD (P = 0.23).
Variability of vascular assessments
Interobserver (ICC = 0.94, mean difference of 1.5 ± 4) and intra-observer (ICC = 0.96, mean difference of 1.0 ± 1.0) agreements for FMD parameters were high. The interobserver (ICC = 0.87, mean difference of 0.02 ± 0.02 cm) and intra-observer (ICC = 0.85, mean difference of 0.01 ± 0.01 cm) variabilities for IMT were similarly high.
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Discussion |
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To the best of our knowledge, this is the first systematic evaluation of clinical vascular abnormalities in a relatively large population of AL patients. Multivariable analysis revealed that carotid IMT was increased and brachial artery FMD was reduced in AL suggesting abnormal vascular morphology and endothelium-dependent endothelial dysfunction, respectively. Abnormalities in IMT and FMD were not related to the presence/absence of cardiac involvement in AL. Vascular abnormalities appear to be an under-recognized phenotype in AL.
Vascular function and the role of the endothelium are being increasingly examined as a potential contributor to morbidity in various pathological conditions including atherosclerosis, hypertension, and diabetes.23–27 In coronary artery disease, endothelial dysfunction in the absence of significant anatomic coronary stenosis is often as symptomatic as in the setting of haemodynamically significant coronary artery stenosis.
Autopsy studies demonstrate amyloid infiltration of the small intramural coronary arteries in 88–90% of AL patients.28,29 Coronary artery endothelial dysfunction may be responsible for angina in the absence of significant coronary stenosis chest pain in AL patients.2 Likewise, endothelial dysfunction has been demonstrated in the cutaneous microcirculation of patients with amyloid neuropathy.3 Organ systems whose function may potentially be adversely influenced by vascular abnormalities, independent of tissue amyloid deposition, include the heart (angina and myocardial ischaemia in the absence of significant epicardial coronary stenosis), kidney (proteinuria and azotemia), gastrointestinal tract (malabsorption, abnormal gastric motility, and bowel ischaemia), muscle (claudication and motor weakness), and the nervous system (neuropathy). A literature search did not reveal a systematic evaluation of peripheral vascular function in AL other than the small studies mentioned earlier.2,3 Al Suwaidi et al. reported on five AL patients who presented with angina and had normal coronaries on angiography. Intracoronary infusions of acetycholine and adenosine suggested abnormal endothelial-dependent and non-endothelial-dependent endothelial function, respectively, in all five subjects. Myocardial biopsies were available in two subjects and demonstrated amyloid deposition in the media of the intramyocardial vessels. Berghoff et al. studied seven patients with AL, of whom one had evidence of peripheral neuropathy and three had evidence of autonomic neuropathy. Cutaneous blood flow measurements during acetycholine iontophoresis and sodium nitroprusside application suggested endothelial-dependent and non-endothelial-dependent endothelial dysfunction, respectively, in the cutaneous microcirculation of the upper extremity. The authors concluded that endothelial dysfunction precedes the appearance of amyloid neuropathy.
We prospectively examined large artery phenotype and endothelium-dependent endothelial function in consecutive patients reporting to our institution's Amyloidosis Clinic. Well-validated, non-invasive, ultrasound-based techniques were used to measure vascular thickness (IMT) and endothelial function (FMD).
An increase in the carotid artery IMT, measured by ultrasound, is thought to be an early pathological change in atherosclerosis and has been validated in several clinical trials.14,15 Similarly, brachial artery FMD has been used to assess endothelial function in a variety of pathologies.16–18,30 Both techniques have emerged as useful tools in assessing vascular function.
Our data clearly demonstrate abnormal vascular structure and function in AL. The association between AL and vascular abnormalities (IMT and FMD) persisted even after controlling for factors known to influence these variables such as age, gender, blood pressure, body surface area, fasting plasma glucose, serum cholesterol, serum triglycerides, and serum creatinine.
The extent of abnormalities in IMT, but not in FMD, appeared to be related to non-cardiac involvement in simple linear regression analysis. However, after controlling for other univariately associated variables, no effect of cardiac involvement on IMT was seen in the AL patients. Thus, our data also suggest that the vascular phenotype is separate from the cardiac phenotype (as recognized by echocardiography criteria).
Potential explanations for the lack of association between the vascular phenotype and the cardiac phenotype in AL include the following: (i) cardiomyocytes and vascular cells may differ in their susceptibility to AL protein/light chains or to oxidant stress and consequent alterations in intracellular calcium handling,31 (ii) cardiac involvement may occur later in the disease process when compared with other organs and the vasculature, and (iii) recent evidence suggests that the usage of the light chain variable region gene in AL determines the organs preferentially affected by amyloid deposition (organ tropism).32 It is therefore possible that certain light chain subtypes preferentially target non-cardiac organs and vessels.
Our data demonstrate an inverse relationship between IMT and the magnitude of FMD abnormality, which suggests that vascular deposition of amyloid protein as reflected by IMT may partially underlie the development of endothelial dysfunction (denoted by FMD).
As our study population was also at high risk for atherosclerosis, it was possible that the observed vascular changes were secondary to atherosclerosis alone. Therefore, we compared the IMT and FMD in a subgroup of AL patients without any co-morbidities to the controls.
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Limitations |
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The sample size of the control group is relatively small because of the difficulty in finding subjects with no co-morbidities and a normal echocardiogram. However, significant differences were demonstrated between AL and control subjects. Echocardiographic criteria were used to define cardiac involvement in AL, and endomyocardial biopsy tissue was available in a minority of AL patients. However, this is a standard clinical practice in most centres managing large volumes of amyloidosis patients. Nitroglycerin-mediated FMD was not measured and thus we did not assess whether AL was also associated with endothelium-independent mechanisms of endothelial dysfunction.
In summary, our prospective study demonstrates altered vascular structure and endothelial function in AL. The implications of vascular involvement in AL on organ function and clinical outcomes will need to be determined.
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Acknowledgement |
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This study was supported by a National Institute of Health grant (HL076513-02).
Conflict of interest: none declared.
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References |
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