doi: 10.1161/CIRCHEARTFAILURE.108.769729
Original Articles |
Angina in Fabry Disease Reflects Coronary Small Vessel Disease
From the Heart and Great Vessels "Attilio Reale" Department (C.C., G.T., E.M., G.C., C.G., A.F.) and Pathology and Experimental Medicine Department (E.M., M.A.R.), La Sapienza University, Rome, Italy; Molecular and Cellular Cardiology Laboratory, National Institute for Infectious Disease "L. Spallanzani" (C.C., A.F.), Rome, Italy; and IRCCS San Raffaele La Pisana (C.C., M.A.R.), Rome, Italy.
Correspondence to Andrea Frustaci, MD, Heart and Great Vessels "Attilio Reale" Department, La Sapienza University, viale del Policlinico 155, 00100 Rome, Italy. E-mail: biocard{at}inmi.it
Received May 5, 2007; accepted July 23, 2008.
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Abstract |
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Background— Chest pain is frequently reported in Fabry disease (FD). However, its mechanism and clinical relevance are unclear.
Methods and Results— Basal troponin I level, exercise stress test, single-photon emission computed tomography imaging with 99mTc sestamibi, coronary angiography with thrombolysis in myocardial infarction (TIMI) frame count and left ventricular angiography and endomyocardial biopsy were obtained in 13 patients with FD with angina. Ratio of external to lumen diameter of intramural arteries (E/L ratio), myocyte diameter, and extent of fibrosis were morphometrically evaluated by using tissue sections. Controls for coronary angiography and histology were 25 patients with FD without angina and 20 mitral stenosis patients with normal left ventricular function. Troponin I level was elevated in 6 of the 13 patients. Exercise stress test showed evidence of myocardial ischemia, and single-photon emission computed tomography was positive for stress-induced perfusion defects in all patients with FD with angina. Epicardial coronaries were structurally normal but showed slow flow in all and were associated with aneurisms of posterior left ventricular wall in 3 cases. Histology showed remarkable lumen narrowing of most intramural arteries (mean E/L ratio=3.5±1.2; P<0.001 versus both control groups), because of hypertrophy and proliferation of smooth muscle and endothelial cells, both engulfed by glycosphingolipids. Replacement fibrosis exceeded that of both controls (P<0.001). Small vessel disease correlated with coronary slow flow and extent of fibrosis, but did not with patients’ age, sex, and degree of left ventricular hypertrophy.
Conclusions— patients with FD with angina have perfusion defects, slow coronary flow, and luminal narrowing of intramural arteries. Small vessel disease may contribute to symptomatic limitation and progressive myocardial dysfunction.
Key Words: angina • cardiomyopathy • Fabry disease • ischemia • microcirculation
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Introduction |
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Fabry disease (FD) is an X-linked disorder caused by deficiency of the lysosomal enzyme
-galactosidase A, resulting in progressive intracellular accumulation of globotriaosylceramide (GB3) and related neutral glycosphingolipids in different tissues, including skin, kidney, central and peripheral nervous system and the heart.1 In the vasculature, glycosphingolipids accumulate in the endothelial and smooth muscle cells, causing structural abnormalities and progressive vascular dysfunction.
In the heart, glycosphingolipids deposition causes progressive left ventricular (LV) hypertrophy that mimics the morphological and clinical picture of hypertrophic cardiomyopathy,2 with dispnea on effort, palpitation, and angina as the typical symptoms.
A higher incidence of coronary heart disease, as a consequence of epicardial coronary endothelial and smooth muscle cells involvement, has been suggested to explain the frequent occurrence of angina, reported in up to 60% of patients.3 Indeed, in contrast with positron emission tomography imaging suggesting an impaired myocardial perfusion reserve,3,4 coronary angiography frequently showed normal vessels pointing toward a compromise of coronary microcirculation. However, the mechanisms of microvascular dysfunction are still unclear and may include increased myocardial oxygen demand, increased LV end-diastolic pressure, decreased capillary density, and small vessel disease.
Editorial 150
The purpose of the present study was to investigate the coronary anatomy, flow and reserve and the histological and ultrastructural findings of LV intramural vessels in a population of patients with FD reporting of angina in comparison with patients with FD without angina and with normal controls.
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Methods |
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Expanded version of methods for coronary angiography, myocardial perfusion tomography, and immunohistochemistry can be found in an online Data Supplement.
Patient Population
From January 1996 to June 2006, 46 consecutive patients (26 mol/L, 20 female, mean age 42.9±15.7 years) with a diagnosis of FD were studied. The patients were either primary diagnosed in our Institution (n=22) either referred from other Italian centers (n=24).
The diagnosis was based on the identification of -galactosidase A mutations and, in males, on the detection of low -galactosidase A activity in peripheral leukocytes.5 Thirteen of them (8 mol/L, 5 female, mean age 48.5±12.1 years) reported of angina and constitute the study population. Among the remaining 33 patients with FD, 25 (15 mol/L,10 female, mean age 47.1±13.3 years) were submitted to cardiac catheterization with endomyocardial biopsy to assess the severity of cardiac involvement and were compared with the study population for echocardiographic, hemodynamic, and histological parameters. The relevance of chest pain was evaluated with a standardized questionnaire modified from Master,6 and in all cases, patients with FD with angina confirmed to have chronic episodes of chest pain referred as "pressure or constriction" mainly precipitated by physical effort or emotional stress and occurring several times a week, whereas the other group of patients with FD failed to report chest or characteristic anginal pain.
Twenty sex and age matched patients with isolated mitral stenosis, undergoing valve replacement, with normal LV function and coronary angiograms were used as normal controls. At the time of endomyocardial biopsy none of patients with FD were receiving enzyme replacement therapy (ERT).
Clinical Studies
Extensive clinical examination, including the assessment of FD systemic manifestations, and noninvasive cardiac studies (resting ECG, 2D echocardiography with tissue Doppler analysis) were performed in all patients as previously described.5 Maximal wall thickness (MWT) was defined as the greatest thickness measured at any segment of LV wall. Invasive studies were performed after patient written informed consent and approval by the Ethical Committees of our Institution and included cardiac catheterization, selective coronary angiography, LV angiography and LV endomyocardial biopsy. In patients with FD with chest pain, basal cardiac troponin I level was also assessed.
Coronary Angiography
To quantitatively evaluate coronary blood flow, the pattern of coronary dye progression was visually and separately evaluated for left and right coronary arteries. The number of frames required for contrast to first reach standardized distal coronary landmarks was measured by the cine viewer frame counter (TIMI counting).7The presence of slow coronary flow, defined as the delayed opacification of the distal vasculature in angiographically normal or nearly normal coronaries,8 was determined.
Exercise Stress Test
In all patients with FD with chest pain a symptom-limited, upright, bicycle ergometry with stepwise increments of 25 W every 2 minutes was performed according to standard protocols. Test end points were achievement of target heart rate (85% of maximum age- and gender-predicted heart rate), horizontal or downsloping ST-segment depression 
2 mm at an interval of 80 ms after the J point compared with baseline, severe angina, systolic blood pressure decrease >40 mm|Hg, blood pressure >240/120 mm|Hg, or significant cardiac arrhythmias. All 13 patients were able to perform exercise stress test.
Myocardial Perfusion Tomography
All patients with FD with angina underwent same-day stress/rest 99mTc sestamibi myocardial perfusional scintigraphy. The coronary vascular distribution of single-photon emission computed tomography perfusion abnormalities was assigned in accordance with established conventions. The resulting profiles were arranged as a series of concentric circles that formed a single 2D polar map with the apex at the center and the base at the periphery.9
Endomyocardial Biopsy Studies
Eight to 10 endomyocardial samples (
3 mm3 each) were obtained from each patient. Five to 6 myocardial samples were processed for routine histological and histochemical analyses, including Sudan black, Masson trichrome and Elastic van Gieson stainings. Two samples were fixed in 2% glutaraldehyde in 0.1 mol/L phosphate buffer (pH=7.3) and embedded in Epon resin; semithin sections were processed for Azur II staining, and ultrathin sections were stained with uranyl acetate and lead hydroxide for transmission electron microscopy.5
Morphometry
Paraffin-embedded histological sections stained with Masson trichrome were examined at x400 magnification with a reticule containing 42 sampling points (105844, Wild Heerbrugg Instruments, Gals, Switzerland) to determine the percentage of area occupied by fibrous tissue.10 The cardiomyocyte diameter was measured across the nucleus in 50 to 100 cells cut transversely. Because of the prevalent subendocardial glycosphingolipids accumulation,11 the same number of cells were counted in the subendocardial and in the inner layer of each specimen and an average value was computed. In female patients, in whom 2 different populations of wild type and diseases cells are present, the cell diameter was calculated only in cardiomyocytes affected by the disease averaging the measurement values of the cells located in the 2 different layers.
The structure of intramural coronary arteries was examined on elastic van Gieson–stained paraffin sections and was confined to those that were viewed in cross section without obvious obliquity and that did not appear to be branches of another intramural vessel.12 Twelve to 20 tissue sections from 4 to 6 samples per patient were examined and the total number of suitable small arteries were counted. The external diameter (bordered by adventitial tissue) and luminal diameter (bound by endothelium) were measured for all suitable vessels by means of a computerized system (Lucia G software (version 4.82, Nikon, Japan), and the ratio of external diameter to luminal diameter was computed (E/L ratio) and used as quantitative index for the degree of luminal narrowing.13 The same measurements were performed in the 25 patients with FD with no angina and in hearts of 20 controls, consisting of surgical LV endomyocardial biopsies from mitral stenosis patients. Because in none of the normal controls, the E/L ratio was >2 for any of the vessels assessed, the severity of the small vessel disease per patient was taken as the percentage of vessels in which the E/L ratio was 2.5.
Immunohistochemistry
Frozen sections from patients of both FD groups were incubated with rat anti-human monoclonal antibody GB3/CD77 (MCA579, clone 8 to 13, AbD Serotec, Oxford, United Kingdom) and treated with biotinylated goat anti-rat immunoglobulins (AbD Serotec) and streptavidin conjugated with horseradish peroxidase (AbD Serotec). Enzyme activity was detected by using diaminobenzidine. Sections from patients with FD stained without using the primary antibody and slides from normal controls served as negative controls.
Enzyme Replacement Therapy
All 13 patients received ERT with Fabrazyme (Genzyme Corporation, Cambridge Mass) at a dose of 1 mg/kg every 2 weeks. They were followed up by physical examination and exercise stress test every 3 months; by single-photon emission computed tomography imaging and 2D-echocardiography at 6th and 12th month of treatment. Five patients (Nos. 1, 2, 3, 7, and 8 from Table 1) underwent a control coronary angiography with LV endomyocardial biopsy after 12 months (17.8±3.5 months; range, 13 to 22 months) of treatment with a new evaluation of slow coronary flow and small vessel disease.
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Statistical Analysis
Normal distribution of explored variables was assessed with Kolmogorov-Smirnov test and Shapiro-Wilk test. Continuous variables were presented as mean±SD. Categorical variables were presented as absolute frequencies or percentages. Because of nonnormality and disomogeneity of variance for some variables (as assessed by Levene test) between-group comparisons were performed with Kruskal-Wallis test; in the case of overall between-group significant differences at Kruskal-Wallis test, direct comparisons were performed with Mann-Whitney test. The categorical variables were compared by
2 test or Fisher exact probability test (in case of 2-by-2 contingency tables with an expected cell count of <5).
In case of multiple comparison, Bonferroni correction was applied to control the experiment-wise type I error probability. Bivariate correlations were analyzed by Spearman 
coefficient computation. Changes of variables before and after 12 months of ERT were analyzed with paired t test. A 2-tailed P value 
0.05 was considered statistically significant.
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Results |
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Clinical Studies
Clinical, echocardiographic and genetic characteristics of the 13 patients with FD with angina are shown in Table 1. Patients 8 and 13 were affected by the cardiac variant of FD, whereas the remaining 11 had additional systemic manifestations. Patients 1 and 2, patients 3, 4, and 5, and patients 8, 9, and 10, pertain to the same family. All patients had other family members affected by FD asymptomatic for angina. Apart from angina, they had other cardiac symptoms consisting in dyspnea (90%) and palpitations (30%). Troponin I level was elevated in 6 of the 13 patients with chest pain and was within normal limits in all patients without angina. All 13 patients had LV hypertrophy, documented at basal ECG (Figure 1A) and at echocardiography (Table 1). None of them was smoking, or had hypercholesterolemia, diabetes, or hypertension. None was taking medications.
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Exercise Stress Test and Myocardial Perfusion Tomography
In all patients there was a significant increase of heart rate and systolic blood pressure from rest to peak stress, respectively. With stress, ST-segment depression occurred in all patients with FD and angina (Figure 1A), and the symptom occurred in 10 patients. The mean workload achieved with exercise was 125±15 W. Conversely, patients with FD without angina did not show significant ST-segment depression or chest pain during the test.
At 99mTc sestamibi myocardial perfusion tomography all patients with FD with angina showed an ischemic response to stress test. The mean values of the summed stress score (SSS) and summed rest score (SRS) of 99mTc sestamibi uptake were 9.4±1.6 and 4.8±1.4, respectively, with a summed difference score (SDS) of 4.5±1.2. These data indicated both the presence of reversible perfusional defects and resting segmental hypoperfusion. A reduced baseline tracer uptake (SRS0.24) was found in 54% of patients. Reversible myocardial perfusional defects were distributed in vascular territories supplied by left coronary artery, whereas fixed defects were observed in myocardial areas perfused by right coronary artery (Figure 1B). The 3 patients with localized aneurysm of the posterobasal wall had fixed perfusional defect at 99mTc sestamibi in the corresponding area. All patients without chest pain showed a postexercise and resting normal myocardial uptake of the tracer (Figure 1C).
Coronary and Ventricular Angiography
Coronary angiography showed structurally normal coronary arteries in all patients with FD and controls. Unlike what was observed in other groups, patients with FD with angina exhibited a prominent slow flow affecting each coronary artery and a slow runoff of the contrast medium (Table 2). Neither angina nor surface ECG abnormalities occurred during the procedure. There was no difference among patients with FD with angina and control groups in coronary diameters, heart rate, or mean arterial pressure during angiography (Table 2).
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There was no correlation between slow flow of each coronary artery and patients’ age, sex, and severity of LV hypertrophy. LV angiography confirmed the presence of a thickened ventricle with normal volumes and contractility in all cases. Unlike in patients with FD asymptomatic for angina, in 3 of the 13 patients with FD with angina a localized aneurysm of the posterobasal wall was evident (Figure 2A and 2B). Left ventricular end-diastolic pressure was similarly increased in both FD groups (Tables 1 and 2
).
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Endomyocardial Biopsy Studies
In all patients with FD, histology showed the presence of large perinuclear vacuoles in cardiomyocytes, endothelial cells and smooth muscle cells, containing material that on frozen section stained positively with periodic acid-Schiff (PAS) and Sudan-black, suggesting the accumulation of glycosphingolipids. These vacuoles consisted at electron microscopy of concentric lamellar figure in single-membrane–bound vesicles (myelin bodies), diagnostic for FD. Intramyocardial arteries from patients with FD with angina showed lumen narrowing with wall thickening because of hypertrophy and hyperplasia of smooth muscle cells and swelling with proliferation of endothelial cells, both engulfed by glycosphingolipids, and to increased fibrosis of the medial and intimal layer (Figures 2C and 3
). Myocardial replacement fibrosis surrounding severely narrowed intramural coronary arteries was often present. In patients with FD without angina, glycosphingolipid deposits affected smooth muscle and endothelial cells, but only mild lumen narrowing on few intramural arteries was detected. Histology of LV samples from normal controls showed regular endomyocardial and vessels structure.
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Morphometry
Morphometric parameters in patients with FD with angina are presented in Table 1 and compared with those of FD without angina and normal controls in Table 2.
External diameter of intramural arteries ranged from 20 to 265 µm (mean, 63±37 µm). The number of small vessels measured in patients and controls ranged from 5 to 9 per patient. In each patient with FD with angina, all the vessels had a E/L ratio >2, and most of them (81±24%) showed a marked thickening of the arterial wall (E/L ratio2.5).
Immunohistochemistry
A diffuse pattern of GB3 staining was observed in the myocardium of patients with FD. In particular, endothelial cells from both group of patients (with and without angina) appeared to be involved by GB3 deposits (Figure 4A).
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The same sections did not react positively in absence of the primary antibody. Slides from patients without FD showed no reactivity for GB3.
Response to Enzyme Replacement Therapy
No significant changes in terms of episodes of angina, degree and threshold of ST-segment deflection at exercise stress test, perfusion defects at single-photon emission computed tomography imaging and the degree of LV hypertrophy at 2D echocardiography was observed in any patient. In the 5 patients who underwent a follow-up coronary angiography and LV endomyocardial biopsy during ERT, an unchanged epicardial coronary anatomy was detected with the persistence of slow coronary flow (baseline versus repeat study, respectively, LAD: 56.2±16.1 versus 56.8±15.0; Cx: 48.6±9.6 versus 48.0±8; right coronary artery (RCA) 52.8±9.9 versus 53.4±12.0; P=NS). At histology, the intracellular glycosphingolipids deposits appeared unmodified and the E/L ratio of intramural arteries did not differ from baseline values (baseline E/L ratio=3.4±1.2 versus follow-up=3.4±1.2, P=NS). In particular, endothelial cells from biopsies performed before and after1 year ERT showed similar intracellular accumulation of glycosphingolipids (Figure 4B and 4C).
Correlations
There was no significant relation between small vessel disease and age, sex, and severity of LV hypertrophy. Conversely, small vessel disease significantly correlated with slow coronary flow (correlation coefficient, 0.97; P>0.001 for LAD; correlation coefficient, 0.95, P>0.001 for Cx; correlation coefficient, 0.98; P>0.001 for RCA), with myocardial fibrosis (correlation coefficient, 0.88; P>0.001) and more strictly with myocardial replacement fibrosis (correlation coefficient, 0.90; P>0.001).
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Discussion |
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Chest pain is a common clinical symptom in patients with FD, being reported in up to 60% of hemizygous males and heterozygous females with or without significant LV hypertrophy3. It is often associated with electrocardiographic abnormalities of ST-segment and T wave and with impaired myocardial perfusion reserve at positron emission tomography imaging,3,4 suggesting the existence of myocardial ischemia. However, the site and mechanism of disturbance of coronary circulation have not yet been clarified.
The rare occurrence of myocardial infarction as well as the observation of normal epicardial coronaries in small FD cohorts symptomatic for angina points toward a compromise of microvascular district.
Our report, combining for the first time noninvasive and invasive studies of patients with FD with LV hypertrophy and angina, shows that severe obstruction of intramural arteries is the main mechanism of myocardial ischemia and that it can affect up to 34% of patients with FD cardiomyopathy. This notion is supported by the presence of abnormal ST-segment deflection at exercise ECG, perfusion defects at stress 99mTc sestamibi myocardial tomography in absence of critical epicardial coronary stenoses, and by the evidence of coronary slow flow phenomenon.
Slow Coronary Flow in FD
Coronary slow flow phenomenon, consisting in the angiographic observation of normal or nearly normal coronary arteries with delayed opacification of the distal vasculature, has been described in patients with recurrent chest pain and associated with the pathological evidence of coronary microvascular disease.8–14 In our study, it has been observed in all patients with FD reporting of angina and correlated strictly with small vessels disease, whereas it was absent in FD controls. Moreover, slow flow did not correlate with the degree of LV hypertrophy and was independent from other possible hemodynamic variables, including larger coronary diameter requiring prolonged contrast filling time or reduced coronary perfusion pressure. Thus, coronary slow flow in patients with FD is caused probably by an underlying microvascular disorder, characterized by structural abnormalities of coronary resistance vessels, resulting in recurrent episodes of myocardial ischemia.
Small Vessel Obstruction and Myocardial Ischemia in FD
Histology and electron microscopy of endomyocardial tissue provided evidence that small vessels obstruction is the result of hypertrophy and hyperplasia of the smooth muscle cells and swelling and proliferation of the endothelial cells, both engulfed by glycosphingolipids. Such alterations were often associated with increase of basal troponin I levels and with loss of cardiomyocytes as documented by the frequent areas of fibrosis surrounding the most affected vessels and by the significant increase in replacement fibrosis detected in patients with FD with angina compared with both control groups.
Moreover, in 3 of the 13 patients exhibiting the most severe small vessels disease, a localized aneurysm of the posterior LV wall could be detected at angiography, possibly as a consequence of focal ischemia with myocardial necrosis and scar formation. The prominent involvement of LV posterior wall by FD has been already described both in vivo, as MRI signal of late enhancement,15 and at postmortem, as extensive areas of myocardial fibrosis16 possibly related to regional wall mechanics or microvascular anatomy.
The documentation in this site of aneurysm formation brings to these patients an additional risk of electric instability and thromboembolic phenomena requiring the eventual consideration of an implantation of an implantable cardioverter-defibrillator and anticoagulation therapy.
No correlation between small vessel disease and age, sex, or severity of LV hypertrophy was observed. This latter aspect is consistent with previous studies in patients with FD, showing no relationship between reduced myocardial perfusion reserve and LV mass3,4 and is not surprising because it is similar to that described in hypertrophic cardiomyopathy.12
To this regard, recent studies showed that plasma of patients with FD contains factors that can trigger the development of vascular hypertrophy and hyperplasia.17 These factors are perhaps variably expressed in different individuals, because in our study an interindividual variability in small vessel structure has been observed in affected family members carrying the same gene mutation.
With regard to the possible factors stimulating cell proliferation, although many factors released by either smooth muscle cells, fibroblasts, or cardiomyocytes are known to induce a proliferative response in smooth muscle cells, a very intriguing hypothesis is that GB3 and its metabolites are the mediators of the proliferative stimulus.18 This mechanism has been already shown in atherosclerotic lesions, in which ceramide has been demonstrated to stimulate the proliferation of aortic smooth muscle cells.19
Response to ERT
Neither attenuation of angina nor reduction of electrocardiographic and scintigraphic signs of myocardial ischemia could be documented after ERT in any of our patients. No improvement of coronary slow flow and intramural coronary artery narrowing was observed in 5 patients undergoing a second invasive study after 12 months of ERT. In particular, no apparent reduction in the accumulation of GB3 in endothelial cells and smooth muscle was observed. This result varies from that of a previous study,20 showing a clearance of microvascular endothelial glycosphingolipid deposits in the endomyocardium of 67% of patients after 6 months of ERT. However, in this study, the patients were younger, a history of chest pain was not reported, and the severity of cardiac involvement was not specified. Probably our patients had a more pronounced cardiac endothelial and vascular involvement, making the disease less susceptible to an intermediate term administration of ERT. This observation, even if limited by the small size of the cohort, is consistent with previous studies showing no significant changes in myocardial blood flow, flow reserve, and coronary vascular resistance after an intermediate term of ERT.3–21 Histopathologic studies with a longer-term follow-up after ERT are needed to elucidate the potential reversibility of glycosphingolipid deposition and lumen narrowing of intramural vessels.
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Conclusions |
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Patients with angina and FD have demonstrable perfusion defects, slow coronary flow, and luminal narrowing of intramural arteries associated with replacement fibrosis of the myocardium. This small vessel disease may contribute not only to symptomatic limitation but to progressive myocardial dysfunction.
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Acknowledgments |
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Disclosures
None.
Sources of Funding
This study was supported by the Telethon Foundation grant GGP05264 (Rome, Italy), and the grant "l’Oreal-UNESCO for women and science 2005" (Italy).
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Footnotes |
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The online Data Supplement can be found with this article at http://circahajournals.org/cgi/content/full/CIRCHEARTFAILURE.108.769729/DC1.
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References |
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