Unexpected, But Reasonable Association Between Anderson-Fabry Disease and Coronary Vasospasm

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease caused by a loss-of-function mutation in the lysosomal enzyme α-galactosidase A (GLA) gene, resulting in progressive intracellular accumulation of neutral glycosphingolipids, particularly globotriaosylceramid (Gb3), in different tissues including skin, kidney, central and peripheral nervous systems, and the heart.¹ Patients with AFD suffer from various cardiac complications, including hypertrophic cardiomyopathy, valvular diseases, conduction defects and arrhythmias, as well as coronary artery stenosis, caused by Gb3 accumulation in vascular endothelial and smooth muscle cells (VSMCs) (Figure);^2,3 however, the prevalence of coronary spastic angina (CSA) has not been clearly demonstrated among AFD patients previously.

Figure.

Endothelial dysfunction and vasospasm in Anderson-Fabry disease (AFD). Thickening of the intima and media with narrowing of the lumen are observed morphologically. Vascular endothelial cells and vascular smooth muscle cells (VSMCs) incorporate globotriaosylceramid (Gb3) into endosomes/lysosomes, which induces reactive oxygen species (ROS) through as yet undetermined mechanisms. ROS activate Rho-kinase (ROCK) in the endothelial cell to inhibit endothelial nitric oxide (NO) synthase (eNOS). Gb3 also inhibit the expression of KCa3.1 in the endothelial cell, which impairs Ca²⁺-mediated release of NO and/or endothelium-derived hyperpolarizing factor (EDHF). In VSMCs, ROS-mediated degradation of NO and activation of ROCK predisposes the muscle to hypercontractility and vasospasm.

Article p 481

In this issue of the Journal, Kitani et al⁴ describe the clinical presentations and results of intracoronary acetylcholine provocation test⁵ in 9 consecutive patients with AFD. They found a high prevalence (8/9 patients) of acetylcholine-induced CSA without coronary artery stenosis.⁴ It should be noted that all 9 patients complained of angina at rest,⁴ which suggests possible self-selection bias to undergo cardiac assessment, and therefore, raises prior probability of a positive diagnosis of CSA even among consecutive AFD patients. Nonetheless, this report is the first to describe a high prevalence of CSA in a series of Japanese patients with AFD. Interestingly, 6 of the 8 acetylcholine-positive patients were female in this study,⁴ in contrast to the fact that as low as 13% of Japanese CSA patients are female.⁵ However, the significance of either sex or ethnicity in the prevalence of CSA was indeterminate in this study.

Endothelial Dysfunction in AFD

Vascular endothelial cells produce endothelium-derived relaxing factors (EDRFs), including prostanoids, nitric oxide (NO) and endothelium-derived hyperpolarizing factor, and orchestrate VSMCs to regulate vascular tonus and blood flow.⁶ CSA is a result of endothelial dysfunction, or VSMC hypercontractility, or both.⁵ Several reports have described an altered NO pathway in AFD. Moore et al reported that enhanced nitrotyrosine staining was observed in dermal and cerebral blood vessels by immunohistochemical analysis, which indicates dysregulated NO production as well as reactive oxygen species (ROS) production.⁷ Shen et al reported that exogenous Gb3 accumulates in the lysosome of cultured endothelial cells, causing ROS production as evidenced by dichlorodihydrofluorescein staining.⁸ ROS enhances the expression of adhesion molecules,⁸ as well as endothelial dysfunction, accelerating inflammatory responses to various pro-atherogenic stimuli under Gb3 accumulation. Indeed, a recent clinical study by Katsuta et al showed the associations among vascular hypertensive and arteriosclerotic changes of the fundus and high serum adhesion molecule levels in Japanese AFD patients.⁹ Also, exogenous Gb3 downregulates KCa3.1 in cultured endothelial cells, which may inhibit EDRF production.^10,11 These notions underpin the endothelial dysfunction per se caused by the accumulation of Gb3 in AFD (Figure).

VSMC Hypercontractility in AFD

Hypercontractility of VSMCs is another mechanism of CSA.⁵ VSMC contraction is determined by phosphorylation of myosin light chain (MLC), which is regulated by MLC kinase and myosin phosphatase. Rho-kinase (ROCK) inhibits myosin phosphatase, promoting MLC phosphorylation, and therefore induces Ca²⁺ sensitization and hypercontractility of VSMCs.¹² Ravarotto et al¹³ examined myosin phosphatase target protein-1 in the peripheral mononuclear cells as a marker of ROCK activation in vascular cells.¹⁴ They found enhanced ROCK activation, as well as with oxidative stress and lipid peroxidation in AFD patients compared with healthy subjects.¹³ Collectively, AFD is associated with oxidative stress and ROCK activation, which may lead to VSMC hypercontractility per se, and predispose the coronary artery to vasospasm and also atherosclerosis, not just hypertrophic changes in the media. It is worth mentioning that ROCK activation destabilizes eNOS messenger RNA in endothelial cells, which is another mechanism associating AFD with endothelial dysfunction (Figure).¹⁵

Clinical Perspectives

In this report by Kitani et al, 8 AFD patients complicated with CSA were treated with anti-anginal agents and galactosidase enzyme replacement therapy (ERT).⁴ The relief of angina was fairly attained; 6 of 8 patients were free from angina. Thurberg et al reported that ERT could clear microvascular endothelial Gb3 deposits in the kidney.¹⁶ Moore et al also suggested that ERT could improve altered NO-mediated cerebrovascular responses.^7,17 Although clinical evidence is awaited, the effects of ERT are expected to ameliorate endothelial dysfunction and VSMC hypercontractility in AFD, especially in the early stage of AFD-associated CSA. Regarding the role of endothelial dysfunction as an initial step in atherogenesis, the management of coronary risk factors is also important for patients with AFD, for whom statins may be effective for improving endothelial and VSMC function by inhibiting ROCK activity.¹⁴ Antioxidants such as vitamin C² may also have positive effects.

Finally, Kitani et al provide an important clinical finding of the high incidence of CSA among patients of AFD without coronary artery stenosis.⁴ Gb3 accumulation can induce not only altered morphology, but also endothelial dysfunction and VSMC hypercontractility through oxidative stress-mediated impairment of endothelial-derived relaxing factors and activation of ROCK. Further investigation of the basic mechanisms of Gb3-induced pathophysiology and clinical evidence of therapeutic interventions may improve the care and prognosis of AFD patients with cardiovascular complications.

Funding

This study was supported by grants from the Ministry of Education, Science, and Culture, Tokyo, Japan (Grants-in-Aid for Scientific Research 25461135 to T.M.).

Conflicts of Interest

T.M. has received lecture fees (MSD). H.T. has received lecture fees (Astellas, Ohtsuka, Takeda, Daiichi-Sankyo, Tanabe-Mitsubishi, Boeheringer-Ingelheim, Novartis, Bayer, and Bristol-Myeres) and research funds (Daiichi-sankyo, Astellas, and Actellion).

References

• 1.   Zarate YA, Hopkin RJ. Fabry’s disease. Lancet 2008; 372: 1427–1435.
• 2.   Schiffmann R. Fabry disease. Pharmacol Ther 2009; 122: 65–77.
• 3.   Chimenti C, Morgante E, Tanzilli G, Mangieri E, Critelli G, Gaudio C, et al. Angina in Fabry disease reflects coronary small vessel disease. Circ Heart Fail 2008; 1: 161–169.
• 4.   Kitani Y, Nakagawa N, Sakamoto N, Takeuchi T, Takahashi F, Momosaki K, et al. Unexpectedly high prevalence of coronary spastic angina in patients with Anderson-Fabry disease. Circ J 2019; 83: 481–484.
• 5.   JCS Joint Working Group. Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013): Digest version. Circ J 2014; 78: 2779–2801.
• 6.   Matoba T, Shimokawa H. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Pharmacol Sci 2003; 92: 1–6.
• 7.   Moore DF, Scott LT, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, et al. Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: Reversal by enzyme replacement therapy. Circulation 2001; 104: 1506–1512.
• 8.   Shen JS, Meng XL, Moore DF, Quirk JM, Shayman JA, Schiffmann R, et al. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol Genet Metab 2008; 95: 163–168.
• 9.   Katsuta H, Tsuboi K, Yamamoto H, Goto H. Correlations between serum cholesterol and vascular lesions in Fabry disease patients. Circ J 2018; 82: 3058–3063.
• 10.   Choi S, Kim JA, Na HY, Cho SE, Park S, Jung SC, et al. Globotriaosylceramide induces lysosomal degradation of endothelial KCa3.1 in Fabry disease. Arterioscler Thromb Vasc Biol 2014; 34: 81–89.
• 11.   Satoh K. Globotriaosylceramide induces endothelial dysfunction in Fabry disease. Arterioscler Thromb Vasc Biol 2014; 34: 2–4.
• 12.   Kandabashi T, Shimokawa H, Mukai Y, Matoba T, Kunihiro I, Morikawa K, et al. Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries. Arterioscler Thromb Vasc Biol 2002; 22: 243–248.
• 13.   Ravarotto V, Carraro G, Pagnin E, Bertoldi G, Simioni F, Maiolino G, et al. Oxidative stress and the altered reaction to it in Fabry disease: A possible target for cardiovascular-renal remodeling? PLoS One 2018; 13: e0204618.
• 14.   Liu PY, Liu YW, Lin LJ, Chen JH, Liao JK. Evidence for statin pleiotropy in humans: Differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 2009; 119: 131–138.
• 15.   Hiroi Y, Noma K, Kim HH, Sladojevic N, Tabit CE, Li Y, et al. Neuroprotection mediated by upregulation of endothelial nitric oxide synthase in Rho-associated, coiled-coil-containing kinase 2 deficient mice. Circ J 2018; 82: 1195–1204.
• 16.   Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB, et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int 2002; 62: 1933–1946.
• 17.   Moore DF, Altarescu G, Herscovitch P, Schiffmann R. Enzyme replacement reverses abnormal cerebrovascular responses in Fabry disease. BMC Neurol 2002; 2: 4.