Primary mitochondrial arteriopathy

Nutrition, Metabolism & Cardiovascular Diseases (2012) 22, 393e399

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/nmcd

REVIEW

Primary mitochondrial arteriopathy J. Finsterer a,*, S. Zarrouk Mahjoub b a b

Danube University Krems, Krems, Postfach 20, 1180 Vienna, Austria Genetics Laboratory, Research Unit “Genetics Epidemiology and Molecular” Faculty of Medicine Tunis, Tunisia

Received 4 October 2011; received in revised form 27 December 2011; accepted 5 January 2012

KEYWORDS Arterial; Vessel; Vascular; Pathology; Perfusion; Metabolic disease; Cytopathy; Mitochondrial

Abstract Aim: Whether arteries are affected in mitochondrial disorders (MIDs) was under debate for years but meanwhile there are strong indications that large and small arteries are primarily or secondarily affected in MIDs. Data synthesis: When reviewing the literature for appropriate studies it turned out that vascular involvement in MIDs includes primary or secondary micro- or macroangiopathy of the cerebral, cervical, and retinal arteries, the aorta, the iliac arteries, the brachial arteries, or the muscular arteries. Arteriopathy in MIDs manifests as atherosclerosis, stenosis, occlusion, dissection, ectasia, aneurysm formation, or arteriovenous malformation. Direct evidence for primary cerebral microangiopathy comes from histological studies and indirect evidence from imaging and perfusion studies of the brain. Microangiopathy of the retina is highly prevalent in Leber’s hereditary optic neuropathy. Macroangiopathy of the carotid arteries may be complicated by stroke. Arteriopathy of the aorta may result in ectasia, aneurysm formation, or even rupture. Further evidence for arteriopathy in MIDs comes from the frequent association of migraine with MIDs and the occurrence of premature atherosclerosis in MID patients without classical risk factors. Conclusions: Mitochondrial arteriopathy most frequently concerns the cerebral arteries and may result from the underlying metabolic defect or secondary from associated vascular risk factors. Vascular involvement in MIDs has a strong impact on the prognosis and outcome of these patients. ª 2012 Elsevier B.V. All rights reserved.

Abbreviations: ADC, Apparent-diffusion coefficient; AVM, Arteriovenous malformation; CADASIL, Cerebral autosomal dominant arteriopathy with stroke and ischemic leucencephalopathy; COX, Cytochrome-C-oxidase; PEO, Progressive external ophthalmoplegia; DWI, Diffusionweighted imaging; FMD, Flow-mediated vasodilation; LHON, Leber’s hereditary optic neuropathy; MELAS, Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; MERRF, Myoclonus epilepsy with ragged-red fibres; MID, Mitochondrial disorder; MIDD, Maternally inherited diabetes and deafness; mtDNA, Mitochondrial DNA; nDNA, Nuclear DNA; SDH, Succinat dehydrogenase; SLE, Stroke-like episode; SLL, Stroke-like lesion; SPECT, Single photon emission computed tomography; SSV, Strongly-succinate dehydrogenase-reactive vessels; VSMC, Vascular smooth muscle cell. * Corresponding author. Tel.: þ43 1 71165 92085; fax: þ43 1 4781711. E-mail addresses: [email protected], [email protected] (J. Finsterer). 0939-4753/$ - see front matter ª 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2012.01.002

394

J. Finsterer, S.Z. Mahjoub

Introduction Since the first description of stroke-like episodes (SLEs) in patients with mitochondrial encephalopathy, lactacidosis and stroke-like episodes (MELAS) syndrome it is under debate whether or not arteries are involved in the pathogenesis of SLEs [1]. It is also unclear whether arteries are generally affected or not by the metabolic defect causing a mitochondrial disorder (MID). During recent years, however, a number of indications have been provided revealing that there is indeed involvement of small or large arteries of various organs in various MIDs. The following review aims at summarizing and discussing recent findings concerning the primary affection and involvement of arteries in MIDs. Table 1

Types of arteriopathy in MIDs Generally, arteriopathy in MIDs may be primary or secondary. Primary mitochondrial arteriopathy is due to affection of arterial structures (endothelium, muscularis, adventitia, pericytes (connective tissue cell that covers endothelial cells to form a capillary)) by the underlying metabolic defect, resulting in the destruction of the vessel wall (primary atherosclerosis) consecutive stenosis, occlusion, dissection. rupture, or aneurysm formation. Secondary arteriopathy in MIDs may result from risk factors for atherosclerosis, such as diabetes, hyperlipidemia, or arterial hypertension, which Table 1

are frequently found in MIDs and are the cause of secondary atherosclerosis in these patients. Secondary arteriopathy may accompany primary arteriopathy why it is often difficult to distinguish between these entities. Aneurysm formation in MID patients with arterial hypertension may be another secondary arteriopathy in MIDs. Secondary arteriopathies were not the topic of this review.

Location of mitochondrial arteriopathy In primary as well as secondary mitochondrial arteriopathy small (microangiopathy) or large arteries (macroangiopathy) may be affected. There is direct and indirect evidence that the microangiopathy in MIDs is more prevalent than macroangiopathy but no systematic studies on this matter are available so far. Affected arteries in mitochondrial arteriopathy may be the intra-cerebral arteries, the extracranial arteries, the retinal arteries, the aorta, the iliac arteries, the brachial arteries, or arteries of the skeletal muscle. Among these, mitochondrial arteriopathy most frequently affects the intra-cerebral arteries and the intra-muscular arteries but generally all vascular beds may be affected.

Primary mitochondrial arteriopathy of the cerebral arteries Direct evidence In a 14yo boy with non-syndromic MID cerebral biopsy revealed spongiform changes, swollen endothelial cells,

Human MIDs in which primary arteriopathy has been reported.

Affected arteries

Pathology

MID

Reference

Cerebral arteries

Zytotoxic edema in SLL Decreased blood flow in SLL Hypo/hyperperfusion in SLL Hypoperfusion in SLL Microangiopathy Capillary shunting Ischemic stroke Migraine-like headache Decreased CO2 reactivity Swollen endothel, mitochondria [ Microangiopathy High COX-deficiency Increased heteroplasmy Peripapillary tortuosity, ectasia Affection of stria vascularis Dissection Carotid artery occlusion Endothelial dysfunction Rupture Dilation of aortic root Leriche syndrome SVV Abnormal mitochondria [ in endothelial and VSMC Oxidative/nitrative stress[ Abnormal endothelial mitochondria

MELAS MELAS MELAS MELAS, PEO ETHE1 Leigh syndrome CIV-defect MELAS MELAS NSMID MELAS MELAS

[8] [12] [11] [13] [15] [9] [41] [42] [14] [2] [3] [4]

LHON MELAS NSMID NSMID MELAS MELAS NSMID NSMID MELAS MELAS

[16,17,18,19,20] [22] [23] [6] [11] [25] [24] [26] [7,11,12,28,29,30,31,32,33,34,35] [12,36]

NSMID MELAS

[37] [43]

Retinal arteries Cochlear arteries Extracranial arteries Brachial arteries Aorta Iliac arteries Muscle

Skin

NDMID: non-syndromic MID, VSMC: vascular smooth muscle cells, SVV: strongly-succinate dehydrogenase-reactive vessels.

Primary arteriopathy in mitochondrial disorders and increased number of mitochondria with concentric whorls of cristae in pericytes and vascular smooth muscle cells (VSMCs) [2]. In an autopsy study of a 13yo girl with MELAS syndrome generalised mitochondrial microangiopathy with reduced COX-activity but normal enzyme content were observed in the cerebrum, muscle and myocardium [3]. MELAS syndrome is one of the most frequent syndromic MIDs and clinically characterized by predominant central nervous system involvement, manifesting as stroke-like episodes, epilepsy, migraine-like headache, confusion, or cognitive decline. Other organs are frequently also affected. MELAS syndrome is the MID with the highest evidence of primary mitochondrial arteriopathy. In a neuropathological study on individual neurons from several brain regions of two MELAS patients carrying the m.3243A>G mutation the number of cytochrome-coxidase (COX)-negative neurons was low but COXdeficiency was most pronounced and the heteroplasmy rate highest in walls of the leptomeningeal and cortical blood vessels in all brain regions [4]. Indirect evidence Indirect evidence for cerebral small vessel disease in MIDs comes from MRI-studies of the cerebrum showing that the distribution of the white matter lesions (WMLs) frequently observed in MIDs mimics leukaraiosis and is often similar to that seen in other hereditary small vessel diseases, such as cerebral autosomal dominant arteriopathy with stroke and ischemic leucencephalopathy (CADASIL), X-linked Fabry’s disease, hereditary cerebroretinal vasculopathy, or homocystinuria, which causes premature atherosclerosis [5]. Though it is often difficult to differentiate such lesions from those resulting from demyelination, single histological studies have provided evidence that the lesions seen on MRI represent indeed mitochondrial arteriopathy. Another strong argument for arteriopathy in MIDs is the occurrence of SLEs in some of the MIDs but most frequently in MELAS syndrome. SLEs are believed to be microangiopathy-related, neurovascular events [6] that may present as stroke-like lesions (SLLs) on imaging studies, characterised by a mixture of cytotoxic and vasogenic edema within these lesions [7]. In the acute and subacute stages of SLLs there may be cortical hyperintensity on diffusion-weighted imaging (DWI) with corresponding hypointensity on ADC [8], a pattern typical for cytotoxic edema due to ischemia. The subcortical areas on the contrary may show hyperintensity on DWI as well as on ADC maps suggesting vasogenic edema [8]. However, acute SLL may also present with hyperintensity of the cortical as well as subcortical areas on DWI and ADC [8]. During the acute stage of the disease angiography is usually normal [9]. In the chronic stage of a SLL, on the contrary, single photon emission computed tomography (SPECT) shows hypoperfusion in this area [10]. A study of 35 MELAS patients measuring the cerebral blood flow by means of the statistical parametric mapping (SPM) SPECT showed areas of hyper- and hypoperfusion, coexisting within a single strokelike lesion [11]. L-arginine administered intravenously in the acute stage of a SLE and orally during the chronic stage of a SLE significantly reduced the extension of hyper- as well as hypoperfusion [11]. When investigating patients with

395 MELAS syndrome by perfusion-weighted imaging it turned out that the cerebral blood flow and cerebral blood volume are decreased during the acute stage of an SLE [12]. Particularly, mean transit time and time-to-peak were prolonged both in lesional as well as non-lesional areas [12]. SLEs are believed to result from dysfunction of endothelial cells with consecutive vulnerability of the blood brain barrier and vasogenic edema [6]. Vasogenic leakage may also result from activation of calcitonin-gene related peptide leading to hyperperfusion or even migraine [6] Further indirect evidence for cerebral microangiopathy comes from a SPECT study of three subjects carrying the m.3243A>G mutation, which manifested as MELAS syndrome, progressive external ophthalmoplegia (PEO), or migraine-like headache [13]. The study showed decreased perfusion in various cerebral areas but predominantly in the posterior and temporal regions in an asymmetric distribution [13]. PEO is a maternally or autosomally inherited condition characterized by ptosis and reduced flexibility of the eye bulbs, initially without affection of other organs. Additional evidence for arteriopathy in MIDs comes from a study on 13 patients with MELAS syndrome showing decreased CO2 reactivity of the median cerebral artery under hypocapnic or hypercapnic conditions as assessed by transcranial Doppler ultrasound [14]. These patients also showed crossed cerebral diaschisis. In patients with Leigh syndrome capillary shunting was documented by MRI in normal and abnormal cerebral regions [9]. In a study on Ethe-deficient mice it has been shown that microangiopathy in patients carrying a ETHE1 mutation is attributable to a deficiency in ethyl-malonic dioxigenase [15]. Deficiency of ethyl-malonic dioxigenase results in insufficient detoxification of sulfides, which are powerful inhibitors of COX and of short-chain fatty-acid oxidation with vasoactive and vasotoxic effects, explaining microangiopathy [15].

Primary mitochondrial arteriopathy of the retinal arteries In addition to the cerebral arteries, microangiopathy in MIDs may also manifest in retinal arteries. Retinal arteriopathy particularly occurs in Leber’s hereditary optic neuropathy (LHON). LHON is clinically characterized by acute onset visual loss in early adulthood due to optic atrophy. Both eyes become affected either simultaneously or sequentially. Though the diagnosis of LHON requires per definition the presence of a retinal microangiopathy, it is not present in all genetically confirmed LHON cases. In a study on 107 patients with LHON, retinal microangiopathy was present in only 64% of them [16]. This is why retinal arteriopathy should be abandoned as an imperative diagnostic criterion but should be regarded as a facultative diagnostic criterion for LHON. Retinal arteries in LHON typically show increased tortuosity (twisted vessels) and ectasias [16e20]. Vascular involvement typically shows a dynamic course. Microangiopathy may be even found in non-manifesting carriers of the disease [20]. Only in a single patient, an old female with LHON, visual impairment due to peripapillary microangiopathy recovered spontaneously [21].

396

Primary mitochondrial arteriopathy of the cochlear arteries There are indications that also the small arteries of the cochlea are involved in MIDs. In three patients with MELAS syndrome bilateral adult-onset, sensori-neural hearing loss was located rather to the cochlea than retrocochlear sites. Hearing loss was assumed to result from affection of the stria vascularis, hair cells, or of neurons of the auditory pathway [22]. Whether impaired perfusion of the inner ear indeed plays a role in the pathogenesis of hearing loss, which is a frequent phenotypic feature of MIDs, remains to be elucidated.

Primary mitochondrial arteriopathy of the cervical arteries In three patients with ischemic stroke due to spontaneous dissection of the internal carotid artery (n Z 2) and the posterior cerebral artery (n Z 1) muscle biopsy showed ragged-red muscle fibers and decreased SDH and COXstaining [23]. Serum lactate was elevated in one of these patients. From these findings it was concluded that spontaneous dissection is attributable to mitochondrial arteriopathy without providing histological evidence for mitochondriopathy at the site of the dissection [23]. In a single patient carrying the m.617G > A mutation in the tRNA(Phe) gene, recurrent embolic ischemic strokes were observed [6]. Strokes were accompanied by transient occlusion of the middle cerebral artery, the anterior cerebral artery and the internal carotid artery [6]. It was assumed that strokes resulted from artery-to artery embolism originating from an internal carotid artery stenosis, being attributable to no other cause than the underlying MID [6].

Primary mitochondrial arteriopathy of the aorta and iliac arteries Affection of the aorta has been recently recognised as a manifestation of MIDs and may manifest as dilation, aneurysm formation or even rupture of the vessel. In a study of 48 patients with non-syndromic MIDs, 10 presented with dilation of the aortic root as expressed by an individual Z-score > 2 [24]. Also the mean Z-score was significantly increased (þ1.14  1.29 (CI 95% þ 0.77 to þ 1.52)), which is 0 by definition [24]. A 15yo girl with MELAS syndrome experienced spontaneous rupture of the thoracic aorta during gastrostomy insertion [25]. During the unsuccessful attempt to repair the rupture, it was noted that the aorta was extremely friable. At autopsy, the aorta was macroscopically normal but microscopic examination revealed disorganized smooth muscle layers and disrupted elastic layers [25]. Staining for COXI was decreased in VSMC and endothelial cells of the vasa vasorum in the adventitial layer [25]. Interestingly, the patient’s mother had died several years earlier of a major vessel rupture during angiography [25]. Affection of the iliac arteries was recently reported in a 54yo patient with Leriche syndrome, caused by premature atherosclerosis of the iliac arteries [26]. Classical risk factors were absent in this patient and

J. Finsterer, S.Z. Mahjoub he was regularly going on for sport activities [26]. Further evidence for involvement of the mitochondrial metabolism in the formation of aortic aneurysms is the finding that perfusion of rat aortas with elastase results in aneurysm formation of the aorta by activation of caspase-9, the key initiator of the intrinsic apoptosis. Apoptosis concerned VSMCs, macrophages, and neutrophils as shown by transmission electron microscopy and TdT-mediated dUTP-biotin nick end labeling (TUNEL) [27]. It was concluded that mitochondrial-dependent apoptosis is involved in abdominal aortic aneurysm formation [27].

Primary mitochondrial arteriopathy of the brachial arteries Affection of the endothelium in MIDs has been demonstrated in a study on 35 Japanese patients with MELAS syndrome [11]. Flow-mediated vasodilation (FMD) was measured by means of the endothelium-dependent brachial artery diameter response to hyperemic flow with highresolution ultrasonography before and 2 h respectively 2y after oral administration of L-arginine in a dosage of 4g. FMD refers to the change in diameter of an artery as assessed by ultrasound in response to release of an inflated cuff proximal to the site of measurement. FMD was generally reduced in MELAS patients. Additionally, L-arginine improved the FMD in MELAS patients not only 2 h after intake but more pronounced after 2y [11]. It was concluded that there is not only endothelial dysfunction in MELAS but improvement of endothelial dysfunction by L-arginine [11].

Primary mitochondrial arteriopathy of the skeletal muscle arteries Direct evidence for involvement of the muscular arteries in MIDs comes from histological studies of muscle biopsies showing that structures of the small arteries are indeed abnormal compared to healthy subjects [28]. Particularly, succinat dehydrogenase (SDH) staining may show marked hyperreactivity of the arterial walls, also known as strongly-succinate dehydrogenase-reactive vessels (SSV) [11]. Presence of SSV in the muscle biopsy was also reported in a study on MELAS patients with SLEs [12]. Electron microscopy revealed cristae swelling and striking increase in the number of mitochondria in VSMCs and endothelial cells [12]. SSV were not only reported in patients with MELAS syndrome [7,29e31] but also in patients with PEO [32], MERRF (myoclonus epilepsy with ragged-red fibres, clinically characterised by myoclonic epilepsy and myopathy) syndrome [33], MERRF/MELAS overlap syndrome [34], and non-syndromic MID [35]. SSV are usually normal for COX [33] but in a study of five patients with MERRF syndrome, SSV were negative for COX [33]. In a 14yo boy with nonsyndromic MID, muscle biopsy revealed vasculopathy with swollen endothelial cells and increased number of mitochondria and abnormal structure of mitochondria in pericytes and VSMCs [36]. Further evidence for involvement of the vessel wall in MIDs comes from a study on muscle biopsies from patients with MIDs using the 3-nitro-tyrosin stain [37]. This study showed that the arterial wall is a target of oxidative/nitrative stress. Increased oxidative/

Primary arteriopathy in mitochondrial disorders

397

nitrative stress reduces NO bioactivity in arterial walls as shown by increased 3-nitro-tyrosin expression on immunohistochemistry and confocal immunofluorescence microscopy particularly in the endothelium and smooth muscle cells of the small vessels from MID patients as compared to controls [37]. Additionally, the flow-mediated vasodilation (FMD) was reduced in MID patients whereas the baseline arterial diameter, blood flow velocity, and endotheliumindependent dilatation were similar to controls [37].

m.11778G>A mutation in the ND4 gene, experienced right thalamic hemorrhage with intrusion to the ventricle at age 9y [40]. Angiography revealed an arteriovenous malformations (AVM) extending from the right posterior thalamus to the midbrain with feeders from the posterior thalamoperforate artery [40]. No reports are available, which describe cerebral aneurysms, cavernomas, or dural arteriovenous fistulas in MIDs.

Conclusion Premature atherosclerosis An argument for arteriopathy in MIDs is the finding of primary premature atherosclerosis in some of the MID patients in the absence of classical risk factors. In a female with MELAS syndrome premature atherosclerosis of the large cerebral arteries was detected on clinical and pathoanatomic investigations [38]. Premature atherosclerosis of the iliac arteries in the absence of classical risk factors was also reported in a 54yo patient with Leriche syndrome [26]. Despite excessive sport activity (cycling), this patient developed occlusion of both iliac arteries [26]. He was suspected to suffer from a MID based upon easy fatigability, exercise intolerance, abnormal lactate increase on the lactate stress test, mitochondrial myopathy on muscle biopsy, and magnetic resonance spectroscopy [26].

Association with migraine A further indicator for the presence of mitochondrial arteriopathy is the frequent association of MIDs with migraine (Table 2) [34,39]. From a neuropathological study on two MELAS patients showing highest COX-deficiency and highest heteroplasmy rates in leptomeningeal and cortical arteries it was concluded that mitochondrial arteriopathy coupled with cortical spreading depression may play a pathogenetic role not only in the development of SLEs but also in migraine [4]. Migraine or migraine-like headache has been particularly reported in MIDs listed in Table 2.

Vascular malformations in MIDs Though it is unknown if the prevalence of vascular malformation is increased in MIDs, there are single reports which show that vascular malformations occasionally occur in patients with MIDs. A single male with LHON due to the

Table 2 MIDs which manifest with collateral migraine or migraine-like headache. MID

Reference

MELAS MERFF LHON PEO Leigh syndrome (adult) MIRAS AHS

[4] [44] [45,46] [47] [48] [49] [50]

There is clear evidence that arteries can be primarily or secondarily affected in MIDs. Most frequently the cerebral arteries are affected although these findings derive from cerebral imaging and perfusion studies and only few autopsy or biopsy studies have been carried out. Second most frequently the skeletal muscle is affected by mitochondrial microangiopathy. Whether this finding is due to the easy accessibility of muscle tissue or the frequent affection of the skeletal muscle by the metabolic defect is unknown. It is also unknown if the distribution of arteriopathy varies within a family, between families, or depending on the heteroplasmy rate or the type and location of the mutation. Generally, it is conceivable that all arteries are affected but, as with specific syndromic MIDs, certain vessel beds may be more predominantly affected than others. To which degree particularly mitochondrial microangiopathy determines the phenotype of a MID is poorly understood and requires further detailed investigations. Further studies are warranted to investigate all open questions, particularly the pathogenetic background of mitochondrial arteriopathy and which regions are involved in mitochondrial arteriopathy.

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