Introduction

Fibromuscular dysplasia (FMD) is a systematic vascular disease that causes abnormal growth of cells in the artery walls. This non-atherosclerotic, non-inflammatory vascular disease makes artery walls overly weak or stiff, which can cause serious complications such as stroke, aneurysm and tearing of arteries(dissection). 

FMD has an incidence of around 3-4% in the general population and is found to be most common in individuals aged 25 to 50.^1,2 Women have a higher chance of experiencing it than men, and it causes 10% to 20% of all cases of renal artery stenosis.^2,3 Although the causes of FMD are unclear, genetic, environmental and hormonal factors are known to contribute to its development.³

Etiology and Risk Factors

Despite significant research efforts, the causesof fibromuscular dysplasia (FMD) remains unclear.³ However, its development is associated with environmental, hormonal and genetic factors.³

Genetic factors

Although most FMD cases are sporadic, the hereditary nature of FMD has been recognised since the 70s, where familial cases represent 3-7% of all  FMD cases.¹ This is supported by a study conducted by Pannier-Moreau et al, which involves the analysis of 104 patients suffering from renal FMD. The team reported an 11% prevalence of familial cases, where at least one sibling had signs of the disease.³

Genetic variants that may contribute to the pathogenesis of FMD have also been identified, where the associated variants are found in arterial-specific regulatory elements.⁴ Associated genes include PHACTR1, LRP1, ATP2B1, LIMA1 and SLC24A3.⁴ The genes are often integral to vascular contraction, playing functional roles in actin cytoskeleton and intracellular calcium homeostasis.⁴

In addition, significant genetic overlap between common cardiovascular diseases and traits and FMD has been reported.⁴ These cardiovascular diseases and traits include blood pressure, coronary artery disease, migraine and intracranial aneurysm.⁴

Hormonal influences

Progesterone receptor density and oestrogen exposure may explain the higher prevalence of FMD found in the female sex.⁵

Environmental factors

Smoking may increase an individual’s chance of developing FMD.⁵ This is supported by a retrospective analysis which showed a higher proportion of smokers among FMD patients.³ Also, the lifetime mechanical stress imposed on the blood vessels involved can also be an influencing factor.

Co-existing conditions

Fibromuscular dysplasia often occurs alongside a wide range of different cardiovascular conditions, including hypertension, arterial dissections, stroke, aneurysms, stroke and coronary artery disease (CAD).¹

Histopathology and Types of FMD                                          

Focal FMD and multifocal FMD

FMD can be classified into focal and multifocal FMD based on their angiographic appearance.³ Focal FMD presents as a single focal stenosis, whereas multifocal FMD presents with a distinctive string-of-beads pattern.⁶ Despite the substantial differences between these subtypes, such that they may be regarded as two distinct diseases, they have been found to coexist in a single patient.⁶

Intimal, medial and adventitial fibroplasia

Another method of classification is histopathological classification, which is based on the arterial layer affected. FMD can be classified into three main types, including intimal, medial, and adventitial fibroplasia.³ These variants of FMD are found to exist on their own or co-exist.³ 

Medial FMD

Medial FMD is the most common variant of FMD, which affects the middle layer of the blood vessel wall.³  It has a distinctive “string of beads” appearance on angiography due to the abnormal and irregular growth of cells, also known as dysplasia, in the wall of the renal artery.³

Intimal FMD

Intimal FMD is the second most common variant of FMD, which affects the innermost layer of the blood vessel wall.³ Collagen builds up around the inner lining of the artery, the intima, leading to fragmentation of the internal elastic lamina.³ A smooth, symmetric narrowing of the artery can be observed on an angiogram.³ 

Adventitial FMD

Adventitial FMD is the rarest variant of FMD, which affects the outermost layer of the blood vessel wall.³ It is characterised by a dense deposition of collagen in the adventitia, leading to a smooth narrowing of the artery that can be observed using an angiogram.³

Pathophysiological Mechanisms

Structural changes in blood vessels and altered blood flow

Collagen disposition and hyperplasia may lead to narrowing (stenosis) and blockage (occlusion) of the arteries. The narrowed arteries can restrict blood flow to the organs and potentially cause organ damage. Ruptures in the internal elastic lamina are also found in FMD lesions, which suggests damage or degradation of elastic fibres responsible for the elasticity of blood vessels.¹

These structural changes can impair the integrity of the vessel walls. Bulges (aneurysms) can develop at the weakened part of the arterial walls, which can increase the risk of rupture or dissection of blood vessels.⁷ 

Endothelial Dysfunction

The endothelium makes up the inner lining of blood vessels, which has important roles in regulating vascular tone, inflammation, wound healing, fibrosis and the formation of new blood vessels. As an indicator of the presence of subclinical lesions, triple signal (TS) has been found in the common carotid artery of patients with renal fibromuscular dysplasia.⁸ 

Among patients with FMD, triple signal (TS) is linked to endothelial dysfunction.⁸ Endothelial dysfunction can impair the ability of arteries to dilate and make them prone to inflammation and clotting. Also, impaired endothelial function has been known to increase the risk of developing serious complications such as aneurysms and stroke.

Vascular Smooth Muscle Cell Abnormalities

Through histological examinations, it was found that there is a widespread disorganisation of the tunica media in FMD-affected arteries.¹ Known as medial fibroplasia, this disorganisation is found in most cases of FMD.¹ In healthy arteries, smooth muscle cells (SMCs) that make up the tunica media are integral in maintaining the strength of the artery and regulating blood flow.¹ Normally, they are regularly arranged perpendicular to the flow of blood.¹ However, in arteries affected by FMD SMCs are found to be irregular in shape and organisation, with patches of fibrous tissue between them.¹

Moreover, research has demonstrated that in patients with renal multifocal fibromuscular dysplasia, their brachial arteries showed an impaired ability to dilate when their smooth muscle cells are directly stimulated by glyceryl trinitrate (GTN).⁹ This shows that patients with the disease have a reduced ability to dilate in response to chemical signals.

Symptoms of fibromuscular dysplasia (FMD)

Symptoms of FMD depend on the arteries affected, which may include any artery but most commonly affects renal and carotid arteries.³

Symptoms of FMD may include

• Headache
• Pulsatile tinnitus
• Hypertension
• High blood pressure
• Neck pain
• Dizziness or vertigo
• Kidney problems
• Changes in vision
• Speech impairment
• Weakness in arms or legs
• Stroke

Clinical Manifestations

The clinical manifestations depend on the blood vessels involved. For example, involvement of the renal artery can cause hypertension, whereas involvement of the carotid or vertebral artery may cause dizziness, thumping sounds in the ears, transient ischemic attack (TIA) and stroke.¹⁰

FAQs

What is the life expectancy of someone with fibromuscular dysplasia?

Most people with FMD can have a normal life expectancy. However, in rare cases, aneurysms may rupture and cause a stroke, permanent damage or death.

How is fibromuscular dysplasia diagnosed?

Imaging techniques including computed tomographic angiography (CTA) and magnetic resonance angiography allow the identification of vascular aneurysm and dissection in patients with FMD.⁵ This allows for early counselling on changing lifestyle risk factors and selection of treatment options and monitoring plans.⁵

How is fibromuscular dysplasia treated?

There is no cure for fibromuscular dysplasia. However, treatment methods to manage symptoms or complications are available. Treatment methods may involve quitting smoking, antiplatelet therapy, ongoing monitoring and anti-hypertensives.¹¹ For patients who don’t respond to hypertension medications,  surgical options such as open surgical dilatation, open access balloon dilatation and percutaneous transluminal angioplasty may be recommended.¹¹

Summary

Fibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disease characterised by abnormal cellular growth within arterial walls. FMD is more likely to occur in women and people from 25 to 50 years of age, and most commonly affects the renal and carotid arteries. 

The condition can be classified into focal and multifocal subtypes based on their angiographic appearance, with an alternative histopathological classification into intimal, medial and adventitial subtypes. The causes of FMD are yet to be elucidated, but studies suggest that a combination of genetic, hormonal and environmental factors may contribute to the disease.

FMD causes pathological changes in blood vessels, including collagen disposition, hyperplasia, endothelial dysfunction, smooth muscle cell abnormalities, and damage or degradation of elastic fibres. These changes can impair the integrity of the vessel walls, increasing the risks of aneurysms and dissections. Depending on the blood vessels involved, the symptoms or clinical manifestations of FMD may include dizziness, hypertension, pulsatile tinnitus, transient ischemic attack (TIA) and stroke.