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Review
Eyes and the heart: what a clinician should know
  1. Jing Yong Ng1,
  2. Essa Zarook1,
  3. Luke Nicholson2,3,
  4. Oculi-Cordis group,
  5. Mohammed Yunus Khanji4,5,6,
  6. Choudhary Anwar Ahmed Chahal5,7,8
    1. 1 Medical Education Department, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK
    2. 2 NIHR Moorfields Biomedical Research Centre, London, UK
    3. 3 Department of Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, UK
    4. 4 Department of Cardiology, University Hospital, Barts Health NHS Trust, London, UK
    5. 5 Department of Cardiology, Barts Heart Centre, London, UK
    6. 6 NIHR Barts Biomedical Research Centre, London, UK
    7. 7 Center for Inherited Cardiovascular Diseases, WellSpan Health, York, Pennsylvania, USA
    8. 8 Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
    1. Correspondence to Dr Mohammed Yunus Khanji, Department of Cardiology, Newham University Hospital, Barts Health NHS Trust, London, E13 8SL, UK; m.khanji{at}qmul.ac.uk; Dr Choudhary Anwar Ahmed Chahal; cchahal{at}wellspan.org

    Abstract

    The eye is prone to various forms of afflictions, either as a manifestation of primary ocular disease or part of systemic disease, including the cardiovascular system. A thorough cardiovascular examination should include a brief ocular assessment. Hypertension and diabetes, for example, would present with retinopathy and dyslipidaemia would present with corneal arcus. Multisystem autoimmune diseases, such as Graves’ disease, rheumatoid arthritis and sarcoidosis, would present with proptosis, episcleritis and scleritis, respectively. Myasthenia gravis, while primarily a neuromuscular disease, presents with fatigable ptosis and is associated with Takotsubo cardiomyopathy and giant cell myocarditis. Connective tissue diseases such as Marfan syndrome, which commonly presents with aortic root dilatation, would be associated with ectopia lentis and myopia. Wilson’s disease, which is associated with arrhythmias and cardiomyopathies, would present usually with the characteristic Kayser-Fleischer rings. Rarer diseases, such as Fabry disease, would be accompanied by ocular signs such as cornea verticillata and such cardiac manifestations include cardiac hypertrophy as well as arrhythmias. This review examines the interplay between the eye and the cardiovascular system and emphasises the use of conventional and emerging tools to improve diagnosis, management and prognostication of patients.

    • Hyperlipidemias
    • Atherosclerosis
    • Hypertension
    • Diabetes mellitus
    • Cardiomyopathies
    http://creativecommons.org/licenses/by-nc/4.0/

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

    https://doi.org/10.1136/heartjnl-2022-322081

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      Introduction

      The eye is frequently affected by systemic diseases, and modern medical practice has become increasingly specialised and focused on specific organ systems. However, patients often present with multiple system involvement, and it is important for clinicians, including cardiologists, to recognise ocular manifestations that may indicate underlying cardiovascular abnormalities. This review examines the complex interplay between the eye and the cardiovascular system and emphasises the use of conventional and emerging tools, such as artificial intelligence (AI), to improve diagnosis, management and prognostication of patients.

      Ocular examination

      Clinical examination is an indispensable aspect of diagnostic workup, and clinicians should continually hone their skills in this area. 1 A thorough cardiovascular examination should include a brief ocular assessment, as it can uncover critical findings that will inform further investigations and management. For cardiologists, a basic eye examination should encompass general inspection, orbit and periorbital inspection, pupils, focused ocular movement assessment and if an ophthalmoscope is available, to examine the fundus. Abnormalities in eyelid position, swelling, redness, eye prominence and skin changes may emerge during close inspection of the eyes and adnexa. A quick assessment of eye movements can also unmask vital signs such as lid lag, diplopia and fatigable ptosis, all of which may indicate underlying systemic conditions. After examination, one may elect to conduct a variety of investigations depending on the presenting issue and respective findings. These are summarised in the online supplemental table 1.

      Supplemental material

      Anatomy

      The structure of the eye can be described as two intersecting spheres with different radii (figure 1)—the smaller anterior segment formed by the cornea and the larger sphere made up primarily of the opaque sclera. The uvea, consisting of the iris, ciliary body and choroid, lies internal to the sclera, with the photosensitive retina located deeper still. The lens, situated behind the iris, is responsible for adjusting the focus of the vision. Along with the iris, they separate the eye into three chambers: namely the vitreous humour, the posterior and anterior chambers. The vitreous comprises the largest region and is located posterior to the lens, and the posterior chamber is located in-between the lens and the iris. The anterior chamber is situated between the iris and the cornea, of which aqueous humour flows through and is drained in the canal of Schlemm.

      Figure 1
      Figure 1

      Eye examination and systemic diseases involving the cardiovascular system. This figure depicts the various parts of the eye, numbered accordingly from anterior to posterior. Correspondingly, each part is co-labelled with the respective pathology of significance. AION, anterior ischaemic optic neuropathy.

      In the next section, common but important ocular signs are discussed, which should be elicited during a cardiovascular examination. A summary table of these signs and the cardiac manifestations of the associated condition can be found in table 1.

      View this table:
      Table 1

      Ocular signs and cardiac manifestations of associated condition

      Socket and skin

      Xanthelasma

      Xanthelasma is a yellowish, soft or semisolid calcareous around the eye socket that is often seen in the inner canthus of the upper eyelid (figure 2A). It is caused by deposition of cholesterol, mainly within the upper reticular dermis or in perivascular and periadnexal areas. In most cases, they tend to be asymptomatic, symmetric and the size of the lesions may grow over time even following correction of underlying lipid levels.2 3 Its prevalence is highest among the middle-aged women.4 Presence of xanthelasma is indicative of elevated low-density lipoproteins or triglycerides in approximately 50%, and is an independent risk factor for ischaemic heart disease and severe atherosclerosis.3 5–7

      Figure 2
      Figure 2

      Image panel depicting the various ophthalmological pathologies that are pertinent to the cardiologist. (A) Xanthelasma palpebarum (white arrows) seen over both inner eyelids bilaterally. (B) Proptosis. (C) Ptosis, seen in a patient with myasthenia gravis. (D) Anterior scleritis. (E) Cornea verticillata (orange arrow) of a patient with Fabry disease. (F) Corneal arcus (red arrow) as seen in a patient with hypercholesterolaemia. (G) Ectopia lentis seen as a superiorly subluxated lens (white arrowhead). (H) Sarcoid nodules (black arrows) seen in the eye of a patient with sarcoidosis. (I) Colour fundus photograph of left eye showcasing central retinal artery occlusion. Thin retinal arterioles and cherry-red spot (red arrowhead). (J) Central retinal vein occlusion with widespread retinal haemorrhages in all four quadrants of the retina. (K) Roth spot (white arrow and box) in a patient who had bacterial endocarditis. (L) Ocular ischaemic syndrome with blot haemorrhages (black arrowheads) in the mid-periphery of the retina. This is caused by reduced perfusion pressure into the retina commonly due to significant carotid stenosis. Permission granted, International Ophthalmology, 20 June 2020.

      Proptosis

      Proptosis (protrusion of the globe from the orbit >2 mm) is present in a wide range of diseases.8 Graves’ disease (autoimmune hyperthyroidism), orbital myositis, metabolic disease, neoplasm, sarcoidosis and orbital cellulitis are some causes of proptosis. Patients with hyperthyroidism may present initially with palpitations due to atrial fibrillation (AF). While the metabolic symptoms are usually overt, patients may initially present with cardiac symptoms; hence, vigilance for characteristic eye signs may prove key to a unifying diagnosis. Thyroid orbitopathy is usually bilateral but can be unilateral. It is also associated with other clinical findings, such as a lid lag, and limitation in extraocular motility. Proptosis accompanied by periorbital oedema, exophthalmos and complex ophthalmoplegia is highly suggestive of Graves’ disease (figure 2B). Other cardiac complications seen in hyperthyroidism include cardiomyopathy, pericardial effusion and heart failure. These are often reversed on appropriate management of thyroid function.

      Eyelid

      Ptosis

      Ptosis, also known as blepharoptosis, describes the abnormally low position of the upper eyelid (figure 2C), usually due to dysfunction of the levator palpebrae superioris, the Müller muscles or both. Patients may experience visual impairment or in severe cases, vision loss from the primary pathology (eg, giant cell arteritis). Variable ptosis, which may be accompanied by diplopia and complex ophthalmoplegia, is a major ocular manifestation of myasthenia gravis (MG). A distinctive feature of ptosis in MG is that the sign is more prominent with repetitive muscle contraction and improves with rest. The cardiac manifestations in MG may be under-recognised given the significant overlap in the classic symptoms of MG, so being attuned to the overall picture would be useful. MG is known to have a high incidence of cardiac involvement, with Takotsubo cardiomyopathy being the most reported cardiac complication.9 Although rare, giant cell myocarditis is another important fatal complication of MG. Other reported cardiac manifestations include QT prolongation, T wave changes and atrioventricular (AV) block.9

      Sclera and conjunctiva

      Scleritis

      Scleritis (figure 2D) often (50% of the time) presents with an underlying systemic illness, most frequently rheumatoid arthritis (RA). The key symptoms of scleritis include red sclera with deep, boring pain exacerbated by eye movements. Although precise pathogenic mechanisms are currently unclear, many studies have shown that coronary artery disease (CAD) is one of the most common causes of mortality in patients suffering from RA.10 11 Other important associations include sarcoidosis which can be associated with conduction system disease, ventricular tachyarrhythmias and heart failure. Other important causes of scleritis which may have cardiovascular effects include vasculitides, Wegner’s granulomatosis and Behcet syndrome, which themselves are associated with pericarditis and myocarditis. Although now rarer in the Western world, untreated syphilis can present with scleritis and aortitis, which may have aortic valve incompetence, and coronary ostial stenosis.12 13

      Blue sclera

      Blue sclera refers to a bluish discolouration of the usually white sclera, which occurs as a result of thinning of the surrounding collagen, showing the underlying uvea and venous system. This may indicate connective tissue disease: Marfan syndrome, Ehlers-Danlos syndrome, pseudoxanthoma elasticum and osteogenesis imperfecta. Ehlers-Danlos has vascular and non-vascular types which are important to be aware of given known association with aortopathy and valvular heart disease. Joint hypermobility syndromes, including Ehlers-Danlos and Marfan syndrome, are also associated with postural orthostatic tachycardia syndrome.14 Patients with pseudoxanthoma elasticum develop cardiovascular disease (CVD) due to elastic fibre degeneration and calcification of the internal elastic lamina of medium-sized arteries, leading to premature CAD, peripheral arterial disease, renovascular hypertension and can also develop a restrictive cardiomyopathy. Radial graft use for coronary artery bypass graft surgery should be avoided (due to radial arteries becoming fibrosed and calcified).15

      Cornea

      Cornea verticillata

      Cornea verticillata is an abnormal deposition seen in the inferior region of the superficial layer of the cornea with a colour ranging from milky to golden brown (figure 2E).16 In the early stage, the deposits may appear as a fine horizontal line, then curve around to form small vortexes, before becoming straight again at the periphery.17 The use of amiodarone or chloroquine may also lead to a similar opacity which can be differentiated by the presence of branches at the peripheral end.18 Cornea verticillata is highly sensitive and specific for Fabry disease, a rare X linked lysosomal storage disorder which can manifest with cardiac conduction system disease and structural abnormalities mimicking all phenotypes of sarcomeric hypertrophic cardiomyopathy. Tortuous vessels in the sclera and cataract may also be seen but they both have a much lower prevalence. Cornea verticillata is also extremely rare in patients without Fabry disease, making it almost pathognomonic of the condition. Hence, its presence should be followed by prompt specialist referral to confirm the diagnosis of Fabry disease (which can be achieved with genetic testing of GLA gene and in males serum alpha-1-galactosidase). It should be noted females can express Fabry disease (due to random X chromosome inactivation, known as lyonisation).

      Corneal arcus

      Corneal arcus are lipid deposits that appear as white or grey rings that form around the cornea (figure 2F). The ring usually forms in the superior and inferior regions that have greater perfusion and capillary permeability. With time, the arcus may grow and eventually form a complete ring surrounding the cornea. Prevalence of corneal arcus is around 20%–35%, more common in men and the African and Southeast Asian ethnicities.19 20 Generally, cases of corneal arcus also increase with age, reaching an incidence rate of 70% in those above 60 years old.21 The sign is usually benign in those above 50 years, but is associated with higher risk of atherosclerosis in those <50 years. Hence, in the younger population, further investigations should be warranted to assess for underlying dyslipidaemia and for possible premature CAD.21

      Kayser-Fleischer rings

      Kayser-Fleischer (KF) rings (figure 3) are golden or brownish rings secondary to copper depositions in the basement membrane of the corneal endothelium. They may also appear as greenish yellow, ruby red, bright green or blue rings. In patients with severe copper overload, the rings may be visible to the naked eye. Like corneal arcus, they always form in the superior and inferior regions in the initial stage, then grow to form a complete circle around the cornea. KF rings are generally recognised as the pathognomonic sign of Wilson’s disease (WD), a rare condition that promotes accumulation of copper and can be associated with cardiac manifestations such as arrhythmias, cardiomyopathy, cardiac death and autonomic dysfunction.22 23 Fleischer rings are partial or complete iron deposition rings in deep epithelium encircling the base of the cone, best visualised with cobalt blue light. The iron deposition can be secondary to WD or hereditary haemochromatosis, which can also present with infiltrative cardiac disease due to iron deposition. This can present with bradycardia as well as restrictive cardiomyopathy.

      Figure 3
      Figure 3

      This is a figure of a patient with Kayser-Fleischer ring (white arrow) secondary to copper overload.

      Lens

      Ectopia lentis

      Ectopia lentis is defined as a dislocation of the crystalline lens of the eyes in which the lens may lie partially or completely outside the hyaloid fossa, in the anterior chamber or free-floating in the vitreous (figure 2G).24 It is most commonly seen in patients with Marfan syndrome which accounts for up to 68% of the cases, and they typically have a bilateral presentation with lenses often displaced towards the superior-temporal direction.24 25 Patients with ectopia lentis normally present with pain, monocular diplopia or episodic blurred vision. When presented alongside aortic root dilatation, the diagnosis of Marfan syndrome is highly indicative. An abnormal red reflex using an ophthalmoscope may give a clue about this, but it will require direct ophthalmoscopy. In some cases, the displaced lens can be visible even to the naked eye. Very mild cases would need the more advanced slit-lamp examination through the ophthalmology referral. Other common cardiac manifestations of Marfan disease include dissection of ascending aorta, valvular heart disease and dilatation of the pulmonary artery. In patients with Marfan syndrome, a wide range of ocular complications can be seen, such as myopia, early-onset cataract, glaucoma, strabismus, phacodonesis (vibration of lens seen with ocular movements) and iridodonesis (tremulousness which can occur with ectopia lentis and subluxation). Therefore, it may also be appropriate to involve an ophthalmologist at an early stage in the care of these patients.

      Uveal tract

      Uveitis

      Uveitis is a type of intraocular inflammation affecting the middle layer of the eye known as the uveal tract. Typically, uveitis is suspected if one presents with ocular redness, pain, photophobia, deteriorating vision or floaters. The ocular sign is commonly seen in patients with sarcoidosis (figure 2H), and may be accompanied by conjunctiva nodules (small, yellowish, millet seed-sized nodules primarily located in the palpebral conjunctiva or on the lacrimal gland). Identifying the presence of cardiac involvements in these patients remains challenging yet essential as it is a major cause of morbidity and mortality. Cardiac sarcoidosis is a diagnosis of exclusion that relies heavily on effective clinical history and examination to support the use of appropriate investigations. Cardinal features of cardiac sarcoidosis include AV blocks, ventricular arrhythmias and cardiomyopathy.26 The presence of uveitis and conduction system disease such as high-degree AV block should be considered sarcoidosis until proven otherwise. Patients may also present with other rarer cardiac manifestations such as pericardial effusion, mitral regurgitation and atrial arrhythmias.25

      Retina

      The microvasculature found in the retina is prone to be affected by a wide range of diseases. Occlusion of the blood vessels results in retinal artery occlusion or retinal vein occlusion. In both, patients generally present with unilateral painless visual loss. Ophthalmoscopy is useful to help differentiate the two conditions. In retinal artery occlusion, an opaque fundus with red fovea (cherry-red spot) is typically seen (figure 2I). Often, an embolus such as Hollenhorst plaque (a cholesterol embolus) may be visible. A relative afferent pupillary defect can also be elicited. Echocardiography should be performed to identify an embolic source. In contrast, widespread haemorrhages and tortuous veins accompanied by retinal oedema are seen in retinal vein occlusion (figure 2J). These patients may also present with hypertension, which is a major risk factor for the condition. While they should be referred to an ophthalmologist for a thorough evaluation, cardiologists should be aware that they are at significantly increased risk of cardiovascular complications including CAD, AF and valvular heart diseases.27 28 Roth spots (white centred retinal haemorrhage) (figure 2K) are seen with multiple pathologies including endocarditis, pre-eclampsia, hypertension, myeloma and carbon monoxide poisoning. Awareness of variability in retinal and general funduscopy appearance between ethnicities should be factored with evaluation.29

      Ocular ischaemic syndrome (OIS) is another rare cause of visual loss and is mostly secondary to atherosclerosis.30 On examination of the retina, narrowed arteries and dilated veins are seen; retinal haemorrhages and microaneurysms are also frequently noted (figure 2L). Importantly, CVD accounts for around 66% of the death in patients with OIS, followed by stroke.31 It has been demonstrated that more than half of these patients have diabetes mellitus or hypertension, and myocardial infarction occurs in around 4% of them.32

      Retinal arteriosclerosis refers to the thickening of what is considered the thin walls of the retinal arterioles, leading to narrowing to be visualised and a change in the colour of the blood from red to either silver or copper. The Scheie classification groups findings into grades as seen in figure 4.

      Figure 4
      Figure 4

      Stages of hypertensive eye disease. The Scheie classification was used to describe the changes associated with retinal hypertensive retinopathy, with grade 1 reflecting the least and grade 4 reflecting the most. (A) Grade 1 hypertensive retinopathy with mild arteriolar narrowing (white arrows). (B) Grade 2 hypertensive retinopathy characterised by focal retinal arteriolar narrowing (white arrowhead). (C) Grade 3 hypertensive retinopathy. Findings are the same as grade 2, with retinal haemorrhages (black arrows) and cotton wool spots (red arrow). (D) Findings are the same as grade 3, with additional optic disc swelling and retinal exudates (black arrowhead).

      Diabetes also has a profound effect on the retina. Important diabetic retinopathies that should not be missed include retinal haemorrhage, aneurysms, hard exudates (small yellowish deposits), cotton wool spots (fluffy white spots) and neovascularisation (hallmark of proliferative diabetic retinopathy (figure 5)). Diabetic microangiopathy can be classified into non-proliferative and proliferative, with the latter referring to neovascularisation taking place either on the surface of the retina or the optic nerve head. The vitreous humour may also be opacified and vitreous haemorrhage may be seen on funduscopy for proliferative diabetic retinopathy. It has been shown that patients with either proliferative retinopathy or diabetic macular oedema are at an increased risk of acute coronary syndrome, stroke, cardiac autonomic neuropathy, as well as cardiovascular-related death.33–35

      Figure 5
      Figure 5

      Stages of diabetic retinopathy. (A) Mild non-proliferative diabetic retinopathy with microaneurysms (black arrow and box) only. (B) Moderate non-proliferative diabetic retinopathy with more than four blot haemorrhages (white arrows) in one hemifield. (C) Severe non-proliferative diabetic retinopathy. More than four blot haemorrhages can be seen in both hemifields. (D) Proliferative diabetic retinopathy with new vessels (black arrow) on disc and other regions.

      Optic disc

      Optic disc swelling can present with papilloedema as well as diabetic papillitis and hypertensive papillopathy, with the latter considered to be urgent should the patient present acutely, as it may point toward accelerated or malignant hypertension. Anterior ischaemic optic neuropathy may lead to unilateral optic disc swelling, and optic disc pallor may be seen in central retinal artery occlusion or diabetes. On examining the optic disc, blood vessel arcades branching from the disc can be observed for retinal vascular disease. More acute retinopathic changes may point in the direction of accelerated hypertension.

      Future perspectives

      Given the link between macrovasculature and microvasculature, there is current research interest in assessing the role of ocular screening for identifying and estimating future CVD risk. The EYE-MI Pilot looked at the link between vascular density of retinal microvasculature and the cardiovascular profile. It was shown that those with a lower retinal vascular density had higher AHA (American Heart Association) and GRACE (The Global Registry of Acute Coronary Events) scores, along with a poorer left ventricular function.36 In recent years, AI has become a viable option for enhancing the effectiveness and accuracy of such predictions. This was further explored in a study that used deep learning, a type of AI, to predict CVD risk factors (namely age, blood pressure, body mass index and HbA1c) from retinal fundus imaging.37 In cardiology, AI is also being trained to analyse ECGs as it may detect patterns that are not visible to the naked eye, hence allowing early detection of arrhythmias and other cardiac conditions.38

      Overall, the results are promising, showing that integration of AI into clinical examination is possible and could revolutionise the industry. While its use in clinical practice is still in the early stages, integration of AI holds the promise of substantially improving the precision and efficiency of medical diagnosis as well as risk stratification.

      However, AI does not come without potential limitations. It is a system that needs perfecting over time and is only as good as the data they are trained on. The algorithms require regular adjustments when new evidence becomes available. As a massive training dataset is needed, there may be potential challenges to information governance and confidentiality. Additionally, there are also other parameters to be considered prior to its implementation, including the hardware requirements, safety of patients, as well as ethical concerns.

      Summary

      Good clinical examination has always been holistic with inclusion of the eyes, as part of any specialty clinical evaluation, including the heart. Increased reliance on investigative tools and increasing bureaucracy are threatening to eliminate the time-honoured clinical examination skills. We have demonstrated the intricacies of pathology of the eye and how these relate to the cardiovascular system. Mastery of cardiology follows mastery of internal medicine—acquiring and maintaining these skills will improve clinical acumen and identify signs which may otherwise be missed thus helping to improve diagnosis and patient management.

      Ethics statements

      Patient consent for publication

      Ethics approval

      Not applicable.

      Acknowledgments

      We would like to express our sincere gratitude to Rachael L Niederer from the Department of Ophthalmology, University of Auckland, Auckland, New Zealand; Marcela Bohn De Albuquerque Alves from West Hertfordshire Teaching Hospitals NHS Trust; Clara Vazquez-Alfageme and Lim Wei Sing from the Royal Eye Unit, Kingston Hospital NHS Foundation Trust, Kingston upon Thames; and Eleftherios Agorogiannis from the Uveitis Service, Manchester Royal Eye Hospital, Oxford Road, Manchester for generously providing us with the photos used in this paper. Their contributions were instrumental in making this review possible.

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      Supplementary materials

      • Supplementary Data

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      Footnotes

      • JYN and EZ contributed equally.

      • MYK and CAAC contributed equally.

      • Collaborators the Oculi-Cordis Group: C Anwar A Chahal; Center for Inherited Cardiovascular Diseases, Genomic and Precision Medicine, WellSpan Health, (USA). Clara Vazquez-Alfageme; Royal Eye Unit, Kingston Hospital NHS Foundation Trust, Kingston upon Thames, (UK). Eleftherios Agorogiannis; Uveitis Service, Manchester Royal Eye Hospital, Manchester, (UK). Essa Zarook; Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, (UK). Jing Yong Ng; Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, (UK). Lim Wei Sing; Royal Eye Unit, Kingston Hospital NHS Foundation Trust, Kingston upon Thames, (UK). Luke Nicholson; Moorfields Eye Hospital, London, (UK). Marcela Bohn De Albuquerque Alves; West Hertfordshire Teaching Hospitals NHS Trust, (UK)/ Mohammed Y Khanji; Newham University Hospital, Barts Health NHS Trust, London, (UK). Rachael L Niederer; Department of Ophthalmology, University of Auckland, Auckland, (New Zealand).

      • Contributors JYN, EZ have equal contribution as first authors. MK and CAAC have equal contributions as senior authors.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.