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Review
Positron emission tomography imaging in cardiovascular disease
  1. Jason M Tarkin1,
  2. Andrej Ćorović1,
  3. Christopher Wall1,
  4. Deepa Gopalan2,
  5. James HF Rudd1
  1. 1 Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
  2. 2 Radiology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, Cambridgeshire, UK
  1. Correspondence to Dr Jason M Tarkin, Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 2QQ, UK; jt545{at}cam.ac.uk

Abstract

Positron emission tomography (PET) imaging is useful in cardiovascular disease across several areas, from assessment of myocardial perfusion and viability, to highlighting atherosclerotic plaque activity and measuring the extent of cardiac innervation in heart failure. Other important roles of PET have emerged in prosthetic valve endocarditis, implanted device infection, infiltrative cardiomyopathies, aortic stenosis and cardio-oncology. Advances in scanner technology, including hybrid PET/MRI and total body PET imaging, as well as the development of novel PET tracers and cardiac-specific postprocessing techniques using artificial intelligence will undoubtedly continue to progress the field.

  • advanced cardiac imaging
  • nuclear cardiac imaging
  • positron emission tomographic (PET) imaging
  • chronic coronary disease
  • systemic inflammatory diseases

https://doi.org/10.1136/heartjnl-2019-315183

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    Introduction

    Unlike other imaging modalities, positron emission tomography (PET) enables the detection of biological processes and molecular expression within the body as they occur in real time. While PET scanning offers only very limited detail on anatomical structure, hybrid PET/CT or PET/MRI scanners effectively combine molecular and structural imaging. In this article, we review the latest advances in clinical and experimental applications of PET imaging in cardiovascular disease (figure 1).

    Figure 1
    Figure 1

    Potential scope of PET imaging in cardiovascular disease. PET, positron emission tomography; CVD, cardiovascular disease; ICD, implantable cardioverter difibrillator; VT, ventricular tachycardia

    Ischaemic heart disease

    Perfusion imaging

    Ischaemia testing is important for risk stratification in stable angina, both as a marker of disease burden and to enable the safe deferral of patients without ischaemia to medical therapy. A study of 16 029 patients found that early revascularisation of ischaemic coronary lesions detected by 82Rubidium PET was associated with improved survival in a propensity score adjusted Cox regression model.1 However, the randomised multicentre ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial confirmed that ischaemia-guided percutaneous coronary intervention for stable angina does not reduce rates of myocardial infarction (MI) or death compared with lifestyle interventions plus medical therapy alone.2

    While single photon emission CT (SPECT) is the most commonly used and accessible nuclear method for imaging myocardial perfusion, PET offers several advantages. The advantages of PET over SPECT include the physical properties of the radiopharmaceuticals (eg, 82Rubidium, 15O-water, 13N-ammonia) and the imaging technology itself, resulting in improved image quality with better spatial and temporal resolution, lower radiation exposure and shorter scan times. In a prospective, single-centre study, 15O-water PET myocardial perfusion imaging with quantitative flow analysis demonstrated superior diagnostic accuracy to SPECT myocardial perfusion imaging with 99mTechnetium/tetrofosmin for the detection of haemodynamically significant coronary stenoses defined by invasive fractional flow reserve.3 Indeed, the close correlation between quantitative flow metrics derived from 15O-water PET and fractional flow reserve was shown in the original clinical validation of this invasive pressure-derived marker of coronary flow.

    PET imaging also allows the quantification of absolute myocardial blood flow, which avoids the problem of balanced ischaemia in patients with multivessel disease (figure 2). Measurement of coronary flow reserve (the ratio of myocardial blood flow at peak hyperaemia to rest) by PET can help diagnose microvascular angina, and provides a marker of overall cardiovascular risk independent of anatomical stenosis severity.4

    Figure 2
    Figure 2

    Myocardial blood flow quantification. 82Rubidium PET/CT images reconstructed in 3D from a man with stable angina showing (A) homogeneous tracer uptake on relative perfusion imaging, but (B) very low absolute myocardial blood flow in all myocardial regions (1.0–1.3 mL/g/min) on quantitative perfusion imaging due to severe multivessel coronary artery disease resulting in balanced ischaemia. 3D, three-dimensional; PET, positron emission tomography.

    Plaque imaging

    Atherosclerosis is a chronic vascular inflammatory disease orchestrated by the innate and adaptive immune responses to endothelial injury, subintimal accumulation of oxidised lipids, necrotic cellular debris and cholesterol crystals associated with danger signalling and inflammasome activation. By examining the molecular signatures of high-risk atherosclerotic plaques using PET, markers of inflammation and disease activity can reveal unique biological insights and help to better understand the underlying mechanisms connecting to wider patient and environmental-level factors.

    18F-fluorodeoxyglucose

    18F-fluorodeoxyglucose (FDG) is a glucose analogue used commonly in clinical medicine in a variety of disease states. 18F-FDG uptake is closely related to macrophage density in atherosclerotic plaques, although vascular signals are also influenced by the efficiency of tracer delivery via the microvasculature, degree of plaque hypoxia, and uptake by smooth muscle cells and other glucose metabolising cells in the vessel wall. Nonetheless, 18F-FDG has been shown to accurately differentiate culprit from non-culprit carotid atherosclerotic plaques, and to predict risk of early stroke recurrence.5 Arterial 18F-FDG signals have also been associated with clinical cardiovascular risk factors, including systemic inflammatory conditions linked to increased cardiovascular risk, such as psoriasis and rheumatoid arthritis, as well as serum biomarkers, high-risk plaque morphology and the incidence of future cardiovascular events.6 Moreover, research examining cardiosplenic and heart–brain interactions using 18F-FDG PET has demonstrated close relationships between both psychological stress and chronic noise exposure, with increased vascular inflammation and cardiovascular risk.7 8

    18F-FDG has also been used successfully as a surrogate marker of early drug efficacy in numerous clinical cardiovascular drug trials. For example, dampening of arterial inflammation has been observed in studies of cardiovascular patients treated with the PCSK9 inhibitor alirocumab9 and the interleukin-1β inhibitor canakinumab,10 two drugs that have been shown to associate with reduction in cardiovascular events. However, despite these promising data arising predominately from non-coronary 18F-FDG imaging studies, even with attempted myocardial suppression, diffuse myocardial uptake precludes coronary signal interpretation in up to half of patients imaged using 18F-FDG.11

    Other PET tracers for coronary imaging

    To overcome the limitations of 18F-FDG for plaque imaging, several alternative PET tracers have been examined for use in atherosclerosis and coronary imaging (figure 3). Among the experimental molecular imaging approaches tested in atherosclerosis research include radioligands targeted at endothelial activation, cell proliferation, cholesterol transport, low-density lipoprotein oxidation, microcalcification, matrix metalloproteases, apoptosis, hypoxia, neoangiogenesis and thrombosis.

    Figure 3
    Figure 3

    Novel PET tracers for coronary atherosclerosis imaging. (A) 18F-NaF, (B) 68Ga-DOTATATE and (C) 68Ga-pentixafor PET/CT images showing increased tracer signals (arrows) in coronary atherosclerotic plaques, with low background activity from the myocardium. Images adapted from (A) Tarkin et al,6 (B) Tarkin et al 17 and (C) Derlin et al.18 18F-NaF, 18F-sodium fluoride; PET, positron emission tomography.

    18F-sodium fluoride (18F-NaF) binds to exposed hydroxyapatite in bone and has been well characterised in atherosclerosis as a marker of developing vascular microcalcifications that cannot be detected by CT scanning.12 With its low myocardial signal, 18F-NaF has demonstrated superior ability in identifying high-risk coronary lesions compared with 18F-FDG.13 When compared with CT, 18F-NaF binding occurs in high-risk low-attenuation atherosclerotic plaques, but with poor sensitivity.14 Pericoronary adipose tissue density is another high-risk CT feature associated with coronary 18F-NaF uptake.15

    A feasibility study of coronary PET/MRI using 18F-NaF and 18F-FDG highlighted the potential advantages and technical challenges of this hybrid imaging approach.16 Cardiac-specific solutions to mitigate the impact of these technical challenges inherent to PET imaging of the coronary arteries, including corrections for cardiorespiratory motion, partial volume effects and patient movement during scanning, are in active development.

    Novel approaches for inflammation imaging include PET tracers targeted at macrophage activation antigen somatostatin receptor subtype-2 (SST2), immune cell C-X-C chemokine receptor-4 (CXCR4) and macrophage folate receptor β. Findings of prospective clinical studies examining the use of the SST2 PET tracer 68Ga-DOTATATE17 and the CXCR4 tracer 68Ga-pentixafor18 for imaging coronary arterial inflammation in patients with atherosclerosis show promise.

    Postinfarct myocardial inflammation imaging

    Acute MI triggers an initial inflammatory surge that allows clearance of necrotic myocardial debris by macrophages and other leucocytes recruited to the infarcted tissue. With resolution of inflammation follows a reparative phase, involving angiogenesis, scar formation and wound healing. However, excessive myocardial inflammation fuelled by maladaptive mononuclear phagocytic trafficking impairs myocardial salvage, leading to adverse remodelling and chronic left ventricular dysfunction.

    Although trials of broad-spectrum immunosuppressive agents after MI have yielded disappointingly negative results to date, PET imaging might be useful in the future to inform the use of more specifically targeted anti-inflammatory therapies that are the subject of ongoing evaluation. Moreover, by combining PET imaging of myocardial inflammation with detailed MRI assessments of ventricular function, tissue characterisation and stress perfusion, hybrid PET/MRI has the potential to offer a truly comprehensive non-invasive work-up for patients with ischaemic heart disease.

    Studies of postinfarct myocardial inflammation imaging have been performed using 18F-FDG and several other PET tracers. A study of 18F-FDG PET/MRI performed in 49 patients within the first week after MI showed increased tracer uptake in infarcted myocardial segments to be associated with peripheral CD14+/CD16− monocyte count, extent of fibrosis identified by late gadolinium enhancement and severity of left ventricular impairment.19 Another study of 12 patients with MI demonstrated increased 68Ga-DOTATATE signals in both recently infarcted myocardium and areas of old myocardial injury.20 The αvβ3 integrin-binding PET tracer 18F-fluciclatide has also been shown to differentiate infarcted from remote myocardium in patients with MI.21 In this study, 18F-fluciclatide uptake in hypokinetic myocardial segments with subendocardial infarction on MRI was associated with an increased probability of functional recovery. Preclinical data on 18F-GE180, which binds to the mitochondrial translocator protein, and 68Ga-pentixafor, highlight the contributions of neuroinflammation and splenic activation to the systemic inflammatory response after MI, and the ability of an ACE inhibitor to attenuate this response in mice.22 23

    Myocardial viability imaging

    Myocardial viability is a key consideration for patients with ischaemic cardiomyopathy when contemplating revascularisation. Viability can be inferred by lack of full-thickness scarring on MRI or by resting SPECT images, as myocardial extraction of perfusion tracers requires intact cell function. However, 18F-FDG PET is the most sensitive viability imaging method for predicting the recovery of left ventricular function. As a glucose analogue taken up by all metabolically active cells using glucose as its substrate, myocardial 18F-FDG uptake implies cellular viability. By comparing viability and perfusion, regions of the so-called ‘hibernating’ myocardium can be distinguished from necrotic tissue. Hibernating myocardium can be assessed by dual PET imaging with 18F-FDG and a perfusion tracer, or potentially with 11C-acetate, which provides measures of both oxidative metabolism and regional blood flow.24

    Non-ischaemic cardio-inflammatory and cardiomyopathic diseases

    18F-FDG PET can be used to confirm cases of acute myocarditis where there is diagnostic uncertainty, to screen for cardiac involvement in systemic vasculitides (figure 4), and potentially to help predict response to steroid therapy in patients with constrictive pericarditis.25 Myocardial 18F-FDG uptake has also been studied in patients with inherited cardiomyopathies, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and Anderson-Fabry disease. The use of novel tracers targeted to specific pathways and receptors, such as myocardial angiotensin II receptor type 1,26 could shed further light on potential cardiomyopathic mechanisms. Current uses for nuclear imaging in the clinic include diagnosis of cardiac involvement in sarcoidosis and amyloidosis.

    Figure 4
    Figure 4

    18F-FDG imaging in cardiac sarcoidosis. 18F-FDG PET/CT and MRI from a woman with cardiac involvement in sarcoidosis. There is avid PET uptake in (A) mediastinal and (D) hilar lymph nodes (arrows), as well as in the myocardium (asterisks) at (B) the base of the right ventricular free wall and (E) the ventricular septum. MRI shows (C) focal right ventricular wall thickening (white arrowhead) and (F) mild mid-wall late gadolinium enhancement in the basal septum (black arrowhead) corresponding to myocardial 18F-FDG PET signals. 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

    Cardiac sarcoidosis

    Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology, characterised histologically by the presence of non-caseating granulomas. Cardiac involvement in sarcoidosis is a poor prognostic feature, which is recognised clinically in roughly 5% of patients with the disease, and is associated with conduction system abnormalities, ventricular arrhythmias and progressive heart failure. Up to two-thirds of patients have isolated cardiac disease, and the finding of silent cardiac involvement is not uncommon in autopsy and MRI studies. While early anti-inflammatory treatment may be effective in slowing cardiac disease progression, due to non-specific electrocardiographic and echocardiographic findings, and the low sensitivity of cardiac biopsy, identification of cardiac sarcoidosis remains a diagnostic challenge.

    Both MRI and 18F-FDG PET are used to diagnose cardiac sarcoidosis (figure 5). Among other features, patchy, multifocal late gadolinium enhancement on MRI, which often occurs in the septum and lateral wall and spares the endocardium, is a common finding in cardiac sarcoidosis. Although detection of myocardial fibrosis by MRI is an adverse prognostic feature in cardiac sarcoidosis, it cannot differentiate active versus inactive disease. To determine disease activity, 18F-FDG PET is the best current imaging method, with focal or focal-on-diffuse uptake patterns with matched perfusion defects indicative of active disease. A typical PET imaging protocol for sarcoidosis involves fasting starting 24 hours before the scan ± high-fat dietary preparation and intravenous heparin, followed by rest perfusion imaging and then 18F-FDG imaging. Rest perfusion defects occur in patients with sarcoidosis because of scarring or microvascular dysfunction due to myocardial inflammation.

    Figure 5
    Figure 5

    Active large vessel vasculitis with cardiac involvement. 18F-FDG PET/CT images in (A) sagittal and (B, C) axial views from a woman with active large vessel vasculitis and previous aortic valve surgery showing increased tracer uptake of the aortic root (arrows), ascending aorta and inferior wall of the left ventricle (asterisks). 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

    Overall, 18F-FDG PET has 90% sensitivity and 78% specificity for detection of cardiac sarcoidosis.27 Hybrid 18F-FDG PET/MRI scanning has further potential to improve the diagnostic accuracy in cardiac sarcoidosis by simultaneously reporting on the pattern of injury and extent of disease activity.28 In the absence of right ventricular 18F-FDG uptake, the positive rate of endomyocardial biopsy for diagnosing cardiac sarcoidosis is very low.29 There is some evidence to suggest that 18F-FDG imaging can help predict the risk of sustained ventricular tachycardia or death.30 However, as non-specific 18F-FDG uptake is seen in up to 20% of patients with suspected cardiac sarcoidosis, several alternative PET tracers with inherently low background myocardial signals have also been tested. These tracers include 68Ga-DOTATATE,31 which may be more specific for inflammation than 18F-FDG, and 18F-fluorothymidine,32 a marker of cell proliferation. Moreover, the application of texture analysis, a computational measure of inhomogeneity among adjacent pixels or voxels on images, to 18F-FDG PET imaging may also improve the diagnostic accuracy for cardiac sarcoidosis and could infer additional prognostic information.33

    Cardiac amyloidosis

    Cardiac involvement in amyloidosis, most commonly due to acquired light-chain or transthyretin-related amyloidosis, is characterised by extracellular deposition of amyloid fibrils within the heart and can manifest clinically as a restrictive cardiomyopathy. While bone scintigraphy is one method of confirming transthyretin amyloidosis, there are several amyloid-binding PET tracers used in cerebral amyloidosis imaging that also show promise for detection of cardiac amyloidosis, including 18F-florbetapir, 18F-florbetaben and 11C-Pittsburg compound B. These amyloid-specific tracers could be useful for monitoring the response to treatments such as tafamidis, a transthyretin-binding therapy which has been shown to be beneficial for the treatment of amyloid cardiomyopathy. An ability of 18F-NaF to differentiate transthyretin cardiac amyloidosis from light-chain amyloidosis and control subjects without the disease was also shown in a pilot study of 14 patients using PET/MRI.34

    Cardiac neuronal imaging and electrophysiology

    The autonomic nervous system contributes substantially to the regulation of heart rate, blood flow and contractility, and is dysfunctional in several disease states, including heart failure. Innervation imaging research using 123I-metaiodobenzylguanidine SPECT has shown that in heart failure, sympathetic nervous system activation leads to downregulation of β-adrenergic receptors and promotes left ventricular remodelling. Ischaemic sympathetic nerve damage has also been observed in patients with stable coronary disease, most likely due to a combination of neuronal stunning, decreased cell function and anatomical denervation. In patients with MI, both the nerve terminals and nerve fibres within the ischaemic zone become damaged, with denervation often extending beyond the scar in transmural infarction.35

    Several PET tracers have been examined for imaging cardiac innervation, including 11C-hydroxyephedrine (HED), 11C-epinephrine and 18F-fluorohydroxyphenethylguanidines. 11C-HED binds to the presynaptic uptake-1 transporter at sympathetic nerve endings. As sympathetic dysfunction after MI is associated with the development of malignant ventricular arrhythmias,36 cardiac neuronal imaging could become a useful method for risk stratification. In a study of patients with severe ischaemic cardiomyopathy, sympathetic denervation identified by 11C-HED PET was a significant predictor of sudden cardiac arrest, independent of left ventricular ejection fraction and infarct volume.37 Moreover, integration of three-dimensional scar maps derived from 18F-FDG PET/CT imaging could help to facilitate substrate-based ventricular tachycardia ablations by identifying non-transmural scar undetectable by endocardial voltage recordings.38

    Valvular heart disease

    Infective endocarditis

    18F-FDG PET imaging is increasingly used in the evaluation of both prosthetic valve endocarditis (figure 6) and cardiac device-related endocarditis. When evaluating prosthetic valves with echocardiography, postsurgical appearances can complicate accurate assessment of endocarditis. In this scenario, current clinical guidelines support the use of 18F-FDG PET in patients with suspected prosthetic valve endocarditis for valves that have been implanted for more than 3 months, as postoperative inflammatory response may also result in non-specific 18F-FDG uptake.39 In addition to postsurgical inflammation, 18F-FDG uptake mimicking endocarditis can also be seen in patients with vasculitis, thrombi, atherosclerosis, cardiac tumours and foreign body reactions.

    Figure 6
    Figure 6

    Infective endocarditis. 18F-FDG PET/CT images from a man with prosthetic valve infective endocarditis showing increased PET uptake in relation to the (A) aortic and (B) mitral valves (arrows), as well as (C) upper and (E) lower limb septic emboli (asterisks) and (D) spinal osteomyelitis (arrowhead). 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

    A study of 160 patients with suspected prosthetic valve-related endocarditis showed 100% sensitivity and 91% specificity using 18F-FDG PET.40 In another study of 173 consecutive patients with endocarditis, 18F-FDG was also predictive of major cardiac events in prosthetic valve endocarditis and new embolic events within the first year following infection.41 In this study, 18F-FDG PET scans were positive in 83% of patients with prosthetic valve endocarditis, but only 16% of native valve endocarditis. All 12 of 14 patients with 18F-FDG PET scans interpreted as consistent with endocarditis prior to valve surgery in another study were associated with operative findings of infection or positive microbiological tests.42 In patients with suspected transcatheter aortic valve replacement infective endocarditis, a multicentre study showed the inclusion of 18F-FDG PET and/or cardiac CT led to significant changes in the clinically adjudicated diagnosis in 33% of patients.43

    Although echocardiography remains the first-line investigation for both prosthetic valve and device-related endocarditis, clinical guidelines also recommend that 18F-FDG PET can be considered in patients with suspected device-related infection, with positive blood cultures and negative echocardiography.39 Indeed, nuclear imaging with either 18F-FDG PET or leucocyte-labelled SPECT has been shown to improve the ability to accurately diagnose device-related infections when the initial diagnosis is inconclusive.44 Unlike echocardiography, 18F-FDG PET can also help to identify extracardiac sources of infection and septic emboli.

    Aortic stenosis

    In addition to its uses in atherosclerosis, and possibly cardiac amyloidosis, 18F-NaF has been identified as an early marker of disease progression and bioprosthetic valve degeneration in aortic stenosis. In a study of 121 individuals imaged with 18F-NaF and 18F-FDG, PET signals from both tracers were elevated in patients with aortic stenosis, compared with control subjects.45 In subsequent studies, 18F-NaF signals in aortic stenosis were shown to represent areas of active tissue calcification histologically, predictive of progressive aortic valve calcification measured by CT,46 as well as cardiovascular death and the need for aortic valve replacement,47 and future bioprosthetic valve dysfunction.48 18NaF PET is currently being evaluated as a surrogate marker of drug efficacy in a randomised, placebo-controlled trial of two drugs currently used for osteoporosis, alendronic acid and denosumab, a human monoclonal antibody that inhibits osteoclast formation, in patients with aortic stenosis (ClinicalTrials.gov: NCT02132026).

    Cardio-oncology

    18F-FDG PET is used commonly for evaluating cardiac masses when the underlying diagnosis cannot be confirmed by anatomical imaging alone (figures 7 and 8). Benign cardiac lesions are typically less 18F-FDG avid than malignant causes.49 Other PET tracers used in oncology may also be useful in classifying cardiac tumours, such as 68Ga-DOTATATE, which is used primarily for neuroendocrine tumour imaging. Another emerging role of PET for cardio-oncology research is in chemotherapy-induced cardiotoxicity. In one study, decreased myocardial perfusion reserve observed using 82Rubidium PET in patients with lymphoma was identified as a potential early marker of doxorubicin-induced cardiotoxicity.50

    Figure 7
    Figure 7

    Benign interatrial mass. (A) 18F-FDG PET/CT, (B, D) CT and (C) MRI showing a homogeneous low signal mass (asterisks) in the interatrial septum, with increased PET signal (arrow). There was high signal on T1-weighted MRI, which reduced with fat suppression, and no enhancement on first pass perfusion or late gadolinium MRI. On CT, the lesion has a Hounsfield unit of −70, consistent with fat. Overall the findings were consistent with lipomatous hypertrophy of the interatrial septum. 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

    Figure 8
    Figure 8

    Malignant intracardiac mass. (A) 18F-FDG PET/CT showing a metabolically active intracardiac mass (arrow). (B) Contrast-enhanced CT and (C) MRI demonstrate a lobulated non-calcific, non-fatty soft tissue mass within the right ventricle (asterisks) that was highly mobile and prolapsing across the tricuspid valve. The mass had low T1-weighted and high T2-weighted signals, no enhancement in the angiographic phase, and heterogeneous enhancement on early and delayed contrast MRI sequences. The underlying diagnosis was cardiac metastases from a synovial sarcoma. 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

    Conclusions and future directions

    The future of PET imaging in cardiovascular disease extends well beyond its core uses in ischaemic heart disease, to include key clinical applications spanning from heart failure to valve disease, cardiac electrophysiology and cardio-oncology. Identification and validation of specifically targeted PET tracers with physiologically low myocardial signals, coupled with advances in hybrid cardiac PET/MRI, motion-corrected reconstruction algorithms and automated image analysis using artificial intelligence, will add further momentum to the field. Moreover, the means to rapidly image the entire human body at very low radiation doses and with excellent signal detection could soon become a reality using total body PET/CT. Such an approach could transform the ability to screen for cardiac involvement in systemic diseases, to monitor the response to emerging anti-inflammatory and nanoimmunotherapeutic therapies for cardiovascular disease, and to examine heart–brain interactions and other dynamic systems-level influences on cardiovascular disease activity.

    Acknowledgments

    Dr Leon Menezes (Barts Heart Centre, London) contributed images for figures 1, 2 and 6.

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    Footnotes

    • Twitter @jmtarkin, @jhfrudd

    • Contributors JMT, AC and CW drafted the manuscript. JMT, DG and JHFR reviewed and edited the manuscript. All authors contributed to its scientific content. JMT and JHFR are responsible for its overall content as guarantors.

    • Funding JMT is supported by a Wellcome Trust Clinical Research Career Development Fellowship (211100/Z/18/Z), the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and the Cambridge British Heart Foundation (BHF) Centre for Research Excellence. JHFR is part-supported by the NIHR Cambridge BRC, the BHF, the Higher Education Funding Council for England, the Engineering and Physical Sciences Research Council and the Wellcome Trust.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Patient consent for publication Not required.

    • Provenance and peer review Commissioned; externally peer reviewed.