Abstract
Objective
Chylopericardium (CPE) is a rare condition associated with accumulation of triglyceride-rich chylous fluid in the pericardial cavity. Due to minimal information on CPE within the literature, we conducted a systematic review of all published CPE cases to understand its clinical characteristics, management and outcomes.
Methods
We performed a literature search and identified cases of patients with CPE from 1946 until May 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified relevant articles for pooled analyses of clinical, diagnostic and outcome data.
Results
A total of 95 articles with 98 patients were identified. Patient demographics demonstrated male predominance (55%), with a mean age of 37±15 years. Time from symptom onset to diagnosis was 5 (Q1 4.5, Q3 14) days, with 74% of patients symptomatic on presentation. Idiopathic CPE (60%) was the most common aetiology. Cardiac tamponade secondary to CPE was seen in 38% of cases. Pericardial fluid analysis was required in 94% of cases. Lymphangiography identified the leakage site in 59% of patients. Medical therapy (total parenteral nutrition, medium-chain triglycerides or octreotide) was undertaken in 63% of cases. In our cohort, 32% progressed towards surgical intervention. During a median follow-up of 180 (Q1 180, Q3 377) days, CPE recurred in 16% of cases. Of the patients with recurrence, 10% were rehospitalised.
Conclusion
CPE tends to develop in younger patients and may cause serious complications. Many patients fail medical therapy, thereby requiring surgical intervention. Although overall mortality is low, associated morbidities warrant close follow-up and possible reintervention and hospitalisations.
Keywords: echocardiography, Magnetic Resonance Imaging, pericarditis, cardiac tamponade, pericardial effusion
WHAT IS ALREADY KNOWN ON THIS TOPIC
Chylopericardium (CPE) is a rare condition resulting from chylous fluid accumulation in the pericardial sac.
Minimal research exists on understanding its associated clinical characteristics.
WHAT THIS STUDY ADDS
The results of our study suggest that patients who develop CPE tend to be younger and that a substantial number of patients fail medical management and thereby require surgical intervention.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Close monitoring is important as there is significant associated morbidity in CPE.
Introduction
Chylopericardium (CPE) or chylous pericardial effusion is a rare disease associated with accumulation of triglyceride-rich fluid in the pericardial space. The aetiology of CPE is multifactorial.1 The primary causes are idiopathic/viral, whereas the secondary causes include postcardiothoracic surgery, radiation exposure, trauma, malignancy and infection.2 The proposed mechanism of CPE is attributed to lymphatic system damage, leading to abnormal communication between the thoracic duct and the pericardial lymphatic channels. This results in the outflow of chyle into the pericardial space from the lymphatic duct and subsequent accumulation. There is a paucity of literature describing the epidemiology, natural history and outcomes in CPE, and to our knowledge only one prior systematic review on CPE exists.3 Therefore, we aimed to conduct a systematic review to study the clinical characteristics and outcomes of patients with CPE, specifically investigating their clinical course and the role of multimodality imaging in diagnosis and management.
Methods
A comprehensive search was performed on 2 December 2020 for published articles on chylous pericardial effusion in the following databases: Ovid Medline, Ovid Embase, CINAHL from EBSCOhost, Scopus (Elsevier), Web of Science’s BIOSIS Citation Index, Science Citation Index Expanded and Conference Proceedings Citation Index-Science. The search was updated on 27 May 2021.
Indexing terms and keywords for both chyle and pericardial effusion or chylopericardium were combined without any language filters. All publication types were considered, and all databases were searched for the concepts. We reviewed identified articles for our selection strategy. Although our inclusion criteria included case reports, we also searched for potential observational studies, clinical trials and registry reports seeking information on CPE. Letters to the editors, animal/paediatric studies and publications in languages other than English were excluded.
We designed our systematic review based on the PICO (patient, intervention, control and outcome) framework. Adult patients (≥18 years) with CPE constituted our study population, medical±surgical therapy composed our intervention, and mortality during index hospitalisation, recurrence of CPE, reinterventions (pericardiocentesis, pericardial window or pericardiectomy), rehospitalisation and mortality after discharge were considered as outcomes. Due to paucity of observational studies, we did not include any comparison group for our analysis. Patient and public involvement is not applicable in this study.
Two independent researchers (AK and AA) screened articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.4 Another reviewer (BV) assisted in the resolution of any conflict during the selection process. Our study used the online tool Covidence to collect, screen and store the selected articles. Indepth information was manually collected from online text manuscripts, tables and figures of the selected articles. Abstracts, review articles, letter to the editors, publications in language other than English, animal studies and studies exclusive to paediatric populations were excluded.
Qualitative data analysis approach involved content analysis to report patterns and frequencies. Extracted data were compiled/pooled for statistical analysis and reporting of the results. Results were presented as clinical characteristics, diagnostic approach, management strategy and outcomes. Categorical variables were represented as proportions (%) and continuous variables as mean (SD). Due to lack of study-level data on this topic, the techniques of meta-analysis for meta-proportion or meta-binary calculations of effect sizes and test of heterogeneity were not feasible.
Results
Our search identified 1169 articles. After deduplication (n=613), 556 articles were screened by title and abstract. Of the articles, 289 met the criteria for full-text screening, of which 95 case reports (98 patients) comprised our final study cohort (figure 1, online supplemental table 1). No observational studies, randomised control studies or clinical trials were identified.
Figure 1.
PRISMA diagram. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
heartjnl-2022-321798supp001.pdf (144.3KB, pdf)
Pooled individual patient-level data demonstrated that our cohort (n=98) had a mean age of 37±15 years and that most patients were male (55%, n=53). CPE was reported as the first occurrence in 97% (n=95) of cases and the median time to symptom onset from diagnosis was 5 (Q1 4.5, Q3 14) days. Majority of the CPE cases were reported in the USA (30%, n=29), followed by the Middle East (16%, n=16) and Europe (16%, n=16). Patient comorbidities included malignancy (12%, n=12), valvular surgery (11%, n=11) and coronary artery bypass grafting (7%, n=7). The predominant aetiology was idiopathic/viral (60%, n=60), followed by postcardiac injury syndrome (23%, n=23) and malignancy (11%, n=11). Dyspnoea (38%, n=39) was the most common initial presenting symptom. Concomitant pericarditis occurred in 7% (n=7) of cases. Cardiac tamponade was seen in 38% (n=37) of cases (table 1).
Table 1.
Clinical characteristics of our study cohort (n=98)
| Demographics | |
| Age (years) | 37 (±15) |
| Male | 53 (55) |
| Country | |
| USA | 29 (30) |
| Middle East | 16 (16) |
| Europe | 16 (16) |
| Japan | 12 (12) |
| Other | 25 (26) |
| Presentation | |
| First | 95 (97) |
| Recurrent | 3 (3) |
| Symptomatic | 73 (74) |
| Asymptomatic | 26 (26) |
| Dyspnoea | 38 (39) |
| Chest discomfort/pain | 11 (11) |
| Abdominal discomfort/pain | 5 (5) |
| Enlarged cardiac silhouette | 6 (6) |
| Other | 15 (15) |
| Shock | 4 (4) |
| Cardiac tamponade | 37 (38) |
| Aetiology | |
| Idiopathic/viral | 60 (61) |
| Postcardiac injury syndrome | 23 (23) |
| Malignancy | 11 (11) |
| Other | 4 (4) |
| Time to symptoms onset (days) | 4.8 (4.5–14) |
| Concomitant pericarditis | 7 (7) |
| Medical history | |
| Coronary artery bypass graft | 7 (7) |
| Valve surgery | 11 (11) |
| Malignancy | 12 (12) |
Values are presented as mean (±SD), absolute numbers with associated percentages or as median with IQR.
Pericardial fluid analysis confirmed CPE in 94% (n=92) of cases. The median cholesterol and triglyceride levels were 105 mg/dL (Q1 55, Q3 136) and 874 mg/dL (Q1 552, Q3 1351), respectively. The median serum erythrocyte sedimentation rate (ESR) was 14 mm/hour (Q1 5, Q3 22). Chest X-ray (CXR) most frequently revealed cardiomegaly (88%, n=52). Fifty-one patients underwent transthoracic echocardiogram, revealing pericardial effusion as small (6%, n=3), moderate (14%, n=7) or large (80%, n=41). The predominant CT chest finding was pericardial effusion (45%, n=15). Cardiac magnetic resonance (CMR) imaging was performed in 10% of cases, and pericardial effusion (70%, n=7) and pleural effusion (20%, n=2) were the most common findings identified. Lymphangiography was required in 59% (n=49) of cases and was able to identify the thoracic duct as the predominant leakage site (70%, n=14) (table 2).
Table 2.
Diagnostic findings of chylopericardium
| Fluid analysis (n=98) | |
| Diagnosis confirmed via fluid analysis | 92 (94) |
| Cholesterol (mg/dL) | 105 (55–136) |
| Triglycerides (mg/dL) | 874 (552–1351) |
| Erythrocyte sedimentation rate (mm/hour) | 14 (5–22) |
| Chest X-ray (n=59) | |
| Enlarged cardiac silhouette | 52 (88) |
| Pleural effusion | 5 (8) |
| Pneumopericardium | 2 (3) |
| Pericardial effusion on echocardiography (n=51) | |
| Small | 3 (6) |
| Moderate | 7 (14) |
| Large | 41 (80) |
| CT (n=33) | |
| Pericardial effusion | 15 (45) |
| Cardiac MRI (n=10) | |
| Pericardial effusion | 7 (70) |
| Pericardial enhancement | 1 (10) |
| Pleural effusion | 2 (20) |
| Other | 3 (30) |
| Lymphangiography (n=49) | |
| Accumulation of fluid in the pericardial sac | 30 (55) |
| Accumulation of fluid in the mediastinum | 5 (9) |
| Thoracic duct fluid accumulation | 14 (70) |
Values are presented as absolute numbers with associated percentages or as median with IQR.
VATS, video assisted thoracoscopic surgery.
Conservative medical management (63%, n=62) included total parenteral nutrition (TPN), medium-chain triglyceride diet (MCTD) or octreotide for a median of 10 (Q1 6, Q3 15) days. Concomitant medical and surgical intervention was undertaken in 16% (n=16) of cases. Progression to surgical management secondary to failure of medical management was reported in 34% (n=33) of cases. Thoracotomy or video-assisted thoracoscopic surgery was required in 35% (n=34) of cases, thoracic duct ligation in 32% (n=31) and pericardiectomy in 15% (n=15) (table 3).
Table 3.
Management of chylopericardium (n=98)
| Conservative/medical management | 62 (63) |
| Duration of medical/conservative therapy (days) | 10 (6–15) |
| Failure of medical/conservative therapy | 33 (34) |
| Thoracotomy or VATS | 34 (35) |
| Thoracic duct ligation | 31 (32) |
| Combined surgery and ligation | 16 (16) |
| Pericardiectomy | 15 (15) |
Values are presented as absolute numbers with associated percentages or as median with IQR.
VATS, video-assisted thoracoscopic surgery.
Follow-up was reported in 72% of cases, with a mean follow-up time of 180 (Q1 90, Q3 377) days. Six (6%) patients died secondary to underlying comorbidities. Rehospitalisation for recurrent dyspnoea or reaccumulation of effusion occurred in 10% (n=10) of our cohort. CPE recurred in 16% (n=16) of cases, while 6% (n=6) required repeat pericardiocentesis or pericardial window (table 4).
Table 4.
Outcomes in patients with chylopericardium (n=98)
| Death (at follow-up) | 6 (6) |
| Rehospitalisation | 10 (10) |
| Recurrent chylopericardium | 16 (16) |
| Repeat pericardiocentesis | 6 (6) |
| Repeat pericardial window | 3 (3) |
| Development of pericarditis | 2 (2) |
| Development of constrictive pericarditis | 1 (1) |
| Development of cardiac tamponade | 1 (1) |
| Regular follow-up | 71 (72) |
| Follow-up (days) | 180 (90–377) |
Values are presented as bsolute numbers with associated percentages or as median with IQR.
Discussion
This systematic review examines and analyses the clinical characteristics and associated mortality and morbidity of patients with CPE. There is limited literature on CPE, and to our knowledge no discrete observational studies exist.
The European Society of Cardiology (ESC) 2015 guidelines suggest CPE can have a variable presentation that ranges from asymptomatic to emergent cardiac tamponade.1 Cardiac complications can include development of acute and constrictive pericarditis.1 Furthermore, it should be noted that CPE rarely presents with concomitant pericarditis (7%). Therefore, this suggests that CPE is primarily a rare aetiological cause of pericardial effusion as compared with a rare cause of acute pericarditis. CPE’s primary aetiology is idiopathic, and CPE most commonly presents with dyspnoea.3 Epidemiological estimates of the prevalence of CPE are currently unknown. Our results demonstrated that CPE has a higher prevalence in developed countries. This may be due to the higher number of patients receiving cardiac surgery and radiation therapy.3 5 6
The proposed pathophysiology of CPE development is damage to the thoracic duct, leading to abnormal communication of lymphatic vessels between the thoracic duct and the pericardial space. This results in heightened thoracic duct pressure, yielding outflow of chyle into the pericardial space from the thoracic duct.7
Imaging findings of CPE are often variable and non-specific for confirmatory diagnosis. CXR, echocardiography (echo), CT, CMR imaging and lymphangiography are the various modalities needed for diagnosis and management.3 CXR will often show enlarged cardiac silhouette, and identification on imaging should direct further evaluation for CPE. Echo is instrumental in detecting the presence of pericardial effusion secondary to CPE. Furthermore, echo can quantify effusion size and haemodynamic impact. However, notably echo does not provide information about the underlying pericardial effusion cause.8
In the setting of pericardial disease, echo is also the initial diagnostic modality for patients who develop or are clinically suspected to have cardiac tamponade or constrictive pericarditis (figure 2). Findings of collapse of the right atrium during systole, presence of inferior vena cava plethora and large pericardial effusion on echo may suggest concomitant cardiac tamponade. Septal bounce, respiratory variation of the mitral and tricuspid inflows on Doppler, plethoric inferior vena cava, and hepatic vein flow diastolic reversal during expiration are suggestive of constrictive pericarditis on echo.9 CT can also provide information about the localisation and quantification of pericardial effusion especially in cases of anterior and superior loculated effusions, which are difficult to detect on echocardiogram.9 CMR is not routinely performed for diagnosis and management of CPE, attributed to its accessibility and high cost in the real-world setting. However, in the setting of pericardial disease, CMR is particularly helpful in pericardial tissue characterisation, specifically identification of inflammation and oedema and assessment of pericardial thickness.9 Suggestive features of constrictive pericarditis on CMR include septal bounce, sudden termination of diastolic filling or respirophasic discrepancy in septal excursion.9 Lymphangiography is used most frequently for anatomical assessment of lymphatic leakage and can greatly guide surgical management of CPE.10
Figure 2.
Breakdown of causes of chylopericardium with associated clinical presentation, diagnosis and management strategies. CXR, chest X-ray; TG, triglyceride.
Confirmatory diagnosis of CPE requires pericardial fluid analysis either via pericardiocentesis or pericardial window. High triglyceride concentration >500 mg/dL, cholesterol to triglyceride ratio less than 1, Sudan III staining, negative fluid cultures and lymphocyte predominance support the diagnosis.3 Although current guidelines suggest that ESR and C reactive protein levels should be elevated, in addition to the standard criteria for confirmatory diagnosis of pericarditis, we found that the median ESR was 14 mm/hour, suggesting no active inflammatory state.1 11 12
Initial treatment of CPE is dependent on the presenting haemodynamic status. A multidisciplinary team of cardiologists, cardiothoracic surgeons and interventional radiologists is required. When haemodynamically stable, in accordance with the 2015 ESC guidelines, initial conservative treatment with TPN, MCTD and octreotide is instituted.1 13 14 TPN and MCTD diminish lymph flow and intralymphatic pressure, while octreotide reduces thoracic duct flow rate and chyle production.3 13 Octreotide has been shown specifically to be therapeutic in patients with CPE secondary to surgery and malignancy.15 Per 2015 ESC guidelines, in patients who are symptomatic or present with cardiac tamponade, pericardiocentesis may be needed.1 Unfortunately, some patients experience failure of medical management, thereby requiring surgical intervention. In most cases, surgery with thoracic duct ligation is curative.16–18 Pericardiectomy may also be considered in recalcitrant patients or in those who develop constrictive physiology.19
We found that mortality among CPE cases is low and is attributed to underlying comorbidities such as malignancy. These patients are also at risk of recurrent CPE, which may require further interventions, such as pericardiocentesis, pericardial window or rehospitalisation.
From a clinical standpoint, our study reiterates the need for close follow-up and surveillance in patients with CPE due to its association with cardiac tamponade, recurrent nature and associated morbidity.
Study limitations
Our study has some expected limitations. Overall, there were less than 100 included patients, thereby restricting the power neccessary to perform multivariable analyses. However, this is the largest systematic review of patients with CPE in the literature. Information was pooled together from the case reports, therefore limiting their generalisability. Case reports from the individual centres could vary in quality and amount of data presented. Under-reporting could underestimate our outcomes providing lower estimates. Due to the inherent nature of the study design, we were unable to compare our cases with a control group, hence limiting validation of treatment effect.
Conclusion
CPE is a rare clinical condition with presentations ranging from asymptomatic to emergent cardiac tamponade. Literature on this topic largely comprises case reports. CPE management is complex and requires a multidisciplinary team. A subset of patients may fail medical therapy, thereby necessitating surgical intervention. While CPE mortality is low, morbidity associated with the disease is high. Therefore, sufficient consideration should be taken during diagnosis and management of patients.
Footnotes
Twitter: @AnkitAgrawalMD
BV and AK contributed equally.
Contributors: BV, AK: conceptualisation, methodology, formal analysis, validation, writing—original draft, writing—review and editing. NV, AA: conceptualisation, methodology, formal analysis, writing—original draft, writing—review and editing. AY, MMF, GM: conceptualisation, methodology, writing—original draft, writing—review and editing. FB, SM: methodology, validation, writing—original draft, writing—review and editing. MS: methodology, formal analysis, validation. PR-G: validation, writing—original draft, writing—review and editing. MN, AJ: conceptualisation, validation, writing—original draft. TKMW: formal analysis, validation, writing—review and editing. ALK: guarantor, writing—original draft, writing—review and editing, supervision, project administration.
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: ALK: research grant and scientific advisory board for Kiniksa Pharmaceuticals, research grant and scientific advisory board for Cardiol Therapeutics, and scientific advisory board for Pfizer.
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.
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.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Not required.
References
- 1. Adler Y, Charron P, Imazio M, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases. Eur Heart J 2015;36:2921–64. 10.1093/eurheartj/ehv318 [DOI] [PubMed] [Google Scholar]
- 2. Mandarry MT, Ru XH, Wei ZQ, et al. Primary idiopathic chylopericardium: a rare case with a synopsis of the literature. Singapore Med J 2012;53:e156–8. [PubMed] [Google Scholar]
- 3. Dib C, Tajik AJ, Park S, et al. Chylopericardium in adults: a literature review over the past decade (1996–2006). J Thorac Cardiovasc Surg 2008;136:650–6. 10.1016/j.jtcvs.2008.03.033 [DOI] [PubMed] [Google Scholar]
- 4. Haddaway NR, Pritchard CC, McGuinness LA. PRISMA2020: R package and ShinyApp for producing PRISMA 2020 compliant flow diagrams (version 0.0.2), 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Romero S. Nontraumatic chylothorax. Curr Opin Pulm Med 2000;6:287–91. 10.1097/00063198-200007000-00006 [DOI] [PubMed] [Google Scholar]
- 6. Arendt T, Bastian A, Lins M, et al. Chylous cardiac tamponade in acute pancreatitis. Dig Dis Sci 1996;41:1972–4. 10.1007/BF02093598 [DOI] [PubMed] [Google Scholar]
- 7. Cho BC, Kang SM, Lee SC, et al. Primary idiopathic chylopericardium associated with cervicomediastinal cystic hygroma. Yonsei Med J 2005;46:439–44. 10.3349/ymj.2005.46.3.439 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Ojeda W, Martínez-Toro JA. Diagnosis and management of pericardial effusions. P R Health Sci J 2006;25:255–8. [PubMed] [Google Scholar]
- 9. Klein AL, Abbara S, Agler DA, et al. American Society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the Society for cardiovascular magnetic resonance and society of cardiovascular computed tomography. J Am Soc Echocardiogr 2013;26:965–1012. 10.1016/j.echo.2013.06.023 [DOI] [PubMed] [Google Scholar]
- 10. Luo X, Zhang Z, Wang S, et al. Chyloptysis with chylopericardium, a rare case and mini-review. BMC Pulm Med 2018;18:21. 10.1186/s12890-018-0583-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Imazio M, Brucato A, Maestroni S, et al. Prevalence of C-reactive protein elevation and time course of normalization in acute pericarditis: implications for the diagnosis, therapy, and prognosis of pericarditis. Circulation 2011;123:1092–7. 10.1161/CIRCULATIONAHA.110.986372 [DOI] [PubMed] [Google Scholar]
- 12. Mager A, Hammer Y, Ofek H, et al. Prognostic and diagnostic significance of serum high-sensitivity C-reactive protein level in patients with acute idiopathic pericarditis. Isr Med Assoc J 2019;21:747–51. [PubMed] [Google Scholar]
- 13. Szabados E, Toth K, Mezosi E. Use of octreotide in the treatment of chylopericardium. Heart Lung 2011;40:574–5. 10.1016/j.hrtlng.2010.01.004 [DOI] [PubMed] [Google Scholar]
- 14. Karaca S, Rager O, Kalangos A. Successful treatment of persistent chylopericardium with somatostatin after operation on ascending aorta. Ann Thorac Surg 2014;97:e97–9. 10.1016/j.athoracsur.2013.11.078 [DOI] [PubMed] [Google Scholar]
- 15. O'Donnell J, Kirkham J, Monteith D, et al. Chylous cardiac tamponade with Chylothoraces secondary to Hodgkin's lymphoma: octreotide in Conjuncture with standard of care dietary fat restriction. Case Rep Crit Care 2019;2019:1406840. 10.1155/2019/1406840 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Mundra V, Savage EB, Novaro GM, et al. Delayed chylous pericardial effusion after aortic valve replacement. Tex Heart Inst J 2011;38:431–2. [PMC free article] [PubMed] [Google Scholar]
- 17. Niznansky M, Prskavec T, Cerny V, et al. Chylous pericardial effusion as a rare complication after pulmonary endarterectomy. Interact Cardiovasc Thorac Surg 2015;21:257–9. 10.1093/icvts/ivv127 [DOI] [PubMed] [Google Scholar]
- 18. Borulu F, Erkut B. Successful conservative treatment of chylopericardium after open-heart surgery: a case report. J Tehran Heart Cent 2020;15:73–6. 10.18502/jthc.v15i2.4187 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Morishita Y, Taira A, Furoi A, et al. Constrictive pericarditis secondary to primary chylopericardium. Am Heart J 1985;109:373–5. 10.1016/0002-8703(85)90614-3 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
heartjnl-2022-321798supp001.pdf (144.3KB, pdf)
Data Availability Statement
Data are available upon reasonable request.