the review of related literature is the heart of a study

“I barely notice the severe symptoms of this diagnosis and sometimes I just forget it. But I get so tired of always being tired” (young man with vEDS).

Nature of fatigue—how do they experience fatigue?

Many of the participants experienced that fatigue was a combination of a bodily sensation and a foggy feeling. They described an overwhelming feeling of tiredness, and that parts of their body was heavy or paralyzed. Some described that their legs felt like lead, and they had trouble with moving. A misty feeling was described as having a glass bowl around their head, including brain fog. They felt it hard to concentrate, speak, listen or sort out impressions. Many described that it interfered with concentration at work and social interaction. The character of fatigue was also described as unpredictable, controlling their life, and being impossible to resist and combat.

“Yes, it’s weird, because I’m so incredibly tired. I can’t leave my bed, because my legs will not move, and my brain feels so foggy and I can’t think and talk right. This is not me… and I don’t know why” (woman with MFS).

Searching for causes of fatigue

Many expressed frustrations of neither knowing the cause of fatigue nor how to deal with an inexplicable exhaustion. Searching for biomedical and other reasonable reasons of fatigue was common. Some claimed that being hypermobile requires more body energy for stabilization of joint and muscles. Medication and use of blood pressure medicine was also mentioned as a possible explanation for fatigue. Others described how chronic pain and constant worrying about the life-threatening aspects of the condition for both them and family members made them exhausted. Many also described that being physically active and doing exercise was challenging, but despite that, exercise was emphasized as important in counteracting fatigue. Some mentioned also that physical activity was associated with anxiety and insecurity, due to the difficulties of finding the right balance between healthy and unhealthy activities. Avoiding physical activity was therefore a coping strategy for some, resulting in a negative spiral of inactivity, more fatigue and a sedentary life.

“I wish I had known the reason for my fatigue, it had been much easier to know what to do and combat it” (young man with LDS).

Another aspect many of the participants described as challenging was the suspicion and lack of understanding from other people about the phenomenon fatigue. When participants tried to convey the gravity of their experiences to others, they were not always understood. Participants described this as exhausting and it increased their uncertainty about the fatigue symptoms. This, in turn led to feeling of guilt, inadequacy and an inner struggle of their desires and what they could achieve.

“It is so invisible and common, everyone is exhausted sometimes… so people might understand in their own way… but they really don’t understand the reality of having “real fatigue” (middle aged woman with MFS).

Dealing with fatigue in daily life

Most of the participants described that fatigue impacted different aspects of daily life, such as family life, employment, and social life. Some emphasized that they had learned to cope with fatigue by energy economizing and prioritizing between different aspects of life. They realized that fatigue was not dangerous, but only frustrating and debilitating, and some tried to accept it as part of their illness. Others described that avoiding important life events because of exhaustion, was part of their daily choices. Difficulty of dealing with fatigue in the work situation was emphasized as a common challenge. With an overwhelming feeling of tiredness, it was impossible to fulfill their obligations as employees. For some, early retirement was the only solution. Others described attempts to strive to maintain full employment and trying to keep up the pace in what they perceived as a “normal life”. They used all their energy at work, which affected both family life and leisure activities. For some the long-term effect of keeping up the pace was increased fatigue because they were not able to rest enough. Others had found strategies for dealing with fatigue in the work life, particularly those who had informed their employer about their condition. More flexible work conditions and agreements with their employers, made it possible to maintain work ability, despite fatigue.

“For me, work is of invaluable value, I appreciate it so much, it gives me energy but it can also drain me of energy, so it is important to be aware and pay attention. Fatigue is so difficult to handle” (middle-aged man with MFS).

Systematic review of relevant research of fatigue in patient with sHTADs

Identified research.

Aim one was to identify, critically appraise and synthesize the research of self-perceived fatigue in sHTADs. We identified 33 articles dealing with fatigue in sHTADs, 3 reviews and 30 primary articles, but in only 8 articles, the primary outcome was to investigate fatigue. The results indicate that the amount and extent of studies on fatigue in sHTADs is very limited. Most articles included patients with MFS, presumably because MFS is more common and better known than the other diagnoses. The prevalence of these diseases worldwide is highly uncertain. Prevalence of MFS is estimated to be 10 per 100,000 [ 75 , 76 ], and prevalence of vEDS is estimated to be 0.5–2 per 100,000 [ 77 ], while prevalence of LDS is unknown but probably much lower than for MFS [ 78 ]. The prevalence of the other sHTADs is even lower [ 5 , 6 ]. Over the past two decades, there has been exponential increase in genetic research on pathogenic variants explaining sHTADs [ 1 , 5 , 6 ]. The increased focus on diagnostics, survival and treatment may have deflected clinical attention away from patient`s less dangerous symptoms, such as fatigue. LDS is a relatively new diagnosis, and first described in 2005 [ 4 , 79 ]. Most studies of LDS concern medical aspects related to the diagnoses. Because most of the symptoms of MFS are overlapping with symptoms of LDS, vEDS and other sHTADs [ 4 , 5 , 6 ], it seems likely that fatigue impacts these patient groups similarly, although the pathophysiological mechanisms of fatigue may be different.

Critical appraisal of included articles

Most studies used quantitative cross-sectional questionnaire design, besides four prospective and four qualitative studies. The identified articles and results consistently were based on small sample sizes and/or low response rates. The respondents were mainly recruited from the clinic where the researchers worked or from patient organizations. These recruitment strategies yield a risk of bias for recruiting motivated persons with particular medical problems. Thus, the findings may be different from the non-respondents and therefore represent a bias related to the total population. Nearly all the patient populations lived in Western developed countries; Europe and USA or Korea. As cross-cultural differences of fatigue have been found in several studies [ 80 ], more research from other countries and cultures is warranted.

Nearly all quantitative questionnaire studies (cross-sectional and prospective) used standardized instruments with generic scale design, besides two papers using study specific questions about “fatigue being present or absent”. The use of standardized instruments can provide quantitative indication of fatigue level, but incompletely reported results, use of different instrument and use of different cut of values for severe fatigue made meta-analyses or statistical pooling difficult. Such meta-analyses could have been useful for clinical practice. The huge variations in prevalence of fatigue and vitality score within and between the different sHTADs may reflect differences in study design, recruitment routines, methodology, and national differences in cultures and perceptions. The representativeness and generalizability of the results may be questioned; however, a strength was that the methodology of included studies was commonly rated as good, and that most emphasized and discussed limitations of their study. This in turn, increased the credibility of the studies.

Synthesis of the literature

The prevalence of fatigue: The results from the reviewed papers are equivalent when indicating that adults with MFS have vastly higher prevalence of fatigue than the general population; and it is likely that individuals with sHTADs may experience a significant impact of fatigue on daily life. This is in accordance with reports of fatigue in other severe conditions such as systemic sclerosis [ 81 ], multiple sclerosis [ 82 ], and cancer [ 83 ].

Fatigue seems to be complex and can occur as primary or secondary symptom, as well as a comorbidity of an underlying disease [ 31 , 68 , 78 ]. Disentangling the origin and nature of fatigue in patients with sHTADs may be challenging. Several studies [ 13 , 16 , 31 , 53 , 55 , 56 ] hypothesized that the biomedical aspects of sHTADs such as cardiovascular and respiratory factors, reduced visual acuity and joint hypermobility may impact fatigue, but only a few studies found such associations.

Fatigue has also been described as a well-recognized side-effect of blood pressure medicine [ 84 ], but the results from the included articles were contradictory. Only one [ 53 ] study found that medication was associated with more fatigue, while three studies found no such associations in patients with sHTADs. Interestingly the study of van Andel et al. [ 32 ] found that the use of losartan was associated with decreased fatigue. The effect of losartan on fatigue may be an under-researched aspect in these patient groups, and the limited and conflicting literature reveals that more research is needed. Our results also indicate that clinicians should be aware that fatigue may be exacerbated by the use of medication, and should enquire about the effects of medication on fatigue when assessing and prescribing new medications.

Chronic pain was also found to be significantly associated to fatigue in the included articles, similar to reports [ 85 , 86 , 87 ] on others chronic diseases. Pain in patients with sHTADs [ 14 , 15 , 16 , 18 ] may contribute to lower energy level and lower sense of well-being [ 64 ]. One explanation is that chronic pain negatively influences sleep quality, and less sleep can decrease one`s pain threshold and pain tolerance as well as intensify the pain, thus exacerbating sleep problems, and thus increasing fatigue [ 87 , 88 ].

Another aspect that emerged from the included articles was the close connection between physical activity and fatigue. Patients with sHTADs are often recommended physical restrictions because hemodynamic changes and increase in blood pressure are associated with an enhanced risk of aortic growth and acute aortic dissection [ 10 , 88 ]. However, they are also recommended to be physical active. Total absence of physical exercise is deleterious and may lead to muscle wasting, joint stiffness, and problems with social and professional reintegration, depression and fatigue [ 10 , 11 , 12 , 88 ]. Lack of exercise and deconditioning can cause tiredness and exhaustion. Finding the right balance between safe and unhealthy exercise for these patient groups can be a major problem [ 12 ]. Patients may experience anxiety related to physical activity, which in turn may lead to a sedentary lifestyle and more fatigue [ 9 , 11 , 12 , 53 , 89 , 90 ], with these effects probably being negatively mutually reinforcing [ 91 ]. There are promising results that exercise-based cardiac rehabilitation in MFS and LDS can help these patients to decrease fatigue and chronic pain, with increased physical endurance and quality of life [ 71 ]. More clinical research, including more knowledge-based practice and rehabilitation guidelines for patients with sHTADs seems to be needed.

Fatigue in children and adolescents: Research on fatigue in children with sHTADs is very limited and the results varied. In three studies [ 60 , 70 , 74 ], fatigue was reported to create challenges in daily life, while in another [ 61 ] children with MFS reported less fatigue than healthy controls. One study [ 59 ] also indicated that fatigue was nearly not mentioned on social media when young people shared experiences about MFS. Nevertheless, more information about the prevalence, associations and experiences of fatigue in these pediatric groups is needed. Studies of children with other chronic diseases have revealed that fatigue negatively impact QoL [ 92 ], so quantifying fatigue in children with sHTADs may be critical. Understanding the impact of fatigue may be the first step for improving the quality of life for these groups.

Focus group interviews combined with results from the review part

Aim two was to investigate the experiences and perceptions of fatigue in adults with different sHTADs. In the focus group interview, we did not measure the extent of fatigue, but our impression was that nearly all of the participants reported that they experienced fatigue. Participants in the focus group interviews emphasized that fatigue is one of the most debilitating symptoms of having a sHTAD, similar to the results from several of the studies from the review part. Fatigue seems to cause significant levels of distress, and the unpredictability and invisibility of the symptoms were emphasized as particularly challenging. Not being taken seriously and constantly being misunderstood was also highlighted as challenging and negatively affecting their self-esteem and self-understanding. Another challenge was to combine fatigue with the ability to work. Fatigue was reported to be the most prevalent reason for early retirement in the some of the included articles in the review [ 16 , 17 , 19 , 66 , 67 ].

Both in the review part and the focus groups it emerged that the subjective perception of the disease may have substantial impact on how people cope with fatigue [ 53 , 64 ]. The physical severity of sHTADs has been discussed [ 13 , 31 ], and in most papers, severity appears to be mainly associated with the cardiovascular manifestations [ 13 , 53 , 67 ]. The cardiovascular manifestations may be underestimated in both adults and children as long as the individuals experience no subjective complaints. The subjective severity seems to be mainly determined by the disease manifestations that is perceived by the patients or caused physical disability. The differences between physical severity and subjective severity may indicate that the patients perceive the disorder differently from the professionals. This is important for health care professionals to recognize when dealing with fatigue in these patient groups.

Overall, the results from our study indicate that the perception of fatigue is probably not an isolated problem, but rather a combination of factors related directly to the disease and psychological stress factors and indirectly to the lack of psychosocial support and the complex response of having a rare chronic disease. Based on these results, it is difficult to determine how widespread severe fatigue is among adults and children with sHTADs. Studies combining qualitative approaches with quantitative measurements such as FSS, MFI-20, CIS or other validated measurements could provide valuable information on both prevalence, associations and experiences of fatigue in these patient groups.

Clinical implications and direction for further research

The third aim was to investigate key concepts of fatigue, identify knowledge gaps, and discuss clinical implications and direction for further research on fatigue in sHTADs.

The research on fatigue in the different sHTADs is limited, particularly in other sHTADs than MFS. Our results indicate that the concept of fatigue can be described in relation to its physical, cognitive, emotional and social impact. Further research in sHTADs can attempt to examine the concept of fatigue and unifying the taxonomy of discrimination between fatigue in sense of self-perception and performance (fatigability). This may help to clarify the complexity of the phenomenon. The negative consequences of fatigue seems to be consistent across sHTADs, as is the uncertainty concerning its underlying pathophysiological mechanisms. Therefore, more research about pathophysiologic mechanisms in sHTADs and other causes of fatigue are warranted.

Our results also indicate that it is important for health professionals to acknowledge and address the impact of fatigue on patients with sHTADs. The unpredictability of sHTAD related fatigue is dominant and pervasive, and is experienced as a vicious circle. Helping people to be able to understand and accept fatigue may be important to enable patients to manage and live with fatigue. Support from health professionals to manage fatigue and develop strategies to increase physical activity and maintain work is important for these patient groups.

Our review has shown that the use of many different fatigue measures and cut-off values, make comparisons across studies difficult. To overcome these challenges, our proposal is that multiple stakeholders like researchers, health professionals and patient organizations can cooperate to create standardized sets of outcomes relevant for the sHTADs. This will enable agreement on what aspects that are important to measure, how it should be measured and how results should be interpreted. International collaboration project for sHTADs may also be appropriate, including outcome measures for fatigue.

Limitations and strengths

Only literature written in English, German, French and the Nordic languages were included in the systematic review, this might be a limitation. However, no studies written in other languages with English abstract were found. Our choice of search words and our cultural conceptual understanding may have limited our identification of papers and our interpretation of the content from the identified studies. We excluded case reports and studies with less than six participants. A strength may be the use of predefined criteria for critically appraising the literature, blinded by two reviewers and independently selected and categorized the studies, with the supervision of one other.

There are several limitations related to the focus group interviews. The retrospective perspective may imply possibility for recall bias. Our findings may also be limited to the patients with sHTADs who were willing to talk about their experiences and challenges. Another limitation may be how the term fatigue and exhaustion were interpreted by the participants. They may have different understanding of these concepts, but one of our intentions was also to examine the differences in perceptions and experiences about the concept of fatigue. Both the moderators and the co-moderators were experienced clinicians and/or researchers, and they underlined the interest in all types of narratives. In the analysis we carefully tried to identify and exclude repetitive patterns concerning our expectation and pre-understandings, as recommended in the literature [ 48 , 50 ]. To ensure the transparency of the study, anonymized data are available on request to the authors (TRS, National resource Center).

Conclusions

This is the first systematic review and qualitative study of fatigue in sHTADs. Our study indicate that fatigue is an under-recognized and under-researched feature in patients with sHTADs. A total of 33 articles were found, including several types of study designs. The majority dealt with MFS, and very few studies addressed other sHTADs. The studies were limited by small study sizes, low response rates, inadequate description of inclusion criteria and the patients’ diagnoses, and incomplete descriptions of the analyses. Despite these limitations, all studies indicated that the prevalence of severe fatigue in sHTADs is much higher than for the general population. The nature and impact of fatigue seems not to be experienced differently between the patients in the various sHTADs. Both the results from the included articles and the focus groups indicated that fatigue seems to have remarkable negative impact on daily life and quality of life. Fatigue may also be a major reason for early retirement. This suggests that fatigue should be considered as a core symptom and outcome measure in clinical trials and clinical practice for all patients with sHTADs. As most patients with sHTADs will not be cured in their lifetime, identifying causes of fatigue and developing appropriate treatment programs is warranted. Therefore, more research on fatigue in the different sHTADs are crucial.

Availability of data and materials

The dataset supporting the systematic review part of the article is included within the article (and its Additional files). The dataset (transcribed interviews) from the qualitative focus group study is available on reasonable request to the corresponding author.

Monda E, Lioncino M, Verrillo F, Rubino M, Caiazza M, Mauriello A, et al. The role of genetic testing in patients with heritable thoracic aortic diseases. Diagnostics. 2023;13(4):772. https://doi.org/10.3390/diagnostics13040772 .

Article CAS PubMed PubMed Central Google Scholar

Isselbacher EM, Preventza O, Black HJ, Augoustides JG, Beck AW, Bolen MA, et al. Guideline for the diagnosis and management of aortic disease: a report of the American heart association/American college of cardiology joint committee on clinical practice guidelines. Circulation. 2022. https://doi.org/10.1161/CIR.0000000000001106 .

Article PubMed Google Scholar

Landstrom AP, Kim JJ, Gelb BD, Helm BM, Kannankeril PJ, Semsarian C, et al. American Heart Association Council on Genomic and Precision Medicine; Council on Lifelong Congenital Heart Disease and Heart Health in the Young; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Lifestyle and Cardiometabolic Health. Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association. Circ Genom Precis Med. 2021. https://doi.org/10.1161/HCG.0000000000000086 .

Article PubMed PubMed Central Google Scholar

Meester J, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg. 2017;6(6):582–94. https://doi.org/10.21037/acs.2017.11.03 .

Brownstein AJ, Ziganshin BA, Kuivaniemi H, Body SC, Bale AE, Elefteriades JA. Genes associated with thoracic aortic aneurysm and dissection: an update and clinical implications. Aorta. 2017;5(1):11–20. https://doi.org/10.12945/j.aorta.2017.17.003 .

Renard M, Francis C, Ghosh R, Scott AF, Witmer PD, Adès LC, et al. Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol. 2018;72(6):605–15. https://doi.org/10.1016/j.jacc.2018.04.089 .

Papatheodorou E, Degiannis D, Anastasakis A. Genetics of heritable thoracic aortic disease (Review). Cardiogenetics. 2022;12:63–79. https://doi.org/10.3390/cardiogenetics12010006 .

Article CAS Google Scholar

Bradley TJ, Bowdin SC, Morel CF, Pyeritz RE. The expanding clinical spectrum of extra cardiovascular and cardiovascular manifestations of heritable thoracic aortic aneurysm and dissection. Can J Cardiol. 2016;32(1):86–99. https://doi.org/10.1016/j.cjca.2015.11.007 .

Jensen TL, Tran P, Kjaer M. Marfan syndrome and exercise: a literature review. Trans Sport Med. 2020;3(6):526–35. https://doi.org/10.1002/tsm2.185 .

Article Google Scholar

Thijssen CGE, Bons LR, Gökalp AL, Van Kimmenade RRJ, Mokhles MM, Pelliccia A, et al. Exercise and sports participation in patients with thoracic aortic disease: a review. Expert Rev Cardiovasc Ther. 2019;17(4):251–66. https://doi.org/10.1080/14779072.2019.1585807 .

Article CAS PubMed Google Scholar

Johansen H, Velvin G, Lidal I. Adults with Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome: a cross-sectional study of patient experiences with physical activity. Disabil Rehabil. 2022;44(10):1968–75. https://doi.org/10.1002/ajmg.a.61396 .

Velvin G, Wilhelmsen JE, Johansen H, Vardeberg K, Lidal I. Physical exercise for people with hereditable thoracic aortic disease. A study of patient perspectives. Disabil Rehabil. 2021;43(17):2464–71. https://doi.org/10.1080/09638288.2019.1703145 .

Rand-Hendriksen S, Johansen H, Semb SO, Geiran O, Stanghelle JK, Finset A. Health-related quality of life in Marfan syndrome: a cross-sectional study of Short Form 36 in 84 adults with a verified diagnosis. Genet Med. 2010;12(8):517–24. https://doi.org/10.1097/gim.0b013e3181ea4c1c .

von Kodolitsch Y, Demolder A, Girdauskas E, Kaemmerer H, Kornhuber K, Muino Mosquera L, et al. Features of Marfan syndrome not listed in the Ghent nosology—the dark side of the disease. Expert Rev Cardiovasc Ther. 2019;17(12):883–915. https://doi.org/10.1080/14779072.2019.1704625 .

Velvin G, Bathen T, Rand-Hendriksen S, Geirdal AØ. Systematic review of chronic pain in persons with Marfan syndrome. Clin Genet. 2016;89(6):647–58. https://doi.org/10.1111/cge.12699 .

Johansen H, Velvin G, Lidal IB. Pain and fatigue in adults with Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome, a questionnaire-based study. Am J Med Genet A. 2022;188(9):2605–16. https://doi.org/10.1002/ajmg.a.62858 .

Bathen T, Velvin G, Rand-Hendriksen S, Robinson HS. Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors. Am J Med Genet A. 2014;164A(8):1931–9. https://doi.org/10.1002/ajmg.a.36574 .

Nelson AM, Walega DR, McCarthy RJ. The incidence and severity of physical pain symptoms in Marfan syndrome: a survey of 993 patients. Clin J Pain. 2015;31(12):1080–6. https://doi.org/10.1097/AJP.0000000000000202 .

Velvin G, Bathen T, Rand-Hendriksen S, Geirdal AØ. Systematic review of the psychosocial aspects of living with Marfan syndrome. Clin Genet. 2015;87(2):109–16. https://doi.org/10.1111/cge.12422 .

Nielsen C, Ratiu I, Esfandiarei M, Chen A, Selamet Tierney ES. A review of psychosocial factors of Marfan syndrome: adolescents, adults, families, and providers. J Pediatr Genet. 2019;8(3):109–22. https://doi.org/10.1055/s-0039-1693663 .

Bathen T, Johansen H, Strømme H, Velvin G. Experienced fatigue in people with rare disorders: a scoping review on characteristics of existing research. Orphanet J Rare Dis. 2022;17(1):14. https://doi.org/10.1186/s13023-021-02169-6 .

Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology. 2013;80(4):409–16. https://doi.org/10.1212/WNL.0b013e31827f07be .

Dittner AJ, Wessely SC, Brown RG. The assessment of fatigue: a practical guide for clinicians and researchers. J Psychosom Res. 2004;56(2):157–70. https://doi.org/10.1016/S0022-3999(03)00371-4 .

Maher C, Crettenden A, Evans K, Thiessen M, Toohey M, Watson A, et al. Fatigue is a major issue for children and adolescents with physical disabilities. Dev Med Child Neurol. 2015;57(8):742–7. https://doi.org/10.1111/dmcn.12736 .

Penner IK, Paul F. Fatigue as a symptom or comorbidity of neurological diseases. Nat Rev Neurol. 2017;13(11):662–75. https://doi.org/10.1038/nrneurol.2017.117 .

Brown LF, Kroenke K, Theobald DE, Wu J. Comparison of SF-36 vitality scale and fatigue symptom inventory in assessing cancer-related fatigue. Support Care Cancer. 2011;19(8):1255–9. https://doi.org/10.1007/s00520-011-1148-2 .

McCabe M. Fatigue in children with long-term conditions: an evolutionary concept analysis. J Adv Nurs. 2009;65(8):1735–45. https://doi.org/10.1111/j.1365-2648.2009.05046.x .

RAND corporation (36-Item Short Form Survey (SF-36) Scoring Instructions|RAND

Overman CL, Kool MB, Da Silva JA, Geenen R. The prevalence of severe fatigue in rheumatic diseases: an international study. Clin Rheumatol. 2016;35(2):409–15. https://doi.org/10.1007/s10067-015-3035-6 .

Menting J, Tack CJ, Bleijenberg G, Donders R, Droogleever Fortuyn HA, Fransen J, et al. Is fatigue a disease-specific or generic symptom in chronic medical conditions? Health Psychol. 2018;37(6):530–43. https://doi.org/10.1037/hea0000598 .

Rand-Hendriksen S, Sørensen I, Holmström H, Andersson S, Finset A. Fatigue, cognitive functioning and psychological distress in Marfan syndrome, a pilot study. Psychol Health Med. 2007;12(3):305–13. https://doi.org/10.1080/13548500600580824 .

van Andel MM, Graaumans K, Groenink M, Zwinderman AH, van Kimmenade RRJ, Scholte AJHA, et al. A cross-sectional study on fatigue, anxiety, and symptoms of depression and their relation with medical status in adult patients with Marfan syndrome. Psychological consequences in Marfan syndrome. Clin Genet. 2022;102(5):404–13. https://doi.org/10.1111/cge.14211 .

Cambell collaboration. Cambell collaboration of systematic review: What is a systematic review? - The Campbell Collaboration.

The Cochrane Handbook for systematic reviews. Cochrane Handbook for Systematic Reviews of Interventions|Cochrane Training.

PRISMA 2020 Checklist for Systematic Review. Microsoft Word - PRISMA 2009 Checklist.doc (prisma-statement.org).

Pluye P. Critical appraisal tools for assessing the methodological quality of qualitative, quantitative and mixed methods studies included in systematic mixed studies reviews. J Eval Clin Pract. 2013;19(4):722. https://doi.org/10.1111/jep.12017 .

Fowkes FG, Fulton PM. Critical appraisal of published research: introductory guidelines. BMJ. 1991;302(6785):1136–40. https://doi.org/10.1136/bmj.302.6785.1136 .

Greenhalgh T. Assessing the methodological quality of published papers. BMJ. 1997;315(7103):305–8. https://doi.org/10.1136/bmj.315.7103.305 .

Jack L Jr, Hayes SC, Scharalda JG, Stetson B, Jones-Jack NH, Valliere M, et al. Appraising quantitative research in health education: guidelines for public health educators. Health Promot Pract. 2010;11(2):161–5. https://doi.org/10.1177/1524839909353023 .

Ryan F, Coughlan M, Cronin P. Step-by-step guide to critiquing research. Part 2: qualitative research. Br J Nurs. 2007;16(12):738–44. https://doi.org/10.12968/bjon.2007.16.12.23726 .

Jeanfreau SG, Jack L Jr. Appraising qualitative research in health education: guidelines for public health educators. Health Promot Pract. 2010;11(5):612–7. https://doi.org/10.1177/1524839910363537 .

CASP. Critical Appraisal Skills Program–Checklist for systematic reviews. 2018. CASP Checklists - Critical Appraisal Skills Programme (casp-uk.net).

Popay J, Roberts H, Sowden A, Arai L, Rogers M, Britten N, et al. Guidance on the conduct of narrative synthesis in systematic reviews: a comparison of guidance-led narrative synthesis. A product from the ESRC Methods Programme. ACADEMIA. Accelerating the world`s research. 2006 (version 1). 02e7e5231e8f3a6183000000-with-cover-page-v2.pdf (d1wqtxts1xzle7.cloudfront.net).

Heyvaert M, Maes B, Onghena P. Mixed methods research synthesis: definition, framework, and potential. Qual Quant. 2013;47:659–76. https://doi.org/10.1007/s11135-011-9538-6 .

Munn Z, Tufanaru C, Aromataris E. Systematic reviews data extraction and syntheses. Am J Nurs. 2014;114(17):49–54. https://doi.org/10.1097/01.NAJ.0000451683.66447.89 .

Tong A, Sainsbury P, Craig J. Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups. Int J Qual Health Care. 2007;19(6):349–57. https://doi.org/10.1093/intqhc/mzm042 .

O`Brien BC, Harris IB, Beckman TJ, Reed DA, Cook DA. Standards for reporting qualitative research: a synthesis of recommendations. Acad Med. 2014;89(9):1245–51. https://doi.org/10.1097/ACM.0000000000000388 .

Malterud K. Qualitative research: standards, challenges and guidelines. Lancet. 2001;358(9280):483–8. https://doi.org/10.1016/S0140-6736(01)05627-6 .

Malterud K. Fokusgrupper som forskningsmetode for medisin og helsefag (Focus groups as research methodology for medicine and health). Oslo: Universitetsforlaget; 2012.

Google Scholar

Liamputtong P. Focus group methodology: principles and practices. Thousand Oaks SAGE Publications ltd London. 2011. ISBNI0: 1847879098. Online Publication 2015. https://doi.org/10.4135/9781473957657 .

Velvin G, Wilhelmsen JE, Johansen H, Bathen T, Geirdal AØ. Systematic review of quality of life in persons with hereditary thoracic aortic aneurysm and dissection diagnoses. Clin Genet. 2019;95(6):661–76. https://doi.org/10.1111/cge.13522 .

Ghanta RK, Green SY, Price MD, Arredondo CC, Wainwright D, Preventza O, et al. Midterm survival and quality of life after extent II thoracoabdominal aortic repair in Marfan syndrome. Ann Thorac Surg. 2016;101(4):1402–9. https://doi.org/10.1016/j.athoracsur.2015.10.018 .

Peters KF, Kong F, Horne R, Francomano CA, Biesecker BB. Living with Marfan syndrome I. Perceptions of the condition. Clin Genet. 2001;60(4):273–82. https://doi.org/10.1034/j.1399-0004.2001.600405.x .

Ratiu I, Virden TB, Baylow H, Flint M, Esfandiarei M. Executive function and quality of life in individuals with Marfan syndrome. Qual Life Res. 2018;27(8):2057–65. https://doi.org/10.1007/s11136-018-1859-7 .

van Dijk N, Boer MC, Mulder BJ, van Montfrans GA, Wieling W. Is fatigue in Marfan syndrome related to orthostatic intolerance? Clin Auton Res. 2008;18(4):187–93. https://doi.org/10.1007/s10286-008-0475-y .

Verbraecken J, Declerck A, Van de Heyning P, De Backer W, Wouters EF. Evaluation for sleep apnea in patients with Ehlers-Danlos syndrome and Marfan: a questionnaire study. Clin Genet. 2001;60(5):360–5. https://doi.org/10.1034/j.1399-0004.2001.600507.x .

Voermans NC, Knoop H, Bleijenberg G, van Engelen BG. Fatigue is associated with muscle weakness in Ehlers-Danlos syndrome: an explorative study. Physiotherapy. 2011;97(2):170–4. https://doi.org/10.1016/j.physio.2010.06.001 .

Thijssen CGE, Doze DE, Gökalp AL, Timmermans J, Peters JB, de Ven Elbers-van LHC, et al. Male-female differences in quality of life and coping style in patients with Marfan syndrome and hereditary thoracic aortic diseases. J Genet Couns. 2020;29(6):1259–69. https://doi.org/10.1002/jgc4.1288 .

Kelleher E, Giampietro PF, Moreno MA. Marfan syndrome patient experiences as ascertained through postings on social media sites. Am J Med Genet A. 2015;167A(11):2629–34. https://doi.org/10.1002/ajmg.a.37255 .

Warnink-Kavelaars J, Beelen A, Dekker S, Nollet F, Menke LA, Engelbert RHH. Marfan syndrome in childhood: parents’ perspectives of the impact on daily functioning of children, parents and family; a qualitative study. BMC Pediatr. 2019;19(1):262. https://doi.org/10.1186/s12887-019-1612-6 .

Warnink-Kavelaars J, de Koning LE, Rombaut L, Alsem MW, Menke LA, Oosterlaan J, et al. Heritable connective tissue disorders in childhood: increased fatigue, pain, disability and decreased general health. Genes. 2021;12(6):831. https://doi.org/10.3390/genes12060831 .

Fusar-Poli P, Klersy C, Stramesi F, Callegari A, Arbustini E, Politi P. Determinants of quality of life in Marfan syndrome. Psychosomatics. 2008;49(3):243–8. https://doi.org/10.1176/appi.psy.49.3.243 .

Moon JR, Cho YA, Huh J, Kang IS, Kim DK. Structural equation modeling of the quality of life for patients with Marfan syndrome. Health Qual Life Outcomes. 2016;2(14):83. https://doi.org/10.1186/s12955-016-0488-5 .

Rao SS, Venuti KD, Dietz HC, Sponseller PD. Quantifying health status and function in Marfan syndrome. J Surg Orthop Adv. 2016;25(1):34–40 ( PMID: 27082886 ).

PubMed Google Scholar

Schoormans D, Radonic T, de Witte P, Groenink M, Azim D, Lutter R, et al. Mental quality of life is related to a cytokine genetic pathway. PLoS ONE. 2012;7(9):e45126. https://doi.org/10.1371/journal.pone.0045126 .

Velvin G, Bathen T, Rand-Hendriksen S, Østertun GA. Work participation in adults with Marfan syndrome: demographic characteristics, MFS related health symptoms, chronic pain, and fatigue. Am J Med Genet A. 2015;167(12):3082–90. https://doi.org/10.1002/ajmg.a.37370 .

Velvin G, Bathen T, Rand-Hendriksen S, Østertun GA. Satisfaction with life in adults with Marfan syndrome (MFS): associations with health-related consequences of MFS, pain, fatigue, and demographic factors. Qual Life Res. 2016;25(7):1779–90. https://doi.org/10.1007/s11136-015-1214-1 .

Schubart JR, Schaefer E, Hakim AJ, Francomano CA, Bascom R. Use of cluster analysis to delineate symptom profiles in an Ehlers-Danlos Syndrome patient population. J Pain Symptom Manage. 2019;58(3):427–36. https://doi.org/10.1016/j.jpainsymman.2019.05.013 .

Johansen H, Velvin G, Fugl-Meyer K, Lidal IB. Adults with Loeys-Dietz syndrome and vascular Ehlers-Danlos syndrome: a cross-sectional study of life satisfaction. J Rehabil Med. 2021;53(11):jrm00236. https://doi.org/10.2340/jrm.v53.572 .

Warnink-Kavelaars J, van Oers HA, Haverman L, Buizer AI, Alsem MW, Engelbert RHH, Menke LA. Parenting a child with Marfan syndrome: distress and everyday problems. Am J Med Genet A. 2021;185(1):50–9. https://doi.org/10.1002/ajmg.a.61906 .

Benninghoven D, Hamann D, von Kodolitsch Y, Rybczynski M, Lechinger J, Schroeder F, Vogler M, Hoberg E. Inpatient rehabilitation for adult patients with Marfan syndrome: an observational pilot study. Orphanet J Rare Dis. 2017;12(1):127. https://doi.org/10.1186/s13023-017-0679-0 .

Percheron G, Fayet G, Ningler T, Le Parc JM, Denot-Ledunois S, Leroy M, et al. Muscle strength and body composition in adult women with Marfan syndrome. Rheumatology. 2007;46(6):957–62. https://doi.org/10.1093/rheumatology/kel450 .

Vanem TT, Rand-Hendriksen S, Brunborg C, Geiran OR, Røe C. Health-related quality of life in Marfan syndrome: a 10-year follow-up. Health Qual Life Outcomes. 2020;18(1):376. https://doi.org/10.1186/s12955-020-01633-4 .

Warnink-Kavelaars J, Beelen A, Goedhart TMHJ, de Koning LE, Nollet F, Alsem MW, et al. Marfan syndrome in adolescence: adolescents’ perspectives on (physical) functioning, disability, contextual factors and support needs. Eur J Pediatr. 2019. https://doi.org/10.1007/s00431-019-03469-7 .

Nienaber CA, Von Kodolitsch Y. Therapeutic management of patients with Marfan syndrome: focus on cardiovascular involvement. Cardiol Rev. 1999;7(6):332–41. https://doi.org/10.1097/00045415-199911000-00011 .

Groth KA, Hove H, Kyhl K, Folkestad L, Gaustadnes M, Vejlstrup N, et al. Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis. 2015;2(10):153. https://doi.org/10.1186/s13023-015-0369-8 .

Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, et al. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C. 2017;175(1):40–7. https://doi.org/10.1002/ajmg.c.31553 .

Gouda P, Kay R, Habib M, Aziza E, Welsh R. Clinical features and complications of LoeysDietz syndrome: a systematic review. Int J Cardiol. 2022;362:158–67. https://doi.org/10.1016/j.ijcard.2022.05.065 .

Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–85. https://doi.org/10.1136/jmg.2009.072785 .

Skapinakis P, Lewis G, Mavreas V. Cross-cultural differences in the epidemiology of unexplained fatigue syndromes in primary care. Br J Psychiatry. 2003;182:205–9. https://doi.org/10.1192/bjp.182.3.205 .

Carandang K, Poole J, Connolly D. Fatigue and activity management education for individuals with systemic sclerosis: Adaptation and feasibility study of an intervention for a rare disease. Musculoskeletal Care. 2022;20(3):593–604. https://doi.org/10.1002/msc.1617 .

Eldemir K, Gucle-Gunduz A, Ozkul C, Eldemir S, Soke F, Irkec C. Associations between fatigue and physical behavior in patients with multiple sclerosis with no or minimal disability. Biomed Health Behav. 2021;9(2):69–78. https://doi.org/10.1080/21641846.2021.1923995 .

Hofman M, Ryan JL, Figueroa-Moseley CD, Jean-Pierre P, Morrow GR. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12(Suppl 1):4–10. https://doi.org/10.1634/theoncologist.12-S1-4 .

Dahlöf C, Dimenäs E. Side effects of β-blocker treatments as related to the central nervous system. Am J Med Sci. 1990;299(4):236–44. https://doi.org/10.1097/00000441-199004000-00004 .

Friedberg F, Caikauskaite I, Adamowicz J, Thomas J, Bivona TJ, Njoku G. Scientific status of fatigue and pain. Publishing and professional activities: 2002–2011. Fatigue Biomed Health Behav. 2013;1(1–2):4–11. https://doi.org/10.1080/21641846.2012.746201 .

Snekkevik H, Eriksen HR, Tangen T, Chalder T, Reme SE. Fatigue and depression in sick-listed chronic low back pain patients. Pain Med. 2014;15(7):1163–70. https://doi.org/10.1111/pme.12435 .

Van Damme S, Becker S, Van der Linden D. Tired of pain? Toward a better understanding of fatigue in chronic pain. Pain. 2018;159(1):7–10. https://doi.org/10.1097/j.pain.0000000000001054 .

Cheng A, Owens D. Marfan syndrome, inherited aortopathies and exercise: What is the right answer? Br J Sports Med. 2016;50(2):100–4. https://doi.org/10.1136/bjsports-2014-306440rep .

Velvin G, Johansen H. Physical activity and exercise for people with familial thoracic aortic aneurysms and dissections. A systematic scoping review. Fysioterapeuten. 2022;1:48–9. https://www.fysioterapeuten.no/fagfellevurdert-fysioterapi-hjerte-og-karsykdommer/fysisk-aktivitet-og-trening-for-personer-med-familiaere-thorakale-aortaaneurismer-og-aortadisseksjoner-en-oversiktsartikkel/138124 .

Johansen H, Velvin G. Physical activity and health competence for people with familial thoracic aortic aneurysms and dissections. Sykepl Forsk. 2022;17(88791):88791. https://doi.org/10.4220/Sykepleienf.2022.88791en .

Manning K, Kauffman BY, Rogers AH, Garey L, Zvolensky MJ. Fatigue severity and fatigue sensitivity: relations to anxiety, depression, pain catastrophizing, and pain severity among adults with severe fatigue and chronic low back pain. Behav Med. 2022;48(3):181–9. https://doi.org/10.1080/08964289.2020.1796572 .

Eddy L, Cruz M. The relationship between fatigue and quality of life in children with chronic health problems: a systematic review. J Spec Pediatr Nurs. 2007;12(2):105–14. https://doi.org/10.1111/j.1744-6155.2007.00099.x .

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We are grateful for the support and inspiration from TRS National Resource Centre for Rare Disorders, the Norwegian Patient Associations (Norwegian Marfan syndrome Association and Norwegian Ehlers-Danlos Association), and special thanks to the study reference group (Kari Anne, Roald and Elin) and all the participants in the focus groups.

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Velvin, G., Johansen, H., Østertun-Geirdal, A. et al. Fatigue in patients with syndromic heritable thoracic aortic disease: a systematic review of the literature and a qualitative study of patients’ experiences and perceptions. Orphanet J Rare Dis 18 , 119 (2023). https://doi.org/10.1186/s13023-023-02709-2

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Review article, single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the scn5a and apoa5 gene mutation: a case report and review of the literature.

1 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
2 Department of Medical Technology, Jinan Vocational College of Nursing, Jinan, Shandong, China
3 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China

We present a 55-year-old man with chest tightness and dyspnoea after activity lasting for 2 months who was diagnosed with single coronary artery (SCA) and presented with dilated cardiomyopathy (DCM) with the c.1858C > T mutation in the SCN5A gene. The computed tomography coronary angiogram (CTCA) showed congenital absence of the right coronary artery (RCA), and the right heart was nourished by the left coronary artery branch with no apparent stenosis. Transthoracic echocardiography (TTE) revealed enlargement of the left heart and cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed DCM. Genetic testing showed that the c.1858C > T variant of the SCN5A gene could lead to Brugada syndrome and DCM. SCA is a rare congenital anomaly of the coronary anatomy, and this case reported as SCA accompanied by DCM is even rarer. We present a rare case of a 55-year-old man with DCM with the c.1858C > T (p. Arg620Cys)/c.1008G > A (p.(Pro336=) variant of the SCN5A gene, congenital absence of RCA, and c.990_993delAACA (p. Asp332Valfs*5) variant of the APOA5 gene. To our knowledge, this is the first report of DCM combined with the SCN5A gene mutation in SCA after searching the PubMed, CNKI and Wanfang databases.

1. Introduction

Coronary artery abnormalities include abnormal number and origin, while single coronary artery (SCA) is relatively rare, accounting for 0.031% in coronary angiography ( 1 , 2 ) and 0.024%–0.066% in the general population ( 3 , 4 ). It is unclear whether SCA is an isolated congenital heart disease or is associated with other congenital abnormalities. Dilated cardiomyopathy (DCM) is currently defined by the presence of left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions (hypertension, valve disease) or coronary artery disease sufficient to cause global systolic impairment ( 5 , 6 ). The causes of DCM are heterogeneous ( 7 ), and we believe this is the result of genetic predisposition interacting with extrinsic or environmental factors ( 8 , 9 ). The SCN5A gene mutation is associated with a range of clinical diseases. Here, we present a rare case of SCA with DCM accompanied by the SCN5A gene mutation.

2. Case presentation

A 55-year-old male was admitted to our hospital because of dyspnoea. That day, he felt dyspnoea after 200 metres of flat walking. Emergency medical services were called, and he was transported to the emergency department at our hospital. On evaluation, the systolic blood pressure was 116/91 mmHg, the pulse was 115 beats per minute, the respiratory rate was 17 breaths per minute, and the oxygen saturation was 100%. An electrocardiogram (ECG) showed sinus bradycardia with T-wave inversions and premature ventricular contractions ( Supplementary Figure S1 ). On arrival, the patient reported paroxysmal dyspnoea. He had multiple similar episodes during the previous 20 days, without fever, cough, vomiting or diarrhoea. The symptoms were usually provoked by physical exertion, mental stress or intense emotion. Evaluations at other hospitals showed chronic bronchitis and emphysema, an enlarged left ventricle and decreased cardiac function, and further treatment was recommended. The patient had no other illnesses. His family history was unremarkable. He was a farmer. He drank alcohol occasionally, and had smoked in the past 30 years, and did not use illicit drugs or herbal preparations. There were no recent exposures to ill persons. Physical examination showed oedema of both lower limbs, while the other limbs were normal. Levels of sodium, chloride, carbon dioxide, D-dimer, magnesium and tests of liver function and renal function were normal. Troponin I and serum NT-proBNP were rising. A 24-h Holter monitor revealed occasional atrial premature beats, frequent multiple ventricular premature beats and ST-T changes. Transthoracic echocardiography (TTE) showed decreased systolic function (LVEF = 29%), an enlarged left ventricle (LVEDD = 60 mm), cardiomyopathy, moderate mitral regurgitation and moderate pulmonary hypertension ( Figure 1 ). There was no family history of cardiovascular disease. Drugs improving microcirculation and cardiac function were administered, and he was then admitted to our ward. Laboratory tests were conducted, and the results are shown in Table 1 .

Figure 1 . Transthoracic echocardiography was routinely examined from left parasternal long-axis view ( A ) and apical four-chamber view ( B ).

Table 1 . Laboratory data.

Based on the above clinical examination, computed tomography coronary angiogram (CTCA) was performed for the patient to rule out atherosclerotic coronary artery disease. To our surprise, the patient had a very rare SCA, a congenital abnormality of the coronary artery system that may provide low perfusion to the entire heart muscle, which causes chest pain, angina or dyspnoea. CTCA showed that a coronary artery from Valsalva's left sinus was divided into the left anterior descending branch (LAD) and the left circumflex branch (LCX). The distal end of the LCX continued its course beyond the crux into the atrioventricular groove, supplying the right atrium and right ventricle with a superdominant LCX without stenosis and a calcium score of zero Agatston units ( Figure 2 ). Because no intervention would be appropriate in the absence of significant coronary artery stenosis in CTCA, we decided not to perform invasive coronary angiography. To identify the cause of heart failure, we performed cardiovascular magnetic resonance (CMR) on the patient. CMR showed reduced left ventricular systolic function (LVEF = 17.2%), left ventricular enlargement (LVEDV = 296.2 ml), thinning of the myocardium and abnormal delayed reinforcement in the basal segment of the ventricular septum, which was consistent with the diagnosis of DCM ( Figure 3 ). Although improved cardiac imaging techniques have made endomyocardial biopsy (EMB) less necessary, it has traditionally been used to confirm the aetiology in some forms of DCM. However, EMB is no longer frequently performed and was not conducted in this case.

Figure 2 . Computed tomography coronary angiogram. ( A ) Course of the LCx on the posterior atrioventricular groove and continuation of its course in the RCA territory along with take-off of the posterior descending artery. ( B ) Absence of take-off of the RCA from the right coronary sinus of Valsalva (yellow arrow) and normal origin of the LMS which bifurcates into the LAD and LCX. LAD, left anterior descending artery; LCX, left circumflex artery; LMS, left main stem artery; RCA, right coronary artery.

Figure 3 . Cardiac magnetic resonance imaging showed DCM. CMR detected dilation of the left ventricle (LVEDV = 296.2 ml), reduction of cardiac systolic function (CO = 3.47l/min, LVEF = 17.2%) and increase of left ventricular mass (LVM = 170.5 g), no signs of storage disease or inflammation. CMR, Cardiac magnetic resonance imaging; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; CO, cardiac output.

We suspected that the mutation of a certain gene caused the patient to have SCA and DCM, therefore, we arranged a clinical gene test of the whole exon. Genetic screening showed the SCN5A ; NM_198056.2:c.1858C > T (p. Arg620Cys) mutation ( 10 – 13 ) and the pathogenicity of this variant has been reported; SCN5A ; NM_ 198056.2:c.1008 g > a [P. (pro336=)] mutation and there is no report on the pathogenicity of this variant. Sanger sequencing result is shown in Figure 4 and NSG data is shown in Supplementary Table S1 . The SCN5A C.1858C > T (P. arg620Cys) mutation may be associated with DCM in this patient. At the same time, APOA5 ; NM_052968.4:c.990_993delAACA (p. Asp332Valfs*5) was mutated in this patient, and its pathogenicity has been reported. According to ACMG Guidelines, this variant is considered a suspected pathogenic variant ( 14 ). The APOA5 gene mutation results in hypertriglyceridemia or hyperlipoproteinemia type 5, which was in line with the diagnosis of hypertriglyceridemia based on the patient's blood test. The relationship between SCA and DCM was not elucidated by genetic testing. There was no previous report on the absence of a RCA with DCM. According to findings of CTCA, TTE, CMR and other test results, we considered that the occurrence of DCM in this patient may not due to the absence of the RCA. Rather, we supposed that a gene mutation may cause the SCA and DCM.

Figure 4 . Sanger sequencing data. ( A ) SCN5A ; NM_198056.2; c.1858C > T; p.Arg620Cys. ( B ) SCN5A ; NM_198056.2; c.1008G > A; p.(Pro336=). ( C ) APOA5 ; NM_052968.4; c.990_993delAACA; p.Asp332Valfs*5. (a) proband (b) the son of proband (c) the daughter of proband.

Therefore, we performed family verification on the two children of the patient. The children of the proband both carried the SCN5A : c.1858C > T(p. Arg620Cys)/c.1008G > A [p.(Pro336=)] variant and APOA5 : c.990_993delAACA (p. Asp332Valfs*5) variant.

3. Discussion

This is a rare case of congenital absence of the RCA in a patient with a DCM-related gene mutation and hyperlipidemia. Our patient had tested positive for a gene variant known to cause DCM and had 2 months of chest tightness and dyspnoea after activity along with hyperlipidemia. The son and daughter of the proband also tested positive for the same mutation. We did not perform a full pedigree of the family since other relatives refused to be tested for the relevant mutations.

3.1. Genetic DCM

The prevalence of DCM and of genetically mediated DCM is not fully known because of geographic variations, patient selection and changes in the diagnostic criteria ( 15 – 18 ). The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presented an update of the existing classification scheme of cardiomyopathies in 2008. They grouped the cardiomyopathies into specific morphological and functional phenotypes, including hypertrophic cardiomyopathies, DCM, arrhythmogenic right ventricular cardiomyopathies (ARVC), restrictive cardiomyopathies and unclassified cardiomyopathies. Each phenotype was then subclassified into genetic and nongenetic forms, but overlaps exist between the two groups ( 6 , 8 ). Meanwhile, studies have shown that 20%–50% of non-ischemia cardiomyopathy patients have a family history ( 19 ). All of these findings suggest that genetic factors play an important role in the pathogenesis of cardiomyopathy.

Familial patterns or genetic causes have been identified in up to 35% of cases of idiopathic DCM ( 20 ). The genetic causes of DCM are diverse. An autosomal dominant trait is the most common, while autosomal recessive, X-linked and mitochondrial inheritance patterns are less common ( 21 ). TTN and LMNA are the main genes associated with the predominant cardiac phenotype, accounting for up to 25% and 5% of all cases of autosomal dominant DCM, respectively ( 22 ). RBM20 and DES are also common in clinical practice ( 23 , 24 ). Other genetic causes of a predominant DCM phenotype include mutations in sarcomere genes, Z-disc protein-encoding genes, genes encoding desmosomal proteins and genes associated with ion channel function ( 10 – 29 ).

The SCN5A gene is associated with ion channel function caused by DCM. With the development of gene detection technology, an increasing number of individual genes have been associated with inheritance in familial DCM cases. Cheng Shen et al. performed a cross-sectional study in Chinese patients with sporadic DCM and suggested that MYBPC3 , SCN5A , MYH7 , MYPN and LDB3 are the major genes hosting the at-risk genomic variants of sporadic DCM ( 30 ).

3.2. SCN5A gene mutation-related clinical diseases

The SCN5A gene, located on chromosome 3p21 with 28 exons, encodes the alpha subunit of the main sodium channel Nav1.5, which enables the rapid influx of Na + ions (INa) ( 19 ). This alpha subunit is expressed in human cardiomyocytes as well as in many other tissues and cells, such as embryonic and denervated skeletal muscle cells in the brain, interstitial cells of Cajal in the human jejunum and colon and smooth muscle cells ( 31 – 36 ). Some studies have shown that the SCN5A splice variant is also expressed in macrophages, where it activates innate immune signalling for antiviral defence ( 37 – 39 ). Voltage-gated Na + channels are crucial in the excitation and propagation of electrical impulses in cardiomyocytes ( 40 ). Nav1.5 interacts with several proteins, including ancillary β -subunits, fascia adherens junctions, desmosomes, gap junctions and intracellular proteins that regulate the gain-of-function and loss-of-function of Nav1.5 proteins ( Figure 5 ) ( 41 ). SCN5A gene mutations are associated with a clinical spectrum, including Brugada syndrome, long-QT syndrome, progressive cardiac conduction disease, sinus node dysfunction, atrial fibrillation, DCM, multifocal ectopic Purkinje-related premature contractions, irritable bowel syndrome (IBS) and other gastrointestinal disorders, such as chronic idiopathic intestinal pseudo-obstruction ( 32 , 34 , 41 , 42 ).

Figure 5 . Genetic test results of the proband and his children, both the proband and his children had the same three genes mutation and were heterozygous. ( A ) Molecular structure of the SCN5A translated into the a-subunit (Nav1.5) of the cardiac sodium channel. ( B ) Nav1.5 consists of an N-terminus, C-terminus and 4 structurally homologous domains.

3.3. SCN5A gene mutation and DCM

The genetic background of patients with DCM is complex: 7% have a single heterozygous mutation, more than 38% have a compound heterozygous or combined mutation, and 12.8% have three or more mutations ( 43 – 45 ). Although many previous works strongly implied that the SCN5A gene mutation plays a critical role in the development of cardiomyopathy, the mechanisms remain controversial. Several mechanisms have been postulated. SCN5A gene mutations related to tachyarrhythmia or other conduction abnormalities induce DCM, especially for some patients with a long history of arrhythmia ( 41 , 46 – 49 ). A primary disruption of Nav1.5 can affect cellular pH and Ca 2+ homeostasis and result in a DCM phenotype ( 42 , 50 – 52 ). The SCN5A channel mutation disrupts the sodium channel domain to target the appropriate cytoskeletal components, such as syntrophins and dystrophins ( 48 , 53 – 57 ). In addition, the environment and common gene variants may act together with SCN5A mutations to cause DCM ( 42 , 52 , 58 , 59 ).

The proband and offspring carried the same three mutations, but they have not shown signs of DCM, and we will continue to follow the family.

3.4. SCA: absence of RCA

In 1979, Lipton et al. defined and classified SCA, which can be divided into 9 types according to origin and anatomical process. The cause of SCA is still unknown ( 60 ). Although isolated reports indicate that specific coronary abnormalities occur in families, no clear pattern of coronary inheritance has been found in humans ( 61 ). We reported a rare L-I pattern of a SCA according to the Lipton classification and summarized a review of identical types of SCA literature, in which the RCA was absent and the LCX was markedly dominant and nourished the right ventricle and atrium beyond the atrioventricular groove. A careful review of the literature revealed 59 cases with a similar anomalous coronary origin and pattern, including demographic characteristics, symptoms, complications, diagnosis and treatment strategy ( Table 2 ) ( 62 – 112 ). Of these 59 patients, 22 were male and 37 were female, and their mean age was 56 years (range 30–87 years).

Table 2 . Summary characteristics of L-1 of SCA.

3.4.1. SCA and coronary heart disease

SCA is generally considered to be a benign abnormality; however, some authors have reported that 15% of SCA patients develop myocardial ischaemia as a direct consequence of coronary artery abnormalities ( 78 ). SCA abnormalities showed a higher risk of coronary atherosclerosis in a study ( 113 ). However, the relationship between congenital abnormalities and atherosclerosis is controversial. Tanriverdi H and Rudan D suggested that atherosclerosis in patients with coronary artery abnormalities was a coincidence ( 114 , 115 ). According to Shirani's review, 15% of patients with isolated SCA have evidence of myocardial ischaemia without significant atherosclerotic stenosis ( 116 ). There were 36 (61%) patients with coronary artery absence combined with coronary atherosclerotic heart disease (CHD); of them, coronary artery bypass grafting was performed in 5 patients, and percutaneous coronary intervention was conducted in 20 patients, which was higher than the general population. SCA anomaly by itself is unlikely to induce myocardial ischaemia, and it has been considered a benign lesion ( 98 ). We consider that SCA promotes the occurrence of CHD. When evaluating clinical symptoms and the degree of myocardial area at risk, it is extremely crucial to refer patients with combined SCA and CHD for selective coronary revascularization. Previous studies have shown that interventional surgery for SCA with atherosclerosis has potentially serious consequences; thus, it is rarely performed ( 92 , 102 ). However, our report revealed that the proportion of patients undergoing interventional surgery in this condition was as high as 69% (25/36). Therefore, interventional operation can be performed successfully in a patient who have SCA with CHD when the anatomy is appropriate.

3.4.2. SCA with congenital heart disease

Congenital heart disease is uncommon in the L-I pattern of SCA, accounting for 7% (4/59). Patent foramen ovale and bicuspid aortic valve were reported in 2 patients, and one of them had annuloaortic ectasia leading to heart failure ( 101 , 105 , 107 ). Congenitally corrected transposition in a situs inversus was shown in a patient ( 1 ).

3.4.3. SCA with arrhythmia

Overall, 10% (6/59) of SCA patients have shown arrhythmia, including 3 patients with right bundle branch block ( 68 , 85 , 102 ), 2 patients with atrial fibrillation ( 30 , 43 ), 1 patient with atrioventricular block ( 72 ) and 1 patient with Brugada syndrome ( 105 ). The risk of complete atrioventricular block in patients with atrioventricular discordance has been demonstrated, and SCA anomaly likely does not present an additional risk for atrioventricular block.

3.4.4. SCA with cardiomyopathy

The present study showed that 12% (7/59) of patients had coexisting cardiomyopathy, 6 had ischaemic cardiomyopathy due to CHD, and 1 had valvular heart disease. To our knowledge, there is no case of SCA with DCM to date. There were 13 patients with hyperlipidemia.

17 patients were diagnosed with SCA by computed tomography (CT). It has been reported that CTCA is the primary method for determining the diagnosis of SCA and can help delineate the course of the proximal artery. CTCA is also an interesting new model; in addition to being noninvasive, it reveals adjacent structures to understand the origin and development of coronary arteries ( 89 ).

Guidelines regarding the management of SCA are difficult to establish, and treatment is guided by symptoms and the presence or severity of atherosclerosis stenosis or the occurrence of acute coronary syndrome. The prognosis of patients ranges from a good normal life expectancy to sudden death.

According to the clinical symptoms and examination results of the patient, we believe that the patient's SCA was benign and was not the cause of his DCM. Another case of absence of the RCA with coexistence of the SCN5A gene mutation was previously reported by Katsaras D et al. ( 106 ). In this case, a patient with familial Brugada syndrome with absence of the RCA tested positive for a SCN5A gene C.664C. > T variant and presented with patent foramen ovale. In contrast, our case did not show Brugada syndrome rather than demonstrating DCM. As we discussed above, the SCN5A gene variant is associated with a spectrum of clinical diseases, and loss of sodium channel function has a critical role in the development of cardiomyopathy ( 48 ). The proband and his children carried the same three mutations. His children refused echocardiography but currently have no symptoms of DCM. The genetic background of patients presenting with DCM is complex; some studies have shown that more than 38% have a compound heterozygous or combined mutation, and 12.8% have three or more mutations ( 43 – 45 ). It is unclear whether the SCN5A gene mutation correlated with RCA absence and DCM in the present case. Meanwhile, the proband and his children carried an APOA5 gene mutation, which is considered a suspected pathogenic variant resulting in hypertriglyceridemia or hyperlipoproteinemia independent of the SCN5A mutation.

5. Conclusion

This is the first case of SCA combined with DCM of the SCN5A C.1858C > T (P.arg620Cys) mutation, which is the cause of DCM and Brugada syndrome. We should carefully identify and reduce life-threatening events in clinical practice to improve the survival rate. As with many other coronary artery abnormalities, coronary angiography is the gold standard method of diagnosis; importantly, CTCA plays a crucial role in diagnosis when considered as a noninvasive operation. Moreover, the underlying aetiological and pathological link between SCA and DCM remains to be explored.

Author contributions

Material preparation, data collection and analysis were performed by JY and XH. The first draft of the manuscript was written by JY and XH. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2023.1113886/full#supplementary-material .

Abbreviations

SCA, single coronary artery; DCM, dilated cardiomyopathy; RCA, right coronary artery; CCTA, computed tomography coronary angiogram; CMR, cardiac magnetic resonance imaging; TTE, transthoracic echocardiography; LVEF, left ventricular systolic function; LVEDD, left ventricular end-diastole diameter; LVEDV, left ventricular end-diastole volume; LAD, left anterior descending; LCX, left circumflex.

1. Cirakoglu OF, Bayraktar A, Sayin MR. An extremely rare clinical entity: congenitally corrected transposition with situs Inversus and single coronary artery presented with complete atrioventricular block in a young man. Cardiol Young . (2018) 28:759–61. doi: 10.1017/S1047951118000069

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Turkmen S, Yolcu M, Sertcelik A, Ipek E, Dokumaci B, Batyraliev T. Single coronary artery incidence in 215,140 patients undergoing coronary angiography. Folia Morphol . (2014) 73:469–74. doi: 10.5603/Fm.2014.0070

CrossRef Full Text | Google Scholar

3. Jordan E, Hershberger RE. Considering complexity in the genetic evaluation of dilated cardiomyopathy. Heart . (2021) 107:106–12. doi: 10.1136/heartjnl-2020-316658

4. Zheng GM, Bai J, Tang JM, Zhu FC, Jing HX. A case of hypertrophic cardiomyopathy combined with muscular ventricular septal defect and abnormal origin of right coronary artery. Bmc Cardiovasc Disor . (2019) 19:16. doi: 10.1186/s12872-018-0997-8

5. Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Bohm M, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J . (2016) 37:1850–8. doi: 10.1093/eurheartj/ehv727

6. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the cardiomyopathies: a position statement from the European society of cardiology working group on myocardial and pericardial diseases. Eur Heart J . (2008) 29:270–6. doi: 10.1093/eurheartj/ehm342

7. Gerullm B, Klaassen S, Brodehl A. The genetic landscape of cardiomyopathies. Genet Causes Card Dis . (2019) 7:45–91. doi: 10.1007/978-3-030-27371-2_2

8. Reichart D, Magnussen C, Zeller T, Blankenberg S. Dilated cardiomyopathy: from epidemiologic to genetic phenotypes A translational review of current literature. J Intern Med . (2019) 286:362–72. doi: 10.1111/joim.12944

9. McNally EM, Mestroni L. Dilated cardiomyopathy genetic determinants and mechanisms. Circ Res . (2017) 121:731–48. doi: 10.1161/Circresaha.116.309396

10. Riuro H, Campuzano O, Berne P, Arbelo E, Iglesias A, Perez-Serra A, et al. Genetic analysis, in silico prediction, and family segregation in long QT syndrome. Eur J Hum Genet . (2015) 23:79–85. doi: 10.1038/ejhg.2014.54

11. Kapplinger JD, Giudicessi JR, Ye D, Tester DJ, Callis TE, Valdivia CR, et al. Enhanced classification of brugada syndrome-associated and long-QT syndrome-associated genetic variants in the SCN5A-encoded na(v)1.5 cardiac sodium channel. Circ-Cardiovasc Gene . (2015) 8:582–95. doi: 10.1161/Circgenetics.114.000831

12. Hoshi M, Du XX, Shinlapawittayatorn K, Liu HY, Chai S, Wan XP, et al. Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ-Cardiovasc Gene . (2014) 7:123–31. doi: 10.1161/Circgenetics.113.000292

13. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, et al. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm . (2010) 7:33–46. doi: 10.1016/j.hrthm.2009.09.069

14. Jin JL, Sun D, Cao YX, Zhang HW, Guo YL, Wu NQ, et al. Intensive genetic analysis for Chinese patients with very high triglyceride levels: relations of mutations to triglyceride levels and acute pancreatitis. Ebiomedicine . (2018) 38:171–7. doi: 10.1016/j.ebiom.2018.11.001

15. Shah RA, Asatryan B, Dabbagh GS, Aung N, Khanji MY, Lopes LR, et al. Frequency, penetrance, and variable expressivity of dilated cardiomyopathy-associated putative pathogenic gene variants in UK biobank participants. Circulation . (2022) 146:110–24. doi: 10.1161/Circulationaha.121.058143

16. Argiro A, Ho C, Day SM, van der Velden J, Cerbai E, Saberi S, et al. Sex-related differences in genetic cardiomyopathies. J Am Heart Assoc . (2022) 11:e024947. doi: 10.1161/JAHA.121.024947

17. Andersson C, Schou M, Schwartz B, Vasan RS, Christiansen MN, D’Souza M, et al. Incidence rates of dilated cardiomyopathy in adult first-degree relatives versus matched controls. Int J Cardiol Heart Vasc . (2022) 41:101065. doi: 10.1016/j.ijcha.2022.101065

18. Miura K, Nakagawa H, Morikawa Y, Sasayama S, Matsumori A, Hasegawa K, et al. Epidemiology of idiopathic cardiomyopathy in Japan: results from a nationwide survey. Heart . (2002) 87:126–30. doi: 10.1136/heart.87.2.126

19. Li W, Yin L, Shen C, Hu K, Ge J, Sun A. SCN5A variants: association with cardiac disorders. Front Physiol . (2018) 9:1372. doi: 10.3389/fphys.2018.01372

20. Weintraub RG, Semsarian C, Macdonald P. Dilated cardiomyopathy. Lancet . (2017) 390:400–14. doi: 10.1016/S0140-6736(16)31713-5

21. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest . (2013) 123:19–26. doi: 10.1172/JCI62862

22. Keller H, Finsterer J, Steger C, Wexberg P, Gatterer E, Khazen C, et al. Novel c.367_369del LMNA mutation manifesting as severe arrhythmias, dilated cardiomyopathy, and myopathy. Heart Lung . (2021) 41:382–6. doi: 10.1016/j.hrtlng.2011.07.007

23. Gaertner A, Klauke B, Felski E, Kassner A, Brodehl A, Gerdes D, et al. Cardiomyopathy-associated mutations in the RS domain affect nuclear localization of RBM20. Hum Mutat . (2020) 41:1931–43. doi: 10.1002/humu.24096

24. Brodehl A, Dieding M, Biere N, Unger A, Klauke B, Walhorn V, et al. Functional characterization of the novel DES mutation p.L136P associated with dilated cardiomyopathy reveals a dominant filament assembly defect. J Mol Cell Cardiol . (2016) 91:207–14. doi: 10.1016/j.yjmcc.2015.12.015

25. Lukas Laws J, Lancaster MC, Ben Shoemaker M, Stevenson WG, Hung RR, Wells Q, et al. Arrhythmias as presentation of genetic cardiomyopathy. Circ Res . (2022) 130:1698–722. doi: 10.1161/CIRCRESAHA.122.319835

26. Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med . (2012) 366:619–28. doi: 10.1056/NEJMoa1110186

27. Taylor MR, Slavov D, Ku L, Di Lenarda A, Sinagra G, Carniel E, et al. Prevalence of desmin mutations in dilated cardiomyopathy. Circulation . (2007) 115:1244–51. doi: 10.1161/CIRCULATIONAHA.106.646778

28. Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, et al. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science . (2003) 299:1410–3. doi: 10.1126/science.1081578

29. Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, et al. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet . (2002) 30:201–4. doi: 10.1038/ng815

30. Shen C, Xu L, Sun X, Sun A, Ge J. Genetic variants in Chinese patients with sporadic dilated cardiomyopathy: a cross-sectional study. Ann Transl Med . (2022) 10:129. doi: 10.21037/atm-21-6774

31. Sarica AS, Bor S, Orman MN, Barajas-Martinez H, Juang JJ, Antzelevitch C, et al. Frequency of irritable bowel syndrome in patients with brugada syndrome and drug-induced type 1 brugada pattern. Am J Cardiol . (2021) 151:51–6. doi: 10.1016/j.amjcard.2021.04.010

32. Pan X, Li Z, Jin X, Zhao Y, Huang G, Huang X, et al. Comparative structural analysis of human Nav1.1 and Nav1.5 reveals mutational hotspots for sodium channelopathies. Proc Natl Acad Sci USA . (2021) 118:e2100066118. doi: 10.1073/pnas.2100066118

33. Strege PR, Mazzone A, Bernard CE, Neshatian L, Gibbons SJ, Saito YA, et al. Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased Na1.5 current and mechanosensitivity. Am J Physiol Gastrointest Liver Physiol . (2018) 314:G494–G503. doi: 10.1152/ajpgi.00016.2017

34. Verstraelen TE, Ter Bekke RM, Volders PG, Masclee AA, Kruimel JW. The role of the SCN5A-encoded channelopathy in irritable bowel syndrome and other gastrointestinal disorders. Neurogastroenterol Motil . (2015) 27:906–13. doi: 10.1111/nmo.12569

35. Neshatian L, Strege PR, Rhee PL, Kraichely RE, Mazzone A, Bernard CE, et al. Ranolazine inhibits voltage-gated mechanosensitive sodium channels in human colon circular smooth muscle cells. Am J Physiol Gastrointest Liver Physiol . (2015) 309:G506–12. doi: 10.1152/ajpgi.00051.2015

36. Strege PR, Ou Y, Sha L, Rich A, Gibbons SJ, Szurszewski JH, et al. Sodium current in human intestinal interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol . (2003) 285:G1111–21. doi: 10.1152/ajpgi.00152.2003

37. Poller W, Escher F, Haas J, Heidecker B, Schultheiss HP, Attanasio P, et al. Missense variant E1295K of sodium channel SCN5A associated with recurrent ventricular fibrillation and myocardial inflammation. JACC Case Rep . (2022) 4:280–6. doi: 10.1016/j.jaccas.2022.01.016

38. Jones A, Kainz D, Khan F, Lee C, Carrithers MD. Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense. J Biol Chem . (2014) 289:35326–40. doi: 10.1074/jbc.M114.611962

39. Rahgozar K, Wright E, Carrithers LM, Carrithers MD. Mediation of protection and recovery from experimental autoimmune encephalomyelitis by macrophages expressing the human voltage-gated sodium channel NaV1.5. J Neuropathol Exp Neurol . (2013) 72:489–504. doi: 10.1097/NEN.0b013e318293eb08

40. Black JA, Waxman SG. Noncanonical roles of voltage-gated sodium channels. Neuron . (2013) 80:280–91. doi: 10.1016/j.neuron.2013.09.012

41. Wilde AAM, Amin AS. Clinical spectrum of SCN5A mutations: long QT syndrome, brugada syndrome, and cardiomyopathy. JACC Clin Electrophysiol . (2018) 4:569–79. doi: 10.1016/j.jacep.2018.03.006

42. Ge J, Sun A, Paajanen V, Wang S, Su C, Yang Z, et al. Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy. Circ Arrhythm Electrophysiol . (2008) 1:83–92. doi: 10.1161/CIRCEP.107.750752

43. Huang W, Xu R, Gao N, Wu X, Wen C. Corrigendum: case report: family curse: an SCN5A mutation, c.611C>A, p.A204E associated with a family history of dilated cardiomyopathy and arrhythmia. Front Cardiovasc Med . (2022) 9:944834. doi: 10.3389/fcvm.2022.944834

44. Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J . (2015) 36:1123–35a. doi: 10.1093/eurheartj/ehu301

45. Akinrinade O, Ollila L, Vattulainen S, Tallila J, Gentile M, Salmenpera P, et al. Genetics and genotype-phenotype correlations in Finnish patients with dilated cardiomyopathy. Eur Heart J . (2015) 36:2327–37. doi: 10.1093/eurheartj/ehv253

46. Mann SA, Castro ML, Ohanian M, Guo G, Zodgekar P, Sheu A, et al. R222q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy. J Am Coll Cardiol . (2012) 160:566–73. doi: 10.1016/j.jacc.2012.05.050

47. Laurent G, Saal S, Amarouch MY, Beziau DM, Marsman RF, Faivre L, et al. Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J Am Coll Cardiol . (2012) 60:144–56. doi: 10.1016/j.jacc.2012.02.052

48. Watanabe H, Yang T, Stroud DM, Lowe JS, Harris L, Atack TC, et al. Striking in vivo phenotype of a disease-associated human SCN5A mutation producing minimal changes in vitro. Circulation . (2011) 124:1001–11. doi: 10.1161/CIRCULATIONAHA.110.987248

49. Hesse M, Kondo CS, Clark RB, Su L, Allen FL, Geary-Joo CTM, et al. Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a. Cardiovasc Res . (2007) 75:498–509. doi: 10.1016/j.cardiores.2007.04.009

50. Moreau A, Gosselin-Badaroudine P, Boutjdir M, Chahine M. Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents. Front Pharmacol . (2015) 6:301. doi: 10.3389/fphar.2015.00301

51. Gosselin-Badaroudine P, Keller DI, Huang H, Pouliot V, Chatelier A, Osswald S, et al. A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype. PLoS One . (2012) 7:e38331. doi: 10.1371/journal.pone.0038331

52. Nguyen TP, Wang DW, Rhodes TH, George AL Jr. Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia. Circ Res . (2008) 102:364–71. doi: 10.1161/CIRCRESAHA.107.164673

53. Petitprez S, Zmoos AF, Ogrodnik J, Balse E, Raad N, El-Haou S, et al. SAP97 And dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes. Circ Res . (2011) 108:294–304. doi: 10.1161/CIRCRESAHA.110.228312

54. Kärkkäinen S, Peuhkurinen K. Genetics of dilated cardiomyopathy. Ann Med . (2007) 39:288–94. doi: 10.1097/HCO.0000000000000845

55. Gavillet B, Rougier J-S, Domenighetti AA, Behar R, Boixel C, Ruchat P, et al. Cardiac sodium channel Nav1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circ Res . (2006) 99:407–14. doi: 10.1161/01.RES.0000237466.13252.5e

56. Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO, de Groot JR, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation . (2005) 112:2769–77. doi: 10.1161/CIRCULATIONAHA.105.532614

57. Towbin JA, Bowles NE. The failing heart. Nature . (2002) 415:227–33. doi: 10.1038/415227a

58. Beckermann TM, McLeod K, Murday V, Potet F, George AL Jr. Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy. Heart Rhythm . (2014) 11:1446–53. doi: 10.1016/j.hrthm.2014.04.042

59. Amin AS. SCN5A-related Dilated cardiomyopathy: what do we know? Heart Rhythm . (2014) 11:1454–5. doi: 10.1016/j.hrthm.2014.05.031

60. Echavarria-Pinto M, Rodriguez-Rodriguez E, Macias E, Kimura-Hayama E. Extremely rare single right coronary artery: multidetector computed tomography findings. Arch Cardiol Mex . (2012) 82:195–6.22735660

PubMed Abstract | Google Scholar

61. Laureti JM, Singh K, Blankenship J. Anomalous coronary arteries: a familial clustering. Clin Cardiol . (2005) 28:488–90. doi: 10.1002/clc.4960281009

62. Krumbhaar EB, Ehrich WE. Varieties of single coronary artery in man, occurring as isolated cardiac anomalies. Am J Med Sci . (1938) 196:407–13. doi: 10.1097/00000441-193809000-00015

63. Ma SH, Kim DH, Hur JY, Kim KS, Byun SJ, Park KH, et al. Right ventricular myocardial infarction due to right coronary artery total occlusion originating from the distal left circumflex artery. Korean Circ J . (2012) 42:565–7. doi: 10.4070/kcj.2012.42.8.565

64. Chen HY. Anomalous origin of coronary arteries from a single sinus of Valsalva. Exp Clin Cardiol . (2012) 17:150–1.23620708

65. Sonmez O, Gul EE, Altunbas G, Ozdemir K. Right coronary artery arising from the distal left circumflex artery. Turk Kardiyol Dern Ars . (2011) 39:325–7. doi: 10.5543/tkda.2011.00769

66. Kalyani R, Thej MJ, Prabhakar K, Kiran J. Single dominant left coronary artery: an autopsy case report with review of literature. J Cardiovasc Dis Res . (2011) 2:130–2. doi: 10.4103/0975-3583.83038

67. Voyce SJ, Abughnia H. An unusual cause of right ventricular myocardial infarction. J Invasive Cardiol . (2010) 22:E172–5.21041857

68. Ghaffari S, Pourafkari L. Pulmonary embolism in a patient with a rare coronary anomaly—a clue to the importance of proximal right coronary artery branches. Kardiol Pol . (2010) 68:844–7.20648453

69. Datta S, Moussa T, Hussain F. Anomalous right coronary artery originating from the distal left circumflex artery: a novel coronary artery anomaly viewed by computed tomography and invasive angiography. Can J Cardiol . (2010) 26:213. doi: 10.1016/s0828-282x(10)70404-9

70. Chung SK, Lee SJ, Park SH, Lee SW, Shin WY, Jin DK. An extremely rare variety of anomalous coronary artery: right coronary artery originating from the distal left circumflex artery. Korean Circ J . (2010) 40:465–7. doi: 10.4070/kcj.2010.40.9.465

71. Choi HY, Kim JW, Moon JM, Kim YJ, Choi CU, Lim HE, et al. Unusual dominant course of left circumflex coronary artery to right coronary artery territory with absent right coronary artery. J Cardiol . (2010) 55:117–9. doi: 10.1016/j.jjcc.2009.03.014

72. Tanawuttiwat T, Harindhanavudhi T, Trivedi D. Anomalous single coronary artery with absent right coronary artery diagnosed with the aid of 64-slice multidetector computed tomographic angiography. Tex Heart Inst J . (2009) 36:362–3.19693319

73. Celik T, Iyisoy A, Yuksel C, Isik E. Anomalous right coronary artery arising from the distal left circumflex coronary artery. Anadolu Kardiyol Derg . (2008) 8:459–60.19103546

74. Kunimasa T, Sato Y, Ito S, Takagi T, Lee T, Saeki F, et al. Absence of the right coronary artery detected by 64-detector-row multislice computed tomography. Int J Cardiol . (2007) 115:249–50. doi: 10.1016/j.ijcard.2006.01.039

75. Kang WC, Han SH, Ahn TH, Shin EK. Images in cardiology. Unusual dominant course of left circumflex coronary artery with absent right coronary artery. Heart . (2006) 92:657. doi: 10.1136/hrt.2005.073668

76. Vijayvergiya R, Kumar Jaswal R. Anomalous left anterior descending, absent circumflex and unusual dominant course of right coronary artery: a case report--R1. Int J Cardiol . (2005) 102:147–8. doi: 10.1016/j.ijcard.2004.03.075

77. Yoshimoto S, Hirooka K, Irino H, Abe H, Yasuoka Y, Yamamoto H, et al. Anomalous right coronary artery originating from the distal left circumflex artery: single coronary artery with chronic atrial fibrillation. Jpn Heart J . (2004) 45:679–83. doi: 10.1536/jhj.45.679

78. Chou LP, Kao C, Lee MC, Lin SL. Right coronary artery originating from distal left circumflex artery in a patient with an unusual type of isolated single coronary artery. Jpn Heart J . (2004) 45:337–42. doi: 10.1536/jhj.45.337

79. Turhan H, Duru E, Yetkin E, Atak R, Senen K. Right coronary artery originating from distal left circumflex: an extremely rare variety of single coronary artery. Int J Cardiol . (2003) 88:309–11. doi: 10.1016/s0167-5273(02)00324-8

80. Asha M, Sriram R, Mukundan S, Abraham KA. Single coronary artery from the left sinus with atherosclerosis. Asian Cardiovasc Thorac Ann . (2003) 11:163–4. doi: 10.1177/021849230301100217

81. Shammas RL, Miller MJ, Babb JD. Single left coronary artery with origin of the right coronary artery from distal circumflex. Clin Cardiol . (2001) 24:90–2. doi: 10.1002/clc.4960240115

82. Desmet W, Vanhaecke J, Vrolix M, Van de Werf F, Piessens J, Willems J, et al. Isolated single coronary artery: a review of 50,000 consecutive coronary angiographies. Eur Heart J . (1992) 13:1637–40. doi: 10.1093/oxfordjournals.eurheartj.a060117

83. Vrolix MC, Geboers M, Sionis D, De Geest H, Van de Werf F. Right coronary artery originating from distal left circumflex: an unusual feature of single coronary artery. Eur Heart J . (1991) 12:746–7. doi: 10.1093/eurheartj/12.6.746

84. Sheth M, Dovnarsky M, Cha SD, Kini P, Maranhao V. Single coronary artery: right coronary artery originating from distal left circumflex. Cathet Cardiovasc Diagn . (1988) 14:180–1. doi: 10.1002/ccd.1810140310

85. Tavernarakis A, Voudris V, Ifantis G, Tsaganos N. Anomalous origin of the right coronary artery arising from the circumflex artery. Clin Cardiol . (1986) 9:230–2. doi: 10.1002/clc.4960090514

86. Lipton MJ, Barry WH, Obrez I, Silverman JF, Wexler L. Isolated single coronary artery: diagnosis, angiographic classification, and clinical significance. Radiology . (1979) 130:39–47. doi: 10.1148/130.1.39

87. Laurie W, Woods JD. Single coronary artery: a report of two cases. Am Heart J . (1964) 67:95–8. doi: 10.1016/0002-8703(64)90404-1

88. Smith JC. Review of single coronary artery with report of 2 cases. Circulation . (1950) 1:1168–75. doi: 10.1161/01.cir.1.5.1168

89. Devidutta S, Sharma G, Jagia P. Coronary stenting in a patient with single coronary artery and double-vessel disease!. J Invasive Cardiol . (2013) 25:E147–50.23813073

90. Pourbehi MR, Amini A, Farrokhi S. Single coronary artery with anomalous origin of the right coronary artery from the distal portion of left circumflex artery: a very rare case. J Tehran Heart Cent . (2013) 8:161–3.24396367

91. Inaba S, Kikuchi K, Higashi H, Sumimoto T. Rare case of isolated single coronary artery causing ischaemia. Eur Heart J . (2015) 36:882. doi: 10.1093/eurheartj/ehu497

92. Garcia-Blas S, Valero E, Escribano D, Bonanad C, Sanchis J, Nunes J. Guideliner use for the percutaneous treatment of right coronary artery arising from the left circumflex (L-type single coronary artery). Int J Cardiol . (2015) 185:2–3. doi: 10.1016/j.ijcard.2015.03.084

93. de Agustin JA, de Diego JJG, Marcos-Alberca P, Rodrigo JL, Almeria C, Nunez-Gil IJ, et al. Single left coronary artery with the right coronary artery arising as a continuation from the distal circumflex coronary artery assessed by multislice computed tomography. Int J Cardiol . (2014) 174:814–5. doi: 10.1016/j.ijcard.2014.04.145

94. Patil S, Rachaiah JM, Ramalingam R, Manjunath CN, Subramanyam K. Percutaneous coronary intervention of hidden coronary artery-unusual type of isolated single coronary artery. J Clin Diagn Res . (2016) 10:OD03-4. doi: 10.7860/JCDR/2016/20629.8266

95. Singh S, Sahoo SK, Tripathy MP, Jena G. Angiographic enigma: a single coronary artery with the right coronary artery originating from the distal left circumflex artery. Heart Views . (2015) 16:104–6. doi: 10.4103/1995-705X.164465

96. Buccheri D, Cortese B, Piraino D, Orrego PS, Seregni R. Left main coronary artery and ostial left anterior descending coronary artery stenting in a single coronary artery during NSTEMI. The OCT response. Int J Cardiol . (2015) 184:499–501. doi: 10.1016/j.ijcard.2015.03.032

97. Zamani J, Zolghadrasli A. Successful percutaneous intervention of proximal left anterior descending artery in a case of single coronary artery trunk. J Cardiol Cases . (2014) 10:205–7. doi: 10.1016/j.jccase.2014.07.011

98. Pourafkari L, Taban M, Ghaffari S. Anomalous origin of right coronary artery from distal left circumflex artery: a case study and a review of its clinical significance. J Cardiovasc Thorac Res . (2014) 6:127–30. doi: 10.5681/jcvtr.2014.027

99. Mishra TK, Mishra CK, Das B. Percutaneous coronary intervention in a patient with single coronary artery. Indian Heart J . (2014) 66:382–5. doi: 10.1016/j.ihj.2014.03.011

100. Ha SJ, Kwon SH, Kim SJ. Funtional significance of the intermediate lesion in a single coronary artery assessed by fractional flow reserve. Korean J Intern Med . (2014) 29:822–4. doi: 10.3904/kjim.2014.29.6.822

101. Egashira T, Shimizu H, Yamada Y, Fukuda K. Successful aortic root replacement and shunt closure in a case with rare coexistence of congenital cardiac malformations: bicuspid aortic valve with annuloaortic ectasia, single coronary artery, and patent foramen ovale. Int J Cardiovasc Imaging . (2014) 30:1267–8. doi: 10.1007/s10554-014-0458-0

102. Dai J, Katoh O, Kyo E, Zhou XJ. Percutaneous intervention in a patient with a rare single coronary artery from the left coronary sinus of valsava. J Res Med Sci . (2014) 19:375–7.25097612

103. Ay Y, Aydin C, Ay NK, Inan B, Basel H, Zeybek R. Single coronary artery anomaly causing ischemic mitral insufficiency. Asian Cardiovasc Thorac Ann . (2014) 22:469–71. doi: 10.1177/0218492313475641

104. Kafkas N, Triantafyllou K, Babalis D. An isolated single L-I type coronary artery with severe LAD lesions treated by transradial PCI. J Invasive Cardiol . (2011) 23:E216–E8.21891816

105. Katsaras D, Sanjeev Kumar BT, Patel B, Chalil S, Abozguia K. A 59-year-old woman with familial brugada syndrome and the c.664C>T variant of the sodium voltage-gated channel alpha subunit 5 (SCN5A) gene, accompanied by congenital absence of the right coronary artery, patent foramen Ovale, and ischemic stroke. Am J Case Rep . (2021) 22:e931535. doi: 10.12659/AJCR.931535

106. Ahmed A, Assaf A, Mantha Y, Small D, Zughaib M. A rare anatomical variant: congenital absence of the right coronary artery with left circumflex artery supplying the right coronary artery (RCA) territory. Am J Case Rep . (2021) 22:e932248. doi: 10.12659/AJCR.932248

107. Phan NT, Nguyen HT, Nguyen TT, Ly ND, Le NT. St elevation myocardial infarction in a patient with an anomalous right coronary artery originating from the distal left circumflex. Int Med Case Rep J . (2019) 12:379–82. doi: 10.2147/IMCRJ.S232401

108. Iftikhar I, Rehman AU, Khan HS. A single coronary artery with an absent right coronary and a superdominant left circumflex giving off a branch supplying the right coronary artery territory. J Coll Physicians Surg Pak . (2019) 29:S80–2. doi: 10.29271/jcpsp.2019.12.S80

109. Blaschke F, Zimmermann E, Greupner J, Zohlnhoeler D, Krackhardt F, Haverkamp W, et al. A rare case of a congenital single coronary artery: right coronary artery originating from the distal left circumflex artery. Vasc Dis Manag . (2013) 10:E244–7.

Google Scholar

110. Gatti G, Belgrano M, Cova MA, Sinagra G. Single coronary artery anomaly and chest pain. J Cardiovasc Med (Hagerstown) . (2017) 18:983–4. doi: 10.2459/JCM.0000000000000582

111. Lee H-C, Lai H-Y, Hsieh KL-C, Lan G-Y. Characterizing an absent right coronary artery through 3-dimensional coronary computed tomography angiography. Rev Cardiovasc Med . (2018) 19:111–2. doi: 10.31083/j.rcm.2018.03.3184

112. da Silva Matte B, Lima Marques FP, de Araujo GN, Gonçalves SC. Superdominant circumflex thrombosis with occluded LAD and absent RCA ostium. J Invasive Cardiol . (2019) 31:E45.30700634

113. Click RL, Holmes DR, Vlietstra RE, Kosinski AS, Kronmal RA. Anomalous coronary arteries: location, degree of atherosclerosis and effect on survival--a report from the coronary artery surgery study. J Am Coll Cardiol . (1989) 13:531–7. doi: 10.1016/0735-1097(89)90588-3

114. Tanriverdi H, Seleci D, Kuru O, Semiz E. Right coronary artery arising as a terminal extension of the circumflex artery (a rare coronary artery anomaly). Can J Cardiol . (2007) 23:737–8. doi: 10.1016/s0828-282x(07)70820-6

115. Rudan D, Todorovic N, Starcevic B, Raguz M, Bergovec M. Percutaneous coronary intervention of an anomalous right coronary artery originating from the left coronary artery. Wien Klin Wochenschr . (2010) 122:508–10. doi: 10.1007/s00508-010-1420-3

116. Shirani J, Roberts WC. Solitary coronary ostium in the aorta in the absence of other major congenital cardiovascular anomalies. J Am Coll Cardiol . (1993) 21:137–43. doi: 10.1016/0735-1097(93)90728-j

Keywords: SCN5A , single coronary artery, dilated cardiomyopathy, genetic mutation, hyperlipidemia

Citation: Hu X, Kong J, Niu T, Chen L and Yang J (2023) Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with the SCN5A and APOA5 gene mutation: A case report and review of the literature. Front. Cardiovasc. Med. 10:1113886. doi: 10.3389/fcvm.2023.1113886

Received: 1 December 2022; Accepted: 23 March 2023; Published: 22 May 2023.

Reviewed by:

© 2023 Hu, Kong, Niu, Chen and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jingjing Yang [email protected]

Specialty Section: This article was submitted to Coronary Artery Disease, a section of the journal Frontiers in Cardiovascular Medicine

Open Access
Published: 19 May 2023

Headache following vaccination against COVID-19 among healthcare workers with a history of COVID-19 infection: a cross-sectional study in Iran with a meta-analytic review of the literature

Somayeh Nasergivehchi 1 , 2 ,
Mansoureh Togha ORCID: orcid.org/0000-0002-9368-6835 1 , 3 ,
Elham Jafari 1 ,
Mehrdad Sheikhvatan 4 , 5 &
Donya Shahamati 6

Head & Face Medicine volume 19 , Article number: 19 ( 2023 ) Cite this article

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There is evidence of the occurrence of headache after vaccination against COVID-19. However, only a few studies have examined the headache characteristics and related determinants, especially among healthcare workers with a history of COVID-19 infection.

We evaluated the incidence of headaches after injection of different types of COVID-19 vaccine to determine factors relating to the incidence of headache after vaccination among the Iranian healthcare workers who had previously contracted COVID-19. A group of 334 healthcare workers with a history of COVID-19 infection were included and vaccinated (at least one month after recovery without any COVID-19 related symptoms) with different COVID-19 vaccines. The baseline information, headache characteristics and vaccine specifications were recorded.

Overall, 39.2% reported experiencing a post-vaccination headache. Of those with a previous history of headache, 51.1% reported migraine-type, 27.4% tension-type and 21.5% other types. The mean time between vaccination and headache appearance was 26.78 ± 6.93 h, with the headache appearing less than 24 h after vaccination in most patients (83.2%). The headaches reached its peak within 8.62 ± 2.41 h. Most patients reported a compression-type headache. The prevalence of post-vaccination headaches was significantly different according to the type of vaccine used. The highest rates were reported for AstraZeneca, followed by Sputnik V. In regression analysis, the vaccine brand, female gender and initial COVID-19 severity were the main determinants for predicting post-vaccination headache.

Participants commonly experienced a headache following vaccination against COVID-19. Our study results indicated that this was slightly more common in females and in those with a history of severe COVID-19 infection.

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Introduction

With the onset of the COVID-19 pandemic in December 2019, efforts began to provide effective and safe drugs to treat the disease and prevent its development. In line with what has been observed in previous pandemics, the efforts to produce effective vaccines increased rapidly. A few months after the start of such efforts and with the rapid spread of COVID-19 and its variants, the first generations of effective immunogenic vaccines were introduced and gradually approved by international scientific reference committees, including the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) [ 1 , 2 ].

It did not take long to generate various brands of vaccines in countries such as the United States, China, Germany, Japan, India, Russia, and even in developing countries such as Iran and Cuba, and introduce them to the world [ 3 , 4 , 5 ]. However, as the production and commercialization of these vaccines accelerated, concerns arose. First, with the emergence of COVID-19 variants, especially the Delta strain, concern increased about reduced immunogenicity against the virus variants. The protective effects of some vaccines initially having an immunogenicity level of over 90% were seen to decrease to less than 70% [ 6 , 7 ]. More importantly, following inoculation with various vaccine brands against COVID-19, potential and, rarely, life-threatening side effects were reported. Common side effects for the COVID-19-vaccines included local inflammation, headache, muscle pain, nausea, fatigue, fever and chills [8]. Anaphylaxis, thromboembolic events, myocarditis, pericarditis and even death were rarely reported, but seriously called into question the safety of some brands [ 9 ].

One of the most common side effects following injection of the different brands of COVID-19 vaccine has been headache. According to the Zoe Health Study, the overall prevalence of headache after vaccination by Pfizer-BioNTech vaccine ranged from 25 to 42% [ 10 ]. The CDC Trusted Source page reported that approximately one-third of people experienced severe post-vaccination headache, regardless of the type or brand of vaccine, at a rate of 1% after the first dose and 3% after the second dose [ 11 ].

One study in Italy reported on the increased likelihood of headache after vaccination by AstraZeneca vaccine, followed by the Pfizer vaccine [ 12 ]. Ekizoglu et al. assessed the history of headache following influenza vaccination and during Covid-19. They found that 30.6% healthcare personnel had experienced headache following Covid vaccination that was more common in females with pre-existing primary headaches, thyroid disorders, headache during COVID-19, or headache related to the influenza vaccine [ 15 ]. Sekiguchi et al. in their study in Japan performed a survey on nursing staff. Their result demonstrated that participants with the history of headache (migraineurs and non-migraineurs) will develop more headache compare to the healthy controls [ 13 ].

However, overall information about headache following those brands, as well as others, has been limited and requires further evaluation. This is especially important for individuals who have experienced COVID-19 infection prior to vaccination. This study evaluated and compared the incidence of headache following inoculation with different types of commonly used COVID-19 vaccines and determined the factors related to the incidence of headache following vaccination among selected Iranian healthcare workers who had previously recovered from COVID-19.

Materials and methods

The participants in this cross-sectional study comprised 334 healthcare personnel who had initially recovered from COVID-19 infections of different intensities. According to our institutional protocol, these individuals were vaccinated at least one month after recovery with one of the brands of COVID-19 vaccine mentioned above between April and September 2021. The brands of corona vaccine that were commonly used among healthcare workers in this study included AstraZeneca, Sinopharm (China), Sputnik V (Russia), Bharat (India) and COVIran Barekat (Iran).

An online questionnaire designed to cover all the necessary data. This questionnaire included the demographics characteristics, the brand of vaccine administered, severity of initial COVID-19 infection (defined as quarantine at home, hospitalization in an isolated ward or ICU), concomitant clinical symptoms, PCR positivity after vaccination, rate of analgesic use after vaccination and COVID-19 positivity between two vaccine doses. In addition, information related to the post-vaccination headache, including time duration between vaccination and headache occurrence, time to reaching peak intensity after onset, pattern and location of the headache and medication used for headache relief also were assessed.

All patients were reassured about the privacy of their information and, after explaining the objectives of the project, verbal consent was obtained from all. The study endpoint was to determine the prevalence of headache and its characteristics following the use of each vaccine brand and then to determine the effect of vaccination of the different brands while adjusting for gender, initial COVID-19 severity and previous history of headache. In this regard, the severity of the COVID-19 was determined based on the Criteria for Clinical Severity of Confirmed COVID-19 as released by WHO [ 1 , 2 ].

For statistical analysis, results were presented as mean ± standard deviation (SD) for the quantitative variables and were summarized by frequency (percentage) for categorical variables. Continuous variables were compared using the t -test or Mann-Whitney test whenever the data did not appear to have a normal distribution or when the assumption of equal variance was violated across the study groups. The multivariable logistic regression model was employed to examine the effect of type of vaccine on post-vaccination headache as adjusted for gender, history of headache and COVID-19 severity. P-values of ≤ 0.05 were considered statistically significant. The statistical software SPSS (version 23.0) for Windows (IBM; USA) was used for statistical analysis.

A total of 334 hospital staff members who had a history of COVID-19 infection and had subsequently been vaccinated with different brands of vaccines in Iran were assessed (Table 1 ). The average age of participants was 36.62 ± 4.36 year. of which 72.8% were female and 27.2% were male. Of the vaccines used, 12.9% were vaccinated with AstraZeneca, 16.2% with Sinopharm, 62.3% with Sputnik V, 6.9% with Bharat and 1.8% with other brands. The initial COVID-19 severity of the participants was assessed and it was determined that 62.6% had quarantined at home, 32.3% had been hospitalized in a general ward and 5.1% had been admitted to an ICU.

Overall, 39.2% of participants reported experiencing post-vaccination headache and 30.8% of participants reported a history of headache. Of those, 51.1% characterized their previous headaches as of the migraine type, 27.4% as tension type and 21.5% as other types. The mean time between injection of the vaccine and the onset of headache was 26.78 ± 6.93 h. Most participants (83.2%) reported the onset of headache to be less than 24 h after vaccination. They reported the headache reaching a peak within about 8.62 ± 2.41 h after the onset and the overall duration of the headache to be 4.22 ± 1.26 h. In 50% of participants, the headache duration was less than 6 h.

With respect to the symptoms accompanying the post-vaccination headache, the most frequent was nausea (9.2%), followed by sensitivity to noise (6.9%) and photophobia (4.6%). In most patients, the headache was of the compression type and most reported that the headache was felt diffusely in various parts of the head. The severity of headache in most participants (93.0%) was such that they resorted to the use of some type of analgesic (Table 2 ).

Figure 1 shows that the prevalence of post-vaccination headache was significantly different according to the brand of vaccine administered. The prevalence of post-vaccination headache was highest for AstraZeneca (62.8%), followed by Sputnik V (40.4%) and Bharat (30.4%) (p < 0.001). Post-vaccine headache was found to be significantly higher in females than in males (43.6% versus 27.5%; p = 0.001). Table 3 reveals that, although the onset of headache (early or delayed) did not differ across vaccine brands, the pattern of headache did differ. Compression headache was reported more often by those vaccinated with AstraZeneca or Sputnik V. Pulsatile headaches were reported to occur most often following vaccination with Sinopharm.

Prevalence of post-vaccine headache according to type of vaccine used (p = 0.001)

Table 4 indicates that, in multivariate logistic regression analysis, the brand of vaccine (OR = 1.328; p = 0.040), female gender (OR = 1.934; p = 0.017) and COVID-19 severity (OR = 3.541; p = 0.001) were the main determinants for prediction of post-vaccination headache. It was noted that a history of headache before vaccination was not significantly associated with the occurrence of post-vaccination headache.

Recent studies have reported on the occurrence of headache after inoculation with COVID-19 vaccines; however, the present study is the first to evaluate this event in individuals who have been vaccinated after initial infection by and recovery from COVID-19 and who experienced post-vaccination headaches. It should be noted that, post-vaccination, there were no signs of re-infection among participants.

The predominant finding of the present study has been that about one-third of the vaccinated individuals in the study group reported various types of post-vaccination headache. A review of the literature (Table 5 ) showed that the incidence of post-vaccination headache ranged from 19.5 to 49.4% regardless of the type of vaccine used or the target population (general population or healthcare workers). In a meta-analysis of these studies, we found an overall prevalence of 31.2% (95% CI: 25.3–37.9%) for headache, with a prevalence of 34.6% (95% CI: 27.4–42.5%) among healthcare workers, but with considerable heterogeneity across the studies (I 2 = 99.037 (Figs. 2 ) and 98.343 (Fig. 3 ), respectively; p < 0.001) [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. These divergent results could relate to the different brands of vaccine used as well as differences in the study populations. It could be concluded that about one-third of individuals who have been vaccinated against COVID-19 experienced various degrees of headache, with a slightly higher incidence rate among healthcare personnel.

Prevalence of post-vaccine headache among total population in different studies

Prevalence of post-vaccine headache among healthcare workers in different studies

More interestingly, most headaches occurred within the first 24 h after vaccination (83.2%) with the mean time between vaccination and headache onset to be 26.78 ± 6.93 h. As indicated by Göbel et al. [ 34 ], the latency between vaccination against COVID-19 and the occurrence of headache was on average 18.0 ± 27.0 h. More than half of their participants perceived the headache in less than 10 h and 80% within 24 h after vaccination, which is similar to our findings. Koji Sekiguchi et al. [ 35 ] also reported that the median onset of headache after the first and second vaccine doses were 10 and 12 h, respectively, and mean duration of headache was 4.5 and 8.0 h, respectively. In that study, the mean time to onset of headache after vaccination was 4.22 ± 1.26 h. In 50% of their participants, the headache duration was less than 6 h and in 80% was less than 22 h. Göbel et al. [ 34 ] reported a mean headache duration of 14.2 + 21.4 h.

About one-third of participants reported generalized headache. Göbel et al. [ 34 ] reported bilateral headache in 73.1% of their subjects, with the most prominent zones being the forehead (38.0%) followed by the temple (32.2%). Sekiguchi et al. [ 35 ] reported the rate of bilateral headache in healthy controls having no history of headache, and history of migraine and non-migraine headaches as being 78.8%, 62.5% and 75.9%, respectively. The participants in the present study primarily reported compression-type headaches. Göbel et al. [ 34 ] reported compression headache and dull pain in 49.2% and 40.7% of participants, respectively. Ekizoglu et al. [ 15 ] reported throbbing headaches in 40.1% of participants and compression headache in 30.4%.

Another important finding was the occurrence of post-vaccination headache as being potentially influenced by the factors of the female gender and severity of the initial COVID-19 infection. Research released by the CDC on the safety of COVID-19 vaccinations indicated post-vaccination side-effects occurred among 79.1% of women but only in 61.2% of men [ 36 ]. As migraine and tension headaches are more prevalent in women than in men [ 37 , 38 ], such a difference may affect the likelihood of post-vaccination headache among women compared to men.

The current study found a significant difference in the prevalence of headache according to vaccine brand used among different countries. As shown, the highest rate of headache was after AstraZeneca vaccination, followed by Sputnik V; however, the literature reviewed (Table 5 ) did not differentiate between vaccines in relation to post-vaccination headache. For example, the rate of post-vaccination headache following vaccination by Pfizer-BioNTech ranged from 6.0 to 48.7%. Additionally, information about the incidence of side-effects of brands such as Sinopharm and Sputnik V vaccines has been limited.

There is no documented and comprehensive explanation of the pathomechanisms of headache following vaccination against COVID-19. Some believe that such a headache may originate from the spike protein of the virus used to produce the vaccine [ 39 ]. Others have speculated that the immune response triggered by such proteins plays a significant role [ 40 ]. This means that flaring pro-inflammatory cascades and secretion of cytokines and prostaglandins may be responsible for vaccination-related headache and other concurrent symptoms [ 41 , 41 ]. It should be noted that the technologies and materials used for creating the vaccines could play a role in post-vaccination headache. This should be evaluated in further studies.

One limitation of the study was that some of the most commonly used brands globally, such as Pfizer, were not widely available in Iran; thus was not possible to evaluate the post-vaccination headache for these brands. Additionally, the pattern of headache among the healthcare workers as participants was not evaluated during the first exposure to COVID-19.

The current study examined the incidence of post-vaccination headache among healthcare workers who were vaccinated against COVID-19 after recovering from a previous bout of the virus. Different brands of vaccine were examined and it was found that 39.2% of participants experienced post-vaccination headache. This incidence was greater among females than males as well as those who had experienced more severe cases of COVID-19 before vaccination. Among the brands used in our population, the highest rate of post-vaccination headache was for the AstraZeneca, followed by Sputnik V. Considering that COVID-19 will continue to infect the global population in the future, vaccination, as well as identification and classification of post-vaccination headache, can improve appropriate management of the virus. The differentiation of such headaches from other post-vaccination side-effects, such as cerebrovascular thrombotic events, can be vital to the targeted management of these events.

Availability of data and materials

Data available on request due to privacy/ethical restrictions.

Ghasemiyeh P, Mohammadi-Samani S, Firouzabadi N, Dehshahri A, Vazin A. A focused review on technologies, mechanisms, safety, and efficacy of available COVID-19 vaccines. Int Immunopharmacol 2021 Sep 17;100:108162. doi: https://doi.org/10.1016/j.intimp.2021.108162 . Online ahead of print.

Khan A, Khan T, Ali S, Aftab S, Wang Y, Qiankun W, Khan M, Suleman M, Ali S, Heng W, Ali SS, Wei DQ, Mohammad A. SARS-CoV-2 new variants: characteristic features and impact on the efficacy of different vaccines. Biomed Pharmacother. 2021 Sep;11:143:112176.

Scott J, Richterman A, Cevik M. COVID-19 vaccination: evidence of waning immunity is overstated. BMJ. 2021 Sep;23:374:n2320. https://doi.org/10.1136/bmj.n2320 .

Gómez-Carballa A, Pardo-Seco J, Bello X, Martinón-Torres F, Salas A. Superspreading in the emergence of COVID-19 variants. Trends Genet. 2021 Sep 8:S0168-9525(21)00262-6. doi: 10.1016/j.tig.2021.09.003. Online ahead of print.

Mehraeen E, Dadras O, Afsahi AM, Karimi A, MohsseniPour M, Mirzapour P, Barzegary A, Behnezhad F, Habibi P, Salehi MA, Vahedi F, Heydari M, Kianzad S, Moradmand-Badie B, Javaherian M, SeyedAlinaghi S, Sabatier JM. Vaccines for COVID-19: A Review of Feasibility and Effectiveness. Infect Disord Drug Targets. 2021 Sep 23. doi: https://doi.org/10.2174/1871526521666210923144837 .

Raman R, Patel KJ, Ranjan K. COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies. Biomolecules 2021 Jul 6;11(7):993. doi: https://doi.org/10.3390/biom11070993 .

Tavilani A, Abbasi E, Kian Ara F, Darini A, Asefy Z. COVID-19 vaccines: Current evidence and considerations. Metabol Open., Iglesias A, Canton J, Ortega-Prieto AM, Jimenez-Guardeño JM, Regla-Nava JA. An Overview of Vaccines against SARS-CoV-2 in the COVID-19 Pandemic Era. Pathogens. 2021 Aug 14;10(8):1030. doi: 10.3390/pathogens10081030.

Changjing Cai 1., Yinghui Peng 1, Edward Shen 2, Qiaoqiao Huang 1, Yihong Chen 1, Ping Liu 1, Cao Guo 1, Ziyang Feng 1, Le Gao 1, Xiangyang Zhang 1, Yan Gao 1, Yihan Liu 1, Ying Han 3, Shan Zeng 4, Hong Shen 5. A comprehensive analysis of the efficacy and safety of COVID-19 vaccines. Mol Ther. 2021 Sep 1;29(9):2794–2805. doi: https://doi.org/10.1016/j.ymthe.2021.08.001 .

Talha Khan Burki. Lifting of COVID-19 restrictions in the UK and the Delta variant. Lancet Respir Med. 2021 Aug;9(8):e85.

Anand P, Stahel VP. Review the safety of COVID-19 mRNA vaccines: a review. Patient Saf Surg. 2021 May 1;15(1):20. doi: https://doi.org/10.1186/s13037-021-00291-9 .

Camilla Mattiuzzi 1. Giuseppe Lippi 2. Headache after COVID-19 vaccination: updated report from the italian Medicines Agency database. Neurol Sci. 2021 Sep;42(9):3531–2. https://doi.org/10.1007/s10072-021-05354-4 . Epub 2021 Jun 18.

Dorcas Serwaa 1 2, Felix Osei-Boakye. Non-life-threatening adverse reactions from COVID-19 vaccine; a cross-sectional study with self-reported symptoms among Ghanaian healthcare workers. Hum Vaccin Immunother. 2021 Sep;21:1–6. Online ahead of print. 3 4, Charles Nkansah 5, Selasie Ahiatrogah 1, Emmanuel Lamptey 1 6, Ratif Abdulai 1, Maxwell Hubert Antwi 7, Eric Yaw Wirekoh 8, Ernest Owusu 9, Tonnies Abeku Buckman 10, Mark Danquah 11.

David García-Azorín 1, Andreas TPhuD, Christoph R. J Schankin 10, Henrik Winther Schytz 5, Alexandra Sinclair 11 12, Guus G Schoonman # 13, Espen Saxhaug Kristoffersen # 14 15. Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis. J Headache Pain. 2021 Sep 17;22(1):108. doi: https://doi.org/10.1186/s10194-021-01324-5 .

Esme Ekizoglu 1., Haşim Gezegen 1, Pınar Yalınay Dikmen 2, Elif Kocasoy Orhan 1, Mustafa Ertaş 1, Betül Baykan 1. The characteristics of COVID-19 vaccine-related headache: Clues gathered from the healthcare personnel in the pandemic. Cephalalgia 2021 Sep 12;3331024211042390. doi: 10.1177/03331024211042390. Online ahead of print.

Carl HG. 1 2, Axel Heinze 2, Sarah Karstedt 1 2, Mascha Morscheck 2, Lilian Tashiro 2, Anna Cirkel 1 2, Qutayba Hamid 3, Rabih Halwani 3, Mohamad-Hani Temsah 4, Malte Ziemann 5, Siegfried Görg 5, Thomas Münte 1, Hartmut Göbel 2. Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: a multicentre observational cohort study. Brain Commun. 2021 Jul 23;3(3):fcab169. doi: https://doi.org/10.1093/braincomms/fcab169 . eCollection 2021.

Koji Sekiguchi 1, Narumi Watanabe 1., Naoki Miyazaki 2, Kei Ishizuchi 1, Chisato Iba 1, Yu Tagashira 1, Shunsuke Uno 3, Mamoru Shibata 1 4, Naoki Hasegawa 3, Ryo Takemura 2, Jin Nakahara 1, Tsubasa Takizawa 1. Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study. Cephalalgia 2021 Aug 18;3331024211038654. doi: 10.1177/03331024211038654. Online ahead of print.

J Yoseph Solomon # 1, Tewodros Eshete # 2, Bersabeh Mekasha # 1, Wubshet Assefa # 3. COVID-19 Vaccine: Side Effects After the First Dose of the Oxford AstraZeneca Vaccine Among Health Professionals in Low-Income Country: Ethiopia. Multidiscip Healthc. 2021 Sep 16;14:2577–2585. doi: https://doi.org/10.2147/JMDH.S331140 . eCollection 2021.

Mohamed Adam 1., Moawia Gameraddin 2, Magbool Alelyani 1, Mohammad Y Alshahrani 3, Awadia Gareeballah 2, Irshad Ahmad 4, Abdulrahman Azzawi 5, Basem Komit 6, Alamin Musa 1. Evaluation of Post-Vaccination Symptoms of Two Common COVID-19 Vaccines Used in Abha, Aseer Region, Kingdom of Saudi Arabia. Patient Prefer Adherence. 2021 Sep 7;15:1963–1970. doi: https://doi.org/10.2147/PPA.S330689 . eCollection 2021.

Khilasa Pokharel 1, Bishwa Raj Dawadi 2, Anup Karki 1. Side Effects after Second Dose of Covishield Vaccine among Health Care Workers: A Descriptive Cross Sectional Study. JNMA J Nepal Med Assoc. 2021 Jul 1;59(238):577–579. doi: https://doi.org/10.31729/jnma.6556 .

Miloslav Klugar 1 2, Abanoub Riad 1 3, Mohamed Mekhemar 4, Jonas Conrad 4, Mayte Buchbender 5, Hans-Peter Howaldt 6, Sameh Attia 6. Side Effects of mRNA-Based and Viral Vector-Based COVID-19 Vaccines among German Healthcare Workers. Biology (Basel). 2021 Aug 5;10(8):752. doi: https://doi.org/10.3390/biology10080752 .

Balsam Qubais Saeed 1., Rula Al-Shahrabi 2, Shaikha Salah Alhaj 2, Zainab Mansour Alkokhardi 2, Ahmed Omar Adrees 2. Side effects and perceptions following Sinopharm COVID-19 vaccination. Int J Infect Dis 2021 Aug 9;111:219–26. doi: 10.1016/j.ijid.2021.08.013. Online ahead of print.

Hind B, Almufty 1, Shinah A, Mohammed M. Abdullah 3, Muayad A Merza 4. Potential adverse effects of COVID19 vaccines among Iraqi population; a comparison between the three available vaccines in Iraq; a retrospective cross-sectional study. Diabetes Metab Syndr. 2021 Jul 12;15(5):102207. doi: https://doi.org/10.1016/j.dsx.2021.102207 . Online ahead of print.

Quiroga 1 B, Sánchez-Álvarez E 2, Goicoechea M 3, de Sequera P, 4, Spanish Society of Nephrology Council. COVID-19 vaccination among Spanish nephrologists: Acceptance and side effects. J Healthc Qual Res. 2021 Jun 8;S2603-6479(21)00051 – 8. doi: 10.1016/j.jhqr.2021.05.002. Online ahead of print.

Sarah Cuschieri 1, Borg M. 2, Steve Agius 3, Jorgen Souness 4, Andre Brincat 2, Victor Grech 5. Adverse reactions to Pfizer-BioNTech vaccination of healthcare workers at Malta’s state hospital. Int J Clin Pract. 2021 Oct;75(10):e14605. doi: https://doi.org/10.1111/ijcp.14605 . Epub 2021 Jul 19.

Ferit Kaya 1, Edibe Pirincci 2. Determining the frequency of serious adverse reactions of inactive SARS-COV-2 vaccine. Work. 2021;69(3):735–9. https://doi.org/10.3233/WOR-210473 .

Article Google Scholar

Abanoub Riad 1 2, Andrea Pokorná 2 3 4, Mohamed Mekhemar 5, Jonas Conrad 5, Jitka Klugarová 1 2 3 4, Michal Koščík 1 6, Miloslav Klugar 1 2 3 4, Sameh Attia 7. Safety of ChAdOx1 nCoV-19 Vaccine: Independent Evidence from Two EU States. Vaccines (Basel). 2021 Jun 18;9(6):673. doi: https://doi.org/10.3390/vaccines9060673 .

Osama Abu-Hammad 1 2, Hamza Alduraidi 3, Shaden Abu-Hammad 4, Ahmed Alnazzawi 1, Hamzah Babkair 1, Abdalla Abu-Hammad 5, Ibrahim Nourwali 1, Farah Qasem 6, Najla Dar-Odeh 1 2. Side Effects Reported by Jordanian Healthcare Workers Who Received COVID-19 Vaccines. Vaccines (Basel). 2021 Jun 1;9(6):577. doi: https://doi.org/10.3390/vaccines9060577 .

Yun Woo Lee 1, So Yun Lim 1. Adverse Reactions of the Second Dose of the BNT162b2 mRNA COVID-19 Vaccine in Healthcare Workers in Korea. J Korean Med Sci. 2021 May;31(21):e153. https://doi.org/10.3346/jkms.2021.36.e153 . Ji Hyang Lee 2, Joon Seo Lim 3, Miseo Kim 4, Seonhee Kwon 4, Jiyeon Joo 4, Sun Hee Kwak 4, Eun Ok Kim 4, Jiwon Jung 1 4, Hyouk Soo Kwon 2, Tae Bum Kim 2, Sung Han Kim 1 4, Seongman Bae 5.

Mei-Xian Zhang 1 2, Zhang T-T. 3, Gui-Feng Shi 3, Feng-Min Cheng 4, Yan-Ming Zheng 3, Tao-Hsin Tung 2, Hai-Xiao Chen 5. Safety of an inactivated SARS-CoV-2 vaccine among healthcare workers in China. Expert Rev Vaccines. 2021 Jul;20(7):891–898. doi: 10.1080/14760584.2021.1925112. Epub 2021 May 13.

Nagla A, El-Shitany S, Harakeh M, Badr-Eldin M. Bagher 1, Basma Eid 1, Haifa Almukadi 1, Badrah S Alghamdi 6, Ahlam A Alahmadi 7, Nibal A Hassan 8, Nariman Sindi 9, Samar A Alghamdi 10, Hailah M Almohaimeed 11, Zuhair M Mohammedsaleh 12, Turki M Al-Shaikh 13, Mohammed S Almuhayawi 14, Soad S Ali 15, Manal El-Hamamsy 16 17. Minor to Moderate Side Effects of Pfizer-BioNTech COVID-19 Vaccine Among Saudi Residents: A Retrospective Cross-Sectional Study. Int J Gen Med. 2021 Apr 19;14:1389–1401. doi: https://doi.org/10.2147/IJGM.S310497 . eCollection 2021.

Renuka AK, Kadali 1 RJ. 2, Sharanya Peruru 3, Srikrishna V Malayala 4. Side effects of BNT162b2 mRNA COVID-19 vaccine: A randomized, cross-sectional study with detailed self-reported symptoms from healthcare workers. Int J Infect Dis. 2021 May;106:376–381. doi: https://doi.org/10.1016/j.ijid.2021.04.047 . Epub 2021 Apr 15.

Si Ho Kim # 1, Wi YM. # 2, Su Yeon Yun 1, Jeong Seon Ryu 1, Jung Min Shin 1, Eun Hui Lee 1, Kyung Hwa Seo 1, Sung Hee Lee 1, Kyong Ran Peck 3. Adverse Events in Healthcare Workers after the First Dose of ChAdOx1 nCoV-19 or BNT162b2 mRNA COVID-19 Vaccination: a Single Center Experience. J Korean Med Sci. 2021 Apr 12;36(14):e107. doi: https://doi.org/10.3346/jkms.2021.36.e107 .

Göbel CH, Heinze A, Karstedt S, Morscheck M, Tashiro L, Cirkel A, Hamid Q, Halwani R, Temsah MH, Ziemann M, Görg S, Münte T, Göbel H. Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: a multicentre observational cohort study. Brain Commun. 2021 Jul 23;3(3):fcab169.

Koji Sekiguchi 1, Narumi Watanabe 1., Naoki Miyazaki 2, Kei Ishizuchi 1, Chisato Iba 1, Yu Tagashira 1, Shunsuke Uno 3, Mamoru Shibata 1 4, Naoki Hasegawa 3, Ryo Takemura 2, Jin Nakahara 1, Tsubasa Takizawa 1. Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study. Cephalalgia. 2021 Aug 18;3331024211038654.doi: 10.1177/03331024211038654. Online ahead of print.

CDC. Coronavirus disease 2019 (COVID-19) in: Cent. Dis. Control Prev; 2020.

Hassan M, Ullah Khan N, Iqbal Chaudhary M, Jan Z, Majid Rajput H, Susan Dewey R, Badshah M. Neurological complications of SARS-CoV-2: a single-center case series. Brain Hemorrhages 2021 Sep 16. doi: https://doi.org/10.1016/j.hest.2021.09.004 . Online ahead of print.

Mouliou DS, Kotsiou OS, Gourgoulianis KI. Estimates of COVID-19 Risk Factors among Social Strata and Predictors for a Vulnerability to the Infection. Int J Environ Res Public Health. 2021 Aug 18;18(16):8701. doi: https://doi.org/10.3390/ijerph18168701 .

Alnefaie A, Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective. Saudi Pharm J. 2020;28(11):1333–52. [PMC free article] [PubMed] [Google Scholar].

Article CAS PubMed PubMed Central Google Scholar

Schlickeiser S, Schwarz T, Steiner S, et al. Disease severity, fever, age, and sex correlate with SARS-CoV-2 neutralizing antibody responses. Front Immunol. 2020;11:628971. [PMC free article] [PubMed] [Google Scholar].

Article CAS PubMed Google Scholar

Steiner S, Sotzny F, Bauer S, et al. HCoV- and SARS-CoV-2 cross-reactive T cells in CVID patients. Front Immunol. 2020;11:607918. [PMC free article] [PubMed] [Google Scholar].

Orsucci D, Ienco EC, Nocita G, Napolitano A, Vista M. Neurological features of COVID-19 and their treatment: a review. Drugs Context. 2020;9:5. [PMC free article] [PubMed] [Google Scholar].

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Acknowledgements

We are grateful to all the healthcare workers who completed the questionnaire carefully.

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Department of Headache, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

Somayeh Nasergivehchi, Mansoureh Togha & Elham Jafari

Department of Neurology, Baharloo University Hospital, Tehran University of Medical Sciences, Tehran, Iran

Somayeh Nasergivehchi

Department of Headache, Neurology Ward, School of Medicine, Sina University Hospital, Tehran University of Medical Sciences, Tehran, Iran

Mansoureh Togha

Tehran University of Medical Sciences, Tehran, Iran

Mehrdad Sheikhvatan

Heidelberg University Hospital, Heidelberg, Germany

Faculty of Nutrition Sciences and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Behehshti University of Medical Sciences Tehran, Tehran, Iran

Donya Shahamati

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Contributions

Somayeh Nasergivehchi contributed to the study conception and design, acquisition of data and drafting of the manuscript. Mansoureh Togha contributed to the study conception and design and the critical revision of the manuscript. Elham Jafari contributed to the study conception and design, acquisition of data and revision of the manuscript. Mehrdad Sheikhvatan contributed to analysis and statistics of the data. Donya Shahamati contributed to data entry and processing.

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Correspondence to Mansoureh Togha .

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The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

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All participants provided informed written consent to participate in this study. The study protocol complied with the guidelines of the 2013 version of the Helsinki Declaration. The study was approved by the Ethics Committee of Tehran University of Medical Sciences: IR.TUMS.NI.REC.1400.054.

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Nasergivehchi, S., Togha, M., Jafari, E. et al. Headache following vaccination against COVID-19 among healthcare workers with a history of COVID-19 infection: a cross-sectional study in Iran with a meta-analytic review of the literature. Head Face Med 19 , 19 (2023). https://doi.org/10.1186/s13005-023-00363-4

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Received : 29 January 2023

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DOI : https://doi.org/10.1186/s13005-023-00363-4

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