Comment by ME Research UK: Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control study

Reprinted with the kind permission of ME Research UK.

Publication

Tomas et al, Open Heart, 2017 Dec 27; 4(2):e000697

 

Comment by ME Research UK

An increasing amount of research has revealed heart abnormalities in patients with ME/CFS. For example, people with the illness have been found to have a short QT interval (a measure of the electrical activity of the heart) and a reduced cardiac output (the amount of blood pumped by the heart per minute). These changes may occur before any symptoms are apparent.

Much of the recent work on cardiac dysfunction in ME/CFS has been carried out by Prof. Julia Newton and her team at Newcastle University, including studies funded by ME Research UK.

In 2012, they used magnetic resonance imaging and cardiac tagging technology to asses a group of ME/CFS patients, and found that several measures of the heart were lower in patients than in healthy control subjects:

  • left ventricular mass (the thickness of the wall of the left ventricle, the main pumping chamber of the heart),
  • stroke volume (the amount of blood pumped by the left ventricle in one contraction),
  • cardiac output, and
  • end-diastolic volume (the volume of blood in each ventricle after they have refilled).

Then, in 2016, they repeated some of these assessments along with measures of blood volume. The total volume of blood (plasma plus red cells) was slightly less in ME/CFS patients than in controls, but there was a strong association between blood volume and cardiac end-diastolic wall mass.

Continuing their work in this area, the team has recently published a paper in the journal Open Heart looking at levels of brain natriuretic peptide in ME/CFS, and correlating these with measures of cardiac dysfunction.

Despite its name, brain natriuretic peptide (or BNP) is a hormone that is actually secreted by the muscle cells of the heart, and is produced when the ventricles are overstretched to accommodate an increase in blood volume.

Circulating BNP causes a decrease in blood pressure and in cardiac output, and has found use clinically as a diagnostic and prognostic marker of heart failure.

In their current study, the investigators recruited 42 patients with ME/CFS and no other illness, as well as 10 sedentary control subjects matched for age and sex.

The participants’ hearts were examined using magnetic resonance techniques to provide a number of measures of cardiac function, including cardiac volumes at the end of systole (after the ventricles have contracted and pumped out their blood) and at the end of diastole (when the ventricles are relaxed and have refilled with blood).

In addition, blood samples were taken, and plasma BNP levels were measured using an enzyme immunoassay.

The first important finding was that BNP levels were significantly higher in ME/CFS patients than in sedentary control subjects, with mean levels of approximately 500 versus 300 pg/mL, respectively.

Furthermore, both end-systolic and end-diastolic cardiac volumes were significantly lower among patients with high BNP levels (defined as being greater than 400 pg/mL) than in those with low BNP levels.

BNP tends to be a sign of cardiac volume overload, so this association is not what one would normally expect to see. One explanation suggested by the researchers is that the high BNP is causing an excessive production of urine, which reduces the total volume of circulating blood (as seen in their earlier study), leading to a smaller cardiac volume.

It is important to note that none of these measures were related to the patients’ duration of ME/CFS, indicating that the results are unlikely to be due to deconditioning (i.e. they were not the result of the heart adapting to less physical activity).

What might these results mean to patients? One possibility put forward by the investigators is that measurement of BNP levels may be a convenient way by which to identify those ME/CFS patients with cardiac abnormalities who might benefit from specific treatments, although additional studies would be needed to confirm this.

This approach may also be valuable in identifying a specific cardiac subgroup of ME/CFS patients, and better understand the diverse nature of this illness.

_________________

ME Research UK commissions and funds high-quality scientific (biomedical) investigation into ME/CFS. 

Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:
Multiple Sclerosis (MS), Myalgic Encephalomyelitis (ME), and Chronic Fatigue syndrome are debilitating chronic illnesses, with some overlapping symptoms. However, few studies have compared and contrasted symptom and disability profiles for these illnesses for the purpose of further differentiating them. The current study was an online self-report survey that compared symptoms from a sample of individuals with MS (N = 120) with a sample of individuals with ME or CFS (N = 269). Respondents completed the self-report DePaul Symptom Questionnaire. Those individuals with ME or CFS reported significantly more functional limitations and significantly more severe symptoms than those with MS. The implications of these findings are discussed.

Source: Jason LA, Ohanian D, Brown A, Sunnquist M, McManimen S, Klebek L, Fox P, Sorenson M. Differentiating Multiple Sclerosis from Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Insights Biomed. 2017;2(2). pii: 11. doi: 10.21767/2572-5610.10027. Epub 2017 Jun 12.

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Abstract:

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease.

A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension.

A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Source: Jonas Blomberg, Gerhard Gottfries, Amal Elfaitouri, Muhammad Rizwan and Anders Rosén. Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Hypothesis and Theory Article, Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229 (Full article)

Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous syndrome in which patients often experience severe fatigue and malaise following exertion. Immune and cardiovascular dysfunction have been postulated to play a role in the pathophysiology. We therefore, examined whether cytokine profiling or cardiovascular testing following exercise would differentiate patients with ME/CFS.

Twenty-four ME/CFS patients were matched to 24 sedentary controls and underwent cardiovascular and circulating immune profiling. Cardiovascular analysis included echocardiography, cardiopulmonary exercise and endothelial function testing. Cytokine and growth factor profiles were analyzed using a 51-plex Luminex bead kit at baseline and 18 hours following exercise. Cardiac structure and exercise capacity were similar between groups.

Sparse partial least square discriminant analyses of cytokine profiles 18 hours post exercise offered the most reliable discrimination between ME/CFS and controls (κ = 0.62(0.34,0.84)). The most discriminatory cytokines post exercise were CD40L, platelet activator inhibitor, interleukin 1-β, interferon-α and CXCL1. In conclusion, cytokine profiling following exercise may help differentiate patients with ME/CFS from sedentary controls.

Source: Kegan J. Moneghetti, Mehdi Skhiri, Kévin Contrepois, Yukari Kobayashi, Holden Maecker, Mark Davis, Michael Snyder, Francois Haddad & Jose G. Montoya. Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Scientific Reports volume 8, Article number: 2779 (2018). doi:10.1038/s41598-018-20941-w. Received:02 November 2017. Accepted:26 January 2018. Published online:09 February 2018. https://www.nature.com/articles/s41598-018-20941-w (Full article)

On chronic fatigue syndrome and nosological categories

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disease which presents with pronounced disabling fatigue, sleep disturbances, and cognitive impairment that negatively affects patients’ functional capability. CFS remains a poorly defined entity and its etiology is still in question. CFS is neither a novel diagnosis nor a new medical condition. From as early as the eighteenth century, a constellation of perplexing symptoms was observed that resembled symptoms of CFS. Commencing with “febricula” and ending with CFS, many names for the disease were proposed including neurocirculatory asthenia, atypical poliomyelitis, Royal Free disease, effort syndrome, Akureyri disease, Tapanui disease, chronic Epstein-Barr virus syndrome, and myalgic encephalitis. To date, it remains unclear whether CFS has an autoimmune component or is a condition that precedes a full-blown autoimmune disease.

Research suggests that CFS may overlap with other diseases including postural orthostatic tachycardia syndrome (POTS), autoimmune syndrome induced by adjuvants (ASIA), and Sjögren’s syndrome. Additionally, it has been postulated that the earliest manifestations of some autoimmune diseases can present with vague non-specific symptoms similar to CFS. Sometimes only when exposed to a secondary stimulus (e.g., antigen) which could accelerate the natural course of the disease would an individual develop the classic autoimmune disease. Due to the similarity of symptoms, it has been postulated that CFS could simply be an early manifestation of an autoimmune disease. This paper will provide a historical background review of this disease and a discussion of CFS as an entity overlapping with multiple other conditions.

Source: Sharif K, Watad A, Bragazzi NL, Lichtbroun M, Martini M, Perricone C, Amital H, Shoenfeld Y. On chronic fatigue syndrome and nosological categories. Clin Rheumatol. 2018 Feb 7. doi: 10.1007/s10067-018-4009-2. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29417255

Time to Reject the PACE Study

Abstract:

The PACE trial investigated the efficacy of graded exercise therapy and cognitive behavioral therapy for ME/CFS. The design and the implementation of the study were flawed, and the conclusions are contradicted by the data. It is time to reject the study.

https://www.researchgate.net/publication/320101462_Time_to_Reject_the_PACE_Study [Full article].

This is a translation of an article that was published in slightly shortened form in Läkartidningen, Stockholm, Sweden, on 28 September 2017. http://www.lakartidningen.se/

Link to the shortened article in Swedish: http://www.lakartidningen.se/Opinion/De-batt/2017/09/Dags-att-forkasta-PACE-studien/

Source: Helmfrid S, Edsberg J. Dags att förkasta PACE-studien. Lakartid-ningen. 2017;114:ETLE.

The international collaborative on fatigue following infection (COFFI)

Abstract:

Background: The purpose of the Collaborative on Fatigue Following Infection (COFFI) is for investigators of post-infection fatigue (PIF) and other syndromes to collaborate on these enigmatic and poorly understood conditions by studying relatively homogeneous populations with known infectious triggers. Utilising COFFI, pooled data and stored biosamples will support both epidemiological and laboratory research to better understand the etiology and risk factors for development and progression of PIF.

Methods: COFFI consists of prospective cohorts from the UK, Netherlands, Norway, USA, New Zealand and Australia, with some cohorts closed and some open to recruitment. The 9 cohorts closed to recruitment total over 3000 participants, including nearly 1000 with infectious mononucleosis (IM), > 500 with Q fever, > 800 with giardiasis, > 600 with campylobacter gastroenteritis (CG), 190 with Legionnaires disease and 60 with Ross River virus. Follow-ups have been at least 6 months and up to 10 years. All studies use the Fukuda criteria for defining chronic fatigue syndrome (CFS).

Results: Preliminary analyses indicated that risk factors for non-recovery from PIF included lower physical fitness, female gender, severity of the acute sickness response, and autonomic dysfunction.

Conclusions: COFFI (https://internationalcoffi.wordpress.com/) is an international collaboration which should be able to answer questions based on pooled data that are not answerable in the individual cohorts. Possible questions may include the following: Do different infections trigger different PIF syndromes (e.g. CFS vs. irritable bowel syndrome)?; What are longitudinal predictors of PIF and its severity?

Source: Ben Z Katz, Simon M Collin, Gabrielle Murphy, Rona Moss-Morris, Vegard Bruun Wyller, Knut-Arne Wensaas, Jeannine L.A. Hautvast, Chantal P Bleeker-Rovers, Ute Vollmer-Conna, Dedra Buchwald, Renée Taylor, Paul Little, Esther Crawley, Peter D White & Andrew Lloyd. The international collaborative on fatigue following infection (COFFI). Fatigue: Biomedicine, Health & Behavior Vol. 0, Iss. 0, 2018. http://www.tandfonline.com/doi/abs/10.1080/21641846.2018.1426086?journalCode=rftg20

A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications

Abstract:

Currently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome(CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation. Evidence is also detailed for biologically based potential therapeutic options, including: nutritional supplementation, for example in order to downregulate the nitric oxide-peroxynitrite cycle to prevent its perpetuation; antiviral therapy; and monoclonal antibody treatment. It is concluded that there is strong evidence of a molecular neurobiological aetiology, and so it is suggested that biologically based therapeutic interventions should constitute a focus for future research into CFS/ME/SEID.

Source: Monro JA, Puri BK. A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. Mol Neurobiol. 2018 Feb 6. doi: 10.1007/s12035-018-0928-9. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29411266

Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons

Abstract:

BACKGROUND: Preliminary evidence suggests that the enteric microbiota may play a role in the expression of neurological symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Overlapping symptoms with the acute presentation of D-lactic acidosis has prompted the use of antibiotic treatment to target the overgrowth of species within the Streptococcus genus found in commensal enteric microbiota as a possible treatment for neurological symptoms in ME/CFS.

METHODS: An open-label, repeated measures design was used to examine treatment efficacy and enable sex comparisons. Participants included 44 adult ME/CFS patients (27 females) from one specialist medical clinic with Streptococcus viable counts above 3.00 × 105 cfu/g (wet weight of faeces) and with a count greater than 5% of the total count of aerobic microorganisms. The 4-week treatment protocol included alternate weeks of Erythromycin (400 mg of erythromycin as ethyl succinate salt) twice daily and probiotic (D-lactate free multistrain probiotic, 5 × 1010 cfu twice daily). 2 × 2 repeated measures ANOVAs were used to assess sex-time interactions and effects across pre- and post-intervention for microbial, lactate and clinical outcomes. Ancillary non-parametric correlations were conducted to examine interactions between change in microbiota and clinical outcomes.

RESULTS: Large treatment effects were observed for the intention-to-treat sample with a reduction in Streptococcus viable count and improvement on several clinical outcomes including total symptoms, some sleep (less awakenings, greater efficiency and quality) and cognitive symptoms (attention, processing speed, cognitive flexibility, story memory and verbal fluency). Mood, fatigue and urine D:L lactate ratio remained similar across time. Ancillary results infer that shifts in microbiota were associated with more of the variance in clinical changes for males compared with females.

CONCLUSIONS: Results support the notion that specific microorganisms interact with some ME/CFS symptoms and offer promise for the therapeutic potential of targeting gut dysbiosis in this population. Streptococcus spp. are not the primary or sole producers of D-lactate. Further investigation of lactate concentrations are needed to elucidate any role of D-lactate in this population. Concurrent microbial shifts that may be associated with clinical improvement (i.e., increased Bacteroides and Bifidobacterium or decreased Clostridium in males) invite enquiry into alternative strategies for individualised treatment.

Trial Registration Australian and New Zealand Clinical Trial Registry (ACTRN12614001077651) 9th October 2014. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366933&isReview=true.

Source: Wallis A, Ball M, Butt H, Lewis DP, McKechnie S, Paull P, Jaa-Kwee A, Bruck D. Open-label pilot for treatment targeting gut dysbiosis in myalgic encephalomyelitis/chronic fatigue syndrome: neuropsychological symptoms and sex comparisons. J Transl Med. 2018 Feb 6;16(1):24. doi: 10.1186/s12967-018-1392-z. https://www.ncbi.nlm.nih.gov/pubmed/29409505

Cardiovascular characteristics of chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) commonly exhibit orthostatic intolerance. Abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli was previously described in numerous studies. The aim of the current study was to describe cardiological and clinical characteristics of Italian patients with CFS. All of the patients were of Caucasian ethnicity and had been referred to our center, the Cardiology Department of the University Hospital of Pavia (Pavia, Italy) with suspected CFS. A total of 44 patients with suspected CFS were included in the present study and the diagnosis was confirmed in 19 patients according to recent clinical guidelines.

The characteristics at baseline of the population confirm findings from various previous reports regarding the prevalence in females with a female to male ratio of 4:1, the age of onset of the pathology and the presence of previous infection by the Epstein-Barr virus, cytomegalovirus and other human herpesviruses. Despite the current data indicating that the majority of the cardiological parameters investigated are not significantly different in patients with and without CFS, a significant association between the disease and low levels of blood pressure was identified. Other pilot studies revealed a higher prevalence of hypotension and orthostatic intolerance in patients with CFS. Furthermore, many of the CFS symptoms, including fatigue, vertigo, decreased concentration, tremors and nausea, may be explained by hypotension.

Source: Bozzini S, Albergati A, Capelli E, Lorusso L, Gazzaruso C, Pelissero G, Falcone C. Cardiovascular characteristics of chronic fatigue syndrome. Biomed Rep. 2018 Jan;8(1):26-30. doi: 10.3892/br.2017.1024. Epub 2017 Nov 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772628/ (Full article)