1. Dilated cardiomyopathy as the first presentation of coeliac disease: association or causation?
Dr Peysh A Patel
Cardiology Registrar & Clinical Research Fellow
Leeds General Infirmary & University of Leeds
England, UK

2. Disclosures
Funding from ZOLL Medical Deutschland GmbH

3. Presentation 19 year old male
6/52 history of SOBOE, orthopnoea and PND
No history of chest pain, palpitations or syncope
PMHx: unremarkable
FHx: father died from MI in 50s, no history of SCD
SHx: snowboarding instructor
DHx: nil, no recreational drug use or steroids

4. Examination 3/6 pansystolic murmur (new) Bibasal coarse crackles
No ascites or peripheral oedema
Observations: HR 96, BP 125/76, RR 20, sats 96% (RA)

5. CXR
Borderline cardiomegaly.
? Fluid in horizontal fissure.

6. ECG
New LBBB. Inferolateral T wave inversion.

7. Investigations Parameter Value Reference range Hb 6.5 13.0 - 18.0 WCC
5.8
MCV
60.0
80 – 98 Na
140
133 – 146 K
4.4
Urea
3.8
Creatinine 72
Parameter
Value
Reference range
Alb 38
35 – 50
ALP 77
30 – 130
ALT 19
0 – 56
Bilirubin 26
0 – 21
CRP 2
0 – 10
New microcytic anaemia.

8. Echocardiography

9. Further management 3 units blood transfusion
conventional pharmacotherapy for CCF (furosemide, ramipril, bisoprolol, spironolactone)
No obvious GI source of bleeding
Further blood profiling:
low ferritin (21µg/l), normal folate/Vit B12
haemolysis screen –ve
serology –ve for autoimmune/viral disease
micronutrient levels -ve
Haemolysis screen confounded as post-transfusion.
Serology screen – ANA, Rh factor, thyroid function, ESR, Hep, HIV, EBV, CMV, Borrelia.
Micronutrients – Ca, magnesium, thiamine, zinc, lead, selenium

10. cMRI 4 chamber view (left) and mid PSAX (right).
Dilated LV when indexed to BSA. LGE confirmed extensive, dense fibrosis affecting both the endocardial and epicardial regions as well as the papillary muscles, with associated myocardial oedema on T2W imaging.
Basal and mid lateral and mid and apical anterior and anterolateral segments.

11. cMRI
4 chamber view confirming a severely dilated (indexed EDV 220mls / m2, (ULN about 110mls/m2) with severely impaired left ventricular systolic function (ejection fraction 23%) with global hypokinesia.
RV non-dilated with preserved function.
Moderate-severe functional MR into dilated LA.

12. Push enteroscopy
Gastroenterology review in view of iron-deficiency anaemia.
Push enteroscopy for visualisation of distal duodenum/proximal jejunum.
Biopsy – loss of villi with flattened architecture, crypt hyperplasia and inflammatory cell infiltration within the lamina propria, consistent with diagnosis of coeliac disease (modified Marsh score 3B).
Corrobarated with +ve testing for IgA TTG and endomysial Abs.

13. Ongoing care dietary gluten abstinence and PO ferrous sulphate
gained weight and rise in Hb
LifeVest wearable defibrillator
persistent ventricular dysfunction (on cMRI)
referred to cardiac transplant centre

14. Ongoing care Manufactured by Zoll.
First highlighted in ESC symposium in 2015 (Seville, Spain).
In Europe, CCF affects 15 million people.
40% 1 year mortality, including risk of SCD due to ventricular dysrhythmia.
SCD is 6-9 times more frequent in HF patients.
Offers protection against SCD in patients at risk but where permanent risk not established. Enables clarification of long-term arrhythmic risk.
Light and easy to wear. Can return to normal ADLs but with peace of mind.
Components – defibrillator attached to leads and electrode pads, and vest.
If it detects abnormal dangerous rhythm, it alerts patient by sounding alarms that become louder and louder. Also offers timely shock if indicated.
An external defibrillator (plus leads and electrode pads) attached to a wearable vest has been shown to successfully identify and interrupt VT and VF.168 No prospective RCTs evaluating this device have been reported, but there are many case reports, case series and registries (held by the manufacturer or independently) that have reported the successful use of the wearable cardioverter defibrillator (WCD) in a relatively small proportion of patients at risk of potentially fatal VAs. For example, Chung et al. 169 found that 80 sustained VT or VF events occurred in 59 of 3569 (1.7%) patients wearing the WCD. The first shock was successful in 76 of 76 (100%) patients with unconscious VT or VF and 79 of 80 (99%) with any VT or VF. More recently, Epstein et al. 170 reported that 133 of 8453 (1.6%) patients received 309 appropriate shocks and 91% were resuscitated from a VA. Thus this device can save lives in vulnerable patients, but its efficacy has not been validated. In patients with transient impaired LVEF, the WCD may be used until LV function has recovered sufficiently, following insults such as myocardial infarction, post-partum cardiomyopathy, myocarditis or interventions such as revascularization associated with transient LV dysfunction.171 Similarly, patients with a history or at risk of life-threatening VAs or who are scheduled for cardiac transplantation may be temporarily protected with the WCD.172

15. Ongoing care
“The LifeVest has really helped to relieve some of my worries about the risk of a sudden cardiac arrest following concerns after my dad’s sudden death last year, due to heart failure. I’m finding the LifeVest really easy to manage. Hopefully, with continuing support and investigation work into the cause of my heart condition by the Cardiology team, my heart will fully repair and I’ll be able to help others identify the symptoms of this heart condition”.
Manufactured by Zoll.
First highlighted in ESC symposium in 2015 (Seville, Spain).
In Europe, CCF affects 15 million people.
40% 1 year mortality, including risk of SCD due to ventricular dysrhythmia.
SCD is 6-9 times more frequent in HF patients.
Offers protection against SCD in patients at risk but where permanent risk not established. Enables clarification of long-term arrhythmic risk.
Light and easy to wear. Can return to normal ADLs but with peace of mind.
Components – defibrillator attached to leads and electrode pads, and vest.
An external defibrillator (plus leads and electrode pads) attached to a wearable vest has been shown to successfully identify and interrupt VT and VF.168 No prospective RCTs evaluating this device have been reported, but there are many case reports, case series and registries (held by the manufacturer or independently) that have reported the successful use of the wearable cardioverter defibrillator (WCD) in a relatively small proportion of patients at risk of potentially fatal VAs. For example, Chung et al. 169 found that 80 sustained VT or VF events occurred in 59 of 3569 (1.7%) patients wearing the WCD. The first shock was successful in 76 of 76 (100%) patients with unconscious VT or VF and 79 of 80 (99%) with any VT or VF. More recently, Epstein et al. 170 reported that 133 of 8453 (1.6%) patients received 309 appropriate shocks and 91% were resuscitated from a VA. Thus this device can save lives in vulnerable patients, but its efficacy has not been validated. In patients with transient impaired LVEF, the WCD may be used until LV function has recovered sufficiently, following insults such as myocardial infarction, post-partum cardiomyopathy, myocarditis or interventions such as revascularization associated with transient LV dysfunction.171 Similarly, patients with a history or at risk of life-threatening VAs or who are scheduled for cardiac transplantation may be temporarily protected with the WCD.172

16. Ongoing care dietary gluten abstinence and PO ferrous sulphate
gained weight and rise in Hb
LifeVest wearable defibrillator
persistent ventricular dysfunction (on cMRI)
referred to cardiac transplant centre

17. Aetiology of DCM Watkins et al, NEJM 2011; Apr28;364(17):1643-56.
DCM is end phenotype of diverse mutations ranging from components of membrane-scaffolding apparatus (e.g. sarcoglycan and dystrophinopathies), sarcomeric proteins, nuclear envelope proteins (e.g. lamin), calcium-handling proteins (e.g. phospholamban) etc. Differs from HCM in this regard.
Although these mutations highly diverse, common features are impaired contraction, cellular compromise with cell death and fibrotic repair. Results in chamber dilatation and systolic dysfunction.
Familial disease thought to account for 33-50% of cases. Most common mode is AD.
Acquired causes: nutritional, alcohol, chemotherapy, myocarditis (e.g. entero, adeno), autoimmune.
NB: Triphasic model for myocarditis – i.e. initial myocardial insult, chronic inflammation, ventricular remodelling and dysfunction.
Overlap between genetics and acquired. Is it that incomplete penetrant genetic disease is unmasked by myocardial insult?!

18. Population-based studies
Curione et al. Lancet 1999
Fonager et al. Lancet 1999
Emilsson et al. JAHA 2012
Curione et al.
Single-centre study (Italy) found positive association between idiopathic DCM and coeliac disease compared to general population, where diagnoses confirmed by biopsy specimens.
Fonager et al.
Corroborated with nationwide population-based prospective cohort study in Denmark relying upon discharge diagnoses. Followed up patients with coeliac disease to assess incidence of DCM.
Emillson et al.
In Swedish cohort study of 29,000 patients, risk of idiopathic DCM was 73% higher in patients with coeliac disease even in subanalyses when adjusted for confounders.

19. Potential mechanisms? COELIAC DISEASE DCM Antigenic mimicry
Co-existent pathologies
Chronic anaemia with high-output failure
Micronutrient depletion
Is this just association or is there mechanistic overlap?
Antigenic mimicry = autoimmune response directed at antigenic components of both small bowel and myocardium. Autoantibodies may have shared affinity to antigen epitopes in different tissues, or alternatively, different antigens could mimic TTG epitopes.
This is supported by Felix et al. JACC 2002, showing that removal of plasma autoantibodies by immunoadsorption in context of DCM improves haemodynamic status.
Moreover, patients diagnosed with coeliac disease and cardiomyopathy that adhere to gluten abstinence demonstrate significant recovery of cardiac volumes and ventricular function, with adjunct suppression of dysrhythmic potential (Frustaci et al. Circulation 2002).
Other propositions implicate nutritional deficiencies in pathogenesis. Chronic anaemia results in a hyperdynamic state due to neurohumoral activation secondary to peripheral vasodilatation, and can progress to high-output cardiac failure (Mehta et al. 2009). Would it normalise after treatment of anaemia?
Malabsorption can additionally result in micronutrient deficits of thiamine, selenium, carnitine, magnesium and calcium. These are perceived as critical mechanistic components of myocardial contractility and deficiencies may have precipitant or exacerbating effects (Curione et al. 2005). Additionally, congestive cardiac failure is associated with gut oedema, secondary to arterial insufficiency and venous stasis with associated endothelial dysfunction (Witte et al. 2001). This reciprocal negative interaction can potentiate nutritional deficits.
Co-existent pathologies. May be that incomplete penetrant genetic disease unmasked by myocardial insult or stress. Had preceding coryzal symptoms so may have arisen from acute myocarditis.

20. Points for discussion.. CRT-P vs CRT-D vs subcutaneous ICD?
Myocardial biopsy?
Cardiac transplantation?
Genetic testing?
Strenuous exercise?
Themes to explore:
Dysrhythmic risk (CRT-D vs ICD). Subcut? Wearable defibrillator and duration?
Subcutaneous ICD indications: difficult access, no pacing/ATP requirement, young age, anticipated higher risk of infection.
2015 ESC guidelines – IIa/b indication
2013 ESC guidelines – Most likely to respond from CRT as he is LBBB, non-ischaemic aetiology
QRS 146ms. No indication if NYHA class I but indication for ICD.
Myocardial biopsy? Potentially non-diagnostic and inherent risks of procedure. Giant cell myocarditis associated with poor prognosis.
Candidate for transplantation?
Referred so they were aware of the case. Depends on clinical course. Re-admission with chest pain, not CCF decompensation. Not yet optimised with meds and device therapy.
Advised to avoid strenuous exercise. Maybe ETT to exclude exercise-induced dysrhythmia due to catecholaminergic surge…
IV vs PO iron infusion.
Intravenous ferric carboxymaltose may be better alternative in patients with GI adverse events from oral supplementation. Avoids long course and replenishes iron stores more promptly.
Genetic testing
Not formally referred as no familial history. Inherited in AD, AR or X-linked manner. Rarely mitochondrial inheritance (not relevant in this case as only maternal). Incomplete penetrance may mask the trends, however.
Diagnosis of idiopathic DCM does not distinguish between genetic and non-genetic causes.