Addition of Digoxin Improves Cardiac Function in Children With the Dilated Cardiomyopathy With Ataxia Syndrome: A Mitochondrial Cardiomyopathy

Accepted Manuscript Addition of Digoxin Improves Cardiac Function in Children with the Dilated Cardiomyopathy with Ataxia Syndrome, a Mitochondrial Cardiomyopathy Steven C. Greenway, MSc, MD, FRCPC, Frederic Dallaire, MD, PhD, FRCPC, Hassan Hazari, BSc, Dhwani Patel, BSc, Aneal Khan, MSc, MD, FRCPC, FCCMG PII:

S0828-282X(18)30180-6

DOI:

10.1016/j.cjca.2018.02.019

Reference:

CJCA 2753

To appear in:

Canadian Journal of Cardiology

Received Date: 18 January 2018 Revised Date:

14 February 2018

Accepted Date: 19 February 2018

Please cite this article as: Greenway SC, Dallaire F, Hazari H, Patel D, Khan A, Addition of Digoxin Improves Cardiac Function in Children with the Dilated Cardiomyopathy with Ataxia Syndrome, a Mitochondrial Cardiomyopathy, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.02.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Addition of Digoxin Improves Cardiac Function in Children with the Dilated Cardiomyopathy with Ataxia Syndrome, a Mitochondrial Cardiomyopathy

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Steven C. Greenway, MSc, MD, FRCPC,a,b Frederic Dallaire, MD, PhD, FRCPC,c Hassan Hazari, BSc,a,d Dhwani Patel, BSc,a,d Aneal Khan, MSc, MD, FRCPC,

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FCCMGa,d

a

Calgary, Calgary, Alberta, Canada b

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Department of Pediatrics, Alberta Children’s Hospital Research Institute, University of

Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of

Calgary, Calgary, Alberta, Canada c

Division of Pediatric Cardiology, University of Sherbrooke, Centre de Recherche du

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Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada d

Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada

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Short title: Benefit of Digoxin in DCMA

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Word count: 3450/4500

Corresponding author: Dr. Steven C. Greenway, Section of Cardiology, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, AB, Canada, T3B 6A8. Tel: 1403-955-5049; FAX: 1-403-955-7621; E-mail: [email protected]

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BRIEF SUMMARY The dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial disease that frequently causes progressive dilated cardiomyopathy, severe heart failure

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and death in early childhood. Effective medical therapy remains elusive for this and many metabolic cardiomyopathies. In a cohort of patients with DCMA our retrospective review demonstrates a significant beneficial impact of digoxin on left ventricular function

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and structure when added to conventional heart failure therapy.

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ABSTRACT Background: The dilated cardiomyopathy with ataxia syndrome (DCMA) is a rare mitochondrial disorder characterized by progressive cardiomyopathy, prolonged QT

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interval and early death in childhood related to intractable heart failure. We present a case series of nine children with DCMA who demonstrated functional improvement and favorable left ventricular remodeling only after digoxin was added to their medical

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therapy.

Methods: A retrospective review of 46 DCMA patients followed at the Alberta Children’s

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Hospital from 2005-2017 identified nine patients who were treated with digoxin and had serial echocardiography data. For each subject, we calculated the difference between baseline and follow-up for left ventricular ejection fraction (LVEF), end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD) as determined by

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echocardiography.

Results: Patients were on average 45.6 ± 59 months of age when digoxin was started with a mean LVEF of 40% ± 11%. Seven patients were on an angiotensin-converting

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enzyme inhibitor (ACEI) at the time of digoxin initiation and all were on a beta-receptor antagonist (BB). After being on digoxin for a mean of 11.7 ± 10.9 months, average

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LVEF improved to 55% ± 10% (p = 0.0005) and there were significant decreases in the Z-scores for LVEDD (+2.1 ± 1.9 to +0.65 ± 1.4, p = 0.02) and LVESD (+3.83 ± 2.07 to +1.79 ± 1.76, p = 0.01).

Conclusions: In children with DCMA we report that digoxin seems to have additive beneficial properties when combined with ACEI and BB therapy. This novel observation may have implications for the medical treatment of mitochondrial cardiomyopathies.

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Introduction The metabolic cardiomyopathies are a diverse group of diseases that result from derangements in cellular energetics and are characterized by rapid disease progression

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and early death.1 Metabolic disorders associated with cardiomyopathy include organic acidemias, fatty acid oxidation defects, storage diseases and mitochondrial disorders, which represent the largest category.2 Diseases of the mitochondria are clinically and

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genetically heterogeneous and result from dysfunction of the electron transport chain (ETC) and insufficient cellular energy. Given the ceaseless demands of the heart,

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cardiomyopathy is common in mitochondrial disease.2-4

The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive disorder that arises from mutations in DNAJC19 and was first described in the Hutterites of southern Alberta.5 This population represents the largest known group of

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patients in the world but sporadic cases have been reported worldwide.5-8 The clinical disease is characterized by 3-methylglutaconic aciduria, dilated cardiomyopathy (DCM), prolongation of the QT interval, cerebellar ataxia and variable systemic features

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including hepatic steatosis, developmental delay, microcytic anemia and abnormalities of male genitalia.5, 9 Affected children frequently develop severe left ventricular (LV)

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dysfunction that leads to early death or heart transplantation. Recent work has demonstrated in vitro that loss of DNAJC19 leads to altered cardiolipin (CL) acylation and mitochondrial defects resembling Barth syndrome.10 Current treatment of the metabolic cardiomyopathies is based upon studies of

heart failure (HF) with reduced ejection fraction in adults with different etiologies (predominantly ischemic cardiomyopathy) and is largely ineffective, likely due to the

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fundamentally different mechanism of disease.11 We undertook a retrospective review of all pediatric patients with DCMA followed at the Alberta Children’s Hospital to assess the effectiveness of medical therapy, and digoxin in particular, in the treatment of this

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condition.

Material and Methods

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Patient Population

With approval from the Conjoint Health Research Ethics Board at the University

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of Calgary we reviewed the medical records of all patients diagnosed with DCMA at the Alberta Children’s Hospital between 2005 and 2017. Those patients with a confirmed diagnosis of DCMA, through identification of the causative genetic mutation (rs137854888) and/or presence of 3-methylglutaconic acidemia or aciduria, were

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included. Available echocardiography reports were reviewed for all patients and measures for left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) were

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extracted. Measurement of LVEF was based on the modified Simpson’s biplane method of disks (if available) or the Teicholz method and acquired using the Philips IE33

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platform. Prescribed medical therapy was documented for all patients as detailed in the hospital chart.

Statistical Analysis

Data are summarized as mean ± standard deviation. Since LVEDD and LVESD are continuous variables that change with somatic growth, Z-scores for these parameters

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were calculated using the Dubois formula to determine body surface area. Mean differences in LVEF and the Z-scores for LVEDD and LVESD from initiation of digoxin to the end of follow-up was estimated by a two-tailed, paired Student’s t-test. To evaluate

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ACEI- and digoxin-mediated changes in LV function and dimensions over time we calculated the difference between baseline and follow-up every 10 days for LVEF,

LVEDD and LVESD. At every 10-day time point, we imputed the echocardiographic

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measures of the closest previous follow-up. Patients were censored at the last followup. Changes between each follow-up time point and baseline are expressed as the

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mean difference and 95% confidence intervals for each variable. The 95% confidence intervals were calculated based on the t statistic. A p-value < 0.05 was considered statistically significant. A similar analysis was performed to evaluate the effect of digoxin on the corrected QT interval (QTc) with data obtained from serial resting

Results

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electrocardiograms (ECGs).

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We identified 46 families followed at the Alberta Children’s Hospital during the study period of 2005-2017. In this cohort, we found that there was 39% mortality in early

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childhood (median age of death 1.1 years) related most commonly to cardiac dysfunction. Of these 46 children, complete serial echocardiography data (≥2 independent studies with reported LVEF, LVEDD and LVESD) was available for 20 patients of whom 14 (70%) developed persistent cardiac dysfunction during the study time period (defined as a LVEF <53% by transthoracic echocardiography for ≥2 consecutive studies). From these 20 patients, we identified nine who received digoxin

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as part of their medical HF therapy (Table). Of the remaining 11 patients, six maintained normal LV systolic function and five (45%) demonstrated decreased cardiac function that resulted in death (n = 4) or heart transplantation (n = 1).

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One patient (#2 in the Table) had been diagnosed with DCMA at birth and due to progressive cardiac dysfunction had been placed on captopril and then atenolol but systolic function continued to deteriorate as documented by transthoracic

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echocardiography. At 21 months of age he was placed on digoxin and subsequently an improvement in LVEF was seen with persistent and stable normalization of LVEF out to

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>4 years post-initiation of digoxin (Figure 1). Improvement in LVEF was noted in eight additional patients who had also been prescribed digoxin (Table and Figure 2). For the nine patients who received digoxin (with doses ranging from 4-8 micrograms/kilogram/day), LVEF improved significantly from 40% ± 11% to 55% ± 11%

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(p = 0.0005) after an average of 11.7 ± 10.9 months of digoxin treatment. Digoxin usage was also associated with favorable LV remodeling as demonstrated by a significant decrease in LVEDD (Figure 3) and a non-significant decrease in LVESD (Figure 4).

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Compared to baseline dimensions at the initiation of digoxin treatment there were significant improvements in LVEDD and LVESD Z-scores with a decrease in the mean

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LVEDD Z-score from +2.1 ± 1.9 to +0.65 ± 1.4 (p = 0.02) and a decrease in the mean LVESD Z-score from +3.83 ± 2.07 to +1.79 ± 1.76 (p = 0.01). The observed effects on LV structure and function appear to be related to the starting of digoxin specifically since for the six patients who were prescribed an ACEI an average of 37.4 ± 32.7 months prior to the initiation of digoxin there were no significant improvements in LVEF (Figure 5), LVEDD (Figure 6) or LVESD (Figure 7) up until the time digoxin was introduced.

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Interestingly, for five patients for whom serial ECG data was available, the initiation of digoxin was also associated with a significant decrease in the duration of the QTc

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interval (Figure 8).

Discussion

DCMA is highly prevalent in the Hutterites of southern Alberta, a genetically-

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isolated group that share common ancestry and a communal lifestyle. DCMA (also

known as 3-methylglutaconic aciduria type V) is a devastating disease with frequent,

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early onset of cardiomyopathy associated with severe HF and mortality in early childhood. DCMA is related to Barth syndrome (3-methylglutaconic aciduria type II) but remains relatively understudied compared to this disorder. In Barth syndrome, mutations in the tafazzin gene affect CL remodeling which leads to a compromised ETC

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and deficient ATP production.12 In our cohort of DCMA patients, we observed that, with a decrease in cardiac function or signs by echocardiography consistent with DCM (i.e. LV dilation, increasing LV sphericity), an ACEI was commonly initiated. Due to

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prolongation of the QTc, which is present in most DCMA patients, all patients were on a BB which was usually initiated early in life even before signs of DCM developed.

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However, despite these medications, progressive LV dilation and dysfunction is common. Our retrospective review of DCMA patients followed at our institution has identified a beneficial effect of digoxin when added to conventional HF therapies. The cardiac glycoside digoxin is
derived from the foxglove plant and has
been

used safely for the treatment of HF
for >200 years.13 However, its role has
diminished recently, being replaced by
drugs directed at preventing
neurohormonal activation,

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which have demonstrated great success in adults with HF and reduced ejection fraction.14, 15 It is
known that inhibition of the Na+/K+ ATPase by digoxin increases

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intracellular
and mitochondrial calcium.16 This
increase in calcium leads to activation of
complex V of the ETC and activation of
mitochondrial dehydrogenases (pyruvate
dehydrogenase, isocitrate dehydrogenase and α-ketoglutarate

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dehydrogenase) to increase mitochondrial NAD+ and further stimulate ATP production.17 Whereas previous studies have classified digoxin as a mitochondrial toxin18, we

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hypothesize that, in DCMA, digoxin acts through this mechanism to increase mitochondrial ATP production and overcome the metabolic deficits created by abnormal CL in DCMA. Although digoxin appears to be necessary to improve LV systolic function and structure, digoxin does not appear to be sufficient by itself to rescue cardiac dysfunction as demonstrated by one patient (#8, Table) whose LVEF continued to

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decrease slowly and whose LV remained mildly dilated on digoxin and BB therapy but who did ultimately demonstrate improvement after an ACEI was added to his regimen. We also noted that digoxin was associated with a significant decrease in QTc but it is

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not clear if this is a digitalis effect19 or related to changes in the underlying disease.

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Clinically we have not noted any obvious improvements in the growth or neurological status of the treated children. There was insufficient serial data to evaluate the effect of digoxin on the microcytic anemia or the elevated levels of 3-methylglutaconic acid or 3methylglutaric acid in the serum and urine. Trials studying the effect of adult-derived renin-angiotensin-aldosterone system (RAAS)-targeted medications in children with HF have been negative20, 21 and, although the neurohormonal response to HF is presumed to be the same in children and adults,

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this has never been conclusively demonstrated.11 A positive effect of digoxin suggests that there may be merit in the addition of mechanism-directed therapy to conventional HF drugs in children with cardiomyopathy.22

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Limitations of our study include its retrospective and single centre nature but we are investigating a very rare and geographically-restricted disease. Comprehensive serial echocardiography data was lacking for many patients due to early death or

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unavailability of studies for review since they were performed in community hospitals in southern Alberta. DCMA is also very clinically heterogeneous which certainly influences

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the clinical course of the disease and may influence individual response to drug therapies. However, we did observe a relatively uniform and positive response to digoxin in our cohort. There is also the possibility for patients to demonstrate spontaneous improvement in myocardial function independent of medical treatment23, 24

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although this may be rarer in children with a metabolic cause for their cardiomyopathy.25, 26 Finally, it remains unknown for most studied patients whether the positive impact of digoxin that we observed will be sustained, although prolonged

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recovery appears to be present in at least one patient for whom longer follow-up data is available (Figure 1). Furthermore, digoxin may not be protective against other

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comorbidities as was seen for patient #7 who died of overwhelming sepsis, despite maintaining normal cardiac function.

Conclusions

In this retrospective review of a cohort of patients with the rare mitochondrial cardiomyopathy DCMA we have identified a positive effect of digoxin on LV function and

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structure when it is added to conventional HF therapy. Our review of the published literature has not identified any previous reports of beneficial digoxin use in mitochondrial or metabolic cardiomyopathies. We suggest that digoxin may have a role

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in the treatment of patients with mitochondrial cardiomyopathy related to its ability to ameliorate the underlying energy deficit of the cells and further study of this old but

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promising therapeutic is warranted.

Funding Sources

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This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. SCG was supported by the Department of Pediatrics, Alberta Children’s Hospital Research Institute and the Libin Cardiovascular

Disclosures

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Institute of Alberta at the University of Calgary.

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The authors have no conflicts of interest to disclose.

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Figure Legends

Figure 1. Improvement in LVEF with digoxin. In a single male child with DCMA, LVEF

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failed to improve with ACEI (A) and BB (B) therapy until digoxin (D) was started. Improvement in LVEF appeared to be sustained to >4 years of age.

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Figure 2. Addition of digoxin is associated with improved LVEF overall for the nine

patients in our cohort. Changes between follow-up and baseline are expressed as the

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mean difference and 95% confidence intervals. When the confidence interval lines exclude zero, the difference is statistically significant (p < 0.05).

Figure 3. Addition of digoxin is associated with a significant improvement in LVEDD in

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all nine patients. Changes between follow-up and baseline are expressed as the mean difference and 95% confidence intervals. When the confidence interval lines exclude

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zero, the difference is statistically significant (p < 0.05).

Figure 4. Addition of digoxin is associated with an improvement in LVESD in all nine

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patients. Changes between follow-up and baseline are expressed as the mean difference and 95% confidence intervals. When the confidence interval lines exclude zero, the difference is statistically significant (p < 0.05).

Figure 5. Initiation of an ACEI is not associated with an improvement in LVEF. Changes in LVEF between the initiation of an ACEI and the initiation of digoxin are expressed as

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the mean difference and 95% confidence intervals for six patients in whom an ACEI was introduced prior to digoxin. When the confidence interval lines exclude zero, the

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difference is statistically significant (p < 0.05).

Figure 6. Initiation of an ACEI is not associated with an improvement in LVEDD.

Changes between the initiation of an ACEI and the initiation of digoxin are expressed as

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the mean difference and 95% confidence intervals. When the confidence interval lines

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exclude zero, the difference is statistically significant (p < 0.05).

Figure 7. Addition of ACEI is not associated with an improvement in LVESD. Changes between the initiation of an ACEI and the initiation of digoxin are expressed as the mean difference and 95% confidence intervals. When the confidence interval lines

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exclude zero, the difference is statistically significant (p < 0.05).

Figure 8. Addition of digoxin is associated with a significant decrease in QTc. Change

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in the QTc (in milliseconds) for five patients since the initiation of digoxin is expressed as the mean difference and 95% confidence intervals. When the confidence interval

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lines exclude zero, the difference is statistically significant (p < 0.05).

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Table. Patient characteristics and baseline with initiation of digoxin and at last follow-up while maintained on digoxin.

Sex

Age

LVEF

LVEDD

LVESD

(months)

(%)

Z-score

Z-score

ACEI

BB

AA

M

6.1

23

+2.6

+4.6

Y

Y

2

M

21.2

27

+3.7

+5.7

Y

Y

N

3

M

13.6

30

+5.6

+8.2

Y

Y

4

M

95.7

45

+1.5

+3.2

Y

5

M

16.3

45

+3.7

+4.5

6

F

74.5

39

+0.41

+2.9

7

M

5.9

50

0

+1.2

8

M

2.8

50

+1.8

9

F

174.4

53

-0.45

+1.5

45.6

40

+2.1

59

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1.9

SD

LVEF

Change

LVEDD

LVESD

(months)

(months)

(%)

in LVEF

Z-score

Z-score

(%)

46

+23

+2.4

+4.3

Dead

58.8

37.5

54

+27

+1.5

+1.5

Alive

Y

14.5

0.9

37

+7

+0.97

+2.9

Dead

Y

Y

108.8

13.1

58

+13

-0.11

+0.64

Alive

N

Y

N

28.1

11.8

51

+6

+2.1

+3.8

Alive

Y

Y

N

86.3

11.8

62

+23

-0.17

+1.4

Alive

Y

Y

N

8

2.1

64

+13

-1.1

+0.15

Dead

N

Y

N

17

15

56

+6

+2.0

+2.9

Alive

Y

Y

N

182.5

9

70

+17

-1.7

-1.5

Alive

+3.83

57.1

11.7

55

15

+0.65

+1.79

2.07

59.3

10.9

10

8

1.4

1.76

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10

Status

4

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Mean

N

Duration

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1

Age

SC

Patient

Most Recent Data

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At Start of Digoxin

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LVEF, left ventricular ejection fraction, SD, standard deviation.

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AA, aldosterone receptor antagonist (spironolactone); BB, beta blocker; ACEI, angiotensin-converting enzyme inhibitor;

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