International Journal of Cardiology xxx (2011) xxx–xxx

IJCA-13849; No of Pages 7

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International Journal of Cardiology

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Review

Cardiac manifestations of myotonic dystrophy type 1☆

Helle Petri a,⁎, John Vissing b, Nanna Witting b, Henning Bundgaard a, Lars Køber a

a Department of Cardiology, National University Hospital Rigshospitalet, Copenhagen, Denmarkb Department of Neurology, National University Hospital Rigshospitalet, Copenhagen, Denmark

☆ Funding: this work was supported by the Research⁎ Corresponding author at: The Heart Centre, Rigsh

Blegdamsvej 9, 2100 Copenhagen Ø, Denmark. Tel.: +45 77 05.

E-mail address: Hellepetri1@gmail.com (H. Petri).

0167-5273/$ – see front matter © 2011 Elsevier Irelanddoi:10.1016/j.ijcard.2011.08.037

Please cite this article as: Petri H, et alj.ijcard.2011.08.037

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 18 July 2011Accepted 17 August 2011Available online xxxx

Keywords:Dystrophia myotonica type 1ArrhythmiaLeft ventricular systolic dysfunctionSudden cardiac death

Aims: To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conductionabnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involve-ment and cytosine–thymine–guanine (CTG)-repeat, neuromuscular involvement, age and gender in patientswith myotonic dystrophy type 1 (MD1).Methods and results: A Pub-Med search for the period 1980 to 2010 was performed according to specified cri-teria. Cardiac parameters including left ventricular ejection fraction (LVEF), conduction abnormalities and ar-rhythmia were compiled and only studies without ascertainment bias were included.Eighteen studies, 1828 MD1-patients, were included. The prevalence of atrioventricular block grade 1 (AVB1)was 28.2%, QTcN440 ms 22%, QRSN120 ms 19.9%, frequent ventricular premature contractions (VPC) 14.6%,

atrial fibrillation/flutter (AF/AFL) 5%, right/left bundle branch block (RBBB/LBBB) 4.4/5.7% and non-sustainedventricular tachycardia (NSVT) 4.1%. Left ventricular systolic dysfunction (LVSD) was reported in 7.2% of thepatients.There was an overall positive association between CTG-repeat size and cardiac involvement and between thedegree of neuromuscular and cardiac involvement. Male gender and age were positively associated with ar-rhythmia and conduction abnormalities.The prevalence of pacemaker- (PM) and implantable cardioverter defibrillator-(ICD) implantations were4.1% and 1.1%, respectively.The risk of SCD in this MD1-population was 0.56% per year.Conclusion: MD1-patients have a high level of cardiac morbidity and mortality, strongly emphasizing theneed of pre-symptomatic screening for arrhythmia and heart failure, as effective and well-documented pre-ventive means are available.

© 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Myotonic dystrophy type 1 (MD1) is the most common musculardystrophy with an incidence of approximately 1:8.000. MD1 is an au-tosomal dominant disorder with a highly variable phenotypic expres-sion. The genetic basis of MD1 is an abnormal expansion of a CTGtrinucleotide repeat on chromosome 19q21.3 [1,2].

MD1 is amultisystem disorder associatedwithmyotonia, progressiveweakness and atrophy of the skeletal muscles, cataract and systemicmanifestations. Cardiac involvement may present as asymptomatic elec-trocardiographic (ECG) abnormalities, e.g. prolongation of the PR-, QRS-and QT-intervals. Arrhythmic events may be due to sinus-node dysfunc-tion, progressive heart block, atrial tachycardia, -flutter or -fibrillation orventricular tachycardia or -fibrillation [2,3].

Foundation of Rigshospitalet.ospitalet, Section 2141/2142,45 35 45 83 65; fax: +45 35

Ltd. All rights reserved.

, Cardiac manifestations of

The conduction abnormalities and the arrhythmia are thought tobe due to myocardial fibrosis, which may lead to degeneration ofthe cardiac conduction system and compose a substrate for re-entrantarrhythmia, e.g. the development of atrioventricular block and ven-tricular arrhythmia. The myocardial fibrosis probably also relates tothe observed systolic ventricular function [3–6]. The symptomaticpresentations include palpitations, pre-syncopes and syncopes,heart failure symptoms and sudden cardiac death (SCD), but the car-diac involvement in MD1 is often clinically asymptomatic.

In a 10-years follow-up study, Mathieu et al. report a mean age ofdeath at 53.2 years in MD1-patients and a significantly increasednumber of observed versus expected deaths for cardiovascular dis-eases [5]. It has been demonstrated that certain ECG abnormalities,including atrial tachyarrhythmia, are independent predictors of sud-den death in patients with MD1 [3].

There are no evidence-based recommendations for the timing ofinitiation, frequency and extent of cardiovascular screening to pre-vent or reduce cardiac morbidity and mortality in patients withMD1. We reviewed the literature to get an overview of the degreeof cardiac involvement regarding left ventricular ejection fraction,

myotonic dystrophy type 1, Int J Cardiol (2011), doi:10.1016/

2 H. Petri et al. / International Journal of Cardiology xxx (2011) xxx–xxx

conduction abnormalities, arrhythmia and the relations between car-diac involvement and CTG-repeat, neuromuscular involvement, ageand gender in MD1-patients. We aimed to provide cardiologistswith a unique and detailed overview of cardiac manifestations inMD1-patients based on the present literature and to provide sugges-tions for patient management.

2. Material and methods

2.1. Search strategy

A Pub-Med search was performed and included all studies published in Englishbetween 1980 and 2010, meeting the search terms myotonic dystrophy in combinationwith one of the following terms; cardiac abnormalities, cardiac involvement, arrhythmia,echocardiography, ECG, Holter, conduction disturbances, structural abnormalities, heartdisease and sudden death, respectively. Studies from both cardiac and non-cardiac jour-nals were included. The primary Pub-Med search resulted in 1617 hits.

2.2. Classification

Clinical cross sectional studies, prospective clinical studies, retrospective register-based studies and case reports were primarily included, resulting in 62 ECG- andHolter studies. In order to avoid ascertainment bias, only studies based on patientswho were not selected due to specific age or cardiac symptoms were included in thefinal review. In case of clinical prospective follow-up studies, baseline data were used.

In some instances, several publications originated from the same multicentre reg-istry. To avoid compiling data from the same patients, we chose to include data fromthe studies including the highest number of data for the parameter of interest. The au-thor is only presented once in the tables, although data from every study in their co-hort is compiled presenting the specific cardiac parameter of interest.

A total of 44 studies were excluded from the final study due to selection bias(n=12), case-reports (n=13), studies originating from the same cohort (n=9), inac-cessibility (n=10). The remaining 18 studies were included in the final review com-prising a total of 1828 MD1-patients.

2.3. Analysis

For ECG and 24/48-hour Holter monitoring the following parameters were registered;AFL/AF, other supraventricular tachycardia (other SVT), VPC, NSVT, AVB grade 1–3,PRN200ms, PQN220ms, QRSN120 ms, RBBB/LBBB and repolarization time (QTN400 ms

Table 1The prevalence of arrhythmia and systolic dysfunction in MD1-patients.

Author Year n F M Age(mea

Wintzen [25] 1987 65 32 33 NAForsberg [43] 1990 7 5 2 20Florek [21] 1990 45 19 26 41Hawley [13] 1991 37 22 15 37Melacini [16] 1995 42 12 30 38Ambroggi [11] 1995 14 5 9 45Colleran [4] 1997 53 26 27 38Mamarella [15] 2000 131 46 85 36Clarke [20] 2001 77 51 26 35Finsterer b [12] 2001 21 8 13 39Merlevede b [17] 2002 79 NA NA 39Nishioka [18] 2005 83 38 45 37Groh d [3] 2008 406 201 205 45Lindqvist [14] 2010 36 14 22 45Cudia [9] 2009 245 112 133 45Total 1341 591 671Examined patients (n) e

Prevalence (%) 46.8 53.2Studies (n)

AF/AFL: atrial fibrillation/atrial flutter.LVEF: Left ventricular ejection fraction.NA: data not available.NSVT: non sustained ventricular tachycardia.SVT: supraventricular tachycardia (all supraventricular arrhythmia except atrial flutter and

a 3 patients had SVT (type not reported).b Only a subgroup was examined with ECG, Holter or echocardiography.c The study reports 14 patients with ventricular arrhythmia (more than 200 ventriculard 4 publications from the same cohort. Only a subgroup was investigated with Holter, ECe n does not add up to total, as not all studies evaluated all patients for the different par

Please cite this article as: Petri H, et al, Cardiac manifestations ofj.ijcard.2011.08.037

and QTcN440 ms). The studies reported AVB1 as either AVB1, PRN200ms or asPQN220 ms. In the final results, these three terms are combined as AVB1. Regarding supra-ventricular arrhythmia, paroxysmal, persistent and chronic episodes were included(Table 1).

Associations between cardiac involvement and CTG-repeat length, neuromuscularinvolvement, age and gender were registered. In this context cardiac involvement wasincluded as conduction abnormalities (AVB grade 1–3, intraventricular block (IVB),RBBB and LBBB) and arrhythmia (supraventricular and ventricular tachyarrhythmia).

In three studies the PR- and the QRS-interval were denoted as median±2 standarddeviations, and it was not possible to retrieve the specific number of patients withPRN200 ms and QRSN120 ms from the studies or from the authors personal communi-cations. We assumed that the distributions of PR- and QRS-intervals were approxi-mately normally distributed. To estimate the number of patients with PRN200 msand QRSN120 ms, we calculated the standard normal distribution. From this value,the area under the frequency distribution curve provided the estimated number ofpatients.

In several studies, it was not possible to retrieve specific data regarding the num-bers of VPC's per time period. We therefore only listed the number of patients, men-tioned by the authors as having frequent or high degree VPC.

Sudden cardiac death (SCD) was defined as death occurring suddenly and unex-pectedly in a patient who was stable before the event [7,8]. If SCD was reported in fol-low-up studies, we registered the numbers and age of the deceased. Risk of SCD in anunselected MD1-population was calculated per follow-up-year.

Cardiac imaging studies assessing left ventricular ejection fraction (LVEF) werereviewed and LVEF above or below 50% was registered as cut-off for LVSD. From fol-low-up studies, we evaluated the progression of cardiac involvement.

3. Results

Detailed information including the authorship, year of publication,number of included patients, mean age, gender, ECG-/24 hour Holter-parameters and LVEF in each study is shown in Tables 1 and 2.

3.1. Conduction abnormalities and arrhythmia

Nine of 18 studies reporting ECGfindings also examined the patientswith Holter monitoring. Two of eighteen studies were register-basedand only included follow-up results.

n)Arrhythmia LVEF

AF/AFL SVT VPC NSVT ≥50% b50%

NA NA NA NA NA NA0 0 0 0 NA NA3a NA 7 0 NA NA0 0 0 0 37 0NA NA NA NA 42 00 0 1 0 12 21 0 0 0 NA NA5 0 7 0 129 24 0 0 0 NA NA0 0 3 0 16 44 NA 37 0 64 24 6 NA 14c 83 033 NA 68 15 146 340 0 NA 0 36 04 13 NA 7 NA NA58 19 123 36 565 441152 704 841 886 609 6095.0 2.7 14.6 4.1 92.8 7.213 10 10 13 9 9

fibrillation).

extrasystoles per hour or NSVT).G or echocardiography.ameters.

myotonic dystrophy type 1, Int J Cardiol (2011), doi:10.1016/

3H. Petri et al. / International Journal of Cardiology xxx (2011) xxx–xxx

In the remaining 16 studies reporting baseline data (n=1299MD1-patients) the weighted mean of age was 39.6 years and the me-dian (range) number of patients in the studies were 71 (7–406).

3.2. Arrhythmia

VPC was the most prevalent arrhythmia (14.6%, n=10 studies)followed by AF/AFL (5.0%, n=13 studies). The prevalence of NSVTwas 4.1% (n=13 studies) (Table 1).

3.3. Conduction and repolarization abnormalities

The highest prevalence of conduction abnormalities was AVB1(28.2%, n=13 studies). LBBB and RBBB had a prevalence of 5.7%(n=14 studies) and 4.4% (n=14 studies), respectively. The prevalenceof QRSN120 ms and QTcN440 ms was 19.9% (n=7 studies) and 22%(n=4 studies), respectively (Table 2).

3.4. Pacemaker and ICD

Thirteen cross-sectional studies (n=1234) reported the number ofpatientswith PMor ICD-implantations. The prevalence of PMor ICD im-plantations was 4.1% and 1.1%, respectively (Table 3). Especially onestudy (n=245) had a high prevalence of patientswith arrhythmia trea-ted with PM or ICD (11.0% and 5.3%, respectively) [9]. In this study, allpatients were examined with Holter and ECG (Table 3).

Nine follow-up studies (n=1248) reported the number of PM andICD implantations during the study period. In total, 108 PM- and 24ICD's were implanted during a total of 10813 follow up years. Therisk of having a PM or ICD-implantation per follow-up year was1.0% and 0.2%, respectively (Table 4).

The specific indications for the implantation of a PM or ICD werenot retrievable from the studies.

Table 2The prevalence of conduction and repolarization abnormalities in MD1-patients.

Author AVB1 AVB2 AVB3 RB

Wintzen [25] NA NA NA 1Forsberg [43] 5 0 0Florek [21] 9 0 0Hawley [13] 9 0 0Ambroggi [11] 10 2 0Colleran [4] 12 0 0Mamarella [15] 22 0 0Clarke [20] 17 0 1Finsterer [12] 5 0 0Merlevedec [17] 23 3 0Nishioka [18] 24 1 2Grohd [3] 183 1 0Lindqvist [14] 16 0 0Cudia [9] 5 13 ¤ NATotal 340 20 3Examined patients (n)e 1205 971 971 122Prevalence (%) 28.2 2.1 0.3Studies (n) 13 13 12

AVB: atrioventricular block.LBBB/RBBB: left/right bundle branch block.NA: data not available.¤ The author found 13 AVB (grade II–III). We placed these AVB as second degree in order n

a 22 patients had BBB. According to the distribution of BBB in the remaining studies, theb The PR and the QRS-interval were calculated from the reported median±2 standard dc Only a subgroup was examined with ECG or Holter.d 3 publications with 342–406 patients and only a subgroup investigated with ECG or Hoe n does not add up to total, as not all studies evaluated all patients for the different par

Please cite this article as: Petri H, et al, Cardiac manifestations ofj.ijcard.2011.08.037

3.5. Cardiac imaging and LVEF

Nine (n=609) studies reported echocardiographic findings onLVEF above or less than 50% [10–18]. The patients' gender was notreported in 266 patients. Of the remaining 343 patients, 213 weremen (62.1%). The median (range) number of patients included inthe studies was 42 (14–131).

In 7.2% of the patients, LVSDwith a LVEFb50%was reported (Table 1).One of eleven follow-up studies (n=406) found that LVSD was

virtually non-existent before the age of 40. Thereafter a steady in-crease in LVSD was reported [10].

3.6. Sudden cardiac death

Eleven follow up studies (n=1365) reported data on the inci-dence of SCD in MD1-patients [4,10,13–15,18–23]. The studiesreported 70 SCDs during a total of 12414 follow up years. The riskof SCD in an unselected MD1-population was 0.56% per follow-upyear (Table 4), corresponding crudely to an incidence rate of 8.69SCDs per 100000 person-years.

One study (n=406) found, that a severe ECG abnormality definedas rhythms other than sinus rhythm, PR interval of 240 ms or more,QRS duration of 120 ms or more, or second- or third-degree atrioven-tricular block (relative risk, 3.30; 95% confidence interval (CI), 1.24 to8.78) and a clinical diagnosis of atrial tachyarrhythmia (relative risk5.18; 95% CI, 2.28 to 11.77) were independent risk factors of SCD [3].

A retrospective registry study (n=428) found that only two vari-ables on ECG (PR≥200 ms and QTc≥450 ms) were predictors of sud-den death, RR 3.7 (95% CI 1.5 to 8.6) and RR 3.0 (95% CI 1.0 to 8.8)respectively [19].

3.7. Correlations to cardiac involvement

3.7.1. CTG repeat length and cardiac involvementGenetic diagnostic tests to evaluate CTG-triplet expansion were

performed in 8 studies. Six (n=847) out of eight studies elaborated

BB LBBB QRSN120 QTN400 QTcN440

0a 12a NA NA NA0 1 1 1 01 3 NA NA NA0 1 1 0 00 2 NA NA NA1 5 10b 27b 17b

5 0 NA NA NA2 1 NA NA NA0 1 NA NA 9

11 1 10 0 NA13 19 20b NA NA10 15 67 NA NA0 7 15 NA NA1 1 NA NA NA

54 69 124 28 260 1220 622 161 1184.4 5.7 19.9 17.4 22.0

14 14 7 4 4

ot to overestimate the severity.y were divided into 10 RBBB and 12 LBBB.eviations.

lter.ameters.

myotonic dystrophy type 1, Int J Cardiol (2011), doi:10.1016/

Table 3Prevalence of pacemaker and ICD-implantation and the association between cardiac involvement and CTG-repeat size, neuromuscular involvement, age and gender in MD1-patients.

Author Year n F M Age(mean)

Devices Associations

PM ICD CTG NMI Age Gender

Wintzen [25] 1987 65 32 33 NA NA NA NA NA No PositiveForsberg [43] 1990 7 5 2 20 0 0 NA NA NA NAFlorek [21] 1990 45 19 26 41 0 0 NA No Positive NAHawley [13] 1991 37 22 15 37 7 0 NA Positive Positive NoAmbroggi [11] 1995 14 5 9 45 1 0 NA No NA NoColleran [4] 1997 53 26 27 38 0 0 NA NA Positive NAMamarella [15] 2000 131 46 85 36 0 0 NA No NA NAClarke [20] 2001 77 51 26 35 1 0 Positive NA NA NAFinsterer [12] 2001 21 8 13 39 1 0 No NA NA NAMerlevede [17] 2002 79 37 42 39 4 0 No NA Positive NANishioka [18] 2005 83 38 45 37 0 0 No Positive NA NAGroha [3] 2008 406 201 205 45 9 0 Positive Positive Positive PositiveLindqvist [14] 2010 36 14 22 45 0 0 NA NA NA NACudia [9] 2009 245 112 133 45 27 13 Positive Positive Positive PositiveTotal 1299 616 683 50 13Examined patients (n) 1234 1234Prevalence (%) 47.4 52.6 4.1 1.1Studies (n) 13 13

ICD: implantable cardioverter defibrillator.NA: data not available.NMI: neuromuscular involvement.PM: pacemaker.

a 3 publications from the same author including 342–406 patients.

4 H. Petri et al. / International Journal of Cardiology xxx (2011) xxx–xxx

on the correlation between CTG repeat length and conduction abnor-malities (AVB 1–3, IVB, RBBB and LBBB). In 2 (n=419) of 6 studies asignificant positive correlation was found between CTG repeat lengthand conduction abnormalities [20,24]. One study (n=245) found apositive non-significant correlation between CTG repeat length andconduction abnormalities [9], whereas three smaller studies (intotal n=183) found no correlation between CTG repeat length andconduction abnormalities [12,17,18] (Table 3).

Five (n=770) of eight studies elaborated on the correlation be-tween CTG repeat length and arrhythmic events (supraventricularand ventricular arrhythmias). In 1 (n=342) of 5 studies there was asignificant positive correlation between CTG repeat length and ar-rhythmic events [24]. Another 1 (n=245) of 5 studies found a non-significant positive correlation between CTG-repeat length and

Table 4The risk of sudden death, PM- and ICD-implantations per follow-up year in MD1-patients.

Author Year n F M Age(me

Florek [21] 1990 45 19 26 41Hawley [13] 1991 37 22 15 37Colleran [4] 1997 53 26 27 38Stöllberger [23] 1998 16 6 10 39Mamarella [15] 2000 83 27 56 43Clarke [20] 2001 77 51 26 35Mladenovic [22] 2006 101 49 52 31Nishioka [18] 2005 83 NA NA 37Breton [19] 2009 428 236 192 33Lindqvist [14] 2010 36 14 22 45Bhakta [10] 2010 406 201 205 42Total 1365 651 631Examined patients (n)Prevalence (%) 50.8 49.2Risc per year (%)Studies (n)

ICD: implantable cardioverter defibrillator.PM: pacemaker.SD: sudden death.

Please cite this article as: Petri H, et al, Cardiac manifestations ofj.ijcard.2011.08.037

arrhythmic events [9]. Three smaller studies (in total n=183) foundno correlation between CTG repeat length and arrhythmic events[12,17,18].

3.7.2. Neuromuscular affection and cardiac involvementSeven of sixteen studies (n=961) assessed the correlation be-

tween neuromuscular involvement and conduction abnormalities. In3 (n=365) of 7 studies, there was a significant positive correlationbetween the severity of muscular involvement and conduction sys-tem impairment [9,13,18]. One study (n=406) found a non-signifi-cant positive association between severity of muscular impairmentand conduction abnormalities. Three studies (n=190) found no cor-relation between neuromuscular involvement and conduction abnor-malities [11,15,21] (Table 3).

an)Follow-up years SD PM ICD

(mean) (total)

4.6 207 1 5 06.3 233 1 8 06.3 334 1 3 01.6 25 1 NA NA5.1 419 5 11 06.2 477 2 5 0

15.6 1576 7 NA NA3.5 292 6 15 4

11.7 5008 11 14 03.0 108 2 1 19.2 3735 33 46 19

12.414 70 108 241365 1248 1248

0.56 1.00 0.2211 9 9

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Six (n=924) of sixteen studies investigated the correlation be-tween neuromuscular involvement and arrhythmia. In 2 (n=328) of6 studies there was a positive correlation between neuromuscular in-volvement and arrhythmic events [9,18]. One study (n=406) found anon-significant positive association between severe muscular impair-ment and arrhythmia [3].

Three studies (n=190) found no correlation between neuromus-cular involvement and arrhythmia [11,15,21].

3.7.3. Age and cardiac involvement and the progression of cardiacabnormalities

Seven (n=919) of sixteen studies assessed the relative correlationbetween age and conduction abnormalities. In 6 (n=854) of 7 studiestherewas a significant positive correlation between age and conductionabnormalities [4,9,13,17,21,24]. One study (n=65) found no correla-tion between age and conduction abnormalities [25] (Table 3).

Three (n=666) of fifteen studies evaluated the correlation be-tween age and arrhythmic events. In 2 (n=587) of 3 studies therewas a significant positive correlation between age and arrhythmicevents [9,24]. One study (n=79) found no correlation between ageand arrhythmia [17].

Eight of eleven follow-up studies (n=513) elaborated on the pro-gression of conduction abnormalities. There was a significant progres-sion of conduction abnormalities in 3 (n=173) of 8 studies [4,13,18].Furthermore, a non-significant progression of conduction abnormalitieswas found in 5 (n=340) of 8 studies [14,15,20,21,23].

The number of PM- and ICD-implantations in all follow-up studiesincreased during the study period, indicating an increasing prevalenceof arrhythmia.

3.7.4. Gender and cardiac involvementFive of sixteen studies (n=703) reported data regarding the corre-

lation between gender and conduction abnormalities. In 3 (n=652) of5 studies therewas a significant positive correlation betweenmale gen-der and conduction abnormalities [9,24,25]. Two studies (n=51) foundno correlation between gender and conduction abnormalities [11,13](Table 3).

The correlation between gender and arrhythmiaswas evaluated in 2of 16 studies, and one study (n=245) found a significant correlationbetween male gender and arrhythmia [9]. The other study (n=14)found no correlation between gender and arrhythmic events [11].

4. Discussion

This review demonstrates that a substantial fraction of MD1-pa-tients has major cardiac involvement, mainly conduction abnormali-ties and arrhythmia.

Our review reveals a high prevalence of AVB1-block (28%).According to a large prospective, community-based cohort including7575 individuals from the Framingham Study (mean age 47 years;54% women), 124 patients (1.6%) had PR intervalN200 ms at baseline.AVB1 was found to be associated with increased risk of atrial fibrilla-tion, PM-implantation and all-cause mortality and therefore chal-lenges the perception that AVB1 has a benign prognosis [26].

A study from the Copenhagen City Heart Study including a popula-tion of 8943 patients, aged 50–89 years, reported an atrial fibrillation-prevalence of 1% for women and 1.9% for men [27]. In comparison,our review reveals a remarkably high prevalence of AF/AFL (5.1%), espe-cially considering the fact that the MD1-patients included had a meanage of only 32.7 years.

It seems that certain ECG-abnormalities, e.g. atrial tachyarrhyth-mia and second- or higher degree of atrioventricular block, are inde-pendent risk factors of sudden cardiac death in MD1-patients [3].

LVSD with a LVEFb50% was found in 7.2% of the MD1 patients. Incomparison, the prevalence of reduced LVEF in the background popu-lation with an average age of 50 years is 3% [28]. It is important to

Please cite this article as: Petri H, et al, Cardiac manifestations ofj.ijcard.2011.08.037

notice that structural abnormalities of the myocardium may be fre-quent even when cardiac symptoms are absent and ventricular func-tion is still preserved [11].

There seems to be a positive association between CTG repeat lengthand cardiac involvement in the majority of MD1-patients. The associa-tion between neuromuscular and cardiac involvement also seems tobe positive. Although arrhythmic events and conduction disturbancesgenerally increase in frequency with severity of the muscular disease,several studies reveal that low peripheral muscle involvement may beassociated with high grade of arrhythmic and/or conduction distur-bances and structural changes [15,18,21].

MD1-patients have an increased risk of SCD, presumably becauseof degeneration of the conduction-system, leading to complete atrio-ventricular block and asystole. In addition, conduction system abnor-malities can be associated with ventricular tachyarrhythmia[4,20,29,30]. This review reveals that the average risk of SCD inMD1-patients is 0.56% per year, incidence rate 8.69 per 100.000 per-son-years. A nationwide Danish study of sudden cardiac death(SCD) in persons aged 1–35 years, median age 29 years, revealed anincidence rate of SCD of 2.8 per 100.000 [31]. Compared to thisstudy, MD1-patients have a 3-fold higher incidence rate of SCD.

It seems that MD1-patients are at risk of repolarization abnormal-ities, which is closely associated with sudden cardiac death [32,33]. Arecent study found a significantly higher QT variability index (QTVI)than in healthy controls and a significant relationship between QTVIand both PR-interval length and CTG repeat expansion size [34]. Sev-eral studies report that patients with moderate-to-high risk of ar-rhythmia have temporally fluctuating repolarization, as a function ofstructural and ultrasound myocardial damage [35–37]. Furthermore,interstitial fibrosis, fatty infiltration and myocardial hypertrophyhave been found in endomyocardial biopsies and post-mortem stud-ies in MD1-patients [6,38,39]. The above findings hypothesize thatsudden cardiac death in MD1-patients derives not only from conduc-tion system degeneration, but also from an increased dispersion ofmyocardial repolarization.

Cardiac involvement has also been reported in several othermusculardystrophies such as Duchenne and Becker, mainly revealing dilated car-diomyopathy [40,41]. A beneficial effect of the combination of an ACE-in-hibitor and a beta-blocker on long-term survival of Duchenne musculardystrophy has previously been reported. [42]. The treatment was partic-ularly effective for asymptomatic patients with LV dysfunction. As thesame structural changes have been reported in MD1-patients, this treat-ment may also be beneficial in these patients.

Mathieu et al. report that the mean age of death in MD1-patientsis 53.2 years (20% due to cardiovascular diseases and 10.7% due tosudden death) which is approximately 25 years earlier than expectedin a normal population [5]. By optimizing the screening proceduresand treatment of MD1-patients, this early mortality may be reduced.

4.1. Study limitations

Our aim with this review was to evaluate cardiac involvement inMD1-patients, whowere not selected e.g. due to age, gender and cardi-ac symptoms. The reported prevalence and risk may be overestimatedin case of publication-bias (if studies reporting cohorts of MD1-patientswithout cardiac manifestations are not published). We cannot excludethat the motivation for examining a group of MD1-patients, couldhave been based on specific patient-cases of MD1-patients with cardiacabnormalities. Furthermore, some studies originating from the 1980sdid not include genetic diagnostic tests, questioning theMD1-diagnosis.These limitationswould also tend to overestimate the results. The prev-alence of QRS- and QTc prolongation was roughly the same — from thegiven data we cannot exclude if the QTc prolongation may be due toQRS prolongation. The indication of PM-/ICD-implantation was notreported in all studies, questioningwhether the deviceswere implantedprophylactic or due to arrhythmia.

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6 H. Petri et al. / International Journal of Cardiology xxx (2011) xxx–xxx

4.2. Proposal for clinical management of MD1-patients

According to our review cardiac abnormalities in MD1-patientsare detectable by ECG-, Holter and echocardiography. On this basisit seems reasonable to recommend the following;

Recommendations for screening for cardiac involvement

– ECG, 48-hour Holter monitoring and transthoracic echocar-

Pleasej.ijcard

diography at time of diagnosis.

Recommendations for follow-up, PM-/ICD-implantation and heartfailure treatment

1. No positive cardiac symptoms or findings in the primary

screening: ECG/48-hour Holter monitoring every second year.Transthoracic echocardiography every third year in patientsabove the age of 40 years.

2. Positivefindings or symptoms in the primary screening: dizziness,

pre-syncope and palpitations should lead to more thorough test-ing including eventmonitoring and possibly invasive electrophys-iological study. An electrophysiological evaluation should also becarried out if syncope occurs, with consideration of PM/ICD-implantation in the presence of tachy- and/or brady-arrhythmia.

In accordance with the 2008 American College of Cardiology/American Heart Association/Heart Rhythm Society Guidelines for im-plantation of cardiac pacemakers and antiarrhythmic devices, pacemakerimplantation in patients with neuromuscular disease is considered aclass IIA indication for patients with prolonged HV intervalsN100 msand a class IIB indication for any degree of AV block (includingfirst-degree AV block), regardless of symptoms, because there maybe unpredictable progression of AV conduction disease.

Heart failure with a documented LVEFb50% should be treatedwith current medical treatment including angiotensin-convertingenzyme inhibitors, angiotensin II receptor blockers, beta-blockers,aldosterone-antagonists and diuretics.

The MD1-patients need to be educated in seeking medical advicein case of heart specific symptoms.

5. Conclusions

Cardiac involvement such as conduction disturbances, arrhythmiaand cardiomyopathy is a common finding in MD1-patients and carriesa raised risk of SCD. In themanagement of MD1-patients it is importantto stay attentive to the variety of cardiac manifestations. Without pre-symptomatic cardiac screening, MD1-patients may be diagnosed laterthan other patients with a cardiac disease, because of themuscular dys-trophy-related reduced physical abilities. A delayed diagnosis of cardiacinvolvement may reduce the effectiveness of the treatment and resultin premature SCD. Effective and well-documented prophylactic meansare available and may include medical treatment and implantation ofa PM/ICD.

Future studies are needed to redefine the current guidelines con-cerning screening, follow-up and treatment of cardiac involvementin MD1-patients and to improve the identification of patients at riskof SCD.

Acknowledgment

The authors of this manuscript have certified that they complywith the Principles of Ethical Publishing in the International Journalof Cardiology [43].

cite this article as: Petri H, et al, Cardiac manifestations of.2011.08.037

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