Predictors of Adverse Outcome in Adolescents and Adults With Isolated Left Ventricular Noncompaction

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Predictors of Adverse Outcome in Adolescents and Adults WithIsolated Left Ventricular Noncompaction

Matthias Greutmann, MDa,*, May Ling Mah, MDb, Candice K. Silversides, MDb,Sabine Klaassen, MDc, Christine H. Attenhofer Jost, MDd, Rolf Jenni, MD, MSEEa, and

Erwin N. Oechslin, MDb

Isolated left ventricular noncompaction is a rare form of primary cardiomyopathy. Al-though increasingly diagnosed, data on the outcomes are limited. To define the predictorsof adverse outcomes, we performed a retrospective analysis of a prospectively definedcohort of consecutive patients (age >14 years) diagnosed with left ventricular noncompac-tion at a single center. The baseline characteristics included presentation with a car-diovascular complication (i.e., decompensated heart failure, systemic embolic event, orsustained ventricular arrhythmia). The primary end point was survival free fromcardiovascular death or transplantation. The predictors of survival were evaluated usingthe Kaplan-Meier method and Cox proportional hazards analysis. A total of 115 patientswere included, 77% of whom were symptomatic at diagnosis. Compared to the asymptom-atic patients, the symptomatic patients were significantly older and had larger left ven-tricular cavities and worse left ventricular ejection fraction. Of the 115 patients, 49 (43%)presented with a cardiovascular complication. During a median follow-up of 2.7 years(range 0.1 to 19.4), none of the asymptomatic patients died or underwent transplantationcompared to 31% (27 of 88) of the symptomatic patients (p � 0.001). The major determi-nants of cardiovascular death or transplantation were presentation with a cardiovascularcomplication (hazard ratio 20.6, 95% confidence interval 4.9 to 87.5, p <0.0001) or NewYork Heart Association class III or greater (hazard ratio 8.8, 95% confidence interval 3.2to 24.0, p <0.0001). Left ventricular dilation and systolic dysfunction were less strongpredictors. In conclusion, in patients with left ventricular noncompaction, New York HeartAssociation class III or greater and cardiovascular complications at presentation are strongpredictors for adverse outcome. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol

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Isolated left ventricular noncompaction (LVNC) is a rarecardiomyopathy with considerable genetic heterogeneity.1,2

Despite its increasing recognition and diagnosis, the clinicaloutcome of this rare entity is not well defined.3–13 The aimf the present study was to examine the clinical outcomes inrelatively large, prospectively defined, cohort of patientsith LVNC and to identify the risk factors for adverse

ardiovascular events.

ethods

The diagnostic criteria previously described by our groupere used.14 In the absence of other congenital or acquired

structural heart disease or neuromuscular disorders, these

aDivision of Cardiology, University Hospital, Zurich, Switzerland;bDivision of Cardiology, Peter Munk Cardiac Centre, University HealthNetwork, Toronto General Hospital, University of Toronto, Toronto, On-tario, Canada; cExperimental and Clinical Research Center, a Joint Coop-eration between the Charité Medical Faculty and Max-Delbrück-Center forMolecular Medicine, Berlin, Germany; and dCardiovascular Center, Klinikm Park, Zurich, Switzerland. Manuscript received June 30, 2011; revisedanuscript received and accepted August 30, 2011.

*Corresponding author: Tel: (�41) 44-255-3883; fax: (�41) 44-255-701.

eE-mail address: [email protected] (M. Greutmann).

002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2011.08.043

criteria included the presence of a typical 2-layered struc-ture of a significantly thickened myocardium. The thickened2-layered myocardium consisted of a thin, compacted outer(epicardial) layer and a much thicker, noncompacted inner(endocardial) layer with deep intertrabecular recesses filledwith blood from the left ventricular cavity. A noncom-pacted/compacted layer ratio of �2, obtained in the para-sternal short-axis view, had to be present at end-systole. Alldiagnoses were established by echocardiography and re-quired independent agreement by 2 experienced echocar-diographers (R.J. and E.O.). These criteria were previouslyvalidated against dilated cardiomyopathy, hypertensiveheart disease, and valvar heart disease and showed goodsensitivity and specificity.15 To define the extent of involve-

ent, the left ventricle was divided into 9 segments, asreviously described.5 The left ventricular dimensions and

function at the diagnosis and during follow-up were as-sessed according to the established guidelines for 2-dimen-sional echocardiography.16 The left ventricular dimensions

ere normalized for the body surface area.Left ventricular noncompaction was diagnosed in 152

onsecutive patients �14 years old at a single tertiary re-erral center, University Hospital, Zurich (0.15% of allchocardiograms) from 1984 to 2006. Twenty patients werexcluded because they had associated congenital heart dis-

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277Cardiomyopathy/Outcome in Patients With LVNC

The lower age limit of 14 years was chosen to allow en-rollment of adolescents identified by family screening but toavoid enrollment of neonatal LVNC or LVNC with symp-tom onset in early childhood, a disease entity that is oftenaccompanied by syndromic association and might have adifferent outcome than LVNC diagnosed in adulthood.4,6,8

The clinical characteristics collected at initial presenta-tion were the presence and nature of cardiac symptoms,functional class (New York Heart Association classifica-tion) and the occurrence of cardiovascular complications atthe initial assessment or before presentation. The latter in-cluded decompensated heart failure requiring hospital ad-mission, systemic embolic events, sustained ventricular ar-rhythmias, and/or presentation with survived sudden cardiacdeath.

Figure 1 depicts the number of newly diagnosed patientsith LVNC at our center during the study period. The

ncreased number of asymptomatic patients after 2000 re-ects our policy of routine family screening.

Of the 132 patients within the study cohort, 115 (87%)ad �1 year of follow-up or died or underwent heart trans-

plantation within the first 12 months after diagnosis. These115 patients were included in the survival analysis. Fol-low-up information was collected by retrospective chartreview. The initial presentation and outcome of the first 34patients of the cohort have been previously reported.5

The primary end point included cardiovascular death orheart transplantation. Other major adverse events were re-corded and included systemic embolism, sustained ventric-ular arrhythmias, and admission for heart failure. Cardio-vascular death was defined as death directly related toprogressive heart failure, sudden death (death within 1 hourof the onset of symptoms, or acute deterioration of a symp-tomatic patient with previously stable symptoms), deathrelated to cardioembolic stroke, death caused by pulmonaryembolism, or death ensuing in the immediate sequence of acardiovascular intervention or operation.

Statistical analysis was performed using the StatisticalPackage for Social Sciences, version 17.0 (SPSS, Chicago,Illinois). The descriptive data are presented as the median(range), mean � SD, and proportions, as appropriate. Acomparison between survivors and nonsurvivors and the

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543211984-1986 1987-1991 1992-1996 1997-2001 2002-2006

Asymptomatic patientsSymptomatic patients

Figure 1. Number of patients newly diagnosed with isolated LVNC at ourcenter from 1984 to 2006.

groups of patients presenting with and without symptoms d

was performed using Student’s t test, the Mann-Whitneytest, or the chi-square test. Kaplan-Meier curves were usedto depict differences between patients with and withoutsymptoms at presentation, cardiovascular complications atpresentation, New York Heart Association class III orgreater, left ventricular end-diastolic diameter indexed tothe body surface area �3.7 cm/m2 and a left ventricularejection fraction �35%. The predictors of survival freefrom cardiovascular death or heart transplantation were de-termined using a Cox proportional hazards model. A p value�0.05 (2-sided) was considered significant.

Results

The clinical, echocardiographic, and electrocardiogra-phic baseline characteristics of the entire study cohort,survivors, and patients with cardiovascular death/transplan-tation are summarized in Table 1. At the diagnosis, 66symptomatic patients (50%) were receiving medical treat-ment. The most common medications were angiotensin-converting enzyme inhibitors or angiotensin receptor antag-onists (36%), � blockers (38%), and diuretics (26%); 48patients (36%) were taking oral anticoagulation drugs and 9(7%) low-dose aspirin.

Of the 132 patients, 95 (72%) were symptomatic atdiagnosis. The most common symptoms reported by thepatients were dyspnea (80%), syncope (16%), and palpita-tions (22%). A large proportion of symptomatic patientspresented with a cardiovascular complication, including 3survivors of sudden cardiac death (Table 1). Three patientshad a history of transient ischemic attack or stroke (at 1month, 2 years, and 10 years before the LVNC diagnosis).All three were known to have some form of cardiomyopathyat the time of the embolic event. Some patients presentingwith symptoms had been previously labeled as having “di-lated cardiomyopathy” (n � 23, 24%). In those cases, thecorrect diagnosis of LVNC was delayed by 5.2 years (range0.2 to 17.3). Five patients (aged 40, 57, 64, 70, and 72 years)were found to have additional coronary artery diseaseduring their initial assessment.

The most common reason for the assessment of asymp-tomatic patients (n � 37) was family screening (49%); 30atients (23%) in our cohort had �1 family members af-ected by LVNC. The other reasons for the assessment ofsymptomatic patients were noncardiac chest pain, hearturmurs, or electrocardiographic abnormalities. The base-

ine characteristics of the patients presenting with and with-ut symptoms are compared in Table 2. At the diagnosis, 5symptomatic patients (14%) had a left ventricular ejectionraction �45% and 1 (3%) a left ventricular ejection frac-ion �35%.

Serial follow-up data were available for 27 asymptom-tic (73%) and 88 symptomatic (93%) patients. The medianollow-up period until the last clinic visit or cardiovasculareath/heart transplantation was 2.7 years (range 0.1 to 19.4)nd was not significantly different between the survivorsnd nonsurvivors (2.7 years, range 1.0 to 15.8, vs 1.9 years,ange 0.1 to 19.4; p � 0.14). The adverse cardiovascularvents in the 115 patients at risk are listed in Table 3. Nonef the asymptomatic patients experienced any adverse car-

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278 The American Journal of Cardiology (www.ajconline.org)

whether they had been diagnosed incidentally or by familyscreening. One asymptomatic patient (4%) had progressiveleft ventricular dilation with an increase in the left ventric-ular end-diastolic diameter from 5.2 cm at presentation to7.2 cm, with a corresponding decrease in the left ventricularejection fraction from 50% to 35% (follow-up period 7.9years). This patient underwent implantation of an automatedimplantable cardioverter defibrillator for primary preventionof sudden cardiac death after induction of polymorphicventricular tachycardia on electrophysiologic testing (1 yearafter diagnosis). At his last clinical follow-up visit, he re-mained asymptomatic, continued to have good exercisetolerance, and had not experienced any automated implant-able cardioverter defibrillator discharges. All other patientswithout symptoms at diagnosis had stable left ventriculardimensions and systolic function during follow-up.

A total of 32 patients (28%) experienced 52 adversecardiovascular events; 21 (18%) died from cardiovascularcauses and 6 (5%) underwent orthotopic heart transplanta-tion. Sudden cardiac death (48%) was the most common

Table 1Baseline characteristics and complications at presentation

Variable

Age (years)Female genderPresentation with any symptoms‡

New York Heart Association class III or greater at presentationPresentation with any complication§

Decompensated heart failureSystemic embolizationTransient ischemic attackPeripheral emboliSustained ventricular arrhythmia

Echocardiographic variablesLeft ventricular ejection fractionLeft ventricular end-diastolic diameter indexed to body surface area (cm

Electrocardiographic abnormalitiesAtrial fibrillationBundle branch block�

* Follow-up information was available for 115 patients.† Comparison of survivors versus nonsurvivors.‡ Dyspnea 80%, palpitations 22%, syncope 16% (some patients had �1§ Some patients presented with �1 cardiovascular complication.� Left bundle branch block in 28 and right bundle branch block in 4.

able 2aseline characteristics in patients with and without symptoms at diagnos

Variable

Age (years)Female genderLeft ventricular ejection fraction at diagnosisLeft ventricular end-diastolic diameter indexed to body surface area (cm/m

lectrocardiographic abnormalitiesAtrial fibrillationBundle branch blockNumber of affected segments

* Statistically significant.

cause of death, followed by death from progressive heart

failure (38%). One patient (5%) died from pulmonary em-bolism and two (10%) from a complication after cardiacdevice implantation. Of the patients experiencing cardiovas-cular complications, 2 had concomitant coronary artery dis-ease on the initial assessment. One of these patients diedfrom progressive heart failure and one from postoperativesepsis after automated implantable cardioverter defibrillatorimplantation.

Of the 5 patients (4%) with systemic embolic eventsduring follow-up, 1 had atrial fibrillation at the event andonly 1 was taking oral anticoagulation agents after success-ful electrical cardioversion 7 months earlier. The interna-tional normalized ratio was in the therapeutic range at thetime of the event. No significant differences were found inage at diagnosis, left ventricular dimensions, or left ventric-ular function between the patients with and without sys-temic embolic events.

The survival free from cardiovascular death or hearttransplantation rate was 86%, 75%, and 36% at 1, 5, and 10years, respectively. The univariate determinants of survival

All Patients*(n � 132)

Nonsurvivors*(n � 27)

Survivors*(n � 88)

p Value†

41 � 17 48 � 17 40 � 17 0.0286 (65%) 18 (67%) 57 (65%) 1.095 (72%) 27 (100%) 61 (69%) �0.000146 (35%) 20 (74%) 23 (26%) �0.000151 (39%) 24 (89%) 26 (30%) �0.000144 (33%) 19 (70%) 24 (27%) �0.00013 (2%) 1 (4%) 2 (2%) 0.561 (1%) — 1 (1%) —2 (2%) 1 (4%) 1 (1%) —9 (7%) 6 (22%) 3 (3%) 0.005

41 � 18% 31 � 11% 43 � 19% 0.0013.4 � 0.7 3.9 � 0.7 3.3 � 0.6 �0.0001

18 (14%) 10 (37%) 8 (9%) 0.00132 (24%) 15 (56%) 16 (18%) �0.0001

ymptom).

Symptomatic Patients(n � 95)

Asymptomatic Patients(n � 37)

p Value

45.9 � 15.5 26.9 � 12.4 �0.0001*63 (66%) 23 (62%) 0.6936 � 17% 57 � 11% �0.0001*

3.5 � 0.7 3.0 � 0.33 �0.0001*

17 (18%) 1 (3%) 0.02*28 (29%) 4 (11%) 0.03*3.0 � 1.2 2.7 � 1.3 0.13

/m2)

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free from cardiovascular death or transplantation are listed

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279Cardiomyopathy/Outcome in Patients With LVNC

in Table 4. Figure 2 shows the Kaplan-Meier survivalcurves for the probability of survival free from cardiovas-cular death or transplantation according to the clinical andechocardiographic characteristics.

Presentation with New York Heart Association func-tional class III or greater or a presentation with a cardio-vascular complication (defined as sustained ventricular ar-rhythmia, systemic embolization, or admission with heartfailure) were the strongest predictors of the primary endpoint, and the echocardiographic (left ventricular dilationand systolic dysfunction) and electrocardiographic parame-

Table 3Adverse cardiovascular events during follow up

Variable Adverse Events*(115 Patients at Risk)

Cardiovascular death or orthotopic hearttransplantation

27 (23%)

Orthotopic heart transplantation 6 (5%)Cardiovascular death 21 (18%)

Sudden cardiac death 10 (9%)Systemic embolism 5 (4%)

Transient ischemic attack 2 (2%)Ischemic stroke 2 (2%)Symptomatic splenic infarction 1 (1%)

Sustained ventricular tachycardia 5 (4%)Admission with decompensated heart failure 15 (13%)

Fifty-two adverse cardiovascular events occurred in 32 patients; noadverse events occurred in asymptomatic patients.

Table 4Univariate determinants of survival free from cardiovascular death ortransplantation

Variable HR 95% CI p Value

Baseline demographicsAge at diagnosis 1.03 1.002–1.054 0.04*Female gender 1.0 0.5–2.8 0.97

Clinical presentationSymptomatic at diagnosis 32.0 0.6–1,592.3 0.08New York Heart Association

III or more at diagnosis8.8 3.2–24.0 �0.0001*

Presented with clinicalcomplication

20.6 4.9–87.5 �0.0001*

Decompensated heart failure 4.5 1.9–10.8 0.001*Sustained ventricular

arrhythmia14.3 5.0–41.1 �0.0001*

Systemic embolization 3.2 0.4–24.8 0.26Electrocardiographic findings

Atrial fibrillation 2.4 1.1–5.6 0.03*Bundle branch block 2.8 1.3–6.1 0.009*

Echocardiographic findingsLeft ventricular ejection

fraction at diagnosis0.96 0.93–0.99 0.004*

Left ventricular end-diastolicdiameter indexed to bodysurface area

1.7 1.2–2.5 0.002*

Diastolic left ventriculardysfunction

3.4 0.4–28.1 0.26

CI � confidence interval; HR � hazard ratio.* Statistically significant.

ters were less strong predictors. Strong colinearity was pres- v

ent between all significant univariate predictors, precludingmultivariate analysis.

Discussion

Although awareness of LVNC has substantially in-creased, and several small series have been published duringrecent years, the overall clinical event rates and predictorsfor a poor outcome remain ill-defined.4–12 In the presentrospectively defined cohort, we were able to define thelinical and echocardiographic characteristics of a relativelyarge population of patients with LVNC and to define dis-inct predictors of cardiovascular death or heart transplan-ation. Symptomatic patients had high mortality and were atigh risk of major adverse cardiovascular events. On uni-ariate analysis, the strongest predictors for cardiovasculareath or heart transplantation were presentation with a car-iovascular complication and functional class III or more.dverse left ventricular remodeling with left ventricularilation and a depressed left ventricular ejection fractionere less predictive.In agreement with previous reports, patients without

ymptoms at the initial presentation had more favorablehort- and midterm outcomes.10–12 None of them developed

symptoms or had cardiovascular complications, albeit 5patients had impaired left ventricular systolic function atpresentation and 1 had progressive left ventricular dilationand systolic dysfunction during follow-up. However, thefollow-up duration for these patients was limited and notlong enough to be reassured about their long-term progno-sis. Some of these patients will likely develop progressiveleft ventricular dysfunction and are at risk of the develop-ment of symptoms and complications later in life.

It is concerning that in our series �1/2 of the symptom-atic patients presented with a clinical cardiovascular com-plication, including 9 patients (9%) with sustained ventric-ular arrhythmias and 3 (3%) with systemic embolization. Byextrapolation from other forms of cardiomyopathy, wespeculate that at least some of these serious complicationsmight have been preventable by early diagnosis, timelyinstitution of evidence-based heart failure medication, andappropriate device therapy.17

The adverse outcomes, including mortality and morbid-ity, for patients with LVNC vary significantly among dif-ferent reports and might have been overestimated in earlierstudies because of the inclusion of primarily symptomaticpatients referred to tertiary referral centers.4–6,9,12 It is ofinterest that the event rates were lower in recently publishedcohorts than in the previous reports.9,13 In 1, recently pub-lished, series, no deaths occurred in patients with a normalleft ventricular ejection fraction, and all patients who diedwere �70 years old.13 These more favorable outcomes in

ore recently published series are likely explained by thenclusion of asymptomatic patients and are consistent withhe findings from our present cohort. The application ofvidence-based heart failure therapy could be another con-ributor to the more favorable outcomes in more recenteries. In 1 series, the outcome of patients with LVNC wasomparable to that of matched patients with dilated cardio-yopathy. This observation suggests that the resultant left

entricular dysfunction, rather than the phenotype or non-

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280 The American Journal of Cardiology (www.ajconline.org)

compacted myocardium itself, is the primary source ofmorbidity and mortality.13

It would be obvious that sarcomere gene mutations mightpredict the clinical phenotype. However, in a recent studycomparing sarcomere mutation-positive and mutation-neg-ative LVNC probands, no significant differences in terms ofthe clinical phenotype were found. Thus, research is neededto clarify the relation between the type of mutation, genetic

Figure 2. Probability of survival free from cardiovascular death or transpresentation with symptoms. (C) Survival stratified by presentation withrrhythmia, systemic embolic event). (D) Survival stratified for New York H

left ventricular dilation at presentation. (F) Survival stratified for severe l

modifiers, and the clinical phenotype.18

Our findings underscore the need for regular follow-upof patients with this rare cardiomyopathy, in particular closefollow-up of symptomatic patients. Given the high inci-dence of complications at presentation, 1 of our primarygoals must be to identify patients at risk before complica-tions occur. Offering family screening to relatives of pa-tients with an established diagnosis is therefore important.This might allow the early identification of asymptomatic

n (Kaplan-Meier curves). (A) Overall survival. (B) Survival stratified forl complication (e.g., decompensated heart failure, sustained ventricularsociation class III or more at presentation. (E) Survival stratified for severericular systolic dysfunction at presentation.

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patients at risk of complications in the future. The timely

281Cardiomyopathy/Outcome in Patients With LVNC

institution of evidence-based heart failure treatment inasymptomatic patients with worsening left ventricular sys-tolic function might prevent the occurrence of complica-tions. There remain, however, some unresolved problems.In the absence of definitive diagnostic criteria, such asgenetic testing, the diagnosis of LVNC is established bycardiac imaging, most commonly echocardiography. Thereare, however, no generally accepted criteria on cardiac im-aging for establishing the diagnosis of LVNC. The criteriaproposed by our group and most frequently used by re-searchers are based on the presence of a thickened, 2-lay-ered myocardium with a ratio between the noncompactedand compacted myocardium in the affected segments of�2:1, measured during systole in the parasternal short-axisview.14 It has been reported that these criteria might be toosensitive, particularly in black patients.19 This leaves uswith the dilemma of potentially overcalling the diagnosis inotherwise healthy patients, with all its implications and evenpotential implications on insurability. In contrast, our cri-teria seem to identify a high-risk group of symptomaticpatients.

Although the present study is 1 of the largest populationsof patients with LNVC, it was still limited by the relativelysmall number of patients, the referral bias, the limited fol-low-up period, and the absence of universally accepteddiagnostic criteria for LVNC. We have tried to overcomesome of the operator-dependent factors, which might affectthe interpretation of images, by independent review of theimages by 2 experienced echocardiographers (R.J. andE.O.). Differences in the interpretation were adjudicated byreviewers by joint interpretation. Systematic family screen-ing of all affected patients was not available, which mighthave underestimated the number of asymptomatic subjects.In addition, our study population was recruited from atertiary referral center and might represent a highly selectedgroup. The true prevalence of LNVC in the general popu-lation and thus the general outcome of asymptomatic pa-tients with LVNC are still not known and need to be furtherelucidated. Because of the strong colinearity between thesignificant univariate predictors, we were unable to performa multivariate survival analysis.

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