International Journal of Cardiology 174 (2014) 249–259

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Left ventricular noncompaction associated with hypertrophic cardiomyopathy: Echocardiographic diagnosis and genetic analysis of a new pedigree in China Li Yuan a,1, Mingxing Xie a,1, Tsung O. Cheng a,b,⁎,1, Xinfang Wang a, Feng Zhu c, Xiangquan Kong d, Devina Ghoorah e a Department of Ultrasonography, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Key Laboratory of Molecular Imaging, Wuhan 430022, People's Republic of China b Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Avenue, N.W., Washington, D.C. 20037, USA c Department of Cardiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China d Department of Radiology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Hubei Provincial Key Laboratory of Molecular Imaging, Wuhan 430022, People's Republic of China e Radiology Department, Flacq Hospital, Ministry of Life & Quality of Life, Mauritius

a r t i c l e

i n f o

Article history: Received 6 March 2014 Accepted 7 March 2014 Available online 15 March 2014 Keywords: Left ventricular noncompaction Hypertrophic cardiomyopathy Contrast echocardiography Familial screening Genetics

a b s t r a c t Background: Hypertrophic cardiomyopathy (HCM) and left ventricular noncompaction (LVNC) are both genetically determined and familial diseases that possess variable but overlapping genetic defects. Previous literature has mostly reported their occurrences as either separate disorders in different members of a family or coexisting entities in sporadic cases rather than familial cases. This study explored the echocardiographic diagnostic values and familial features in a family with coexistence of HCM and LVNC. Methods: A four-generation family comprised of 30 members was studied; 28 members underwent familial screening by routine transthoracic echocardiography (TTE), contrast echocardiography (CE), and/or cardiac magnetic resonance imaging (cMRI). Echocardiographic and cMRI findings were then compared. Results: Four members (13.3%) died of sudden death or heart failure. Eleven members (39%) suffered from HCM, LVNC or both. There were 13 left ventricular hypertrophic segments among the echocardiographic images of 9 locally archived patients, including septal, inferior and anterior wall segments (8, 3, 2 respectively) as well as 20 noncompaction segments, including lateral, apical, anterior, antero-septal and inferior wall segments (8, 5, 4, 2, 1 respectively). Left atrial dilatation and diastolic dysfunction were significant in these subjects. Findings from TTE and CE were in accordance with those from cMRI in lesion locations. CE provided more information about noncompaction segments located in the antero-septum and near field than TTE. Conclusions: HCM and LVNC coexist in one Chinese family, with overlapping phenotypes and different ages, clinical manifestations and multimodality imaging findings. TTE is an excellent tool to diagnose HCM and LVNC with supplementation by CE. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Left ventricular noncompaction cardiomyopathy (LVNC) and hypertrophic cardiomyopathy (HCM) are primary types of cardiomyopathy with predominant myocardial involvement. Both diseases have been widely accepted as distinct cardiomyopathies and have been classified as genetic cardiomyopathies by the American Heart Association [1]. Recent literature has documented genetic evidence to prove LVNC and

⁎ Corresponding author at: The George Washington University Medical Center, 2150 Pennsylvania Avenue, N.W., Washington, D.C. 20037, USA. Tel.: +1 202 741 2426; fax: +1 202 741 2324. E-mail address: [email protected] (T.O. Cheng). 1 Co-first authors: Li Yuan, Mingxing Xie & Tsung O. Cheng.

http://dx.doi.org/10.1016/j.ijcard.2014.03.006 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

HCM as having causative genes which are overlapping [2–4]. Cardiac beta myosin heavy chain defect in two families linking noncompaction cardiomyopathy and hypertrophic cardiomyopathy was reported by Hoedemaekers et al. [3]. Alpha cardiac actin gene mutation, previously known to cause HCM or dilated cardiomyopathy (DCM), was identified in another five families with HCM, LVNC and atrial septal defects [4]. Shared sarcomere defects and the occurrence of HCM & DCM in families with LVNC patients indicated that at least some forms of LVNC are part of a broader cardiomyopathy spectrum [2]. This new insight into the genetic linkage between LVNC and HCM has expanded our knowledge about the heterogeneity of these diseases and demands more attention. Here, we report the clinical and imaging findings of a multigeneration Chinese family, in whom features of LVNC coexist with features of HCM in some of the kindred. Previous literature has only

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reported HCM & LVNC occurring separately in different members of a family, or both demonstrating aggregation in sporadic cases but not familial. To our knowledge, our study is the first documentation of coexistence of the two types of cardiomyopathies in different members of a large family. We also focus on the role of routine echocardiography, as well as contrast echocardiography (CE), as the initial diagnostic tools in hypertrophic and noncompaction cardiomyopathies family screening. 2. Methods 2.1. Study population The study was comprised of 30 members (20 males and 10 females) from a single family, identified via the proband — a 48-year-old man with HCM & LVNC. With the exception of 2 undiagnosed deceased kindred, all 28 remaining family members had undergone familial screening through routine TTE and/or CE, and/or cardiac magnetic resonance imaging (cMRI). Nine affected patients were enrolled and archived in our hospital — including 3 adult males, 3 adult females, 2 male children and 1 female child, with ages ranging from 5 to 49 years and a mean age of 28 ± 19 years.

were performed in 6 patients. Only 1 patient underwent coronary arteriography and left ventriculography. 2.5. Diagnostic criteria LVNC diagnostic criteria were as follows: (1) an excessively thickened LV myocardium with a two-layered structure consisting of a compacted epicardial layer (C) and a noncompacted endocardial layer (NC) with prominent trabeculations and deep intertrabecular recesses; (2) a maximal end-systolic N/C ratio N 2 in adults, measured at the parasternal short axis; and a N/C ratio N 1.4 in children; (3) color Doppler evidence of deep perfused intertrabecular recesses. And (4) absence of other cardiovascular abnormalities [7,8]. HCM diagnostic criteria were as follows: (1) LV thickness, evaluated at interventricular septum (IVS) and free wall level ≥ 15 mm; (2) Ventricular septal to left ventricular posterior wall thickness ratio N 1.3; (3) Absence of other possible systemic or cardiac causes of LV hypertrophy; (4) hypertrophic obstructive cardiomyopathy (HOCM) with a resting or dynamic LVOT pressure gradient ≥ 30 mm Hg; (5) In the cases involving children, ≥ 95% confidence interval of the theoretic value diagnostic for HCM [9,10]. 3. Results

2.2. Routine transthoracic echocardiography (TTE) 3.1. Proband's clinical and imaging information All family members were examined by routine TTE, including twodimensional echocardiography, M-mode, color Doppler imaging and tissue Doppler imaging (TDI). The echocardiographic instrument used was a Philips iE33 (Philips Medical Systems, Andover, MA) equipped with S5-1 and S8-3 probes. HCM and LVNC segments were localized; hypertrophic myocardial thickness was measured; thickness ratio of noncompaction to compaction myocardium (N/C ratio) was calculated; cardiac function and left ventricular outflow tract (LVOT) pressure gradient were evaluated; and left ventricular outflow tract obstruction (LVOTO) as well as other complications were recorded. The LVOTO was reliably quantified by continuous or pulsed wave Doppler. E & A peak velocities of mitral inflow pulsed wave Doppler were used for diastolic function assessment. When a pseudo-normal left ventricular filling was suspected, TDI was applied to record mitral annulus velocities (e′ & a′ peak) at their septal and lateral areas, and the average values recorded. Ejection fraction (EF) was acquired using the M-mode Teichholz method. These measurements were carried out 3 times, with the mean values recorded. 2.3. Contrast echocardiography (CE) We performed CE in 4 patients, with left ventricular (LV) opacification mode applied, mechanical index held around 0.2 and real-time imaging of wall motion performed during a SonoVue (Bracco Diagnostics Inc., Milan, Italy) bolus injection to the patient's left antecubital vein. The rate of the bolus injection was 0.5–1.0 ml/s, and after bolus injections (with dose of 1.5–2.0 ml for adults & 0.8 ml for children), a rapid 5 ml saline flush was administered [5,6]. An additional contrast agent dose was administered as required by imaging. Apical 4-, 2- and 3-chamber views and parasternal LV short axis view in different levels were obtained by CE. HCM and LVNC segments were localized, thickness of hypertrophic myocardium was measured, and N/C ratio was calculated. 2.4. Cardiac magnetic resonance imaging (cMRI) & other clinical examinations Four patients underwent cMRI using a Siemens 1.5 T Magnetom Avanto (Siemens, Germany) instrument. We selected axial, coronal, sagittal, 4-chamber, 2-chamber and short-axis views to optimize imaging. Either electrocardiograms or 24-hour Holter monitoring

The proband, II2, first presented clinically in August 2007, with the main complaints of dyspnea, chest tightness, cough and abdominal distension for two weeks. Patient's blood pressure was 92/60 mm Hg, heart rate was 72 beats per minute, and he was classified as NYHA II. He had a history of smoking and alcohol drinking for 30 years. ECG showed sinus rhythm, indeterminate intraventricular block, premature atrial contractions, left atrial (LA) dilatation and ST-T segment changes. Echocardiography revealed the following: non-obstructive HCM, interventricular septal hypertrophy (middle segment thickness of 1.9 cm); LV anterior wall & lateral wall hypertrophy with thickness of 1.6 cm; LA dilatation with antero-posterior diameter (APD) of 5.9 cm; mild to moderate mitral regurgitation; diastolic dysfunction; and normal LV systolic function with ejection fraction (EF) of 60%. After 10 months, the patient's condition deteriorated with more frequent dyspnea & palpitation; so he necessitated hospitalization. His heart failure classification then was graded as NYHA IV, and 24-hour Holter monitoring showed atrial fibrillation, premature ventricular contractions, ventricular tachycardia, intraventricular block, and ST-T segment change. Echocardiographic findings were similar to those at the initial examination, whereas left atrium (6.5 cm in APD) and right atrium (4.5 cm in left–right diameter) were both dilated, and LV systolic function decreased with EF of 44%. Meanwhile, congestive hepatomegaly was detected by ultrasound. One week later, the patient was transferred to our hospital for further care. Once again, echocardiography showed similar findings as before except for additional mild pulmonary hypertension. This time, a cardiac MRI showed hypertrophy in the mid IVS, and noncompacted myocardium in the LV anterior and lateral walls (Fig. 1). Thus, our proband was diagnosed as having both HCM and LVNC. Five months later, the patient expired from heart failure at the age of 48. 3.2. Pedigree analysis In order to explore the spectrum of LVNC and HCM in the proband's family, a pedigree analysis was performed (Fig. 2). Among the 30 familial members, 2 suffered heart failure-related deaths and 2 suffered premature sudden deaths, with a mortality rate of 13.3%. Of the 2 members who did not undergo screening, I1 was diagnosed with heart failure but not identified as HCM, whereas II1 suffered from premature sudden death before any cardiac disease was diagnosed. We strongly

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Fig. 1. Cardiac MRI of patient II2, the proband. The 4-chamber view (A) and short-axis view (B) showed ventricular septal wall thickening (triangle), measured as 2.1 cm in mid-segment during diastole and an extremely thickened lateral LV wall, with prominent trabecular network on the endocardial side and thin compacted myocardium on the epicardial side (arrow). Note the marked dilatation of both the left and right atria in A.

suspected that both of them were affected with HCM. Familial screening revealed that 11 out of the remaining 28 members suffered from HCM, LVNC or both, with a morbidity of 39% (Table 1). HCM was prevalent in every generation without obvious age and gender preferences. Affected male members slightly outnumbered female members (n = 7 vs. n = 4), and there were more males than females in this whole family (n = 20 vs. n = 10). The mean age of affected members was 27 ± 18 years. The diagnoses of affected individuals were as follows: 8 with LVNC & HCM (62%), 2 with HCM (18%), 1 with isolated LVNC (9%). Among the HCM cases, 2 were further classified as HOCM. Nearly half of all offspring of the proband were affected, including boys and girls. All of the affected offspring were found to have at least one affected parent. The unaffected daughter (III3) gave birth to 2 healthy sons.

3.3. Clinical data The clinical symptoms of the affected and the dead ranged from asymptomatic to heart failure. Most of the patients were symptomatic in rest or after activities, mainly with dyspnea and syncope. Their NYHA classes ranged from I to IV, with Class I accounting for 69% and Classes III & IV accounting for 23%. ECG abnormalities were present in most patients (Table 1). Beta-blockers, calcium channel blockers (CCB), and angiotensin conversion enzyme inhibitors (ACEI) — either individually or in combination — were recommended for the patients with HCM. II6 was diagnosed as HOCM and LVNC, and received percutaneous transluminal septal myocardial ablation with subsequent relief of. LVOT pressure gradient and symptoms. II8 underwent coronary and left ventricular angiography, the latter of which showed an abnormal

Fig. 2. Pedigrees of the 4-generation family reported in this study. Males are represented by squares and females by circles. Cases of HCM are indicated by parallel oblique lines, cases of LVNC by parallel horizontal lines, and deceased family members by slashes. Question mark indicates non-examined case. Cases of LVNC + HCM are represented by shades of both parallel oblique as well as parallel horizontal lines. The proband is labeled by the arrow. The patients examined in our department are each indicated by a star.

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Table 1 Clinical features of the RIP & affected patients. No.

Sex Age

NYHA Clinical manifestations

ECG/Holter

LVG/CAG

MRI diagnosis

Echo diagnosis

RIP

I1

M

50

IV

Palpitation, dyspnea,

N/A

N/A

N/A

N/A

II1

M

Youth N/A

N/A

N/A

N/A

N/A

N/A

II2

M

48

IV

N/A

HCM + NC

HCM

II4

F

49

III

N/A

N/A

HCM + NC

II6 II8

F M

42 37

I I

Palpitation, dyspnea, abdominal AF, LAFB, fast ventricle rate distension Dyspnea after exercise, cough Sinus bradycardia, CRBBB, Q-wave in lead V2–V4 Chest tightness, syncope PACs, AT, ST-T wave changes Chest tightness, syncope Multifocal PVCs, PACs

RIP/ HF RIP/ SD RIP/ HF

HOCM + NC HOCM + NC HCM + NC HCM + NC

III1

F

29

I

Dyspnea after exercise

HCM + NC

HCM + NC

III5 M III8 M III10 M

25 27 14

I I I

Dyspnea after exercise Dyspnea after exercise Chest tightness, syncope

Sinus bradycardia, ST-T wave changes N/A N/A N/A

N/A Feather-shaped LV outline, normal CAG, normal LVOT PG N/A N/A N/A N/A

N/A N/A N/A

HCM + NC HCM HOCM

III14 M IV1 M IV5 F

5 8 5

I I I

Normal Dyspnea after exercise Normal

N/A SA, T wave changes N/A

N/A N/A N/A

N/A N/A N/A

HCM + NC HCM + NC NC

RIP/ SD

N/A means not recorded, means patient's data not in our ultrasound department archive; the age at death was used as the deceased patients' ages. AF = atrial fibrillation; LAFB = left anterior fascicular block; CRBBB = complete right bundle branch block; PACs = premature atrial contractions; PVCs = premature ventricular contractions; AT = atrial tachycardia; SA = sinus arrhythmia; LVG = left ventricular angiography; CAG = coronary angiography; HCM = hypertrophic cardiomyopathy; HOCM = hypertrophic obstructive cardiomyopathy; NC = left ventricular noncompaction; RIP = rest in peace; SD = sudden death; HF = heart failure.

feathery appearance of endocardium with poorly defined boundaries and residual contrast agent in intertrabecular recesses (Fig. 3); there was neither LVOT pressure gradient nor stenosis of the coronary arteries. 3.4. Echocardiographic findings HCM & LVNC occurred in nearly all of the archived cases, with wall thickness of 1.5–2.1 cm in adult and N/C ratios of 2.5–4.4 (Table 2). In noncompacted segments, left ventricular hypertrabeculation with deep intertrabecular recesses and a two-layered myocardium were present. Color Doppler imaging showed deeply perfused intertrabecular recesses communicating with blood in the left ventricular cavity. Furthermore, 3 children were also found to have HCM & LVNC or isolated LVNC with typical lesions on echocardiography (Figs. 4–6).

CE revealed better endocardial border definitions, demonstrating the direct communication between intertrabecular spaces and LV cavity and defining the N/C ratio with great definition (Figs. 7 and 8). Left atrial dilatation occurred in all HCM patients, with a progressive increase in size with age. Complications mainly emerged in adult patients. Although some patients showed LV dilatation, ejection fraction remained within the normal range, with the notable exceptions of patients II2 & II4, in whom multivalvular regurgitation, pulmonary hypertension and pericardial effusion were noted. Diastolic dysfunction was found in almost all patients using a combination of mitral valve (MV) inflow pattern and TDI MV annulus motion analysis. E/e′ ratio was mostly above 15 in pseudo-normal LV filling cases, demonstrating advanced diastolic dysfunction [11]. In particular, triphasic mitral inflow pattern with mid-diastolic flow, as well as corresponding triphasic mitral annulus motion pattern in TDI spectrum [12] were detected in 2 patients (Fig. 9). 3.5. Lesion locations & comparison among routine TTE, CE and cMRI

Fig. 3. Left ventricular (LV) angiography of patient II8. LV abnormal feathery appearance of endocardium with ill-defined boundaries and residual contrast agent in intertrabecular recesses.

Locations of HCM & LVNC by routine TTE, CE and cMRI noted in Table 3 suggested that findings from TTE combined with CE were in good accordance with those from cMRI in lesion location. There were 13 hypertrophic segments, involving IVS in 8, inferior wall in 3 and anterior wall in 2. At the same time, there were 20 noncompaction segments, involving lateral wall in 8, apex in 5, anterior wall in 4, antero-septum in 2 and inferior wall in 1. Noncompaction as well as hypertrophy were found to be distributed in multiple segments in most patients, with similar locations in family members (Fig. 6). Two cases of suspected antero-septal hypertrophy and 3 cases of suspected noncompaction segments (anterior, inferior & apical), which were overlooked on routine TTE, were finally diagnosed by further confirmation on CE. However, 2 inferior hypertrophic segments were missed by CE due to obvious attenuation. Measured results of wall thickness and N/C ratio showed excellent agreement between TTE & CE. Also, CE provided more depth in details about cardiac structures. In the apical segment of II8, the N/C ratio from CE was slightly greater than that from TTE (4 vs. 3) due to better definition of the apical myocardium. For II6, IVS thickness from CE was less than that from TTE (1.6 cm vs. 1.9 cm), because of aberrant bands attached to IVS as delineated on CE (Figs. 10 and 11).

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Table 2 Echocardiographic findings of the local archived patients. No.

Age/sex

LV-T (cm)

LAs(A–P) (cm)

LVd(A–P) (cm)

RAs(L–R) (cm)

RVd(L–R) (cm)

VLVOT (m/s)

VAV (m/s)

N/C

EF (%)

MV E/A (m/s)

TDI e′/a′ (cm/s)

Other impacts

II2 II4 II6 II8 III1 III5 III14 IV1 IV5

48/M 49/F 42/F 37/M 29/F 25/M 5/M 8/M 5/F

2.1 1.6 1.6–2.0 1.6–2.0 1.5–1.8 1.5–1.7 1.0–1.2 0.9 0.6

6.5 5.9 6.0 5.6 5.6 4.0 2.8 3.6 2.3

5.2 5.6 4.9 5.7 4.5 5.0 3.2 4.5 2.8

4.5 5.3 3.5 3.8 3.6 3.7 2.1 2.6 2.6

3.4 3.8 3.0 3.8 3.2 4.1 2.5 2.4 2.2

0.6 0.9 2.1 1.5 1.1 0.9 0.8 1.6 0.8

0.9 1.0 1.6 1.3 1.3 1.1 0.9 1.9 1.2

N/A 3 4.4 4 3.3 3 4 3 2.5

44 49 69 72 66 61 63 66 70

70 (single E) 50/30 (triphasic) 70/40 50/80 50/40 (triphasic) 50/50 60/90 80/60 60/60

N/A 3/2.5 (triphasic) 4/4 N/A 5/5 (triphasic) N/A N/A 7/7 N/A

MR++, TR++, AR+, PE+, PAH+ MR++, TR+,AR+, PE+, PAH+ MR+, PE+, post-PTSMA MR+,PE+ MR+ (–) (–) (–) (–)

All values represent the most recent echocardiographic examination results. N/A = not recorded; M = male; F = female; LV-T = thickness of hypertrophic LV wall; LAs(A–P) = systolic antero-posterior diameter of left atrium; LVd(A–P) = diastolic antero-posterior diameter of left ventricle; RAs(L–R) = systolic left–right diameter of right atrium; RVd(L–R) = diastolic left–right diameter of right ventricle; VLVOT = Maximal rest velocity of left ventricular outflow tract; N/C = non-compacted to compacted myocardial thickness ratio; EF = ejection fraction (M-mode); triphasic = triphasic LV inflow pattern/MV annulus tissue motion spectrum; PTSMA = percutaneous transluminal septal myocardial ablation; MR = mitral regurgitation; TR = tricuspid valve regurgitation; AR = aortic valve regurgitation; PE = pericardial effusion; PAH = pulmonary artery hypertension; + = mild; ++ = moderate; (–) means nil.

Except for the missed diagnosis of noncompaction in the proband, routine TTE has provided the majority of lesion information, especially in patients with optimal images. CE was a good supplement in case of suboptimal TTE images, especially in diagnosing antero-septum noncompaction. All in all, findings from the routine TTE combined with CE were in good accordance with those from MRI in lesion location. 4. Discussion 4.1. Background of HCM & LVNC HCM is the most prevalent cardiomyopathy, which is characterized morphologically by a hypertrophied, nondilated LV in the absence of another systemic or cardiac disease that is capable of producing this magnitude of wall thickening [1]. The British pathologist Teare [13] first described the asymmetrical appearance of hypertrophy and the familial nature of the disease in 1958. HCM is a relatively common cardiomyopathy affecting at least 1 in 500 persons in the general population worldwide [14]. It is recognized that not only symptoms but also hypertrophy can develop at any point in life. LVNC is a relatively new disease. Isolated LVNC was first described in 1984 by Engberding and Bender [15] as “persistence of isolated myocardial sinusoids” and also reported its typical echocardiographic features. The subsequent years saw more light being shed on the developmental physiology of the pathology, and in 1990 Chin et al. [16] coined the term

“isolated non-compaction of the left ventricular myocardium”. The left ventricle is characterized by multiple trabeculations with deep intertrabecular recesses in communication with the ventricular cavity. LVNC may either occur as an isolated lesion without other cardiac anomalies or be associated with other congenital heart diseases, such as Ebstein's anomaly, bicuspid aortic valve, aorta-to-left ventricular tunnel, congenitally corrected transposition, hypoplastic left heart syndrome, and isomerism of the left atrial appendage [17]. Other associations are with coronary artery abnormalities, ventricular and atrial septal defects, patent ductus arteriosus and neuromuscular disorders [18]. Neuromuscular disorders, particularly metabolic myopathy, myotonic dystrophy, Becker's muscular dystrophy and Barth syndrome have been frequently reported in LVNC [19]. The pathogenesis of LVNC is still unclear, but it is generally considered to be a congenital and genetic disorder, due to arrest in the normal embryogenesis of endocardium and myocardium [20]. Bley et al. [21] have also reported 3 infants whose intrauterine echocardiograms showed no features of noncompacted myocardium but who then developed LVNC later in life [21]. Both HCM and LVNC are accepted as distinct cardiomyopathies and have been classified as genetic cardiomyopathies. Familial, as well as sporadic, forms of LVNC have been reported. Some authors have suggested familial recurrence in up to 44% of cases [22]. The rate of familial involvement was 18%, 25%, and 33% in three of the largest patient series studied [23–25]. Various patterns of familial transmission have been described. Except for the most common one of autosomal dominant

Fig. 4. Echocardiography after percutaneous transluminal septal myocardial ablation of patient II6. In the apical 4-chamber view (A), hypertrophy of interventricular septum (IVS) and hypertrabeculation with deep intertrabecular recesses in the left ventricular lateral wall can be seen. Color Doppler echocardiography (B) showed deeply perfused intertrabecular recesses communicating with blood in the ventricular cavity. In LV short axis view (C), triangles indicated hypertrophy of IVS and inferior wall (with thicknesses of 1.6 cm and 2.0 cm, respectively).

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Fig. 5. Echocardiography of patient II8. In the LV short axis view (A) and parasternal LV long axis view (B), triangles indicated hypertrophy of IVS, anterior and inferior walls. In the apical 4chamber view (C), hypertrophy of IVS was indicated by a triangle, and LVNC indicated by an arrow (C). In zoom mode (D), typical 2 layers of LVNC, i.e. a thin, compacted outer layer (single arrow) and a much thicker, non-compacted inner layer (2 arrows), were clearly visualized, with the ratio of noncompacted inner layer to compacted outer layer equal to 4.

inheritance, there are X-linked and mitochondrial inheritance. LVNC has genetic heterogeneity and variable phenotypes. Among the 14 different genes identified, sarcomeric protein gene defects are the most common genetic cause, involving 33% of patients with isolated LVNC. More than 40 types of mutations in sarcomere genes comprising thick (MYH7), intermediate (MYBPC3), and thin filaments (TNNT2, TNN13, ACTC) have been identified. MYH7 accounts for approximately 21% of isolated LVNC. Other non sarcomeric genetic mutations associated with isolated LVNC are ACTC alpha-cardiac actin gene, taffazin (TAZ), ZASP, DMPK, DTNA and mutations in calcium handling genes CASQ2, PLN [2,26]. HCM manifests mainly as a familial rather than sporadic disease [27]. It is genetically heterogeneous but relatively commonly inherited as

autosomal dominant mode; however, autosomal recessive inheritance and idiovariation may also be related to it [2]. Until now, more than 20 gene mutations have been found. Mutations can be located in many genes, but are most commonly found in the genes encoding sarcomeric proteins. The most common mutations are in cardiac myosin protein binding c (MYBPC3) and beta myosin heavy chain gene (MYH7), each accounting for one fourth to one third of HCM cases, with other genes each affecting less than 1% to 5% of cases. HCM and LVNC appear to be linked to each other by the same disease-causing genes. The genetic studies about ACTC, MYH7 and other sarcomeric gene mutations provide the link between these cardiomyopathies, revealing them as overlapping entities. Biagini et al. [28] described 2

Fig. 6. Echocardiography in a 5-year old male child, III14. In the apical short axis view (A), hypertrabeculation with deep intertrabecular recesses in the apex can be seen, and the color Doppler echocardiography (B) showed deeply perfused intertrabecular recesses communicating with blood in the ventricular cavity. In LV short axis view at the papillary muscle level (C), triangles indicated hypertrophy in IVS and inferior wall (with thicknesses of 1.2 cm and 1.0 cm, respectively).

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Fig. 7. Contrast-enhanced left ventricular echocardiography (CE) of patient III1 showed LVNC in apical, anterior & inferior walls (arrows) in apical 2-chamber view ( A), and the same LVNC locations (arrows), as well as hypertrophic IVS (triangle) in short axis view (B). Thus, previously suspected LVNC located in the apex and inferior wall on routine echocardiography was further confirmed by CE.

adult cases of clear cut hypertrophic cardiomyopathy in a series of 73 patients diagnosed with noncompaction. Pignatelli et al. [8] described a child with LVNC whose father had hypertrophic cardiomyopathy. Monserrat et al. [4] confirmed the pathogenetic role of E101K mutation in alpha cardiac actin gene (ACTC) which co-aggregate with LVNC and HCM in the families they studied. Alday et al. [29] reported a case of complex overlapping phenotypes of LVNC, HCM and Wolf–Parkinson– White syndrome. Ripoll et al. [30] found R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats and hypertrophic cardiomyopathy and left ventricular noncompaction in humans. Recently, Hoedemaekers et al. [3] reported cardiac betamyosin heavy chain defects in two families with noncompaction cardiomyopathy, linking noncompaction to hypertrophic, restrictive and dilated cardiomyopathies. Xia et al. [31] described a pedigree genetic analysis in which they found association between LVNC and HCM. 4.2. Pedigree clinical genetics characteristic analysis Previous literature [7,19,28] reported LVNC and HCM occurring separately in different members of a family, or as co-aggregation in sporadic cases but not familial, while familial coexistence of HCM & LVNC among different family members has not been previously studied. Family screening revealed 39% morbidity and overlapping phenotypes of LVNC and HCM in our study. The results supported the shared genetic defect and familial aggregation of LVNC and HCM. Our pedigree chart demonstrated the following features: (1) any parent of an affected member was revealed to be affected too; (2) there seems to be an

almost 50% incidence among offspring; (3) male and female patients were mostly equally affected; (4) this disease was inherited in continuous generations. All of these traits strongly implied an autosomal dominant inheritance pattern [32], which was the most common inheritance pattern of LVNC as well as HCM. Familial screening allowed us to reveal additional affected members even though some were asymptomatic and to offer counseling as well as follow-up. Remarkably, phenotypes of the affected members were similar but varied with respect to age, clinical manifestations and imaging findings. Their diagnoses included HCM, LVNC or both. Some patients had HOCM. Locations of hypertrophy and noncompaction showed excellent consistency. Nearly all the patients were found with IVS hypertrophy and lateral wall noncompaction, with similar IVS thickness and N/C ratio respectively. Even some rare locations, such as hypertrophic anterior & inferior walls and noncompacted anterior wall and antero-septum, were detected in different members of this family. However, there is a great variability in presentations, ranging from being fully asymptomatic to congestive heart failure. Arrhythmias of different types occurred also in these members. 4.3. Family screening, misdiagnosis & missed diagnosis of HCM & LVNC It should be noted that the proband was first misdiagnosed as HCM by TTE and subsequently found to have LVNC by cMRI. LVNC may be mistaken for dilated, ischemic and hypertrophic cardiomyopathy, especially of the apical variety, because of abnormal wall thickening and/or prominent hypertrabeculation [33–35]. With further checking by MRI

Fig. 8. Contrast-enhanced left ventricular echocardiography (CE) of patient II8 showed LVNC in the apex and lateral wall (indicated by arrows) in apical 4-chamber view (A), in good accordance with routine echocardiography & MRI. In apical 3-chamber view (B), CE of patient IV1 showed specially located LVNC in the anterior portion of septum (indicated by arrow), which was missed in diagnosis by routine echocardiography.

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Fig. 9. Pulsed-wave Doppler spectrum (A) showed triphasic mitral valve (MV) inflow pattern with mid-diastolic flow. Pulsed-wave tissue Doppler spectrum (B) showed triphasic MV annulus motion pattern at the interventricular septal area.

and contrast echocardiography (CE), LVNC was finally diagnosed. Our earlier misdiagnosis could be attributed to an initial lack of knowledge about coexistence of these two cardiomyopathies and poor echocardiographic image quality, the latter of which was improved by cMRI and CE. In our study, CE played an important supplemental role in locating and quantifying the lesions. We utilized SonoVue for opacification of the LV chamber to allow a better display of the two myocardial layers of LVNC, and the real border of hypertrophic myocardium. In some suboptimal imaged segments, CE confirmed the diagnosis in accordance with cMRI, especially for IVS, lateral and anterior wall lesions, which are located in near field with less attenuation. As for the inferior wall lesions in far field, when the images are suboptimal and obvious attenuation happens, diagnosis may potentially be missed [36,37]. In our experience, avoiding too large a contrast agent bolus and too rapid an injection can reduce attenuation. IVS is a rare location for LVNC, the diagnosis of which may be easily missed, especially when using 2DE and color Doppler flow imaging [38]. For a more accurate diagnosis, we should bear in mind these relatively rare locations and use CE and cMRI when necessary [39]. Contrast echocardiography is very useful in clinical practice. Usage of contrast can improve image alignment and helps to avoid off-axis scanning. In our study, SonoVue, which is stabilized sulfur hexafluoride microbubbles surrounded by a phospholipid shell with a mean size of 2.5 μm, is used. After mixing with saline, a manual process that takes less than one minute, a suspension is obtained with SonoVue microbubbles. With a bolus injection and low MI contrast imaging, we can get better left ventricular opacification. CE has been used for many indications, such as LV ejection fraction assessment, myocardial perfusion, LVNC, assessment of right ventricular function and morphology, stress echocardiography, LV thrombus detection and differentiation between intra- and extra-cardiac structures [40].

After Koo et al. [41] first reported in 2002 their study of using a transpulmonary contrast agent in the diagnosis of LVNC, the usefulness of contrast echocardiography in LVNC has been reported in several subsequent studies with much improved diagnostic accuracy and reproducibility [6,42]. CE currently is used to enhance endocardial definition as well as Doppler signals, and to evaluate myocardial perfusion during percutaneous transluminal septal myocardial ablation (PTSMA). The introduction of the echo contrast has been proven to be effective in reducing the complications of PTSMA: it selects the appropriate septal perforator branch perfusing the precise area of septum to be targeted for alcohol ablation and also evaluates whether selected septal perforator also perfuses other distant and unintended target areas of LV, right ventricular myocardium or papillary muscles [9]. A potential role for contrast enhancement in the diagnosis of apical HCM has also been demonstrated, although systematic studies have not yet been performed [43]. Finally, we wish to emphasize the diagnostic accuracy of routine TTE & CE in our series of patients with HCM and LVNC. Traditionally, TTE has been the diagnostic modality of choice in evaluation of patients with cardiomyopathies. cMRI is emerging as the gold standard of diagnostic methodology. The apical region of the heart being commonly involved in LVNC may not be properly viewed in routine echocardiography in some patients, thus resulting in underestimation of the extent of LVNC. However, cMRI can provide a better anatomical visualization of the apex. cMRI, in comparison to TTE, is particularly useful in certain situations, such as subtle LVNC in asymptomatic patients and patients with a poor acoustic window as in obese patients and patients with obstructive lung disease. Cases with hypertrabeculation due to other causes may give rise to an overestimation of the number of LVNC patients. In such instances, cMRI can differentiate the trabeculae of aberrant bands, false tendons and abnormal insertion of papillary muscles

Table 3 Hypertrophic and noncompacted left ventricle segments location by echo, CE & cMRI. No.

Hypertrophic LV segments

II2 II4 II6

Echo IVS, anterior, lateral IVS IVS, inferior

CE N/A N/A IVS

MRI IVS N/A IVS, inferior

Echo Missed Lateral, apex Lateral, anterior

IVS, anterior, inferior IVS(mid)

IVS, anterior IVS(mid)

IVS, anterior, inferior IVS(mid)

Lateral, apex

II8 III1

Noncompacted LV segments

III5 IVS III14 IVS, anterior IV1 IVS, inferior

N/A N/A N/A N/A IVS, inferior N/A

Lateral, anterior, apex & inferior (suspected) Lateral Lateral, apex Lateral, anterior(suspected)

IV5

N/A

apex

Nil

N/A

CE N/A N/A Lateral, anterior, antero-septal (mid) Lateral, apex

MRI Anterior, lateral N/A lateral, anterior, antero-spectal (mid) Lateral, apex

Lateral, anterior, apex, inferior

Lateral, anterior, apex, inferior

N/A N/A Lateral, anterior, antero-septal (mid) N/A

N/A N/A N/A

CE = contrast echocardiography; cMRI = cardiac magnetic resonance imaging, IVS = interventricular septum; N/A = not recorded.

N/A

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Fig. 10. Cardiac MRI of patient II6 with concurrent LVNC and HCM following percutaneous transluminal septal myocardial ablation. In the 2-chamber view (A), LVNC was indicated by an arrow along the anterior wall of LV and hypertrophy indicated by a triangle in the inferior LV wall (thickness = 2.0 cm). In the 4-chamber view (B), LVNC was indicated by an arrow along the lateral wall of LV and hypertrophy indicated by a triangle in the interventricular septum (thickness = 1.6 cm).

and also aid in the differential diagnosis of mural thrombi, apical hypertrophic cardiomyopathy, fibroma, obliterative process, intramyocardial hematoma, cardiac metastases and intramyocardial abscesses [41,44]. In our study, the location of the lesions in our subjects, as detected by TTE, showed a good correlation with that revealed by cMRI, thus supporting the TTE as a reliable modality. For II6, due to her poor IVS echocardiographic images after PTSMA, noncompaction in anteroseptum middle segment was initially missed in diagnosis but subsequently confirmed by CE. According to our experience, in the diagnosis of cardiomyopathies, contrast can provide additional information about the lesion location and quantification. Therefore, echocardiography remains a sensitive first-line, readily available, mobile, relatively cheap, and non-invasive diagnostic tool, and its diagnostic accuracy can be further enhanced by contrast injection. 4.4. Clinical features and pathophysiology Our echocardiographic screening revealed that all the adult members of the family had left atrial dilatation and LV diastolic dysfunction. Impaired filling of the left ventricle may have been due to abnormal relaxation and increased stiffness of the hypertrophic myocardium [1, 45], as well as abnormal relaxation and restrictive filling caused by numerous prominent trabeculae [41]. All of these lead to elevated LV end-diastolic pressure and pulmonary congestion. The proband finally presented with systolic dysfunction, which was prospectively ascribed to subendocardial hypoperfusion and microcirculatory dysfunction [2]. Comprehensive echocardiographic studies were employed in our evaluation of the LV diastolic function. In the presence of impaired LV

relaxation and irrespective of the left atrial pressure, e′ velocity is reduced and delayed. For patients with suspected diastolic dysfunction, measurement of E/e′ ratio is recommended to evaluate LV relaxation and to predict LV filling pressure [46]. The average mitral annulus e′ velocity is adopted to avoid differences of septal and lateral e′. In most cases with suspected pseudonormal LV filling, E/E′ is above 15, indicative of increased LV filling pressures [11]. Triphasic mitral inflow pattern with obvious mid-diastolic flow and corresponding triphasic TDI mitral annulus motion PW spectrum were recorded in 2 patients, and demonstrated advanced diastolic dysfunction. Triphasic mitral inflow with mid-diastolic flow is related to elevated filling pressure, delayed myocardial relaxation, and slow heart rate, indicating advanced diastolic dysfunction, in a patient with marked LV hypertrophy [47]. Corresponding to mid-diastolic mitral flow, there sometimes is a L′ wave in the TDI spectrum. Frommelt et al. [48] described that the prolonged LV pressure decrease into mid-diastole was preceded by mid-diastolic mitral annular motion. Thus, they thought that mid-diastolic mitral annular motion, a delayed wave of active relaxation, might create a diastolic suction effect in mid-diastole and lead to mid-diastolic inflow across the mitral valve [48]. According to Ha et al. [12], the presence of L′ in subjects with triphasic mitral inflow velocity pattern with mid-diastolic flow is associated with higher E/E′, elevated proBNP and enlarged left atrium, indicating advanced diastolic dysfunction with elevated filling pressures. It should also be noted that the proband initially had pre-existing cardiac arrhythmias. As the arrhythmias worsened, atrial fibrillation occurred and was followed by congestive heart failure and death. Arrhythmias in LVNC have been postulated to be the result of trabecular

Fig. 11. Cardiac MRI of patient II8. The 4-chamber view (A) demonstrated HCM in IVS and inferior wall of LV (triangles); and LVNC in lateral wall (arrow). The short axis view (B) showed HCM along IVS, anterior and inferior walls of LV (triangles).

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fibrosis and subendocardial ischemia with ventricular arrhythmias being a more common occurrence [49]. Anatomic change in HCM can also be a substrate for arrhythmias. Atrial fibrillation is another frequent symptom in HCM (about 20%), which is associated with advanced age, congestive symptoms, and dilated left atrium, resulting in increasing risk of heart failure-related death [2,50]. In the 4 patients who died, 2 middle-aged patients died of congestive heart failure, and 2 died of premature sudden death. These two causes of death are common both in HCM and LVNC [51,52], and HCM is the most common cause of sudden cardiac death in the young.

5. Study limitations Our study was performed for clinical screening, and the genotype analysis has not been finished yet. Not all members recruited could be screened and archived in our hospital, and thus, cMRI and CE examinations were not performed in all members. We expect further study in the follow-up of the pedigrees.

6. Conclusions Genetic studies providing mounting evidence of LVNC and HCM acting as overlapping entities should inform us of the possibility of the two pathologic processes coexisting in the same individual. Therefore, all cardiologists should be aware of this coexistence which may help avoid misdiagnosis as well as identify many more such cases. Cardiac screening of family members should be carried out to make earlier diagnosis of a larger number of cases. HCM and LVNC coexist in this family, while the phenotypes of this family are similar but varied. Routine echocardiography as an initial diagnostic tool has proven to be effective in family screening and diagnosing HCM and LVNC. Contrast-enhanced echocardiography can provide more information about noncompaction segments located in the anterior portion of the interventricular septum and near field than routine echocardiography, which sometimes may miss the diagnosis due to poor image quality [53]. Finally, to unravel other shared genetic defects, we suggest further analysis of genes which would enlighten us more on the genetic heterogeneity of LVNC and HCM. Our future understanding of LVNC depends on an integration of cardiac morphology, physiology, pathophysiology and evolving genetics [54].

References [1] Maron BJ, Towbin JA, Thiene G, et al. Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807–16. [2] Baars HF, van der Smagt JJ, Doevendans PAFM. Clinical cardiogenetics. Springer; 2010 102–4. [3] Hoedemaekers YM, Caliskan K, Majoor-Krakauer D, et al. Cardiac beta-myosin heavy chain defects in two families with non-compaction cardiomyopathy: linking noncompaction to hypertrophic, restrictive, and dilated cardiomyopathies. Eur Heart J 2007;28:2732–7. [4] Monserrat L, Hermida-Prieto M, Fernandez X, et al. Mutation in the alpha-cardiac actin gene associated with apical hypertrophic cardiomyopathy, left ventricular non-compaction, and septal defects. Eur Heart J 2007;28:1953–61. [5] Mulvagh SL, Rakowski H, Vannan MA, et al. American Society of Echocardiography Consensus Statement on the clinical applications of ultrasonic contrast agents in echocardiography. J Am Soc Echocardiogr 2008;21:1179–201. [6] Gianfagna P, Badano LP, Faganello G, Tosoratti E, Fioretti PM. Additive value of contrast echocardiography for the diagnosis of noncompaction of the left ventricular myocardium. Eur J Echocardiogr 2006;7:67–70. [7] Jenni R, Oechslin E, Schneider J, Attenhofer JC, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 2001;86:666–71. [8] Pignatelli RH, McMahon CJ, Dreyer WJ, et al. Clinical characterization of left ventricular noncompaction in children: a relatively common form of cardiomyopathy. Circulation 2003;108:2672–8.

[9] Losi MA, Nistri S, Galderisi M, et al. Echocardiography in patients with hypertrophic cardiomyopathy usefulness of old and new techniques in the diagnosis and pathophysiological assessment. Cardiovasc Ultrasound 2010;8:7. [10] Konno T, Shimizu M, Ino H, et al. Diagnostic value of abnormal Q waves for identification of preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis. Eur Heart J 2004;25:246–51. [11] Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation 2000;102:1788–94. [12] Ha JW, Ahn JA, Moon JY, et al. Triphasic mitral inflow velocity with mid-diastolic flow: the presence of mid-diastolic mitral annular velocity indicates advanced diastolic dysfunction. Eur J Echocardiogr 2006;7:16–21. [13] Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J 1958;20:1–8. [14] Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary artery risk development in (young) adults. Circulation 1995;92:785–9. [15] Engberding R, Bender F. Identification of a rare congenital anomaly of the myocardium by two-dimensional echocardiography: persistence of isolated myocardial sinusoids. Am J Cardiol 1984;53:1733–4. [16] Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 1990;82:507–13. [17] Friedberg MK, Ursell PC, Silverman NH. Isomerism of the left atrial appendage associated with ventricular noncompaction. Am J Cardiol 2005;96:985–90. [18] Stöllberger C, Finsterer J, Blazek G. Left ventricular hypertrabeculation/noncompaction and association with additional cardiac abnormalities and neuromuscular disorders. Am J Cardiol 2002;90:899–902. [19] Finsterer J, Stollberger C, Blazek G. Neuromuscular implications in left ventricular hypertrabeculation/noncompaction. Int J Cardiol 2006;110:288–300. [20] Engberding R, Yelbuz TM, Breithardt G. Isolated noncompaction of the left ventricular myocardium — a review of the literature two decades after the initial case description. Clin Res Cardiol 2007;96:481–8. [21] Bleyl SB, Mumford BR, Brown-Harrison MC, et al. Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals. Am J Med Genet 1997;72:257–65. [22] Ichida F, Tsubata S, Bowles KR, et al. Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome. Circulation 2001;103:1256–63. [23] Aras D, Tufekcioglu O, Ergun K, et al. Clinical features of isolated ventricular noncompaction in adults long-term clinical course, echocardiographic properties, and predictors of left ventricular failure. J Card Fail 2006;12:726–33. [24] Oechslin EN, Attenhofer Jost CH, Rojas JR, Kaufmann PA, Jenni R. Long-term followup of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 2000;36:493–500. [25] Xing Y, Ichida F, Matsuoka T, et al. Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity. Mol Genet Metab 2006;88:71–7. [26] ICIN Working Group on Hereditary Heart Diseases. Genetic diagnostics and genetic counselling in hypertrophic cardiomyopathy (hcM). Neth Heart J 2010;18:144–59. [27] Campbell SG, McCulloch AD. Multi-scale computational models of familial hypertrophic cardiomyopathy: genotype to phenotype. J R Soc Interface 2011;8:1550–61. [28] Biagini E, Ragni L, Ferlito M, et al. Different types of cardiomyopathy associated with isolated ventricular noncompaction. Am J Cardiol 2006;98:821–4. [29] Alday L, Moreyra E, Bruno E, Rossi N, Maisuls H. Left ventricular noncompaction associated with hypertrophic cardiomyopathy and Wolff–Parkinson–White syndrome. Health 2010;2(3):200–3. [30] Ripoll Vera T, Monserrat Iglesias L, Hermida Prieto M, et al. The R820W mutation in the MYBPC3 gene, associated with hypertrophic cardiomyopathy in cats, causes hypertrophic cardiomyopathy and left ventricular non-compaction in humans. Int J Cardiol 2010;145:405–7. [31] Xia S, Wang H, Zhang X, Zhu J, Tang X. Clinical presentation and genetic analysis of a five generation Chinese family with isolated left ventricular noncompaction. Intern Med 2008;47:577–83. [32] Hoedemaekers YM, Caliskan K, Majoor-Krakauer DF. Noncompaction cardiomyopathy. In: Baars HF, et al, editors. Clinical cardiogenetics. ©Springer-Verlag London Limited; 2011. http://dx.doi.org/10.1007/978-1-84996-471-5_6. [33] Murphy RT, Thaman R, Blanes JG, et al. Natural history and familial characteristics of isolated left ventricular non-compaction. Eur Heart J 2005;26:187–92. [34] Salemi VMC, Rochitte CE, Lemos P, Benvenuti LA, Pita CG, Mady C. Long-term survival of a patient with isolated noncompaction of the ventricular myocardium. J Am Soc Echocardiogr 2006;19:354. [35] Perez-David E, Garcia-Fernandez MA, Gomez-Anta I, de Diego JJ, Garcia-Robles JA, Lafuente J. Isolated noncompaction of the ventricular myocardium: infrequent because of missed diagnosis? J Am Soc Echocardiogr 2007;20:439.e1–4. [36] Masugata H, Yukiiri K, Takagi Y, Ohmori K, Mizushige K, Kohno M. Potential pitfalls of visualization of myocardial perfusion by myocardial contrast echocardiography with harmonic gray scale B-mode and power Doppler imaging. Int J Cardiovasc Imaging 2004;20:117–25. [37] Masugata H, Cotter B, Ohmori K, Kwan OL, Mizushige K, DeMaria AN. Feasibility of right ventricular myocardial opacification by contrast echocardiography and comparison with left ventricular intensity. Am J Cardiol 1999;84:1137–40 [A11]. [38] Mariotti E, Pierantozzi A, Bocconcelli P. A rare case of isolated left ventricular noncompaction. Importance of image technology and disease awareness for a correct diagnosis. J Cardiovasc Med 2006;7:563–5.

L. Yuan et al. / International Journal of Cardiology 174 (2014) 249–259 [39] Finsterer J, Stollberger C. Cardiac MRI versus echocardiography in assessing noncompaction in children without neuromuscular disease. Pediatr Radiol 2006;36:720–1. [40] Galema TW, Geleijnse ML, Vletter WB, De LL, Michels M, Ten Cate FJ. Clinical usefulness of SonoVue contrast echocardiography: the Thoraxcentre experience. Neth Heart J 2007;15:55–60. [41] Koo BK, Choi D, Ha JW, Kang SM, Chung N, Cho SY. Isolated noncompaction of the ventricular myocardium: contrast echocardiographic findings and review of the literature. Echocardiography 2002;19:153–6. [42] Lampropoulos KM, Dounis VG, Aggeli C, Iliopoulos TA, Stefanadis C. Contrast echocardiography: contribution to diagnosis of left ventricular non-compaction cardiomyopathy. Hellenic J Cardiol 2011;52:265–72. [43] Soman P, Swinburn J, Callister M, Stephens NG, Senior R. Apical hypertrophic cardiomyopathy: bedside diagnosis by intravenous contrast echocardiography. J Am Soc Echocardiogr 2001;14:311–3. [44] Rosa LV, Salemi VM, Alexandre LM, Mady C. Noncompaction cardiomyopathy — a current view. Arq Bras Cardiol 2011;97:e13–9. [45] Sanderson JE, Gibson DG, Brown DJ, Goodwin JF. Left ventricular filling in hypertrophic cardiomyopathy. An angiographic study. Br Heart J 1977;39:661–70. [46] Nagueh SF, Appleton CP, Gillebert TC, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009;22:107–33.

259

[47] Ha JW, Oh JK, Redfield MM, Ujino K, Seward JB, Tajik AJ. Triphasic mitral inflow velocity with middiastolic filling: clinical implications and associated echocardiographic findings. J Am Soc Echocardiogr 2004;17:428–31. [48] Frommelt PC, Pelech AN, Frommelt MA. Diastolic dysfunction in an unusual case of cardiomyopathy in a child: insights from Doppler and Doppler tissue imaging analysis. J Am Soc Echocardiogr 2003;16:176–81. [49] Chrissoheris MP, Ali R, Vivas Y, Marieb M, Protopapas Z. Isolated noncompaction of the ventricular myocardium: contemporary diagnosis and management. Clin Cardiol 2007;30:156–60. [50] Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517–24. [51] Maron BJ. Cardiology patient pages. Hypertrophic cardiomyopathy. Circulation 2002;106:2419–21. [52] Stollberger C, Blazek G, Wegner C, Finsterer J. Heart failure, atrial fibrillation and neuromuscular disorders influence mortality in left ventricular hypertrabeculation/ noncompaction. Cardiology 2011;119:176–82. [53] Finsterer J, Dumser M. Noncompaction in a septic heart, missed on echocardiography. Int J Cardiol 2014;171:e70–1. [54] Paterick TE, Tajik AJ. Left ventricular noncompaction: a diagnostically challenging cardiomyopathy. Circ J 2012;76:1556–62.