Heart transplantation in an adult patient with isolated noncompaction of the left ventricular myocardium

Sigita Glaveckaitė1, Kęstutis Ručinskas1, Jelena Čelutkienė1, Vytė Maneikienė1, Diana Zakarkaitė1, Sigita Aidietienė1, Nomeda Valevičienė2, Mindaugas Matačiūnas2, Edvardas Žurauskas3, Pranas Šerpytis1, Aleksandras Laucevičius1 1Clinic of Heart and Vascular Medicine, Faculty of Medicine, Vilnius University, 2Clinic of Chest Diseases, Allergology and Radiology, Faculty of Medicine, Vilnius University, 3Center of Pathology, Faculty of Medicine, Vilnius University, Lithuania


Case report
A 35-year-old white male was referred to the Cardiac Intensive Care Unit of Vilnius University Hospital Santariškių Klinikos because of fever, dyspnea, and cough.The patient had a history of undefi ned asymptomatic heart disease from the childhood (pathological heart murmur was heard from the age of 7 years).At the age of 17 years, diagnosis of hypertrophic cardiomyopathy was established based on echocardiographic fi ndings.The patient had no symptoms even performing moderate-tosevere physical activity until age of 35 years, when after severe physical activity, he experienced fever, cough, dyspnea, and abdominal pain.There was no family history of cardiomyopathy, although fi rstdegree relatives had not been screened.
On admission during physical examination, the patient was slightly pallid with a regular heart rate of 32-36 beats per minute (on subsequent days after admission, patient's heart rate increased up to 100 beats per minute) and blood pressure of 105/65 mm Hg.Lung auscultation revealed wheezes in both the lungs.Abdominal palpation showed slight distention and tenderness to palpation in the epigastric, left and right hypochondriac regions; the liver was 3-4 cm below the right costal margin.
The electrocardiogram (ECG) showed sinus rhythm, 32 beats per minute, fi rst-degree AV block, hypertrophy of both ventricles, and features of myocardial scar in inferior leads.
Transthoracic echocardiography (TTE) demonstrated marked thickening and heavy trabeculation of the left ventricle apex, inferior, septal, anterior, and lateral walls.Thrombi in the projection of deep intertrabecular recesses in the apical region of the left ventricle were seen on TTE (Figs. 1 and 2).Color Doppler displayed fl ow within the deep intertrabecular recesses.The left ventricle was slightly dilated, and marked dilatation of both atria was observed with a restrictive pattern of left ventricular fi lling.There was hypokinesis of the left ventricle apex, septal and anterior walls with reduction of global left ventricular ejection fraction (LV EF about 30%).The right ventricle appeared to be more heav-Key words: isolated noncompaction of the left ventricular myocardium; echocardiography; computed tomography; cardiovascular magnetic resonance; heart transplantation.

Summary. Isolated noncompaction of the ventricular myocardium is defined as a rare cardiomyopathy caused by intrauterine arrest of compaction of the myocardial fibers and meshwork, an important process in myocardial development, in absence of any coexisting congenital heart lesions.
A lot of controversies exist about diagnostic criteria, nomenclature, origin, pathogenesis, and prognosis of this disease.Here, we describe an adult patient with isolated left ventricular noncompaction who presented with worsening congestive heart failure and was successfully treated with heart transplantation.
ily trabeculated than usual.Mild relative mitral and tricuspid regurgitation jets were seen.No additional abnormalities were present.Based on above-mentioned fi ndings, isolated ventricular noncompaction (IVNC) was suspected.
For clarifi cation of diagnosis, cardiovascular magnetic resonance (CMR) was performed.CMR demonstrated prominent, numerous trabeculations in the apical region and midventricular segments of the left ventricle with deep intertrabecular recesses communicating with the left ventricle cavity.The enddiastolic ratio of noncompacted to compacted myocardium was >2.3, consistent with diagnosis of left ventricular noncompaction according to Petersen et al. (1) (Fig. 3).CMR examination showed a totally reduced LV EF of about 30% and traces of fl uid in both the pleural cavities and in the pericardium.Using segmented inversion-recovery turboFLASH sequence 15 min after contrast administration, a hyperintense focus 1.8×1.9cm in size was observed in the projection of the midventricular segment of the inferoseptal wall, consistent with the region of myocardial fi brosis or necrosis.The right ventricle appeared to be more trabeculated than usual; however, we did no attempt to diagnose involvement of the right ventricle, as the exact differentiation between normal variants of the usually highly trabeculated right ventricle and pathological forms may be diffi cult.CMR images were not informative about the presence of thrombi in the left ventricle because of artifacts due to cardiac arrhythmia.
Abdominal sonography revealed hepatomegaly with signs of mild venous stasis and focal changes in the spleen.Contrast-enhanced chest and abdominal computed tomography (CT) was performed to refi ne focal pulmonary changes seen on chest xray and focal changes in the spleen.Abdominal CT confi rmed multiple hypointense splenic foci typical of spleen infarctions.Left ventricular noncompaction and apical thrombi reported on echocardiography were clearly seen on chest CT (Fig. 4).
The fi ndings from coronary angiography and neurological examination were normal.
The diagnosis of isolated left ventricular noncompaction with possible embolization of ventricular thrombi, causing splenic and myocardial infarctions, was established based on clinical, laboratory, and radiological fi ndings.
Our patient was treated conservatively with anticoagulants, antibiotics, antifungal agents, betablockers, diuretics, and angiotensin-converting enzyme inhibitors.During treatment, an improvement in symptoms and exercise tolerance, reduction of left lung infi ltration were noted, and the patient was  Heart transplantation in an adult patient with isolated noncompaction of the left ventricular myocardium referred to ambulatory treatment.On subsequent outpatient follow-up visits, the patient complained of frequent palpitations, increasing dyspnea, and reduced exercise tolerance despite adequate treatment.On follow-up ECG, multiple episodes of paroxysmal self-limiting atrial fi brillation and couplets of ventricular premature beats were registered.During ambulatory treatment despite adequate anticoagulation, the patient experienced cerebral infarction with left hemiparesis, which regressed partially.
Four months after establishment of diagnosis, the patient was admitted to the Heart Surgery Center of Vilnius University Hospital Santariškių Klinikos for the assessment of indications for heart transplantation because of refractory congestive heart failure and cerebral embolization despite adequate anticoagulation.
On admission during physical examination, the patient was slightly cyanotic, subicteric with irregular heart rate of 90 beats per minute, blood pressure of 120/70 mm Hg.The liver was 4 cm below the right costal margin.
The ECG showed atrial fi brillation, 100 beats per minute, couplets of ventricular premature beats.TTE and cardiac CMR were repeated for the assessment of disease progression.TTE displayed negative echocardiographic dynamics.The left ventricle remained only slightly dilated, LV EF reduced from 30% to 25%, multiple thrombi were seen in both the ventricles, dilation of both the atria progressively increased, signs of pulmonary hypertension were observed.CMR scan revealed multiple thrombi not only within deep intertrabecular recesses of both the ventricles but also in the left appendage and in the right pulmonary artery.Reduction in systolic function of both the ventricles was pronounced (LV EF of 14% and right ventricle EF of 16%) with an increased amount of fl uid in the pericardial and pleural cavities.Using segmented inversion-recovery turboFLASH sequence 15 min after contrast administration, an enlarged hyperintense focus not only in the projection of the midventricular segment of the inferoseptal wall but also extending to the left ventricle apical region was observed.
Based on clinical fi ndings and results of investigations, the patient was placed on emergency waiting list for the heart transplantation.Orthotopic heart transplantation was performed without signifi cant complications.Macroscopic examination of explanted native heart (Fig. 5) revealed dilated heart with  prominent trabeculations and invaginations at the left ventricular apex, anterior, inferior, and lateral walls with multiple thrombi.The layer of noncompaction was markedly thicker when compared with the layer of compacted myocardium in the abovementioned left ventricle areas.The coronary arteries were normal.
Histological examination of the explanted heart showed prominent trabeculations of the left ventricle, left ventricle endocardial thickening and fi brosis, prominent hypertrophy of cardiomyocytes, with some areas of interstitial and focal fi brotic changes, discordance of myocardial fi bers, and thrombi in all cardiac chambers (Fig. 6).
The patient was discharged from the hospital with signs of minimal heart transplant rejection reaction on heart biopsy and without any clinical symptoms and remained well and fully active for the subsequent 1.5 years.

Discussion
IVNC of the ventricular myocardium is defi ned as a rare cardiomyopathy caused by intrauterine arrest of compaction of the myocardial fi bers and meshwork, an important process in myocardial development (2).IVNC is characterized by the presence of deep intertrabecular recesses in hypertrophied and often hypokinetic segments of the myocardium of the left or both ventricles.By defi nition, IVNC occurs in the absence of other coexisting cardiac abnormalities (3).In IVNC, the deep intertrabecular recesses communicate with the cavity of the left ventricle but not with the coronary circulation, whereas in non compaction associated with other congenital heart disease (nonisolated noncompaction), the intertra becular recesses communicate both with the left ven tricular cavity and the coronary circulation (4).
The major clinical manifestations are impaired left ventricular systolic and diastolic function, systemic embolism, ventricular tachyarrhythmias, conduction disorders, and neurological abnormalities (5,6).Systolic dysfunction is most probably the result of relative ischemia of the myocardium due to mismatch of myocardial oxygen supply and demand (5).Mechanisms implicated in the diastolic dysfunction include a combination of abnormal ventricular relaxation and restriction to ventricular fi lling secondary to the prominence of intracavitary trabeculations (5).The age at onset of heart failure is variable.It ranges from infancy to old age, possibly because of variable degree of myocardial trabeculations and the effects of chronic myocardial ischemia.Various patterns of arrhythmias, ranging from atrial fi brillation to sustained ventricular tachycardia, can be observed.When the series of adult patients is com pared with the pediatric series ( 7), the most important differences are the lack of facial dysmorphism and Wolff-Parkinson-White syndrome in the adult population.This may be due to a different genetic background but with the same morphological appearance of the cardiac anomaly.
Recent epidemiological studies or single-center experience showed that IVNC was responsible for 9.2-9.5% of cardiomyopathies diagnosed in children (6,8).In the largest series of adult patients with IVNC (4), the prevalence was 0.014% in patients referred to the echocardiography laboratory.The true prevalence of IVNC in adults remains unclear.
IVNC is a genetically heterogeneous disorder.Neonatal IVNC can be a disease caused by mutations in the G 4.5 gene located on the X chromosome, associated with Barth syndrome (9), other X-linked infantile cardiomyopathies, and X-linked endocardial fi broelastosis.Adult forms of IVNC are genetically distinct from X-linked infantile cases and suggest to be transmitted by an autosomal dominant trait (10).Because of generally poor prognosis and because of the familial association of IVNC, fi rstdegree relatives should be screened by echocardiography.
Prominent left ventricular trabeculation can be found in healthy hearts as well as in hypertrophic cardiomyopathy and in LVH secondary to dilated, valvular, or hypertensive cardiomyopathy.Thus, the differentiation between variants and IVNC may often be challenging (3).IVNC should be differentiated from normal heart with prominent left ventricular trabeculations (the normal variants have up to 3 trabeculations) (11), apical hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia, endocardial fi broelastosis, cardiac metastases, left ventricular thrombus (12).Echocardiography is considered the reference standard for the diagnosis of IVNC.Diagnostic echocardiographic criteria for isolated noncompaction of the myocardium (13) are listed below: 1. Absence of coexisting cardiac abnormalities (other than 2-4) by defi nition.2. Typical two-layered structure of the myocardium with a thin, compacted outer (epicardial) band and a much thicker, noncompacted inner (endocardial) layer consisting of trabecular meshwork with deep endocardial spaces (the maximum endsystolic ratio of the noncompacted endocardial layer to the compacted myocardium of >2 is characteristic).3. Predominant segmental location of the abnormality (that is, noncompacted myocardium is predominantly (>80%) found in the apical and midventricular areas of both the inferior and the lateral wall.4. Color Doppler echocardiographic evidence of deeply perfused intertrabecular recesses (in contrast to myocardial sinusoids, intertrabecular spaces do not communicate with the coronary circulation).
Transesophageal echocardiography and contrast echocardiography may be helpful when the quality of standard echocardiographic image is limited or the diagnosis is questionable.
Although ultrafast CT provides high-resolution imaging of noncompacted myocardium, CT, unlike CMR, has not been widely used in the diagnosis of IVNC and will perhaps not be used in the future.Clear diagnostic criteria for IVNC have not been established in CT (13).
Currently, several echocardiographic defi nitions of IVNC exist, and up to now, attempts were made to determine specifi c magnetic resonance criteria of IVNC.One study reported that the ratio of noncompacted to compacted myocardium of >2.3 in diastole in the 17-segment model accurately distinguishes pathological noncompaction from the degrees of noncompaction observed in healthy, dilated, and hypertrophied hearts (1).The CMR measurements are taken in diastole, perhaps because the presence of deep recesses fi lled with blood, and trabeculations of the myocardium are evident during diastole, whereas during systole, the recesses collapse and the myocardium appears to be compacted.
The pathological anatomical examination usually confi rms the localization of the noncompacted my-ocardium corresponding to the echocardiographic recordings.Histological examination confi rms that the recesses are covered by ventricular endocardium in continuity with the left ventricular cavity (3).No specifi c histological fi nding has been described in IVNC, although increased subendocardial fi brosis and endocardial fi broelastosis were found in IVNC cases (13).
The prognosis of IVNC is quite poor.During the six-year follow-up of patients in the study by Ritter and colleagues ( 14), 8 of the 17 patients died and 2 underwent heart transplantation.In the larger series of patients ( 4), long-term follow-up (44±39 months) showed that 35% of patients died, half of them because of sudden cardiac death, and 12% (four patients) had undergone heart transplantation.The high incidence of both thromboembolic events (24%) and ventricular tachycardia (41%) in that series underscores the poor clinical prognosis for patients with impaired left ventricular function.
Management of patients with IVNC includes an appropriate treatment for heart failure, management of arrhythmias and oral anticoagulation to prevent systemic emboli in patients with simultaneous atrial fi brillation or severe left ventricular dysfunction.Implantation of an internal cardioverter defi brillator system and early listing of symptomatic patients for heart transplantation have to be seriously considered.In particular, patients with a high-risk clinical constellation for nonsurvivors (higher left ventricular end-diastolic diameter at the time of initial presentation, New York Heart Association class III/IV, chronic atrial fi brillation, and bundle branch block) should be chosen for an early, more aggressive strategy.If standard drug treatment for heart failure is unsuccessful, emergency cardiac transplantation is ultimately the only therapeutic possibility.Due to thromboembolic events and prominent trabeculations of the left ventricle, using left ventricle assist devices as the bridge to transplantation could be dangerous in this group of patients.Until 2008, only 9 cases of IVNC leading to cardiac transplantation have been published to date (15).
In conclusion, the present case suggests that diagnosis of IVNC is often challenging and delayed.Multimodality imaging helps in most cases to establish proper diagnosis.Cardiac transplantation is the best solution for those patients who have refractory congestive heart failure due to IVNC.

Fig. 1 .
Fig. 1.Echocardiographic two-dimensional (left ) and three-dimensional (right) short axis views of the left ventricle at the levels of papillary muscles (top) and apex (bottom) show prominent trabeculation with deep intertrabecular recesses and thrombus (arrow) in the apical region of the left ventricle

Fig. 2 .
Fig. 2. Echocardiographic two-dimensional (A) and three-dimensional (B) four-chamber views Th ree intertrabecular thrombi (arrows) are seen in the apex of the left ventricle.

Fig. 3 .
Fig. 3. Electrocardiographically gated cardiovascular magnetic resonance images A, TrueFisp short axis image in end-diastole at the midventricular level shows excessive trabecularization of anterior, lateral, and inferior left ventricular walls; B, TrueFisp end-diastolic short axis image more apical to A revealing the end-diastolic ratio of noncompacted to compacted myocardium of 2.4.

Fig. 4 .
Fig. 4. Nongated contrast-enhanced chest computed tomography images A, reformatted short axis image at the midventricular level shows hypertrabecularization of anterior, lateral, and inferior left ventricular wall; B, abnormal left ventricular apex and anterolateral wall depicted in reformatted four-chamber view; C and D images confi rm thrombi in the apical region of the left ventricle seen on echocardiography (arrowheads).

Fig. 5 .
Fig. 5. Macroscopic specimen of native heart A, prominent trabeculations and intertrabecular recesses at the left ventricular walls, thickened noncompacted myocardial layer as compared to compacted myocardial layer, thrombus (arrow) in the left ventricle; B, multiple thrombi in heart chambers.