Non-compacted cardiomyopathy: clinical-echocardiographic study

Noncompaction of ventricular myocardium is recently included in the 2006 classsification of cardiomyopathies as a Genetic Cardiomyopathy [1, 2]. Ventricular noncompaction occurs because of a disorder of endomyocardial morphogenesis that results in a failure of trabecular compaction of the developing myocardium [3–5]. Ventricular noncompaction is often associated with other congenital cardiac malformations [6–8]. In adult patients one or more segments of the left ventricle, and sometimes both ventricles, are characterized by numerous sinusoids or trabeculae that are excessive in number and abnormal in prominence and by deep intratrabecular recesses covered by endothelium that exhibits continuity with ventricular endocardium. Two-dimensional echocardiography provides definition of typical anatomic features. Jenni et al.[9] established four morphologic criteria for echocardiographic diagnosis that allow accurate differentiation from other forms of left ventricular hypertrophy. On the basis of echocardiographic studies, the prevalence of ventricular noncompaction has been estimated at 0.05% in the general population [3, 10].

The aim of the present study was to describe the clinical and echocardiographic data of isolated and non-isolated ventricular noncompaction in adult patients from the Outpatient Clinic of the Instituto Nacional de Cardiología "Ignacio Chávez".

A total of 125,438 patients were studied in the period between May 2000 and August 2005 in our hospital and from these patients fifty-three had ventricular noncompaction. Patients were identified on their scheduled routine visits to the Outpatient Clinic and included 25 men and 28 women with an average age of 43.17 years (range 16 to 74 years). Isolated noncompacted cardiomyopathy was present in 39 (74%) and noncompacted cardiomyopathy associated with other congenital malformations of the heart in 14 (26%). All underwent complete clinical histories, 12 lead surface electrocardiogram and transthoracic M-mode, two-dimensional and Doppler echocardiograms. The clinical condition of each patient was noted until the end of the study or until the patient succumbed. Functional class was assessed according to the criteria of the New York Heart Association. Sudden death was defined as occurring within one hour of the patient's usual state of health or as unwitnessed death during sleep. Twenty-four hour electrocardiographic monitoring was performed on patients with histories of palpitations or cardiogenic syncope. Short runs of ventricular tachycardia were considered to be more than three premature ventricular contractions lasting up to 30 seconds. A ventricular run of more than 30 seconds was defined as sustained ventricular tachycardia [3, 11].

In the human embryo of Streeter's horizon [Streeter's horizons are stages of early human embryonic development, which establish criteria of external form and internal structure that characterize each group ("horizon")] XII appear trabeculated or sinusoidal pouches in both cardiac ventricles [13]. One is in the bulbis cordis (right ventricle) and the other in the primitive ventricle (left ventricle). The proliferation of the myocardial trabeculae covered with endothelium and a thin layer of cardiac gelatin diminishes the central lumen of the ventricles during their centrifugal growth. In horizon XVII [14, 15] the trabeculae have extended from the apical to the inlet portions, leaving only the outflow tracts smooth. Because of this the ventricles have a non-compacted spongy nature (Figure 6). The cardiac chambers undergo compaction as the trabeculae fuse with each other and with the ventricular walls. This process is very advanced in Streeter's horizon XVIII [14]. The first reported cases of ventricular noncompaction were associated with such congenital malformations as obstruction of the left and right ventricular outflow tracts, complex congenital malformations and coronary anomalies [16].

Isolated noncompaction of the ventricular myocardium was first reported by Chin in 1990 [17]. In these cases the sinusoids are open to the ventricular chamber but do not communicate with the coronary circulation. In adults familial recurrence ranges between 18% and 50% [18]; in our series familial recurrence was 30.2%.

Noncompacted myocardium can be considered an inherited congenital alformation since the genes responsible for its development have been identified on chromosome 11p15 [19] or as mutations of the gene 4.5 of chromosome Xq28, where other cardiomyopathies have been identified [20]. New mutations of gene 4.5 have been reported, and mutations of the alpha-distrobrevine gene have been found in patients with ventricular noncompaction associated with other congenital malformations of the heart [16]. Mutation of the FKBP12 gene produces ventricular septal defects, dilated cardiomyopathy and noncompacted cardiomyopathy [21]. The CSX gene has been implicated in the development of some cases of isolated noncompacted cardiomyopathy [22].

The clinical manifestations of noncompacted cardiomyopathy are variable. Patients may be asymptomatic or may demonstrate evidence of congestive heart failure, arrhythmias or systemic emboli [11, 21, 23, 24], as seen in our series.

The echocardiogram is the diagnostic procedure of choice, and diagnosis is based on established criteria [9]. Contrast-enhanced echocardiography has recently emerged as a noninvasive tool for better visualization of the endocardial blood-interface [25]. Its use in the diagnosis of ventricular noncompaction should be recommended, especially in sub-optimal studies, because allows a better delineation of the trabeculae and deep intratrabecular recesses, also the intertrabecular spaces filled by microbubbles is clearly observed.

However, diagnosis is sometimes overlooked or delayed because this disease is rare and not well-known [11]. This occurred in 79% of our patients, who were initially diagnosed with other conditions. In our institution the prevalence of noncompacted cardiomyopathy was 4/10,000/5years. While 77% of our patients were in functional class I/II, the remaining 33% manifested frank congestive heart failure. Ventricular arrhythmias (premature ventricular contractions and short runs of ventricular tachycardia) were documented in more than a third of the patients. Precordial pain, syncope and cerebral embolism also occurred less frequently.

Ventricular noncompaction involving three or more segments was found in 80% of the cases. Left ventricular apical, inferior and lateral walls were predominantly affected. Ventricular noncompaction was initially reported only in middle and apical portions of the left ventricle. However, in a minority of patients it also affected basal segments. A finding relevant to our series is that patients with a noncompacted:compacted ratio greater than 3 and ventricular noncompaction in three or more segments are in functional class III/IV rather than functional class I/II. For patients in functional class III/IV with ventricular arrhythmia and noncompaction of three or more segments, probability of survival to 9 months was 75%. Probability of survival to 15 months in these patients was 48% (Figure 7).

In 26% of our patients noncompacted cardiomyopathy was associated with other congenital malformations of the heart, some of which have been reported previously [6–8], while others such as Uhl's anomaly, atrial septal defects and right ventricular double outlet, have not been described in association with ventricular noncompaction.

Noncompacted ventricular myocardium typically involves one or more segments of the left ventricle. The right ventricular apex is often intensely trabecular, which makes it difficult to distinguish normal and pathologic patterns. However, prominent trabeculae and hypokinesis of right ventricular wall accompanied by left ventricular noncompaction permits diagnosis of right ventricular involvement [6]. In Ritter's series of noncompacted cardiomyopathy, the right ventricle was affected in 41% of patients with concomitant left ventricular noncompaction [3]. We found noncompaction of both ventricles in 38% of the patients in our series.

On the basis of our findings we may conclude that:

a) Noncompacted cardiomyopathy is a congenital malformation that can occur as an isolated entity or associated with other pathologies of the heart and can often involve both ventricles.

b) A ratio of noncompacted:compacted wall greater than 3 and involvement of three or more segments are signs of poor prognosis associated with greater clinical deterioration (functional class III/IV) and ventricular arrhythmias.

c) Inasmuch as the clinical picture does not provide sufficiently specific evidence to establish the diagnosis, the echocardiogram is the diagnostic cornerstone. It makes it possible to document noncompacted ventricular myocardium and to identify the factors of poor prognosis.