Background
Before the fifth week of intrauterine life, the myocardium forms a loose network of fibers and sinusoids which are in continuity with the ventricular cavity. Subsequently, the meshwork of fibers becomes 'compacted' and the sinusoids disappear. Pathological arrest of this compaction process leads to the persistence of ventricular hypertrabeculation, so called spongy myocardium or left ventricular (LV) non-compaction (NC). [
1]
In both children and adults, NC is related to a cardiomyopathy which is hitherto unclassified. [
2] The childhood form of NC was first described in association with other congenital abnormalities, such as cyanotic congenital heart disease, coronary artery anomalies and both right and LV outflow tract obstruction. [
3‐
5] Furthermore, it may be associated with neuromuscular abnormalities. In 1990, Chin et al described a group of 8 patients with NC which was not associated with other congenital cardiac abnormalities. [
6] Whilst some reports indicate that NC is a rare condition with a poor prognosis, [
3,
7,
8] others suggest that it is more common and that its prognosis is better than expected[
9]Application of the current diagnostic criteria may identify a significant pool of patients who are asymptomatic. [
10] Although NC has generally been regarded as a familial cardiomyopathy, [
11] a family history of cardiomyopathy is not always present in adults [
7,
9] or children [
8] with the morphological characteristics of NC. Given that NC can be present in asymptomatic individuals, Murphy et al have hypothesised that the condition may have a long pre-clinical phase. [
9] Interestingly, there are anecdotal reports of cases of patients with phenotypic non-compaction which resolves with standard heart failure treatment. [
12]
Most studies have employed echocardiography for the identification of NC. [
3,
7,
9] Recently, however, an increasing number of case reports [
13‐
16] and series [
11] of patients with NC have demonstrated the superiority of cardiovascular magnetic resonance (CMR) over echocardiography in the assessment of NC. However, tere is only one report where the CMR findings were confirmed with direct visualisation of the myocardium. [
15] We report the clinical features and CMR findings of 42 patients who were consecutively identified as having morphological features of NC.
Discussion
We have shown that NC is associated with asymptomatic LVSD, heart failure dysrrhythmias, thromboembolic events and chest pain. Most patients in this study had abnormal ECGs and all had abnormal echocardiograms. Even patients who did not present with dyspnoea had higher LVEDVs than controls. It could be argued that these associations of NC are coincidental, as trabeculations are common even in normal hearts. [
19] The fact that these patients presented with either symptoms or significant abnormalities on ECG, echocardiography and/or CMR, however, does suggest that NC contributes to pathogenesis. Anatomical correlation of suspected cases of NC could improve the diagnostic utility of investigations.
There is little consensus on the diagnostic criteria of NC. With respect to clinical criteria, Petersen et al have stipulated that the typical appearances of NC on CMR have to be accompanied by NC in a first degree relative, a neuromuscular disorder or complications, such as systemic embolisation or regional wall motion abnormalities. [
11] Implicit in this approach, however, is the definition of NC
per se as a distinct familial cardiomyopathy, rather than a pathological phenomenon that can occur in the absence of a family history. In this respect, a family history of cardiomyopathy is not always present in adults [
7,
9] or children [
8] with NC. In the present study, no patient was found to have a family history of NC and only 11% had a family history of other cardiac conditions, such as dilated cardiomyopathy, sudden cardiac death or hypertrophic cardiomyopathy. Whilst our findings suggest that NC
per se is not necessarily familial, they raise the possibility of a genetic link between NC, dilated cardiomyopathy, sudden cardiac death and hypertrophic cardiomyopathy. Other studies have shown that familial NC encompasses abnormalities that overlap with those seen in families with dilated cardiomyopathy. [
9] Whether or not these two conditions are genetically linked or whether they share a common etiology remains unclear.
The extent of NC has also been adopted as a diagnostic criterion for NC. Several authors have stipulated diagnostic thresholds for NC using various measures of NC [
2,
6,
7,
11] Using either the x:y ratio proposed by Chin et al [
6] or the NC area on the two-chamber view, we have found no difference in the extent of NC between patients presenting with dyspnoea and those without. Interestingly, significant clinical problems occurred even in patients with mild degrees of NC. An example is patient #28, an 18 year old male with a history of multiple strokes, intermittent atrial fibrillation, an ejection fraction of 36%, a mild degree of NC and an otherwise structurally normal heart on both echocardiography and CMR.
In this study, 38% of patients with NC had a CMR-derived LVEF < 40%. These findings are consistent with other studies showing that adult NC is frequently associated with LVSD, with reports ranging from 63% to 82%. [
3,
6,
7,
9] In the whole study group, no correlation emerged between the x:y ratio or the NC area on the two-chamber view and LVEF. In patients who did not present with dyspnoea, however, there was an inverse correlation between NC area and LVEF, suggesting that disruption of myocardial architecture associated with NC [
15] contributes to LVSD, at least up to the point that the patient develops dypsnoea.
Some authors have underlined the tendency to interpret the appearance of NC on transthoracic echocardiography as concentric LVH, [
20] hypertrophic cardiomyopathy [
21] or an apical tumor. [
22] In this study, NC was suspected in 10% of transthoracic echocardiograms performed in referring centres. The majority had been reported as showing concentric LVH or LVSD. This supports the finding of other authors [
11,
20,
22] that CMR is superior to transthoracic echocardiography in detecting NC. The relatively low sensitivity of transthoracic echocardiography for detecting LVNC was not explored in this study.
The high incidence of symptomatic cases presented in this series is consistent with work from other tertiary referral centres. [
7,
9,
23] It is likely that the left ventricular impairment is responsible for a high proportion of the symptoms. The higher incidence of NC in males compared with females is difficult to interpret in this retrospective study, and is not statistically significant. It may reflect referral bias or possibly, a higher prevalence of NC in males.
All patients in our series had abnormalities of the resting ECG, including voltage signs of left ventricular hypertrophy, inverted T waves in the chest leads, ST segment depression, axis deviation and intraventricular conduction abnormalities. A left bundle branch block was observed in 33%. In one case, NC was associated with Wolf-Parkinson White syndrome, which has been reported in 15% of the childhood form of NC. [
8]
Arrhythmias occur frequently is association with NC. We, as others, [
3,
7] have found an association between NC and atrial fibrillation, which was the presenting problem in 29% of patients. Although the largest study of NC in children showed no association with ventricular tachycardia, [
8] other studies of adult NC found ventricular tachycardia in 20 to 40% patients. [
9,
6] No association with ventricular tachycardia was found in the present study, although screening with Holter monitoring was not undertaken.
Thromboembolic events have been reported in 21% to 38% of patients with NC. [
3,
6,
7] In this study, some patients suffered a stroke, pulmonary embolism or a peripheral embolism. These events may be attributable to atrial fibrillation, which was found in 2/4 of these patients. Alternatively, thromboembolic events may be due to thrombus formation within the intertrabecular recesses in NC myocardium. [
6]
Chest pain was the presenting symptoms in 19% of patients. Angiography revealed non-obstructive coronary heart disease in one patient and normal coronary arteries in 7 patients. In this respect, reduced coronary blood flow reserve [
24] and subendocardial perfusion defects [
25,
26] are known to occur in association with NC. These are thought to relate to failure of the coronary circulation to grow with the myocardial mass and/or compression of the intramural capillaries by hypertrophied myocardium. [
25] Severe hyperplasia of the vascular media [
15] may also be relevant. The possible link between NC, ischemia and chest pain, however, remains unexplored.
One of the limitations of this study is that the data presented are derived from opportunistic investigations, prompted by the clinical presentation and the results of other investigations. It is possible, therefore, that the prevalence of dysrhythmias, for example, is higher than that observed in this study. We have not undertaken family screening and we cannot, therefore, discount the presence of clinically occult NC in patients' relatives. The echocardiograms were not systematically re-studied after the CMR scan; however, this study suggests that CMR allows greater detection of NC.
A further limitation of the study is that some of the patients included in this study had been referred specifically from other centres for CMR. The majority of patients were seen at this centre, where CMR is a routine investigation. This study must be regarded as including a very selected group of patients, and as such this study may not be generalisable to all patients with NC.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
ZRY wrote the manuscript and organised data analysis. PF re-drafted manuscript. SC, HM, KK, NUHM were involved in analysis of the data. FL co-wrote manuscript. All author read and approved the final version of the manuscript.