Identification of myocardial disarray in patients with hypertrophic cardiomyopathy and ventricular arrhythmias

BACKGROUND

Myocardial disarray is a likely focus for fatal arrhythmia in hypertrophic cardiomyopathy (HCM). This microstructural abnormality can be inferred by mapping the preferential diffusion of water along cardiac muscle fibres using diffusion tensor cardiac magnetic resonance (DT-CMR) imaging. Fractional anisotropy (FA) quantifies directionality of diffusion in 3 dimensions, ranging from 0 -random diffusion- to 1 -single linear direction-. The authors hypothesized that FA would be reduced in HCM due to disarray and fibrosis that may represent the anatomic substrate for ventricular arrhythmia. Late gadolinium enhancement (LGE) correlates with myocardial fibrosis but not with disarray, allowing to separate the fibrosis component of FA and providing an in vivo measure of disarray.

OBJECTIVES

This study sought to assess FA as a non-invasive in vivo biomarker of HCM myoarchitecture and its association with ventricular arrhythmia.

METHODS

A total of 50 HCM patients (47 ± 15 years of age, 77% male) and 30 healthy age- and sex-matched control subjects (46 ± 16 years of age, 70% male) underwent DT-CMR in diastole, cine, LGE, and extracellular volume (ECV) imaging at 3-T. Ventricular arrhythmias were defined as ≥3 consecutive ventricular beats of ≥120 bpm/min detected previously or during follow up with a 24-hour Holter monitor.

RESULTS

Most of the HCM patients were in NYHA class I (76%), 30% had non-sustained ventricular tachycardia (NSVT) captured on 24-hour Holter monitor and 8% received an implantable cardioverter defibrillator.

On DT-CMR, diastolic FA was reduced in HCM compared with control subjects (0.49 ± 0.05 vs. 0.52 ± 0.03; p = 0.0005). Control subjects had a mid-wall ring of high FA. In HCM patients this ring was disrupted by reduced FA, consistent with published histology demonstrating that disarray and fibrosis invade circumferentially aligned mid-wall myocytes. LGE and ECV were significant predictors of FA, in line with fibrosis contributing to low FA. Yet FA adjusted for LGE and ECV remained reduced in HCM (p = 0.028).

FA in the hypertrophied segment was reduced in HCM patients with ventricular arrhythmia compared to patients without (n = 15; 0.41 ± 0.03 vs. 0.46 ± 0.06; p = 0.007). A decrease in FA of 0.05 increased odds of ventricular arrhythmia by 2.5 (95% confidence interval: 1.2 to 5.3; p = 0.015) in HCM and remained significant even after correcting for LGE, ECV, and wall thickness (p = 0.036).

CONCLUSIONS

DT-CMR assessment of left ventricular myoarchitecture matched patterns reported previously on histology. Low diastolic FA in HCM was associated with ventricular arrhythmia and is likely to represent disarray after accounting for fibrosis. The authors propose that diastolic FA could be the first in vivo marker of disarray in HCM and a potential independent risk factor.

COMMENT

In 1958, Donald Tear, a British forensic pathologist, described 9 cases of sudden cardiac death in young people. He was surprised by the asymmetrical distribution of the left ventricular hypertrophy and the microscopic appearance of the myocardium. Indeed, the thickened areas of the myocardium showed a “very bizarre arrangements of muscle bundles”, myocardial fibre disarray and significant amounts of interstitial fibrosis (1). Time has shown that myocardial disarray is not a pathognomonic finding of hypertrophic cardiomyopathy (HCM) and small foci of disarray may also be found in normal hearts and other hypertrophied conditions (2). Myocardial disarray is, however, always present in hypertrophic cardiomyopathy and occurs beyond the areas of junction between the left and the right hearts (3). 

Hypertrophic cardiomyopathy (HCM) is the most frequent of the cardiomyopathies with a prevalence of 1:200-1:500 (4). In up to 60% of the adult cases is due to an inherited monogenic disorder due to mutations in genes encoding the sarcomeric proteins (5). Morphologically, is typically characterised by unexplained left ventricular hypertrophy and histologically, by myocyte disarray, fibrosis and abnormalities in the intramyocardial vessels (6). In vivo, the diagnosis is based on the demonstration of unexplained left ventricular hypertrophy. The presence of focal myocardial fibrosis can be studied with cardiac magnetic resonance (CMR) by the detection of interstitial myocardial expansion with gadolinium-based contrasts agents. The presence of late gadolinium enhancement is rare in non-thickened areas of the myocardium (5).

Multiple risk factors have been identified in the search of predictors for fatal ventricular arrhythmias and sudden cardiac death in hypertrophic cardiomyopathy. The ESC risk predictor model includes well established risk factors as age, unexplained syncope, family history of sudden cardiac death (SCD), maximal wall thickness, left atrial size, non-sustained ventricular tachycardia and left ventricular outflow tract obstruction (5). Data on late gadolinium enhancement (LGE) has shown promising added value in disease severity characterization and relation with sudden cardiac death (7).

The heterogeneous behaviour of the condition still remains not completely understood.  The wide group of patients with HCM and a low/medium risk profile presenting with malignant arrhythmias warrants a more personalised approach for the substrate of ventricular arrhythmias beyond current understanding. 

Studies have suggested that disarray occurs early in the HCM heart, that it is a primary problem followed by ischemia and that fibrosis could be a reactive and/or a later manifestation of the phenotype (8).  Myocardial disarray has also been related with increased SCD risk but has not been widely studied as it can only be evaluated post-mortem (9).

To date, there has been no in vivo technique to assess directly the myocardial disarray using non-invasive methods. The authors postulate that microstructural abnormalities in the myocardium can be inferred by mapping the diffusion of the water along the cardiac fibres with diffusion tensor cardiac magnetic resonance (DT-CMR) imaging. By quantifying the directionality of the diffusion in 3 dimensions and comparing their analysis of the fractional anisotropy (FA) with a group of healthy subjects, they proposed that diastolic FA could be the first in vivo marker of disarray in HCM.

In this study the presence of ventricular arrhythmias and its association with a low FA after adjusting by the marker of myocardial fibrosis, LGE and ECV is also explored. In this small cohort of patients, lower FA was associated with ventricular arrhythmias.

Only time and histological validation will allow us to conclude if diastolic FA is a true in vivo marker for disarray, but for time being is certainly a technique very much worth exploring in the whole spectrum of HCM patients.  The interplay of fibrosis, arrhythmias and the value of FA is, however, a more complex matter and whether disarray more than fibrosis contribute to ventricular arrhythmias in HCM is and will be a matter of future debate. 

The heterogeneity of HCM and the relative benign behaviour of the condition for the majority of the patients needs to be highlighted.

The interplay between genotype, phenotype and the histological features in vivo has not been characterised beyond the presence of fibrosis and microvascular ischemia. An in vivo marker of disarray will possibly offer a wide range of possibilities from diagnosis, disease progression, prognosis and therapeutic targets. 

In summary, this is an exciting article on a small cohort of middle age, mostly males, patients with HCM undergoing DT-CMR with major strengths. Future larger studies might bring better understanding of a multiphaceted disease by bringing closer in vivo “histological“ findings with the whole spectrum of the disease. The independent relationship between this potential surrogate marker of myocardial disarray and significant ventricular arrhythmias will need to be tested in larger cohorts and in a variety of LVH related conditions.