Myocardial Strain Assessment by 2D Speckle-Tracking Echocardiography in Patients with Congenital Myopathy.

Background: Congenital myopathies (CMs) are a group of rare genetic muscle disorders. Cardiac involvement can be seen in these patients. We aimed to evaluate the myocardial strain parameters by 2D speckle-tracking echocardiography (STE) in patients with CM. Materials and
Methods: Twenty-four patients with CM whose diagnosis was confirmed by genetic analysis or muscle biopsy were included in the study, and 48 patients were involved as a control group. Left ventricular ejection fraction (LVEF%) was calculated by biplane Simpson method, and myocardial strain analysis was performed by 2D STE.
Results: The median age of the study population was 26 (19-35 interquartile range [IQR]) and 43 (60%) were women. In the analysis performed after the exclusion of two patients with multiminicore disease (MMD) who developed heart failure, although mild, LVEF% (62 [60-65 IQR] vs. 64 [63-66 IQR], P = 0.008) and right ventricular global longitudinal strain (RVGLS) were significantly lower in the CM group (-21.8 [-19.7, -24.9 IQR] vs. -23.9 [-22.4, -25.6 IQR], P = 0.0017). Left ventricular global longitudinal strain (LVGLS) was observed similarly in both groups (-19.9 [-18.7, -20.7 IQR] vs. -20.5 [-19.3, -21.9 IQR], P = 0.069). LVEF% (33 and 46), LVGLS (-7.5 and -10.7), and RVGLS (-14.9 and -16.1) values were low in two siblings with MMD.
Conclusion: Although LVEF% and RVGLS were significantly lower in the CM group, LVGLS was similar. The decrease in RVGLS and LVEF% was mild, and heart failure was not observed in any patient except MMD patients who were not included in the analysis. Copyright:

INTRODUCTION

Congenital myopathies (CMs) are a clinical, histopathological, and genetic heterogeneous group of rare inherited muscle diseases. Its prevalence is estimated at one in 26,000–28,000.[1] Although symptoms usually begin at birth or in infancy, an increasing number of cases are diagnosed where symptoms begin in adolescence or adulthood.[2] CMs are clinically characterized by hypotonia and weakness that usually begin from birth and progress slowly.[34] Diagnosis is made by family history, clinical and neurologic examination, nerve conduction studies and electromyography, laboratory, muscle biopsy, and genetic tests.[56] Data on the precise epidemiology of CMs are limited and mostly focused on five main pathological variants: core myopathies (central core disease [CCD] and multiminicore disease [MMD]), centronuclear myopathy(CNM), nemaline myopathy (NM), congenital fiber-type disproportion, and myosin storage myopathy.[5]

Cardiac involvement in myopathies may present as myocardial abnormalities, conduction abnormalities, and valve insufficiency.[7] Heart failure may occur due to dilated, hypertrophic, restrictive, or noncompaction cardiomyopathy along with various arrhythmias.[68] There are insufficient data on cardiac involvement in CM. In a study evaluating 130 patients with congenital myopathy, it was found that cardiac involvement was mild, and its prevalence was low in patients with classified and unclassified CM, except for some subgroups.[9] With the myocardial strain parameters measured by 2D speckle-tracking echocardiography (STE), significant changes can be detected in the heart even when conventional measurements are normal. STE can quantify myocardial strain and detect subclinical left ventricular dysfunction before the reduction in left ventricular ejection fraction (LVEF).[1011] There is no previous study evaluating myocardial strain parameters in patients with CM. This study aims to evaluate the myocardial strain parameters in patients with CM.

MATERIALS AND METHODS

For the study, the patients followed by the muscular diseases clinic were evaluated. Among 32 patients with preliminary CM diagnosis, 24 patients whose diagnosis was confirmed by biopsy and/or genetic test as CM were included in this study. As the control group, 48 patients who applied to the cardiology clinic with atypical complaints were included in the study. Only those with normal physical examination, electrocardiography, and conventional echocardiography results were included in the control group, and patients with any chronic disease or receiving treatment were not included in the control group. Laboratory parameters of the patients were taken from the electronic records of the hospital.

Echocardiographic analysis

All echocardiographic images were acquired using Vivid S70 systems (GE Healthcare, Horten, Norway) and transferred to the EchoPAC workstation. Three consecutive heart cycles were recorded and images were acquired at a frame rate of 60–80 frames/s. Biplane LVEF was calculated using the modified Simpson method. Left ventricular systolic dysfunction was defined as a biplane LVEF ≤50%. Two experienced cardiologists performed strain analysis by 2D STE according to guidelines from 2D grayscale images recorded using EchoPAC software.[12] Analyzes were performed for three apical (LV four-chamber, two-chamber, and three-chamber views) and three short-axis views (LV basal, mid, and apical views). The software automatically followed the boundaries of the LV myocardium; manual adjustments were made if necessary. After manual adjustments, the software calculated the strain values in each view. End systole was defined according to aortic valve closure in apical long-axis view. After processing all three apical views, a 17-segment bull's-eye view was created. The software automatically calculated left ventricular global longitudinal strain-transmural, endocardial, and epicardial values Left ventricular global longitudinal strain (LVGLS-trans, LVGLS-endo, and LVGLS-epi, respectively). Global circumferential strain (GCS) and global radial strain (GRS) were calculated as average strain values based on apical, mid-ventricular, and basal short-axis parasternal views. Right ventricular global longitudinal strain (RVGLS) and right ventricular free wall strain measurements were obtained from the apical four-chamber view. LVGLS layer strain analysis of a patient with multiminicore disease and a patient in the control group is shown in Figures 1 and 2.

Figure 1

Left ventricular global longitudinal layer strain analysis of a patient in the control group

Figure 2

Left ventricular global longitudinal layer strain analysis of a patient with multiminicore disease

This study was approved by the local institutional ethics committee. The study protocol conformed to the Declaration of Helsinki.

Statistical analysis

Continuous variables were presented as median and interquartile range 25%–75% (IQR) due to nonnormally distribution. Histogram and Shapiro–Wilk test were used to verify the normal distribution of the data. Categorical variables were expressed as percentages. Continuous variable comparison was made using the Mann–Whitney U-test. Categorical variables were compared using the Chi-square test or Fisher's exact test. In all statistical analyzes, a value of P < 0.05 is considered statistically significant. The data were analyzed using the IBM SPSS 24.0 software (SPSS Inc., Chicago, IL, USA).

RESULTS

A total of 72 patients were included in the study. The study population's median age was 26 (19–35 IQR), and 43 (60%) were women. With genetic analysis, nine patients were diagnosed with CNM, six patients with NM, and six patients with CCD. According to the biopsy results, two patients were diagnosed with MMD, and one patient was diagnosed with CNM. The most common gene was RYR1 and was seen in six patients. Since myocardial strain parameters of patients with normal LVEF% were examined, two MMD patients with heart failure were excluded from the analysis. The patients were divided into two groups as congenital myopathy group (n = 22) and the control group (n = 48). Creatinine and creatine kinase values were significantly different between the two groups (P = 0.001 and P < 0.001, respectively). The demographic laboratory and echocardiographic parameters of the patients are given in Table 1.

Table 1

Demographic, laboratory, and echocardiographic parameters of patients

	Total (n=70)	Congenital myopathy (n=22)	Control Group (n=48)	P
Age (year)	25 (19-35)	28 (21-40)	25 (19-35)	0.219
Gender (female), n (%)	40 (57)	15 (68)	28 (58)	0.316
Body surface area (m2)	1.73 (1.54-1.92)	1.70 (1.55-1.95)	1.72 (1.54-1.91)	0.945
BMI (kg/m2)	23.1 (21.1-25.4)	23.1 (21.4-27.9)	23.1 (20.9-25.2)	0.429
Creatinine (mg/dL)	0.70 (0.62-0.85)	0.62 (0.55-0.71)	0.79 (0.65-0.92)	0.001
Creatine kinase (U/L)	118 (87-217)	329 (151-770)	104 (72-123)	<0.001
Hemoglobin (gr/dL)	14.0 (13.0-15.7)	14.2 (13.4-15.3)	14.0 (12.8-16.0)	0.834
White blood cell (103/uL)	7.80 (6.35-9.25)	7.84 (6.47-9.18)	7.66 (6.23-9.33)	0.865
LV diastolic diameter (mm)	45 (42-48)	45 (41-47)	46 (42-48)	0,259
LV systolic diameter (mm)	27 (26-29)	27 (25-28)	27 (26-29)	0.628
Septum thickness (mm)	9 (8-10)	9 (8-10)	9 (8-10)	0.322
LV posterior wall thickness (mm)	9 (8-10)	9 (8-10)	9 (8-10)	0.780
LV diastolic volume index (mL/m2)	56 (50-61)	51 (48-61)	57 (52-62)	0.129
LV systolic volume index (mL/m2)	20 (18-22)	20 (17-24)	20 (18-22)	0.790
Biplane LVEF (%)	64 (62-66)	62 (60-65)	64 (63-66)	0.008
Apical four-chamber LS (%)	−19.8 (−18.8-−21.1)	−19.7 (−18.0-−20.7)	−19.9 (−18.9-−21.2)	0.362
Apical two-chamber LS (%)	−20.4 (−19.4-−22.1)	−19.8 (−18.4-−20.9)	−20.6 (−19.4-−22.6)	0.038
Apical three-chamber LS (%)	−20.0 (−18.8-−21.7)	−19.9 (−18.3-−20.6)	−20.3 (−18.9-−21.9)	0.068
LV GLS (%)	−20.2 (−19.2-−21.3)	−19.9 (−18.7-−20.7)	−20.5 (−19.3-−21.9)	0.069
LV GLS-endocardium (%)	−23.2 (−22.1-−24.4)	−22.5 (−21.7-−23.9)	−23.4 (−22.5-−25.0)	0.082
LV GLS-epicardium (%)	−17.6 (−16.6-−18.5)	−17.6 (−16.0-−18.3)	−17.6 (−16.8-−18.9)	0.164
Global circumferential strain (%)	−21.6 (−20.1-−22.5)	−21.4 (−19.1-−22.2)	−21.7 (−20.4-−22.9)	0.291
Global radial strain (%)	45 (39-49)	43 (39-48)	46 (40-49)	0.252
RVGLS total (%)	−23.6 (−21.2-−25.1)	−21.8 (−19.7-−24.9)	−23.9 (−22.4-−25.6)	0.017
RV free wall longitudinal strain (%)	−28.0 (−25.5-−30.1)	−27.1 (−23.4-−29.7)	−28.4 (−26.1-−30.2)	0.101
Heart rate (beat/min)	87 (76-94)	85 (75-98)	88 (78-94)	0.467

Continuous variables are presented given as mean±SD or median (IQR) and categorical variables were expressed as number (%). LV=Left ventricle, LVEF=LV ejection fraction, LS=Longitudinal strain, GLS=Global LS, RV=Right ventricle, BMI=Body mass index, IQR=İnterquartile range, SD=Standard deviation

LVEF% was observed to be significantly lower in the CM group (62 [60–65 IQR]) compared to the control group (64 [63–66 IQR], P = 0.008). The median LVGLS was −19.9 (−18.7, 20.7 IQR) in the CM group, whereas it was −20.5 (−19.3, −21.9 IQR) in the control group, and the difference between the two groups was not statistically significant (P = 0.069). RVGLS was significantly lower in the CM group (−21.8 [−19.7, −24.9 IQR]) than in the control group (−23.9 [−22.4, −25.6 IQR], P = 0.017). There was no significant difference between the two groups in terms of GCS and GRS. LVEF% (33 and 46), LVGLS (−7.5 and −10.7), RVGLS (−14.9 and −16.1), GCS (−9.3 and −10.7), and GRS (21 and 25) values were low in two siblings with MMD. The echocardiographic measurements of each patient are given in Table 2.

Table 2

Echocardiographic measurements of each patient with congenital myopathy

Total (n=24)	Age (years)	Sex	Gene	LVEF (%)	LV GLS	Four-CH GLS	Two-CH GLS	APLAX GLS	GCS	GRS	RVGLS
Patient 1 (centronuclear)	40	Female	DNM2	60	−19.9	−20.0	−19.7	−20.0	−24.0	48	−21.0
Patient 2 (centronuclear)	18	Male	DNM2	63	−20.6	−20.7	−21.1	−20.2	−21.5	49	−24.2
Patient 3 (centronuclear)	30	Male	DNM2	67	−20.9	−20.4	−20.2	−22.2	−22.5	52	−22.8
Patient 4 (centronuclear)	23	Male	DNM2	54	−17.5	−17.5	−18.5	−16.5	−22.0	40	−19.8
Patient 5 (centronuclear)	37	Female	DNM2	61	−18.6	−19.6	−17.8	−18.5	−19.1	39	−24.9
Patient 6 (centronuclear)	53	Female	BIN1	60	−15.5	−17.6	−14.6	−14.4	−19.3	46	−17.8
Patient 7 (centronuclear)	21	Female	BIN1	58	−18.3	−18.5	−18.2	−18.2	−24.0	42	−24.1
Patient 8 (centronuclear)	40	Female	-	65	−19.2	−19.5	−19.9	−18.2	−21.5	51	−25.2
Patient 9 (centronuclear)	56	Male	MYF6	61	−20.0	−20.3	−19.6	−20.1	−18.9	45	−20.6
Patient 10 (centronuclear)	23	Female	MTM1	60	−22.1	−23.4	−22.8	−20.2	−20.9	50	−21.3
Patient 11 (multiminicore)	38	Male	-	33	−7.5	−8.1	−7.3	−7.0	−9.3	21	−14.9
Patient 12 (multiminicore)	33	Male	-	46	−10.7	−11.0	−10.3	−10.8	−10.7	25	−16.1
Patient 13 (central core)	25	Female	RYR1	58	−16.0	−16.1	−15.8	−16.2	−17.50	37	−22.9
Patient 14 (central core)	22	Female	RYR1	62	−19.3	−17.6	−19.9	−18.8	−18.1	31	−18.5
Patient 15 (central core)	14	Female	RYR1	58	−19.0	−17.8	−18.2	−21.1	−22.1	34	−22.3
Patient 16 (central core)	41	Female	RYR1	68	−21.8	−22.0	−21.7	−21.6	−24.5	44	−26.3
Patient 17 (central core)	30	Female	RYR1	65	−21.4	−19.8	−24.0	−20.5	−23.0	44	−25.0
Patient 18 (central core)	19	Female	RYR1	62	−19.9	−20.1	−20.8	−18.7	−18.6	44	−20.9
Patient 19 (nemaline rod myopathy)	23	Male	ACTA1	64	−20.6	−21.3	−20.8	−19.7	−21.4	43	−27.7
Patient 20 (nemaline rod myopathy)	63	Female	TPM3	64	−20.3	−20.7	−20.1	−20.7	−19.0	33	−18.8
Patient 21 (nemaline rod myopathy)	37	Female	TPM3	64	−20.2	−22.8	−19.3	−18.4	−21.0	49	−20.2
Patient 22 (nemaline rod myopathy)	18	Female	TPM3	67	−18.7	−18.1	−19.1	−19.0	−21.9	39	−25.4
Patient 23 (nemaline rod myopathy)	21	Male	TPM3	65	−21.2	−19.5	−22.2	−22.0	−22.0	39	−19.3
Patient 24 (nemaline rod myopathy)	32	Male	TPM3	62	−19.7	−18.8	−19.4	−20.9	−20.5	45	−19.5

LV=Left ventricle, LVEF=LV ejection fraction, LS=Longitudinal strain, GLS=Global LS, GRS=Global radial strain, GCS=Global circumferential strain, RV=Right ventricle, CH=Chamber, APLAX=Apical long axis

DISCUSSION

The results of this study showed that LVEF% and RVGLS were significantly lower in the CM group compared to the control group, and LVGLS was similar in both groups. Except for two siblings with MMD who were excluded from the analysis, no heart failure was observed in the CM group.

CMs are a genetically heterogeneous group of early-onset neuromuscular diseases characterized by varying degrees of muscle weakness and different structural abnormalities in muscle biopsy. Initially, nemaline myopathy was considered the most common type, but emerging data indicate that the most common subgroup is CMs with core (CCD and MMD). RYR1 tends to be the most common gene in CMs, in particular CCD and MMD.[4] In our study, the most common gene was RYR1 gene, and it was noticed in six patients. Hypertrophic CMP, noncompaction CMP, dilated CMP, valve diseases, and various arrhythmias may occur in patients with congenital myopathy.[68] Although there are not enough studies on cardiac involvement in CMs, in a study by Petri et al., it was found that the prevalence of cardiac involvement was low and the involvement was generally mild in CMs.[9]

Myocardial strain calculated by STE is an advanced echocardiographic technique that enables measurement of myocardial deformation using a semiautomatic software initially developed for application to the left ventricle (LV) and then used for the evaluation of all cardiac chambers. STE provides additional information about cardiac function by an angle-independent segmental measurement of myocardial fibers’ movement throughout the cardiac cycle. It achieved early diagnosis of subclinical myocardial impairment even when conventional measurements such as LVEF were normal.[111314] Studies conducted in Duchenne muscular dystrophy patients revealed a decrease in global longitudinal strain parameters measured even when LVEF was normal, and clinical practice demonstrated that measuring strain parameters in muscle diseases where such cardiac involvement may occur will enable early detection of myocardial impairment.[1516] In our study, LVGLS was similar in both groups, but RVGLS values were significantly lower in the CM group compared to the control group. Although RVGLS and LVEF% values were low in the CM group, they were within the normal range. In muscle diseases including CM, an increase in creatine kinase may occur due to muscle damage.[17] In our study, creatine kinase was observed to be higher in the CM group. In patients with neuromuscular diseases, muscle mass diminishes and a corresponding decrease in creatinine levels can be observed.[18] In our study, the decrease in creatine in the CM group may be due to this.

The core myopathies (MMD and CCD) are the disorder derives its name from characteristic the histochemical appearance of pathologically reduced oxidative enzyme activity and myofibrillar changes in ultrastructural studies.[19] Although cardiac involvement is not common in these patients, heart failure can be seen in MMD disease with TTN and MHY-7 gene mutations.[92021] MHY-7 mutation was observed in a 44-year-old patient who was followed up with MMD, and EF was found to be 29%.[9] In our study, LVEF% (33 and 46), LVGLS (−7.5 and −10.7), RVGLS (−14.9 and −16.1), GCS (−9.3 and −10.7), and GRS (21 and 25) values were significantly lower in two siblings aged 33 and 39 years whose diagnosis of MMD disease was confirmed by muscle biopsy. This cardiac involvement in two siblings without genetic tests may be due to TTN or MHY-7 genetic mutation.

Considering both the results of our study and previous studies’ results, cardiac involvement is less frequent and mostly mild in patients with congenital myopathy, but MMD disease may have significant cardiac involvement, and these patients should be closely monitored for heart failure.

CONCLUSION

Although LVEF% and RVGLS were significantly lower in the CM group, LVGLS was similar. The decrease in RVGLS and LVEF% was mild, and heart failure was not observed in any patient except MMD patients who were not included in the analysis.

Limitation

The low number of patients is one of the most important limitations of the study, and this is because the disease is rare. The lack of genetic analysis of some patients is another limitation. GCS and GRS measurements are suboptimal, as parasternal short-axis views are insufficient in some patients due to chest deformity.

Ethical clearance

This study was approved by the local institutional ethics committee (date: 04.07.2019 and number: 320).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.