Valvular heart complications in children with osteogenesis imperfecta

doi:10.21203/rs.3.rs-1602896/v1

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Valvular heart complications in children with osteogenesis imperfecta

https://doi.org/10.21203/rs.3.rs-1602896/v1

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Purpose: The aim of this study was to determine the cardiovascular function and prevalence of valvular diseases in children with osteogenesis imperfecta (OI).

Methods: Twenty-eight OI children (mean age: 9.9±6.0 years) underwent echocardiography. Heart function, heart dimensions, and valvular complications were assessed calculating standard deviation (SD) scores referring to body surface area, and compared retrospectively in clinical types according to Sillence’s classification and with height SD scores.

Results: Of the 28 OI children, 17 (61%) were complicated with valvular diseases. The mean height SD scores was lower in more severe clinical types (p<0.01). Tricuspid regurgitation was detected in 54%, mitral regurgitation occurred in 21%, and aortic regurgitation was observed in 4% of the patients. Any valvular disease was detected in 86% (6/7), 46% (5/11), and 60% (6/10) of the patients with OI type 1, 4, and 3, respectively. A negative correlation was detected between aortic root diameters and height SD scores (r=-0.55). Interventricular septum (IVS) thicknesses were within ±2 SD in all cases, but those in 79% of the patients were indicated above the mean value of normal population. The mean IVS SD scores was +0.62±0.72. All measured values, including ventricular diastolic dimensions and ejection fraction, were within normal range and not different between the clinical types.

Conclusions: Valvular dysfunction is a frequent complication of OI patients, even in childhood. Aortic root enlargement and hypertrophic IVS appeared to be negatively impacted by the disease. Thus, careful echocardiographic follow-up during childhood, especially for patients with severe short stature, should be performed.

osteogenesis imperfecta

children

valvular disease

hypertrophic interventricular septum

aortic root enlargement

short stature

Osteogenesis imperfecta (OI) is an inherited disorder of the systemic connective tissue associated with bone fragility caused mainly by mutations in the COL1A1 [MIM*120150] and COL1A2 [MIM*120160] genes, which encode type I collagen alfa chains [1]. The prevalence of OI at birth is 21.8 per 100,000 and the population prevalence is 10.6 per 100,000 [2]. The main symptoms of OI patients are recurrent fractures, blue sclera, dentinogenesis imperfecta, scoliosis, and short stature. In adulthood, heart failure and deafness are profound problems. OI is classified clinically by Sillence’s classification (originally in 1979, updated in 2014) based on the clinical severity as follows: Type 1 (non-deformed) [MIM#166200], Type 2 (perinatal lethal) [MIM#166210], Type 3 (progressive deformity) [MIM#259420], Type 4 (moderate) [MIM#166220], and Type 5, (interosseous calcification and hyperplastic pseudostrils) [MIM#610967] [3, 4].

Although the skeletal phenotype of OI is well understood, less is known about other complications including cardiovascular changes. However, all-cause mortality in OI patients was almost three times higher than that in an age- and sex-matched target population, and frequently reported cause of death was cardiovascular disease [5]. Although some cardiovascular studies in OI adults were reported, there have been a few reports on cardiovascular complications in pediatric patients with OI and no consensus on their management. In the present study, we analyzed the cardiac function and prevalence of valvular heart disease focusing on OI children.

The aim of this study was to determine the cardiovascular function and prevalence of valvular diseases in OI children. This was a single center retrospective study conducted from January 2018 to December 2019.

Multiple comparison analysis of variance (ANOVA) was used to compare the three clinical types with ordering types 1, 4, and 3 by severity with reference to Sillence’s classification. A p-value <0.05 was considered statistically significant. Pearson’s correlation coefficient (r) value was calculated to determine whether heart dimensions correlated with height SD scores, and an r-value >0.2 was considered to show statistical correlation. All statistical analyses were performed using SPSS software V23.0 (IBM, Japan, Tokyo).

PATIENTS’ MEDICAL REPORTS

Twenty-eight OI children under 20 years of age, out of 50 OI patients, followed in our hospital during the study period, were included. All included patients were diagnosed genetically with mutations in COL1A1 or COL1A2 genes. Their height and body weight were measured, and standard deviation (SD) scores for height were calculated based on Japanese standard growth curves.

Patients were grouped into three clinical types with ordering types 1, 4, and 3 by severity with reference to Sillence’s classification (Table 1). Seventeen patients were male and 11 were female, ranging in age from 2 to 19 years (mean: 9.9±6.0 years). Seven patients were classified clinically as type 1, 11 patients were type 4, and 10 patients were type 3. Although there were no differences in age and weight, the mean height SD scores was different between the three clinical types (p<0.01) and reflected the severity of the disease.

All patients underwent two-dimension, M-mode, and Doppler echocardiography using a Philips ie33 system (Philips Medical Systems, Andover, MA). Heart function, heart dimensions, and valvular complications were assessed based on the standards recommended by the American Society of Echocardiography guidelines [6]. Left ventricular diastolic dimensions (LVD), left ventricular ejection fraction (LVEF), right ventricular diastolic dimensions (RVD), thickness of the interventricular septum (IVS), and aortic root diameter were measured. The aortic root diameter was measured at the end of the diastole in a parasternal long-axis view at the sinuses of Valsalva levels. All these measurements were evaluated by calculating SD scores for body surface area according to a previous report [7].

Valvular complications

Valvular complications were analyzed by echocardiography in the three clinical types with ordering types 1, 4, and 3 by severity with reference to Sillence’s classification (Table 2). Of the 28 patients with OI, 17 (61%) were complicated with valvular diseases. For each clinical type, any valvular disease was detected in 6/7 patients (86%) of OI type 1, 5/11 patients (46%) of OI type 4, and 6/10 patients (60%) of OI type 3.

Tricuspid regurgitation (TR) was detected in 15/28 patients (54%). Ten cases with TR were mild and 5 cases were moderate. Mitral regurgitation (MR) occurred in 6/28 patients (21%) and aortic regurgitation (AR) was observed in 1 case (4%). None of the 28 cases of OI was complicated with aortic stenosis. No patients required medical therapy or surgery for cardiovascular disease.

Heart functions

LVD were within ± 2 SD in all cases. The mean LVD SD scores were + 0.49 ± 0.58 for OI type 1, + 0.19 ± 0.61 for OI type 4, and + 0.24 ± 0.67 for OI type 3, and they were not significantly different between the three clinical types (p = 0.67) (Fig. 1a). LVD SD scores were not correlated with height SD scores (r = 0.19) (Fig. 1b).

LVEF was not decreased in any cases. The mean LVEF was 84.2 ± 4.9%, 81.5 ± 6.3%, and 77.3 ± 6.6% for OI types 1, 4, and 3, respectively. The mean LVEF was not different between the three clinical types (p = 0.08) (Fig. 1c), but there was a weak correlation between LVEF and height SD scores (r = 0.25) (Fig. 1d).

RVDs were within ± 2 SD in all cases. The mean RVD SD scores were + 0.62 ± 0.39, + 0.61 ± 0.75, and + 0.73 ± 0.57 for OI types 1, 4, and 3, respectively. The mean RVD SD scores were not different between the three clinical types (p = 0.90) (Fig. 1e), and did not correlate with the height SD scores (r = 0.08) (Fig. 1f).

Heart dimensions

IVS thicknesses were within ± 2 SD in all cases, but those in 79% (22/28) of the patients were indicated above the mean value of normal population. The mean IVS SD scores of all 28 patients were + 0.62 ± 0.72. The mean IVS SD scores were + 0.97 ± 0.90, + 0.62 ± 0.42, and + 0.36 ± 0.79 for OI types 1, 4, and 3, respectively, and were not different between the three clinical types (p = 0.22) (Fig. 2a). There was a weak positive correlation between IVS thickness SD scores and height SD scores (r = 0.30) (Fig. 2b).

In four cases (two cases with type 3 and two cases with type 4), aortic root diameter exceeded + 2 SD, but no AR was observed in any of the four cases. The mean aortic root diameter SD scores were + 0.32 ± 0.90, + 1.09 ± 0.95, and + 1.43 ± 0.93 for OI types 1, 4, and 3, respectively. There was no significant difference in aortic root diameter SD scores between the three clinical types (p = 0.07) (Fig. 2c). However, a negative correlation was found between the aortic root diameter SD score and height SD scores (r=-0.55) (Fig. 2d).

In the present study, we evaluated heart complications in OI children and revealed that over half of the patients had valvular complications. We also found that OI children frequently had relative hypertrophic IVS and aortic root enlargement indicating potential heart failure in adulthood.

The incidence of valvular disease in OI children was 61% in our study, which is obviously higher compared with that in healthy children. The reported incidences of TR and MR in OI adults were 67.4% and 3.4–26.1%, respectively [8–10]. This study focused on OI children, and we found the frequencies of TR and MR in these cases were 54% and 21%, respectively. Therefore, TR and MR might occur in OI children at the high frequency as in adult OI patients. These incidences are expected to be much higher than those in healthy adults, because the complication rate of MR was 4–8% in the general population [11, 12]. However, AR was observed in 1 of 28 cases (4%) in this study, although 6.5–10.1% of adult OI patients were complicated with AR [8, 13]. Dysfunction of aortic valve in OI patients may be developed with age because the incidence of AR was reported to be increased with age in the general adult population [14].

Although IVS thickness SD score in each patient was within normal range, the mean value tended to be high referring to normal population. This result was consistent with a previous report describing that IVSs in OI patients were enlarged comparing to normal population [15]. Interestingly, the thickness of IVS showed a weak positive correlation with height SD scores in this study. This looked suggesting that the IVS thickness of OI children with severe short stature was close to normal value. However, LVEF was also weakly correlated with height SD scores in our data, and IVS is generally thinned by volume loading [16]. Thus our data may imply that hypertrophic IVS was existent in OI children with any severity, and that the IVS in OI children with severe phenotype was thinned to near normal values by slight volume overloading.

We demonstrated that 4 patients had enlarged aortic root diameter, over + 2 SD. Additionally, there was a negative correlation between aortic root diameter SD scores and height SD scores in this study. These data suggest that aortic root enlargement might be detected frequently in patients with a severe clinical phenotype, which is consistent with previous reports. An enlarged aortic root was reported in 12% of adult patients with type 1 OI, and 28% of pediatric patients with type 3 OI [9, 10]. Our study showed that the aortic root diameter in patient with AR was within the normal range. In addition, aortic root enlargement was observed in 4/28 patients (14%) although none of them had AR. In Marfan syndrome, a connective tissue disease similar to OI, aortic root enlargement was reported to lead to AR and chronic heart failure [17, 18]. Therefore, the careful follow-up for cardiovascular complications in OI patients is essential, even in childhood. Furthermore, height SD scores might be a good indicator of heart complications because the classification of clinical types is sometimes ambiguous.

Because AR and IVS thickness might not be associated with aortic root enlargement and volume loading, respectively, it was suggested that structural defects in type I procollagen in OI may be a more important factor for valve regurgitation and wall formation. This idea is supported by previous reports [19–22]. Type I collagen was reported as an important component of various parts of the cardiovascular system including heart valves, tendon cords, fiber rings, ventricular septum, aorta, and most other arteries [19, 20]. Approximately 74% of the collagen content of the mitral valve is type I collagen [21], whereas the aorta and other arteries are rich in type III and type I collagen [20]. The collagen fibers in the ventricular myocardium maintain tensile stiffness and cardiomyocyte structure [22]. Therefore, considering our clinical data together, valvular heart complications in OI children should be caused by inherited defects of type I collagen.

In conclusion, this study demonstrated that valvular dysfunction is a frequent complication of OI patients, even in childhood. Relative hypertrophic IVS and aortic root enlargement appeared to be negatively impacted by the disease. Although left and right ventricular functions were not impaired in OI children, hypertrophic IVS were tended to be thinned by mild volume overloading. Thus, careful clinical follow-up on heart function including valvular heart disease using echocardiography during childhood, especially for patients with severe short stature, should be performed independently of clinical classification.

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.

Conflicts of interest: Not applicable.

Availability of data and material: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Code availability: Not applicable.

Authors' contributions: Masafumi Izui performed and evaluated echocardiography, Daisuke Harada and Kaoru Ueyama managed patients as pediatric endocrinologists, and Hiroko Kashiwagi performed genetic counseling as a medical geneticist. Kyoko Oriyama, Yoshihito Isiura, Hiroyuki Yamada, and Yoshiki Seino were involved in the clinical management of the patients. Masafumi Izui and Daisuke Harada wrote the paper. All the authors reviewed and discussed the data and the manuscript.

Ethics approval: This study was approved by the Medical Ethic Committee of JCHO Osaka Hospital (ID: 2021-062). All procedures performed in this study involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate: This study was an observational study by clinical chart review without any interventions and we disclosed the details of research information on our website providing an opportunity for patients and their patients to opt-out.

Consent for publish: Not applicable.

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Table1 Characteristics of study population　

OI (total n=28)

OI type 1 (n=7)

OI type 4 (n=11)

OI type 3 (n=10)

ANOVA

Mean±SD

Range

Mean±SD

Range

Mean±SD

Range

Gender (F/M)

11/17

1/6

3/8

7/3

Age (years)

9.9±6.0

12.1±4.9

6~19

9.1±6.6

2~18

9.1±6.1

2~19

0.52

Height (cm)

114.0±32.1

143.1±27.2

118.7~179.8

112.3±27.5

78.7~158.5

94.0±21.6

73.4~141.5

<0.01

Height SD scores

-3.38±3.24

-0.36±1.82

-2.59~+1.82

-2.44±1.33

-5.76~-1.12

-6.52±2.85

-3.23~-11.23

<0.01

Weight (kg)

26.9±20.3

40.0±24.0

18.7~69.9

24.8±16.9

9.8~54.3

29.0±17.9

8.4~67.0

0.10

OI, osteogenesis imperfecta; ANOVA, analysis of variance; SD, standard deviation; F, female; M, male

Table2 Valvular complications in the OI children
	total OI (n=28)	OI type 1 (n=7)	OI type 4 (n=11)	OI type 3 (n=10)
	n (%)	n (%)	n (%)	n (%)
Tricuspid valve regurgitation	15 (53.6)	5 (71.4)	4 (36.4)	6 (60.0)
Mitral valve regurgitation	6 (21.4)	2 (28.6)	2 (18.2)	2 (20.0)
Aortic valve regurgitation	1 (3.6)	0 (0)	0 (0)	1 (10.0)
Incidence of valvular complication	17 (60.7)	6 (85.7)	5 (45.5)	6 (60.0)
OI, osteogenesis imperfecta

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Valvular heart complications in children with osteogenesis imperfecta

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