Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults

Gert J H Snel; Riemer H J A Slart; Birgitta K Velthuis; Maaike van den Boomen; Christopher T Nguyen; David E Sosnovik; Vincent M van Deursen; Rudi A J O Dierckx; Ronald J H Borra; Niek H J Prakken

doi:10.1371/journal.pone.0278308

. 2022 Dec 1;17(12):e0278308. doi: 10.1371/journal.pone.0278308

Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults

Gert J H Snel ^1,^*, Riemer H J A Slart ^2,³, Birgitta K Velthuis ⁴, Maaike van den Boomen ^1,^5,⁶, Christopher T Nguyen ^5,⁶, David E Sosnovik ^5,^6,⁷, Vincent M van Deursen ⁸, Rudi A J O Dierckx ², Ronald J H Borra ^1,², Niek H J Prakken ¹

Editor: Eduard Shantsila⁹

¹Department of Radiology, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

²Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

³Faculty of Science and Technology, Department of Biomedical Photonic Imaging, University of Twente, Enschede, The Netherlands

⁴Department of Radiology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands

⁵Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America

⁶Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America

⁷Division of Health Sciences and Technology, Harvard-MIT, Boston, MA, United States of America

⁸Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

⁹University of Liverpool, UNITED KINGDOM

Competing Interests: The authors have declared that no competing interests exist.

^✉

* E-mail: g.j.h.snel@umcg.nl

Roles

Gert J H Snel: Data curation, Formal analysis, Project administration, Writing – original draft

Riemer H J A Slart: Conceptualization, Supervision, Writing – review & editing

Birgitta K Velthuis: Conceptualization, Writing – review & editing

Maaike van den Boomen: Investigation, Software, Writing – review & editing

Christopher T Nguyen: Conceptualization, Writing – review & editing

David E Sosnovik: Conceptualization, Writing – review & editing

Vincent M van Deursen: Conceptualization, Writing – review & editing

Rudi A J O Dierckx: Funding acquisition, Resources, Writing – review & editing

Ronald J H Borra: Resources, Software, Supervision, Writing – review & editing

Niek H J Prakken: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft

Eduard Shantsila: Editor

PMCID: PMC9714856 PMID: 36454872

Abstract

In young adults, overweight and hypertension possibly already trigger cardiac remodeling as seen in mature adults, potentially overlapping non-ischemic cardiomyopathy findings. To this end, in young overweight and hypertensive adults, we aimed to investigate changes in left ventricular mass (LVM) and cardiac volumes, and the impact of different body scales for indexation. We also aimed to explore the presence of myocardial fibrosis, fat and edema, and changes in cellular mass with extracellular volume (ECV), T₁ and T₂ tissue characteristics. We prospectively recruited 126 asymptomatic subjects (51% male) aged 27–41 years for 3T cardiac magnetic resonance imaging: 40 controls, 40 overweight, 17 hypertensive and 29 hypertensive overweight. Myocyte mass was calculated as (100%–ECV) * height^2.7-indexed LVM. Absolute LVM was significantly increased in overweight, hypertensive and hypertensive overweight groups (104 ± 23, 109 ± 27, 112 ± 26 g) versus controls (87 ± 21 g), with similar volumes. Body surface area (BSA) indexation resulted in LVM normalization in overweights (48 ± 8 g/m²) versus controls (47 ± 9 g/m²), but not in hypertensives (55 ± 9 g/m²) and hypertensive overweights (52 ± 9 g/m²). BSA-indexation overly decreased volumes in overweight versus normal-weight (LV end-diastolic volume; 80 ± 14 versus 92 ± 13 ml/m²), where height^2.7-indexation did not. All risk groups had lower ECV (23 ± 2%, 23 ± 2%, 23 ± 3%) than controls (25 ± 2%) (P = 0.006, P = 0.113, P = 0.039), indicating increased myocyte mass (16.9 ± 2.7, 16.5 ± 2.3, 18.1 ± 3.5 versus 14.0 ± 2.9 g/m^2.7). Native T₁ values were similar. Lower T₂ values in the hypertensive overweight group related to heart rate. In conclusion, BSA-indexation masks hypertrophy and causes volume overcorrection in overweight subjects compared to controls, height^2.7-indexation therefore seems advisable.

Introduction

Western lifestyle is increasingly characterized by high fat and high sodium food intake combined with a sedentary daily routine, driving the worldwide pandemic of overweight (body mass index (BMI) ≥ 25 kg/m²) and obesity (BMI ≥ 30 kg/m²) [1]. Overweight, obesity and related hypertension are most prevalent in mature adults [2]. Over the last decades, however, especially young adults are gaining weight faster, increasing early-onset hypertension rates (i.e. onset at age below 55 years), and cardiovascular disease risk [3,4].

In young adults, sudden cardiac death (SCD) is predominantly caused by non-ischemic cardiomyopathies [5,6]. When symptoms are non-specific, and initial examinations are inconclusive, cardiac magnetic resonance imaging (MRI) can non-invasively assess volumes, ejection fractions and left ventricular (LV) mass (LVM) to rule-out cardiomyopathy [7]. Important MRI findings include LVM and chamber size alterations, which could be masked by overlapping overweight and hypertension induced cardiac changes, comparable to cardiac remodeling in athletes [8,9]. At early disease stages, this could lead to misdiagnosis and possible SCD. Large cohort studies in adults over 40 years of age demonstrated that increased BMI is associated with increased LVM and cardiac volumes caused by continuous high blood volume circulation, while hypertension is associated with increased LVM caused by elevated systemic vascular resistance [10–12]. In young adults this data is lacking, forcing the use of healthy reference ranges [13]. Indexation of LVM and volumes for body surface area (BSA) is recommended to correct for body size [14]. However, several studies showed that BSA-indexation in overweight individuals masks the presence of left ventricular hypertrophy (LVH), leaving only the effect of hypertension, while other body dimensions could be more appropriate for indexation [15,16].

T₁ mapping can determine myocardial changes like fibrosis natively, and extracellular volume (ECV) when repeated after administering contrast-agent [17]. Many cardiomyopathies have an expanded extracellular matrix caused by fibrosis, leading to increased native T₁ values and ECV, while myocardial fat infiltration lowers native T₁ values [18,19]. In athletes, increased LVM is mainly related to hypertrophy of cardiomyocytes as evidenced by reduced ECV [20]. Detraining in athletes results in a decrease of LVM, comparable to weight loss in overweight and obesity, and antihypertensive treatment in hypertension [21]. T₂ mapping measures myocardial water content [17], and these values are often prolonged in cardiomyopathies [22], while these changes are absent in athletes [23], and unknown in overweight and hypertensive young adults.

We hypothesized that in young adults overweight results in increased LVM and volumes, and hypertension in increased LVM. We evaluated the effect of different body scales for indexation. We also hypothesized that the expected increased LVM in young adults is predominantly caused by elevated cellular mass rather than fibrosis, fat or edema.

Materials and methods

Study population

This single center study was approved by the local medical ethical committee of the University Medical Center Groningen (no. 2016/476) and complied with the Declaration of Helsinki. All subjects signed informed consent before participation. We prospectively recruited volunteers aged 18–45 years with at least one cardiac risk factor: overweight (BMI ≥ 25 kg/m²) or hypertension, defined as under treatment with antihypertensive medication, or three consecutive blood pressure measurements ≥140/90 mmHg. Age- and gender-matched normotensive normal-weight individuals were recruited to serve as controls. Exclusion criteria were type 2 diabetes, cardiac symptoms, history of cardiovascular disease, amateur athletes (physical exercise >3 hours/week) [8], smoking, and standard MRI contraindications.

All included subjects were classified on overweight and hypertension status as: 1. normotensive normal-weight (i.e. controls); 2. normotensive overweight; 3. hypertensive normal-weight; 4. hypertensive overweight. Correct group classification was confirmed with a questionnaire including height, and measurements of weight, blood pressure and HbA1c level. Haematocrit and HbA1c were measured from a blood sample obtained prior to the MRI scan.

Cardiac MRI

All examinations were performed on a 3T MRI-scanner (MAGNETOM Prisma, Siemens Healthineers, Erlangen, Germany) with a 60-channel phased-array coil. Steady-state free precession (SSFP) sequences were used to acquire multiple long- and short-axis cines covering the entire heart [24]. Mapping data was acquired from a basal, midventricular and apical short-axis slice [17]. T₁ mapping was performed using a Modified Look-Locker Inversion Recovery 5(3)3 sequence before and at least 10 minutes after administration of 0.2 mmol/kg Gadoteric acid (Dotarem, Guerbet, France). T₂ mapping was performed using a T₂-prepared SSFP sequence. Acquisition parameters are provided in S1 Table.

Image analysis

Image analysis was performed using cvi42 version 5.10.1 (Circle Cardiovascular Imaging, Calgary, Alberta, Canada). Short-axis cines were manually contour-traced for assessment of cardiac morphology and function using a validated protocol [25]. Trabecula were included in the blood pool. As recommended, LVM and volumes were indexed for BSA calculated using the DuBois formula [14], and also for body scales aimed at normalization in overweight, including estimated lean body mass, height, height to the power of 1.7 (height^1.7) and height^2.7 [26].

For each short-axis slice, T₁ and T₂ maps were generated offline using motion-corrected images with different inversion and echo times. All maps were segmented by outlining endocardial and epicardial contours [14]. In T₁ maps, a blood pool contour was additionally traced for ECV assessment. Apical segments were excluded from global values, because of artefacts and wide standard deviations in mapping outcomes [27]. The height^2.7-indexed LVM was used to calculate myocyte mass and extracellular mass [20]:

i n d e x e d m y o c y t e m a s s = {h e i g h t}^{2.7} - i n d e x e d L V M * (100 % - E C V)

(1)

i n d e x e d e x t r a c e l l u l a r m a s s = {h e i g h t}^{2.7} - i n d e x e d L V M * E C V

(2)

Statistical analysis

Statistical analysis was performed using SPSS version 24 (IBM SPSS Statistics, Armonk, New York, USA). Continuous variables were reported as mean ± standard deviation. Normality was assessed using the Shapiro-Wilk test and visual inspection of the Q-Q plot [28]. Comparison of two groups was performed using the independent samples t-test, comparison of multiple groups with the analysis of variance and Bonferroni post-hoc testing. Correlations were tested with Pearson correlation. P values < 0.05 were considered significant.

The sample size was calculated using previously published data in athletes [29]. In that study, the mean difference between athletes and controls was ±9 g, and the standard deviation was ±13 g. With a one-sided significance level of 0.05 (i.e., α) and 80% power (i.e., β = 0.20), a sample size of 26 was needed per group.

For some analyses, overweight subjects were further subdivided into mild overweight (BMI 25–29.9 kg/m²) and obese (BMI ≥ 30 kg/m²) to further explore possible differences in cardiac MRI parameters.

Results

One hundred and twenty-six subjects (mean age 35 ± 4 years; 51% males) were included (Table 1). There were no significant differences in age or gender between all four groups.

Table 1. Study population characteristics.

	Normotensive		Hypertensive
	Normal-weight	Overweight	Normal-weight	Overweight
	n = 40	n = 40	n = 17	n = 29
Age (years)	34 ± 4	35 ± 4	36 ± 3	36 ± 4
Gender, male n (%)	20 (50)	20 (50)	10 (59)	14 (48)
Height (cm)	178 ± 8	177 ± 9	181 ± 10	178 ± 10
Weight (kg)	70 ± 9	100 ± 16 ^*	76 ± 11	98 ± 12 ^*
Body mass index (kg/m²)	22 ± 2	32 ± 4 ^*	23 ± 1	31 ± 4 ^*
Body surface area (m²)	1.9 ± 0.2	2.2 ± 0.2 ^*	2.0 ± 0.2	2.2 ± 0.2 ^*
Lean body mass (kg)	49 ± 9	61 ± 13 ^*	53 ± 10	60 ± 12 ^*
Overweight duration (years)	-	14 ± 9	-	11 ± 7
Systolic blood pressure (mmHg)	117 ± 8	122 ± 7	141 ± 16 ^*	144 ± 14 ^* ^†
Diastolic blood pressure (mmHg)	79 ± 6	81 ± 7	95 ± 9 ^*	94 ± 10 ^* ^†
Antihypertensive drugs, n (%)	0 (0)	0 (0)	10 (59) ^*	17 (59) ^* ^†
Hypertension duration (years)	-	-	7 ± 5	6 ± 7
HbA1c (mmol/mol)	33 ± 3	34 ± 3	32 ± 4	34 ± 3
Haematocrit (%)	40 ± 4	42 ± 3	43 ± 3	42 ± 4
Heart rate (bpm)	66 ± 12	67 ± 12	68 ± 8	76 ± 12 ^* ^†

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Data reported as mean ± standard deviation. Bonferroni post-hoc tests

*P < 0.05 vs normotensive normal-weight

†P < 0.05 vs normotensive overweight.

Cardiac morphology and function

The normotensive overweight group had significantly higher LVM than controls (P = 0.015), while cardiac and stroke volumes were similar (Table 2 and Fig 1). After subdividing the overweight group into mild overweight and obese, the obese group showed higher LVM (108 ± 24 g) compared to mild overweight (97 ± 19 g, P = 0.483) and controls (87 ± 21 g, P < 0.001) (S2 Table). The obese group also demonstrated non-significantly higher cardiac volumes than controls and mild overweight. The mass-volume ratio in the normotensive overweight group (0.61 ± 0.12 g/ml) was significantly higher compared to controls (0.51 ± 0.09 g/ml) (P < 0.001) (Fig 2). Gender-specific cardiac morphology and function outcomes are reported in S3–S6 Tables.

Table 2. Cardiac morphology, function and tissue characteristics per group.

	Normotensive		Hypertensive
	Normal-weight	Overweight	Normal-weight	Overweight
Left ventricle
Mass (g)	87 ± 21	104 ± 23 ^*	109 ± 27 ^*	112 ± 26 ^*
Indexed mass (g/m^2.7)	18.5 ± 3.6	21.9 ± 3.2 ^*	21.6 ± 3.0 ^*	23.6 ± 4.1 ^*
Myocyte mass (g/m^2.7)	14.0 ± 2.9	16.9 ± 2.7 ^*	16.5 ± 2.3 ^*	18.1 ± 3.5 ^*
Extracellular mass (g/m^2.7)	4.5 ± 0.8	5.1 ± 0.7 ^*	5.1 ± 0.9	5.5 ± 0.9 ^*
End-diastolic volume (ml)	171 ± 29	173 ± 36	171 ± 36	168 ± 38
End-systolic volume (ml)	68 ± 13	71 ± 19	70 ± 17	65 ± 20
Stroke volume (ml)	103 ± 20	103 ± 21	100 ± 21	102 ± 21
Ejection fraction (%)	60 ± 4	60 ± 5	59 ± 4	62 ± 5
Mass-volume ratio (g/ml)	0.51 ± 0.09	0.61 ± 0.12 ^*	0.64 ± 0.11 ^*	0.67 ± 0.09 ^*
Right ventricle
End-diastolic volume (ml)	192 ± 34	196 ± 42	191 ± 47	186 ± 43
End-systolic volume (ml)	90 ± 18	93 ± 25	91 ± 30	84 ± 25
Stroke volume (ml)	102 ± 19	102 ± 21	100 ± 21	102 ± 21
Ejection fraction (%)	53 ± 4	53 ± 5	53 ± 6	55 ± 5
Global mapping values
Native T₁ (ms)	1147 ± 30	1153 ± 34	1151 ± 35	1153 ± 37
Extracellular volume (%)	24.7 ± 2.1	23.3 ± 2.1 ^*	23.7 ± 1.9	23.5 ± 2.5 ^*
T₂ (ms)	39.2 ± 2.1	38.5 ± 1.7	38.2 ± 1.4	37.5 ± 2.2 ^*

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Data reported as mean ± standard deviation. Bonferroni post-hoc tests

*P < 0.05 vs normotensive normal-weight.

Fig 1 — Indexation of left ventricular (LV) mass (upper panel) and LV end-diastolic volume (lower panel) for several body scales in the four study groups. Indexation for height^1.7 and height^2.7 were not included in the graph, since these results were similar to the height-indexed results. Bonferroni post-hoc tests: *P < 0.05 vs normotensive normal-weight.

Fig 2 — Mass-volume ratio was defined as the ratio between the left ventricular (LV) mass and LV end-diastolic volume. Bonferroni post-hoc tests: *P < 0.001 vs normotensive normal-weight controls.

The hypertensive normal-weight group had significantly higher LVM than controls (P = 0.012), while cardiac and stroke volumes were similar (Table 2 and Fig 1). The mass-volume ratio in the hypertensive normal-weight group (0.64 ± 0.11 g/ml) was also significantly higher compared to controls (P < 0.001) (Fig 2).

The hypertensive overweight group had significantly higher LVM than controls (P < 0.001), while cardiac and stroke volumes were similar (Table 2 and Fig 1). The mass-volume ratio in the hypertensive overweight group (0.67 ± 0.09 g/ml) was higher than in the control group (P < 0.001) and normotensive overweight group (P = 0.075) (Fig 2).

Results of cardiac morphology and function in hypertensive populations with normal-weight, mild overweight and obese are reported in S7 Table. Although not significant, in the obese group, LVM was higher and cardiac volumes were lower. After height^2.7 indexation, the mild overweight and obese groups showed non-significantly higher end-diastolic volumes, stroke volumes and LVM compared to normal-weights.

Indexation methods

After indexation for BSA, the LVM in the normotensive overweight group was normalized compared to controls, while LVM remained significantly higher in the hypertensive normal-weight group (P = 0.007) (Fig 1 and S8 Table). In the hypertensive overweight group, BSA-indexed LVM remained higher compared to controls, though only significant in the female subgroup (S3 and S4 Tables). In groups with overweight, cardiac and stroke volumes became significantly lower compared to controls after BSA-indexation (all P < 0.01). Indexation with lean body mass showed the same impact as indexation with BSA.

After indexation for height, height^1.7 or height^2.7, LVM remained significantly higher in all risk groups compared to controls (all P < 0.05) (Fig 1 and S8 Table), where cardiac and stroke volumes remained similar.

Myocardial tissue characteristics

Height^2.7-indexed LVM and myocardial tissue characteristics are reported in Table 2. Native T₁ values were similar between all groups and were not significantly correlated with height^2.7-indexed LVM, BMI or systolic blood pressure (SBP) (Fig 3 and S1 Fig).

Fig 3 — From left to right, native T₁ mapping (r = 0.152, P = 0.093), extracellular volume (ECV) (r = –0.413, P < 0.001) and T₂ mapping (r = –0.168, P = 0.063).

ECV was significantly lower in all risk groups compared to controls (all P < 0.01), except for the normal-weight hypertensive group (P = 0.113). ECV was negatively correlated with height^2.7-indexed LVM (r = –0.413, P < 0.001), also after adjusting for gender (r = –0.314, P < 0.001) (Fig 3). In normotensive subjects, ECV correlated negatively with BMI (P = 0.020) (S1 Fig). In normal-weight subjects, ECV decreased with increasing SBP (P < 0.001).

T₂ values were only significantly lower in the hypertensive overweight group compared to controls (P = 0.004). This difference related to the correlation between T₂ values and heart rate (r = –0.57, P < 0.001), as only the hypertensive overweight group showed significantly higher heart rate than controls (P = 0.002). No correlation was found between T₂ values and height^2.7-indexed LVM (Fig 3).

In the normotensive overweight group, the height^2.7-indexed LVM was 19% higher compared to controls (P < 0.001) (Fig 4). This increase was predominantly caused by elevated myocyte mass relative to controls (+20%, P < 0.001), and to a lesser extent by extracellular mass growth (+12%, P = 0.024). In the hypertensive normal-weight group, the height^2.7-indexed LVM was 17% higher than in controls (P = 0.017), and related to an increase of 18% in myocyte mass (P = 0.014) and 13% in extracellular mass (P = 0.185). In the hypertensive overweight group, the height^2.7-indexed LVM was 28% higher compared to controls (P < 0.001), accompanied by an increase of 30% myocyte mass and 22% extracellular mass (both P < 0.001).

Discussion

This study shows that young adults with overweight and hypertension have increased LVM, predominantly caused by hypertrophy of cardiomyocytes instead of fibrosis or fatty infiltration, as evidenced by similar T₁ values and lower ECV. Indexation using the weight-related body scales BSA and lean body mass normalized LVM and overly lowered cardiac volumes in overweight groups compared to controls, while LVM remained higher in the hypertensive normal-weight group.

In young adults with overweight and/or hypertension, the increased LVM was highest when both conditions were present. Our findings in overweight groups were consistent with previous studies reporting increasing LVM with higher BMI versus controls; in mature adults (aged 61 ± 9 years, no sex-specific results) [10–12,30], in young adult obese males (aged 30 ± 7 years, BMI 35 ± 3 kg/m²) [31], and in severely obese adolescents (aged 18 ± 4 years, BMI 41 ± 6 kg/m²) [32]. Increased LVM in hypertensives is thoroughly reported, however, available studies included only mature adults (mean age, range 49–61 years) as hypertension at younger age is less prevalent [33–36]. Some of these studies classified hypertensives into a group with and without LVH to investigate differences in underlying myocardial tissue properties [33,34]. The combined effect of overweight and hypertension in young adults as observed in the current study is in line with findings in mature populations (age range 45–84 years) [10,12].

Overweight subjects have higher circulating blood volume than normal-weights to meet increased metabolic demands [37]. We found correspondingly higher cardiac volumes in our obese groups, however, not in all mild overweight groups. Previous studies confirm our findings in the obese for different age groups, including adolescents [31,38,39]. Another study showed increasing cardiac and stroke volumes with increasing BMI categories, however, comparable to our findings, these increases were not significant in the group with mild overweight [30].

Long-term increased mass-volume ratio is associated with major adverse cardiovascular events in asymptomatic populations [40]. Diet aimed at weight loss and antihypertensive treatment is often initiated, resulting in decreased concentric LV remodeling [21]. Confirming literature, we found a higher mass-volume ratio in our young mild overweight, obese and hypertensive subjects [30,31,33,34,39].

The increased absolute LVM in overweight subjects was normalized after BSA-indexation, causing an undesirable underestimation of LVH which is also in line with previous studies [15,41]. With indexation for any height variable, the absolute LVM remained higher in overweight subjects. In a previous study, height^2.7 was stated as best normalization method for identification of LVH as it was most closely associated with adverse outcomes [42]. Moreover, in the echocardiographic guideline, height^2.7-indexation was already acknowledged as standard, while BSA-indexation remained acceptable in normal-weight patients [43]. We also showed that volumes were underestimated in overweight groups after BSA-indexation, confirmed by one other study [15]. Considering these findings, additionally reporting height^2.7-indexed values in clinical reports seems advisable. Furthermore, as BSA-indexation normalizes the increased LVM in overweight populations without cardiovascular disease, this could potentially help differentiating between LVM adaptation to overweight and cardiomyopathy.

Our results suggest that increased LVM in young adults with overweight and/or hypertension is mainly caused by increased myocyte mass and to a lesser extent by fibrosis, as evidenced by similar T₁ values and lower ECV. This is confirmed by a study in athletes that reported 30% higher myocyte mass and 16% higher extracellular mass relative to controls [20]. Two studies have reported on T₁ mapping and ECV in obese young adults [39,44]. One study in obese young adults (aged 31 ± 6 years, BMI 33 ± 2 kg/m²) showed T₁ values, ECV, and LVM comparable to controls [44]. In the other study, severely obese adolescents (aged 18 ± 4 years, BMI 41 ± 6 kg/m²) showed increased ECV and LVM, contradicting our findings, possibly related to the greater overweight severity of their study population [39].

Previous studies in more mature adults (mean age, range 49–61 years) with hypertension and LVH showed increased native T₁ values and ECV, suggesting a component of interstitial fibrosis, probably related to the duration of this condition [33,34,45], as without LVH, T₁ values and ECV were mostly similar to controls.

To our best knowledge, this study is the first to report T₂ mapping values in overweight and hypertensive populations [22]. Only the hypertensive overweight group showed lower T₂ values than controls, corresponding to increased heart rates in this group, a known effect in SSFP-based T₂ mapping [46].

This study has several limitations. First, we included all hypertensive subjects in one group, irrespective of anti-hypertensive treatment. However, before hypertensives with and without treatment were merged, all cardiac outcomes showed no significant differences (S9 Table). Second, only asymptomatic subjects without known cardiovascular disease were included. Results could therefore not be compared directly to patients with known cardiac disease. Third, this is a cross-sectional study without follow-up, therefore long-term consequences of the demonstrated cardiac alterations could not be investigated. Fourth, the hypertensive normal-weight group was smaller than the sample size calculated with the power analysis.

Conclusion

Overweight and hypertension increase LVM in young adults, mainly by hypertrophy of cardiomyocytes instead of fibrosis or fatty infiltration. In overweight, BSA indexation results in normalization of LVM and smaller cardiac volumes than controls. Indexation with height^2.7 circumvents this effect and seems advisable.

Supporting information

S1 Fig. Correlations between risk factors and tissue characteristics.

In the upper panel, only normotensive subjects are included to show the correlation between body mass index (BMI) and native T₁ (P = 0.170), and between BMI and extracellular volume (ECV) (r = –0.271, P = 0.020). In the lower panel, only normal-weight subjects are included to show the correlation between systolic blood pressure (SBP) and native T₁ (P = 0.751), and between SBP and ECV (r = –0.471, P < 0.001).

(TIF)

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S1 Table. Acquisition parameters.

(DOCX)

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S2 Table. Cardiac morphology and function in normotensive subjects divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

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S3 Table. Cardiac morphology and function per male subgroup.

Data reported as mean ± standard deviation (SD) (range for reference). Ranges for reference were calculated as mean ± t_0.975,n-1 ·√((n+1)/n) · SD. *P < 0.05 versus normotensive normal-weight EDV end-diastolic volume, ESV end-systolic volume, SV stroke volume, EF ejection fraction, BSA body surface area.

(DOCX)

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S4 Table. Cardiac morphology and function per female subgroup.

Data reported as mean ± standard deviation (SD) (range for reference). Ranges for reference were calculated as mean ± t_0.975,n-1 ·√((n+1)/n) · SD. *P < 0.05 versus normotensive normal-weight, †P < 0.05 versus normotensive overweight EDV end-diastolic volume, ESV end-systolic volume, SV stroke volume, EF ejection fraction, BSA body surface area.

(DOCX)

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S5 Table. Cardiac morphology and function in normotensive males divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

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S6 Table. Cardiac morphology and function in normotensive females divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

Click here for additional data file.^{(24.3KB, docx)}

S7 Table. Cardiac morphology and function in hypertensive subjects divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

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S8 Table. Indexation of volumes and mass for different body scales.

Data reported as mean ± standard deviation. *P < 0.05 versus normotensive normal-weight.

(DOCX)

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S9 Table. Differences between hypertensive subjects on presence anti-hypertensive medication.

Data reported as mean ± standard deviation. Indexed indexed with body surface area, EDV end-diastolic volume, ESV end-systolic volume, SV stroke volume.

(DOCX)

Click here for additional data file.^{(24.3KB, docx)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

G.S. and N.P. were supported by a grant from the Dutch Heart Association (2016T042, https://www.hartstichting.nl/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0278308.r001

Decision Letter 0

Joshua M Hare

21 Jun 2022

PONE-D-21-38012Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults.PLOS ONE

Dear Dr. Snel,

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Additional Editor Comments (if provided):

The manuscript by Snel et al. discusses a novel approach toward measuring cardiac structure in overweight individuals. Additional analysis of these normalization methods regarding LV volumes are needed. There was also some concern regarding the classification of some overweight individuals as obese in only some analyses. A discussion of the difference of the analysis between males and females is also needed.

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Snel et al. used MRI analysis to examine cardiac structure in normal and overweight normotensive and hypertensive young adults. They conclude that increased LV mass is masked when using BSA as the normalizing factor and that using height2.7 does not. The increase in the number of overweight and obese young people make this topic particularly relevant. There are some comments to be addressed.

Major comments:

1. Obese participants are only reported separately for some comparisons but are combined with the overweight group in most comparisons. What is the rationale for this limited analysis and can the authors differentiate between obese and overweight participants in additional studies? The majority of overweight normotensives are obese, what was the number of obese vs. overweight hypertensive.

2. The authors discuss results from obese males. Are these results reported in a Table? Please indicate the number of obese females is not indicated. the number of obese males and females.

3. Table S4 shows that BSA masks LV mass but accentuates differences in volumes (ESV, EDV, SV), particularly in obese patients and to a lesser extent RV volumes (EDV; SV in obese). In Table S6 male normotensives overall follow this pattern in overweight normotensives but Table S8 shows that in females, BSA masks mass in normotensive but not in hypertensives and volumes are accentuated in both overweight groups. Please elaborate

4. 4. In Table 2, differences in the global mapping the values extracellular volume and T2 are virtually identical in overweight normotensive and both hypertensive groups, although, some are significant. What is the relevance of these differences?

Minor comments:

1. Please define the parameters for obese in the Methods section

2. In Table S8 it states that “data reported as mean ± SD”. Please similarly indicate, either in the Methods section or in the legend for each table.

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PLoS One. 2022 Dec 1;17(12):e0278308. doi: 10.1371/journal.pone.0278308.r002

Author response to Decision Letter 0

11 Jul 2022

Dear editor and reviewer,

Thank you for handling our manuscript and for providing helpful comments.

Please find below our point-to-point response to each comment.

As requested, we uploaded a marked-up copy of the manuscript with changes tracked and an unmarked version without changes tracked.

Also, we uploaded the newest versions of the supplementary materials.

Your sincerely,

Gert Jan Snel – Corresponding author

Major comments:

We thank the reviewer for these questions. One of our hypotheses was that being overweight without hypertension would result in measurably larger cardiac volumes compared to being normal weight. The cardiac adaptation in our normotensive overweight population was non-significantly different from controls. We therefore performed an analysis in which we subdivided our normotensive overweight group into mild overweight and obese.

We agree that it would also be of interest to subdivide the hypertensive overweight population (n = 29) into mild overweight (n = 14) and obese (n = 15). We compared these new subgroups to our hypertensive normal-weight group and investigated the impact of overweight in these subjects. The differences between these groups were all non-significant and are added in supplementary tables (S14 and S15). The following text is added to the section Results – Cardiac morphology and function:

“Results of cardiac morphology and function in hypertensive populations with normal-weight, mild overweight and obese are reported in S14 and S15 Tables. Although not significant, in the obese group, LVM was higher and cardiac volumes were lower. After height2.7 indexation, the mild overweight and obese groups showed non-significantly higher end-diastolic volumes, stroke volumes and LVM compared to normal-weights.”

2. The authors discuss results from obese males. Are these results reported in a Table? Please indicate the number of obese females is not indicated. the number of obese males and females.

Thank you for this clarification request. Results from obese males were indeed not reported in a table. We added supplementary tables to report the results of both obese males (n = 13, Tables S10 and S11) and obese females (n = 12, Tables S12 and S13). We referred to these tables in the section Results – Cardiac morphology and function.

For clarity, we rephrased the sentence of the discussion to state:

“Our findings in overweight groups were consistent with previous studies reporting increasing LVM with higher BMI versus controls; in mature adults (aged 61 ± 9 years, no sex-specific results) [10–12,29], in young adult obese males (aged 30 ± 7 years, BMI 35 ± 3 kg/m2) [30], and in severely obese adolescents (aged 18 ± 4 years, BMI 41 ± 6 kg/m2) [31].”

In both normotensive overweight and hypertensive overweight groups, BSA-indexation indeed resulted in lower volumes compared to normal-weights. This pattern was observed in the entire population (Table S4 and S14), and separately for males (Table S6) and females (Table S8).

BSA-indexation masked LV mass in normotensive overweights as well. There was less masking of LV mass in hypertensive overweights because of the additional cardiac adaptation to hypertension. As a result, BSA-indexed LV mass remained higher in both hypertensive overweight males (Table S6) and females (Table S8) compared to controls, though only significant in females.

We added the following clarifying sentence in Results – Indexation Methods:

“In the hypertensive overweight group, BSA-indexed LVM remained higher compared to controls, though only significant in the female subgroup (S6 and S8 Tables).”

We also rephrased one sentence in the abstract to state:

“Body surface area (BSA) indexation resulted in LVM normalization in overweights (48 ± 8 g/m2) versus controls (47 ± 9 g/m2), but not in hypertensives (55 ± 9 g/m2) and hypertensive overweights (52 ± 9 g/m2).”

Thank you for pointing this out. We originally rounded T2 and extracellular volume (ECV) up to the closest integer, which made these results appear more identical and statistically relevant differences less apparent. We added one decimal for T2 and ECV in Tables 2 and S18.

T2 mapping values were only significantly different in the hypertensive overweight group compared to controls, because of higher heart rates causing lower T2 values, which is a known effect in SSFP-based sequences, as stated in the discussion (R256-258).

All risk groups showed lower ECV values compared to controls, though not significant in the normal-weight hypertensive group. These changes suggest that the increased LV mass mainly related to hypertrophy of myocytes, and to a lesser extent fibrosis (since T1 values were similar). We rephrased one sentence in the discussion to state:

“Our results suggest that increased LVM in young adults with overweight and/or hypertension is mainly caused by increased myocyte mass and to a lesser extent by fibrosis, as evidenced by similar T1 values and lower ECV.”

Minor comments:

1. Please define the parameters for obese in the Methods section

Thank you for this request. In the inclusion criteria of the study, we used a BMI of 25 kg/m2 as cut-off to classify subjects as either normal-weight or overweight. Since we considered the severity of overweight to be potentially of interest during the analysis, we subdivided the overweight population into mild overweight and obese to explore possible differences. Therefore, we defined mild overweight and obese in the section Methods – Statistical Analysis by adding the following text:

“For some analyses, overweight subjects were further subdivided into mild overweight (BMI 25–29.9 kg/m2) and obese (BMI ≥ 30 kg/m2) to further explore possible differences in cardiac MRI parameters.”

In the section Results – Cardiac morphology and function, we removed “BMI 25-29.9 kg/m2” and “BMI 30-43 kg/m2”, to avoid redundancy after defining these groups in the Methods section. Furthermore, we renamed overweight (BMI 25–29.9 kg/m2) as mild overweight to prevent confusion with the original overweight group as stated in inclusion criteria (BMI ≥ 25 kg/m2).

2. In Table S8 it states that “data reported as mean ± SD”. Please similarly indicate, either in the Methods section or in the legend for each table.

In the original manuscript, we stated in the section Methods – Statistical analysis that “Continuous variables were reported as mean ± standard deviation”. We agree that it would be clearer to also include this in the table legends. We added this information in all relevant tables; 1, 2, S4, S16 and S18.

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PLoS One. doi: 10.1371/journal.pone.0278308.r003

Decision Letter 1

Eduard Shantsila

24 Oct 2022

PONE-D-21-38012R1Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults.PLOS ONE

Dear Dr. Snel,

Please submit your revised manuscript by Dec 08 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Eduard Shantsila

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

This is an interesting and well-conducted study. The comments of the original reviewer have been adequately addressed. The comments of the new reviewer are relatively minor and should be easily addressable.

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Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: Title

Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive

young adults.

Synopsys

This work aimed to assess whether overweight and hypertension could induce increased left ventricular mass (LVM) and myocardial hypertrophy in young adults. The authors hence conducted a prospective study enrolling 126 subjects (40 age- and sex-matched healty controls, 40 normotensive overweight, 17 hypertensive and 29 hypertensive overweight). It was observed that LVM increased in all risk groups compared to controls, and that indexation by body surface area (BSA) led to LVM normalization in overweights but not in the hypertensive groups. Furthermore, BSA indexation underestimated ventricular volumes in overweight patients, whereas height^2.7 did not. Finally, the authors observed a lower myocardial extracellular volume (ECV) in all risk groups, whereas myocardial native and post-contrast T1 and T2 did not show significative alterations, suggesting myocytes hypertrophy.

Strengths

• Prospective design

• Very detailed report on all the analysis performed

Weaknesses

• No sample size calculation reported

• High number of supplementary tables results in a dispersive fruition

Abstract

1. Please state explicitly the aims of your work in the abstract within the first sentences.

Introduction

2. Page 3 lines 63-64: perhaps the word “volume” is missing in “cardiac volumes caused by continuous high blood circulation”.

Materials and methods

3. Please report a sample size calculation if such analysis was performed in the study planning stages. Otherwise, I would suggest conducting a statistical power analysis, given the high number of comparisons performed and the relatively small sizes of the study groups.

Results

4. While I appreciate the detailed report on all the analysis performed, I found very dispersive to scroll between 18 different supplementary tables. Therefore, I would suggest the authors to reduce such number, perhaps by collapsing similar tables into one or by avoiding to report non-fundamental data.

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2022 Dec 1;17(12):e0278308. doi: 10.1371/journal.pone.0278308.r004

Author response to Decision Letter 1

4 Nov 2022

Dear editor and reviewers,

Thank you for handling our manuscript and providing helpful comments.

Please find below our point-to-point response to each comment.

As requested, we uploaded a marked-up copy of the manuscript with tracked changes and an unmarked version.

Also, we uploaded the newest versions of the supplementary materials.

Your sincerely,

Gert Jan Snel – Corresponding author

Reviewer #1: (No Response)

Reviewer #2:

Abstract

1. Please state explicitly the aims of your work in the abstract within the first sentences.

Thank you for this clarification request. We rephrased the first sentences in the abstract to state:

“In young adults, overweight and hypertension possibly already trigger cardiac remodeling as seen in mature adults, potentially overlapping non-ischemic cardiomyopathy findings. To this end, in young overweight and hypertensive adults, we aimed to investigate changes in left ventricular mass (LVM) and cardiac volumes, and the impact of different body scales for indexation. We also aimed to explore the presence of myocardial fibrosis, fat and edema, and changes in cellular mass with extracellular volume (ECV), T1 and T2 tissue characteristics.”

Introduction

2. Page 3 lines 63-64: perhaps the word “volume” is missing in “cardiac volumes caused by continuous high blood circulation”.

Thank you for pointing this out. We added the word “volume” in that sentence to state:

“Large cohort studies in adults over 40 years of age demonstrated that increased BMI is associated with increased LVM and cardiac volumes caused by continuous high blood volume circulation, while hypertension is associated with increased LVM caused by elevated systemic vascular resistance [10–12].”

Materials and methods

Thank you for this request. We indeed performed a sample size analysis in the study planning stages. We added the following paragraph to the “Statistical Analysis” section:

“The sample size was calculated using previously published data in athletes [29]. In that study, the mean difference between athletes and controls was ±9 g, and the standard deviation was ±13 g. With a one-sided significance level of 0.05 (i.e., α) and 80% power (i.e., β=0.20), a sample size of 26 was needed per group.”

Our group sizes of controls, normotensive overweight and hypertensive overweight were sufficiently large. Due to the relatively low prevalence of hypertension in the general normal-weight population between 18 and 45 years of age, our included hypertensive normal-weight group size was smaller than the number calculated in our power analysis. We added the smaller group size as a limitation by stating:

“Fourth, the hypertensive normal-weight group was smaller than the sample size calculated with the power analysis.”

Results

We thank the reviewer for this suggestion. We removed the supplementary tables containing solely P-values since the fundamental data and significant differences are reported in other tables. As a result, the number of supplementary tables was reduced from 18 to 9.

Attachment

Submitted filename: PONE-D-21-38012R1 - Rebuttal letter.docx

Click here for additional data file.^{(22.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0278308.r005

Decision Letter 2

Eduard Shantsila

15 Nov 2022

Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults.

PONE-D-21-38012R2

Dear Dr. Snel,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Eduard Shantsila

Academic Editor

PLOS ONE

PLoS One. doi: 10.1371/journal.pone.0278308.r006

Acceptance letter

Eduard Shantsila

22 Nov 2022

PONE-D-21-38012R2

Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults.

Dear Dr. Snel:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Eduard Shantsila

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Correlations between risk factors and tissue characteristics.

(TIF)

Click here for additional data file.^{(962.7KB, tif)}

S1 Table. Acquisition parameters.

(DOCX)

Click here for additional data file.^{(20.8KB, docx)}

S2 Table. Cardiac morphology and function in normotensive subjects divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

Click here for additional data file.^{(23.7KB, docx)}

S3 Table. Cardiac morphology and function per male subgroup.

(DOCX)

Click here for additional data file.^{(27.3KB, docx)}

S4 Table. Cardiac morphology and function per female subgroup.

Data reported as mean ± standard deviation (SD) (range for reference). Ranges for reference were calculated as mean ± t_0.975,n-1 ·√((n+1)/n) · SD. *P < 0.05 versus normotensive normal-weight, †P < 0.05 versus normotensive overweight EDV end-diastolic volume, ESV end-systolic volume, SV stroke volume, EF ejection fraction, BSA body surface area.

(DOCX)

Click here for additional data file.^{(27KB, docx)}

S5 Table. Cardiac morphology and function in normotensive males divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

Click here for additional data file.^{(24.3KB, docx)}

S6 Table. Cardiac morphology and function in normotensive females divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

Click here for additional data file.^{(24.3KB, docx)}

S7 Table. Cardiac morphology and function in hypertensive subjects divided on BMI.

Data reported as mean ± standard deviation. *P < 0.05 versus normal-weight, †P < 0.05 versus mild overweight BMI body mass index.

(DOCX)

Click here for additional data file.^{(26KB, docx)}

S8 Table. Indexation of volumes and mass for different body scales.

Data reported as mean ± standard deviation. *P < 0.05 versus normotensive normal-weight.

(DOCX)

Click here for additional data file.^{(28.2KB, docx)}

S9 Table. Differences between hypertensive subjects on presence anti-hypertensive medication.

Data reported as mean ± standard deviation. Indexed indexed with body surface area, EDV end-diastolic volume, ESV end-systolic volume, SV stroke volume.

(DOCX)

Click here for additional data file.^{(24.3KB, docx)}

Attachment

Submitted filename: PONE-D-21-38012 - Rebuttal letter.docx

Click here for additional data file.^{(29.6KB, docx)}

Attachment

Submitted filename: PONE-D-21-38012R1 - Rebuttal letter.docx

Click here for additional data file.^{(22.7KB, docx)}

Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Interpretation of pre-morbid cardiac 3T MRI findings in overweight and hypertensive young adults

Gert J H Snel

Riemer H J A Slart

Birgitta K Velthuis

Maaike van den Boomen

Christopher T Nguyen

David E Sosnovik

Vincent M van Deursen

Rudi A J O Dierckx

Ronald J H Borra

Niek H J Prakken

Roles

Abstract

Introduction

Materials and methods

Study population

Cardiac MRI

Image analysis

Statistical analysis

Results

Table 1. Study population characteristics.

Cardiac morphology and function

Table 2. Cardiac morphology, function and tissue characteristics per group.

Fig 1.

Fig 2. The mass-volume ratio per group visualized as mean with one standard deviation.

Indexation methods

Myocardial tissue characteristics

Fig 3. Correlation between myocardial tissue characteristics and left ventricular mass indexed for height to the power of 2.7.

Fig 4. Left ventricular (LV) mass indexed for height to the power of 2.7 visualized as mean with standard deviation.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Joshua M Hare

Roles

Author response to Decision Letter 0

Decision Letter 1

Eduard Shantsila

Roles

Author response to Decision Letter 1

Decision Letter 2

Eduard Shantsila

Roles

Acceptance letter

Eduard Shantsila

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