Of the eighteen subjects with Mustard procedure in the analysis, twelve were male and six were female with an age range of 30 to 46 years. In the Mustard group, nine (50%) subjects were assigned to NYHA class II, and nine (47%) subjects to class III. The control group was asymptomatic and was matched for age to the Mustard group with a range of 22 to 49 years and included six males and 12 females.
The average age of the Mustard subjects was 34.9 years (± 1.1 years) and was not different from the control cohort (32.6 ± 1.7 years). All subjects in the Mustard cohort were Caucasian versus the control cohort with 78% Caucasian, 17% Hispanic, and 5% Asian. The Mustard cohort was 67% male compared to 33% male in the control cohort. A male predominance is known for D-TGA and no attempt was made to control for gender or race in this study.
Biomarker averages for Mustard subjects compared to controls are shown in Table 1. Soluble ST2 levels were significantly elevated in the Mustard group when compared to control groups with an average of 42.93 ± 6.90 versus 29.71 ± 1.24, respectively (p = 0.0071). Of the Mustard patients, 56% had elevated levels while 17% had elevated levels in the control group (p = 0.035) as shown in Fig. 1D.
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Levels of HDL, total cholesterol, and cholesterol / HDL ratio in the Mustard subjects compared to the control group were also significantly different (Table 1 and Fig. 1A-1C). Both HDL and total cholesterol were low in the Mustard group, whereas the total cholesterol to HDL ratio was elevated in Mustard subjects. Triglycerides and insulin levels were not different between the groups.
Cardiac troponin I (cTnI) was significantly elevated in the Mustard cohort when compared to controls (Fig. 2), with the average Mustard cTnI at 0.21 ± 0.14 ng/mL and the average control cTnI at < 0.03 ng/mL (p = 0.008). None of the control subjects had an elevated cTnI level (defined as ≥ 0.03 ng/mL) whereas 39% of the Mustard cohort had an elevated cTnI level (p = 0.008). BNP was also significantly elevated in the Mustard group (Fig. 2) with an average of 145.90 ± 55.07 pg/mL, while the control subjects were at 30.28 ± 5.01 pg/mL (p < 0.0001). None of the control subjects had an elevated BNP level, whereas 44% of the Mustard cohort had a BNP level > 100 pg/mL (p < 0.001). Of the seven (out of 16) Mustard subjects with elevated BNP levels, 5 (71%) also had elevated sST2 levels. The BNP assay for two Mustard subjects was not available.
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A significant correlation between the elevation of sST2 within the Mustard cohort and markers of cardiac injury or strain was noted (Table 2). Of the Mustard subjects with elevated sST2 (n = 10), 60% had elevated cardiac troponin I (cTnI) (p = 0.027) and 60% also had elevation of BNP (> 100 pg/mL) (p = 0.022). In contrast, only 12% of the Mustard group without elevated sST2 had elevated cTnI or BNP levels, respectively. Additionally, 90% of the patients with elevated sST2 levels had low HDL, whereas only 50% of the Mustards without sST2 elevation had depressed HDL levels (< 40 mg/dL) but did not reach significance (p = 0.06). None of the control cohort had low HDL levels. Of the control subjects with elevated sST2 (n = 3), no correlations with any biomarkers were found (Table 2).
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In-depth correlations between biochemical measures in the Mustard population and the controls were explored. Table 3 show a significant positive relationship between sST2 and cTnI with a correlation by Pearson’s r of p < 0.0001. Other significant correlations were seen between LDL and triglycerides, LDL and total cholesterol, and the total cholesterol / HDL ratio. Interestingly, significant correlation was observed between glucose levels, triglycerides, and the cholesterol / HDL ratio. No significant correlations were found for insulin levels.
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Clinical outcomes of the Mustard subjects were determined at the most recent 5 years of follow-up (Table 4). Of those with elevated sST2, there was a 10% increase in cardiac medication and a 20% increase in arrhythmias. Of the Mustard patients without elevated sST2, there was no increase in cardiac medication usage and a 10% increase in arrhythmias. Of the subjects with elevated levels, 70% had at least one hospitalization across five years and 100% had either an ablation, pacemaker implantation, or both. Of those without elevated levels, 50% were hospitalized over five years and 75% had an ablation, pacemaker, or both. One subject died but did not have elevated sST2 levels, and one subject with elevated sST2 was transplanted.
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