We have previously reported that left ventricular (LV) diastolic function in those with cardiac asymptomatic hereditary hemochromatosis (HH) is similar to that of volunteer control (VC) subjects, despite a presence of augmented left atrial contractile function. However, concern still exists that those with HH might gradually develop LV diastolic dysfunction despite receiving conventional phlebotomy treatment. To address this concern, we prospectively monitored the LV diastolic function of those with HH and VCs during a 5-year period. A total of 14 subjects with newly diagnosed HH (age 51 ± 12 years, 4 women, group A), 20 with chronic HH (age 51 ± 9 years, 7 women, group B), and 18 VCs (age 50 ± 8 years, 6 women, group C) successfully completed both the baseline evaluation of LV diastolic function, including tissue Doppler imaging, strain rate analysis with color-coded tissue Doppler, and the same studies repeated at 5 years of follow-up. All those with HH were New York Heart Association functional class I, were positive for the C282Y homozygote, and received conventional phlebotomy therapy. No VC had HH genetic mutations. The measures of LV diastolic function were comparable among the groups at 5 years of follow-up by analysis of variance. The echocardiographic measures of active left atrial contraction tended to decrease in the HH groups at 5 years of follow-up from baseline. In conclusion, LV diastolic function does not significantly deteriorate statistically during a 5-year period in subjects with cardiac asymptomatic HH after conventional phlebotomy treatment, regardless of their treatment history.
Hereditary hemochromatosis (HH) causes cardiac complications if untreated. Thus, it is critical to identify these persons with HH before irreversible damage occurs. This task has been made easier with the availability of genetic testing, enabling subjects to be diagnosed with HH during an asymptomatic phase. We have previously reported that left atrial (LA) contractile function is augmented, despite the absence of left ventricular (LV) diastolic abnormalities, in the asymptomatic phase of HH. We speculated that the augmentation of LA function might be a compensatory mechanism for underlying undetected LV relaxation abnormalities. If this hypothesis were correct, LV diastolic dysfunction might appear during the course of follow-up. We also recently reported that biomarkers of oxidative stress correlate with the tissue Doppler-measured strain rate from the basal septum in those with HH. Thus, subjects with HH might subsequently develop LV diastolic dysfunction because these subjects would continue to be exposed to high oxidative stress levels despite optimal phlebotomy therapy. Thus, we followed up subjects with asymptomatic HH for 5 years to evaluate changes in LV diastolic function.
Methods
We recruited 43 subjects with HH and 21 age- and gender-matched healthy volunteer control (VC) subjects to participate in a National Heart, Lung, and Blood Institute-sponsored “Heart Study of Hemochromatosis” (trial number NCT00068159 ; institutional review board-approved protocol number 03-H-0282), as previously described. The study period was September 2003 to August 2005. All subjects provided written informed consent. The eligibility criteria for those with HH included age ≥21 years, New York Heart Association functional class I, HFE genotype showing homozygosity for the C282Y HFE gene mutation, transferrin saturation >60% or serum ferritin >400 μg/L at the original diagnosis, and the absence of significant end-organ damage secondary to HH. The subjects with HH were categorized into 2 groups. Group A consisted of those with newly diagnosed HH who had undergone <3 lifetime phlebotomy treatments. Group B included those who had undergone standard phlebotomy treatment for ≥6 months and were documented to be in a stable maintenance phase of therapy, achieving a transferrin saturation of <45% and serum ferritin <30 μg/L during therapy. The VC subjects were designated group C, and their eligibility criteria included age ≥21 years, New York Heart Association functional class I, the absence of C282Y or H63D mutations in the HFE gene, and normal transferrin saturation and serum ferritin. The exclusion criteria included current use of β-adrenergic blockers or calcium channel blockers. The study details have been previously described. All subjects were contacted for a 5-year follow-up visit, and all those with HH were treated according to the current therapeutic phlebotomy guidelines.
The subjects underwent standard 2-dimensional and Doppler echocardiography, as previously described. The digital 2-dimensional images were transferred to a Digisonics review station (Digisonics, Houston, Texas) for measurements of the atrial volumes, as described. Pulsed Doppler tissue imaging signals were also obtained at the septal and lateral mitral annulus in apical 4-chamber views, as previously reported. The LA volumes were measured using the modified Simpson biplane method of stacked disks incorporating orthogonal apical 2- and 4-chamber views. The outline of the atrial endocardium was traced at the end of ventricular systole at the point of the maximum LA dimension. The minimum LA volume was measured at the end of the atrial contraction during ventricular diastole. The LA volume before atrial contraction was measured at the onset of the electrocardiographic P wave. The total, active, and passive emptying volumes and total, active, and passive emptying fraction were calculated as previously reported. The LA ejection force, the product of mass and the acceleration of blood into the left ventricle, was determined as previously described by Manning et al, and the LA kinetic energy was calculated as previously reported by Stefanadis et al. All reported LA volumes were normalized to the body surface area. All measurements in each category were performed by 2 readers (Y.S., S.S.) who were unaware of the subject information.
Continuous data are presented as the mean values ± SD. Comparisons of the 3 study groups were performed at baseline and 5 years for changes in the clinical variables and diastolic function using a 3 × 2 repeated measures analysis of variance design, with post hoc group comparisons performed using the Tukey-Kramer Honestly Significant Difference (a Studentized range test on main effect mean values). Paired Student’s t tests were also used to compare the variables at 5 years of follow-up to those at the baseline evaluation within the groups. In addition, a nonparametric approach (Kruskal-Wallis test to compare the 3 groups of subjects at either baseline or 5 years of follow-up and the Wilcoxon signed rank test to compare the baseline and 5-year follow-up data within the groups) was used when the normality of data could not be established using the Shapiro-Wilks test. All presented results are from parametric testing, and the conclusions from the parametric and nonparametric testing were consistent.
Results
A total of 14 subjects in group A, 20 in group B, and 18 in group C completed both the baseline and the 5-year follow-up testing (81% overall return rate). The average age of those not returning in group C was significantly younger than that of the entire group C (39 ± 3 vs 48 ± 8 years, p <0.01). Otherwise, those not returning at 5 years were comparable demographically to those in their respective study groups (data not shown). Those not returning were also comparable to the completers in health status in our records. At 5 years of follow-up, the ferritin levels were not significantly different statistically among the 3 groups ( Table 1 ). The levels of transferrin and transferrin saturation had markedly decreased from baseline to 5 years of follow-up in group A (those with newly diagnosed HH; p <0.001), indicating therapeutic improvement in the iron overload. However, the level of transferrin saturation was still slightly greater in group A than in groups B and C at 5 years of follow-up.
| Variable | HH | Controls (Group C, n = 18) | ||||
|---|---|---|---|---|---|---|
| Group A (n = 14) | Group B (n = 20) | |||||
| BL | 5Y | BL | 5Y | BL | 5Y | |
| Age (years) | 50 ± 12 | 55 ± 12 § | 51 ± 10 | 56 ± 9 § | 50 ± 8 | 55 ± 8 § |
| Women | 4 (29%) | 4 (29%) | 7 (35%) | 7 (35%) | 6 (33%) | 6 (33%) |
| Heart rate (beats/min) | 77 ± 12 | 74 ± 13 | 78 ± 11 | 71 ± 7 | 74 ± 11 | 69 ± 12 |
| Systolic blood pressure (mm Hg) | 120 ± 14 | 127 ± 16 | 125 ± 17 | 127 ± 16 | 124 ± 14 | 129 ± 18 |
| Diastolic blood pressure (mm Hg) | 71 ± 11 | 78 ± 10 | 80 ± 12 | 75 ± 12 | 82 ± 10 | 83 ± 11 |
| Body surface area (m 2 ) | 2.0 ± 0.2 | 2.1 ± 0.3 | 2.0 ± 0.2 | 2.0 ± 0.2 | 1.9 ± 0.2 | 2.0 ± 0.3 |
| Ferritin (μg/L) ⁎ | 1,161 ± 808 † ‡ | 213 ± 28 § | 134 ± 268 | 205 ± 20 | 88 ± 72 | 96 ± 73 |
| Transferrin saturation (%) | 74 ± 21 † ‡ | 55 ± 22 † ‡ § | 44 ± 20 | 50 ± 72 | 23 ± 8 | 26 ± 11 |
| Hemoglobin (g/dl) | 14.4 ± 1.9 | 14.7 ± 1.4 | 14.2 ± 0.9 | 14.5 ± 1.1 | 14.1 ± 1.1 | 14.4 ± 0.9 |
| Hematocrit (%) ⁎ | 44.6 ± 5.1 | 42.9 ± 3.7 | 42.0 ± 2.8 | 44.9 ± 11.4 | 42.3 ± 3.4 | 43.3 ± 2.9 |
| Alanine aminotransferase (IU/ml) ⁎ | 55 ± 26 † ‡ | 37 ± 14 § | 29 ± 17 | 27 ± 10 | 24 ± 11 | 34 ± 11 § |
| Aspartate aminotransferase (IU/ml) ⁎ | 38 ± 10 † ‡ | 21 ± 10 § | 27 ± 10 | 24 ± 11 | 25 ± 5 | 20 ± 7 § |
| Glucose (mg/dl) | 99 ± 16 | 98 ± 12 | 95 ± 13 | 113 ± 47 | 101 ± 11 | 98 ± 11 |
| Creatinine (mg/dl) | 0.9 ± 0.1 | 0.9 ± 0.3 | 1.0 ± 0.2 | 0.9 ± 0.2 | 1.0 ± 0.2 | 0.9 ± 0.2 |
At 5 years of follow-up, the LV ejection fraction and LV mass index were comparable among the 3 groups ( Table 2 ). However, the peak A velocity of mitral inflow was significantly higher statistically in group B than in group C at 5 years of follow-up (p = 0.002). No other statistically significant differences in the echocardiographic measures of LV function were noted among the 3 groups ( Table 2 ) at 5 years of follow-up. The mitral inflow propagation slope did not differ significantly among the 3 groups. However, it had decreased in both groups A and C from baseline during the 5-year period ( Table 2 ). The LA volume was not significantly different among the 3 groups ( Table 3 ). The increase in LA ejection force was prominent in both HH groups compared with the VC subjects at baseline, consistent with the findings from our previous study, and tended to be greater in the HH groups at 5 years of follow-up. However, the difference only reached statistical significance (p = 0.026; Table 3 ) in group B. The LA kinetic energy tended to be greater in the HH groups at baseline. However, the differences did not reach statistical significance at 5 years of follow-up ( Table 3 ). Compared to baseline, a significant decrease in LA kinetic energy was noted at 5 years of follow-up in group A (p <0.001) and tended to decrease in group B as well. In addition, the LA ejection force tended to decrease in group A. The normalized LA active emptying volume decreased significantly from baseline in both group B (p = 0.024) and group A (p = 0.019) during 5 years of follow-up. The LA active emptying fraction decreased significantly from baseline in group B (p = 0.018). The pulmonary flow parameters were also comparable among the 3 groups ( Table 4 ). In addition, these major findings did not change if the 5-year follow-up missing data were imputed with the mean levels for the group and the statistical analyses repeated (data not shown).
| Variable | HH | Controls (Group C) (n = 18) | ||||
|---|---|---|---|---|---|---|
| Group A (n = 14) | Group B (n = 20) | |||||
| BL | 5Y | BL | 5Y | BL | 5Y | |
| Left ventricular ejection fraction (%) | 68 ± 8 | 64 ± 7 | 68 ± 6 | 67 ± 7 | 64 ± 5 | 65 ± 7 |
| Left ventricular mass index (g/m 2 ) | 71 ± 7 | 67 ± 17 | 67 ± 19 | 77 ± 22 ⁎ | 68 ± 12 | 65 ± 10 |
| E vel (m/s) | 0.70 ± 0.10 | 0.63 ± 0.07 ⁎ | 0.69 ± 0.15 | 0.71 ± 0.17 | 0.64 ± 0.15 | 0.63 ± 0.16 |
| A vel (m/s) | 0.61 ± 0.12 | 0.62 ± 0.17 | 0.65 ± 0.16 † | 0.74 ± 0.18 † | 0.51 ± 0.09 | 0.54 ± 0.12 |
| E/A ratio ‡ | 1.2 ± 0.2 | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.0 ± 0.3 | 1.3 ± 0.4 | 1.3 ± 0.5 |
| DT (ms) ‡ | 199 ± 20 | 220 ± 28 | 216 ± 35 | 207 ± 36 | 201 ± 47 | 226 ± 56 ⁎ |
| IVRT (ms) | 82 ± 5 | 83 ± 13 | 86 ± 9 | 89 ± 15 | 85 ± 13 | 82 ± 20 |
| Vp (cm/s ) | 60 ± 13 | 46 ± 10 ⁎ | 55 ± 17 | 46 ± 12 | 65 ± 21 | 47 ± 13 ⁎ |
| Sep-E′ vel (cm/s) | 8.7 ± 1.2 | 9.2 ± 1.1 | 8.6 ± 2.2 | 8.7 ± 2.0 | 9.3 ± 1.7 | 9.0 ± 2.1 |
| Sep-A′ vel (cm/s) ‡ | 9.6 ± 2.7 | 10.8 ± 2.1 | 9.7 ± 2.0 | 10.2 ± 2.3 | 8.7 ± 1.7 | 10.2 ± 1.9 ⁎ |
| Sep-E′/A′ ‡ | 0.9 ± 0.2 | 0.9 ± 0.2 | 0.9 ± 0.3 | 0.9 ± 0.3 | 1.1 ± 0.4 | 0.9 ± 0.3 ⁎ |
| Sep-SRI-E (S −1 ) ‡ | 1.8 ± 0.7 | 1.8 ± 0.8 | 1.9 ± 0.6 | 1.8 ± 0.8 | 2.0 ± 0.9 | 1.7 ± 0.8 |
| Sep-SRI-A (S −1 ) | 1.8 ± 0.6 | 1.4 ± 0.2 ⁎ | 1.8 ± 0.8 | 1.5 ± 0.6 ⁎ | 1.6 ± 0.6 | 1.3 ± 0.3 ⁎ |
| Sep-SRI-E/A ‡ | 1.2 ± 0.8 | 1.3 ± 0.6 | 1.3 ± 1.0 | 1.6 ± 1.2 | 1.3 ± 0.4 | 1.3 ± 0.5 |
| Lat-E′ (cm/s) | 11.3 ± 3.0 | 11.4 ± 2.4 | 10.9 ± 3.3 | 11.0 ± 3.3 | 11.5 ± 2.5 | 10.9 ± 2.9 |
| Lat-A′ (cm/s) | 9.8 ± 2.9 | 10.2 ± 2.5 | 10.4 ± 3.0 | 11.7 ± 2.3 ⁎ | 9.1 ± 2.1 | 9.9 ± 2.4 |
| Lat-E′/A′ ‡ | 1.3 ± 0.5 | 1.2 ± 0.5 | 1.2 ± 0.7 | 1.0 ± 0.4 | 1.4 ± 0.6 | 1.2 ± 0.5 |
| Lat-SRI-E (S −1 ) | 2.7 ± 1.4 § | 1.8 ± 0.8 ⁎ | 1.8 ± 0.8 | 1.8 ± 0.8 | 2.3 ± 0.7 | 2.0 ± 0.9 |
| Lat-SRI-A (S −1 ) ‡ | 1.5 ± 0.8 | 1.6 ± 0.9 | 1.6 ± 0.7 | 1.8 ± 0.8 | 1.4 ± 0.9 | 1.4 ± 0.4 |
| Lat-SRI-E/A | 2.0 ± 1.0 § | 1.4 ± 0.9 | 1.4 ± 0.8 | 1.2 ± 0.9 | 1.8 ± 0.7 | 1.6 ± 0.9 |
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