Hereditary hemochromatosis (HH) is the most common metabolic genetic disorder and affects approximately 1 in 180 members of the Caucasian population (18,19). Although the number is small, HH in non-Caucasian populations has been reported (1). Iron overload, which is induced by HH, has been shown to cause diastolic and systolic dysfunction (23).
Because of the recent availability of genetic testing, hereditary hemochromatosis (HH) is frequently diagnosed in asymptomatic subjects at an early stage in the disorder (9,19). Although asymptomatic subjects constitute a large proportion of HH subjects, little is known about how the early stages of iron overload affect the heart and its performance. We have previously reported that left ventricular (LV) systolic function is preserved during supine bicycle exercise using echocardiography in HH subjects who were New York Heart Association (NYHA) functional class I (20). However, there is still concern that LV diastolic dysfunction may occur in this population (17) secondary to iron overload and that, as a result, exercise performance may be impaired.
In addition, a higher frequency of HFE (hemochromatosis gene) mutations that cause HH is reported among endurance runners, and it is proposed (5) that these mutations may promote athleticism. Therefore, investigating the effect of iron overload among asymptomatic HH subjects may supplement our knowledge of the role of iron levels in exercise capacity in general.
In this study, we assessed the overall exercise capacity of HH subjects who were in NYHA functional class I, and we compared these results to an age- and gender-matched group of normal volunteers. The correlation between iron levels and exercise capacity was assessed, and the effect of therapeutic reduction of iron level on exercise performance was investigated in 18 newly diagnosed HH subjects who underwent 6 months of induction phlebotomy therapy.
The study was conducted at the clinical center of the National Institutes of Health. Forty-three subjects with HH and 21 age and gender-matched healthy controls were recruited to participate in a National Heart, Lung, and Blood Institute (NHLBI) institutional review board-approved protocol, 03-H-0282, between September 2003 and August 2005. All subjects provided written informed consent and the protocol was consistent with the principles of the Declaration of Helsinki (24). Eligibility criteria for study participation among HH subjects included 1) age 21 yr or older, 2) NYHA functional class I, 3) genetic studies showing homozygosity for the C282Y HFE gene mutation, 4) documented evidence of iron overload with serum ferritin levels > 400 μg·L−1 or transferrin saturation >60%, and 5) absence of significant end-organ damage secondary to HH. Study eligibility for control subjects included 1) age 21 yr or older, 2) NYHA functional class I, 3) genetic studies showing absence of C282Y or H63D mutations in the HFE gene, and 4) normal ferritin and transferrin saturation levels. All subjects with excessive alcohol ingestion, uncontrolled hypertension, diabetes requiring insulin or more than one oral hypoglycemic agent, tobacco use in the past 3 months, and beta-adrenergic blocker or calcium channel blocker use were excluded from our study. Patients were recruited with the assistance of the NIH Clinical Center Patient Recruitment and Public Liaison Office and via direct mailings of study information to physicians (Appendix).
Metabolic exercise testing.
Treadmill exercise tests were performed using the standard Bruce protocol (4). Electrocardiography (ECG) tracings, clinical symptoms, blood pressure, and respiratory gas analysis were recorded continuously throughout the test. Workload was expressed as metabolic equivalents (METs) by dividing peak oxygen uptake (V˙O2), in milliliters per kilogram per minute, by 3.5. Simultaneous respiratory gas analysis was performed using breath-by-breath analysis of O2 and CO2 on a SensorMedics VMAX 229 instrument (SensorMedics, Yorba Linda, CA) (21,22). The oxygen and carbon dioxide sensors were calibrated before each exercise test. The ventilatory sensor was likewise calculated before each exercise test using a 3-L syringe. Minute ventilation (V˙E), oxygen uptake (V˙O2), carbon dioxide production (V˙CO2), and respiratory exchange ratio were measured, and peak V˙O2 was defined as the highest 20-s averaged V˙O2 achieved during exercise. Peak V˙O2 was normalized to age and gender using the formula published by Jones et al. (13). Ventilatory threshold was determined using the V-slope analysis method (3). The V˙E/V˙CO2 slope, a parameter used to assess ventilatory efficiency during exercise (2,6,8,11,14), was calculated before reaching ventilatory threshold (14) because HH has been linked to cardiac dysfunction (23). A V˙E/V˙CO2 slope < 34 is considered a normal response to exercise (2,6,14).
Exercise ECG response.
An abnormal ischemic exercise electrocardiogram was defined by a cardiologist (YS) using conventional criteria of ≥ 1 mm of horizontal or downsloping ST segment depression for at least 80 ms after the end of QRS complex (10). A complex arrhythmia was defined as ventricular couplets, ventricular tachycardia, or supraventricular tachycardia.
A nonparametric test (Wilcoxon rank-sum test) was used to compare measurements between groups when normality of data could not be established; otherwise, an unpaired Student's t-test was used. The correlation analysis between the metabolic exercise parameters and iron levels was performed using a nonparametric Spearman rank correlation test because of small sample sizes of data. The effect of iron-depletion phlebotomy therapy was ascertained using paired Student's t-tests. Data are expressed as means ± SD. A P value < 0.05 was considered statistically significant, and a P value ≥ 0.05 indicates that there was little evidence in the data to support the equality assertion specified in the null hypothesis.
Among 43 HH subjects, 21 were in the stable maintenance phase of phlebotomy therapy with steady iron levels, and 22 were newly diagnosed persons who had undergone three or fewer phlebotomy sessions (having had less than 2% of the number of phlebotomies needed for initial iron depletion) (15). Both HH and control groups contained a similar proportion of female subjects (30 vs 33%, HH subjects vs control subjects), and the details of the baseline characteristics have been published (20). The mean age was comparable between the HH and control group (50 ± 10 vs 48 ± 8 yr). Compared with control subjects, the HH subjects showed significantly higher iron levels and liver enzymes (ferritin 657 ± 839 vs 98 ± 76 μg·L−1, P < 0.01; serum iron 149 ± 62 vs 88 ± 27 μg·dL−1, P < 0.01; transferrin saturation 58 ± 26 vs 26 ± 10%, P < 0.01; alanine aminotransferase 42 ± 27 vs 28 ± 13 IU·mL−1, P < 0.01; aspartate aminotransferase 31 ± 11 vs 25 ± 6 IU·mL−1, P < 0.01; data are for HH subjects vs control subjects and means ± SD). However, hemoglobin, hematocrit, and lipid panel results were comparable between groups. The Framingham 10-yr estimated cardiovascular risk was also comparable between the groups (4.6 ± 4.1 vs 2.8 ± 3.6, P = 0.407).
Exercise performance parameters.
Exercise capacity measured by exercise time, peak V˙O2, and ventilatory threshold in HH subjects did not differ significantly compared with control subjects (Table 1). Ventilatory efficiency (V˙E/V˙CO2 slope) was comparable between the groups (Table 1). The respiratory exchange ratio (RER), an index of exercise effort (12), was also comparable between the groups.
Exercise ECG responses.
The incidence of abnormal ischemic ECG response was increased in asymptomatic HH subjects (42 vs 5% of subjects, P < 0.05), as previously seen with supine bicycle exercise (20). The overall incidence of any cardiac arrhythmias tended to be higher in asymptomatic HH subjects, but it did not reach statistical significance (51 vs 33% of subjects, P = 0.138). The most common type of cardiac arrhythmia recorded during exercise testing was isolated ventricular premature beats, which were seen in 40% of HH subjects and in 29% of control subjects (P = 0.259). However, complex cardiac arrhythmias occurred more frequently in asymptomatic HH subjects (19 vs 0% subjects, P < 0.05). Complex cardiac arrhythmias seen in HH subjects included ventricular couplets (16%), nonsustained ventricular tachycardia (5%), nonsustained supraventricular tachycardia (5%), and sustained supraventricular tachycardia (2%).
Relation between exercise parameters and iron levels.
As shown in Table 2, no statistically significant correlation was noted between exercise parameters (peak workload, exercise time, peak V˙O2, ventilatory threshold, and V˙E/V˙CO2 slope) and iron levels (ferritin, serum iron, transferrin saturation).
Effect of phlebotomy on exercise performance.
Eighteen newly diagnosed HH subjects underwent repeat metabolic exercise testing after 6 months of phlebotomy therapy. The average number of phlebotomies at the time of baseline measurements in these subjects was 0.9 ± 0.9. Iron levels were significantly lowered by phlebotomy (ferritin 1237 ± 932 vs 297 ± 486 μg·L−1, P < 0.01; serum iron = 197 ± 42 vs 143 ± 76 μg·dL−1, P < 0.01; transferrin saturation 76 ± 18 vs 50 ± 28%, P < 0.01; data are before (≤ 3 phlebotomies) and after 6 months of phlebotomy therapy). Activity/exercise training patterns were similar for each subject before and after phlebotomy therapy. However, measurements of exercise performance, exercise time, peak V˙O2, and ventilatory threshold did not change as a result of this therapeutic intervention (exercise time 562 ± 119 vs 579 ± 118 s, P = 0.691; peak V˙O2 29.5 ± 5.7 vs 29.1 ± 4.7 mL·kg−1·min−1, P = 0.600; ventilatory threshold 18.5 ± 2.8 vs 17.9 ± 3.8 mL·kg−1·min−1, P = 0.651; data are before and after phlebotomy therapy, Fig. 1). In addition, ventilatory efficiency did not change (V˙E/V˙CO2 slope 24.5 ± 2.0 vs 24.2 ± 2.5, P = 0.693, Fig. 1). The incidence of cardiac arrhythmias during exercise did not change significantly after 6-month phlebotomy therapy in this group (45 vs 56%; data are before and after phlebotomy therapy, P = 0.949).
Our study demonstrates that 1) overall exercise capacity and ventilatory efficiency in cardiac asymptomatic HH subjects was not statistically different from that seen in healthy control subjects; 2) iron levels do not seem to be correlated with exercise capacity; 3) iron removal by 6 months of phlebotomy therapy did not affect exercise capacity, although it did improve iron parameters; and 4) abnormal ischemic ECG responses and complex cardiac arrhythmias were more frequently seen in HH subjects.
Iron overload attributable to HH has been reported to cause both systolic and diastolic dysfunction in studies in which the average age was 50-53 yr old and the average duration from diagnosis was 13 months to 4 yr (7,16,17). Once systolic dysfunction is documented, exercise capacity becomes compromised (7,16). However, no data are available regarding exercise capacity in HH during the asymptomatic stage of the disorder, when such patients are frequently diagnosed. In addition, no recommendation for exercise activity is available for this stage of HH, but intuitively, it should be no different than that for the general population. Our study shows that overall exercise capacity is not impaired in asymptomatic patients. Our previous study indicates that systolic LV function during exercise is preserved in asymptomatic HH subjects (20). The current study supports this conclusion.
The beneficial effect of increased iron on exercise performance has been the subject of debate (5). The lack of a significant association between the iron levels and exercise capacity parameters in our study population suggests that iron levels are an unlikely determinant of exercise capacity.
Our study indicates that the incidence of ischemic ECG responses is significantly increased in HH subjects. Our previous report reveals that none of the asymptomatic subjects with ischemic ECG responses demonstrate abnormal LV wall motion during symptom-limited supine bicycle exercise (20). This observation suggests that these ECG changes are false-positive changes in asymptomatic HH subjects (20). Complex cardiac arrhythmias are also seen more frequently in HH subjects in our study. These findings do not seem to affect exercise capacity in our study population; however, their effect on exercise capacity in HH subjects with more advanced disease is not certain, and further investigation to evaluate this concern is warranted.
Our study size was too small to allow comparisons of exercise capacity in different clinical subsets, such as male versus female. Also, it is possible that a larger study may detect slight differences in exercise capacity between HH and control subjects.
Self-reported joint pains were more frequently seen in HH subjects than in normal subjects (58 vs 10%, P < 0.01), and this might have affected exercise performance in HH subjects. However, the measured RER and maximal HR, both indices of effort, as well as ventilatory threshold, an index of submaximal exercise, which is independent of maximum effort, were equivalent between HH and normal subjects. These observations favor the conclusion that cardiovascular capacity (and not joint pains) is the limiting factor on exercise capacity in HH subjects in our study.
Our subjects' exercise habits were not matched between HH and control groups, and this might introduce bias into the results. However, this was a community-based study, and we assume that our recruited subjects reflect general exercise habits of our community population.
We studied only HH subjects who were homozygous for the C282Y mutation in the HFE gene. Patients with the compound heterozygote genotype (C282Y/H63D), the second most common genotype associated with iron overload, were not enrolled. A future study of compound heterozygote subjects is possible, with our reported subjects serving as the reference group.
In conclusion, our study shows that aerobic exercise capacity is comparable between cardiac asymptomatic HH subjects and normal controls. The lack of association between iron levels and exercise capacity parameters and the lack of effect of iron removal by phlebotomy therapy on metabolic exercise testing variables suggest that the iron levels do not affect functional capacity in asymptomatic subjects.
This study was funded by grants from the intramural research program of National Heart, Lung, and Blood Institute, National Institutes of Health.
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APPENDIX: Medical Facilities from Which Our Patients Were Referred
Abington Hematology Oncology Associates, Abington, PA 19001; California Pacific Medical Center, San Francisco, CA 94118; Jacinto Medical Group, Baytown TX 77521; Kinston Medical Specialists, Kinston, NC 28501; National Institutes of Health Clinical Center, National Naval Medical Center, Bethesda MD 20810; Southern California Permanente Medical Group, North Hollywood, CA 91605; Walter Reed Army Medical Center, Washington DC 20306; Washington County Hospital Association, Hagerstown, MD 21742.