Does oxidative stress modulate left ventricular diastolic function in asymptomatic subjects with hereditary hemochromatosis?

BACKGROUND: Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography-derived measure of diastolic function, may detect such changes. AIM: we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects. MATERIALS AND METHODS: Ninety-four consecutive visits of 43 HH subjects, age 30-74 (50 +/- 10, mean +/- SD), and 37 consecutive visits of 21 normal volunteers, age 30-63 (48 +/- 8), were evaluated over a 3-year period. SR was obtained from the basal septum in apical four-chamber views. All patients had confirmed C282Y homozygosity, a documented history of iron overload, and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH. RESULTS: In the HH subjects, the SR demonstrated moderate but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR. CONCLUSION: Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.

Exercise capacity of cardiac asymptomatic hereditary hemochromatosis subjects.

PURPOSE: The exercise capacity of cardiac asymptomatic subjects with hereditary hemochromatosis (HH) has not been well described. In this study, we tested whether the iron overload associated with HH affected exercise capacity with a case control study design. METHODS: Forty-three HH and 21 normal control subjects who were New York Heart Association functional class I underwent metabolic stress testing using the Bruce protocol at the clinical center of the National Institutes of Health. Exercise capacity was assessed with minute ventilation (.VE), oxygen uptake (.VO2), and carbon dioxide production (.VCO2) using a breath-by-breath respiratory gas analyzer. RESULTS: The exercise capacity of HH subjects was not statistically different from that of control subjects (exercise time 564 +/- 135 vs 673 +/- 175 s, P = 0.191; peak .VO2 29.6 +/- 6.4 vs 32.5 +/- 6.7 mL.kg(-1).min(-1), P = 0.109; ventilatory threshold 19.0 +/- 3.4 vs 21.0 +/- 5.0 mL.min(-1).kg(-1), P = 0.099; data are for HH vs control subjects). Ventilatory efficiency was comparable between groups (.VE/.VCO2 slope 23.7 +/- 3.2 vs 23.4 +/- 4.2, P = 0.791). No significant correlation between the markers of iron levels and the markers of exercise capacity was noted. Iron depletion by 6-month phlebotomy therapy in 18 subjects who were newly diagnosed did not affect exercise testing variables (exercise time 562 +/- 119 vs 579 +/- 118 s, P = 0.691; peak .VO2 29.5 +/- 3.7 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 from before and after phlebotomy therapy). Abnormal ischemic electrocardiographic responses and complex arrhythmias were more frequently seen in HH subjects. CONCLUSIONS: The aerobic exercise capacity of asymptomatic HH subjects seems not to be statistically different from that of normal subjects. The iron levels do not seem to affect exercise capacity in asymptomatic HH subjects.

Significance of left atrial contractile function in asymptomatic subjects with hereditary hemochromatosis.

Patients with hereditary hemochromatosis (HH) have been reported to develop diastolic functional abnormalities detectable by echocardiography, but it is unknown whether these occur in asymptomatic subjects. Thus, this study tested whether echocardiographic left ventricular (LV) relaxation abnormalities are detectable in subjects with asymptomatic HH. Forty-three asymptomatic subjects with HH (C282Y homozygosity in the HFE gene) and 21 age- and gender-matched control subjects without known HFE mutations underwent echocardiography with comprehensive diastolic functional evaluations. Subjects with HH were in New York Heart Association functional class I and consisted of 22 newly diagnosed patients (group A) and 21 chronically phlebotomized subjects with stable iron levels (group B). Group A subjects showed significant iron overload compared with group B subjects and controls (group C) (ferritin 1,164 +/- 886 [p <0.05 vs groups B and C], 128 +/- 262, and 98 +/- 76 microg/L and transferrin saturation 79 +/- 19% [p <0.05 vs groups B and C], 42 +/- 21%, and 26 +/- 10% for groups A, B, and C, respectively). Echocardiographic evaluation revealed (1) no statistically significant abnormalities of Doppler LV relaxation in HH groups; (2) significant augmentation of atrial contractile function in subjects with HH compared with controls, which was not correlated with iron levels and treatment status; and (3) the preservation of overall LV systolic function in HH groups. In conclusion, the results of this study suggest that the augmentation of atrial contraction appears to be an early detectable echocardiographic cardiac manifestation of abnormal diastolic function in asymptomatic subjects with HH, which may reflect undetectable subclinical LV relaxation abnormalities.

Left ventricular systolic function during stress echocardiography exercise in subjects with asymptomatic hereditary hemochromatosis.

There is no information available on left ventricular (LV) systolic function and the response to stress echocardiography in asymptomatic subjects with hereditary hemochromatosis (HH). To evaluate this topic, 43 asymptomatic subjects with HH homozygous for the C282Y HFE gene mutation (22 untreated subjects [group A] and 21 long-term treated subjects [group B]) were compared with 21 age- and gender-matched normal volunteers negative for HFE mutations. Contractile reserve, as a measure of LV systolic function, was assessed using continuous echocardiographic imaging and electrocardiography during supine bicycle exercise. Nineteen subjects in group A had repeat tests after 6 months of induction phlebotomy therapy to assess the effect of iron removal. Exercise performance and hemodynamic variables of supine bicycle exercise were comparable between subjects with HH and controls. LV contractile reserve of asymptomatic subjects with HH was not impaired at either a 75-W submaximal exercise level (mean +/- SD difference in ejection fraction from baseline 13.8 +/- 6.2%, 11.5 +/- 6.8%, and 13.4 +/- 7.8% in groups A, B, and C, respectively; p = NS for all by analysis of variance) or at peak exercise (difference in ejection fraction from baseline 18.9 +/- 6.9%, 18.4 +/- 7.8%, and 20.3 +/- 8.1% in groups A, B, and C, respectively; p = NS for all by analysis of variance). However, the incidence of abnormal ischemic stress electrocardiographic responses was more frequent in subjects with HH as a whole (33%) compared with normal subjects (10%). Stress imaging revealed no regional wall motion abnormalities, suggesting that these were false-positive results. Iron removal by induction phlebotomy did not affect stress echocardiographic performance. In conclusion, LV systolic function during exercise in asymptomatic subjects with HH is preserved, and 6-month induction phlebotomy does not affect stress echocardiographic performance.

Iron Overload or Oxidative Stress? Insight into a Mechanism of Early Cardiac Manifestations of Asymptomatic Hereditary Hemochromatosis Subjects with C282Y Homozygosity.

Hereditary hemochromatosis (HH) is a genetic disorder which affects the heart due to systemic iron overload and concomitant elevated oxidative stress. Increasing numbers of patients are diagnosed at an asymptomatic stage due to genetic testing. Subclinical abnormal left ventricular diastolic function (LVDF) and increased arrhythmias are noted in this population; however, the mechanism leading to these observances has not been well understood. In this study, we assessed the relationship between arrhythmia activity and biomarkers of oxidative stress and iron overload in order to elucidate the role of oxidative stress in this population since we observed a significant association with LVDF previously. A significant correlation between plasma malondialdehyde, a biomarker of oxidative stress, and supraventricular arrhythmia activity without a significant association with iron overload was identified (n = 22). Our findings further highlight a possible role of oxidative stress in early cardiac manifestations of HH. Further investigation is warranted to assess this role.

Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation.

Changes in exercise capacity in subjects with cardiac asymptomatic hereditary hemochromatosis during a follow-up after 5 yrs.

OBJECTIVE: A long-term effect of hereditary hemochromatosis (HH) on aerobic exercise capacity (AEC) has not been well described. DESIGN: Forty-three HH and 21 volunteer control subjects who were asymptomatic underwent cardiopulmonary exercise testing using the Bruce protocol. AEC was assessed with minute ventilation (V(E)), oxygen uptake (V(O)(2)), and carbon dioxide production (V(CO)(2)) at baseline and at a follow-up assessment after 5 yrs. A paired t test was used for analyses of normality data; otherwise, Wilcoxon's signed rank-sum test was used. RESULTS: Thirty-three HH subjects and 18 volunteer control subjects returned for a repeat cardiopulmonary exercise testing at the fifth-year follow-up (80% overall return rate). At the fifth-year follow-up, AEC was not different between the two groups. Compared with baseline measurements, exercise time, peak V(O)(2), and the V(E)/V(CO)(2) slope did not differ statistically at the fifth-year follow-up between both groups. Iron depletion through phlebotomy for 5 yrs did not significantly affect AEC in newly diagnosed HH subjects at baseline (n = 14) and cardiac arrhythmias during exercise tended to decrease after 5 yrs of therapy in this group. CONCLUSIONS: The AEC of asymptomatic HH subjects treated using conventional therapy is not statistically affected by the disease during a 5-yr period.

Changes in left ventricular diastolic function of asymptomatic hereditary hemochromatosis subjects during five years of follow-up.

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.

Iron overload cardiomyopathy: better understanding of an increasing disorder.

The prevalence of iron overload cardiomyopathy (IOC) is increasing. The spectrum of symptoms of IOC is varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. Biochemical markers and tissue biopsy, which have traditionally been used to diagnose and guide therapy, are not sensitive enough to detect early cardiac iron deposition. Newer diagnostic modalities such as magnetic resonance imaging are noninvasive and can assess quantitative cardiac iron load. Phlebotomy and chelating drugs are suboptimal means of treating IOC; hence, the roles of gene therapy, hepcidin, and calcium channel blockers are being actively investigated. There is a need for the development of clinical guidelines in order to improve the management of this emerging complex disease.

Heart rate recovery is lower following supine exercise in asymptomatic hereditary hemochromatosis subjects compared with healthy controls.

INTRODUCTION: Heart rate recovery (HRR) has become an important diagnostic and prognostic marker in recent years. Subjects with hereditary hemochromatosis (HH) demonstrate arterial wall changes that reduce compliance. Arterial compliance may influence HRR by altering baroreceptor discharge. The purpose of the present study is to examine differences in HRR between subjects with HH and healthy controls during treadmill (TM) and supine lower extremity ergometry (SLEE) exercise testing. METHODS: Forty subjects with asymptomatic HH (27 men/13 women; mean age: 49.7 +/- 9.9 years) and 21 healthy controls (14 men/7 women; mean age: 47.8 +/- 8.4 years) participated in this study. Each subject underwent a symptom-limited 25-W Supine Lower Extremity Ergometry (SLEE) and Bruce TM exercise test within 1 week of each other. Heart rate recovery was the value obtained at 1 minute postexercise. Peak heart rate, systolic blood pressure, and the double product were also obtained during each exercise test. RESULTS: Peak heart rate was significantly higher, whereas HRR and peak systolic blood pressure were significantly lower during TM compared with SLEE exercise testing in both groups (P < .01). A significantly lower HRR during SLEE in subjects with HH was the only significant difference between groups (35.4 +/- 9.0 vs. 29.2 +/- 8.5, P < .01). DISCUSSION: Heart rate recovery was not significantly different between HH and control subjects during upright exercise. However, HRR was significantly lower during SLEE in HH subjects compared with controls. A higher venous return during SLEE may have allowed for differences in arterial compliance between groups to influence HRR.

A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus.

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (Vo(2max)) or their skeletal muscle mitochondrial copy number. The baseline Vo(2max) correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, Vo(2max) reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.