Hereditary hemochromatosis with homozygous C282Y HFE mutation: possible clinical model to assess effects of elevated reactive oxygen species on the development of cardiovascular disease.

Hereditary hemochromatosis with the homozygous C282Y HFE mutation (HH-282H) is a genetic condition which causes iron overload (IO) and elevated reactive oxygen species (ROS) secondary to the IO. Interestingly, even after successful iron removal therapy, HH-282H subjects demonstrate chronically elevated ROS. Raised ROS are also associated with the development of multiple cardiovascular diseases and HH-282H subjects may be at risk to develop these complications. In this narrative review, we consider HH-282H subjects as a clinical model for assessing the contribution of elevated ROS to the development of cardiovascular diseases in subjects with fewer confounding clinical risk factors as compared to other disease conditions with high ROS. We identify HH-282H subjects as a potentially unique clinical model to assess the impact of chronically elevated ROS on the development of cardiovascular disease and to serve as a clinical model to detect effective interventions for anti-ROS therapy.

Advancement of echocardiography for surveillance of iron overload cardiomyopathy: comparison to cardiac magnetic resonance imaging.

The prevalence of iron overload cardiomyopathy (IOC) is increasing. Patients with transfusion-dependent anemias or conditions associated with increased iron absorption over time are at a significant risk for the development of iron-overloaded states such as IOC. Current guidelines regarding the diagnostic evaluation and follow-up of patients at risk for IOC exist, and are composed of multiple components, including such as echocardiography, genetic testing, magnetic resonance imaging of liver, and cardiac magnetic resonance imaging (CMR). While these are considered reliable for the evaluation of patients at risk for an iron-overloaded state, there is an access challenge associated with initial and serial CMR scanning in this patient population. Furthermore, there are other limiting factors, such as patient characteristics that may preclude the use of CMR as a viable diagnostic imaging modality for these patients. On the other hand, recent evidence in the literature suggests that transthoracic echocardiography, which has had significant technological advances, can equal or even outperform CMR to identify cardiac functional abnormalities such as subclinical left ventricular strain and left atrial functional abnormalities in iron overload conditions. Therefore, there is a potential role of more frequent use of echocardiography for surveillance of the development of IOC. Our purpose with this narrative review is to describe recent advances in echocardiography and propose a potential increased use of echocardiography in the surveillance of the development of IOC.

Iron overload and arrhythmias: Influence of confounding factors.

Arrhythmias as a cardiac complication of iron overload (IO) have been well described for decades in the clinical literature. They are assumed to be directly associated with the myocardial accumulation of iron. However, the influence of heart failure and elevated oxidative stress, which are major arrhythmogenic confounding factors associated with IO on arrhythmias, has not been critically reviewed in the published literature. A comprehensive narrative review of published articles in PubMed was conducted to address the influence of confounding factors of IO on arrhythmias. The previous data may have been largely confounded by the other cardiac complications of IO, particularly heart failure. The previous studies on IO-related arrhythmias lack proper age-gender-matched control subjects and/or comparison groups with properly controlled confounding factors to assess accurately their etiology and clinical significance. Given the above considerations, further mechanistic investigations to clarify the etiology and clinical relevance of IO-induced arrhythmias are needed. In addition, investigations to develop arrhythmia management strategy specific to IO, are warranted.

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.

Complex single ostium coronary artery from the right coronary sinus with unique course of anomalous left circumflex coronary artery.

Single ostium coronary artery is a rare coronary artery anomaly. It is reported to occur in only 0.0448% of cases who underwent invasive coronary angiography. It can be associated with angina, arrhythmias, and possibly sudden death and is a clinically important entity to rule out in patients presenting with chest pain. We report the case of a 68-year old man who presented with worsening resting chest pain and underwent invasive coronary angiography and a single ostium coronary artery was identified. Subsequent coronary computed tomography (CT) angiography revealed it to be a unique variation of class R-III of Lipton classification of single ostium coronary artery. Lipton R-III single ostium coronary artery is rare and its incidence is reported to be 0.004% in patients who had invasive coronary angiography. In our case, anomalous left coronary circumflex artery was retroaortic course combined with intramyocardial course. It also divided into multiple obtuse marginal branches in the myocardium and never coursed along the anterior and lateral aspects of the arterioventricular groove. This variation has not been reported in the literature. Coronary CT angiography played an essential role to delineate this complex coronary anomaly. .

A new variation of dual left anterior descending coronary artery.

A 63-year-old male with past medical history of type II diabetes mellitus, hypertension, hyperlipidemia, stroke, and permanent pacemaker implant for poor chronotropic response to exercise underwent coronary computed tomography angiography (CCTA) for worsening atypical chest pain. The patient had normal myocardial perfusion by nuclear stress testing 3 months prior to this test. A rare variation of dual left anterior descending coronary artery (LAD) was identified by CCTA and subsequent coronary angiography confirmed a dual LAD and revealed no significant stenosis of the coronary arteries. Six types of dual LADs have been previously reported. However, this case showed a short LAD directly originating from the left coronary sinus and long LAD originating from the left main coronary artery. This configuration has not been reported previously in the literature to our knowledge. The short LAD main stem showed an intramyocardial course and provided septal perforators to the basal-mid interventricular septum (IVS) and right ventricular branches. The long LAD provided both diagonal branches and septal perforators to the distal IVS. CCTA in conjunction with coronary angiography played an essential role to characterize this anomaly and awareness of this anomaly merits reducing misinterpretation of coronary angiography for cardiology care providers. .

Clinical significance of left atrial volume in clinical outcomes of heart transplant recipients.

BACKGROUND: Left atrial volume (LAV) is surgically kept enlarged in heart transplant (HT) recipients. On the other hand, LAV has been known an independent predictor of various cardiovascular diseases and is associated with exercise capacity of HT recipients. Thus, we evaluated the hypothesis that LAV is still associated with clinical outcomes in HT recipients whose left atria are artificially enlarged. METHODS: Clinical outcomes over 5 years after HT were retrospectively evaluated in 35 HT recipients who had a LAV measurement with echocardiography at 1 year after HT at the University of Cincinnati Medical Center. The LAV was derived from a stacked disc method using apical 4 and 2 chamber views. RESULTS: The average LAV normalized to body surface area was 38.3 ± 9.9 ml/m(2) (mean ± SD) at 1 year after HT. Two deaths and one drop-out occurred during 5-year follow up. A total of 552 cardiac symptom-related hospitalizations occurred in the recipients. The average time to first hospitalization was 166 ± 279 days and average number of hospitalizations of each recipient was 15 ± 16. The indexed LAV failed to correlate with the time to first hospitalization and number of hospitalizations of each recipient (Spearman's p-value; 0.141 and 0.519 respectively). When the patients were divided to groups of large LAV (n = 17) and small LAV (n = 18) using the cut off value of the mean LAV, no significant difference was noted in mortality, hospitalization, and new onset of atrial fibrillation between the groups. CONCLUSIONS: Although our study is limited by a retrospective study design and relatively small number of patients, our results implicate that LAV is not significantly associated with clinical outcomes in HT recipients over 5 years after HT.

Functional assessment of donor and recipient left atrium in heart transplant patients using full-volume three-dimensional echocardiography.

BACKGROUND: Atrial function plays an important role in many cardiac conditions, how recipient and donor compartments of left atrium (LA) of transplanted hearts differentially contribute to overall LA function in transplanted hearts has not been described. We tested whether three-dimensional transthoracic echocardiography (3DE) could be used to calculate these compartment-specific atrial functions. METHODS AND RESULTS: We analyzed 3DE images of 22 consecutive transplant patients who had diagnostic imaging quality (ages 59 ± 16 years) using TomTec Research Arena. The contour of the recipient and total LA were traced frame by frame, and the donor LA volume was calculated as the difference of the total LA volume minus the recipient LA volume. The LA ejection fractions of total LA, donor LA, and recipient LA were also calculated as (LA atrial end-diastolic volume - LA atrial end-systolic volume)/LA atrial end-diastolic volume of each compartment. Interobserver variability of LA volumes for the total, recipient, and donor compartments were 5.6 ± 2.4, 5.4 ± 2.0, and 9.3 ± 3.2 mL, respectively (n = 11). The donor LA ejection fraction was higher than that of recipient (41 ± 18% vs. 30 ± 14%, P = 0.013). When the patients were categorized as asymptomatic (New York Heart Association functional class [NYHA] functional class I) and symptomatic (NYHA functional class II-III), indexed donor LA atrial end-diastolic volume was significantly lower in asymptomatic patients as compared with symptomatic patients. CONCLUSIONS: Compartment-specific LA volumes can be calculated in orthotopic heart transplant patients using full-volume 3DE. Our findings may suggest that unique contribution of each LA compartment of transplanted hearts toward the symptoms of these patients.

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.

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 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.

Diagnostic performance of computed tomography angiography for differentiating ischemic vs nonischemic cardiomyopathy.

BACKGROUND: Although the use of computed tomography angiography (CTA) is considered "appropriate" to distinguish ischemic vs nonischemic etiology in patients with cardiomyopathy under the current clinical practice guideline, the evidence to support this has not been evaluated in larger scale studies. Thus, we conducted a meta-analysis of available studies published by October 2010 to address this question. METHODS: Studies evaluating the diagnostic accuracy of CTA versus invasive coronary angiography (as the gold standard) for significant coronary artery disease (CAD) detection (ischemic cardiomyopathy) in patients with no known history of CAD with significantly depressed left ventricular function (ejection fraction; EF < 35%) were selected for the meta-analysis. Sensitivity, specificity, positive, and negative likelihood ratios were calculated on per patient and per segment basis using random effects model (DerSimonian-Laird Method) for computing summary estimates and receiver operator curve (ROC) analysis for evaluating overall diagnostic accuracy. RESULTS: Six studies comprising 452 patients met the selection criteria for the meta-analysis. The pooled patient population was 62 ± 3 years old, with 29% females, 16% diabetics, and 43% with a history of hypertension. Mean EF was 32% ± 1%. The pooled summary estimate of sensitivity of CTA for diagnosis of ischemic cardiomyopathy was 98% [95% confidence interval (CI); 94% to 99%] and specificity was 97% (CI 94% to 98%), yielding a negative likelihood ratio of 0.06 (CI 0.02 to 0.13) and positive likelihood ratio of 20.85 (CI 12 to 36). There was no significant heterogeneity between studies for these estimates. The receiver operator curve analysis showed a robust discriminate diagnostic accuracy of ischemic etiology with an area under curve of 0.99 (P < .00001). CONCLUSION: CTA appears as a clinically applicable accurate diagnostic modality to exclude ischemic etiology in patients with cardiomyopathy of undetermined cause and this further supports the appropriateness of the use of CTA to determine the cause of new onset cardiomyopathy of unknown etiology.

Personalized echocardiography: clinical applications of advanced echocardiography and future directions.

Future cardiology practice will be increasingly individualized, and thus to maintain its central role, echocardiography must keep pushing to expand the boundaries of real-time data acquisition from tissue and fluid motion, and yet still provide efficient and timely data analysis that leads to succinct, clear clinical recommendations tailored to each person in our care. In this article, recent efforts to expand echocardiography techniques into an era of increasingly personalized cardiology, including advances in color-coded tissue Doppler, 3D echocardiography and complex exercise stress echocardiography are described. The common metric for success in each of these efforts is the development of robust and institutionally supportable echocardiography protocols for specific cardiology disease populations that currently may be underdiagnosed and/or undertreated. The common result in each case should be the creation of new guidelines that can supplement the current standard protocols advocated by professional echocardiography organizations.

Does left atrial volume affect exercise capacity of heart transplant recipients?

BACKGROUND: Heart transplant (HT) recipients demonstrate limited exercise capacity compared to normal patients, very likely for multiple reasons. In this study we hypothesized that left atrial volume (LAV), which is known to predict exercise capacity in patients with various cardiac pathologies including heart failure and hypertrophic cardiomyopathy is associated with limited exercise capacity of HT recipients. METHODS: We analyzed 50 patients [age 57 ±2 (SEM), 12 females] who had a post-HT echocardiography and cardiopulmonary exercise test (CPX) within 9 weeks time at clinic follow up. The change in LAV (ΔLAV) was also computed as the difference in LAV from the preceding one-year to the study echocardiogram. Correlations among the measured parameters were assessed with a Pearson's correlation analysis. RESULTS: LAV (n = 50) and ΔLAV (n = 40) indexed to body surface area were 40.6 ± 11.5 ml·m-2 and 1.9 ± 8.5 ml·m-2·year-1, data are mean ± SD, respectively. Indexed LAV and ΔLAV were both significantly correlated with the ventilatory efficiency, assessed by the VE/VCO2 slope (r = 0.300, p = 0.038; r = 0.484, p = 0.002, respectively). LAV showed a significant correlation with peak oxygen consumption (r = -0.328, p = 0.020). CONCLUSIONS: Although our study is limited by a retrospective study design and relatively small number of patients, our findings suggest that enlarged LAV and increasing change in LAV is associated with the diminished exercise capacity in HT recipients and warrants further investigation to better elucidate this relationship.

Characteristics of exercise-induced intrapulmonary arteriovenous fistula in patients with unexplained exertional dyspnea.

Dynamic appearance of intrapulmonary arteriovenous fistula (AVF) during exercise may be associated with unexplained exertional dyspnea (UED) and can be diagnosed with an agitated saline contrast study during exercise echocardiography. However, the occurrence of AVF during exercise in patients with UED has not been well described. Thus, the frequency of exercise-induced intrapulmonary AVF in the outpatients with UED was retrospectively analyzed. Thirty-nine outpatients (age: 53 ± 12, 33 female) with UED underwent symptom-limited supine bicycle exercise echocardiography. Ten patients (26%) developed exercise-induced intrapulmonary AVF. Patients with and without AVF showed the similar peak exercise heart rate, systolic blood pressure, and rate-pressure product. The patients with AVF demonstrated a small but significant decrease in arterial oxygen saturation with exercise as compare to baseline (95.6 ± 2.8% at peak, vs. 97.5 ± 2.5% at baseline, P < 0.05 with a paired Student t-test). Our study suggests that exercise-induced intrapulmonary AVF is relatively common in the outpatients with UED and associated with mild exercise desaturation; however, the mechanism of desaturation could not be determined by this study. Further investigation to characterize and determine the clinical significance of AVF is warranted.