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.

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.

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.

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.

Customized exercise echocardiography: beyond detection of coronary artery disease.

Exercise echocardiography has been established as a reliable diagnostic tool for assessment of myocardial ischemia. However, more recent advances in its technique have expanded its routine clinical use to include quantification of exercise-induced diastolic dysfunction, exercise-induced pulmonary hypertension, and dynamic assessment of mitral and aortic valve function. The indications for exercise echocardiography have increased to include cardiac symptoms such as exertional dyspnea, fatigue, and limited exercise capacity. In light of its expanded capability for evaluating cardiovascular function, we believe that exercise echocardiography should be utilized in a new paradigm of personalized cardiology, in which we regularly investigate individual patient symptoms for endpoints beyond critical myocardial ischemia, for example, exercise-induced pulmonary hypertension. We refer to this refocused use of exercise echocardiography as "customized exercise echocardiography." In this review article, we present current scientific evidence to support our proposed role and discuss the logistical requirements for proper test performance of customized exercise echocardiography.

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.

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.

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.

Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

BACKGROUND: The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. METHODS: We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. RESULTS: Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. CONCLUSIONS: Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated.

Pulmonary artery pressure in lymphangioleiomyomatosis: an echocardiographic study.

BACKGROUND: Exercise-induced hypoxemia is frequent in patients with lymphangioleiomyomatosis (LAM) and could be associated with pulmonary hypertension. The aims of this study were to determine the prevalence of pulmonary hypertension in patients with LAM, to identify physiologic parameters associated with its occurrence, and to evaluate the effect of oxygen on response to exercise. METHODS: Studies were performed in 120 patients. Complete data, including exercise echocardiography, pulmonary function testing, and standard cardiopulmonary exercise testing, were obtained in 95 patients. RESULTS: Resting pulmonary artery pressure (PAP) was 26+/-0.7 mm Hg (mean+/-SEM). Eight patients had pulmonary hypertension (43+/-3 mm Hg), and two patients had right ventricular dilatation. Ninety-five patients exercised (room air, n=64; oxygen, n=31) to a power of 58+/-2 W (49% of predicted) and an estimated peak oxygen uptake of 938+/-30 mL/min (56% of predicted). Sixty-one patients had a decline in arterial oxygen saturation (SaO2)>3%, and 56 patients had an elevation in PAP>40 mm Hg. Peak exercise PAP was negatively correlated with exercise Sao2 (p=0.0005). Multivariate analysis showed that exercise SaO2 was the best predictor of exercise PAP (p=0.012). CONCLUSIONS: Although resting pulmonary hypertension is rare in patients with LAM, a rise in PAP at low exercise levels occurs frequently, in part related to exercise-induced hypoxemia. Optimization of oxygen administration during activities of daily living should be undertaken in patients with LAM to prevent hypoxemia and exercise-induced pulmonary hypertension.

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.

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. .

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. .

Left atrial volumetric remodeling is predictive of functional capacity in nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The left atrium is afterload sensitive, responding to immediate changes in left ventricular (LV) diastolic pressure, and left atrial volumetric remodeling has been reported in conditions associated with abnormal diastolic function. We examined the relationship between left atrial volumetric remodeling and objective measures of exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (HCM). METHODS: We compared LA volume indices, other 2-dimensional and Doppler echocardiographic parameters, invasive hemodynamic measures, and magnetic resonance imaging (MRI)-derived LV mass with exercise duration, maximal oxygen uptake (MV* O2), anaerobic threshold (AT), and ventilatory efficiency (VE/V* CO2 slope) in 43 patients with nonobstructive HCM. Patients underwent cardiac catheterization within 48 hours and metabolic stress testing within 1 week of their echocardiogram and MRI examinations. RESULTS: Left atrial volume at end-ventricular systole (LA max) and end-atrial emptying (LA min) correlated with MV* O2 (r = -0.39, P < .01 for both), AT (r = -0.42, r = -0.39, respectively, P < .01 for both), and VE/V* CO2 slope (r = 0.45, P = .003; r = 0.41, P = .008). Patients with an LA max > or =33 mL/m2 had significantly lower MV* O2 (P = .025) and AT levels (P = .017) and higher VE/V* CO2 slope levels (P = .004) as compared with patients with a smaller LA size. In multivariate analysis, MRI-determined LV mass, which was not a univariate correlate of exercise tolerance, provided additional effect when combined with LA volume index. CONCLUSIONS: Left atrial volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reflect chronic LV diastolic burden. This simple noninvasive measure of LA size may provide a long-term indication of the effects of chronically elevated filling pressures in patients with HCM and further studies testing its prognostic value are necessary.