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.

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.

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.

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.

Spontaneous left main coronary artery dissection complicated by pseudoaneurysm formation in pregnancy: role of CT coronary angiography.

We report a case of a 26-year-old female, who presented at 34 weeks of an uncomplicated pregnancy with an acute ST elevation anterior wall myocardial infarction. Cardiac catheterization suggested a left main coronary artery dissection with pseudoaneurysm formation. The patient's course was complicated by congestive heart failure. She was initially managed conservatively by a multidisciplinary team including heart failure specialists, obstetricians, and cardiovascular surgeons. 4 days after admission, her LMC was imaged by dual-source 64 slice Cardiac computed tomography, coronary dissection was identified extending to the lumen, and the presence of pseudoaneurysm was confirmed. She underwent subsequently a staged procedure, which included placement of an intra-aortic balloon pump, cesarean section, and coronary artery bypass grafting. This case illustrates the utility of coronary artery CT imaging to assess the complexity and stability of coronary artery dissections, thereby helping to determine the need for, and timing of revascularization procedures.

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.

Targeted disruption of p53 attenuates doxorubicin-induced cardiac toxicity in mice.

Use of the chemotherapeutic agent doxorubicin (Dox) is limited by dose-dependent cardiotoxic effects. The molecular mechanism underlying these toxicities are incompletely understood, but previous results have demonstrated that Dox induces p53 expression. Because p53 is an important regulator of the cell birth and death we hypothesized that targeted disruption of the p53 gene would attenuate Dox-induced cardiotoxicity. To test this, female 6-8 wk old C57BL wild-type (WT) or p53 knockout (p53 KO) mice were randomized to either saline or Dox 20 mg/kg via intraperitoneal injection. Animals were serially imaged with high-frequency (14 MHz) two-dimensional echocardiography. Measurements of left ventricle (LV) systolic function as assessed by fractional shortening (FS) demonstrated a decline in WT mice as early as 4 days after Dox injection and by 2 wk demonstrated a reduction of 31 +/- 16% (P < 0.05) from the baseline. In contrast, in p53 KO mice, LV FS was unchanged over the 2 wk period following Dox injection. Apoptosis of cardiac myocytes as measured by the TUNEL and ligase reactions were significantly increased at 24 h after Dox treatment in WT mice but not in p53 KO mice. After Dox injection, levels of myocardial glutathione and Cu/Zn superoxide dismutase were preserved in p53 KO mice, but not in WT animals. These observations suggest that p53 mediated signals are likely to play a significant role in Dox-induced cardiac toxicity and that they may modulate Dox-induced oxidative stress.

Evaluation of pulsed Doppler tissue velocity imaging for assessing systolic function of murine global heart failure.

The feasibility of Doppler tissue imaging (DTI) for assessing global systolic function has not been determined in small animals, particularly at near-conscious heart rates. Therefore, we compared DTI measurements with conventional M-mode-derived fractional shortening in murine global left ventricular systolic dysfunction induced by intraperitoneal doxorubicin (Dox) injection. In all, 13 female C57BL mice received 20 mg/kg of Dox and 12 mice received saline injection (controls). DTI signals were obtained from the inferior wall through parasternal short-axis views. The heart rate was kept at near-conscious level throughout DTI measurements (approximately 500/min). Left ventricular systolic dysfunction was detectable by measurements of fractional shortening from 4 to 14 days after Dox administration. Among DTI measurements, peak systolic velocity and time to peak systolic velocity decreased from 4 to 14 days after Dox injection. Our results indicate that these new DTI measurements appear feasible to assess global left ventricular systolic dysfunction in mice.

Subtype specific roles of beta-adrenergic receptors in apoptosis of adult rat ventricular myocytes.

We have previously reported that beta-adrenergic receptor (beta-AR) stimulation promotes apoptosis in adult ventricular myocytes through PKCepsilon-mediated suppression of ERK. In this study, we investigated differential effects of beta-AR subtypes on this signal pathway. The apoptosis induced by the non-specific beta-AR agonist isoproterenol was largely blocked by the beta(1)-selective antagonist CGP 20712A, but not by the beta(2)-selective antagonist ICI 118551. A pro-apoptotic effect of beta(1)-AR was also blocked by the PKA inhibitor H89, while the protein kinase A (PKA) activators forskolin and dibutyryl-cAMP both induced apoptosis. These results indicate that beta(1)-AR-mediated PKA activation is largely responsible for the apoptosis induced by beta-AR in adult rat cardiac myocytes. This conclusion was also supported by the finding that PKA was preferentially activated by beta(1)-AR over beta(2)-AR. beta(2)-AR selectively induced anti-apoptotic ERK activation in the presence of PKCepsilon suppression, and this ERK activation was sensitive to pertussis toxin. PKCepsilon itself as well as Akt, the other anti-apoptotic factor were activated by both beta-AR subtypes. Thus, beta(1)-AR induces pro-apoptotic signals mainly through PKA activation. In contrast, beta(2)-AR is linked to Gi-mediated ERK activation, which is involved in the anti-apoptotic pathway, and is regulated by PKCepsilon. Therefore, our findings suggest a rather complex role for beta-AR subtypes in the regulation of apoptosis in adult ventricular myocytes.

Protein kinase C-delta modulates apoptosis induced by hyperglycemia in adult ventricular myocytes.

We evaluated the direct effect of hyperglycemia on apoptosis of adult rat ventricular myocytes (ARVM) in vitro. Hyperglycemia (16.5 mM) for 24 h increased apoptosis by greater than threefold (48.2 +/- 4.4%, by the TdT-mediated dUTP nick-end labeling method) compared with baseline (14.7 +/- 2.5%). Hyperosmolarity with mannitol (11.0 mM) in the presence of 5.5 mM glucose also increased apoptosis by approximately twofold of baseline. Both glucose and mannitol treatment resulted in the membrane translocation of protein kinase C (PKC)-delta, and the activation of PKC-delta was confirmed by immune complex kinase assay. PKC-delta-specific translocation inhibitor peptide (deltaV1-1) attenuated only apoptosis induced by hyperglycemia but not by mannitol. A PKC-epsilon-specific translocation inhibitor peptide (epsilonV1-1) affected neither type of apoptosis. Moderate overexpression of PKC-delta by adenovirus gene transfer prevented the antiapoptotic effect of deltaV1-1. Furthermore, deltaV1-1 attenuated the production of reactive oxygen species (ROS) by glucose. Taken together, our results indicate that increased ROS production regulated by PKC-delta is in part responsible for the induction of apoptosis by hyperglycemia and that apoptosis by hyperglycemia is mechanistically different from that by hyperosmolarity.

Protein kinase C-zeta modulates thromboxane A(2)-mediated apoptosis in adult ventricular myocytes via Akt.

We hypothesized that thromboxane A(2) (TxA(2)) receptor stimulation directly induces apoptosis in adult cardiac myocytes. To investigate this, we exposed cultured adult rat ventricular myocytes (ARVM) to a TxA(2) mimetic [1S-[1alpha,2alpha(Z),3beta(1E,3S*),4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) for 24 h. Stimulation with I-BOP induced apoptosis in a dose-dependent manner and was completely prevented by a TxA(2) receptor antagonist, SQ-29548. We further investigated the role of protein kinase C (PKC) in this process. TxA(2) stimulation resulted in membrane translocation of PKC-zeta but not PKC-alpha, -betaII, -delta, and -epsilon at 3 min and 1 h. The activation of PKC-zeta by I-BOP was confirmed using an immune complex kinase assay. Treatment of ARVM with a cell-permeable PKC-zeta pseudosubstrate peptide (zeta-PS) significantly attenuated apoptosis by I-BOP. In addition, I-BOP treatment decreased baseline Akt activity and its decrease was reversed by treatment with zeta-PS. The inhibition of phosphatidylinositol 3-kinase upstream of Akt by wortmannin or LY-294002 abolished the antiapoptotic effect of zeta-PS. Therefore, our results suggest that the activation of PKC-zeta modulates TxA(2) receptor-mediated apoptosis at least, in part, through Akt activity in adult cardiac myocytes.