Yukitaka Shizukuda

β-Adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy

To establish whether catecholamines per se in the absence of significant increases in systolic load induce myocardial damage via apoptosis, rats were treated with vehicle or isoproterenol (400 μg ⋅ kg-1 ⋅ h-1). Apoptotic cardiocytes (Apo) were identified in paraffin-embedded sections using terminal deoxynucleotide transferase-mediated dUTP nick end labeling. Results were confirmed using an independent ligase assay. Systolic blood pressures were comparable in isoproterenol-treated and control rats. Twenty-four hours of treatment with isoproterenol resulted in significant numbers of Apo compared with control [7.9 ± 2.5 vs. 0.3 ± 0.3 (SE) cm-2, P < 0.05]. A cohort of animals was subjected to ventricular pacing to induce a tachycardia equivalent to that induced by isoproterenol, and these animals did not show an increase in Apo. The left ventricular hypertrophy induced by 2 wk of abdominal aortic banding also increased Apo (∼7.2-fold); however, 24 h of isoproterenol infusion did not induce additional Apo in these rats. Thus catecholamines, in the absence of altered systolic load, induce Apo which is not mediated solely by tachycardia. Left ventricular hypertrophy secondary to abdominal aortic banding is associated with Apo, but this does not increase sensitivity to isoproterenol-induced Apo.

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.

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.

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 patients 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.

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. (ECHOCARDIOGRAPHY, Volume 26, November 2009)

Current and Future Applications of SAGE to Cardiovascular Medicine

The recently sequenced mammalian genomes represent unprecedented resources for advancing our understanding of human diseases. Characterizing gene expression is an important step in translating genomic sequences into clinically useful information. Currently, gene expression studies are revolutionizing the approaches taken to address both basic science and clinical questions. Two major methods have emerged for the global examination of the transcriptome: microarrays and Serial Analysis of Gene Expression (SAGE). The SAGE technique comprehensively maps gene transcription by using the genomic database, yet it remains relatively underutilized for studying cardiovascular biology. This review describes current cardiovascular studies using the SAGE technique and outlines some potential strategies for employing this powerful tool to further our understanding of the cardiovascular system in health and in disease.

Does left atrial volume affect exercise capacity of heart transplant recipients

BackgroundHeart 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.MethodsWe 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 Pearsons correlation analysis.ResultsLAV (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).ConclusionsAlthough 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.

Effect of a Histone Deacetylase Inhibitor on Human Cardiac Mass

T he histone deacetylase (HDAC) inhibitors are a promising new class of cancer chemotherapeutic agents [1]. Interestingly, growing evidence indicates that this class of drugs can also affect post-mitotic cells such as cardiac myocytes. In particular, both Class I and II HDACs appear to play an important role in regulating cardiac hypertrophy [2,3]. Based on these pre-clinical observations, there is also concern, however, that cardiac mass may be adversely affected by the longterm use of HDAC inhibitors for oncological therapy. Depsipeptide (FR901228 or FK228), a relative class I HDAC inhibitor (inhibiting HDAC1 and HDAC2) [4], is undergoing phase 2 testing for patients with T-cell lymphoma in our Institutes [5]. Thus, we reviewed the cardiac mass determinations in patients who were enrolled in our protocols using depsipeptide as a therapeutic agent. Twelve patients treated at the NIH had the cardiac mass assessment with echocardiograms performed prior to and at set times after initiation of therapy as part of the protocol and had received treatment for a minimum of three months. All patients provided written informed consent for testing and treatment approved by the Institutional Review Board of the National Cancer Institute. Ten patients with cutaneous T-cell lymphoma and two with peripheral T-cell lymphoma were treated with 10.5 or 14 mg/m2 (depending on individual patient tolerability) of depsipeptide once a week for three out of four weeks. As previously described, this amount of drug produced significant EKG changes in all patients and was sufficient to induce changes in histone acetylation levels in circulating blood cells [5]. Seven patients responded to therapy (3 complete responders, 4 partial responders), two patients maintained stable disease for 6 months duration, and three patients had progressive disease (2 after 3 months of therapy and one after 6 months). Despite the observed effect on the patients’ cancer, the cardiac mass, as assessed by two-dimensional echocardiography, did not change significantly during the prolonged course of therapy (Fig. 1). Fig. 1. Cardiac mass during the depsipeptide therapy. Mass was assessed by two-dimensional echocardiography using the recommendations of the American Society of Echocardiography [6]. Mass measurements were made by a single, blinded observer. White circles with a horizontal bar show mean values. The vertical bars at the white circles indicate S.E.M. BL = measurements at baseline before the initiation of treatment.

Use of bicycle exercise echocardiography for unexplained exertional dyspnea.

Unexplained exertional dyspnea is a common and perplexing clinical problem. Myocardial ischemia and left ventricular systolic dysfunction are important cardiac causes, but are often not detected in these patients. Recently, exercise‐induced left ventricular diastolic dysfunction and exercised‐induced pulmonary hypertension have emerged as common alternative mechanisms. While conventional exercise treadmill echocardiography effectively diagnoses left ventricular systolic dysfunction and myocardial ischemia, it has limited ability to detect exercise‐induced diastolic dysfunction or pulmonary hypertension. The latest advances in exercise echocardiography, including utilization of tissue Doppler imaging and harmonic imaging, make noninvasive evaluation of both conventional and alternative cardiac causes of exertional dyspnea possible. These advancements, when coupled with newly designed supine exercise platforms for bicycle exercise echocardiography (BE), facilitate the detection of exercise‐induced diastolic dysfunction and pulmonary hypertension. Moreover, BE using supine ergometry additionally permits the dynamic evaluation of valvular function and interatrial shunting and detection of pulmonary arteriovenous fistula, uncommon but important causes of unexplained exertional dyspnea. Therefore, we propose that because of its superior diagnostic capabilities, BE should be included as part of a comprehensive cardiac evaluation of patients with unexplained exertional dyspnea. Copyright

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.