Introduction: Takotsubo cardiomyopathy or stress cardiomyopathy is a syndrome of transient left ventricular (LV) dysfunction mimicking myocardial infarction, but lacking obstruction of coronary artery disease (CAD) or acute plaque rupture. A characteristic differentiation from CAD is that regional motional abnormality extends beyond a territory perfused with a single epicardial coronary artery. Clinically, it is characterized by apical ballooning of the LV due to due to depression of mid and apical segments, with hyperkinesis of cardiac basal walls. Women are affected more than men, predominantly in the postmenopausal age. Case Report: A 54-year-old Caucasian female with a history of COPD, hypertension, uncontrolled diabetes mellitus, hyperlipidemia, depression and ongoing tobacco use presented with complaints of worsening shortness of breath two days prior to admission. She denied chest pain, worsened cough, palpitations, nausea or vomiting. On examination, she was in distress and anxious, with labored breathing. Upon examining the chest, decreased air entry was present in both lung fields with bibasilar wheezing. Initial lab tests showed mild respiratory acidosis, with pH of 7.24, pCO2 of 47.4 and pO2 of 65. Troponins on the day of admission was Soon after admission, she started complaining of severe right neck pain. Repeat EKG revealed localized lateral J point, anteroseptal q waves and 4mm ST-segment elevation in leads V3 and V4 reciprocal changes and without chest pain. Repeat troponins were slightly elevated to 0.42 ng/ml and CK-MB was elevated to 20.2 ng/ml. A transthoracic echocardiogram showed regional abnormalities in left ventricle with the apex, mid to distal septum and the anterior part of septum was akinetic. Discussion: Takotsubo cardiomyopathy presents in 1 to 2 percent of troponin-positive acute coronary syndrome (ACS) with various clinical manifestations and various outcomes. Some patients have favorable outcomes based on their clinical performance and extent of cardiac muscle involvement. As in the case we presented, this syndrome can be entirely idiopathic, without a definitive underlying cause. Supportive management while hospitalized and early identification of complications improve the prognosis.

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) and pre-diabetic cardiomyopathy (pre-DC) are two cardiac diseases characterized by dysfunction in sarcoplasmic reticulum (SR) Ca2+ release channel RyR2. Despite similar defects in RyR2 leading to aberrant Ca2+ release (ACR), CPVT and pre-DC display divergent pathological phenotypes. Recent findings suggest SR-mitochondria interplay could contribute to pathological development; therefore, the role of SR-mitochondria interplay in shaping intracellular Ca2+ signaling was examined in CPVT and pre-DC by pharmacologically modulating mitochondria Ca2+ handling. Mitochondria can affect cytosolic/global Ca2+ dynamics through at least two mechanisms: buffering cytosolic Ca2+, or generating ROS to modulate RyR2 functionality via posttranslational modifications. Our data from cellular experiments suggests that CPVT mitochondria buffer Ca2+ to alleviate ACR, while pre-DC mitochondria cannot handle excess Ca2+, generating excess ROS to exacerbate ACR. These results were further consolidated by genetic models specifically targeting mitochondria Ca2+ handling proteins, which provided additional evidence SR-mitochondria crosstalk shapes cardiac pathological phenotypes.

Heart disease has been the leading cause of death in the United States for more than 90 years. The leading cause of death in individuals aged 65 and older has remained diseases of the heart from 1950 to the current time. According to the CDC, once diagnosed with heart disease, individuals have an approximately 50% chance of dying within 5 years, regardless of race. Mortality related to heart disease increased dramatically from the start of the 1900s to 1921, but subsequently experienced a steady decline from the mid-1960’s to 2000. However, when the decrease in heart disease is examined at the level of race it is clear that the decrease is not equally shared. While the leading cause of death among both Caucasian American men and women and African American men and women remains heart disease, the decrease in incidence of coronary heart disease among African American men was only half of the decrease in incidence among Caucasian American men. Genetic variants in BAG3 (Bcl-2 associated athanogene 3), a highly evolutionarily conserved gene that has recently emerged as a major dilated cardiomyopathy locus, are prevalent in isolated populations. This led us to hypothesize that variants in BAG3 might contribute to the increased prevalence of IDC in individuals of African ancestry. Expressed predominantly in the heart, the skeletal muscle and in many cancers, BAG3 has pleotropic effects in the heart. It inhibits apoptosis by binding to Bcl-2, facilitates protein quality control by binding to both large and small heat shock proteins, mediates adrenergic responsiveness by coupling the β-adrenergic receptor and the L-type Ca2+ channel, and maintains the integrity of the sarcomere by anchoring actin filaments to the Z disc. However, a paucity of subjects of African ancestry have been included in cohorts of probands with familial dilated cardiomyopathy whose exomes or genomes have been sequenced. Based on our previous observations and reports from other groups we postulated: 1) that mice with haplo-insufficiency of BAG3 will re-capitulate disease seen in humans and serve as a model for studying the pathogenesis of BAG3. 2) The prevalence or identification of specific BAG3 variants will differ by race and/or ethnicity. 3) SNVs of BAG3 may contribute to disease progression and thereby be pathogenic. Our study points out that we cannot understand population-based differences without enhancing the diversity of populations included in genomic studies. Similarly, in the era of big data, efforts must be undertaken to assess the genetic profile of both probands and their family members as without the ability to measure segregation, penetrance and plasticity we can only ascribe associations to functional genetic variants. / Biomedical Sciences

Dilated cardiomyopathy (DCM) or round heart disease is a muscle disease of the heart characterized by left ventricular dilatation and abnormal systolic and diastolic ventricular function. In animals, including turkeys and humans, DCM is a major cause of morbidity and mortality that results in heart failure. In the turkey, DCM can be idiopathic or induced. Since idiopathic or spontaneous DCM occurs in about 2-4 % of normal turkeys, it is of significant concern to the poultry industry. This dissertation was designed to increase our understanding of the pathophysiology of DCM in commercial turkeys. Specific objectives included: evaluating the influence of dietary selenium (Se) and vitamin E on poults fed toxic levels of furazolidone (Fz). Evaluating differences among reciprocal crosses of turkey varieties in susceptibility to a toxic level of Fz that induces DCM were used to assess the role of genetics in DCM. Using glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and plasma uric acid (PUA) as biomarkers, oxidative stress (OS) levels were evaluated. Oxidative stress was also evaluated in poults fed diets containing varying concentration and combinations of vitamin E (0, 50 and 100 IU/kg) and Se (0.0, 0.3 and 0.5 mg/kg). Results from echocardiography measurements at four weeks of age, for poults fed toxic levels of Fz, showed the Narragansett x Bourbon Red reciprocal cross had the lowest internal-diastolic (LVIDd) and systolic dimensions (LVISd), while the Bourbon Red x Narragansett reciprocal cross had the largest LVIDd and LVISd. Left ventricular internal-diastolic and systolic dimension were lower for cross bred than parental poults. In treatment poults, heterosis for ventricular dilation was most significant for Bourbon Red x Narragansett cross. The data suggest that reciprocal crosses respond differently to toxin that induces DCM and genetics may influence a turkey's response to toxic levels of Fz that causes DCM. Results from OS measurements in poults fed normal and those fed normal diets with Fz at two weeks of age, showed no significant differences in MDA and GPx levels. PUA and GSH levels were however significantly increased for poults fed Fz-containing diets. At four weeks of age, no differences were observed for MDA and GPx measurements between poults fed normal and Fz-containing diets. PUA levels increased for poults fed normal diets with Fz, while GSH levels increased only for those fed normal diets. Differences between poults fed normal and Fz-containing diets were significant for GPx measurements. Results of this study showed that, feeding diets with Fz does not increase OS. Measure of the influence of feeding diets supplemented with different concentrations and combinations of Se and vitamin E to poults fed either normal or normal diets with Fz at two and four wks of age, showed higher MDA levels for poults fed Fz-containing diets supplemented with 0.3 mg/kg Se and 100 IU/kg vitamin E. For antioxidant biomarkers, GPx activity were increased for poults fed normal diets with Fz supplemented with 0.5 mg/kg Se and those fed 100 IU/kg vitamin E. Poults fed normal diets supplemented with 100 IU/kg vitamin E had the highest GPx. PUA levels were higher for poults fed normal diets with Fz supplemented with 0.5 mg/kg Se at two wks of age. At four wks of age, PUA concentrations were higher for poults fed Fz-containing diets supplemented with 100 IU/kg vitamin E. Increased PUA were also observed for poults fed diets supplemented with 0.5 mg/kg Se and 50 IU/kg vitamin E and 0.5 mg/kg and 100 IU/kg vitamin E. Poults fed diets supplemented with 50 and 100 IU/kg vitamin E had the highest GSH at two wks of age. Measurements taken at 2 wks of age, for poults fed normal diets supplemented with different concentrations and combinations of Se and vitamin E had increased GSH levels when compared with those fed diets with Fz at four wks of age. In this study, we showed that supplementation of poults fed normal diets with Fz with different concentrations and combinations of Se and vitamin E did not reduce DCM at 2 wks of age. However, at 4 wks of age, though DCM was not decreased by feeding diets supplemented with different concentrations and combinations of Se and vitamin E, reduced oxidant and antioxidant biomarkers were observed. / Ph. D.

Dilated cardiomyopathy (DCM), a disease of the myocardium, causes morbidity and premature death in humans and other domestic animals including turkeys. Though DCM results from many different factors including those that are unknown or idiopathic, genetic factor is a major cause of idiopathic DCM. In this study, I assessed the molecular basis of toxin-induced DCM in turkeys by evaluating the association and effect of mutations in candidate genes in the nucleus and mitochondria on the incidence and severity of this disease. Echocardiographic measurements at 3 weeks of age showed that birds on furazolidone-containing diet exhibited a significant DCM phenotype (increased left ventricular end diastolic dimension and left ventricular end systolic dimension) with a marked decrease in the left ventricular shortening fraction. Pathological phenotype confirmed the dilated heart with extended cell necrosis. Two mutations, both in NADH dehydrogenase genes, were found to be associated with DCM. Real-time RT-PCR quantification indicated that mRNA expression of alpha cardiac actin gene (ACTC) were significantly different between control and treatment birds. While ACTC expression increased, though moderately, in control birds from week 1 to 3, it decreased significantly in treatment birds. These findings suggest that the mitochondrial DNA variation and ACTC expression may be associated with the turkey's response to toxin. Therefore, further research is needed to investigate the molecular mechanism of toxin-induced DCM in the turkey. / Master of Science

Dilated cardiomyopathy (DCM), a heart disease, affects many vertebrates including humans and poultry. The disease can be either idiopathic (IDCM) or toxin-induced. Idiopathic DCM often occurs without a consensus cause. Though genetic and other studies of IDCM are extensive, the specific etiology of toxin-induced is still unknown. Here, our objective was to compare the level of mRNA expression of two candidate genes including troponin T (cTnT) and phospholamban (PLN) using quantitative reverse transcription polymerase chain reaction (RT-PCR) in toxin-induced DCM affected and unaffected turkeys. Cardiac TnT and PLN were chosen because their spontaneous expression has been reported to be associated with IDCM. We also scanned these genes for single nucleotide polymorphisms (SNPs) that could be useful in evaluating their functions in the incidence and severity of toxin-induced DCM in turkeys. There were no significant differences between affected and unaffected birds in the expression of both cTnT and PLN. A total of 12 SNPs were detected in cTnT and PLN DNA sequences. One of the seven haplotypes detected in cTnT was the most frequent. Linkage analysis showed that cTnT gene was unlinked on the current turkey genetic map. Resources developed here, including SNPs, haplotypes, cDNA sequences, and the PCR-RFLP genotype procedure will be used for future investigations involving cTnT and PLN and toxin-induced DCM. / Master of Science

No description available.

Stress cardiomyopathy can cause significant morbidity in the functional life of patients. The most common finding is apical ballooning of the left ventricle on cardiac catheterization. Some cases present with atypical imaging findings. This report presents a case of atypical stress cardiomyopathy with midventricular hypokinesis.