Browsing by Subject "Ventricular Function, Left"
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Item Clinical assessment of myocardial viability(1995-07-13) Grayburn, Paul A.Item Novel Roles for BET Bromodomain Protein 4 (BRD4) in Cardiac Physiology and Disease(2020-08-01T05:00:00.000Z) Kim, Soo Young; Munshi, Nikhil; Chiang, Cheng-Ming; Rothermel, Beverly A.; Gupta, Rana K.; Hill, Joseph A.; Gillette, Thomas G.Bromodomain (BRD) protein of the BET (Bromodomain and Extra-Terminal) family are epigenetic reader proteins that have emerged as novel therapeutic targets in cardiovascular disease as well as in a variety of cancers. Small molecule BET inhibitors, such as JQ1, have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BRD proteins in the heart have not been conducted to validate pharmacological findings and unveil potential side effects. Focusing on BRD4, we tested the hypothesis that cardiomyocyte BRD4 drives pathological cardiac remodeling in the setting of disease-related stress. To facilitate these studies, we engineered a cardiomyocyte-specific BRD4 knockout mouse. Using this model, we investigated the role of BRD4 in cardiac physiology and disease. To our surprise, loss of BRD4 protein triggered a spontaneous and progressive decline in myocardial contractile performance, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse hearts showed early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria confirmed that BRD4 ablation results in specific changes in protein levels and activity of the mitochondrial electron transport chain. Comparative analysis of the JQ1-altered transcriptome suggests that a BRD4-dependent effect of BET inhibition includes changes in transcription of nucleus-encoded mitochondrial genes, raising concerns for cardiotoxicity with potent pharmacological BET inhibition. Furthermore, we tested the roles of BRD4 isoforms, BRD4-L and BRD4-S(a), in cardiomyocyte biology. Isoform-specific knockdown of BRD4 using siRNAs in primary cardiomyocyte culture demonstrated that BRD4-S(a) is required for cardiomyocyte hypertrophy. BRD4-S(a) expression was low in naïve hearts, but it increased significantly in remodeling and failing hearts. Moreover, transgenic over-expression revealed that the BRD4-S(a) isoform is sufficient to induce hypertrophic remodeling and heart failure. In contrast, restoring BRD4-L expression partially rescued systolic dysfunction in animals with a cardiomyocyte specific deletion of BRD4. In conclusion, present study provides evidence that BRD4 regulates cardiomyocyte mitochondrial homeostasis, and that it is required for maintaining normal cardiac function in rodents. Moreover, we demonstrated that the BRD4 short isoform is a driver of pathological cardiac hypertrophy, whereas the long isoform may have a homeostatic role. In aggregate, we have identified novel roles of BRD4 in cardiomyocyte biology, unveiling critical insights - as well as caveats - regarding the therapeutic targeting of BRD proteins in heart failure.Item Point of Care Ultrasonography by Novice Medical Students for Detecting Inferior Vena Cava Collapsibility, Aortic Diameter and Overall Left Ventricular Function in Euvolemic Pediatric Patients(2020-01-21) Dixon, Bryant; Han, Anthony; Hoang, Khiem; Cooper, Michael; Dickinson, Jennifer; Rendon, Juan Mark; Field, Steven; Roppolo, LynnBACKGROUND: Point of care ultrasound (POCUS) is a useful tool in assessing volume status and cardiac function in the emergency department (ED). Research has shown that medical students (MS) are capable of learning and performing POCUS, however further research is warranted to assess MS ability to perform POCUS, specifically in the pediatric population. METHODS: 5 MS were trained in POCUS techniques over a 2-week period. Training included a one hour lecture followed by hands on practice with the MS performing an average of 2.4 aorta scans, 4.4 IVC (inferior vena cava) scans and 6.8 cardiac scans on healthy pediatric and adult volunteers during the training period. MS then began staffing a pediatric ED 24 hours a day for 5 weeks in 12 hour shifts. The MS identified euvolemic patients age 13 years or younger and obtained written consent for 135 patients. The MS collected ultrasound images of the IVC, aorta, and heart with a parasternal long view and apical view of each patient. The MS assessed left ventricular ejection fraction, then measured IVC diameter and aorta diameter. Each scan was reviewed for quality of image acquisition and accuracy of interpretation by an ultrasound fellowship trained emergency medicine physician and reviewed by a second faculty if the first disagreed with the MS interpretation. Quality of the scans were graded based on the American College of Emergency Physician's emergency ultrasound standard reporting guidelines' 5-point scale with a score of 3 or above meeting minimum criteria for diagnosis. RESULTS: Each MS averaged 2.4 aorta, 4.4 IVC and 6.8 heart scans on healthy pediatric and adult volunteers during the training period. 135 patients age 1 week to 13 years were enrolled. Complete studies were available for 115 cardiac scans, 112 IVCs and 113 aortas. Faculty graded 110/115 cardiac scans 3 or above (95.6%; 95% CI 90.1-98.6%) and agreed with 106/112 MS interpretations (94.6%; 95% CI 88.7-98.0%). Faculty graded 95/112 IVC scans as a 3 or above (84.8%; 95% CI 76.8-90.9%) and agreed with 97/110 MS interpretations (88.2%; 95% CI 80.6-93.6%). Faculty graded 97/113 aorta scans as a 3 or above (85.8%; 95% CI 78.0-91.7%) and agreed with 99/111 MS interpretations (89.2%; 95% CI 81.9-94.3%). CONCLUSIONS: MS with minimal training can accurately detect IVC collapsibility, measure aortic size and assess cardiac contractility in euvolemic pediatric patients.Item Time-sensitive decision making in severe heart failure: STAGE D, SCAI E, IMACS 1, UNOS 2, and more(2022-02-11) Farr, Maryjane