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Gwathmey, Judith Karen

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Gwathmey

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Judith Karen

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Gwathmey, Judith Karen

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1994 - 199912000 - 20031

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Author's Publications: search.filters.isAuthorOfPublication.4ec7caad-9eff-434c-957d-484ffa8f6a6b

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    Chronic Treatment with Carvedilol Improves Ventricular Function and Reduces Myocyte Apoptosis in an Animal Model of Heart Failure
    (BioMed Central, 2003) Okafor, Chukwuka C; Perreault-Micale, Cynthia; Hajjar, Roger J; Lebeche, Djamel; Skiroman, Klara; Jabbour, George; Doye, Angelia A; Lee, Michael X.; Laste, Nancy; Gwathmey, Judith Karen
    Background: \(\beta\)-blocker treatment has emerged as an effective treatment modality for heart failure. Interestingly, \(\beta\)-blockers can activate both pro-apoptotic and anti-apoptotic pathways. Nevertheless, the mechanism for improved cardiac function seen with \(\beta\)-blocker treatment remains largely unknown. Carvedilol is a non-selective \(\beta\)-blocker with \(\alpha\)-receptor blockade and antioxidant properties. We therefore studied the impact of the effects of carvedilol in an animal model of end-stage heart failure. Results: To test whether chronic treatment with \(\beta\)-blockade decreases apoptosis, we treated myopathic turkeys with two dosages of carvedilol, 1 mg/kg (\(DCM_1\)) and 20 mg/kg (\(DCM_{20}\)), for four weeks and compared them to non-treated DCM animals (\(DCM_0\)) and to control turkeys (CON). Echocardiographic measurements showed that non-treated DCM animals had a significantly lower fractional shortening (FS) when compared to CON (68.73 \(\pm\) 1.37 vs. 18.76 \(\pm\) 0.59%, p < 0.001). Both doses of carvedilol significantly improved FS (33.83 \(\pm\) 10.11 and 27.73 \(\pm\) 6.18% vs. 18.76 \(\pm\) 0.59 % for untreated DCM, p < 0.001). DCM left ventricles were characterized by a higher percentage of apoptotic nuclei when compared to CON (5.64 \(\pm\) 0.49 vs. 1.72 \(\pm\) 0.12%, respectively p < 0.001). Both doses of carvedilol significantly reduced the number of apoptotic nuclei (2.32 \(\pm\) 0.23% and 2.36 \(\pm\) 0.26% 1 mg and 20 mg/kg respectively). Conclusions: Carvedilol improves ventricular function. Furthermore, treatment with carvedilol decreased the incidence of apoptosis in cardiac myocytes from failing hearts at both doses. These data suggest that the inhibition of apoptosis with carvedilol may lead to improvement in ventricular function and may underlie a beneficial effect of \(\beta\)-blockade independent of heart rate lowering effects.
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    [Ca2+]i in Human Heart Failure: A Review and Discussion of Current Areas of Controversy.
    (Yale Journal of Biology and Medicine, 1994) Liao, Ronglih; Helm, P. A.; Hajjar, R. J.; Saha, C.; Gwathmey, Judith Karen
    Multiple abnormalities have been reported in the setting of human heart failure. It is unclear whether detected changes reflect adaptive alterations in myocardium subjected to increased and sustained hemodynamic overload or are pathogenic to the disease process. As a result of the observation that the primary defect in heart failure is decreased pump function, investigators have concentrated their efforts on determining systolic [Ca2+]i as a logical corollary and a causative mechanism for contractile dysfunction. A simple cause and effect relationship has therefore been proposed with regard to contractile dysfunction and [Ca2+]i. Yet some investigators have found no difference in peak systolic [Ca2+]i between failing and non-failing human myocardium, whereas others have found peak [Ca2+]i to be significantly reduced in failing hearts. Resting calcium concentrations have been reported either to be elevated in failing human myocardium or not different from non-failing human myocardium. Investigators should now appreciate that the force-calcium relationship is not a simple relationship. One must take into account the prolonged time course and slowed mobilization of [Ca2+]i as opposed to simply peak [Ca2+]i. When put in perspective of mechanisms and determinants of the Ca(2+)-force relationship, we begin to realize that failing human myocardium has the "potential" to generate normal levels of force. Only when stressed by [Ca2+]i overload and/or frequency perturbation does myocardium from patients with end-stage heart disease demonstrate contractile failure. Although [Ca2+]i availability and mobilization are likely to play a role in the systolic as well as diastolic dysfunction reported in human heart failure, it is likely that other mechanisms are involved as well (e.g., myocardial energetics). Myocardial energetics is directly related to [Ca2+]i and mobilization in failing human myocardium, because metabolites, e.g., ADP, inhibit pumps, such as sarcoplasmic reticulum Ca2+ ATPase activity. We therefore conclude that there is a role for intracellular calcium mobilization and myocardial energetics for systolic and diastolic dysfunction seen in human heart failure.