Sangjin Lee

Oxidative Stress Regulates Left Ventricular PDE5 Expression in the Failing Heart

Background— Phosphodiesterase type 5 (PDE5) inhibition has been shown to exert profound beneficial effects in the failing heart, suggesting a significant role for PDE5 in the development of congestive heart failure (CHF). The purpose of this study is to test the hypothesis that oxidative stress causes increased PDE5 expression in cardiac myocytes and that increased PDE5 contributes to the development of CHF. Methods and Results— Myocardial PDE5 expression and cellular distribution were determined in left ventricular samples from patients with end-stage CHF and normal donors and from mice after transverse aortic constriction (TAC)–induced CHF. Compared with donor human hearts, myocardial PDE5 protein was increased ≈4.5-fold in CHF samples, and the increase of myocardial PDE5 expression was significantly correlated with myocardial oxidative stress markers 3′-nitrotyrosine or 4-hydroxynonenal expression (P<0.05). Histological examination demonstrated that PDE5 was mainly expressed in vascular smooth muscle in normal donor hearts, but its expression was increased in both cardiac myocytes and vascular smooth muscle of CHF hearts. Myocardial PDE5 protein content and activity also increased in mice after TAC-induced CHF (P<0.05). When the superoxide dismutase (SOD) mimetic M40401 was administered to attenuate oxidative stress, the increased PDE5 protein and activity caused by TAC was blunted, and the hearts were protected against left ventricular hypertrophy and CHF. Conversely, increased myocardial oxidative stress in superoxide dismutase 3 knockout mice caused a greater increase of PDE5 expression and CHF after TAC. In addition, administration of sildenafil to inhibit PDE5 attenuated TAC-induced myocardial oxidative stress, PDE5 expression, and CHF. Conclusions— Myocardial oxidative stress increases PDE5 expression in the failing heart. Reducing oxidative stress by treatment with M40401 attenuated cardiomyocyte PDE5 expression. This and selective inhibition of PDE5 protected the heart against pressure overload-induced left ventricular hypertrophy and CHF.

Effects of the HeartMate II continuous-flow left ventricular assist device on right ventricular function

BACKGROUND Continuous-flow devices have become the standard of care for mechanical circulatory support for end-stage heart failure patients because of improved survival and durability. The effects of these devices, such as the HeartMate II (HMII) left ventricular assist device (LVAD), on right ventricular (RV) function have not been evaluated in detail. This study evaluated the incidence of RV failure, alterations in RV function, severity of tricuspid regurgitation (TR), and cardiac hemodynamics after HMII implantation. METHODS Echocardiograms (n = 22) and right heart catheterizations (n = 40) were performed before and after 4 to 6 months of HMII support in 40 bridge-to-transplant patients. Right heart failure was defined as the requirement for inotropes and/or nitric oxide requirement after LVAD implantation for >14 days or the need for right-sided mechanical circulatory support. RESULTS Overall, RV failure after HMII implantation occurred in 2 of 40 patients (5%). Significant improvements occurred in cardiac index, with reductions in right atrial pressure, RV stroke work index, tricuspid annular motion, mean pulmonary artery pressure, and pulmonary vascular resistance after HMII support. There was a trend towards reduction in TR after LVAD support (p = 0.075). CONCLUSIONS The incidence of RV failure after support with continuous-flow devices such as the HMII is low. The favorable effects of the HMII on cardiac hemodynamics result in improved RV function, improved right- and left-sided hemodynamic profiles, and a reduction in TR severity. These findings may have important implications for LVAD patients needing longer-term support.

The Biological Basis of Thrombosis and Bleeding in Patients with Ventricular Assist Devices

The clinical success of left ventricular assist devices (LVADs) has been tempered by significant hemorrhagic and thromboembolic complications. In the case of LVADs, where the biomaterial is in direct contact with the blood circulation, significant changes in systemic immunologic and thrombostatic functions have been well documented. Although further investigation is warranted, significant advances have been made in both cellular biology and LVAD technology to better understand the delicate balance between the procoagulant milieu predisposing to thrombosis and the risks of both surgical and non-surgical bleeding.

Sex and Age Dimorphism of Myocardial Gene Expression in Nonischemic Human Heart Failure

Background—We report the first comprehensive analysis of gene expression differences by sex and age in left ventricular samples from 102 patients with dilated cardiomyopathy. Methods and Results—Gene expression data (HG-U133A gene chip, Affymetrix) were analyzed from 30 females and 72 males from 3 separate centers. More than 1800 genes displayed sexual dimorphism in the heart (adjusted P value <0.05). A significant number of these genes were highly represented in gene ontology pathways involved in ion transport and G-protein-coupled receptor signaling. Localization of these genes revealed enrichment on both the sex chromosomes as well as chromosomes 3, 4, and 14. The second goal of this study was to determine the effect of age on gene expression. Within the female cohort, >140 genes were differentially expressed in the <55 years age group compared with the >55 years age group. These genes were highly represented in gene ontology pathways involved in DNA damage. In contrast, zero genes in the male cohort <55 years met statistical significance when compared with the >55 years age group. Conclusions—Gene expression in dilated cardiomyopathy displayed evidence of sexual dimorphism similar to other somatic tissues and age dimorphism within the female cohort.

Common clinical dilemmas in left ventricular assist device therapy ; A glimpse into current trends

Background Left ventricular assist device (LVAD) therapy has been thrust into the forefront of surgical treatment for advanced heart failure (HF). Despite advancements in survival and quality of life with these devices, the multi-disciplinary care for these patients remains far from standardized across institutions. Citation: Kilic A.et al. (2017) “Common clinical dilemmas in left ventricular assist device therapy: A glimpse into current trends”. The VAD Journal, 3. doi: https://doi.org/10.13023/VAD.2017. 02 Editor-in-Chief: Maya Guglin, University of Kentucky Received: January 10, 2017 Accepted: February 1, 2017 Published: February 2, 2017