Mengyun Zhu

Growth Arrest–Specific 6 Exacerbates Pressure Overload–Induced Cardiac Hypertrophy

Growth arrest–specific 6 (GAS6) is a member of the vitamin K–dependent protein family that is involved in the regulation of the cardiovascular system, including vascular remodeling, homeostasis, and atherosclerosis. However, there is still no study that systemically elucidates the role of GAS6 in cardiac hypertrophy. Here, we found that GAS6 was upregulated in human dilated cardiomyopathic hearts, hypertrophic murine hearts, and angiotensin II–treated cardiomyocytes. Next, we examined the influence of GAS6 expression in response to a cardiac stress by inducing chronic pressure overload with aortic banding in wild-type and GAS6-knockout mice or cardiac-specific GAS6 overexpressing mice. Under basal conditions, the GAS6-knockout mice had normal left ventricular structure and function but after aortic banding, the mice demonstrated less hypertrophy, fibrosis, and contractile dysfunction when compared with wild-type mice. Conversely, cardiac-specific overexpression of GAS6 exacerbated aortic banding–induced cardiac hypertrophy, fibrosis, and dysfunction. Furthermore, we demonstrated that GAS6 activated the mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 pathway during pressure overload–induced cardiac hypertrophy, and the pharmacological mitogen-activated protein kinase kinase 1/2 inhibitor U0126 almost completely reversed GAS6 overexpression–induced cardiac hypertrophy and fibrosis, resulting in improved cardiac function. Collectively, our data support the notion that GAS6 impairs ventricular adaptation to chronic pressure overload by activating mitogen-activated protein kinase kinase 1/2–extracellular signal-regulated kinase 1/2 signaling. Our findings suggest that strategies to reduce GAS6 activity in cardiac tissue may be a novel approach to attenuate the development of congestive heart failure.

Comparison of Carotid‐Femoral and Brachial‐Ankle Pulse‐Wave Velocity in Association With Target Organ Damage in the Community‐Dwelling Elderly Chinese: The Northern Shanghai Study

Background Carotid‐femoral pulse‐wave velocity (cf‐PWV) and brachial‐ankle PWV (ba‐PWV) are the 2 most frequently applied PWV measurements. However, little is known about the comparison of hypertensive target organ damage (TOD) with cf‐PWV and ba‐PWV. Methods and Results A total of 1599 community‐dwelling elderly subjects (age >65 years) in northern Shanghai were recruited from June 2014 to August 2015. Both cf‐PWV and ba‐PWV were measured using SphygmoCor and VP1000 systems, respectively. Within the framework of comprehensive cardiovascular examinations, risk factors were assessed, and asymptomatic TOD, including left ventricular mass index, peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), carotid intima‐media thickness, arterial plaque, creatinine clearance rate, and urinary albumin‐creatinine ratio were all evaluated. Both PWVs were significantly associated with male sex, age, waist/hip circumference, fasting plasma glucose, and systolic blood pressure, and ba‐PWV was also significantly related to body mass index. Both PWVs were significantly correlated with most TOD. When cf‐PWV and ba‐PWV were both or separately put into the stepwise linear regression model together with cardiovascular risk factors and treatment, only cf‐PWV, but not ba‐PWV, was significantly associated with carotid intima‐media thickness and creatinine clearance rate (P<0.05). When cf‐PWV and ba‐PWV were both or separately put into the same full‐mode model after adjustment for confounders, only cf‐PWV, but not ba‐PWV, showed significant association with carotid intima‐media thickness and creatinine clearance rate (P<0.05). Similar results were observed in logistic regression analysis. Conclusions Taken together, in the community‐dwelling elderly Chinese, cf‐PWV seems to be more closely associated with hypertensive TOD, especially vascular and renal TOD, as compared with ba‐PWV. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02368938.

Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy

Background Translocase of inner membrane 50 (TIM50) is a member of the translocase of inner membrane (TIM) complex in the mitochondria. Previous research has demonstrated the role of TIM50 in the regulation of oxidative stress and cardiac morphology. However, the role of TIM50 in pathological cardiac hypertrophy remains unknown. Methods and Results In the present study we found that the expression of TIM50 was downregulated in hypertrophic hearts. Using genetic loss‐of‐function animal models, we demonstrated that TIM50 deficiency increased heart and cardiomyocyte size with more severe cardiac fibrosis compared with wild‐type littermates. Moreover, we generated cardiomyocyte‐specific TIM50 transgenic mice in which the hypertrophic and fibrotic phenotypes were all alleviated. Next, we tested reactive oxygen species generation and the activities of the antioxidant enzymes superoxide dismutase and catalase, and also respiratory chain complexes I, II, and IV, finding that all the activities were regulated by TIM50. Meanwhile, expression of the ASK1‐JNK/P38 axis was increased in TIM50‐deficient mice, and TIM50 overexpression decreased the activity of the ASK1‐JNK/P38 axis. Finally, we treated mice with the antioxidant N‐acetyl cysteine to reduce oxidative stress. After N‐acetyl cysteine treatment, the deteriorative hypertrophic and fibrotic phenotypes caused by TIM50 deficiency were all remarkably reversed. Conclusions These data indicated that TIM50 could attenuate pathological cardiac hypertrophy primarily by reducing oxidative stress. TIM50 could be a promising target for the prevention and therapy of cardiac hypertrophy and heart failure.

Smad Nuclear Interacting Protein 1 Acts as a Protective Regulator of Pressure Overload‐Induced Pathological Cardiac Hypertrophy

Background Smad nuclear interacting protein 1 (SNIP1) plays a critical role in cell proliferation, transformation of embryonic fibroblasts, and immune regulation. However, the role of SNIP1 in cardiac hypertrophy remains unclear. Methods and Results Here we examined the role of SNIP1 in pressure overload–induced cardiac hypertrophy and its mechanisms. Our results demonstrated that SNIP1 expression was downregulated in human dilated cardiomyopathic hearts, aortic banding‐induced mice hearts, and angiotensin II–treated cardiomyocytes. Accordingly, SNIP1 deficiency significantly exacerbated aortic banding–induced cardiac hypertrophy, fibrosis, and contractile dysfunction, whereas cardiac‐specific overexpression of SNIP1 markedly recovered pressure overload–induced cardiac hypertrophy and fibrosis. Besides that, SNIP1 protected neonatal rat cardiomyocytes against angiotensin II–induced hypertrophy in vitro. Moreover, we identified that SNIP1 suppressed nuclear factor‐κB signaling during pathological cardiac hypertrophy, and inhibition of nuclear factor‐κB signaling by a cardiac‐specific conditional inhibitor of κBS 32A/S36A transgene blocked these adverse effects of SNIP1 deficiency on hearts. Conclusions Together, our findings demonstrated that SNIP1 had protective effects in pressure overload–induced pathological cardiac hypertrophy via inhibition of nuclear factor‐κB signaling. Thus, SNIP1 may be a novel approach for the treatment of heart failure.

Overlay Technique for Transcatheter Left Atrial Appendage Closure

The Overlay technique is popular in peripheral artery interventions, but not in coronary or cardiac structural procedures. We present an initial experience using three-episode overlays during a transcatheter left atrial appendage closure. The first overlay was applied to facilitate advancement of the delivery sheath into left atrium. The second overlay was used to navigate the advancement of prepped delivery system containing the compressed occluder into its optimal position in the left atrium. The third overlay facilitated the real-time deployment of the closure device. This case report demonstrates the effectiveness of the overlay technique in facilitating each step of the transcatheter left atrial appendage closure.

Association of arteriosclerosis and/or atherosclerosis with hypertensive target organ damage in the community-dwelling elderly Chinese: the Northern Shanghai Study

Objective Vascular abnormality includes two forms, arteriosclerosis (ARS) and atherosclerosis (ATS), which coexist in patients with cardiovascular (CV) diseases. However, whether their combination may lead to a worsening status in those patients remains unclear. We therefore aimed to investigate the association of ARS and/or ATS with hypertensive target organ damage (TOD). Methods From June 2014 to August 2015, a total of 1,599 community-dwelling elderly subjects (aged >65 years) from northern Shanghai were recruited. Vascular measurements, such as carotid–femoral pulse wave velocity (cf-PWV), ankle–brachial index (ABI) and carotid plaque, were conducted on each participant, and ARS was defined as cf-PWV >12 m/s, while ATS was defined as participants who have carotid plaque or ABI <0.9. Within the framework of comprehensive CV examinations, CV risk factors were assessed, and asymptomatic TOD was evaluated by measuring participants’ left ventricular mass index (LVMI), peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), urinary albumin–creatinine rate (UACR) and estimated glomerular filtration rate (eGFR). Results Although LVMI, E/Ea and eGFR were significantly different among subjects with or without ARS and/or ATS (P<0.02), in full adjustment model, only E/Ea showed the independent and significant difference (P=0.023). Moreover, E/Ea was significantly different between participants with ARS or ATS and those without ARS or ATS (P=0.045), while there was no significant difference between participants with ARS and ATS and those without ARS or ATS (P=0.28). Similar results were obtained in the multivariate logistic regression of left ventricular diastolic dysfunction (LVDD). With similar adjustment, LVDD was significantly associated with ATS (P=0.01) but not with ARS (P=0.99). Conclusion In the community-dwelling elderly Chinese, among hypertensive TOD, LVDD was significantly associated with ATS but not with ARS. The proportion of patients with LVDD was not significantly different despite the presence of both ATS and ARS, when compared to patients with ATS alone.