Cardioprotective role of growth/differentiation factor 1 in post-infarction left ventricular remodelling and dysfunction.

Growth/differentiation factor 1 (GDF1) is a secreted glycoprotein of the transforming growth factor-ß (TGF-ß) superfamily that mediates cell differentiation events during embryonic development. GDF1 is expressed in several tissues, including the heart. However, the functional role of GDF1 in myocardial infarction (MI)-induced cardiac remodelling and dysfunction is not known. Here, we performed gain-of-function and loss-of-function studies using cardiac-specific GDF1 transgenic (TG) and knockout (KO) mice to determine the role of GDF1 in the pathogenesis of functional and architectural cardiac remodelling after MI, which was induced by surgical left anterior descending coronary artery ligation. Our results demonstrate that overexpression of GDF1 in the heart causes a significant decrease in MI-derived mortality post-MI and leads to attenuated infarct size expansion, left ventricular (LV) dilatation, and cardiac dysfunction at 1 week and 4 weeks after MI injury. Compared with control animals, cardiomyocyte apoptosis, inflammation, hypertrophy, and interstitial fibrosis were all remarkably reduced in the GDF1-TG mice following MI. In contrast, GDF1 deficiency greatly exacerbated the pathological cardiac remodelling response after infarction. Further analysis of the in vitro and in vivo signalling events indicated that the beneficial role of GDF1 in MI-induced cardiac dysfunction and LV remodelling was associated with the inhibition of non-canonical (MEK-ERK1/2) and canonical (Smad) signalling cascades. Overall, our data reveal that GDF1 in the heart is a novel mediator that protects against the development of post-infarction cardiac remodelling via negative regulation of the MEK-ERK1/2 and Smad signalling pathways. Thus, GDF1 may serve as a valuable therapeutic target for the treatment of MI.

Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction.

Dickkopf-3 (DKK3) is a secreted glycoprotein of the Dickkopf family (DKK1-4) that modulates Wnt signalling. DKK3 has been reported to regulate cell development, proliferation, apoptosis, and immune response. However, the functional role of DKK3 in cardiac remodelling after myocardial infarction (MI) has not yet been elucidated. This study aimed to explore the functional significance of DKK3 in the regulation of post-MI remodelling and its underlying mechanisms. MI was induced by surgical left anterior descending coronary artery ligation in transgenic mice expressing cardiac-specific DKK3 and DKK3 knockout (KO) mice as well as their non-transgenic and DKK3(+/+) littermates. Our results demonstrated that after MI, mice with DKK3 deficiency had increased mortality, greater infarct size, and exacerbated left ventricular (LV) dysfunction. Significantly, at 1 week post-MI, the hearts of DKK3-KO mice exhibited increased apoptosis, inflammation, and LV remodelling compared with the hearts of their DKK3(+/+) littermates. Conversely, DKK3 overexpression led to the opposite phenotype after infarction. Similar results were observed in cultured neonatal rat cardiomyocytes exposed to hypoxia in vitro. Mechanistically, DKK3 promotes cardioprotection by interrupting the ASK1-JNK/p38 signalling cascades. In conclusion, our results indicate that DKK3 protects against the development of MI-induced cardiac remodelling via negative regulation of the ASK1-JNK/p38 signalling pathway. Thus, our study suggests that DKK3 may represent a potential therapeutic target for the treatment of heart failure after MI.

Advances in basic and translational research in atrial fibrillation.

Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

[Value of QT hysteresis during treadmill exercise test for diagnosing coronary heart disease].

OBJECTIVE: To investigate the value of QT hysteresis index during treadmill exercise test (TET) in diagnosing coronary heart disease (CHD). METHODS: One hundred consecutive patients suspected for CHD were referred for TET and selective coronary angiography (CAG). Patients were divided into positive [n = 55, age (56.0 ± 7.9) years] and negative [n = 45, age (53.2 ± 6.7) years] group based on their CAG results. For each TET recording, 50 points were selected for the RR, QTp, and QTe interval measurements. QTp and QTe interval was plotted against corresponding RR interval. QT/RR curve was constructed by connect all point, QT hysteresis index was calculated for each patient. RESULTS: The QTp [(22.4 ± 10.3) ms vs. (6.7 ± 4.6) ms, P < 0.001] and QTe [(27.1 ± 11.1) ms vs. (7.6 ± 4.6) ms, P < 0.001] hysteresis index of patients in positive group were significantly higher than those in negative group. The sensitivity of QTp and QTe hysteresis index for diagnosing CHD was 89.1% (49/55) and 94.5% (52/55), respectively, and the specificity was 82.2% (37/45) and 80.0% (36/45), respectively. If the patient fulfilled both the classical TET and QT hysteresis criteria, the sensitivity for diagnosing CHD increased to 94.3% (33/35, QTp) and 94.6% (35/37, QTe), and the specificity were both 100% (26/26, 26/26). Moreover, QTp (r = -0.399, P < 0.001) and QTe (r = -0.547, P < 0.001) hysteresis index highly correlated to Duke treadmill score. CONCLUSION: QT hysteresis index is useful parameter for CHD diagnosis and which could improve the diagnostic value of TET for CHD in combination with the classical TET criteria for diagnosis of CHD.

[Predictive value of QT interval dynamicity for sudden death in patients with idiopathic dilated cardiomyopathy].

OBJECTIVE: To explore the predictive value of QT interval dynamicity for sudden death in patients with idiopathic dilated cardiomyopathy (DCM). METHODS: Fifty-five patients with DCM (DCM group) and 27 healthy subjects (Control group, Con) were enrolled. Investigations included history collection, clinical examination, echocardiography, electrocardiogram and 24 h ambulatory electrocardiogram. Following indexes were determined: left ventricle end diastolic dimension (LVEDD), left ventricle ejection fraction (LVEF), QT dispersion (QTd), SDNN, the slope of QT/RR plots of the linear regression, ventricular premature beats (VPB) and non-sustained ventricular tachycardia (NSVT). Primary end point for patients with DCM was all cause death. RESULTS: LVEDD, QTd, VPB/24 h, NSVT/24 h, QTe/RR slope and QTp/RR slope were significantly higher while LVEF and SDNN were significantly lower in DCM group than in Con group (all P < 0.05). LVEDD, LVEF, QTd, SDNN, QTe/RR slope and QTp/RR slope were significantly different among DCM sudden death group, DCM non sudden death group and Con group (P < 0.05). LVEF, SDNN, QTe/RR slope and QTp/RR slope were significantly different between DCM sudden death and non sudden death group (P < 0.05). LVEF, QTd, VPB/24 h, QTe/RR slope and QTp/RR slope were significantly different between DCM with NSVT and DCM without NSVT group (P < 0.05). The sudden death rate of DCM patients with QTe/RR slope ≥ 0.210 was significantly higher than DCM patients with QTe/RR slope < 0.210 (54.5% vs. 21.1%, P < 0.05). Sudden death rate of QTp/RR slope ≥ 0.190 was also higher than those < 0.190 (52.2% vs. 21.9%, P < 0.05). The sudden death rate of DCM patients with both LVEF ≤ 35% and NSVT+ was 62.5%. Combining QTe/RR ≥ 0.210 with NSVT+ or LVEF ≤ 35%, the sudden death rates were 62.5% or 66.7%. Combining QTp/RR ≥ 0.190 with NSVT+ or LVEF ≤ 35%, the sudden death rates were 66.7% or 61.5%. Combining QTe/RR ≥ 0.210 or QTp/RR ≥ 0.190 with NVST+ and LVEF ≤ 35%, the sudden death rates were 77.8% or 70.0%. CONCLUSIONS: High QT/RR slope is a risk factor for sudden death of DCM patients. QT/RR slope is a useful predictor for sudden death in DCM patients either independently or combined with NSVT or LVEF.

[Effects of curcumin on sarcoplasmic reticulum Ca2+-ATPase in rabbits with heart failure].

OBJECTIVE: To investigate the effects of curcumin on sarcoplasmic reticulum Ca2+-ATPase in heart failure rabbits. METHODS: Rabbit heart failure model was made with aortic regurgitation and abdominal aorta constriction and 40 rabbits were randomly divided into 4 groups including: (1) heart failure treated with curcumin; (2) heart failure treated with placebo; (3) healthy control treated with curcumin and (4) healthy control treated with placebo. All rabbits were administrated with curcumin capsules or placebo capsules 100 mg x kg(-1) x d(-1), respectively. All groups were sacrificed after eight weeks. Myocardial ultrastructural organization was detected by transmission electron microscope. RT-PCR and Western blot were used to measure the expression of sarcoplasmic reticulum Ca2+-ATPase in mRNA and protein levels, respectively. Malachite green colorimetric assay was used to evaluate the activity of sarcoplasmic reticulum Ca2+-ATPase. RESULTS: All detected parameters were similar between control curcumin group and control placebo group. Compared with the control groups (Groups 3 and 4), the heart/body weight ratio was significantly increased in the heart failure-curcumin group (Group 1) and the heart failure-placebo group (Group 2, all P < 0.05), but the ratio was significantly lower in heart failure-curcumin group than in heart failure-placebo group (P < 0.05). The degree of heart failure was decreased by curcumin. Activity and mRNA and protein expression for sarcoplasmic reticulum Ca2+-ATPase were significantly reduced in the heart failure-placebo group and which could be significantly attenuated by curcumin (all P < 0.05). CONCLUSION: Curcumin could improve cardiac function via upregulating the expression of sarcoplasmic reticulum Ca2+-ATPase in this model.

[Curcumin attenuates left ventricular dysfunction and remodeling in rabbits with chronic heart failure.].

OBJECTIVE: To investigate the effects of Curcumin on rabbits with chronic heart failure. METHODS: Heart failure was induced by combined aortic regurgitation and aortic stenosis in 20 New Zealand rabbits and treated with placebo (HF, n = 10) and Curcumin (Cur, 100 mgxkg(-1)xd(-1), n = 10) for 8 weeks, 10 sham operated rabbits served as controls (Con). Echocardiography was performed in all rabbits at baseline and 8 weeks later. Aortic diameter (AO), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-systolic dimension (LVDs), left ventricular end-diastolic dimension (LVDd), left ventricular posterior wall thickness (LVPW) and interventricular septum thickness (IVS) were measured. Myocardial matrix metalloproteinase (MMP)-2 and MMP-9 expressions and fibrosis were determined by immunohistochemistry and Masson staining respectively. RESULTS: Compared to baseline, LVEF and LVFS were significantly decreased, AO, LVDs, LVDd, LVPW, and IVS significantly increased at 8 weeks after operation in HF group while these changes could be significantly attenuated in Curcumin treated rabbits. The protein expressions of MMP-2 and MMP-9 were significantly down-regulated in HF group and could be significantly up-regulated by Curcumin treatment. The increased collagen deposition in HF group was also significantly reduced by Curcumin treatment. CONCLUSION: Curcumin attenuated left ventricular dysfunction and remodeling by up-regulating MMPs expressions and reducing myocardial fibrosis.

[Transmural heterogeneity of calcium handling proteins in the mechanism of porcine model of ventricular fibrillation].

OBJECTIVE: To investigate the role of heterogeneous expression of calcium handling proteins and spatial heterogeneity of APD restitution in the maintenance mechanism of ventricular fibrillation. METHODS: During programmed electrical simulation, APD restitution curves in the endocardium and epicardium of LV were constructed by plotting APD100 and diastolic interval. APD alternans, delayed after depolarization events were recorded simultaneously. Endocardial and epicardial myocytes were isolated from LV base and apex. Real time-PCR and Western blotting were performed to determine the relative messenger RNA and protein expression levels of calcium handling proteins. RESULTS: The normal hearts have spatial heterogeneity of action potential restitution property and transmural heterogeneity of calcium handling proteins. The slopes of the APD restitution curve in the endocardium were significantly steeper than those in epicardium, and the slopes of APD curve at the LV apex were significantly steeper than those in LV base. However, delayed after depolarization events with larger amplitude and earlier onset consistently occurred in the endocardium of LV base. After programmed electrical simulation, the expression of messenger RNA of RyR2, SERCA2a except for Calstabin2 significantly decreased (by 57% and 41%, respectively, P < 0.05) in the endocardium of the base, while the expression of RyR2, SERCA2a, Calstabin2 significantly increased (by 90%, 78%and 64%, respectively, P < 0.05) in the epicardium of LV base. Although transmural heterogeneity of calcium handling proteins at the LV apex were also observed after rapid pacing, there is no significant differences in the transmural heterogeneity at the LV apex compared to the LV base. The base of LV has unique calcium handling properties. CONCLUSIONS: It has been shown that Calcium cycling could modulate APD restitution property in the intact heart. The interaction between action potential and calcium dynamics instabilities is one of the most important reasons why simple criterion such as the APD restitution slope > 1 may fail to accurately predict the onset of APD alternans.

[The prevalence of J wave in apparently healthy subjects in Hubei province of China].

OBJECTIVE: To observe the prevalence of J wave in apparently healthy subjects in Wuhan. METHODS: The study subjects comprised of 1817 apparently healthy subjects (1131 males, mean age 46.38 +/- 15.81 years; 686 females, mean age was 42.77 +/- 14.15 years). ECG and routine medical examinations were performed. J wave was defined as a wave followed QRS complexes with amplitude of at least 0.05 mV and 0.03 s. RESULTS: The overall incidence of J wave was 7.26%. The incidence of J wave in males was significantly higher than in females (10.53% vs. 1.87%, P < 0.01). The incidence of J wave in leads of inferior wall (II, III, avF), right wall (V(1 - 3)) and left wall (V(4 - 6)) was 4.57%, 0.50%, and 2.20%, respectively. J wave located in leads of inferior wall was more than in left and right walls (both P < 0.05). The incidence of J wave positively correlated with age (y = 0.1387x + 1.6318, r = 0.78, P < 0.01). CONCLUSIONS: J wave is more likely seen in males and aged people and is more likely located in leads of inferior wall, than in leads of left and right walls.

A cross-sectional survey on the prevalence of anxiety symptoms in Chinese patients with premature ventricular contractions without structural heart disease.

BACKGROUND: Anxiety appears to be more common in patients with coronary artery disease (CHD) than in the general population, and anxiety symptoms may precede onset of CHD and play an important role in development of CHD. Little is known about the prevalence of anxiety symptoms in Chinese patients with premature ventricular contractions (PVCs). Our objective was to study anxiety symptoms and potential risk factors in a Chinese population with PVCs but without structural heart disease. METHODS: The Zung self-rating anxiety scale (ZSAS) was used to assess anxiety symptoms. Correlation between anxiety symptoms and socio-demographics and medical factors were analyzed by Logistic regression. RESULTS: Of 1144 patients with PVCs (487 males and 657 females), age (53 ± 23) years old, disease duration 1 month to 24 years, a total of 381 (33.3%) patients were categorized as having anxiety symptoms. Anxiety symptoms increased with age, low income, low education level, nationality, PVC count/24 hours, bad social support, village settlement type (P < 0.05). Multivariate Logistic regression indicated that six variables-education level, ethnic minorities, dwelling place, age, PVC count/24 hours, and social support-significantly and independently related with anxiety symptoms (P < 0.05). CONCLUSIONS: In the Chinese population, anxiety symptoms in subjects with PVCs were frequent. Education level, ethnic minorities, dwelling place, age, PVC count/24 hours, and social support were independent risk factors for anxiety symptoms. Further research on the relationship between PVCs and anxiety symptoms in China is necessary.