Lin Xu

The correlation between peripartum cardiomyopathy and autoantibodies against cardiovascular receptors.

Background Peripartum cardiomyopathy (PPCM) is characterized by left ventricular systolic dysfunction and heart failure. However, its pathogenesis is not clear. Our preliminary study revealed that autoantibodies against β1-adrenergic receptors (β1R-AABs) and M2-muscarinic receptors (M2R-AABs) participated in heart failure regardless of primary heart disease. Whether β1R-AABs and M2R-AABs participate in the pathogenesis of PPCM is still unknown. Methods Totally 37 diagnosed PPCM patients and 36 normal pregnant women were enrolled in this study. Clinical assessment and 2-dimensional echocardiographic studies as well as the measurement of β1R-AABs or M2R-AABs by enzyme linked immunosorbent assay (ELISA) were performed. Results The positive rates for β1R-AABs and M2R-AABs were 59.5% (22/37) and 45.9% (17/37) in PPCM patients, and 19.4% (7/36) (P<0.001) and 16.67% (6/36) (P<0.001) in normal pregnant women, respectively. Both β1R-AABs and M2R-AABs had a positive correlation with serum expression level of NT-proBNP, left ventricular dimension and NYHA FC (rs: 0.496–0.892, P<0.01). In addition, a negative correlation between the activity of β1R-AABs and M2R-AABs and LVEF, LVFS was observed (rs: −0.488–0.568, P<0.01). Moreover, autoantibodies against cardiovascular receptors increased the risk of the onset of PPCM (OR = 18.786, 95% confidence interval 1.926–183.262, P = 0.012). Conclusions The β1R-AABs and M2R-AABs reveal a significant elevation and are correlated with the increased left ventricular dimension and worse cardiac contraction function. The autoantibodies of cardiovascular receptors are independent risk factors for the onset of PPCM.

Autoantibodies against β1-adrenergic receptor: response to induction therapy with bortezomib-containing regimens for multiple myeloma patients

Abstract This study aims to investigate the predictive value of pre-chemotherapy β1R-AABs by evaluating the response of newly diagnosed symptomatic multiple myeloma (MM) patients to their treatment with a bortezomib-containing regimen. Forty-five de novo MM patients and 50 normal controls (NCs) were prospectively enrolled in this study. Serum titers of β1R-AABs were detected by ELISA. These 45 MM patients were divided into two groups (positive and negative groups) according to their β1R-AABs. Follow-up examinations were performed on these patients during chemotherapy induction. The final analysis covered all 45 MM patients, including 19 patients who were positive for MM and 26 patients who were negative for MM. Multivariate analysis revealed that pre-chemotherapy β1R-AABs are possibly independent predictors for less than very good partial response (VGPR) after the bortezomib-containing regimen treatment (odds ratio: 5.967, 95% confidence interval: 1.513–23.531; p = .011). This study demonstrates for the first time that the presence of β1R-AABs is associated with MM. Pre-chemotherapy β1R-AABs are independent predictors for less than VGPR in de novo MM patients after the bortezomib-containing regimen was administrated. Bortezomib might not significantly give rise to cardiac impairment in MM patients.

Palmitic Acid Increases Endothelin-1 Expression in Vascular Endothelial Cells through the Induction of Endoplasmic Reticulum Stress and Protein Kinase C Signaling

Objective: We investigated the regulation of endothelin-1 (ET-1) expression in in vivo high-fat diet (HFD)-fed mice and in vitro cultured human aortic endothelial cells (HAECs). Methods: Male C57BL/6 mice were fed on standard chow, serum was prepared, and ET-1 levels were analyzed using an ELISA kit. Quantitative PCR was performed using iQ SYBR Green Supermix. Statistical significance was assessed using SPSS, with p < 0.05 considered significant. Results: The serum ET-1 content and endothelial expression of ET-1 mRNA were increased in the HFD-fed mice compared to the chow-fed control mice. Moreover, the mRNA expression of ET-1 was significantly increased in cultured HAECs in response to acute (< 24 h) and chronic (12–16 days) treatments with palmitic acid (PA), one of the most abundant saturated fatty acids in obesity. We found that the induction of ET-1 expression by PA was abolished by pretreating the cells with the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid or the protein kinase C (PKC) inhibitor Gö 6850. Conclusion: Our findings demonstrate for the first time that PA increases ET-1 expression in endothelial cells through the induction of ER stress and the activation of PKC, providing novel mechanistic insights into the pathogenesis of obesity-associated hypertension and cardiovascular diseases.

The Effect of Autoantibody against M 2 -Muscarinic Acetylcholine Receptor in Heart Failure Patients on Digoxin Treatment

Background: Autoantibody against M2-muscarinic acetylcholine receptor (anti-M2AChR) has a biological effect similar to a vagus agonist. Digoxin has a function of vagus nervous system stimulation. We hypothesized that anti-M2AChR is highly correlated with digoxin in patients with chronic heart failure (CHF). Methods: Synthetic M2AChR peptides served as the target antigen in an ELISA were used to screen the sera of 80 CHF patients, who were separated into a negative (–) or positive (+) anti-M2AChR group according to their anti-M2AChR reactivity. Echocardiography and serum digoxin concentration (SDC) were performed at baseline and after 1 year of digoxin in combination with the standard treatment regime. The end-point events were compared over 1 year of follow-up. Results: Seventy-two CHF patients completed the final data analysis, including 32 (+)anti-M2AChR and 40 (–)anti-M2AChR patients. The resting heart rate of the positive group was higher than that of the negative group at baseline (p < 0.05; 89.0 ± 1.6 vs. 83.8 ± 1.1 bpm). Both groups showed improvement in the left ventricular end-diastolic and end-systolic dimensions and ejection fraction with digoxin in combination with the standard treatment regime for 1 year (all p < 0.01). However, the 32 patients with (–)anti-M2AChR had greater improvements than the 40 patients with (+)anti-M2AChR, and this was accompanied by a marked decrease of rehospitalization (all p < 0.01) but not of cardiovascular mortality after 1 year. The SDC of patients with (–)anti-M2AChR was significantly lower than that of patients with (+)anti-M2AChR (p < 0.05; 0.63 ± 0.05 vs.1.16 ± 0.06 ng/mL) and had a positive correlation with anti-M2AChR (r = 0.81, p < 0.001). Conclusion: These results suggested that anti-M2AChR could be a useful biomarker of vagus nerve overactivation and is associated with a poor response to digoxin treatment in CHF patients.

A severity index study of long-term prognosis in patients with chronic heart failure

Aims: The present study describes the derivation and validation of the Chronic Heart Failure Severity Index (CHFSI). Main methods: The CHFSI was derived using data obtained from a single‐center prospective cohort study (2000–2014) that enrolled 756 patients. Logistic regression was used to identify independent predictors of mortality and quality of life over a 15‐year follow‐up period. Key findings: The score was validated at the first 5‐year (n = 644), second 5‐year (n = 364), and third 5‐year (n = 262). Independent predictors of mortality were older age (OR = 2.04, P < 0.001), etiology score (OR = 2.61, P < 0.001), faster heart rate (OR = 1.46, P = 0.027), higher systolic blood pressure (OR = 2.35, P < 0.001), and left ventricular ejection fraction ≤45% (OR = 1.97, P = 0.018). The derived CHFSI predicted the mortality, and the AUC for the logistic model was 0.78 (95% confidence interval = 0.74–0.81, P < 0.001). Based on the logistic model, an integer scoring system was derived. Patients were classified into three groups: low risk (0–7 points), intermediate risk (8–11 points) and high risk (≥12 points) groups. The cumulative mortality for 15 years was 45.5% (125/275), 84.0% (204/243), and 100% (99/99), respectively (P < 0.001). The 6‐min walk test revealed a significant difference in quality of life among patients in the low, medium and high risk groups (all, P < 0.0001). Significance: The CHFSI is a very useful clinical predictive tool that identifies patients at risk of future mortality and their quality of life across healthcare systems.

GW24-e0403 Autoantibodies against angiotensin II type 1 receptor-positive patients with heart failure have better clinical efficacy to perindopril treatment

Objectives Previously, we reported that autoantibodies specific for the angiotensin II type 1 receptor (anti-AT1-AR) is implicated in the pathogenesis of congestive heart failure (CHF). We hypothesised that the presence of anti-AT1-AR is associated with the left ventricular function of CHF patients in response to perindopril. Methods Synthetic angiotensin II type 1 receptor (AT1-R) peptides were used as the target antigen. An ELISA was used to screen the sera of 156 CHF patients with NYHA class II-IV. The patients were then divided into positive or negative groups based on their anti-AT1-AR reactivity. Each patient of each group was subjected to an echocardiography and a 6-minute walk test. Performance at baseline and after one year of perindopril therapy with β-receptor blockers, diuretics, and digoxin were documented. Results A total of 138 patients completed the final analysis in this study, including 82 patients with (+) anti-AT1-AR and 56 patients with (–) anti-AT1-AR. Compared to the patients with (–) anti-AT1-AR, patients with (+) anti-AT1-AR had a greater improvement in left ventricular end-diastolic, end-systolic dimensions, and ejection fraction (all P < 0.05). Similar trends were also observed in patients subjected to a 6-minute walk test (P < 0.05) after one year of perindopril therapy in combination with standard treatment. CHF patients that were (+) anti-AT1-AR responded better to target perindopril dose than those that were (–) anti-AT1-AR (P < 0.01). After 5 years of follow-up, there was no significant difference for hospitalisation, death, or cardiovascular failures between patients with (+) anti-AT1-AR and (–) anti-AT1-AR. Conclusions Compared to (–) anti-AT1-AR, patients that were (+) anti-AT1-AR had a greater clinical therapeutic benefit on left ventricluar remodeling and function. This result potentially presents a novel biomarker of the renin-angiotensin-aldosterone system for assess of the level of receptor activation, as well as therapeutic intervention in patients with heart failure.

GW24-e0404 Proteomics screen to reveal molecular changes mediated by C722G missense mutation in CHRM2 gene

Objectives Previously, we reported that a missense mutation (C722G) in the M2-muscarinic acetylcholine receptor (CHRM2) geneis associated with familial dilated cardiomyopathy (DCM). However, the exact molecular mechanisms by the fundamental changes involved in the CHRM2 signalling pathways in patients with the C722G mutation are still not clear. Methods In this study, we generated CHRM2 and CHRM2-C722G lentiviral vector and applied to infect the CHO cells. Then we performed proteomic analyses by label free shotgun strategy and analysed the most changed proteins by the STRING 9.0 software–Known and Predicted Protein-Protein Interactions. Results A total of 102 proteins with at least 2-fold change in the cells transfected with CHRM2-C722G were identified, 42 proteins were up-regulated, whereas 57 proteins were down-regulated. These altered proteins belong to three broad functional categories: (i) metabolic [e.g. Ubiquitin-like modifier-activating enzyme 1, Cytosolic acyl coenzyme A thioester hydrolase, Malate dehydrogenase and Arginyl-tRNA synthetase]; (ii) cytoskeletal (e.g. Actin-related protein, Myosin light polypeptide 6 and Alpha-actinin-1) and (iii) stress response (e.g. heat shock protein 70, Ras-related protein Rab-10 and Ras GTPase-activating protein-binding protein2). Interestingly, the marked differences in the expression of selected eight proteins (change > 4.0-fold), including heat shock protein 70, Malate dehydrogenase, Sodium/potassium -transporting ATPase subunit alpha-1, Ubiquitin-like modifier-activating enzyme 1, et al were connected with many proteins related to apoptosis and immune/inflammatory response such as: FOS, BAX, MYC, TP53 and IL6, which are involved in the pathology of congestive heart failure. Conclusions We have carried out a full-scale screening of the proteomics research under condition of C722G mutation in the CHRM2 gene related to familial DCM and profiled the eight proteins which may be critical in cardiac dysfunction for future mapping.