Case report: Catheter ablation for persistent atrial fibrillation in a patient with heart of stone.

Myocardial calcification is a rare condition, with only a few reports in the literature. For the first time, we report a case of diffuse myocardial calcification who underwent successful catheter ablation for persistent atrial fibrillation (AF). In this case, catheter ablation was recommended due to repeated hospitalization for palpitation and heart failure, but preoperative computed tomography showed massive myocardial calcification. Electroanatomic mapping of the atrium was performed with a Pentaray catheter before ablation, which showed areas of low voltage in the calcified region. As the persistent AF was terminated after circumferential pulmonary vein isolation and posterior wall isolation, and no further ablation was performed. The patient recovered well, with no recurrence of palpitation or heart failure during the one-year follow-up.

Telomere length and the risk of cardiovascular diseases: A Mendelian randomization study.

Background: The causal direction and magnitude of the associations between telomere length (TL) and cardiovascular diseases (CVDs) remain uncertain due to susceptibility of reverse causation and confounding. This study aimed to investigate the associations between TL and CVDs using Mendelian randomization (MR). Materials and methods: In this two-sample MR study, we identified 154 independent TL-associated genetic variants from a genome-wide association study (GWAS) consisting of 472,174 individuals (aged 40-69) in the UK Biobank. Summary level data of CVDs were obtained from different GWASs datasets. Methods of inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), Mendelian Randomization robust adjusted profile score (MR-RAPS), maximum likelihood estimation, weighted mode, penalized weighted mode methods, and Mendelian randomization pleiotropy residual sum and outlier test (MR-PRESSO) were conducted to investigate the associations between TL and CVDs. Results: Our findings indicated that longer TL was significantly associated with decreased risk of coronary atherosclerosis [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.75-0.95; P = 4.36E-03], myocardial infarction (OR, 0.72; 95% CI, 0.63-0.83; P = 2.31E-06), ischemic heart disease (OR, 0.87; 95% CI, 0.78-0.97; P = 1.01E-02), stroke (OR, 0.87; 95% CI, 0.79-0.95; P = 1.60E-03), but an increased risk of hypertension (OR, 1.12; 95% CI, 1.02-1.23; P = 2.00E-02). However, there was no significant association between TL and heart failure (OR, 0.94; 95% CI, 0.87-1.01; P = 1.10E-01), atrial fibrillation (OR, 1.01; 95% CI, 0.93-1.11; P = 7.50E-01), or cardiac death (OR, 0.95; 95% CI, 0.82-1.10; P = 4.80E-01). Both raw and outlier corrected estimates from MR-PRESSO were consistent with those of IVW results. The sensitivity analyses showed no evidence of pleiotropy (MR-Egger intercept, P > 0.05), while Cochran's Q test and MR-Egger suggested different degrees of heterogeneity. Conclusion: Our MR study suggested that longer telomeres were associated with decreased risk of several CVDs, including coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke, as well as an increased risk of hypertension. Future studies are still warranted to validate the results and investigate the mechanisms underlying these associations.

Mitochondrial dysfunction in heart failure and its therapeutic implications.

The ATP consumption in heart is very intensive to support muscle contraction and relaxation. Mitochondrion is the power plant of the cell. Mitochondrial dysfunction has long been believed as the primary mechanism responsible for the inability of energy generation and utilization in heart failure. In addition, emerging evidence has demonstrated that mitochondrial dysfunction also contributes to calcium dysregulation, oxidative stress, proteotoxic insults and cardiomyocyte death. These elements interact with each other to form a vicious circle in failing heart. The role of mitochondrial dysfunction in the pathogenesis of heart failure has attracted increasing attention. The complex signaling of mitochondrial quality control provides multiple targets for maintaining mitochondrial function. Design of therapeutic strategies targeting mitochondrial dysfunction holds promise for the prevention and treatment of heart failure.

Phosphoproteomic Analysis Reveals Downstream PKA Effectors of AKAP Cypher/ZASP in the Pathogenesis of Dilated Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major cause of heart failure worldwide. The Z-line protein Cypher/Z-band alternatively spliced PDZ-motif protein (ZASP) is closely associated with DCM, both clinically and in animal models. Our earlier work revealed Cypher/ZASP as a PKA-anchoring protein (AKAP) that tethers PKA to phosphorylate target substrates. However, the downstream PKA effectors regulated by AKAP Cypher/ZASP and their relevance to DCM remain largely unknown. Methods and Results: For the identification of candidate PKA substrates, global quantitative phosphoproteomics was performed on cardiac tissue from wild-type and Cypher-knockout mice with PKA activation. A total of 216 phosphopeptides were differentially expressed in the Cypher-knockout mice; 31 phosphorylation sites were selected as candidates using the PKA consensus motifs. Bioinformatic analysis indicated that differentially expressed proteins were enriched mostly in cell adhesion and mRNA processing. Furthermore, the phosphorylation of ß-catenin Ser675 was verified to be facilitated by Cypher. This phosphorylation promoted the transcriptional activity of ß-catenin, and also the proliferative capacity of cardiomyocytes. Immunofluorescence staining demonstrated that Cypher colocalised with ß-catenin in the intercalated discs (ICD) and altered the cytoplasmic distribution of ß-catenin. Moreover, the phosphorylation of two other PKA substrates, vimentin Ser72 and troponin I Ser23/24, was suppressed by Cypher deletion. Conclusions: Cypher/ZASP plays an essential role in ß-catenin activation via Ser675 phosphorylation, which modulates cardiomyocyte proliferation. Additionally, Cypher/ZASP regulates other PKA effectors, such as vimentin Ser72 and troponin I Ser23/24. These findings establish the AKAP Cypher/ZASP as a signalling hub in the progression of DCM.

Multiple Non-coding ANRIL Transcripts Are Associated with Risk of Coronary Artery Disease: a Promising Circulating Biomarker.

Multiple ANRIL transcriptional isoforms, such as lncANRIL and circANRIL have been identified. We sought to explore their diagnostic value in patients with coronary artery disease (CAD). First, we selected six target ANRIL isoforms and measured their expression in CAD patients and controls in the peripheral blood. Their diagnostic values were evaluated. circANRIL(exon14-4) was identified as the best potential biomarker. Afterwards, we validated its diagnostic value and evaluated its prognostic value in a larger clinical cohort. Among six tested ANRILs, lncANRIL(exon1) and lncANRIL(exon4-6) in the CAD patients were significantly increased, while circANRIL(exon14-4) was downregulated. circANRIL(exon14-4) had the highest diagnostic value among the three isoforms. The combination of circANRIL(exon14-4) and other factors resulted in a more accurate differentiation of CAD patients. Moreover, lower expression of circANRIL(exon14-4) was associated with higher incidence of MACE. circANRIL(exon14-4) is closely associated with CAD risk and severity, which provides a promising circulating biomarker for CAD diagnosis and prognosis.

MAGGIC Risk Model Predicts Adverse Events and Left Ventricular Remodeling in Non-Ischemic Dilated Cardiomyopathy.

PURPOSE: We aimed to study the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) risk model's prognostic value and relationship with left ventricular remodeling in dilated cardiomyopathy. PATIENTS AND METHODS: Dilated cardiomyopathy patients were prospectively recruited and underwent clinical assessments. MAGGIC risk score was calculated. Patients were followed up for adverse events and echocardiography. Primary endpoints were all-cause mortality and first rehospitalization due to heart failure. Secondary endpoint was left ventricular remodeling defined as a decline in left ventricular ejection fraction >10% or an increase in left ventricular end-diastolic diameter >10%. Survival status was examined using Cox regression analysis. The model's ability to discriminate adverse events and left ventricular remodeling was calculated using a receiver operating characteristics curve. RESULTS: In total, 114 patients were included (median follow-up time = 31 months). The risk score was independently related to adverse events (2-year all-cause mortality: hazard ratio [HR] = 1.122; 95% confidence interval [CI], 1.043-1.208; 1-year first rehospitalization due to heart failure: HR = 1.094; 95% CI, 1.032-1.158; 2-year first rehospitalization due to heart failure: HR = 1.088; 95% CI, 1.033-1.147, all P < 0.05). One-year change in left ventricular end-diastolic diameter was correlated with the risk score (r = 0.305, P = 0.002). The model demonstrated modest ability in discriminating adverse events and left ventricular remodeling (all areas under the curve were 0.6-0.7). CONCLUSION: The MAGGIC risk score was related to adverse events and left ventricular remodeling in dilated cardiomyopathy.

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway.

Background: Dilated cardiomyopathy (DCM) is considered as the most common form of non-ischemic cardiomyopathy with a high mortality worldwide. Cytoskeleton protein Cypher plays an important role in maintaining cardiac function. Genetic studies in human and animal models revealed that Cypher is involved in the development of DCM. However, the underlying molecular mechanism is not fully understood. Accumulating evidences suggest that apoptosis in myocytes may contribute to DCM. Thus, the purpose of this study is to define whether lack of Cypher in cardiomyocytes can elevate apoptosis signaling and lead to DCM eventually. Methods and Results: Cypher-siRNA sufficiently inhibited Cypher expression in cardiomyocytes. TUNEL-positive cardiomyocytes were increased in both Cypher knockdown neonatal rat cardiomyocytes and Cypher knockout mice hearts, which were rare in the control group. Flow cytometry further confirmed that downregulation of Cypher significantly increased myocytes apoptosis in vitro. Cell counting kit-8 assay revealed that Cypher knockdown in H9c2 cells significantly reduced cell viability. Cypher knockdown was found to increase cleaved caspase-3 expression and suppress p21, ratio of bcl-2 to Bax. Cypher-deficiency induced apoptosis was linked to downregulation of Akt activation and elevated p-p38 MAPK accumulation. Pharmacological activation of Akt with SC79 attenuated apoptosis with enhanced phosphorylation of Akt and reduced p-p38 MAPK and Bax expression. Conclusions: Downregulation of Cypher participates in the promotion of cardiomyocytes apoptosis through inhibiting Akt dependent pathway and enhancing p38 MAPK phosphorylation. These findings may provide a new potential therapeutic strategy for the treatment of DCM.

Prognostic Value of Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Parameters in Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Background Cardiac right ventricular remodeling plays a substantial role in pathogenesis, progression, and prognosis of pulmonary hypertension. Cardiac magnetic resonance is considered an excellent tool for evaluation of right ventricle. However, value of right ventricular remodeling parameters derived from cardiac magnetic resonance in predicting adverse events is controversial. Methods The Pubmed (MEDLINE), Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure platform (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched until November 2019. Studies reporting hazard ratios (HRs) for all-cause death and composite end point of pulmonary hypertension were included. Univariate HRs were extracted from the included studies to calculate pooled HRs of each right ventricular remodeling parameter. Results Eight studies with 1120 patients examining all-cause death (female: 44%-92%, age: 40-67 years old, follow-up time: 27-48 months) and 10 studies with 604 patients examining composite end point (female: 60%-83%, age: 29-57 years old, follow-up time: 10-68 months) met the criteria. Right ventricular ejection fraction was the only parameter which could predict both all-cause death (pooled HR=0.95; P=0.014) and composite end point (pooled HR=0.95; P<0.001), although right ventricular end-diastolic volume index (pooled HR=1.01; P<0.001), right ventricular end-systolic volume index (pooled HR=1.01, P=0.045), and right ventricular mass index (pooled HR=1.03, P=0.032) only predicted composite outcome. Similar results were observed when we conducted the meta-analysis among patients with World Health Organization type I of pulmonary hypertension. Conclusions Cardiac magnetic resonance-derived right ventricular remodeling parameters have independent prognostic value for all-cause death and composite end point of patients with pulmonary hypertension. Right ventricular ejection fraction was the strongest prognostic factor among all the right ventricular remodeling parameters. Right ventricular mass index, right ventricular end-diastolic volume index, and right ventricular end-systolic volume index also demonstrated prognostic value.

Novel polymorphisms in PDLIM3 and PDLIM5 gene encoding Z-line proteins increase risk of idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDCM), characterized by ventricular dilation and impaired systolic function, is a primary cardiomyopathy resulting in heart failure. During heart contraction, the Z-line is responsible for transmitting force between sarcomeres and is also a hot spot for muscle cell signalling. Mutations in Z-line proteins have been linked to cardiomyopathies in both humans and mice. Actinin-associated LIM protein (ALP) and enigma homolog protein (ENH), encoded by PDLIM3 and PDLIM5, are components of the muscle cytoskeleton and localize to the Z-line. A PDLIM3 or PDLIM5 deficiency in mice leads to dilated cardiomyopathy. Since PDLIM3 and PDLIM5 are candidate IDCM susceptibility genes, the current study aims to investigate whether polymorphisms within PDLIM3 and PDLIM5 could be correlated with IDCM. We designed a case-control study, and exons of the PDLIM3 and PDLIM5 were amplified by polymerase chain reactions in 111 IDCM patients and 137 healthy controls. We found that five synonymous polymorphisms had statistical distribution differences between IDCM patients and controls, including rs4861669, rs4862543, c.731 + 131 T > G, c.1789-3 C > T and rs7690296, according to genotype and allele distribution. Haplotype G-C-C-C and A-T-C-T (rs2306705, rs10866276, rs12644280 and rs4635850 synthesized) were regarded as risk factors for IDCM patients when compared with carriers of other haplotypes (all P < .05). Furthermore, IDCM patients with two novel polymorphisms (c.731 + 131 T > G and c.1789-3 C > T) had lower systolic blood pressure. In conclusion, these five synonymous polymorphisms might constitute a genetic background that increases the risk of the development of IDCM in the Chinese Han population.

Meta-analysis of the association of the CYP2J2 G-50T polymorphism with coronary artery disease.

The association of the CYP2J2 G-50T polymorphism with coronary artery disease has been explored, but the results remain controversial. Thus, a meta-analysis was conducted to provide a comprehensive estimate of this association. We selected ten articles encompassing 12 independent case-control studies with 7063 cases and 10,453 controls for this meta-analysis. Overall, we found significant associations between the CYP2J2 G-50T polymorphism and coronary artery disease risk in three genetic models (allele model: odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.05-1.34; homozygote model: OR = 2.25, 95% CI = 1.27-4.01; recessive model: OR = 2.17, 95% CI = 1.22-3.86). In these three genetic models, a significant association was observed in Caucasians but not in Asians when the data were stratified by ethnicity. However, no significant associations were found between the CYP2J2 polymorphism G-50T and coronary artery disease risk in heterozygote model and dominant model. In conclusion, our meta-analysis suggested that the CYP2J2 G-50T polymorphism was associated with coronary artery disease risk in the allele, homozygote and recessive models in Caucasians.