Prognostic nutritional index during hospitalization correlates with adverse outcomes in elderly patients with acute myocardial infarction: a single-center retrospective cohort study.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) is one of the most prevalent illnesses endangering the elderly's health. The predictive nutritional index (PNI) has been shown in several studies to be a good predictor of nutritional prognosis. In this study, we explored the correlation between PNI during hospitalization and the outcome of elderly AMI patients. METHODS: Elderly AMI patients in the Cardiac Intensive Care Unit of Huadong Hospital from September 2017 to April 2020 were recruited for analysis. The clinical and laboratory examination data of subjects were retrieved. All enrolled patients were monitored following discharge. The primary clinical endpoints encompass major adverse cardiovascular events (MACEs) and Composite endpoint (MACEs and all-cause mortality). Survival analyses were conducted via the Kaplan-Meier and the log-rank analyses, and the Cox, proportional hazards model, was employed for hazard rate (HR) calculation. RESULTS: 307 subjects were recruited for analysis. The optimal PNI threshold is 40.923. Based on the Kaplan-Meier analysis, the elevated PNI group experienced better prognosis (P < 0.001). Cox analysis demonstrated that the PNI group was a stand-alone predictor for elderly AMI patient prognosis (HR = 1.674, 95% CI 1.076-2.604, P = 0.022). Subgroup analysis showed that the HR of the PNI group was the highest in the ST-segment elevation myocardial infarction (STEMI) subgroup (HR = 3.345, 95% CI 1.889-5.923, P = 0.05), but no discernible difference was observed in the non-ST-segment elevation myocardial infarction (NSTEMI) subgroup. CONCLUSION: Based on our analyses, the PNI during hospitalization can accurately predict the prognosis of elderly STEMI patients but not that of elderly NSTEMI patients.

Hourly Ultrafine Particle Exposure and Acute Myocardial Infarction Onset: An Individual-Level Case-Crossover Study in Shanghai, China, 2015-2020.

Associations between ultrafine particles (UFPs) and hourly onset of acute myocardial infarction (AMI) have rarely been investigated. We aimed to evaluate the impacts of UFPs on AMI onset and the lag patterns. A time-stratified case-crossover study was performed among 20,867 AMI patients from 46 hospitals in Shanghai, China, between January 2015 and December 2020. Hourly data of AMI onset and number concentrations of nanoparticles of multiple size ranges below 0.10 µm (0.01-0.10, UFP/PNC0.01-0.10; 0.01-0.03, PNC0.01-0.03; 0.03-0.05, PNC0.03-0.05; and 0.05-0.10 µm, PNC0.05-0.10) were collected. Conditional logistic regressions were applied. Transient exposures to these nanoparticles were significantly associated with AMI onset, with almost linear exposure-response curves. These associations occurred immediately after exposure, lasted for approximately 6 h, and attenuated to be null thereafter. Each interquartile range increase in concentrations of total UFPs, PNC0.01-0.03, PNC0.03-0.05, and PNC0.05-0.10 during the preceding 0-6 h was associated with increments of 3.29, 2.08, 2.47, and 2.93% in AMI onset risk, respectively. The associations were stronger during warm season and at high temperatures and were robust after adjusting for criteria air pollutants. Our findings provide novel evidence that hourly UFP exposure is associated with immediate increase in AMI onset risk.

Relationship between the Ratio of Red Cell Distribution Width to Albumin and 28-Day Mortality among Chinese Patients over 80 Years with Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is a prevalent heart arrhythmia in elderly adults aged 80 years or older. The red cell distribution width (RDW) to albumin ratio has been acknowledged as a reliable prognostic marker for poor outcomes in a variety of disorders. However, there exists limited scientific evidence on the association of RDW to albumin (RAR) with mortality in geriatric individuals with AF. METHODS: From January 2015 to June 2020, a retrospective study was conducted in a tertiary academic institution that diagnosed 1,141 elderly adults with AF. The RAR value was calculated as the ratio of RDW (%) to albumin (g/dL). The potential association between RAR and cardiovascular mortality and the risk of all-cause mortality within 28 days was evaluated by means of multivariable Cox regression analysis. RESULTS: The 28-day all-cause and cardiovascular mortality rates were 8.7% and 3.3%, respectively. Increased RAR tertiles were found to be significantly associated with greater all-cause mortality (T1: 1.6%; T2: 6.2%; T3: 18.1%, p < 0.001) and cardiovascular mortality (T1: 0.8%; T2: 2.9%; T3: 6.3%, p < 0.001) using Kaplan-Meier analysis. Continuous RAR had a positive association with all-cause mortality (hazard ratios [HR] = 1.42, 95% confidence interval [CI] 1.23-1.65) and cardiovascular mortality (HR = 1.31, 95% CI: 1.05-1.64), even after accounting for numerous confounding variables. In comparison to the T1 group, individuals with the highest RAR levels displayed a greater risk of all-cause mortality (HR = 2.73, 95% CI: 1.11-6.74) and cardiovascular mortality (HR = 2.59, 95% CI: 0.69-9.78). Increased RAR levels were related to higher rates of cardiovascular and all-cause mortality across almost all subgroups. CONCLUSION: RAR is independently correlated with 28-day all-cause mortality and cardiovascular mortality in AF-affected individuals aged ≥80.

Angiographic quantitative flow ratio-guided coronary intervention (FAVOR III China): a multicentre, randomised, sham-controlled trial.

BACKGROUND: Compared with visual angiographic assessment, pressure wire-based physiological measurement more accurately identifies flow-limiting lesions in patients with coronary artery disease. Nonetheless, angiography remains the most widely used method to guide percutaneous coronary intervention (PCI). In FAVOR III China, we aimed to establish whether clinical outcomes might be improved by lesion selection for PCI using the quantitative flow ratio (QFR), a novel angiography-based approach to estimate the fractional flow reserve. METHODS: FAVOR III China is a multicentre, blinded, randomised, sham-controlled trial done at 26 hospitals in China. Patients aged 18 years or older, with stable or unstable angina pectoris or patients who had a myocardial infarction at least 72 h before screening, who had at least one lesion with a diameter stenosis of 50-90% in a coronary artery with a reference vessel of at least 2·5 mm diameter by visual assessment were eligible. Patients were randomly assigned to a QFR-guided strategy (PCI performed only if QFR ≤0·80) or an angiography-guided strategy (PCI based on standard visual angiographic assessment). Participants and clinical assessors were masked to treatment allocation. The primary endpoint was the 1-year rate of major adverse cardiac events, a composite of death from any cause, myocardial infarction, or ischaemia-driven revascularisation. The primary analysis was done in the intention-to-treat population. The trial was registered with ClinicalTrials.gov (NCT03656848). FINDINGS: Between Dec 25, 2018, and Jan 19, 2020, 3847 patients were enrolled. After exclusion of 22 patients who elected not to undergo PCI or who were withdrawn by their physicians, 3825 participants were included in the intention-to-treat population (1913 in the QFR-guided group and 1912 in the angiography-guided group). The mean age was 62·7 years (SD 10·1), 2699 (70·6%) were men and 1126 (29·4%) were women, 1295 (33·9%) had diabetes, and 2428 (63·5%) presented with an acute coronary syndrome. The 1-year primary endpoint occurred in 110 (Kaplan-Meier estimated rate 5·8%) participants in the QFR-guided group and in 167 (8·8%) participants in the angiography-guided group (difference, -3·0% [95% CI -4·7 to -1·4]; hazard ratio 0·65 [95% CI 0·51 to 0·83]; p=0·0004), driven by fewer myocardial infarctions and ischaemia-driven revascularisations in the QFR-guided group than in the angiography-guided group. INTERPRETATION: In FAVOR III China, among patients undergoing PCI, a QFR-guided strategy of lesion selection improved 1-year clinical outcomes compared with standard angiography guidance. FUNDING: Beijing Municipal Science and Technology Commission, Chinese Academy of Medical Sciences, and the National Clinical Research Centre for Cardiovascular Diseases, Fuwai Hospital.

Endothelial GATA5 positively regulates angiogenesis via cathepsin S-mediated Angpt2/Flk1 and MMP2/9 signaling pathways.

Although GATA5 is vital in maintaining the function of endothelial cells, the relationship between GATA5 and angiogenesis, however, remains unclear. Our study aims to determine how endothelial GATA5 mediates angiogenesis. Using the ischemic hindlimb of mice with GATA5 overexpression in the endothelia (EC-Ad mice), we showed that GATA5 overexpression could improve blood perfusion and increase capillary density. Furthermore, we showed that overexpression of GATA5 can increase the protein and mRNA levels of angiopoietin-2 (Angpt2) and fetal liver kinase 1 (Flk1) in the endothelia of EC-Ad mice, while GATA5 knockdown can inhibit the VEGF-165-induced proliferation, tube formation, and migration of human umbilical vein endothelial cells (HUVECs). In addition, we observed a decrease in the Angpt2 and Flk1, and the matrix metalloproteinase (MMP) family proteins: MMP2 and MMP9 while GATA5 was decreased. Meanwhile, our study also demonstrated that the expression of cathepsin S (Cat S) decreases when GATA5 is downregulated. Immunoprecipitation assay indicated that GATA5 could bind to Cat S directly. Furthermore, GATA5 or Cat S overexpression can promote tube formation and migration of HUVECs, restore the Angpt2 and Flk1 expression levels in the GATA5 knockdown HUVECs, and upregulate MMP2 and MMP9 protein levels. In summary, our study demonstrated that endothelial GATA5 could mediate angiogenesis by inducing the expression of Cat S, which mediates the Angpt2/Flk1 and MMP2/9 signaling pathways.

The association between the prognostic nutritional index and 28-day mortality among atrial fibrillation patients in China over 80 years of age.

BACKGROUNDS AND AIMS: The most prevalent form of cardiac rhythm abnormality among older populations is atrial fibrillation (AF). The prognostic nutritional index (PNI) is a reliable predictor of mortality in various diseases. The association between the PNI and mortality among AF patients over 80 years remains uncleared. METHODS AND RESULTS: A retrospective assessment of AF cases admitted to a single cardiovascular disease unit in China between January 2015 and June 2020 was performed. The PNI at admission was defined as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (per mm3). The association between PNI and cardiovascular disease (CVD)-related or all-cause mortality within 28 days was assessed via multivariable Cox regression. The analysis included 1141 patients. The CVD-related and all-cause mortality rates were 3.3% and 8.7%. Kaplan-Meier analyses revealed that cases with lower PNI tertiles exhibited higher all-cause mortality (T1: 7.6%; T2: 6.1%; T3: 2.4%, P < 0.001) or CVD mortality (T1: 6.3%; T2: 2.9%; T3: 0.8%, P < 0.001). After adjusting for potential confounders, continuous PNI was negatively related to the hazard of all-cause mortality (HR 0.92, 95% CI 0.89, 0.96) and CVD-related mortality (HR 0.90, 95% CI 0.84, 0.95). Compared to the T1 group, patients with a higher PNI exhibited a lower risk of all-cause mortality (P for trend 0.003) and CVD-related mortality (P for trend 0.005). Among most subgroups, CVD-related and all-cause mortality decreased with elevating PNI values. CONCLUSIONS: PNI is significantly negatively correlated with CVD-related and all-cause mortality among AF cases over 80 years.

Resting distal to aortic pressure ratio and fractional flow reserve discordance affects the diagnostic performance of quantitative flow ratio: Results from an individual patient data meta-analysis.

OBJECTIVE: To evaluate the diagnostic performance of quantitative flow ratio (QFR) related to fractional flow reserve (FFR) and resting distal-to-aortic pressure ratio (resting Pd/Pa) concordance. BACKGROUND: QFR is a method for computation of FFR based on standard coronary angiography. It is unclear how QFR is performed in patients with discordance between FFR and resting pressure ratios (distal-to-aortic pressure ratio [Pd/Pa]). MATERIALS AND METHODS: The main comparison was the diagnostic performance of QFR with FFR as reference stratified by correspondence between FFR and resting Pd/Pa. Secondary outcome measures included distribution of clinical or procedural characteristics stratified by FFR and resting Pd/Pa correspondence. RESULTS: Four prospective studies matched the inclusion criteria. Analysis was performed on patient level data reaching a total of 759 patients and 887 vessels with paired FFR, QFR, and resting Pd/Pa. Median FFR was 0.85 (IQR: 0.77-0.90). Diagnostic accuracy of QFR with FFR as reference was higher if FFR corresponded to resting Pd/Pa: accuracy 90% (95% CI: 88-92) versus 72% (95% CI: 64-80), p < .001, and sAUC 0.95 (95% CI: 0.92-0.96) versus 0.73 (95% CI: 0.69-0.77), p < .001. Resting Pd/Pa and FFR discordance were related to age, sex, hypertension, and lesion severity. CONCLUSION: Diagnostic performance of QFR with FFR as reference is reduced for lesions with discordant FFR (≤0.80) and resting Pd/Pa (≤0.92) measurements.

NAD+ administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux.

Microvascular damage is a key pathological change in myocardial ischemia/reperfusion (I/R) injury. Using a rat model of myocardial I/R, our current study has provided the first evidence that nicotinamide adenine dinucleotide (NAD+) administration can significantly attenuate myocardial I/R-induced microvascular damage, including reduced regional blood perfusion, decreased microvessel density and integrity, and coronary microvascular endothelial cells (CMECs) injury. In studies with primary cultured CMECs under hypoxia/reoxygenation (HR) and a rat model of I/R, our results suggested that the protective effect of NAD+ on CMECs exposed to HR or I/R is at least partially mediated by the NAD+-induced restoration of autophagic flux, especially lysosomal autophagy: NAD+ treatment markedly induced transcription factor EB (TFEB) activation and attenuated lysosomal dysfunction in the I/R or HR-exposed cells. Collectively, our study has provided the first in vivo and in vitro evidence that NAD+ significantly rescued the impaired autophagic flux and cell apoptosis that was induced by I/R in rat CMECs, which is mediated in part through the action of TFEB-mediated lysosomal autophagy.

Coronary Computed Tomography (CT) Angiography Characteristics of High-Risk Plaque: Correlation with Stress Myocardial Perfusion Imaging in Patients with Moderate Coronary Stenosis.

BACKGROUND The aim of this study was to investigate the ability of coronary computed tomographic angiography (CCTA) characteristics of high-risk plaque (HRP) in moderate stenosis to improve differentiation of myocardial ischemia detected by stress CT perfusion (CTP) imaging. MATERIAL AND METHODS Sixty-two patients with coronary plaques and moderate stenosis confirmed by invasive coronary angiography (ICA) had stress CTP and 26 of these patients were found to have myocardial ischemia. The other 36 patients without myocardial ischemia were defined as controls. Characteristics of major plaques on CCTA images of the ischemia and non-ischemia groups were analyzed and compared. RESULTS Differences between the 2 groups were observed in plaque volume, burden and rough inner surface necrotic core volume, plaque-lipid interface and plaque length. In a multivariable analysis, plaque burden and necrotic core volume were significantly associated with myocardial ischemia: plaque burden odds ratio (OR) was 1.28 (95% confidence interval [CI], 1.12-1.48); necrotic core volume OR was 1.78 (95% CI, 1.03-1.34). Compared with other quantitative measurements, optimized thresholds for plaque burden (area under the curve was 0.852) and necrotic core volume (area under the curve was 0.730) showed significantly higher diagnostic performance for ischemia with threshold values of 60.8% and 11.25 mm³, respectively. CONCLUSIONS CCTA characteristics of major plaques may improve the discrimination of ACS patients with myocardial ischemia on stress CTP.

Chemical renal denervation-induced upregulation of the ACE2/Ang (1-7)/Mas axis attenuates blood pressure elevation in spontaneously hypertensive rats.

OBJECTIVE: Evidence has shown that the ACE2/Ang (1-7)/Mas axis plays an important role in the control of hypertension. Thus, we hypothesized that chemical renal denervation (RDN) could reduce blood pressure by regulating the ACE2/Ang (1-7)/Mas axis in spontaneously hypertensive rats. METHODS: Twelve rats were randomly divided into sham group and chemical RDN group. All the rats were sacrificed 4 weeks later. Plasma samples were collected to measure the renin-angiotensin system (RAS) activities and reactive oxygen species levels by radioimmunoassay, chromatometry and ELISA. Paraventricular nucleus (PVN) tissues were collected to examine the expression of the components of the ACE2/Ang (1-7)/Mas axis by western bolt and immunofluorescence. RESULTS: The systolic blood pressure (169.33 ± 7.50 vs 182.67 ± 7.00 mmHg, p < .05) and the diastolic blood pressure (97.50 ± 4.68 vs 109.33 ± 4.41 mmHg, p < .05) in the RDN group were obviously lower than the baseline levels, whereas the opposite results were observed in the sham group. The RDN group exhibited a significant reduction in the plasma ROS (91.59 ± 13.12 vs 72.34 ± 11.76 U/ml, p < .05) and NADPH oxidase (171.86 ± 1.14 vs 175.75 ± 1.74 nmol/ml, p < .001) compared with the sham group, while the plasma eNOS (3.47 ± 0.42 vs 2.49 ± 0.51 U/ml, p < .05) and NO (55.92 ± 8.10 vs 43.53 ± 4.58 µmol/L, p < .05) were increased. The expression of the components of the ACE2/Ang (1-7)/Mas axis was upregulated while the expression of the components of the ACE/Ang II/AT1 R axis was downregulated in the plasma and PVN in the RDN group. CONCLUSION: Our findings suggested that the reduction in blood pressure was regulated by chemical RDN-induced upregulation of the components of the ACE2/Ang (1-7)/Mas axis.

Comparison of transcatheter and surgical treatment of paravalvular leak: Results from a 5-year follow-up study.

OBJECTIVE: This study aimed to compare the efficacy and safety of two different treatments of paravalvular leak (PVL). BACKGROUND: PVL is a common complication after surgical valve replacement. Re-operation is associated with high mortality, morbidity, and risk of re-leak. Catheter-based repair has emerged as a promising new therapy. METHODS AND RESULTS: Eighty-seven consecutive patients with symptomatic PVL received either transcatheter (n = 46) or surgical (n = 41) treatment at Shanghai Chest Hospital between January 2009 and December 2015.The procedural and clinical success rates were similar between the transcatheter group and the surgical group (82.6 vs. 90.2%; P = 0.30; and 69.5 vs. 73.0%; P = 0.71, respectively). There were fewer in-hospital total major adverse events in the transcatheter group (56.09 vs. 17.39%; P < 0.001), and transcatheter repair was more cost-effective, with fewer blood transfusions, shorter procedure durations, shorter hospital stays, and less expenditure. However, there were six cases of hemolysis aggravation in the transcatheter group (13.04%). The 5-year overall survival rates after transcatheter and surgical repair were 74.39 and 71.95% (P = 0.45), respectively, and the cardiac-related survival rates were 84.08 and 74.72% (P = 0.19), respectively. CONCLUSION: Transcatheter and surgical repairs are both effective treatments for selected patients with PVL. And, transcatheter closure seems to be safer and more cost-effective. Nonetheless, this new treatment may be risky for post-procedure hemolysis when unsuitable devices are used.

Diagnostic performance of quantitative flow ratio in prospectively enrolled patients: An individual patient-data meta-analysis.

OBJECTIVES: We aimed to provide robust performance estimates for quantitative flow ratio (QFR) in assessment of intermediary coronary lesions. BACKGROUND: Angiography-based functional lesion assessment by QFR may appear as a cost saving and safe approach to expand the use of physiology-guided percutaneous coronary interventions. QFR was proven feasible and showed good diagnostic performance in mid-sized off-line and on-line studies with fractional flow reserve (FFR) as reference standard. METHODS: We performed a collaborative individual patient-data meta-analysis of all available prospective studies with paired assessment of QFR and FFR using the CE-marked QFR application. The main outcome was agreement of QFR and FFR using a two-step analysis strategy with a multilevel mixed model accounting for study and center level variation. RESULTS: Of 16 studies identified, four studies had prospective enrollment and provided patient level data reaching a total of 819 patients and 969 vessels with paired FFR and QFR: FAVOR Pilot (n = 73); WIFI II (n = 170); FAVOR II China (n = 304) and FAVOR II Europe-Japan (n = 272). We found an overall agreement (mean difference 0.009 ± 0.068, I2 = 39.6) of QFR with FFR. The diagnostic performance was sensitivity 84% (95%CI: 77-90, I2 = 70.1), specificity 88% (95%CI: 84-91, I2 = 60.1); positive predictive value 80% (95%CI: 76-85, I2 = 33.4), and negative predictive value 95% (95%CI: 93-96, I2 = 75.9). CONCLUSIONS: Diagnostic performance of QFR was good with FFR as reference in this meta-analysis of high quality studies. QFR could provide an easy, safe, and cost-effective solution for functional evaluation of coronary artery stenosis.

AMPK/NF-κB signaling pathway regulated by ghrelin participates in the regulation of HUVEC and THP1 Inflammation.

Endothelial inflammation and monocyte plays an essential role in the initiation and progression of atherosclerosis. Ghrelin is beneficial for atherosclerosis progression. However, the detailed and precise molecular mechanisms of how ghrelin regulates endothelial inflammation are not clear. In this study, we investigated the regulation mechanism of ghrelin on TNF-α-activated endothelial inflammation and monocyte adhesion. It was found that TNF-α-induced monocyte adhesion on HUVEC was significantly attenuated by ghrelin. Furthermore, we found that ghrelin effectively suppressed TNF-α-induced inflammatory factors' (including ICAM-1, VCAM-1, MCP-1, and IL-1ß) expression through inhibiting AMPK phosphorylation and p65 expression both in HUVEC and THP-1. This phenomenon was further demonstrated by using AMPK agonist AICAR and inhibitor compound C, respectively. Our findings suggest that ghrelin may mediate TNF-α-induced endothelial inflammation and monocyte adhesion, in part via AMPK/NF-κB signaling pathway. These novel anti-inflammatory and immunoregulatory actions of ghrelin may play a certain role in understanding the formation and development of atherosclerosis.

MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy.

BACKGROUND: The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated. METHODS: The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM. CONCLUSIONS: This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.

ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common primary myocardial disease leading to congestive heart failure, arrhythmia and sudden cardiac death. Increasing studies demonstrate substantial genetic determinants for DCM. Nevertheless, DCM is of substantial genetic heterogeneity, and the genetic basis for DCM in most patients remains unclear. The present study was sought to investigate the association of a genetic variant in the ZBTB17 gene with DCM. A cohort of 158 unrelated patients with idiopathic DCM and a total of 230 unrelated, ethnically matched healthy individuals used as controls were recruited. The coding exons and splicing boundaries of ZBTB17 were sequenced in all study participants. The functional effect of the mutant ZBTB17 was characterized by a dual-luciferase reporter assay system. A novel heterozygous ZBTB17 mutation, p.E243X, was discovered in an index patient. Genetic scan of the mutation carrier's available relatives showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation was absent in the 460 control chromosomes. Functional assays demonstrated that the truncated ZBTB17 protein had no transcriptional activity as compared with its wild-type counterpart. This study firstly associates ZBTB17 loss-of-function mutation with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, implying potential implications for genetic counseling and personalized management of DCM.

CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy.

BACKGROUND: The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear. METHODS: The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. RESULTS: A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity. CONCLUSIONS: The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease.

TBX20 loss-of-function mutation responsible for familial tetralogy of Fallot or sporadic persistent truncus arteriosus.

Congenital heart disease (CHD), the most common form of developmental abnormality in humans, remains a leading cause of morbidity and mortality in neonates. Genetic defects have been recognized as the predominant causes of CHD. Nevertheless, CHD is of substantial genetic heterogeneity and the genetic defects underlying CHD in most cases remain unclear. In the current study, the coding regions and splicing junction sites of the TBX20 gene, which encodes a T-box transcription factor key to cardiovascular morphogenesis, were sequenced in 175 unrelated patients with CHD, and a novel heterozygous TBX20 mutation, p.K274X, was identified in an index patient with tetralogy of Fallot (TOF). Genetic analysis of the proband's available family members showed that his father, elder brother and son had also TOF. In addition, his father and elder brother had also atrial septal defect, and his niece had persistent truncus arteriosus and ventricular septal defect. Analysis of the pedigree revealed that the mutation co-segregated with CHD transmitted in an autosomal dominant fashion, with complete penetrance. The nonsense mutation, which was absent in the 800 control chromosomes, was predicted to produce a truncated protein with only the amino terminus and partial T-box domain left. Functional analyses by using a dual-luciferase reporter assay system showed that the mutant TBX20 lost the ability to transactivate the target gene ANF. Furthermore, the mutation reduced the synergistic activation between TBX20 and NKX2.5 as well as GATA4, two other transcriptional factors previously associated with various CHD, encompassing TOF. This study firstly links TBX20 loss-of-function mutation to familial TOF or sporadic persistent truncus arteriosus, providing novel insight into the molecular pathogenesis of CHD.

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.

HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy.

BACKGROUND: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown. METHODS: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. RESULTS: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM. CONCLUSIONS: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM.

TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy.

The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder.