Kai Tang

GATA5 loss-of-function mutation in familial dilated cardiomyopathy

Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is an important cause of sudden cardiac death and heart failure and is the leading indication for heart transplantation in children and adults worldwide. Recent studies have revealed a strong genetic basis for idiopathic DCM, with many distinct genes causally implicated. Nevertheless, DCM is a genetically heterogeneous disorder and the genetic determinants underlying DCM in a substantial proportion of patients remain unclear. In this study, the whole coding exons and flanking introns of the GATA binding protein 5 (GATA5) gene, which codes for a zinc-finger transcription factor essential for cardiovascular development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were genotyped for GATA5. The functional characteristics of the mutant GATA5 were analyzed in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.G240D, 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 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional analyses revealed that the GATA5 mutant was associated with significantly diminished transcriptional activity. This study firstly links GATA5 mutation to DCM, which provides novel insight into the molecular mechanisms of DCM, suggesting a potential molecular target for the prenatal prophylaxis and allele-specific treatment of DCM.

Prognostic significance of fragmented QRS in patients with non-ST elevation myocardial infarction: results of a 1-year, single-center follow-up.

ObjectivesThe aim of this study was to evaluate the predictive value of fragmented QRS (fQRS) among non-ST elevation acute coronary syndrome (ACS) patients.DesignThe fQRS on standard 12-lead ECGs in 179xa0patients (63% males, mean age 60.9u2009±u200912.3xa0years) were analyzed. Cardiac events and cardiac mortality were regarded as two outcomes to determine whether fQRS was a clinical prognostic factor; its prognostic value was then assessed adjusting for other covariates.ResultsCardiac mortality (18 (17.0%) vs. 4 (5.5%)) and major cardiac event rate (46 (43.4%) vs. 22 (30.1%)) were higher in the fQRS group compared with the non-fQRS group during a mean follow-up of 12xa0months. A Kaplan–Meier survival analysis revealed significantly lower event-free survival for cardiac events (pu2009=u20090.030) and cardiac mortality (pu2009=u20090.020). Multivariate Cox regression analysis revealed that significant fQRS was an independent significant predictor for cardiac events and cardiac mortality.ConclusionThese results indicate that the occurrence of fQRS in the ECG is a powerful predictor of decreased survival in NSTEMI. The prognostic importance of fQRS was incremental to clinical and conventional factors.ZusammenfassungZielsetzungZiel dieser Studie war es, den Vorhersagewert des fragmentierten QRS-Komplexes (fQRS) bei Patienten mit akutem Koronarsyndrom ohne ST-Hebung zu untersuchen.StudiendesignDie fQRS-Komplexe im Standard-12-Kanal-EKG von 179xa0Patienten (63% männlich; Durchschnittsalter: 60,9±12,3xa0Jahre) wurden analysiert. Anhand der kardialen Ereignisse und der kardialen Mortalität wurde bestimmt, ob der fQRS-Komplex ein klinischer Prognosefaktor ist. Der prognostische Wert wurde daraufhin unter Adjustierung für Kovariablen überprüft.ErgebnisseDie kardiale Mortalität [18 (17,0%) vs. 4 (5,5%)] und die Rate schwerwiegender kardialer Ereignisse [46 (43,4%) vs. 22 (30,1%)] lagen in der fQRS-Gruppe in einem durchschnittlichen Follow-up von 12xa0Monaten höher als in der Nicht-fQRS-Gruppe. Eine Kaplan-Meier-Überlebensanalyse ergab ein signifikant niedrigeres ereignisfreies Überleben für kardiale Ereignisse (p=0,030) und die kardiale Mortalität (p=0,020). Die multivariate Cox-Regressionsanalyse zeigte, dass ein signifikanter fQRS-Komplex ein unabhängiger, signifikanter Prädiktor für kardiale Ereignisse und die kardiale Mortalität war.SchlussfolgerungDie Ergebnisse zeigen, dass das Auftreten von fQRS-Komplexen im EKG ein starker Prädiktor für ein vermindertes Überleben beim Nicht-ST-Hebungsinfarkt ist. Unabhängig von klinischen und herkömmlichen Faktoren ist der fQRS-Komplex von prognostischer Bedeutung.

Prognostic significance of fragmented QRS in patients with non-ST elevation myocardial infarction

ObjectivesThe aim of this study was to evaluate the predictive value of fragmented QRS (fQRS) among non-ST elevation acute coronary syndrome (ACS) patients.DesignThe fQRS on standard 12-lead ECGs in 179xa0patients (63% males, mean age 60.9u2009±u200912.3xa0years) were analyzed. Cardiac events and cardiac mortality were regarded as two outcomes to determine whether fQRS was a clinical prognostic factor; its prognostic value was then assessed adjusting for other covariates.ResultsCardiac mortality (18 (17.0%) vs. 4 (5.5%)) and major cardiac event rate (46 (43.4%) vs. 22 (30.1%)) were higher in the fQRS group compared with the non-fQRS group during a mean follow-up of 12xa0months. A Kaplan–Meier survival analysis revealed significantly lower event-free survival for cardiac events (pu2009=u20090.030) and cardiac mortality (pu2009=u20090.020). Multivariate Cox regression analysis revealed that significant fQRS was an independent significant predictor for cardiac events and cardiac mortality.ConclusionThese results indicate that the occurrence of fQRS in the ECG is a powerful predictor of decreased survival in NSTEMI. The prognostic importance of fQRS was incremental to clinical and conventional factors.ZusammenfassungZielsetzungZiel dieser Studie war es, den Vorhersagewert des fragmentierten QRS-Komplexes (fQRS) bei Patienten mit akutem Koronarsyndrom ohne ST-Hebung zu untersuchen.StudiendesignDie fQRS-Komplexe im Standard-12-Kanal-EKG von 179xa0Patienten (63% männlich; Durchschnittsalter: 60,9±12,3xa0Jahre) wurden analysiert. Anhand der kardialen Ereignisse und der kardialen Mortalität wurde bestimmt, ob der fQRS-Komplex ein klinischer Prognosefaktor ist. Der prognostische Wert wurde daraufhin unter Adjustierung für Kovariablen überprüft.ErgebnisseDie kardiale Mortalität [18 (17,0%) vs. 4 (5,5%)] und die Rate schwerwiegender kardialer Ereignisse [46 (43,4%) vs. 22 (30,1%)] lagen in der fQRS-Gruppe in einem durchschnittlichen Follow-up von 12xa0Monaten höher als in der Nicht-fQRS-Gruppe. Eine Kaplan-Meier-Überlebensanalyse ergab ein signifikant niedrigeres ereignisfreies Überleben für kardiale Ereignisse (p=0,030) und die kardiale Mortalität (p=0,020). Die multivariate Cox-Regressionsanalyse zeigte, dass ein signifikanter fQRS-Komplex ein unabhängiger, signifikanter Prädiktor für kardiale Ereignisse und die kardiale Mortalität war.SchlussfolgerungDie Ergebnisse zeigen, dass das Auftreten von fQRS-Komplexen im EKG ein starker Prädiktor für ein vermindertes Überleben beim Nicht-ST-Hebungsinfarkt ist. Unabhängig von klinischen und herkömmlichen Faktoren ist der fQRS-Komplex von prognostischer Bedeutung.

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.

QT restitution properties of middle-aged women with different exercise capacities

BACKGROUNDnFramingham Study data indicate an incremental risk of cardiovascular death in relation to low exercise capacity in women. The reason for death is still not clear.nnnMETHODSnQT restitution properties in 80 middle-aged women were investigated to confirm whether the cardiac restitution property was affected by the exercise capacity. Exercise tests were performed according to the Bruce protocol. Seventy cases were divided into the low-exercise capacity group (LEC group) and high-exercise capacity group (HEC group) by median exercise capacities. Sequential QT intervals and their preceding TQ intervals were measured, and the QT restitution curve (QTRC) was constructed. Two exponential equations were used to match the data and calculate the maximum slope (Smax) of QTRC, respectively.nnnRESULTSnWith elevation in the exercise level, the women in the LEC group had a higher change rate of QT intervals (41 ± 10 vs 29 ± 3 ms/Met, P = .001) and TQ intervals (46 ± 12 vs 41 ± 7 ms/Met, P = .046); and the ratio of QT interval alterations to TQ interval alterations increased (0.41 ± 0.09 vs 0.36 ± 0.07, P = .003). The Smax of the QTRC in the LEC group was higher than that in the HEC group (1.43 ± 0.44 vs 1.13 ± 0.34, P = .002). There was an inverse relationship between Smax and exercise capacity (r = -0.43, P = .001).nnnCONCLUSIONnMiddle-aged women with low exercise capacity have steeper QTRCs than those with high exercise capacity, denoting a more unstable alternation of QT interval with elevation in exercise level.

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.

Increased plasma microfibrillar-associated protein 4 is associated with atrial fibrillation and more advanced left atrial remodelling

Introduction This study aimed to evaluate the relationship of plasma microfibrillar-associated protein 4 (MFAP4) to atrial fibrillation (AF) and atrial structural remodelling. Material and methods Plasma MFAP4 levels were measured in 92 patients with AF (61 paroxysmal AF (PAF) patients and 31 persistent AF (PersAF) patients) and 71 control subjects without AF. Linear and logistic multivariate regression analyses were performed to determine the potential value of MFAP4 for predicting the incidence of AF and left atrial size. Then, plasma and atrial protein levels of MFAP4 and its association with atrial fibrosis ratio were analysed in an atrial-specific fibrosis rat model. Results There were significant differences in MFAP4 levels based on clinical group, with a gradient from control (1.71 ±0.53 ng/ml) to PAF (1.98 ±0.53 ng/ml) to PersAF (2.09 ±0.76 ng/ml) (p < 0.01). With multivariate analyses, plasma MFAP4 was found to be an independent determinant of left atrial diameter in AF patients. In atrial fibrosis rats, both plasma MFAP4 and atrial MFAP4 protein levels increased in atrial fibrosis rats and positively correlated with atrial fibrosis severity. Conclusions Plasma MFAP4 was increased in patients with AF and was highest in those with PersAF; both plasma MFAP4 and atrial MFAP4 protein expression were directly associated with the extent of LA structural remodelling.

Air emboli during the procedure of transcatheter left atrial appendage closure

atrial appendage closure Shuang Li, MD, Wei Chen, MD, PhD, Shuang Li, MD, Dongdong Zhao, MD, PhD, FHRS, Kai Tang, MD, PhD, FHRS, Yat-yam Lam, MD, PhD, Yawei Xu, MD, PhD, FHRS From the Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China, and Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.

The roles of pacing interval and pacing strength in ventricular fibrillation induced by rapid pacing with 1 : 1 capture.

Introduction The roles of pacing interval (PI) and pacing strength (PS) in ventricular fibrillation (VF) induced by rapid pacing with 1 : 1 capture remain unclear. Material and methods Epicardial unipolar electrograms (UEs) were simultaneously recorded using contact mapping in 11 swine. Activation-recovery interval (ARI) restitution was constructed at 4 sites, i.e. the apex and base of the left and right ventricles, respectively. A steady state pacing (SSP) protocol was performed to induce VF. The longest PI and the lowest PS for inducing VF were recorded. Statistical correlation analysis was performed to determine the relationship between local ARI restitution properties and PI and PS for VF induction. Results Forty restitution curves were constructed from 11 SSP procedures. The maximal slope (Smax) of the ARI restitution curve of the right ventricular apex was positively correlated with the PI for VF induction (r = 0.761, p < 0.05). Spatial dispersions of ARI and Smax were negatively correlated with the PS for VF induction (r = –0.626 and r = –0.722, respectively, both p < 0.05). Conclusions Ventricular fibrillation can be induced by rapid ventricular pacing with 1 : 1 capture. The PI for VF induction was related to the Smax of the ARI restitution curve of the right ventricular apex, while PS for VF induction was associated with the spatial dispersions of ARI and its restitution property.

Prognostic significance of fragmented QRS in patients with non-ST elevation myocardial infarction@@@Prognostische Bedeutung des fragmentierten QRS-Komplexes bei Patienten mit Nicht-ST-Hebungsinfarkt: Results of a 1-year, single-center follow-up@@@Ergebnisse eines monozentrischen 1-Jahres-Follow-ups

ObjectivesThe aim of this study was to evaluate the predictive value of fragmented QRS (fQRS) among non-ST elevation acute coronary syndrome (ACS) patients.DesignThe fQRS on standard 12-lead ECGs in 179xa0patients (63% males, mean age 60.9u2009±u200912.3xa0years) were analyzed. Cardiac events and cardiac mortality were regarded as two outcomes to determine whether fQRS was a clinical prognostic factor; its prognostic value was then assessed adjusting for other covariates.ResultsCardiac mortality (18 (17.0%) vs. 4 (5.5%)) and major cardiac event rate (46 (43.4%) vs. 22 (30.1%)) were higher in the fQRS group compared with the non-fQRS group during a mean follow-up of 12xa0months. A Kaplan–Meier survival analysis revealed significantly lower event-free survival for cardiac events (pu2009=u20090.030) and cardiac mortality (pu2009=u20090.020). Multivariate Cox regression analysis revealed that significant fQRS was an independent significant predictor for cardiac events and cardiac mortality.ConclusionThese results indicate that the occurrence of fQRS in the ECG is a powerful predictor of decreased survival in NSTEMI. The prognostic importance of fQRS was incremental to clinical and conventional factors.ZusammenfassungZielsetzungZiel dieser Studie war es, den Vorhersagewert des fragmentierten QRS-Komplexes (fQRS) bei Patienten mit akutem Koronarsyndrom ohne ST-Hebung zu untersuchen.StudiendesignDie fQRS-Komplexe im Standard-12-Kanal-EKG von 179xa0Patienten (63% männlich; Durchschnittsalter: 60,9±12,3xa0Jahre) wurden analysiert. Anhand der kardialen Ereignisse und der kardialen Mortalität wurde bestimmt, ob der fQRS-Komplex ein klinischer Prognosefaktor ist. Der prognostische Wert wurde daraufhin unter Adjustierung für Kovariablen überprüft.ErgebnisseDie kardiale Mortalität [18 (17,0%) vs. 4 (5,5%)] und die Rate schwerwiegender kardialer Ereignisse [46 (43,4%) vs. 22 (30,1%)] lagen in der fQRS-Gruppe in einem durchschnittlichen Follow-up von 12xa0Monaten höher als in der Nicht-fQRS-Gruppe. Eine Kaplan-Meier-Überlebensanalyse ergab ein signifikant niedrigeres ereignisfreies Überleben für kardiale Ereignisse (p=0,030) und die kardiale Mortalität (p=0,020). Die multivariate Cox-Regressionsanalyse zeigte, dass ein signifikanter fQRS-Komplex ein unabhängiger, signifikanter Prädiktor für kardiale Ereignisse und die kardiale Mortalität war.SchlussfolgerungDie Ergebnisse zeigen, dass das Auftreten von fQRS-Komplexen im EKG ein starker Prädiktor für ein vermindertes Überleben beim Nicht-ST-Hebungsinfarkt ist. Unabhängig von klinischen und herkömmlichen Faktoren ist der fQRS-Komplex von prognostischer Bedeutung.