Xiaofeng Hou

Transvenous Phrenic Nerve Stimulation in Patients With Cheyne-Stokes Respiration and Congestive Heart Failure A Safety and Proof-of-Concept Study

BACKGROUND Cheyne-Stokes respiration (CSR), which often occurs in patients with congestive heart failure (CHF), may be a predictor for poor outcome. Phrenic nerve stimulation (PNS) may interrupt CSR in patients with CHF. We report the clinical use of transvenous PNS in patients with CHF and CSR. METHODS Nineteen patients with CHF and CSR were enrolled. A single stimulation lead was placed at the junction between the superior vena cava and brachiocephalic vein or in the left-side pericardiophrenic vein. PNS stimulation was performed using Eupnea System device (RespiCardia Inc). Respiratory properties were assessed before and during PNS. PNS was assessed at a maximum of 10 mA. RESULTS Successful stimulation capture was achieved in 16 patients. Failure to capture occurred in three patients because of dislocation of leads. No adverse events were seen under maximum normal stimulation parameters for an overnight study. When PNS was applied following a series of central sleep apneic events, a trend toward stabilization of breathing and heart rate as well as improvement in oxygen saturation was seen. Compared with pre-PNS, during PNS there was a significant decrease in apnea-hypopnea index (33.8 ± 9.3 vs 8.1 ± 2.3, P = .00), an increase in mean and minimal oxygen saturation as measured by pulse oximetry (89.7% ± 1.6% vs 94.3% ± 0.9% and 80.3% ± 3.7% vs 88.5% ± 3.3%, respectively, all P = .00) and end-tidal CO2 (38.0 ± 4.3 mm Hg vs 40.3 ± 3.1 mm Hg, P = .02), but no significant difference in sleep efficiency (74.6% ± 4.1% vs 73.7% ± 5.4%, P = .36). CONCLUSIONS The preliminary results showed that in a small group of patients with CHF and CSR, 1 night of unilateral transvenous PNS improved indices of CSR and was not associated with adverse events.

Whole-exome sequencing identify a new mutation of MYH7 in a Chinese family with left ventricular noncompaction.

BACKGROUND Left ventricular noncompaction (LVNC) is a genetic cardiomyopathy results from the failure of myocardial development during embryogenesis. Previous reports show that defects in TAZ, SCN5A, TPM1, YWHAE, MYH7, ACTC1 and TNNT2 are associated with LVNC. Sequencing of individuals using family-based design is a powerful approach for hereditary disease. In this study, we used whole-exome sequencing to screen potentially novel causal mutations in a Chinese Han family with LVNC. METHODS DNA from 3 individuals belonging to the same family was extracted and sequenced based on standard whole-exome sequencing protocol. The exome sequence data was analyzed using BWA, PICARD and Genome Analysis Toolkit (GATK v2.8). Non-silent single nucleotide variants (SNVs) were further selected if they exist in both LVNC patients and not in the health control. A web-based software Snv Prioritization via the INtegration of Genomic data (SPRING), was used to prioritize the causal SNV by calculating a q-value which indicates the statistical significance that a variant is causative for a query disease. RESULTS From the LVNC family in which the mother and son were affected, a novel single nucleotide variant c.C1492G in exon 15 of MYH7 was identified probably to be the causal SNV of the family with P-value of 3.45E-05 and q-value of 4.65E-03 by SPRING. The SNV was predicted as deleterious in SIFT, PolyPhe2 and MutatioTaster database. Another 12 SNVs were also identified with P-value less than 0.05 by SPRING. CONCLUSIONS A novel genetic variant in the coding regions of MYH7 gene was identified in a Chinese LVNC-family. The results support the previous evidence that MYH7 is a pathogenic gene for LVNC.

Right-Sided Free Wall Accessory Pathway Refractory to Conventional Catheter Ablation: Lessons From 3-Dimensional Electroanatomic Mapping

Right Free Wall Accessory Pathway Ablation. Introduction: The aim of this study was to delineate the electroanatomic substrates of right‐sided free wall (RFW) accessory pathways (APs) that were refractory to conventional catheter ablation utilizing 3‐dimensional (3‐D) mapping.

Resveratrol inhibits angiotensin II-induced ERK1/2 activation by downregulating quinone reductase 2 in rat vascular smooth muscle cells

Our previous studies showed that resveratrol could inhibit the proliferation of vascular smooth muscle cells (VSMCs) and repress mRNA and protein expression of quinone reductase 2 (NQO2). This study further explored the potential mechanisms whereby resveratrol inhibits the proliferation of rat VSMCs. Lentiviral vectors that incorporated NQO2 small interfering RNA (siRNA) were constructed and transduced into rat VSMCs. The cell proliferation was detected using the bromodeoxyuridine (BrdU) assay. Cultured rat VSMCs were stimulated with angiotensin II and the level of reactive oxygen species (ROS) was measured using a ROS assay kit. A realtime quantitative PCR was used to detect NQO2 mRNA levels. Extracellular signal-regulated kinase (ERK1/2) and NQO2 protein expression were determined by Western blotting analysis. The inhibitory effect of resveratrol (10 and 50 µmol/L) on the proliferation of rat VSMCs in the NQO2 siRNA group was significantly weaker than that in the normal and scrambled siRNA group (P < 0.01). The ROS level in the NQO2 siRNA and resveratrol (50 µmol/L) treatment groups were lower than that in the normal and scrambled siRNA groups (P < 0.01 in both). Compared with the normal and scrambled siRNA group, the phosphorylation of ERK1/2 was significantly decreased in the NQO2 siRNA and resveratrol (50 µmol/L) treatment group (P < 0.01 in both). In conclusion, high concentration of resveratrol inhibits angiotensin II-induced ERK1/2 phosphorylation and subsequent proliferation by down-regulation of NQO2 in cultured rat VSMCs.

Inhibiting N-cadherin-mediated adhesion affects gap junction communication in isolated rat hearts

Cadherin-mediated adherens junctions is impaired concomitant with a decrease in connexin 43 (Cx43) in diseases or pathological processes. We have investigated the acute effects of adherens junction impairment in isolated rat hearts by introducing Ala-His-Ala-Val-Asp-NH2 (AHAVD, a synthetic peptide) as a specific inhibitor of N-cadherin. Effect of AHAVD on N-cadherin mediated adhension was analyzed by Cardiomy-ocyte aggregation assay. Laser confocal microscopy showed disrupted cell-cell contacts in cultured neonatal cardiomyocytes co-incubated with 0.2 mM AHAVD. In isolated adult rat hearts, Cx43 was redistributed along the bilateral of cardiomyocytes from the intercalated discs and significant dephosphorylation of Cx43 on serine368 occurred concomitantly with decreased gap junction (GJ) function in dose dependent manner after 1 h perfusion with AHAVD. These results indicate that impairing cad-herin-mediated adhesion by AHAVD rapidly results in Cx43 redistribution and dephosphorylation of serine368, thereby impairing GJ communication function.

β2 adrenergic receptor activation governs cardiac repolarization and arrhythmogenesis in a guinea pig model of heart failure

β2-AR activation increases the risk of sudden cardiac death (SCD) in heart failure (HF) patients. Non-selective β-AR blockers have greater benefits on survival than selective β1-AR blockers in chronic HF patients, indicating that β2-AR activation contributes to SCD in HF. This study investigated the role of β2-AR activation on repolarization and ventricular arrhythmia (VA) in the experimental HF model. The guinea pig HF was induced by descending aortic banding. The effective refractoriness period (ERP), corrected QT (QTc) and the incidence of VA were examined using Langendorff and programmed electrical stimulation. Ikr and APD were recorded by the whole cell patch clamp. Selective β2-AR agonist salbutamol significantly increased the incidence of VA, prolonged QTc and shortened ERP. These effects could be prevented by the selective β2-AR antagonist, ICI118551. Salbutamol prolonged APD90 and reduced Ikr in guinea pig HF myocytes. The antagonists of cAMP (Rp-cAMP) and PKA (KT5720) attenuated Ikr inhibition and APD prolongation induced by salbutamol. However, the antagonists of Gi protein (PTX) and PDE III (amrinone) showed opposite effects. This study indicates that β2-AR activation increases the incidence of VA in the experimental HF model via activation of Gs/cAMP/PKA and/or inhibition of Gi/PDE pathways.

Comparison of the effects of selective and non-selective His bundle pacing on cardiac electrical and mechanical synchrony

Aims This study aimed to assess the acute effect of selective His bundle pacing (S-HBP), non-selective His bundle pacing (NS-HBP), and right ventricular septum pacing (RVSP) on electrical synchrony and left ventricular (LV) mechanical synchrony using electrocardiogram and phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Methods and results Totally 39 patients eligible for pacemaker were enrolled. Thirty-seven patients underwent successful His bundle pacing (HBP) including S-HBP in 23 and NS-HBP in 14 patients, respectively. Thirty-one patients simultaneously underwent backup RVSP. Twenty-three patients received SPECT MPI scans under different pacing modes, including S-HBP low- and high-output, NS-HBP low- and high-output, and RVSP mode. The paced QRS duration (QRSd) in the S-HBP low- and high-output mode and in the NS-HBP high-output mode were similarly compared with the baseline intrinsic QRSd. QRS duration in the NS-HBP low-output mode was slightly longer than the baseline. QRS duration was the longest in the RVSP group. Left ventricular mechanical synchrony parameters in both the S-HBP and the NS-HBP groups were remarkably better than those in the RVSP group. Moreover, LV mechanical synchrony parameters were much better in the S-HBP groups and NS-HBP high-output group. Conclusion Selective His bundle pacing and high-output NS-HBP could restore normal electrical and LV mechanical synchrony.

Premature ventricular contractions originating from the right ventricular outflow tract: three-dimensional distribution of the target sites and their electrocardiographic characteristics.

1 The purpose of the present study was to explore the relationship between electrocardiogram (ECG) patterns of right ventricular outflow tract (RVOT) premature ventricular contractions and the three‐dimensional distribution of the target sites. 2 Thirty‐three consecutive patients were included in the study. The target sites were identified by non‐contact mapping and confirmed by successful ablation. The distribution of the target sites in the three‐dimensional reconstructed geometry of the RVOT was classified in three directions: (i) anterior (A)/posterior (P); (ii) free wall (F)/septal (Se); and (iii) superior (Su)/inferior (I). The ECG characteristics were then analysed according to the three‐dimensional distribution of the target sites. 3 The following indices were helpful to identify the position of the target site: (i) QRS duration (≥ 150 msec = F; < 150 msec = Se; P < 0.05); (ii) the R wave pattern in the inferior leads (RR′ or Rr′ = F; R = Se; P < 0.05); (iii) the R wave amplitude in the inferior leads (high = Se; low = F; P < 0.05); (iv) the initial r wave width in lead V1 (wide = F; narrow = Se; P < 0.05); (v) the QS wave amplitude in aVR and aVL (if aVR < aVL, A; if aVR ≥ aVL, P; P < 0.05); and (vi) the initial r wave amplitude in lead V1 and V2 (if V1 ≥ 0.15 mV and V2 ≥ 0.3 mV, Su; if V1 < 0.15 mV or V2 < 0.3 mV, I; P < 0.05). 4 In conclusoin, the ECG characteristics were associated with target site locations in all three directions.

Development and validation of an automatic method to detect the latest contracting viable left ventricular segments to assist guide CRT therapy from gated SPECT myocardial perfusion imaging

ObjectivesThe purpose of this study is to use ECG-gated SPECT MPI to detect the latest contracting viable left ventricular (LV) segments to help guide the LV probe placement used in CRT therapy and to validate segment selection against the visual integration method by experts.MethodsFor each patient, the resting ECG-gated SPECT MPI short-axis images were sampled in 3D to generate a polar map of the perfusion distribution used to determine LV myocardial viability, and to measure LV synchronicity using our phase analysis tool. In the visual integration method, two experts visually interpreted the LV viability and mechanical dyssynchrony from the short-axis images and polar maps of viability and phase, to determine the latest contracting viable segments using the 17-segment model. In the automatic method, the apical segments, septal segments, and segments with more than 50% scar were excluded as these are not candidates for CRT LV probe placement. Amongst the remaining viable segments, the segments, whose phase angles were within 10° of the latest phase angle (the most delayed contracting segment), were identified for potential CRT LV probe placement and ranked based on the phase angles of the segments. Both methods were tested in 36 pre-CRT patients who underwent ECG-gated SPECT MPI. The accuracy was determined as the percent agreement between the visual integration and automatic methods. The automatic method was performed by a second independent operator to evaluate the inter-operator processing reproducibility.ResultsIn all the 36 patients, the LV lead positions of the 1st choices recommended by the automatic and visual integration methods were in the same segments in 35 patients, which achieved an agreement rate of 97.2%. In the inter-operator reproducibility test, the LV lead positions of the 1st choices recommended by the two operators were in the same segments in 25 patients, and were in the adjacent segments in 7 patients, which achieved an overall agreement of 88.8%.ConclusionsAn automatic method has been developed to detect the latest contracting viable LV segments to help guide the LV probe placement used in CRT therapy. The retrospective clinical study with 36 patients suggests that this method has high agreement against the visual integration method by experts and good inter-operator reproducibility. Consequently, this method is promising to be a clinical tool to recommend the CRT LV lead positions.

CLOCK-BMAL1 regulate the cardiac L-type calcium channel subunit CACNA1C through PI3K-Akt signaling pathway.

The heterodimerized transcription factors CLOCK-BMAL1 regulate the cardiomyocyte circadian rhythms. The L-type calcium currents play important role in the cardiac electrogenesis and arrhythmogenesis. Whether and how the CLOCK-BMAL1 regulate the cardiac L-type calcium channels are yet to be determined. The functions of the L-type calcium channels were evaluated with patch clamping techniques. Recombinant adenoviruses of CLOCK and BMAL1 were used in the expression experiments. We reported that the expressions and functions of CACNA1C (the α-subunit of the L-type calcium channels) showed circadian rhythms, with the peak at zeitgeber time 3 (ZT3). The endocardial action potential durations 90 (APD90) were correspondingly longer at ZT3. The protein levels of the phosphorylated Akt at threonine 308 (pAkt T308) also showed circadian rhythms. Overexpressions of CLOCK-BMAL1 significantly reduced the levels of CACNA1C while increasing the levels of pAkt T308 and pik3r1. Furthermore, the inhibitory effects of CLOCK-BMAL1 on CACNA1C could be abolished by the Akt inhibitor MK2206 or the PDK1 inhibitor GSK2334470. Collectively, our findings suggested that the expressions of the cardiac CACNA1C were under the CLOCK-BMAL1 regulation, probably through the PI3K-Akt signal pathway.