Chien-Hua Huang

A Role for Toll-like Receptor 3 Variants in Host Susceptibility to Enteroviral Myocarditis and Dilated Cardiomyopathy

The innate antiviral response is mediated, at least in part, by Toll-like receptors (TLRs). TLR3 signaling is activated in response to viral infection, and the absence of TLR3 in mice significantly increases mortality after infection with enteroviruses that cause myocarditis and/or dilated cardiomyopathy. We screened TLR3 in patients diagnosed with enteroviral myocarditis/cardiomyopathy and identified a rare variant in one patient as well as a significantly increased occurrence of a common polymorphism compared with controls. Expression of either variant resulted in significantly reduced TLR3-mediated signaling after stimulation with synthetic double-stranded RNA. Furthermore, Coxsackievirus B3 infection of cell lines expressing mutated TLR3 abrogated activation of the type I interferon pathway, leading to increased viral replication. TLR3-mediated type I interferon signaling required cellular autophagy and was suppressed by 3-methyladenine and bafilomycin A1, by inhibitors of lysosomal proteolysis, and by reduced expression of Beclin 1, Atg5, or microtubule-associated protein 1 light chain 3β (MAP1LC3β). However, TLR3-mediated signaling was restored upon exogenous expression of Beclin 1 or a variant MAP1LC3β fusion protein refractory to RNA interference. These data suggest that individuals harboring these variants may have a blunted innate immune response to enteroviral infection, leading to reduced viral clearance and an increased risk of cardiac pathology.

Relations of Epicardial Adipose Tissue Measured by Multidetector Computed Tomography to Components of the Metabolic Syndrome Are Region-Specific and Independent of Anthropometric Indexes and Intraabdominal Visceral Fat

CONTEXT Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot. Its distribution is asymmetrical and primarily concentrated in the grooves. To date, it remains unclear which measurement of EAT best reflects its metabolic risk. OBJECTIVE We aimed to examine the correlations between various multidetector computed tomographic measurements of EAT, metabolic syndrome components, and plasma levels of high-sensitivity C-reactive protein and adipokines. DESIGN, SETTING, AND PARTICIPANTS This study included 148 consecutive patients undergoing multidetector computed tomography prior to diagnostic coronary angiography. Thickness in the grooved segments, cross-sectional areas, and total volume of EAT were measured. The cross-sectional areas of sc and visceral abdominal fat depots were additionally measured in 70 randomly selected patients. RESULTS Thickness of EAT in the left atrioventricular groove was the only EAT measurement significantly correlated with all three metabolic syndrome components (blood pressure, lipid, and glucose components) and plasma levels of resistin and high-sensitivity C-reactive protein after age and gender adjustments. The association between left atrioventricular groove thickness and increasing number of metabolic syndrome components remained significant after additional adjustments for body mass index, waist circumference, and intraabdominal visceral fat area. By using the receiver operating characteristic analysis, the optimal cutoff point for left atrioventricular groove thickness to predict the presence of at least two metabolic syndrome components was 12.4 mm. CONCLUSIONS A simple measurement of EAT thickness in the left atrioventricular groove may provide a more accurate assessment of metabolic risk associated with EAT, which could not be accounted for by anthropometric indexes and intraabdominal visceral fat.

Tracheal rapid ultrasound exam (T.R.U.E.) for confirming endotracheal tube placement during emergency intubation

OBJECTIVES This study aimed to assess the diagnostic accuracy and timeliness of using tracheal ultrasound to examine endotracheal tube placement during emergency intubation. METHODS This was a prospective, observational study, conducted at the emergency department of a national university teaching hospital. Patients received emergency intubation because of impending respiratory failure, cardiac arrest, or severe trauma. The tracheal rapid ultrasound exam (T.R.U.E.) was performed during emergency intubation with the transducer placed transversely at the trachea over the suprasternal notch. Quantitative waveform capnography was used as the criterion standard for confirmation of tracheal intubation. The main outcome was the concordance between the T.R.U.E. and the capnography. RESULTS A total of 112 patients were included in the analysis, and 17 (15.2%) had esophageal intubations. The overall accuracy of the T.R.U.E. was 98.2% (95% confidence interval [CI]: 93.7-99.5%). The kappa (κ) value was 0.93 (95% CI: 0.84-1.00), indicating a high degree of agreement between the T.R.U.E. and capnography. The sensitivity, specificity, positive predictive value, and negative predictive value of the T.R.U.E. were 98.9% (95% CI: 94.3-99.8%), 94.1% (95% CI: 73.0-99.0%), 98.9% (95% CI: 94.3-99.8%) and 94.1% (95% CI: 73.0-99.0%). The median operating time of the T.R.U.E. was 9.0s (interquartile range [IQR]: 6.0, 14.0). CONCLUSIONS The application of the T.R.U.E. to examine endotracheal tube placement during emergency intubation is feasible, and can be rapidly performed.

Toll-Like Receptor 2 Mediates Staphylococcus aureus–Induced Myocardial Dysfunction and Cytokine Production in the Heart

Background—Staphylococcus aureus sepsis is associated with significant myocardial dysfunction. Toll-like receptor 2 (TLR2) mediates the inflammatory response to S aureus and may trigger an innate immune response in the heart. We hypothesized that a TLR2 deficiency would attenuate S aureus–induced cardiac proinflammatory mediator production and the development of cardiac dysfunction. Methods and Results—Wild-type and TLR2-deficient (TLR2D) mice were studied. S aureus challenge significantly increased tumor necrosis factor, interleukin-1&bgr;, and nitric oxide expression in hearts of wild-type mice. This response was significantly blunted in TLR2D mice. Hearts from TLR2D mice had impaired S aureus–induced activation of interleukin-1 receptor–associated kinase, c-Jun NH2 terminal kinase, nuclear factor-&kgr;B, and activator protein-1. Moreover, hearts from TLR2D mice were protected against S aureus–induced contractile dysfunction. Conclusions—These results show for the first time that TLR2 signaling contributes to the loss of myocardial contractility and cytokine production in the heart during S aureus sepsis.

The effect of hyperoxia on survival following adult cardiac arrest: A systematic review and meta-analysis of observational studies

OBJECTIVE Studies have shown the detrimental effect of hyperoxia in animals with return of spontaneous circulation (ROSC) after cardiac arrest. To maximize the value of existing clinical studies, we performed the systemic review and meta-analysis of human observational studies to examine the effect of hyperoxia on outcomes of post-ROSC patients. METHODS We searched PubMed and Embase from the inception to October 2013. We selected adult observational studies that compared different levels of partial pressure of arterial oxygen (PaO2) in post-ROSC patients with mortality or neurological status at hospital discharge as outcome. Studies comparing hypoxia with normoxia only were excluded. RESULTS Fourteen studies were identified from 2982 references. Odds ratio (OR) was used as effect estimate. OR was reconstructed if not provided in original articles. Hyperoxia was defined as a PaO2>300 mmHg. Meta-analysis indicated that hyperoxia appeared to be correlated with increased in-hospital mortality (OR, 1.40; 95% CI, 1.02-1.93; I2, 69.27%; 8 studies) but not worsened neurological outcome (OR, 1.62; 95% CI, 0.87-3.02; I2, 55.61%; 2 studies). However, the results were inconsistent in subgroup and sensitivity analyses. CONCLUSIONS Hyperoxia appears to be correlated with increased in-hospital mortality of post-ROSC patients. This result should be interpreted cautiously because of the significant heterogeneity and limited number of studies analyzed. However, because exposure to hyperoxia had no obvious benefits, clinicians should monitor PaO2 closely and titrate oxygen administration cautiously.

Factors influencing the outcomes after in-hospital resuscitation in Taiwan

BACKGROUND The effects on prognosis of some advanced interventions established before cardiopulmonary resuscitation are not clear. The outcomes and patterns of various factors of in-hospital resuscitation are also influenced by different disease patterns in different areas. We studied the factors related to outcomes in an oriental country. MATERIALS AND METHODS We studied the in-hospital resuscitation events in a tertiary medical center in Taipei city, Taiwan. All events and variables were recorded using the Utstein style for in-hospital resuscitation. We measured the influence of patients and event variables on the outcomes of return of spontaneous circulation (ROSC) and survival to discharge. RESULTS The rate of establishing a ROSC was 67% and the rate of survival to discharge was 17% in the studied population. The 1-year survival rate was 3.9%. Only 17% of the patients resuscitated had coronary artery disease. VT/VF was the initial rhythm in only 13.6% patients. Nearly half (49%) of the resuscitation attempts took place in emergency department (ED). Patients who were already intubated or had received mechanical ventilation before resuscitation had reduced chances of achieving ROSC. (P<0.05). Favorable prognostic factors of survival to discharge were shorter time intervals from patient collapse to arrival of the resuscitation team (69 vs. 154 s, P<0.05) and to confirmation of arrest (93 vs. 217 s, P<0.05). CONCLUSION Intubation and mechanical ventilation already established before arrest implies an underlying critical illness and reduce the chances of ROSC. Shorter intervals from collapse to resuscitation improve the chance of survival to discharge. The high proportion of resuscitation events occurring in the ED, reflecting ED overcrowding, and low frequency of pre-existing coronary artery disease are unique to our country.

Association of epicardial adipose tissue with coronary atherosclerosis is region-specific and independent of conventional risk factors and intra-abdominal adiposity

OBJECTIVE To elucidate which measurement of epicardial adipose tissue (EAT) best reflects its atherogenic risk, we examined the associations between different EAT measurements and various atherosclerotic parameters of the entire coronary tree and individual coronary arteries. METHODS This study included 224 consecutive patients underwent multidetector computed tomography before diagnostic coronary angiography. Regional thickness, cross-sectional areas, and total volume of EAT were measured. Four atherosclerotic parameters, including severity score, extent score, calcium volume score, and number of coronary arteries with ≥50% luminal stenosis, of the entire coronary tree and individual coronary arteries were assessed. RESULTS Both total EAT volume and thickness of EAT in the left atrioventricular groove were unanimously associated with the presence of coronary atherosclerosis dichotomously defined by the 4 scoring systems. However, only EAT thickness in the left atrioventricular groove, but not total EAT volume, was significantly associated with all 4 parameters of coronary atherosclerosis in a dose-dependent manner, even after adjustments for conventional risk factors, body-mass index, waist circumference, C-reactive protein, and intra-abdominal visceral fat area. Using the receiver-operating-characteristic analysis, 12.2mm was the optimal cutoff point for left atrioventricular groove thickness to predict the presence of significant coronary stenosis (≥50% diameter stenosis). Among the three coronary arteries, left atrioventricular groove thickness was most strongly correlated with ≥50% diameter stenosis in the embedded left circumflex artery by multivariate regression model. CONCLUSIONS Thickness of EAT in the left atrioventricular groove provides a more accurate assessment of its atherogenic risk and is therefore a better coronary risk factor than total EAT volume.

S3 Detection as a Diagnostic and Prognostic Aid in Emergency Department Patients With Acute Dyspnea

STUDY OBJECTIVE Dyspneic emergency department (ED) patients present a diagnostic dilemma. Recent technologic advances have made it possible to capture information about pathologic heart sounds at ECG recording. This study evaluates the effect of an S3 captured by acoustic cardiography on emergency physician diagnostic accuracy and confidence in their diagnosis of acute decompensated heart failure, as well as the patients prognosis. METHODS Dyspneic ED patients older than 40 years who were not dialysis dependent were prospectively enrolled in this multinational study. Treating emergency physicians, initially blinded to all laboratory and acoustic cardiography results, estimated acute decompensated heart failure probability from 0% to 100% on a visual analog scale. The emergency physician repeated the visual analog scale after acoustic cardiography results were provided. Physician diagnostic accuracy for and confidence in acute decompensated heart failure were evaluated against a reference standard diagnosis, as determined by 2 independent cardiologists blinded to acoustic cardiography. Patients were followed through 90 days to determine the relationship of the S3 to adverse events. RESULTS Nine hundred ninety-five patients with acoustic cardiography results were enrolled from March to October 2006 at 7 US and 2 international sites. Median age was 63 years, 55% were men, and 44% were white. The reference diagnosis was acute decompensated heart failure in 41.5%. After initial history and physical examination, the treating physicians initial sensitivity, specificity, and accuracy for acute decompensated heart failure as a possible diagnosis were 89.0% (95% confidence interval [CI] 85.5% to 91.8%), 58.2% (95% CI 54.0% to 62.2%), and 71.0% (95% CI 68.4% to 73.8%), respectively. Acoustic cardiography had an accuracy of 68% (95% CI 65.4% to 71.3%), sensitivity of 40.2% (95% CI 35.5% to 45.1%), and specificity of 88.5% (95% CI 85.5% to 90.9%). Emergency physician confidence and diagnostic accuracy were influenced by adding information about the presence or absence of S3. In a multivariable model, the S3 added no independent prognostic information for 30-day (odds ratio 1.20; 95% CI 0.67 to 2.14) or 90-day events (odds ratio 1.22; 95% CI 0.78 to 1.90). CONCLUSION In patients presenting with acute dyspnea, the acoustic cardiography S3 was specific for acute decompensated heart failure and affected physician confidence but did not improve diagnostic accuracy for acute decompensated heart failure, largely because of its low sensitivity. Further, the acoustic cardiography S3 provided no significant independent prognostic information.

Cardioprotective effect of therapeutic hypothermia for postresuscitation myocardial dysfunction.

Mild-to-moderate therapeutic hypothermia after resuscitation from cardiac arrest is neuroprotective, but its effect on postresuscitation myocardial dysfunction is not clear. We hypothesized that therapeutic hypothermia is cardioprotective in postresuscitation. Male adult Wistar rats underwent asphyxia-induced cardiac arrest and manual resuscitation with epinephrine. Therapeutic hypothermia is induced immediately after successful resuscitation and the return of spontaneous circulation (ROSC). One hour after ROSC, the rats achieved a target temperature of 30°C to 31°C, which was maintained for 1.5 h and then transitioned to the passive rewarming process in the hypothermia group. A temperature between 36.5°C and 37.5°C was maintained in the normothermia group. Echocardiography revealed that hypothermia resulted in significantly better systolic function of fractional shortening in 60 and 120 min after ROSC (both P < 0.05). The benefit of cardioprotection was also confirmed by the general linear mixed-models analysis of dP/dt, which revealed significantly better systolic function in positive dP/dtR(40) and diastolic function in maximal negative dP/dt (both P < 0.001). The 4-h and 3-day survival analyses both revealed better outcomes in the hypothermia groups in the log-rank test (P < 0.001 for the 4-h analysis, and P < 0.05 for the 3-day analysis). Serum level of heart-type, fatty acid-binding protein at 4 h after resuscitation as the myocardium damage marker was also significantly lower in the hypothermia group (52.4 ng/mL vs 186.5 ng/mL in the normothermia group; P < 0.05). Western blotting of myocardium showed that myocardial Akt and ERK1/2 were more activated in the hypothermia group 2 h after spontaneous circulation returned. In conclusion, postresuscitation mild-to-moderate therapeutic hypothermic is cardioprotective in the asphyxia-induced cardiac arrest animal model. It stabilizes hemodynamics, improves short-term survival, and decreases myocardial damage. The cardioprotective effect is associated with Akt and ERK1/2 activation in signal transduction.

Ultrasonographic lung sliding sign in confirming proper endotracheal intubation during emergency intubation.

AIM OF STUDY Unrecognized one-lung intubations (also known as main-stem intubation) can lead to hypoventilation, atelectasis, barotrauma, and even patient death. Many traditional methods can be employed to detect one-lung intubation; however, each of these methods has limitations and is not consistently reliable in emergency settings. This study aimed to assess the accuracy and timeliness of ultrasound to confirm proper endotracheal intubation. METHODS This was a prospective, single-center, observational study conducted at the emergency department of a national university teaching hospital. Patients received emergency tracheal intubation because of respiratory failure or cardiac arrest. After intubation, bedside ultrasound was performed with a transducer placed on the chest bilaterally at the mid-axillary line, to identify lung sliding over the lungs bilaterally during ventilation. Chest radiography was used as the criterion standard for confirmation of endotracheal tube position. RESULTS One hundred and fifteen patients needing tracheal intubation were included, and nine (7.8%) had one-lung intubations. The overall accuracy of ultrasound to confirm proper endotracheal intubation was 88.7% (95% confidence interval (CI): 81.6-93.3%). The positive predictive value was 94.7% (95% CI: 87.1-97.9%) in the non-cardiac-arrest group and 100% (95% CI: 87.1-100.0%) in the cardiac-arrest group. The median operating time of ultrasound was 88 s (interquartile range [IQR]: 55.0, 193.0), and of chest radiography was 1349 s (IQR: 879.0, 2221.0) post intubation. CONCLUSIONS In this study, the positive predictive value of bilateral lung sliding in confirming proper endotracheal intubation was high, especially among patients with cardiac arrest. Considerable time advantage of ultrasound over chest radiography was demonstrated.