Acute exposure to low-dose bisphenol A delays cardiac repolarization in female canine heart - Implication for proarrhythmic toxicity in large animals.

Bisphenol A (BPA) is a common environmental chemical with a range of potential adverse health effects. The impact of environmentally-relevant low dose of BPA on the electrical properties of the hearts of large animals (e.g., dog, human) is poorly defined. Perturbation of cardiac electrical properties is a key arrhythmogenic mechanism. In particular, delay of ventricular repolarization and prolongation of the QT interval of the electrocardiogram is a marker for the risk of malignant arrhythmias. We examined the acute effect of 10-9 M BPA on the electrical properties of female canine ventricular myocytes and tissues. BPA rapidly delayed action potential repolarization and prolonged action potential duration (APD). The dose response curve of BPA on APD was nonmonotonic. BPA rapidly inhibited the IKr K+ current and ICaL Ca2+ current. Computational modeling indicated that the effect of BPA on APD can be accounted for by its suppression of IKr. At the tissue level, BPA acutely prolonged the QT interval in 4 left ventricular wedges. ERß signaling contributed to the acute effects of BPA on ventricular repolarization. Our results demonstrate that BPA has QT prolongation liability in female canine hearts. These findings have implication for the potential proarrhythmic cardiac toxicity of BPA in large animals.

The rise, fall, and future direction of computer-assisted personalized sedation.

PURPOSE OF REVIEW: The first computer-assisted personalized sedation (CAPS) device was developed to address the growing demand for routine endoscopy procedures in the United States in the early 2000s. This review will describe the environment that gave rise to CAPS and summarize the design of that first device. It will then discuss the market forces that led to the fall of CAPS, with sales of the device ending 2 years after commercialization. RECENT FINDINGS: CAPS was initially conceived as a means to enable proceduralists to administer conscious sedation with propofol safely. In the nearly 20 years since its conception, the expectations of patients and proceduralists for endoscopy sedation, have evolved from conscious sedation to deep. Due to the increased risk inherent in deep sedation, future CAPS devices should be tools for anesthesiologists, not proceduralists. SUMMARY: Over $2 billion are spent annually for anesthesia services in routine endoscopic procedures for low-risk patients; a spending rate that is not sustainable. CAPS, in an 'anesthesia oversight' model similar to medical supervision, has a future as a cost-efficient means for anesthesia services to provide sedation in endoscopy and other nonoperating room venues. Anesthesiologists should work with medical device companies and payers to develop a CAPS 'anesthesia oversight' model.

Patient safety during sedation by anesthesia professionals during routine upper endoscopy and colonoscopy: an analysis of 1.38 million procedures.

BACKGROUND AND AIMS: Sedation for GI endoscopy directed by anesthesia professionals (ADS) is used with the intention of improving throughput and patient satisfaction. However, data on its safety are sparse because of the lack of adequately powered, randomized controlled trials comparing it with endoscopist-directed sedation (EDS). This study was intended to determine whether ADS provides a safety advantage when compared with EDS for EGD and colonoscopy. METHODS: This retrospective, nonrandomized, observational cohort study used the Clinical Outcomes Research Initiative National Endoscopic Database, a network of 84 sites in the United States composed of academic, community, health maintenance organization, military, and Veterans Affairs practices. Serious adverse events (SAEs) were defined as any event requiring administration of cardiopulmonary resuscitation, hospital or emergency department admission, administration of rescue/reversal medication, emergency surgery, procedure termination because of an adverse event, intraprocedural adverse events requiring intervention, or blood transfusion. RESULTS: There were 1,388,235 patients in this study that included 880,182 colonoscopy procedures (21% ADS) and 508,053 EGD procedures (23% ADS) between 2002 and 2013. When compared with EDS, the propensity-adjusted SAE risk for patients receiving ADS was similar for colonoscopy (OR, .93; 95% CI, .82-1.06) but higher for EGD (OR, 1.33; 95% CI, 1.18-1.50). Additionally, with further stratification by American Society of Anesthesiologists (ASA) class, the use of ADS was associated with a higher SAE risk for ASA I/II and ASA III subjects undergoing EGD and showed no difference for either group undergoing colonoscopy. The sample size was not sufficient to make a conclusion regarding ASA IV/V patients. CONCLUSIONS: Within the confines of the SAE definitions used, use of anesthesia professionals does not appear to bring a safety benefit to patients receiving colonoscopy and is associated with an increased SAE risk for ASA I, II, and III patients undergoing EGD.

A novel index of hypoxemia for assessment of risk during procedural sedation.

BACKGROUND: Procedural sedation is essential for many procedures. Sedation has an excellent safety profile; however, it is not without risks. Assessment of risk using clinical outcomes in clinical studies is difficult due to their rare occurrence. Therefore, surrogate end points are frequently used in a clinical study in lieu of clinical outcomes. As a clinician integrates multiple aspects of a physiological variable to determine potential risk, a surrogate end point should consider a similar approach. In this study, we identified and tested the appropriateness of a new surrogate end point that may be used in clinical studies, area under the curve of oxygen desaturation (AUCDesat). A review of patient sedation records by anesthesiologists was conducted to assess its relationship to the anesthesia professional perception of risk. METHODS: This study was a post hoc analysis and assessment of perceived risk by anesthesiologists. It consisted of 13 U.S.-trained board-certified anesthesiologists ranking physiological variables as indicators of risk and then reviewing 204 records from 3 completed sedation studies involving the SEDASYS System. After review, each anesthesiologist assigned a Likert score based on his or her perception of risk for oversedation-related sequelae in each record. These scores were analyzed to determine their relationship to desaturation presence/absence, duration, depth, number of events, and AUCDesat that incorporates each component. RESULTS: Anesthesiologists ranked arterial oxygenation to be the most important factor in assessing risk post hoc (mean rank of 4.69 of 5, P = 0.0007 compared with next highest ranked factor-respiratory rate, N = 13). AUCDesat was better correlated to the Likert scores (rs = 0.85) when compared with the individual elements of AUCDesat, binary assessment of desaturation (rs = 0.73), desaturation depth (rs = -0.70), desaturation duration (rs = 0.70), and incidence of desaturations (rs = 0.55) (all 4 comparisons versus rs = 0.85, P < 0.0001). CONCLUSIONS: Anesthesiologists determined arterial oxygenation to be the most important physiological variable in assessing sedation risk and the potential for adverse clinical outcomes. AUCDesat, a composite index that incorporates duration, incidence, and depth of oxygen desaturation, was better correlated to the Likert scores. AUCDesat, given that it is a single numerical variable, is an ideal end point for assessment of risk of adverse clinical outcomes in clinical sedation studies. Future studies using AUCDesat and actual physiological outcomes may be useful in further defining this end point.

SERCA2a superinhibition by human phospholamban triggers electrical and structural remodeling in mouse hearts.

Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling with a significant role in heart failure. We previously showed that the single amino acid difference between human and mouse PLN results in increased inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress responses in transgenic mice expressing the human PLN (hPLN) in the null background. Here we dissect the molecular and electrophysiological processes triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary approach, we performed global gene expression analysis, electrophysiology, and mathematical simulations on hPLN mice. We identified significant changes in a series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) exchanger, transient outward K(+) current). Simulation analysis suggests that this electrical remodeling has a critical role in rescuing cardiac function by improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. Furthermore, multiple structural and transcription factor gene expression changes indicate an ongoing structural remodeling process, favoring hypertrophy and myogenesis while suppressing apoptosis and progression to heart failure. Our findings expand current understanding of the hPLN function and provide additional insights into the downstream implications of SERCA2a superinhibition in the mammalian heart.

Ionic mechanisms of cellular electrical and mechanical abnormalities in Brugada syndrome.

The Brugada syndrome (BrS) is a right ventricular (RV) arrhythmia that is responsible for up to 12% of sudden cardiac deaths. The aims of our study were to determine the cellular mechanisms of the electrical abnormality in BrS and the potential basis of the RV contractile abnormality observed in the syndrome. Tetrodotoxin was used to reduce cardiac Na(+) current (I(Na)) to mimic a BrS-like setting in canine ventricular myocytes. Moderate reduction (<50%) of I(Na) with tetrodotoxin resulted in all-or-none repolarization in a fraction of RV epicardial myocytes. Dynamic clamp and modeling show that reduction of I(Na) shifts the action potential (AP) duration-transient outward current (I(to)) density curve to the left and has a biphasic effect on AP duration. In the presence of a large I(to), I(Na) reduction either prolongs or collapses the AP, depending on the exact density of I(to). These repolarization changes reduce Ca(2+) influx and sarcoplasmic reticulum load, resulting in marked attenuation of myocyte contraction and Ca(2+) transient in RV epicardial myocytes. We conclude that I(Na) reduction alters repolarization by reducing the threshold for I(to)-induced all-or-none repolarization. These cellular electrical changes suppress myocyte excitation-contraction coupling and contraction and may be a contributing factor to the contractile abnormality of the RV wall in BrS.

Role of the transient outward current in regulating mechanical properties of canine ventricular myocytes.

INTRODUCTION: The transient outward current (I(to)) is a major repolarizing current in the heart. Reduction of I(to) density is consistently observed in human heart failure (HF) and animal HF models. It has been proposed that I(to), via its influence on phase-1 repolarization of the action potential, facilitates L-type Ca(2+) current (I(Ca-L)) activation and sarcoplasmic reticulum Ca(2+) release, and that its down-regulation may contribute to the impaired contractility in failing heart. METHODS AND RESULTS: We used the dynamic clamp to quantitatively examine the influence of I(to) on the mechanical properties of canine left ventricular myocytes at 34 degrees C. In endocardial myocytes, where the native I(to) is small, simulation of an epicardial-level artificial I(to) accentuated the phase-1 repolarization and significantly suppressed cell shortening. The peak amplitude of Ca(2+) transient was also reduced in the presence of simulated I(to), although the rate of rise of the Ca(2+) transient was increased. Conversely, subtraction, or "blockade" of the native I(to) enhanced contractility in epicardial cells. These results agree with the inverse correlation between I(to) levels and myocyte contractility and Ca(2+) transient amplitude in epicardial and endocardial myocytes. Action potential clamp studies showed that the phase-1 repolarization/I(to) versus I(Ca-L) relationship had an inverted-J shape; small I(to) enhanced peak I(Ca-L) while moderate-to-large I(to) decreased peak I(Ca-L) and markedly reduced early Ca(2+) influx. CONCLUSION: Our results show that epicardial-level of I(to) acts as a negative, rather than positive regulator of myocyte mechanical properties in canine ventricular myocytes.