Tricuspid Valve Replacement in a Patient with a Leadless Cardiac Pacemaker: Current Guidelines and Recommendations for Perioperative Management.

Leadless cardiac pacemakers were developed to reduce complications associated with conventional transvenous pacemakers. While this technology is still relatively new, devices are increasingly being implanted. The perioperative management of patients with these devices has been underreported; we thus seek to add to the limited body of knowledge of perioperative management of patients with leadless cardiac pacemakers. An elderly female patient with a Micra VR transcatheter pacing system leadless cardiac pacemaker placed for tachycardia-bradycardia syndrome with intermittent complete heart block was scheduled for elective tricuspid valve replacement for severe tricuspid regurgitation. Pacemaker interrogation was performed several hours prior to the scheduled surgery based on the electrophysiologist's availability; the device was kept in its programmed VVIR mode, and the base rate was increased from 60 to 80 beats per minute in anticipation of the upcoming surgery. Upon preoperative evaluation, the anesthesiologist asked that the electrophysiology team be placed on standby intraoperatively due to the concern that either oversensing in the setting of pacemaker dependence and/or undesirable tachycardia from rate-responsive pacing could occur. The surgeon used monopolar electrocautery for the duration of the cardiac surgery. Despite the patient having evidence of pacemaker dependence in the intensive care unit preoperatively, no electromagnetic interference leading to oversensing nor rate modulation was detected during intraoperative electrocardiographic and intraarterial invasive monitoring. Evidence-based guidelines regarding perioperative management specifically of leadless cardiac pacemakers do not exist. As these devices become more prevalent, further evaluation will be paramount to determine whether existing guidelines for perioperative management of conventional transvenous pacemakers apply.

Anesthetic Choice for Atrial Fibrillation Ablation: A National Anesthesia Clinical Outcomes Registry Analysis.

OBJECTIVE: The authors evaluated the type of anesthesia administered in atrial fibrillation ablation, hypothesizing that monitored anesthesia care is used less frequently than general anesthesia. DESIGN: A retrospective study. SETTING: National Anesthesia Clinical Outcomes Registry data, which are multi-institutional from across the United States. PARTICIPANTS: Adult patients who underwent elective atrial fibrillation ablation between 2013 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: National Anesthesia Clinical Outcomes Registry data were evaluated, and covariates were selected a priori within multivariate models to assess for predictors of anesthetic type. A total of 54,321 patients underwent atrial fibrillation ablation; 3,251 (6.0%) received monitored anesthesia care. Patients who received monitored anesthesia care were more likely to be >80 years old (12.4% v 4.9%; p < 0.0001), female (36.1% v 34.3%; p < 0.0001), have American Society of Anesthesiologists physical status >III (17.28% v 10.48%; p < 0.0001), and reside in urban areas (62.23% v 53.37%; p < 0.0001). They received care in the Northeast (17.6% v 10.1%; p < 0.0001) at low-volume centers (median 224 v 284 procedures; p < 0.0001). Multivariate analysis revealed that each five-year increase in age, being female, and having an American Society of Anesthesiologists physical status >III resulted in a 7% (p < 0.0001), 9% (p = 0.032), and 200% (p < 0.0001) increased odds of receiving monitored anesthesia care, respectively. Requiring additional ablation of atria or of a second arrhythmia and residing outside the Northeast resulted in a decreased odds of monitored anesthesia care (adjusted odds ratio 0.24 [p=0.002] and < 0.5 [p < 0.03], respectively). For each 50 cases performed annually at a center, the odds decreased by 5% (p = 0.005). CONCLUSIONS: General anesthesia is the most common type of anesthesia administered for atrial fibrillation ablation. The type of anesthesia administered, however, varies with patient, procedural, and hospital characteristics.

New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT).

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.

Discovery of the First Potent and Selective Inhibitor of Centromere-Associated Protein E: GSK923295.

Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.

Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.

Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.

Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375.

1. SB-706375 potently inhibited [(125)I]hU-II binding to both mammalian recombinant and 'native' UT receptors (K(i) 4.7+/-1.5 to 20.7+/-3.6 nM at rodent, feline and primate recombinant UT receptors and K(i) 5.4+/-0.4 nM at the endogenous UT receptor in SJRH30 cells). 2. Prior exposure to SB-706375 (1 microM, 30 min) did not alter [(125)I]hU-II binding affinity or density in recombinant cells (K(D) 3.1+/-0.4 vs 5.8+/-0.9 nM and B(max) 3.1+/-1.0 vs 2.8+/-0.8 pmol mg(-1)) consistent with a reversible mode of action. 3. The novel, nonpeptidic radioligand [(3)H]SB-657510, a close analogue of SB-706375, bound to the monkey UT receptor (K(D) 2.6+/-0.4 nM, B(max) 0.86+/-0.12 pmol mg(-1)) in a manner that was inhibited by both U-II isopeptides and SB-706375 (K(i) 4.6+/-1.4 to 17.6+/-5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT receptor binding domain. 4. SB-706375 was a potent, competitive hU-II antagonist across species with pK(b) 7.29-8.00 in HEK293-UT receptor cells (inhibition of [Ca(2+)](i)-mobilization) and pK(b) 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (K(app) approximately 20 nM). 5. SB-706375 was a selective U-II antagonist with >/=100-fold selectivity for the human UT receptor compared to 86 distinct receptors, ion channels, enzymes, transporters and nuclear hormones (K(i)/IC(50)>1 microM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 microM). 6. In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals.

Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.

BACKGROUND: Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. METHODS AND RESULTS: All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. CONCLUSIONS: Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.

Carbon monoxide poisoning: a case report of reversible cardiormyopathy.

Acute carbon monoxide poisoning is the most common cause of poison-related deaths in the U.S. A 21-year-old white woman was referred to Ruby Memorial Hospital after exposure to carbon monoxide (CO) from a faulty furnace. She developed acute weakness, dyspnea, nausea and vomiting. An electrocardiogram revealed sinus tachycardia, non-specific ST-T wave abnormalities, and a prolonged QTc interval. The chest X-ray revealed pulmonary edema and the 2-D echocardiography revealed decreased left ventricular systolic function with an ejection fraction of 25%. She was treated with high-flow oxygen and supportive medical therapy with complete resolution of the left ventricular dysfunction six weeks later. She has been followed for over one year without medical therapy and without recurrence of her symptoms. This case illustrates that the depressant effect of CO poisoning on the myocardium can be reversed in the short term with supportive medical therapy and recovery sustained in the long term without medical therapy.