Surgical ablation for atrial fibrillation (AF) can be performed without additional risk of operative mortality or major morbidity, and is recommended at the time of concomitant mitral operations to ...restore sinus rhythm. (Class I, Level A) Surgical ablation for AF can be performed without additional operative risk of mortality or major morbidity, and is recommended at the time of concomitant isolated aortic valve replacement, isolated coronary artery bypass graft surgery, and aortic valve replacement plus coronary artery bypass graft operations to restore sinus rhythm. (Class I, Level B nonrandomized) Surgical ablation for symptomatic AF in the absence of structural heart disease that is refractory to class I/III antiarrhythmic drugs or catheter-based therapy or both is reasonable as a primary stand-alone procedure, to restore sinus rhythm. (Class IIA, Level B randomized) Surgical ablation for symptomatic persistent or longstanding persistent AF in the absence of structural heart disease is reasonable, as a stand-alone procedure using the Cox-Maze III/IV lesion set compared with pulmonary vein isolation alone. (Class IIA, Level B nonrandomized) Surgical ablation for symptomatic AF in the setting of left atrial enlargement (≥4.5 cm) or more than moderate mitral regurgitation by pulmonary vein isolation alone is not recommended. (Class III no benefit, Level C expert opinion) It is reasonable to perform left atrial appendage excision or exclusion in conjunction with surgical ablation for AF for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C limited data) At the time of concomitant cardiac operations in patients with AF, it is reasonable to surgically manage the left atrial appendage for longitudinal thromboembolic morbidity prevention. (Class IIA, Level C expert opinion) In the treatment of AF, multidisciplinary heart team assessment, treatment planning, and long-term follow-up can be useful and beneficial to optimize patient outcomes. (Class I, Level C expert opinion).
First-in-man studies of leadless pacemakers have demonstrated high rates of implant success, and safety and efficacy objectives were achieved. Outside of the investigational setting, there are ...concerns, particularly over cardiac effusion and perforation, device dislodgement, infection, telemetry, and battery issues.
The acute performance of the Micra transcatheter pacemaker from a worldwide Post-Approval Registry is reported.
The registry is an ongoing prospective single-arm observational study designed to assess the safety and effectiveness of Micra in the post-approval setting. The safety end point was system- or procedure-related major complications at 30 days post implant. We compared the major complication rate with that of the 726 patients from the investigational study. Electrical performance was also characterized.
The device was successfully implanted in 792 of 795 registry patients (99.6%) by 149 implanters at 96 centers in 20 countries. Through 30 days post implant, a total of 13 major complications occurred in 12 patients, for a major complication rate of 1.51% (95% confidence interval, 0.78%-2.62%). Major complications included cardiac effusion/perforation (1, 0.13%), device dislodgement (1, 0.13%), and sepsis (1, 0.13%). After adjusting for baseline differences, the rate of major complications in the registry trended lower than the investigational trial (odds ratio, 0.58, 95% confidence interval, 0.27-1.25; P = .16). Early pacing capture thresholds were low and stable.
Performance of the Micra transcatheter pacemaker in a real-world setting demonstrates a high rate (99.6%) of implant success and low rate (1.51%) of major complications through 30 days post implant. In particular, the rates of pericardial effusion, device dislodgement, and infection were low, reinforcing the positive results seen in the investigational study.
Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative ...injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion.
We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD).
There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects.
Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.
Cardiovascular magnetic resonance (CMR) with extensive late gadolinium enhancement (LGE) is a novel marker for increased risk for sudden death (SD) in patients with hypertrophic cardiomyopathy (HC). ...Small focal areas of LGE confined to the region of right ventricular (RV) insertion to ventricular septum (VS) have emerged as a frequent and highly visible CMR imaging pattern of uncertain significance. The aim of this study was to evaluate the prognostic significance of LGE confined to the RV insertion area in patients with HC. CMR was performed in 1,293 consecutive patients with HC from 7 HC centers, followed for 3.4 ± 1.7 years. Of 1,293 patients (47 ± 14 years), 134 (10%) had LGE present only in the anterior and/or inferior areas of the RV insertion to VS, occupying 3.7 ± 2.9% of left ventricular myocardium. Neither the presence nor extent of LGE in these isolated areas was a predictor of adverse HC-related risk, including SD (adjusted hazard ratio 0.82, 95% confidence interval 0.45 to 1.50, p = 0.53; adjusted hazard ratio 1.16/10% increase in LGE, 95% confidence interval 0.29 to 4.65, p = 0.83, respectively). Histopathology in 20 HC hearts show the insertion areas of RV attachment to be composed of a greatly expanded extracellular space characterized predominantly by interstitial-type fibrosis and interspersed disorganized myocyte patterns and architecture. In conclusion, LGE confined to the insertion areas of RV to VS was associated with low risk of adverse events (including SD). Gadolinium pooling in this region of the left ventricle does not reflect myocyte death and repair with replacement fibrosis or scarring.
Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab ...enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov , number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities included upper respiratory tract infections (in 28 57% of 49 patients), diarrhoea (27 55%), and nausea (25 51%). Grade 3–4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 53%), thrombocytopenia (eight 16%), anaemia (seven 14%), febrile neutropenia (six 12%), and leucopenia (six 12%). The most common serious adverse events were pyrexia (six 12%), febrile neutropenia (five 10%), lower respiratory tract infection, and pneumonia (each three 6%). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66–91) and 89% (95% CI 72–96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax. Interpretation A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies. Funding AbbVie Inc and Genentech Inc.
Abstract Background Patients present to police, Emergency Medical Services, and the emergency department with aggressive behavior, altered sensorium, and a host of other signs that may include ...hyperthermia, “superhuman” strength, diaphoresis, and lack of willingness to yield to overwhelming force. A certain percentage of these individuals will go on to expire from a sudden cardiac arrest and death, despite optimal therapy. Traditionally, the forensic community would often classify these as “Excited Delirium” deaths. Objectives This article will review selected examples of the literature on this topic to determine if it is definable as a discrete medical entity, has a recognizable history, epidemiology, clinical presentation, pathophysiology, and treatment recommendations. Discussion Excited delirium syndrome is characterized by delirium, agitation, acidosis, and hyperadrenergic autonomic dysfunction, typically in the setting of acute-on-chronic drug abuse or serious mental illness or a combination of both. Conclusions Based upon available evidence, it is the consensus of an American College of Emergency Physicians Task Force that Excited Delirium Syndrome is a real syndrome with uncertain, likely multiple, etiologies.
A substantial increase in the knowledge of the genetic basis of cardiomyopathy has occurred, and noninvasive phenotypic characterization has become significantly more sophisticated. ...the American ...Heart Association (AHA) (7) and the European Society of Cardiology (ESC) (8) in the last decade have proposed revisions to the classification of cardiomyopathic disorders. In the ESC 2008 classification, the cardiomyopathy was defined as familial when present in more than 1 member of the family.\n Disease MIM# Phenotype Inheritance Age of Onset Disease Gene Cardiac Phenotype Extracardiac Markers/Involvement of Other Organs Treatment Multiple acyl-CoA dehydrogenase deficiency Glutaric acidemia IIA 231680 AR Neonatal ETFA DCM, neonatal Nervous, skeletal, muscle, liver, kidney (often polycystic), metabolic acidosis, hypoglycemia  Glutaric acidemia IIB 231680 AR Neonatal, childhood ETFB Sudden neonatal death Nervous, skeletal, muscle, liver  Glutaric acidemia IIC 231680 AR Childhood to adult ETFDH DCM Nervous, skeletal, muscle, liver, kidney (often polycystic), lung, metabolic acidosis, hypoglycemia  Primary, systemic, carnitine transporter deficiency 212140 AR Childhood to adult SLC22A5 DCM, HCM < Total plasma carnitine, hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, > creatine kinase, in childhood; cardiomyopathy, arrhythmias, or fatigability in adulthood Carnitine supplementation Chanarin-Dorfman syndrome (NLSD-I) 275630 AR Childhood to adult ABHD5 DCM Skin (ichthyosiform erythroderma), liver, muscle, nervous (with possible MR), ocular Suggested: diet low in long-chain fatty acids; retinoids for skin in patients w/o liver dysfunction Neutral lipid storage disease with myopathy (NLSD-M) 610717 AR Childhood to adult PNPLA2low * DCM Myopathy  Table 5 Major Lipid Storage Disorders With Possible Myocardial Involvement MR = mental retardation; other abbreviations as in Table 1.
Maternal insulin resistance and preeclampsia Hauth, John C., MD; Clifton, Rebecca G., PhD; Roberts, James M., MD ...
American journal of obstetrics and gynecology,
04/2011, Volume:
204, Issue:
4
Journal Article
Peer reviewed
Open access
Objective The purpose of this study was to determine whether mid-trimester insulin resistance is associated with subsequent preeclampsia. Study Design This was a secondary analysis of 10,154 ...nulliparous women who received vitamin C and E or placebo daily from 9-16 weeks gestation until delivery. Of these, 1187 women had fasting plasma glucose and insulin tested between 22 and 26 weeks gestation. Insulin resistance was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index. Results Obese women were twice as likely to have a HOMA-IR result of ≥75th percentile. Hispanic and African American women had a higher percentage at ≥75th percentile for HOMA-IR than white women (42.2%, 27.2%, and 16.9%, respectively; P < .001). A HOMA-IR result of ≥75th percentile was higher among the 85 nulliparous women who subsequently had preeclampsia, compared with women who remained normotensive (40.5% vs 24.8%; adjusted odds ratio, 1.9; 95% confidence interval, 1.1–3.2). Quantitative insulin sensitivity check index results were similar to the HOMA-IR results. Conclusion Midtrimester maternal insulin resistance is associated with subsequent preeclampsia.
Summary Background Deletion of chromosome 17p (del17p) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral ...small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov , number NCT01889186 . Follow-up is ongoing, and patients are still receiving treatment. Findings Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 40%), infection (21 20%), anaemia (19 18%), and thrombocytopenia (16 15%). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven 7% each), pneumonia (six 6%), and febrile neutropenia (five 5%). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding AbbVie and Genentech.
Abstract Background The oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of ...patients with acute heart failure (AHF). Objectives To address the acute use of tolvaptan to improve congestion in AHF, we conducted the Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF, NCT01644331) study. Methods TACTICS-HF randomized patients within 24 hours of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 hours, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 hours. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. Results A total of 257 patients were randomized. Dyspnea relief by Likert scale was similar between tolvaptan and placebo at 8 hours (25% moderately or markedly improved for tolvaptan vs. 28% placebo, p=0.59) and at 24 hours (50% tolvaptan vs. 47% placebo, p=0.80). Need for rescue therapy was also similar at 24 hours (21% tolvaptan, 18% placebo, p=0.57). The proportion defined as responders at 24 hours (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p=0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared to placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. Conclusions In patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 hours despite greater weight loss and fluid loss.
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