Spatial correlation of left atrial low voltage substrate in sinus rhythm versus atrial fibrillation: The rhythm specificity of atrial low voltage substrate

Introduction

Improved sinus rhythm (SR) maintenance rates have been achieved in patients with persistent atrial fibrillation (AF) undergoing pulmonary vein isolation plus additional ablation of low voltage substrate (LVS) during SR. However, voltage mapping during SR may be hindered in persistent and long-persistent AF patients by immediate AF recurrence after electrical cardioversion. We assess correlations between LVS extent and location during SR and AF, aiming to identify regional voltage thresholds for rhythm-independent delineation/detection of LVS areas. (1) Identification of voltage dissimilarities between mapping in SR and AF. (2) Identification of regional voltage thresholds that improve cross-rhythm substrate detection. (3) Comparison of LVS between SR and native versus induced AF.

Methods

Forty-one ablation-naive persistent AF patients underwent high-definition (1 mm electrodes; >1200 left atrial (LA) mapping sites per rhythm) voltage mapping in SR and AF. Global and regional voltage thresholds in AF were identified which best match LVS < 0.5 mV and <1.0 mV in SR. Additionally, the correlation between SR-LVS with induced versus native AF-LVS was assessed.

Results

Substantial voltage differences (median: 0.52, interquartile range: 0.33–0.69, maximum: 1.19 mV) with a predominance of the posterior/inferior LA wall exist between the rhythms. An AF threshold of 0.34 mV for the entire left atrium provides an accuracy, sensitivity and specificity of 69%, 67%, and 69% to identify SR-LVS < 0.5 mV, respectively. Lower thresholds for the posterior wall (0.27 mV) and inferior wall (0.3 mV) result in higher spatial concordance to SR-LVS (4% and 7% increase). Concordance with SR-LVS was higher for induced AF compared to native AF (area under the curve[AUC]: 0.80 vs. 0.73). AF-LVS < 0.5 mV corresponds to SR-LVS < 0.97 mV (AUC: 0.73).

Conclusion

Although the proposed region-specific voltage thresholds during AF improve the consistency of LVS identification as determined during SR, the concordance in LVS between SR and AF remains moderate, with larger LVS detection during AF. Voltage-based substrate ablation should preferentially be performed during SR to limit the amount of ablated atrial myocardium.     

Low–Molecular-Weight-Heparins as Periprocedural Anticoagulation for Patients on Long-Term Warfarin Therapy: A Standardized Bridging Therapy Protocol

Background: Over 2 million patients in North America are on warfarin anticoagulation therapy for prevention of thromboembolism. Suspension of warfarin therapy is often required to prepare patients for invasive procedures or surgeries. To protect these patients against thromboembolism while they are off warfarin, shorter-acting parenteral agents such as low-molecular-weight heparins (LMWHs) are often used. We conducted a retrospective observational study of our anticoagulation clinic patients to assess the safety and efficacy of LMWHs using a standardized protocol for periprocedural anticoagulation therapy.Methods: We included 69 consecutive patients who required interruption of their long-term warfarin therapy between August 2001 and August 2002, and were deemed by the treating physician to be at high enough risk for perioperative thromboembolism to justify bridging anticoagulation. We used a standard bridging therapy protocol in our anticoagulation clinic. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death.Results: There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.Conclusions: LMWH administration using our standard outpatient bridging protocol for perioperative anticoagulation appears to be relatively safe and efficacious, offering an alternative to inpatient administration of intravenous unfractionated heparin (UFH). Our study provides additional evidence to the limited published observational data regarding the safety and efficacy of LMWH as bridging therapy in the perioperative and periprocedural setting. Large, multicenter, randomized controlled trials are necessary to fully assess the safety and efficacy of LMWH for perioperative anticoagulation.Abbreviated Abstract We conducted a retrospective observational study of 69 consecutive anticoagulation clinic patients on warfarin between August 2001 and August 2002, who were undergoing a procedure or surgery. The study was done to assess the safety and efficacy of an outpatient LMWH bridging protocol. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 3 days preoperatively and 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death. There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.     

Acute, severe noncardiac conditions in patients with acute myocardial infarction

Purpose

The study’s purpose was to determine the prevalence and prognostic importance of acute, severe, noncardiac conditions present at the time of an acute myocardial infarction (AMI).

Methods

We identified consecutive patients with AMI who were discharged from Yale-New Haven Hospital between January 1, 1997, and June 30, 2000. Acute, noncardiac conditions that were present at admission were abstracted from patient records and graded by severity (imminent threat to life; other significant condition that would warrant admission). We examined the prognostic importance of these conditions on hospital mortality in multivariable logistic models. The study included 1145 patients with AMI, of whom 8.5% (n = 97) presented with an acute, life-threatening, noncardiac condition at admission and 19.5% (n = 223) presented with another significant noncardiac condition.

Results

Hospital mortality was 25.8% and 9.0%, respectively, for patients who presented with life-threatening and other significant noncardiac conditions, compared with 4.6% for patients without either of these conditions. In multivariable analysis, life-threatening noncardiac conditions were associated with increased hospital mortality after adjusting for demographic factors, medical history, clinical presentation, cardiac severity, and initial therapy (odds ratio 2.5; 95% confidence interval [CI], 1.2-5.2). No increased hospital mortality risk was found for other significant noncardiac conditions in the risk-adjusted analyses (odds ratio 1.0; 95% CI, 0.5-1.7).

Conclusions

A subgroup of patients with AMI presented with a life-threatening noncardiac condition, which was associated with a marked increase in the risk of death during the hospitalization. Despite the excessive mortality risk associated with concomitant noncardiac conditions, this subset of patients with AMI are poorly described in current literature.     

Statin Use in Patients with Cirrhosis: A Retrospective Cohort Study

Background

Statins reduce cardiovascular risk. Patients with cirrhosis have decreased hepatic clearance of statins and potentially increased risk for complications. No studies assess mortality in patients with biopsy-confirmed cirrhosis.

Aim

Compare mortality in patients with cirrhosis on statins to those not on statins.

Methods

A retrospective cohort study evaluated patients from 1988 to 2011 at Partners Healthcare Hospitals. The Partners Research Patient Data Registry identified patients with biopsy-proven cirrhosis on statins at biopsy and at least 3 months following. Controls were matched 1:2 by age, gender and Child–Pugh class. Decompensation was defined as ascites, jaundice/bilirubin >2.5 mg/dL, and/or hepatic encephalopathy or variceal hemorrhage. Primary outcome was mortality. Secondary outcome was decompensation in baseline-compensated patients. Chi-square and two-way ANOVA testing compared groups. Cox proportional hazards models for mortality controlled for age, Child–Pugh class, diabetes, coronary artery disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Kaplan–Meier curves graphed mortality.

Results

Eighty-one statin users and 162 controls were included. Median follow-up: 36 months in statin users and 30 months in controls. 70.4 % of patients were Child–Pugh A. Model for End-Stage Liver Disease (MELD), albumin, varices and beta-blocker use were not significantly different between groups. Statin users had lower mortality on multivariate analysis (HR 0.53, p = 0.01), and Child–Pugh A patients had longer survival on Kaplan–Meier analysis. Cox multivariate analysis for decompensation showed lower risk of decompensation with statins while increased decompensation with low albumin, high MELD score and beta-blocker use.

Conclusions

In patients with cirrhosis, statin therapy is not associated with increased mortality and may delay decompensation.     

Sequential switching of binding partners on PCNA during in vitro Okazaki fragment maturation

The homotrimeric sliding clamp proliferating cell nuclear antigen (PCNA) mediates Okazaki fragment maturation through tight coordination of the activities of DNA polymerase δ (Pol δ), flap endonuclease 1 (FEN1) and DNA ligase I (Lig1). Little is known regarding the mechanism of partner switching on PCNA and the involvement of PCNA''s three binding sites in coordinating such processes. To shed new light on PCNA-mediated Okazaki fragment maturation, we developed a novel approach for the generation of PCNA heterotrimers containing one or two mutant monomers that are unable to bind and stimulate partners. These heterotrimers maintain the native oligomeric structure of PCNA and exhibit high stability under various conditions. Unexpectedly, we found that PCNA heterotrimers containing only one functional binding site enable Okazaki fragment maturation by efficiently coordinating the activities of Pol δ, FEN1, and Lig1. The efficiency of switching between partners on PCNA was not significantly impaired by limiting the number of available binding sites on the PCNA ring. Our results provide the first direct evidence, to our knowledge, that simultaneous binding of multiple partners to PCNA is unnecessary, and if it occurs, does not provide significant functional advantages for PCNA-mediated Okazaki fragment maturation in vitro. In contrast to the “toolbelt” model, which was demonstrated for bacterial and archaeal sliding clamps, our results suggest a mechanism of sequential switching of partners on the eukaryotic PCNA trimer during DNA replication and repair.Proliferating cell nuclear antigen (PCNA) is a central coordinator of genome duplication and maintenance pathways in eukaryotes (1, 2). A member of the conserved sliding clamp family, PCNA is a homotrimeric ring-shaped protein that encircles DNA and serves as a processivity factor for DNA polymerases and a binding platform for many DNA modifying enzymes. PCNA interacts with partners involved in numerous processes, including DNA replication, recombination and repair, chromatin remodeling, and cell-cycle regulation. PCNA recruits these partners to replication forks or other chromosomal locations, enhances their catalytic activities, and orchestrates their cooperation in multistep enzymatic processes. Because most partners interact with the same binding site on PCNA, competition for binding must be tightly regulated during complex PCNA-mediated processes. The switching of partners on the PCNA platform has been shown to be crucial for the proper progression of multiple DNA replication and repair pathways, such as lagging strand replication, translesion synthesis, and mismatch repair (1). In recent years, several regulatory mechanisms, mostly involving posttranslational modifications of PCNA by ubiquitin or small ubiquitin-like modifier, have been shown to affect partner switching on PCNA by favoring the recruitment of specific partners (3–5).Despite extensive research into the regulation of PCNA-mediated processes, very little is known regarding how PCNA coordinates the activity of several enzymes during sequential processes. Two simple models have been proposed to explain this coordination (1, 2, 6, 7). The first model assumes highly dynamic partner switching on PCNA due to sequential binding and release events on the same or different PCNA monomers (Fig. 1, Upper). This model predicts that a single functional binding site on the PCNA trimer should be sufficient for the coordination of the entire process. In contrast, the second model assumes simultaneous binding of two or three partners to different monomers on the PCNA trimer (Fig. 1, Lower). In this case, the partners are stably associated with PCNA, which acts as a “toolbelt” throughout the process. According to this model, only PCNA trimers with two or three functional binding sites would be able to coordinate the process.Open in a separate windowFig. 1.Two possible models describing PCNA-mediated Okazaki fragment maturation. (Upper) A dynamic model in which Pol δ, FEN1, and Lig1 are bound and released from PCNA in a sequential manner. (Lower) The toolbelt model in which the three enzymes are simultaneously bound to PCNA using all available PCNA binding sites. The red segments represent the RNA primers; glowing circles represent enzymes currently active on the substrate.One of the best studied examples of such a multipartner PCNA-mediated process is the synthesis and maturation of Okazaki fragments during lagging strand DNA replication. This process involves the sequential activity of three PCNA binding partners—DNA polymerase δ (Pol δ), flap endonuclease 1 (FEN1), and DNA ligase I (Lig1), which mediate DNA synthesis, flap cleavage, and ligation, respectively (7–9). This is a fast and efficient process that is estimated to take place ∼100,000 times during each yeast cell division with a low tolerance for errors (8). The enzymes involved must cooperate through PCNA in a tightly regulated manner, acting sequentially on the same substrate while repeatedly exchanging access to it (Fig. 1). In particular, removal of the initiator RNA requires several rapid iterative switches between Pol δ and FEN1 (7). This PCNA-dependent cooperation is particularly important to ensure that flaps will not become too long for processing by this short-flap pathway (7, 10, 11).To directly examine the mechanism of partner switching on PCNA and the functional significance of its homotrimeric structure, we developed a novel approach for the generation of PCNA heterotrimers that contain both wild-type (WT) and mutant monomers that are unable to bind different partners. We used these heterotrimers to determine whether simultaneous binding of more than one partner to a PCNA trimer is necessary to coordinate PCNA-mediated nick translation and Okazaki fragment maturation. Contrary to the toolbelt model, our findings indicate that simultaneous binding is not required, and sequential switching of partners on a single monomer of PCNA is sufficient to coordinate Okazaki fragment maturation. Our findings suggest that PCNA can efficiently orchestrate complex processes by regulating sequential binding and release events of several partners without binding them simultaneously.     

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms and susceptibility to chronic hepatitis B

AIM:To assess the three polymorphism regions withincytotoxic T-lymphocyte antigen 4(CTLA-4)gene,a C/Tbase exchange in the promoter region-318(CTLA-4-318C/T),an A/G substitution in the exon 1 position49(CTLA-4 49A/G),a T/C substitution in 1172(CTLA-4-1172T/C)in patients with chronic hepatitis B.METHODS:Fifty-one patients with chronic hepatitis Bvirus infection and 150 healthy subjects were recruitedsequentially as they presented to the hepatic clinic.Clas-sification of chronic hepatitis B virus(HBV)-infected pa-tients was as asymptomatic carrier state(26 patients)and chronic hepatitis B(25 patients).Genomic DNA wasisolated from anti-coagulated peripheral blood Buffy coatusing Miller's salting-out method.The presence of theCTLA-4 gene polymorphisms was determined using poly-merase chain reaction amplification refractory mutationsystem(ARMS).RESULTS:We observed a significant association be-tween-318 genotypes frequency(T C-,T C ,T-C )and susceptibility to chronic hepatitis B(P=0.012,OR=0.49,95%CI:0.206-1.162).However,we did notobserve a significant association for 49 genotype fre-quency(T C ,T C- T-C )and -1172 genotype fre-quency(C T ,T C- C T-)and state of disease.CONCLUSION:Our results suggest that CTLA-4 genepolymorphisms may partially be involved in the suscepti-bility to chronic hepatitis B.     

Persistence in Staphylococcus aureus bacteremia: incidence, characteristics of patients and outcome

Staphylococcus aureus bacteremia often persists. The reasons for persistence and its outcome are poorly defined. We conducted a prospective-observational study among 245 consecutive S. aureus (MRSA: n=125; MSSA: n=120) bacteremias (>or=1 positive blood cultures (BC)) among 234 adults (18-103-y-old; median=59 y) hospitalized during 1 January 2002-31 December 2002 at a 600-bed teaching hospital. Measurements included bacteremia duration, complication-rate (metastatic infection, relapse or attributable mortality) and outcome. Bacteremia duration was measured based on follow-up BC among 193 patients and estimated based on symptoms resolution in the rest. Measured (1-59 d; median=2) and estimated (median=1 d) duration correlated (r=0.885) though positive follow-up BC was often detected without fever (57/105 patients, 54.3%). Persistence (defined as bacteremia for >or=3 d) was noted in 84 cases (38.4%). Complication-rate increased steadily with bacteremia duration (6.6%, 24.0% and 37.7% in bacteremia for 1-2, 3 and >or=4 d, respectively; p=0.05). Cox regression analysis revealed that bacteremia duration correlated positively with endovascular sources (p=0.006), vancomycin treatment (p=0.016), cardiovascular prosthesis (p=0.025), metastatic infections (p=0.025) and diabetes (p=0.038). It is concluded that persistent bacteremia is a feature of S. aureus infection, irrespective of oxacillin susceptibility, associated with worse outcome. Risk factors include endovascular sources, cardiovascular prosthesis, metastatic infections, vancomycin treatment and diabetes. Patients at risk may benefit from novel treatment strategies.     

Septic Coronary Artery Embolism Treated with Aspiration Thrombectomy: Case Report and Review of Literature

Coronary embolization is a potentially fatal sequela of endocarditis. We report a case of Candida endocarditis with septic embolism to the left anterior descending coronary artery. This embolism was successfully treated with aspiration thrombectomy followed by balloon angioplasty. The treatment of acute coronary syndrome in the presence of septic embolism is controversial. Aspiration thrombectomy has been performed in this situation before, and it appears to be safer and more feasible than is thrombolysis or percutaneous transluminal angioplasty.