Robert Ploutz-Snyder

Spectral Analysis Identifies Sites of High-Frequency Activity Maintaining Atrial Fibrillation in Humans

Background—The identification of sites of dominant activation frequency during atrial fibrillation (AF) in humans and the effect of ablation at these sites have not been reported. Methods and Results—Thirty-two patients undergoing AF ablation (19 paroxysmal, 13 permanent) during ongoing arrhythmia were studied. Electroanatomic mapping was performed, acquiring 126±13 points per patient throughout both atria and coronary sinus. At each point, 5-second electrograms were obtained to determine the highest-amplitude frequency on spectral analysis and to construct 3D dominant frequency (DF) maps. The temporal stability of the recording interval was confirmed in a subset. Ablation was performed with the operator blinded to the DF maps. The effect of ablation at sites with or without high-frequency DF sites (maximal frequencies surrounded by a decreasing frequency gradient ≥20%) was evaluated by determining the change in AF cycle length (AFCL) and the termination and inducibility of AF. The spatial distribution of the DF sites was different in patients with paroxysmal and permanent AF; paroxysmal AF patients were more likely to harbor the DF site within the pulmonary vein, whereas in permanent AF, atrial DF sites were more prevalent. Ablation at a DF site resulted in significant prolongation of the AFCL (180±30 to 198±40 ms; P<0.0001; &kgr;= 0.77), whereas in the absence of a DF site, there was no change in AFCL (169±22 to 170±22 ms; P=0.4). AF terminated during ablation in 17 of 19 patients with paroxysmal and 0 of 13 with permanent AF (P<0.0001). When 2 patients with nonsustained AF during mapping were excluded, 13 of 15 (87%) had AF termination at DF sites (54% at the initially ablated DF site): 11 pulmonary veins and 2 atrial. In addition, AF could no longer be induced in 69% with termination of AF at a DF site. There were no significant differences in the number or percentage of DF sites detected (5.4±1.6 versus 4.9±2.1; P=0.3) and ablated (1.9±1.0 versus 2.4±1.0; P=0.3) in those with and without AF termination. The duration of radiofrequency ablation to achieve termination was significantly shorter than that delivered in those with persisting AF (34.8±24.0 versus 73.5±22.9 minutes; P=0.0002). All patients with persisting AF had additional DF sites outside the ablated zones. Conclusions—Spectral analysis and frequency mapping identify localized sites of high-frequency activity during AF in humans with different distributions in paroxysmal and permanent AF. Ablation at these sites results in prolongation of the AFCL and termination of paroxysmal AF, indicating their role in the maintenance of AF.

Mechanisms of Wave Fractionation at Boundaries of High-Frequency Excitation in the Posterior Left Atrium of the Isolated Sheep Heart During Atrial Fibrillation

Background— High-frequency fractionated electrograms recorded during atrial fibrillation (AF) in the posterior left atrium (PLA) and elsewhere are being used as target sites for catheter ablation. We tested the hypothesis that highly periodic electric waves emerging from AF sources at or near the PLA give rise to the most fractionated activity in adjacent locations. Methods and Results— Sustained AF was induced in 8 isolated sheep hearts (0.5 &mgr;mol/L acetylcholine). Endocardial videoimaging (DI-4-ANEPPS) and electric mapping of the PLA enabled spatial characterization of dominant frequencies (DFs) and a regularity index (ratio of DF to total power). Regularity index showed that fractionation was lowest within the area with the maximal DF (DFmax domain; 0.19±0.02) and highest within a band of ≈3 mm (0.16±0.02; P=0.047) at boundaries with lower-frequency domains. The numbers of spatiotemporal periodic episodes (25.9±2.3) and rotors per experiment (1.9±0.7) were also highest within the DFmax domain. Most commonly, breakthrough waves at the PLA traveled toward the rest of the atria (76.8±8.1% outward versus 23.2±8.1% inward; P<0.01). In both experiments and simulations with an atrial ionic model, fractionation at DFmax boundaries was associated with increased beat-to-beat variability of conduction velocity and directionality with wavebreak formation. Conclusions— During stable AF, the PLA harbors regular, fast, and highly organized activity; the outer limit of the DFmax domain is the area where the most propagation pattern variability and fractionated activity occur. These new concepts introduce a new perspective in the clinical use of high-frequency fractionated electrograms to localize sources of AF precisely at the PLA and elsewhere.

Real-time dominant frequency mapping and ablation of dominant frequency sites in atrial fibrillation with left-to-right frequency gradients predicts long-term maintenance of sinus rhythm

BACKGROUND Spectral analysis identifies localized sites of high-frequency activity during atrial fibrillation (AF). OBJECTIVE This study sought to determine the effectiveness of using real-time dominant frequency (DF) mapping for radiofrequency ablation of maximal DF (DFmax) sites and elimination of left-to-right frequency gradients in the long-term maintenance of sinus rhythm (SR) in AF patients. METHODS DF mapping was performed in 50 patients during ongoing AF (32 paroxysmal, 18 persistent), acquiring a mean of 117 +/- 38 points. Ablation was performed targeting DFmax sites, followed by circumferential pulmonary vein isolation. RESULTS Ablation significantly reduced DFs (Hz) in the LA (7.9 +/- 1.4 vs. 5.7 +/- 1.3, P <.001), coronary sinus (CS) (5.7 +/- 1.1 vs. 5.3 +/- 1.2, P = .006), and RA (6.3 +/- 1.4 vs. 5.4 +/- 1.3, P <.001) abolishing baseline left-to-right atrial DF gradient (1.7 +/- 1.7 vs. 0.2 +/- 0.9; P <.001). Only a significant reduction in DFs in all chambers with a loss of the left-to-right atrial gradient after ablation was associated with a higher probability of long-term SR maintenance in both paroxysmal and persistent AF patients. After a mean follow-up of 9.3 +/- 5.4 months, 88% of paroxysmal and 56% of persistent AF patients were free of AF (P = .02). Ablation of DFmax sites was associated with a higher probability of remaining both free of arrhythmias (78% vs. 20%; P = .001) and free of AF (88% vs. 30%; P <.001). CONCLUSION Radiofrequency ablation leading to elimination of LA-to-RA frequency gradients predicts long-term SR maintenance in AF patients.

Activation of Inward Rectifier Potassium Channels Accelerates Atrial Fibrillation in Humans Evidence for a Reentrant Mechanism

Background— It is unclear whether atrial fibrillation (AF) drivers in humans are focal or reentrant. To test the hypothesis that functional reentry is involved in human AF maintenance, we determined the effects of adenosine infusion on local dominant frequency (DF) at different atrial sites. By increasing inward rectifier potassium channel conductance, adenosine would increase DF of reentrant drivers but decrease it in the case of a focal mechanism. Methods and Results— Thirty-three patients were studied during AF (21 paroxysmal, 12 persistent) using recordings from each pulmonary vein–left atrial junction (PV-LAJ), high right atrium, and coronary sinus. DFs were determined during baseline and peak adenosine effect. In paroxysmal AF, adenosine increased maximal DF at each region compared with baseline (PV-LAJ, 8.03±2.2 versus 5.7±0.8; high right atrium, 7±2.2 versus 5.4±0.7; coronary sinus, 6.6±1.1 versus 5.3±0.7 Hz; P=0.001) and increased the left-to-right DF gradient (P=0.007). In contrast, in persistent AF, adenosine increased DF only in the high right atrium (8.33±1.1 versus 6.8±1.2 Hz; P=0.004). In 4 paroxysmal AF patients, real-time DF mapping of the left atrium identified the highest DF sites near the PV-LAJ, where adenosine induced an increase in DF (6.7±0.29 versus 4.96±0.26 Hz; P=0.008). Finally, simulations demonstrate that the frequency of reentrant drivers accelerates proportionally to the adenosine-modulated inward rectifier potassium current. Conclusions— Adenosine accelerates drivers and increases frequency differently in paroxysmal compared with persistent human AF. The results strongly suggest that AF is maintained by reentrant sources, most likely located at the PV-LAJ in paroxysmal AF, whereas non-PV locations are more likely in persistent AF.

Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children

Perennial and intense malaria transmission (holoendemic malaria) and Epstein-Barr virus (EBV) infection are 2 cofactors in the pathogenesis of endemic Burkitt lymphoma (eBL). In the present study, we compared EBV loads in children living in 2 regions of Kenya with differing malaria transmission intensities: Kisumu District, where malaria transmission is holoendemic, and Nandi District, where malaria transmission is sporadic. For comparison, blood samples were also obtained from US adults, Kenyan adults, and patients with eBL. Extraction of DNA from blood and quantification by polymerase chain reaction give an EBV load estimate that reflects the number of EBV-infected B cells. We observed a significant linear trend in mean EBV load, with the lowest EBV load detected in US adults and increasing EBV loads detected in Kenyan adults, Nandi children, Kisumu children, and patients with eBL, respectively. In addition, EBV loads were significantly higher in Kisumu children 1-4 years of age than in Nandi children of the same age. Our results support the hypothesis that repeated malaria infections in very young children modulate the persistence of EBV and increase the risk for the development of eBL.

Total knee replacement outcome and coexisting physical and emotional illness

Despite widespread acceptance of total knee replacement surgery’s clinical effectiveness, variation persists in long-term functional outcome. Our aim was to quantify the relative contributions of physical and emotional coexisting conditions to the variation in improvement in 12-month post-total knee replacement physical function. Data from 165 patients who had primary total knee replacement (62% women; mean age 68 years) were evaluated. Eighty-four percent had at least one comorbid illness, with cardiovascular conditions the most prevalent (61%). Mean improvement in 12-month general function (Short Form-36 Physical Component Score) and knee-specific function (Western Ontario and McMaster Universities Osteoarthritis Index) was similar for patients with and without comorbid medical diagnoses. Adding coexisting conditions to age, gender, and baseline physical function did not improve the model’s ability to explain variation in 12-month physical function as measured by either Short Form-36 Physical Component Score or Western Ontario and McMaster Universities Osteoarthritis Index. Although coexisting medical conditions did not predict the degree of 12 month post-total knee replacement functional improvement, poorer pre-total knee replacement emotional health (Short Form-36 Mental Component Score) was associated with smaller improvements in Short Form-36 Physical Component Score and Western Ontario and McMaster Universities Osteoarthritis Index. The lack of a relationship between the presence of coexisting medical diagnoses and 12-month physical function in this study is important for patients and orthopedic surgeons. Level of Evidence: Prognostic study, Level 1 (prospective study). See the Guidelines for Authors for a complete description of levels of evidence.

Early Age at Time of Primary Epstein–Barr Virus Infection Results in Poorly Controlled Viral Infection in Infants From Western Kenya: Clues to the Etiology of Endemic Burkitt Lymphoma

BACKGROUND Infection with Epstein-Barr virus (EBV) early in life and repeated malaria exposure have been proposed as risk factors for endemic Burkitt lymphoma (eBL). METHODS Infants were enrolled from 2 rural sites in Kenya: the Kisumu District, where malaria transmission is holoendemic and risk for eBL is high, and the Nandi District, where malaria transmission is limited and the risk for eBL is low. Blood samples were taken from infants through 2 years of age to measure EBV viral load, EBV antibodies, and malaria parasitemia. RESULTS We observed a significantly younger age at time of primary EBV infection in children from Kisumu compared with children from Nandi (mean age, 7.28 months [±0.33 SEM] in Kisumu vs 8.39 months [±0.26 SEM] in Nandi), with 35.3% of children in Kisumu infected before 6 months of age. To analyze how different predictors affected EBV viral load over time, we performed multilevel mixed modeling. This modeling revealed that residence in Kisumu and younger age at first EBV infection were significant predictors for having a higher EBV viral load throughout the period of observation. CONCLUSIONS Children from a region at high risk for eBL were infected very early in life with EBV, resulting in higher viral loads throughout infancy.

Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

Hypercalciuria is the major risk factor promoting stone formation in Dents disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dents disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein. Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P < 0.002) and the combination of chlorthalidone and amiloride (P < 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (<4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dents disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P <.04) and by chlorthalidone in combination with amiloride (P <.02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dents disease.

Diagnostic accuracy of serum hyaluronic acid, FIBROSpect II, and YKL-40 for discriminating fibrosis stages in chronic hepatitis C.

OBJECTIVES:Noninvasive serum markers of liver fibrosis are being used as an alternative to liver biopsy. Currently available tests distinguish, with accuracy, only absent/minimal fibrosis (Ishak stages 0–1) and advanced fibrosis/cirrhosis (Ishak stages 4–6), but not intermediate fibrosis (Ishak stages 2–3). Our aim was to evaluate the diagnostic accuracy of hyaluronic acid (HA), FIBROSpect II (FS-II), and YKL-40 (chondrex, human cartilage glycoprotein-39) in various clinically important categories of fibrosis, and further correlate these serum markers with digital quantification of fibrosis (DQF) and Ishak stages.METHODS:Serum HA, YKL-40, and FS-II were retrospectively assessed and correlated with Ishak stages and DQF scores in 75 patients with chronic hepatitis C (HCV). Spearmans rho statistics assessed relationships among all parameters, and receiver operator characteristic curves evaluated accuracy of each parameter when compared to the Ishak stages.RESULTS:All three serum markers and DQF correlated highly with one another (P ≤ 0.01) and with Ishak stages of fibrosis. Among the serum markers, HA was effective in discriminating between Ishak stages 0–1 and Ishak stages 2–3 compared with FS-II, with an area under the curve of 0.76 versus 0.66 and a false-positive rate of 0.33 versus 0.67, respectively. All three serum markers predicted advanced fibrosis and cirrhosis. YKL-40 had the highest false-positive rates in all categories of fibrosis.CONCLUSIONS:HA can be utilized as a reliable surrogate marker in distinguishing three clinically relevant stages of fibrosis: absent/minimal, intermediate, and advanced/cirrhosis. HA should be considered as a cost-effective alternative to other serum markers for staging fibrosis and for determining the timing and selection of HCV treatment.

Alterations on peripheral B cell subsets following an acute uncomplicated clinical malaria infection in children

BackgroundThe effects of Plasmodium falciparum on B-cell homeostasis have not been well characterized. This study investigated whether an episode of acute malaria in young children results in changes in the peripheral B cell phenotype.MethodsUsing flow-cytofluorimetric analysis, the B cell phenotypes found in the peripheral blood of children aged 2–5 years were characterized during an episode of acute uncomplicated clinical malaria and four weeks post-recovery and in healthy age-matched controls.ResultsThere was a significant decrease in CD19+ B lymphocytes during acute malaria. Characterization of the CD19+ B cell subsets in the peripheral blood based on expression of IgD and CD38 revealed a significant decrease in the numbers of naive 1 CD38-IgD+ B cells while there was an increase in CD38+IgD- memory 3 B cells during acute malaria. Further analysis of the peripheral B cell phenotype also identified an expansion of transitional CD10+CD19+ B cells in children following an episode of acute malaria with up to 25% of total CD19+ B cell pool residing in this subset.ConclusionChildren experiencing an episode of acute uncomplicated clinical malaria experienced profound disturbances in B cell homeostasis.