Developmental lineage of human pluripotent stem cell-derived cardiac fibroblasts affects their functional phenotype.

Cardiac fibroblasts (CFBs) support heart function by secreting extracellular matrix (ECM) and paracrine factors, respond to stress associated with injury and disease, and therefore are an increasingly important therapeutic target. We describe how developmental lineage of human pluripotent stem cell-derived CFBs, epicardial (EpiC-FB), and second heart field (SHF-FB) impacts transcriptional and functional properties. Both EpiC-FBs and SHF-FBs exhibited CFB transcriptional programs and improved calcium handling in human pluripotent stem cell-derived cardiac tissues. We identified differences including in composition of ECM synthesized, secretion of growth and differentiation factors, and myofibroblast activation potential, with EpiC-FBs exhibiting higher stress-induced activation potential akin to myofibroblasts and SHF-FBs demonstrating higher calcification and mineralization potential. These phenotypic differences suggest that EpiC-FBs have utility in modeling fibrotic diseases while SHF-FBs are a promising source of cells for regenerative therapies. This work directly contrasts regional and developmental specificity of CFBs and informs CFB in vitro model selection.

Multicellular Human Cardiac Organoids Transcriptomically Model Distinct Tissue-Level Features of Adult Myocardium.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms (2D iPSC-CM, 3D iPSC-CM and hCOs) to deduce the strengths and limitations of these in vitro models. We further compared iPSC-CM models to human myocardium samples. Our data show that the 3D in vitro environment of 3D hiPSC-CMs and hCOs stimulates the expression of genes associated with tissue formation. The hCOs demonstrated diverse physiologically relevant cellular functions compared to the hiPSC-CM only models. Including other cardiac cell types within hCOs led to more transcriptomic similarities to adult myocardium. hCOs lack matured cardiomyocytes and immune cells, which limits a complete replication of human adult myocardium. In conclusion, 3D hCOs are transcriptomically similar to myocardium, and future developments of engineered 3D cardiac models would benefit from diversifying cell populations, especially immune cells.

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1.

BACKGROUND: Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. METHODS: 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. RESULTS: For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. CONCLUSIONS: Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants.

An Evidence-Based Approach to Reducing Cardiac Telemetry Alarm Fatigue.

BACKGROUND: It is estimated that between 80% and 99% of alarms in the clinical areas are in actionable alarms (Gross, Dahl, & Nielson). Alarm management is one of the Joint Commission's National Patient Safety Goals (2014) because sentinel events have directly been linked to the devices generating these alarms. PURPOSE: At an acute care facility in Boston, a multidisciplinary team consisting of Nursing, Biomedical Engineers, Patient Safety and Providers was formed to conduct a pilot study on the state of telemetry alarms on a surgical floor. METHODS: An evidence-based approach was taken utilizing Philips Real-time data exporter alarms tracking software to capture all telemetry alarms during a 43-day time span. Likewise, noise meters were placed near telemetry alarm speakers to track decibel levels within the aforementioned timeframe for 21 days. Analysis of the data showed that clinically insignificant Premature Ventricular Contractions (PVC) alarms accounted for more than 40% of all alarms in the unit within the time span, while also contributing to an average noise level of 58.49 dB. In response to the data, the interdisciplinary team approved to permanently default the settings for PAIR PVC, MULTIFORM PVC, and RUN PVC alarms to off. RESULTS: The results showed a 54% decrease in the rate of alarms per bed per day, and an average noise reduction of 2.3 dB between the two selected noise measurement areas. LINKING EVIDENCE TO ACTION: Organizing a multidisciplinary team provides an effective framework toward analyzing and addressing cardiac telemetry alarm fatigue. Looking at quantitative datasets for clinical care areas through various lenses helps identify opportunities for improvement in regards to highlighting alarms that are not actionable. Pilot changes to alarm parameters can be tested for their environmental impact in the care area.

Impact of cardiac resynchronization therapy on hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure trial.

BACKGROUND: This study reports the impact of cardiac resynchronization therapy (CRT) on hospitalizations in patients randomized to implantable cardioverter-defibrillator (ICD) or ICD-CRT in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). METHODS AND RESULTS: Hospitalization rates and lengths of hospital stay were compared between the 2 groups. At the 18-month follow-up, the numbers of patients hospitalized for any cause were similar in the ICD (n=351, 38.8%) and ICD-CRT (n=331, 30.0%) groups. The number of patients hospitalized for heart failure was significantly lower in the ICD-CRT (n=101, 11.3%) compared with the ICD (n=141, 15.6%; P=0.003) group. The number of patients hospitalized for a device-related indication was similar in the ICD-CRT group (n=147, 16.4%) and ICD group (n=126, 13.9%; P=0.148). The total number of hospitalizations for any cause (n=1448 versus n=1553; P=0.042), any cardiovascular cause (n=667 versus n=790; P=0.017), and any heart failure cause (n=385 versus n=505; P<0.0001) was significantly lower in ICD-CRT group compared with the ICD group, whereas the number of hospitalizations for device-related causes was significantly higher in the ICD-CRT group compared with the ICD group (246 versus 159; P<0.001). Although the reduction in hospitalizations for heart failure in the CRT-ICD group was offset by an increased number of hospitalizations for device-related indications, the length of hospital stay for any cause was significantly shorter in the ICD-CRT group (8.83±13.30 days) compared with the ICD group (9.59±14.40 days; P=0.005). CONCLUSION: ICD-CRT therapy significantly reduces hospitalizations and total days in hospital in patients with New York Heart Association class II/III heart failure compared with ICD therapy despite increased admissions for device-related indications. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00251251.

Lead Integrity Alert Is Useful for Assessment of Performance of Biotronik Linox Leads.

INTRODUCTION: Medtronic's Lead Integrity Alert (LIA) software algorithm is useful for detecting abnormal parameters across various ICD-lead families. However, its utility in the assessment of the Biotronik Linox™ family of high-voltage (HV) leads is unknown. METHODS: We conducted a retrospective cohort study to assess the performance of the LIA algorithm to detect abnormalities and lead failure in Linox ICD-leads. All LIA-enabled Medtronic devices connected to an active Linox lead were included. The alerts were adjudicated by 2 blinded electrophysiologists and correlated with clinical data. RESULTS: Between 2008 and 2012, data from 208 patients with 564 patient-years of follow-up were available for analysis. The median follow-up duration was 32 (IQR 21-41 months). Twenty-one LIA triggers were noted in 20 different patients. The median delay until a positive LIA was 32 months (IQR 21-41 months) postimplant with a 5-year lead survival free from LIA of 76%. Ninety-five percent (19/20) LIA alerts were true lead failures. The most common LIA triggers were short V-V intervals (85%) and nonsustained ventricular tachycardia (85%). Abrupt changes of the ICD-lead impedance occurred in 5/20 triggers. Inappropriate ICD-shocks were strongly associated with a positive LIA (30% vs. 7.4%; P = 0.006). Of the explanted Linox leads 53% had visible abnormalities. The sensitivity, specificity, and positive predictive value for lead failure in the presence of a LIA trigger were 87%, 99.5%, and 95.2%, respectively. CONCLUSIONS: A positive LIA trigger in Biotronik Linox ICD-leads is highly predictive of lead failure. LIA is useful in ongoing surveillance of lead performance.

Decellularized heart extracellular matrix alleviates activation of hiPSC-derived cardiac fibroblasts.

Human induced pluripotent stem cell derived cardiac fibroblasts (hiPSC-CFs) play a critical role in modeling human cardiovascular diseases in vitro. However, current culture substrates used for hiPSC-CF differentiation and expansion, such as Matrigel and tissue culture plastic (TCPs), are tissue mismatched and may provide pathogenic cues. Here, we report that hiPSC-CFs differentiated on Matrigel and expanded on tissue culture plastic (M-TCP-iCFs) exhibit transcriptomic hallmarks of activated fibroblasts limiting their translational potential. To alleviate pathogenic activation of hiPSC-CFs, we utilized decellularized extracellular matrix derived from porcine heart extracellular matrix (HEM) to provide a biomimetic substrate for improving hiPSC-CF phenotypes. We show that hiPSC-CFs differentiated and expanded on HEM (HEM-iCFs) exhibited reduced expression of hallmark activated fibroblast markers versus M-TCP-iCFs while retaining their cardiac fibroblast phenotype. HEM-iCFs also maintained a reduction in expression of hallmark genes associated with pathogenic fibroblasts when seeded onto TCPs. Further, HEM-iCFs more homogenously integrated into an hiPSC-derived cardiac organoid model, resulting in improved cardiomyocyte sarcomere development. In conclusion, HEM provides an improved substrate for the differentiation and propagation of hiPSC-CFs for disease modeling.

Vascular Amputees: A Study in Disappointment.

Despite optimistic reports about the results of amputation for advanced vascular disease, the patient's assessment of advantages and disadvantages is seldom acknowledged. A detailed social study of 67 amputees has revealed considerable disparity between the patient's views and those of the medical staff. About a third of the patients are forced to retire from active work by the amputation; about three-quarters report a serious decline in their social activities; only about half are really independent with prostheses in the long term; a quarter report severe and intractable symptoms related to their amputation stumps; only about a quarter feel that the amputation was definitely beneficial; and only about one in five feel that the medical staff have provided adequate support during their hospital stay. Amputees face physical and financial disability, isolation, and discomfort. Every effort must be made to explain the implications of amputation honestly and realistically and to ensure continuing patient assessment and support.

Human cardiac organoids to model COVID-19 cytokine storm induced cardiac injuries.

Acute cardiac injuries occur in 20%-25% of hospitalized COVID-19 patients. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1ß is an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1ß treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1ß treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1ß treated hCOs thus provide a defined and robust model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.

Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries.

Acute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1ßis an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1 ß treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1ß treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1ß treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Canadian Registry of ICD Implant Testing procedures (CREDIT): current practice, risks, and costs of intraoperative defibrillation testing.

BACKGROUND: There is uncertainty about the proper role of defibrillation testing (DT) at the time of implantable cardioverter defibrillator (ICD) insertion. METHODS: A prospective registry was conducted at 13 sites in Canada between January 2006 and October 2007. OBJECTIVES: To document the details of DT, the reasons for not conducting DT, and the costs and complications associated with DT. RESULTS: DT was conducted at implantation in 230 of 361 patients (64%). DT was more likely to be conducted for new implants compared with impulse generator replacements (71% vs 32%, P = 0.0001), but was similar for primary and secondary prevention indications (64% vs 63%, P = NS). Among patients not having DT, the reason(s) given were: considered unnecessary (44%); considered unsafe, mainly due to persistent atrial fibrillation (37%); lack of an anesthetist (20%); and, patient or physician preference (6%). When performed, DT consisted of a single successful shock > or = 10J below maximum device output in 65% of cases. A 10J safety-margin was met by 97% of patients, requiring system modification in 2.3%. Major perioperative complications occurred in 4.4% of patients having DT versus 6.6% of patients not having DT (P = NS). ICD insertion was $844 more expensive for patients having DT (P = 0.16), largely due to increased costs ($28,017 vs $24,545) among patients having impulse generator replacement (P = 0.02). CONCLUSIONS: DT was not performed in a third of ICD implants, usually due to a perceived lack of need or relative contraindication.

Characteristics of patients and implantable defibrillators associated with failure to sense device alert systems.

AIMS: In the era of increasing implantable cardioverter defibrillator (ICD) complexity, the ICD patient alert is deemed to be an important feature in the early detection of ICD system malfunction and is either an audible or a vibratory alert. We sought to evaluate the patient's ability to detect these ICD alerts in the device clinic setting as a surrogate endpoint of clinical utility. METHODS AND RESULTS: From 1 November 2006 to 31 March 2008, 563 patients with an ICD equipped with either an audible patient alert (APA, Medtronic and Guidant; n = 485) or a vibratory monitoring alert ([VMA, St Jude Medical; n = 78) had their alarm demonstrated in the quiet clinic setting. The ability to recognize the alert was analysed and then stratified by gender, age, manufacturer, type of alert, and pocket location. The average patient age was 63.3 (± 13.6) years and 82.8% of patients were male. Implantable cardioverter defibrillator manufacturers were Medtronic (n = 464), Boston Scientific (n = 21), and SJM (n = 78). The APA was heard in 86.0% of patients. This was less likely in patients who were older, male, and where the device was placed in the submuscular position. Every patient with a VMA sensed their alert. CONCLUSION: In the current ICD alert technology, the ability to sense the ICD alert in the device clinic appears to be higher for the VMA than for the APA. In particular, older patients and male patients are less likely to sense the APA.

Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity.

Environmental factors are the largest contributors to cardiovascular disease. Here we show that cardiac organoids that incorporate an oxygen-diffusion gradient and that are stimulated with the neurotransmitter noradrenaline model the structure of the human heart after myocardial infarction (by mimicking the infarcted, border and remote zones), and recapitulate hallmarks of myocardial infarction (in particular, pathological metabolic shifts, fibrosis and calcium handling) at the transcriptomic, structural and functional levels. We also show that the organoids can model hypoxia-enhanced doxorubicin cardiotoxicity. Human organoids that model diseases with non-genetic pathological factors could help with drug screening and development.

Cost comparison of ablation versus antiarrhythmic drugs as first-line therapy for atrial fibrillation: an economic evaluation of the RAAFT pilot study.

INTRODUCTION: Radiofrequency ablation (RFA) has become an accepted therapy for atrial fibrillation (AF). The objective of this study was to perform an economic evaluation of RFA versus antiarrhythmic drug therapy (AAD) as first-line treatment of symptomatic paroxysmal AF. METHODS: To estimate and compare the costs of RFA versus AAD, a decision analytic model was developed using data on AF recurrence, hospitalization rates, AAD use, and treatment crossover rates derived directly from the Randomized Trial of RFA versus AAD as First-Line Treatment of Symptomatic Atrial Fibrillation (RAAFT). Resource utilization was modeled to reflect Canadian clinical practice in AF management. Unit costs of healthcare interactions were based on available Canadian government resources and published literature. Costs were assessed based on intention-to-treat. Total expected costs were computed to include initial treatment, hospital stay, physician fees, diagnostic tests, and outpatient visits. Sensitivity analyses were performed to account for the uncertainties. The study was conducted from the third party payer's perspective and costs are reported in 2005 Canadian dollars with 3% discount rate used in the analysis. RESULTS: During the 2-month blanking period following therapy selection, total average costs for RFA and AAD were $10,465 and $2,556, respectively; at 1-year follow-up, these were $12,823 and $6,053; and total 2-year cumulative total average costs were $15,303 and $14,392. Sensitivity analyses did not alter the results, suggesting the model is robust. CONCLUSIONS: RFA as first-line treatment strategy in patients with symptomatic paroxysmal AF was cost neutral 2 years after the initial procedure compared to AAD.

Association Between Patient and Physician Sex and Physician-Estimated Stroke and Bleeding Risks in Atrial Fibrillation.

BACKGROUND: Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain. METHODS: We pooled data from 2 national primary care physician chart audit databases of patients with AF (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation and Coordinated National Network to Engage Physicians in the Care and Treatment of Patients with Atrial Fibrillation Chart Audit) with a combined 1035 physicians (133 female, 902 male) and 10,927 patients (4567 female and 6360 male). RESULTS: Male physicians underestimated stroke risk in female patients and overestimated risk in male patients. Female physicians estimated stroke risk well in female patients but underestimated the risk in male patients. Risk of bleeding was underestimated in all. Despite differences in risk assessment by physician and patient sex, > 90% of patients received anticoagulation across all subgroups. There was modest agreement between physician estimated and calculated (ie, CHADS2 score) stroke risk: Kappa scores were 0.41 (0.35-0.47) for female physicians and 0.34 (0.32-0.36) for male physicians. CONCLUSIONS: Our study is the first to examine the association between patient and physician sex influences and stroke and bleeding risk estimation in AF. Although there were differences in agreement between physician estimated stroke risk and calculated CHADS2 scores, these differences were small and unlikely to affect clinical practice; further, despite any perceived differences in the accuracy of risk assessment by sex, most patients received anticoagulation.

Statin use and recurrence of atrial fibrillation after successful cardioversion.

BACKGROUND: Statins have important pleiotropic effects and have been shown to reduce vascular inflammation and the incidence of atrial fibrillation (AF) after cardiac surgery. The role of statins in patients with existing AF is poorly understood. We examined the effect of statins on recurrence of AF in patients after successful cardioversion. METHODS: Statin use and documented recurrence of AF after successful cardioversion were evaluated in 625 patients with new onset AF who were followed prospectively in the Canadian Registry of Atrial Fibrillation. Logistic regression was used to model the effect of statin use on the recurrence of AF at 1 year while adjusting for potential confounders including concurrent medications. RESULTS: In a predominantly male population (62%) with median age 63 years, 12.3% were on statins at baseline. Overall, 32.5% had documented recurrence of AF at 1 year; 23.4% in patients on statins compared to 33.8% in those not on statins (P = .07). After adjustment for baseline differences and concomitant beta-blocker use, statin use was associated with a 74% reduction in AF recurrence, but only in statin users on beta-blockers (OR 0.26, 95% CI 0.10-0.66); statin users not on beta-blockers (OR 1.07, 95% CI 0.44-2.58). CONCLUSIONS: In an observational study of patients with new onset AF, statin use was associated with a significant 74% reduction in the odds of recurrent AF, but only in patients also taking beta-blockers. Importantly, statin without concomitant beta-blocker use was not associated with any changes in AF recurrence.

Cost comparison of catheter ablation and medical therapy in atrial fibrillation.

INTRODUCTION: There is emerging evidence for clinical superiority of catheter ablation over rate and rhythm control strategies in paroxysmal atrial fibrillation (PAF). The objective of this study was to compare costs related to medical therapy versus catheter ablation for PAF in Ontario (Canada). METHODS: Costs related to medical therapy in the analysis included the cost of anticoagulation, rate and rhythm control medications, noninvasive testing, physician follow-up visits, and hospital admissions, as well as the cost of complications related to this management strategy. Costs related to catheter ablation were assumed to include the cost of the ablation tools (electroanatomic mapping or intracardiac echocardiography-guided pulmonary vein ablation), hospital and physician billings, and costs related to periprocedural medical care and complications. Costs related to these various elements were obtained from the Canadian Registry of Atrial Fibrillation (CARAF), government fee schedules, and published data. Sensitivity analyses looking at a range of initial success rates (50-75%) and late attrition rates (1-5%), prevalence of congestive heart failure (CHF) (20-60%), as well as discounting varying from 3% to 5% per year were performed. RESULTS: The cost of catheter ablation ranged from $16,278 to $21,294, with an annual cost of $1,597 to $2,132. The annual cost of medical therapy ranged from $4,176 to $5,060. Costs of ongoing medical therapy and catheter ablation for PAF equalized at 3.2-8.4 years of follow-up. CONCLUSION: Catheter ablation is a fiscally sensible alternative to medical therapy in PAF with cost equivalence after 4 years.

The effect of atrial-based pacing on exercise capacity as measured by the 6-minute walk test: a substudy of the Canadian Trial of Physiological Pacing (CTOPP).

BACKGROUND: Although several randomized trials have detected no reduction in major cardiovascular events with the routine use of dual-chamber as opposed to ventricular pacemakers, many individuals continue to advocate their use as a means of improving exercise capacity. METHODS: The Canadian Trial of Physiological Pacing (CTOPP) trial is the largest trial comparing ventricular pacing to atrial-based pacing (atrial or dual-chamber) in patients with bradycardia. All patients in this trial were asked to complete a 6-minute hall walk test (6MWT) at the time of their first study follow-up. The distance walked in 6 minutes and the patient's heart rate before and immediately after the walk were recorded. RESULTS: Of the 2568 patients in the CTOPP, 76% completed the 6MWT. The mean distance walked was 350 +/- 127 m in the ventricular pacing group and 356 +/- 127 m in the atrial-based group (P = NS). Similarly, there was no difference in the change in heart rate between the two groups (17 +/- 13 vs. 18 +/- 12 bpm: P = NS). However, among patients with an unpaced heart rate of