Rate-Adaptive Atrial Pacing for Heart Failure With Preserved Ejection Fraction: The RAPID-HF Randomized Clinical Trial.

Importance: Reduced heart rate during exercise is common and associated with impaired aerobic capacity in heart failure with preserved ejection fraction (HFpEF), but it remains unknown if restoring exertional heart rate through atrial pacing would be beneficial. Objective: To determine if implanting and programming a pacemaker for rate-adaptive atrial pacing would improve exercise performance in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: Single-center, double-blind, randomized, crossover trial testing the effects of rate-adaptive atrial pacing in patients with symptomatic HFpEF and chronotropic incompetence at a tertiary referral center (Mayo Clinic) in Rochester, Minnesota. Patients were recruited between 2014 and 2022 with 16-week follow-up (last date of follow-up, May 9, 2022). Cardiac output during exercise was measured by the acetylene rebreathe technique. Interventions: A total of 32 patients were recruited; of these, 29 underwent pacemaker implantation and were randomized to atrial rate responsive pacing or no pacing first for 4 weeks, followed by a 4-week washout period and then crossover for an additional 4 weeks. Main Outcomes and Measures: The primary end point was oxygen consumption (V̇o2) at anaerobic threshold (V̇o2,AT); secondary end points were peak V̇o2, ventilatory efficiency (V̇e/V̇co2 slope), patient-reported health status by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Results: Of the 29 patients randomized, the mean age was 66 years (SD, 9.7) and 13 (45%) were women. In the absence of pacing, peak V̇o2 and V̇o2 at anaerobic threshold (V̇o2,AT) were both correlated with peak exercise heart rate (r = 0.46-0.51, P < .02 for both). Pacing increased heart rate during low-level and peak exercise (16/min [95% CI, 10 to 23], P < .001; 14/min [95% CI, 7 to 21], P < .001), but there was no significant change in V̇o2,AT (pacing off, 10.4 [SD, 2.9] mL/kg/min; pacing on, 10.7 [SD, 2.6] mL/kg/min; absolute difference, 0.3 [95% CI, -0.5 to 1.0] mL/kg/min; P = .46), peak V̇o2, minute ventilation (V̇e)/carbon dioxide production (V̇co2) slope, KCCQ-OSS, or NT-proBNP level. Despite the increase in heart rate, atrial pacing had no significant effect on cardiac output with exercise, owing to a decrease in stroke volume (-24 mL [95% CI, -43 to -5 mL]; P = .02). Adverse events judged to be related to the pacemaker device were observed in 6 of 29 participants (21%). Conclusions and Relevance: In patients with HFpEF and chronotropic incompetence, implantation of a pacemaker to enhance exercise heart rate did not result in an improvement in exercise capacity and was associated with increased adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT02145351.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.

Program and patient characteristics for the United States Expanded Access Program to COVID-19 convalescent plasma.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to COVID-19 convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19). While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents particularly for vulnerable racial and ethnic minority populations who were disproportionately affected by the pandemic. The objective of this study is to report on the demographic, geographic, and chronological access to COVID-19 convalescent plasma in the US via the EAP. METHODS AND FINDINGS: Mayo Clinic served as the central IRB for all participating facilities and any US physician could participate as local physician-principal investigator. Registration occurred through the EAP central website. Blood banks rapidly developed logistics to provide convalescent plasma to hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal trends in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate on a state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions as well as assessing enrollment in metropolitan and less populated areas which did not have access to COVID-19 clinical trials.From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. A majority of patients were older than 60 years of age (57.8%), male (58.4%), and overweight or obese (83.8%). There was substantial inclusion of minorities and underserved populations, including 46.4% of patients with a race other than White, and 37.2% of patients were of Hispanic ethnicity. Severe or life-threatening COVID-19 was present in 61.8% of patients and 18.9% of patients were mechanically ventilated at time of convalescent plasma infusion. Chronologically and geographically, increases in enrollment in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled patients in the EAP, including both in metropolitan and less populated areas. CONCLUSIONS: The EAP successfully provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The efficient study design of the EAP may serve as an example framework for future efforts when broad access to a treatment is needed in response to a dynamic disease affecting demographic groups and areas historically underrepresented in clinical studies.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience.

IMPORTANCE: Passive antibody transfer is a longstanding treatment strategy for infectious diseases that involve the respiratory system. In this context, human convalescent plasma has been used to treat coronavirus disease 2019 (COVID-19), but the efficacy remains uncertain. OBJECTIVE: To explore potential signals of efficacy of COVID-19 convalescent plasma. DESIGN: Open-label, Expanded Access Program (EAP) for the treatment of COVID-19 patients with human convalescent plasma. SETTING: Multicenter, including 2,807 acute care facilities in the US and territories. PARTICIPANTS: Adult participants enrolled and transfused under the purview of the US Convalescent Plasma EAP program between April 4 and July 4, 2020 who were hospitalized with (or at risk of) severe or life threatening acute COVID-19 respiratory syndrome. INTERVENTION: Transfusion of at least one unit of human COVID-19 convalescent plasma using standard transfusion guidelines at any time during hospitalization. Convalescent plasma was donated by recently-recovered COVID-19 survivors, and the antibody levels in the units collected were unknown at the time of transfusion. Main Outcomes and Measures: Seven and thirty-day mortality. RESULTS: The 35,322 transfused patients had heterogeneous demographic and clinical characteristics. This cohort included a high proportion of critically-ill patients, with 52.3% in the intensive care unit (ICU) and 27.5% receiving mechanical ventilation at the time of plasma transfusion. The seven-day mortality rate was 8.7% [95% CI 8.3%-9.2%] in patients transfused within 3 days of COVID-19 diagnosis but 11.9% [11.4%-12.2%] in patients transfused 4 or more days after diagnosis (p<0.001). Similar findings were observed in 30-day mortality (21.6% vs. 26.7%, p<0.0001). Importantly, a gradient of mortality was seen in relation to IgG antibody levels in the transfused plasma. For patients who received high IgG plasma (>18.45 S/Co), seven-day mortality was 8.9% (6.8%, 11.7%); for recipients of medium IgG plasma (4.62 to 18.45 S/Co) mortality was 11.6% (10.3%, 13.1%); and for recipients of low IgG plasma (<4.62 S/Co) mortality was 13.7% (11.1%, 16.8%) (p=0.048). This unadjusted dose-response relationship with IgG was also observed in thirty-day mortality (p=0.021). The pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units. CONCLUSIONS AND RELEVANCE: The relationships between reduced mortality and both earlier time to transfusion and higher antibody levels provide signatures of efficacy for convalescent plasma in the treatment of hospitalized COVID-19 patients. This information may be informative for the treatment of COVID-19 and design of randomized clinical trials involving convalescent plasma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04338360.

Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients.

OBJECTIVE: To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized coronavirus 2019 (COVID-19) patients, having previously demonstrated safety in 5000 hospitalized patients. PATIENTS AND METHODS: From April 3 to June 2, 2020, the US Food and Drug Administration Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events was low; these included transfusion reactions (n=78; <1%), thromboembolic or thrombotic events (n=113; <1%), and cardiac events (n=677, ~3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=75) and cardiac events (n=597) were judged to be unrelated to the plasma transfusion per se. The 7-day mortality rate was 13.0% (12.5%, 13.4%), and was higher among more critically ill patients relative to less ill counterparts, including patients admitted to the intensive care unit versus those not admitted (15.6 vs 9.3%), mechanically ventilated versus not ventilated (18.3% vs 9.9%), and with septic shock or multiple organ dysfunction/failure versus those without dysfunction/failure (21.7% vs 11.5%). CONCLUSION: These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.

Clinical implications of elective replacement indicator setting changes in patients with dual-chamber pacemaker devices.

OBJECTIVE: This study sought to determine if single-chamber operation and/or loss of rate response (RR) during elective replacement indicator (ERI) in patients with dual-chamber pacemakers lead to increased symptom burden, healthcare utilization, and atrial fibrillation (AF). BACKGROUND: Dual-chamber pacemakers often change from dual- to single-chamber pacing mode and/or lose RR functionality at ERI to preserve battery. Single-chamber pacing increases the incidence of heart failure, AF, and pacemaker syndrome suggesting these changes may be deleterious. METHODS: A retrospective analysis of 700 patients was completed. Three comparisons were analyzed: Comparison 1: mode change and RR loss versus no change; Comparison 2: RR loss only versus no change; Comparison 3: mode change only versus no change (in patients with no RR programmed at baseline). RESULTS: In Comparison 1, 121 (46%) patients with setting changes experienced symptoms (most often dyspnea and fatigue/exercise intolerance) versus 3 (4%) without setting changes (p < .0001). Similar results were noted in Comparisons 2 and 3 (p = .0016 and p = .0001, respectively). In Comparison 1, patients with setting change sought provider contact more than patients without setting changes (p = .0001). A significant difference was not noted in Comparison 2 or 3. Overall 14 (2%) patients were hospitalized, all of whom had setting changes. CONCLUSIONS: Setting changes at ERI including a change from dual- to single-chamber pacing and/or loss of RR results in a significantly increased symptom burden and increased healthcare utilization.

Early Safety Indicators of COVID-19 Convalescent Plasma in 5,000 Patients.

BACKGROUND: Convalescent plasma is the only antibody based therapy currently available for COVID-19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19. METHODS: Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma. RESULTS: The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury (TRALI; n=11), and severe allergic transfusion reactions (n=3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The seven-day mortality rate was 14.9%. CONCLUSION: Given the deadly nature of COVID-19 and the large population of critically-ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.

Early safety indicators of COVID-19 convalescent plasma in 5000 patients.

BACKGROUNDConvalescent plasma is the only antibody-based therapy currently available for patients with coronavirus disease 2019 (COVID-19). It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.METHODSThus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma in 5000 hospitalized adults with severe or life-threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA expanded access program for COVID-19 convalescent plasma.RESULTSThe incidence of all serious adverse events (SAEs), including mortality rate (0.3%), in the first 4 hours after transfusion was <1%. Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (n = 7), transfusion-related acute lung injury (n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 of 36 SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The 7-day mortality rate was 14.9%.CONCLUSIONGiven the deadly nature of COVID-19 and the large population of critically ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.TRIAL REGISTRATIONClinicalTrials.gov NCT04338360.FUNDINGMayo Clinic, Biomedical Advanced Research and Development Authority (75A50120C00096), National Center for Advancing Translational Sciences (UL1TR002377), National Heart, Lung, and Blood Institute (5R35HL139854 and R01 HL059842), National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK07352), Natural Sciences and Engineering Research Council of Canada (PDF-532926-2019), National Institute of Allergy and Infectious Disease (R21 AI145356, R21 AI152318, and AI152078), Schwab Charitable Fund, United Health Group, National Basketball Association, Millennium Pharmaceuticals, and Octapharma USA Inc.

Mitigation of Exercise Oscillatory Ventilation Score by Cardiac Resynchronization Therapy.

BACKGROUND: Exercise oscillatory ventilation (EOV) is a consequence of ventilatory control system instability and is commonly observed in patients with advanced heart failure (HF); it is associated with adverse prognosis. The goal of this study was to evaluate the effects of cardiac resynchronization therapy (CRT) on oscillatory ventilation as quantified by a proposed EOV score. METHODS AND RESULTS: Consecutive patients with HF (N = 35) who underwent clinically indicated CRT, cardiopulmonary exercise testing and carbon dioxide (CO2) chemosensitivity by rebreathe before and 4-6 months after CRT were included in this post hoc analysis. With CRT, EOV scores improved in 22 patients (63%). In these patients, left ventricular ejection fraction, left atrial volume, brain natriuretic peptide concentration, and CO2 chemosensitivity significantly improved after CRT (P < 0.05). Furthermore, minute ventilation per unit CO2 production significantly decreased, and end-tidal CO2 increased at rest and at peak exercise post-CRT. Multiple regression analysis showed only the change of CO2 chemosensitivity to be significantly associated with the improvement of the EOV score (b = 0.64; F = 11.3; P = 0.004). In the group without EOV score improvement (n = 13), though left ventricular ejection fraction significantly increased with CRT (P = 0.015), no significant changes in ventilation or gas exchange were observed. CONCLUSION: The EOV score was mitigated by CRT and was associated with decreased CO2 chemosensitivity.

Real-world experience with leadless cardiac pacing.

BACKGROUND: Leadless cardiac pacing (LCP) has emerged as a new modality for permanent pacing. We sought to describe comparative outcomes between LCP and transvenous pacemakers. METHODS: Patients receiving LCP (Micra [Medtronic, Minneapolis, MN, USA] and Nanostim [St. Jude Medical/Abbott Laboratories, Chicago, IL, USA]) between 2014 and 2017 at the Mayo Clinic Heart Rhythm Enterprise practice (Rochester, MN, USA; Jacksonville, FL, USA; and Scottsdale, AZ, USA) were identified. We identified 1:1 age- and sex-matched controls receiving single-chamber transvenous ventricular pacemakers (TVP). Statistical analyses were performed with JMP 13.0.0 (SAS, Institute Cary, NC, USA). RESULTS: Ninety patients underwent LCP implantation (73 Micra and 17 Nanostim) with a median follow-up duration of 62 (interquartile range 28-169) days. Both groups had 100% successful device implant rates. There were no differences in procedure-related major (0% vs 1%) or minor complications (8% vs 3%) in the LCP versus TVP groups (P > 0.05). Excluding Nanostim patients, there was a lower rate of device-related revision or extraction in the Micra versus TVP groups (0% vs 5%, P = 0.028). Device endocarditis was more common in the TVP group (0% vs 3%, P = 0.04). Estimated longevity was greater for the LCP group (median 12.0 vs 10.0 years, P < 0.0001). An increase in severity of tricuspid valve regurgitation (TR) by ≥2 grades occurred in none of the LCP patients, and in 19% of the TVP patients (P = 0.017). CONCLUSION: There are no significant differences in procedural complications among patients receiving LCP versus TVP. The Micra group had lower rates of device-related revision/extraction compared to the TVP group. Patients with leadless pacemaker were less likely to develop endocarditis or worsening TR.

Stroke in patients with cardiovascular implantable electronic device infection undergoing transvenous lead removal.

BACKGROUND: Stroke can be a devastating complication in patients with cardiovascular implantable electronic device (CIED) infection. Paradoxical septic embolism can occur in the presence of device leads and patent foramen ovale (PFO) via embolic dislodgment during transvenous lead removal (TLR). OBJECTIVE: The purpose of this study was to examine stroke and its associated factors in patients undergoing TLR for CIED infection. METHODS: We performed a retrospective analysis of all patients undergoing TLR for CIED infection from January 1, 2000, to July 30, 2017, from all 3 tertiary referral centers at the Mayo Clinic (Rochester, Phoenix, and Jacksonville). The primary outcome was stroke and was further categorized into preprocedural and postprocedural stroke. Associated risk factors were analyzed. RESULTS: A total of 774 patients (mean age 67.6 ± 14.9 years) underwent TLR for CIED infection. The stroke rate in this cohort was 1.9% (95% confidence interval [CI] 1.1%-3.2%). The preprocedural and postprocedural stroke rate was 0.9% (95% CI 0.4%-1.9%) and 1.0% (95% CI 0.4%-2.0%), respectively. PFOs were identified in 46.7% of patients with stroke and in 12.9% of patients without stroke, and were independently associated with stroke (P = .0002). This was especially in patients with right-sided vegetations with right-to-left shunting (odds ratio 6.4; 95% CI 1.3-31.0; P = .022). CONCLUSION: In patients with CIED infection undergoing TLR, the presence of PFO, especially with right-sided vegetation with right-to-left shunting, was associated with an increased risk of stroke. This finding suggests that PFO screening before TLR warrants meticulous attention.

Long-Term Mortality Effect of Early Pacemaker Implantation After Surgical Aortic Valve Replacement.

BACKGROUND: The need for pacemaker implantation is a well-described complication of aortic valve replacement. Not so well described is the effect such an event has on long-term outcome. This study reviewed a 21-year experience at the Mayo Clinic (Rochester, Minnesota) with aortic valve replacement to understand the influence of early postoperative pacemaker implantation on long-term mortality rates more clearly. METHODS: This study retrospectively reviewed the records of 5,842 patients without previous pacemaker implantation who underwent surgical aortic valve replacement from January 1993 through June 2014. The median age of these patients was 73 years (range, 65 to 79 years), the median ejection fraction was 62% (range, 53% to 68%), 3,853 patients were male (66%), and coronary artery bypass graft operation was performed in 2,553 (44%) of the patients studied. Early pacemaker implantation occurred in 146 patients (2.5%) within 30 days of surgical aortic valve replacement. RESULTS: The median follow-up of patients was 11.1 years (range, 5.8 to 16.5 years), and all-cause mortality rates were 2.4% at 30 days, 6.4% at 1 year, 23.1% at 5 years, 48.3% at 10 years, and 67.9% at 15 years postoperatively. Early pacemaker implantation was associated with an increased risk of death after multivariable adjustment for baseline patients' characteristics (hazard ratio, 1.49; 95% confidence interval, 1.20, 1.84; p < 0.001). CONCLUSIONS: Early pacemaker implantation as a complication of surgical aortic valve replacement is associated with an increased risk of long-term death. Valve replacement-related pacemaker implantation rates should be important considerations with respect to new valve replacement paradigms, especially in younger and lower-risk patients.

Modulation of ventilatory reflex control by cardiac resynchronization therapy.

BACKGROUND: Heart failure (HF) is characterized by heightened sensitivities of the CO2 chemoreflex and the ergoreflex which promote increased ventilatory drive manifested as increased minute ventilation per volume of expired CO2 (VE/VCO2). The aims of this study were to evaluate the effects of cardiac resynchronization therapy (CRT) on carbon dioxide (CO2) chemosensitivity and the arterial CO2 setpoint. METHODS AND RESULTS: Consecutive HF patients (n = 35) who underwent clinically indicated CRT were investigated by means of cardiopulmonary exercise testing and CO2 chemosensitivity evaluation with the use of a rebreathe method before and 4-6 months after CRT. Pre- and post-CRT measures were compared with the use of either paired t test or Wilcoxon test. Decreased peak VE/VCO2 (44 ± 10 vs 40 ± 8; P < .01), CO2 chemosensitivity (2.2 ± 1.1 vs 1.7 ± 0.8 L min(-1) mm Hg(-1); P = .04), and increased peak end-tidal CO2 (29 ± 5 vs 31 ± 5 mm Hg; P < .01) were also observed after CRT. Multivariate analysis adjusted for age and sex showed the decrease of peak VE/VCO2 from before to after CRT to be most strongly associated with the increase of peak end-tidal CO2 (ß = -0.84; F = 21.5; P < .0001). CONCLUSIONS: Decrease of VE/VCO2 after CRT is associated with decreased CO2 chemosensitivity and increase of the arterial CO2 setpoint, which is consistent with decreased activation of both the CO2 chemoreflex and the ergoreflex.

Cardiac device complications in the cognitively impaired.

BACKGROUND: Patients with preexisting mild cognitive impairment or dementia may be at increased risk for developing cardiac device complications due to an impaired ability to follow postimplant care instructions. We sought to determine whether rates of infection, lead dislodgement, or appropriate or inappropriate implantable cardioverter defibrillator (ICD) shocks are increased in this population. METHODS: Medical charts of 561 patients with mild cognitive impairment or dementia who underwent pacemaker (PM) or ICD implantation between January 2002 and October 2009 at Mayo Clinic were identified. A total of 134 patients who were diagnosed with cognitive impairment or dementia before device implantation or within 1 year of implantation were compared with 134 matched controls. Information was collected on patient characteristics, comorbid medical conditions, ejection fraction, complications, device type, device therapy, and mortality. Device information was prospectively entered into a database and retrospectively reviewed. RESULTS: Of the 134 patients with mild cognitive impairment and dementia, 99 underwent PM implantation and 35 underwent ICD implantation. Compared to controls, there was no difference in patient characteristics, ejection fraction, or comorbidities except for diabetes, which was more prevalent in the cognitively impaired and demented group (18.7% vs 30.6%, P = 0.02). There was no difference in device therapy and complications (14.4% vs 5.8%, P = 0.268). However, there was a decreased survival in patients with cognitive impairment and dementia when compared to the control group (42% vs 67% at 5 years, P = 0.007). CONCLUSION: Patients with cognitive impairment and standard device indications are not at increased risk for device complications and therapy but their survival is much lower than in matched controls. The cause of this lower survival is unknown but may be related to the underlying neurological disease. Presence of cognitive impairment should therefore be considered when contemplating implantation of a cardiac device.

Effect of cardiac resynchronization therapy on pulmonary function in patients with heart failure.

Pulmonary congestion due to heart failure causes abnormal lung function. Cardiac resynchronization therapy (CRT) is a proven effective treatment for heart failure. The aim of this study was to test the hypothesis that CRT promotes increased lung volumes, bronchial conductance, and gas diffusion. Forty-four consecutive patients with heart failure were prospectively investigated before and after CRT. Spirometry, gas diffusion (diffusing capacity for carbon monoxide), cardiopulmonary exercise testing, New York Heart Association class, brain natriuretic peptide, the left ventricular ejection fraction, left atrial volume, and right ventricular systolic pressure were assessed before and 4 to 6 months after CRT. Pre- and post-CRT measures were compared using either paired Student's t tests or Wilcoxon's matched-pair test; p values <0.05 were considered significant. Improved New York Heart Association class, left ventricular ejection fraction, left atrial volume, right ventricular systolic pressure, and brain natriuretic peptide were observed after CRT (p <0.05 for all). Spirometry after CRT demonstrated increased percentage predicted total lung capacity (90 ± 17% vs 96 ± 15%, p <0.01) and percentage predicted forced vital capacity (80 ± 19% vs 90 ± 19%, p <0.01). Increased percentage predicted total lung capacity was significantly correlated with increased peak exercise end-tidal carbon dioxide (r = 0.43, p = 0.05). Increased percentage predicted forced vital capacity was significantly correlated with decreased right ventricular systolic pressure (r = -0.30, p = 0.05), body mass index (r = -0.35, p = 0.02) and creatinine (r = -0.49, p = 0.02), consistent with an association of improved bronchial conductance and decreased congestion. Diffusing capacity for carbon monoxide did not significantly change. In conclusion, increased lung volumes and bronchial conductance due to decreased pulmonary congestion and increased intrathoracic space contribute to an improved breathing pattern and decreased hyperventilation after CRT. Persistent alveolar-capillary membrane remodeling may account for unchanged diffusing capacity for carbon monoxide.

Capsule Endoscopy in Patients with Implantable Electromedical Devices is Safe.

Background and Study Aims. The presence of an implantable electromechanical cardiac device (IED) has long been considered a relative contraindication to the performance of video capsule endoscopy (CE). The primary aim of this study was to evaluate the safety of CE in patients with IEDs. A secondary purpose was to determine whether IEDs have any impact on images captured by CE. Patients and Methods. A retrospective chart review of all patients who had a capsule endoscopy at Mayo Clinic in Scottsdale, AZ, USA, or Rochester, MN, USA, (January 2002 to June 2010) was performed to identify CE studies done on patients with IEDs. One hundred and eighteen capsule studies performed in 108 patients with IEDs were identified and reviewed for demographic data, method of preparation, and study data. Results. The most common indications for CE were obscure gastrointestinal bleeding (77%), anemia (14%), abdominal pain (5%), celiac disease (2%), diarrhea (1%), and Crohn's disease (1%). Postprocedure assessments did not reveal any detectable alteration on the function of the IED. One patient with an ICD had a 25-minute loss of capsule imaging due to recorder defect. Two patients with LVADs had interference with capsule image acquisition. Conclusions. CE did not interfere with IED function, including PM, ICD, and/or LVAD and thus appears safe. Additionally, PM and ICD do not appear to interfere with image acquisition but LVAD may interfere with capsule images and require that capsule leads be positioned as far away as possible from the IED to assure reliable image acquisition.

Effect of pacing method on risk of sudden death after atrioventricular node ablation and pacemaker implantation in patients with atrial fibrillation.

BACKGROUND: Sudden death may occur after radiofrequency catheter ablation of the atrioventricular node (AVN) and permanent pacemaker implantation. It is unclear whether a faster initial heart rate with gradual rate reduction decreases the risk of sudden death. OBJECTIVE: To evaluate the effects of initial pacing at a faster rate after AVN ablation, with a gradual rate decrease over 3 months, on the rate of sudden death in patients with atrial fibrillation. METHODS: We compared the rate of likely or possible procedure-related sudden death in 2 groups of patients who had AVN ablation and pacemaker implantation. The study cohort was treated between January 2005 and December 2009, and pacemakers were programmed to a lower rate of 90 beats/min after the procedure, with a monthly decrement of 10 beats/min until 60 beats/min was reached. The control group was treated between July 1990 and December 1998 when pacemakers were programmed to a lower rate of 60 beats/min immediately after ablation. RESULTS: The study cohort included 520 patients (mean age 73.6 ± 10.3 years), and the control cohort comprised 334 patients (mean age 68.1 ± 1.1 years). Sudden death deemed likely or possibly related to ablation and pacemaker implantation occurred in 1 patient in the study cohort (0.2%) and in 7 patients (2.1%) in the control group (P = .007). CONCLUSIONS: Sudden death was significantly decreased in the study cohort compared to controls. The faster lower pacing rate immediately after AVN ablation with a gradual decrease is a plausible mechanism for the improved clinical outcome.