Association of a device-based remote management heart failure pathway with outcomes: TriageHF Plus real-world evaluation.

AIMS: Clinical pathways have been shown to improve outcomes in patients with heart failure (HF). Although patients with HF often have a cardiac implantable electronic device, few studies have reported the utility of device-derived risk scores to augment and organize care. TriageHF Plus is a device-based HF clinical pathway (DHFP) that uses remote monitoring alerts to trigger structured telephone assessment for HF stability and optimization. We aimed to evaluate the impact of TriageHF Plus on hospitalizations and describe the associated workforce burden. METHODS AND RESULTS: TriageHF Plus was a multi-site, prospective study that compared outcomes for patients recruited between April 2019 and February 2021. All alert-triggered assessments were analysed to determine the appropriateness of the alert and the workload burden. A negative-binomial regression with inverse probability treatment weighting using a time-matched usual care cohort was applied to estimate the effect of TriageHF Plus on non-elective hospitalizations. A post hoc pre-COVID-19 sensitivity analysis was also performed. The TriageHF Plus cohort (n = 443) had a mean age of 68.8 ± 11.2 years, 77% male (usual care cohort: n = 315, mean age of 66.2 ± 14.5 years, 65% male). In the TriageHF Plus cohort, an acute medical issue was identified following an alert in 79/182 (43%) cases. Fifty assessments indicated acute HF, requiring clinical action in 44 cases. At 30 day follow-up, 39/66 (59%) of initially symptomatic patients reported improvement, and 20 (19%) initially asymptomatic patients had developed new symptoms. On average, each assessment took 10 min. The TriageHF Plus group had a 58% lower rate of hospitalizations across full follow-up [incidence relative ratio: 0.42, 95% confidence interval (CI): 0.23-0.76, P = 0.004]. Across the pre-COVID-19 window, hospitalizations were 31% lower (0.69, 95% CI: 0.46-1.04, P = 0.077). CONCLUSIONS: These data represent the largest real-world evaluation of a DHFP based on multi-parametric risk stratification. The TriageHF Plus clinical pathway was associated with an improvement in HF symptoms and reduced all-cause hospitalizations.

Impact of maintaining serum potassium concentration ≥ 3.6mEq/L versus ≥ 4.5mEq/L for 120 hours after isolated coronary artery bypass graft surgery on incidence of new onset atrial fibrillation: Protocol for a randomized non-inferiority trial.

BACKGROUND: Atrial Fibrillation After Cardiac Surgery (AFACS) occurs in about one in three patients following Coronary Artery Bypass Grafting (CABG). It is associated with increased short- and long-term morbidity, mortality and costs. To reduce AFACS incidence, efforts are often made to maintain serum potassium in the high-normal range (≥ 4.5mEq/L). However, there is no evidence that this strategy is efficacious. Furthermore, the approach is costly, often unpleasant for patients, and risks causing harm. We describe the protocol of a planned randomized non-inferiority trial to investigate the impact of intervening to maintain serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on incidence of new-onset AFACS after isolated elective CABG. METHODS: Patients undergoing isolated CABG at sites in the UK and Germany will be recruited, randomized 1:1 and stratified by site to protocols maintaining serum potassium at either ≥ 3.6 mEq/L or ≥ 4.5 mEq/L. Participants will not be blind to treatment allocation. The primary endpoint is AFACS, defined as an episode of atrial fibrillation, flutter or tachycardia lasting ≥ 30 seconds until hour 120 after surgery, which is both clinically detected and electrocardiographically confirmed. Assuming a 35% incidence of AFACS in the 'tight control group', and allowing for a 10% loss to follow-up, 1684 participants are required to provide 90% certainty that the upper limit of a one-sided 97.5% confidence interval (CI) will exclude a > 10% difference in favour of tight potassium control. Secondary endpoints include mortality, use of hospital resources and incidence of dysrhythmias not meeting the primary endpoint (detected using continuous heart rhythm monitoring). DISCUSSION: The Tight K Trial will assess whether a protocol to maintain serum potassium ≥ 3.6 mEq/L is non inferior to maintaining serum potassium ≥ 4.5 mEq/L in preventing new-onset AFACS after isolated CABG. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04053816. Registered on 13 August 2019. Last update 7 January 2021.

Primary care heart failure service identifies a missed cohort of heart failure patients with reduced ejection fraction.

AIMS: We explored whether a missed cohort of patients in the community with heart failure (HF) and left ventricular systolic dysfunction (LVSD) could be identified and receive treatment optimization through a primary care heart failure (PCHF) service. METHODS AND RESULTS: PCHF is a partnership between Inspira Health, National Health Service Cardiologists and Medtronic. The PCHF service uses retrospective clinical audit to identify patients requiring a prospective face-to-face consultation with a consultant cardiologist for clinical review of their HF management within primary care. The service is delivered via five phases: (i) system interrogation of general practitioner (GP) systems; (ii) clinical audit of medical records; (iii) patient invitation; (iv) consultant reviews; and (v) follow-up. A total of 78 GP practices (864 194 population) have participated. In total, 19 393 patients' records were audited. HF register was 9668 (prevalence 1.1%) with 6162 patients coded with LVSD (prevalence 0.7%). HF case finder identified 9725 additional patients to be audited of whom 2916 patients required LVSD codes adding to the patient medical record (47% increase in LVSD). Prevalence of HF with LVSD increased from 0.7% to 1.05%. A total of 662 patients were invited for consultant cardiologist review at their local GP practice. The service found that within primary care, 27% of HF patients identified for a cardiologist consultation were eligible for complex device therapy, 45% required medicines optimization, and 47% of patients audited required diagnosis codes adding to their GP record. CONCLUSION: A PCHF service can identify a missed cohort of patients with HF and LVSD, enabling the optimization of prognostic medication and an increase in device prescription.

Maintenance of Serum Potassium Levels ≥3.6 mEq/L Versus ≥4.5 mEq/L After Isolated Elective Coronary Artery Bypass Grafting and the Incidence of New-Onset Atrial Fibrillation: Pilot and Feasibility Study Results.

OBJECTIVE: Serum potassium levels frequently are maintained at high levels (≥4.5 mEq/L) to prevent atrial fibrillation after cardiac surgery (AFACS), with limited evidence. Before undertaking a noninferiority randomized controlled trial to investigate the noninferiority of maintaining levels ≥3.6 mEq/L compared with this strategy, the authors wanted to assess the feasibility, acceptability, and safety of recruiting for such a trial. DESIGN: Pilot and feasibility study of full trial protocol. SETTING: Two university tertiary-care hospitals. PARTICIPANTS: A total of 160 individuals undergoing first-time elective isolated coronary artery bypass grafting. INTERVENTIONS: Randomization (1:1) to protocols aiming to maintain serum potassium at either ≥3.6 mEq/L or ≥4.5 mEq/L after arrival in the postoperative care facility and for 120 hours or until discharge from the hospital or AFACS occurred, whichever happened first. MEASUREMENTS AND MAIN RESULTS: Primary outcomes: (1) whether it was possible to recruit and randomize 160 patients for six months (estimated 20% of those eligible); (2) maintaining supplementation protocol violation rate ≤10% (defined as potassium supplementation being inappropriately administered or withheld according to treatment allocation after a serum potassium measurement); and (3) retaining 28-day follow-up rates ≥90% after surgery. Between August 2017 and April 2018, 723 patients were screened and 160 (22%) were recruited. Potassium protocol violation rate = 9.8%. Follow-up rate at 28 days = 94.3%. Data on planned outcomes for the full trial also were collected. CONCLUSIONS: It is feasible to recruit and randomize patients to a study assessing the impact of maintaining serum potassium concentrations at either ≥3.6 mEq/L or ≥4.5 mEq/L on the incidence of AFACS.

Inconsistent Methodology as a Barrier to Meaningful Research Outputs From Studies of Atrial Fibrillation After Cardiac Surgery.

Atrial fibrillation after cardiac surgery (AFACS) is a serious postoperative complication. There is significant research interest in this field but also relevant heterogeneity in reported AFACS definitions and approaches used for its identification. Few data exist on the extent of this variation in clinical studies. The authors reviewed the literature since 2001 and included manuscripts reporting outcomes of AFACS in adults. They excluded smaller studies and studies in which patients did not undergo a sternotomy. The documented protocol in each manuscript was analyzed according to six different categories to determine how AFACS was defined, which techniques were used to identify it, and the inclusion and/or exclusion criteria. They also noted when a category was not described in the documented protocol. The authors identified 302 studies, of which 92 were included. Sixty-two percent of studies were randomized controlled trials. There was significant heterogeneity in the manuscripts, including the exclusion of patients with preoperative AF, the definition and duration of AF needed to meet the primary endpoint, the type of screening approach (continuous, episodic, or opportunistic), the duration of monitoring during the study period in days, the diagnosis with predefined electrocardiogram criteria, and the requirement for independent confirmation by study investigators. Furthermore, the definitions of these criteria frequently were not described. Consistent reporting standards for AFACS research are needed to advance scientific progress in the field. The authors here propose pragmatic standards for trial design and reporting standards. These include adequate sample size estimation, a clear definition of the AFACS endpoints, and a protocol for AFACS detection.

Are Serum Potassium and Magnesium Levels Associated with Atrial Fibrillation After Cardiac Surgery?

OBJECTIVES: Potassium and magnesium are frequently administered after cardiac surgery to reduce the risk of atrial fibrillation (AF). The evidence for this practice is unclear. This study was designed to evaluate the relationship between serum potassium and magnesium levels and AF after cardiac surgery. DESIGN: Observational cohort study. SETTING: A cardiac intensive care unit in the United Kingdom. PARTICIPANTS: Patients undergoing cardiac surgery between January 2013 and November 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Cardiac rhythm was assessed using continuous electrocardiogram (ECG) monitoring in 3,068 patients on the cardiac intensive care unit. Associations between serum potassium and magnesium concentrations extracted from hospital databases and postoperative AF were assessed using univariable and multivariable analyses. The association between electrolyte supplementation therapy and AF was also analyzed. AF developed within 72 hours of cardiac surgery in 545 (17.8%) of the 3,068 patients. After adjusting for logistic EuroSCORE, surgery type, cardiopulmonary bypass time and age, mean serum potassium concentration <4.5 mmol/L was associated with an increased risk of AF (odds ratio [OR] 1.43 (95% confidence interval (CI): 1.17-1.75), p < 0.001). Mean magnesium concentration <1.0 mmol/L was not associated with an increased risk of AF (OR 0.89, 0.71-1.13, p = 0.342), but the administration of magnesium was associated with increased risk of developing AF (OR 1.61, 1.33-1.96, p < 0.001). CONCLUSIONS: Maintaining a serum potassium concentration ≥4.5 mmol/L after cardiac surgery may reduce the incidence of postoperative AF. Magnesium supplementation was associated with an increased risk of postoperative AF. Prospective randomized trials are required to clarify these associations.

New-Onset Atrial Fibrillation in Adult Patients After Cardiac Surgery.

PURPOSE OF REVIEW: An overview of recent literature regarding pathophysiology, risk factors, prophylaxis, and treatment of new-onset atrial fibrillation (AF) in post-cardiac surgical patients. RECENT FINDINGS: AF is the most frequent adverse event after cardiac surgery with significant associated morbidity, mortality, and financial cost. Its causes are multifactorial, and models to stratify patients into risk categories are progressing but a consistent, evidence-based system has not yet been developed. Pharmacologic and surgical interventions to prevent and treat this complication have been an area of ongoing research and recent societal guidelines reflect this. SUMMARY: Inconsistencies remain surrounding how to best identify higher-risk AF patients, which interventions should be used to prevent and treat AF, and which patient groups should receive these interventions. The evidence for these available strategies and their place in contemporary guidelines are summarized.

Brachial plexus impingement secondary to implantable cardioverter defibrillator: A case report.

Overall complication rates of 9.1% have been reported following implantable cardioverter defibrillator (ICD) placement. Brachial plexus injury is infrequently reported in the literature. We describe a 26-year-old female experiencing left arm nerve pain, a positive Tinel's sign, numbness in the median nerve distribution of the hand and biceps muscle weakness following revision ICD via subclavian vein approach. Nerve conduction studies identified severe partial left brachial plexopathy, which remained incompletely resolved with conservative management. Surgical exploration revealed lateral cord impingement by the ICD generator and a loop of the ICD lead, along with fibrosis, necessitating surgical neurolysis and ICD generator repositioning. As increasing numbers of patients undergo cardiac device implantation, it is incumbent on practitioners to be aware of potential increases in the prevalence of this complication.

The impact of maintaining serum potassium ≥3.6 mEq/L vs ≥4.5 mEq/L on the incidence of new-onset atrial fibrillation in the first 120 hours after isolated elective coronary artery bypass grafting - study protocol for a randomised feasibility trial for the proposed Tight K randomized non-inferiority trial.

BACKGROUND: Atrial fibrillation (AF) occurs in approximately one in three patients after cardiac surgery, and is associated with increased short-term and long-term mortality, intensive care unit (ICU) and hospital stay, and increased cost of care. In an attempt to reduce AF incidence in these patients, serum potassium (K+) levels are commonly maintained at the high end of normal (4.5-5.5 mEq/L). However, such potassium supplementation is without proven benefit, and is not without negative consequences. It carries clinical risk, negatively impacts patient experience and is both time-consuming and costly. This protocol describes a randomised controlled pilot trial to assess the feasibility of a proposed randomised non-inferiority trial to investigate the impact of maintaining serum potassium ≥ 3.6 mEq/L vs ≥ 4.5 mEq/L on the incidence of new-onset atrial fibrillation in the first 120 hours after isolated elective coronary artery bypass grafting. METHODS: Design: this is a randomized feasibility trial as a pilot for a randomized non-inferiority trial. PARTICIPANTS: are 160 patients undergoing isolated coronary artery bypass grafting at two centres. Allocation: patients will be randomized (1:1) to protocols aiming to maintain serum potassium at either ≥ 3.6 mEq/L ("relaxed control") or ≥ 4.5 mEq/L ("tight control"). Primary analytic aim: was to assess the feasibility and acceptability of planning and delivering the intervention and trial methods to inform a full-scale non-inferiority trial. OUTCOME: the primary indicative efficacy outcome measures being field-tested are feasibility of participant recruitment and randomization, maintaining a protocol violation rate < 10%, and retaining 90% patient follow up 28 days after surgery. The primary clinical outcome measure of the future full "Tight K Study" will be incidence of AF after cardiac surgery. DISCUSSION: The Tight K Pilot will assess the feasibility of conducting the full trial, which is intended to confirm or refute the efficacy of current potassium management in preventing AF after cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03195647 . Registered on 23 May 2017. Last updated 19June 2017.

Chronic total occlusion in an infarct-related coronary artery and the risk of appropriate ICD therapies.

INTRODUCTION: Risk stratification for ventricular arrhythmias in patients with ischemic cardiomyopathy needs to be improved. Coronary chronic total occlusions in an infarct-related artery (IRA-CTOs) have been associated with an increased arrhythmic risk. This study aimed to evaluate the association between IRA-CTOs and appropriate implantable cardioverter-defibrillator (ICD) therapies. METHODS AND RESULTS: Observational cohort study that included 342 patients with ischemic cardiomyopathy, an ICD implanted for primary or secondary prevention, and a coronary angiography performed shortly before ICD implantation. The ICD was implanted for primary prevention in 163 patients (48%). IRA-CTO was found in 161 patients (47%). During a median follow-up of 33 months, 41% of patients experienced at least one appropriate ICD therapy. Patients with IRA-CTO had higher proportions of appropriate ICD therapies (57% vs. 26%, P < 0.001) and appropriate ICD shocks (40% vs. 17%, P < 0.001). At multivariate Cox regression, IRA-CTO was the only variable that consistently resulted as independent predictor of appropriate ICD therapies and shocks both in the global population of the study (HR 2.3, P < 0.001 and HR 3, P < 0.001, respectively) and when analyzing separately patients with primary or secondary prevention ICD. CONCLUSIONS: IRA-CTO is an independent predictor of appropriate ICD therapies, including appropriate ICD shocks. This association is consistent across all the subgroups analyzed. Patients with IRA-CTO have a very high risk of appropriate ICD therapies. These findings may help improving risk stratification as well as the management of ventricular arrhythmias in patients with ischemic cardiomyopathy.

Late Gadolinium Enhancement and the Risk for Ventricular Arrhythmias or Sudden Death in Dilated Cardiomyopathy: Systematic Review and Meta-Analysis.

OBJECTIVES: The aim of this study was to evaluate the association between late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging and ventricular arrhythmias or sudden cardiac death (SCD) in patients with dilated cardiomyopathy (DCM). BACKGROUND: Risk stratification for SCD in DCM needs to be improved. METHODS: A systematic review and meta-analysis were conducted. A systematic search of PubMed and Ovid was performed, and observational studies that analyzed the arrhythmic endpoint (sustained ventricular arrhythmia, appropriate implantable cardioverter-defibrillator [ICD] therapy, or SCD) in patients with DCM, stratified by the presence or absence of LGE, were included. RESULTS: Twenty-nine studies were included, accounting for 2,948 patients. The studies covered a wide spectrum of DCM, with a mean left ventricular ejection fraction between 20% and 43%. LGE was significantly associated with the arrhythmic endpoint both in the overall population (odds ratio: 4.3; p < 0.001) and when including only those studies that performed multivariate analysis (hazard ratio: 6.7; p < 0.001). The association between LGE and the arrhythmic endpoint remained significant among studies with mean left ventricular ejection fractions >35% (odds ratio: 5.2; p < 0.001) and was maximal in studies that included only patients with primary prevention ICDs (odds ratio: 7.8; p = 0.008). CONCLUSIONS: Across a wide spectrum of patients with DCM, LGE is strongly and independently associated with ventricular arrhythmia or SCD. LGE could be a powerful tool to improve risk stratification for SCD in patients with DCM. These results raise 2 major questions to be addressed in future studies: whether patients with LGE could benefit from primary prevention ICDs irrespective of their left ventricular ejection fractions, while patients without LGE might not need preventive ICDs despite having severe left ventricular dysfunction.

Cell Size Critically Determines Initial Retention of Bone Marrow Mononuclear Cells in the Heart after Intracoronary Injection: Evidence from a Rat Model.

Intracoronary injection of bone marrow mononuclear cells (BMMNC) is an emerging treatment for heart failure. Initial donor cell retention in the heart is the key to the success of this approach, but this process remains insufficiently characterized. Although it is assumed that cell size of injected cells may influence their initial retention, no scientific evidence has been reported. We developed a unique model utilizing an ex-vivo rat heart perfusion system, enabling quantitative assessment of retention of donor cells after intracoronary injection. The initial (5 minutes after intracoronary injection) retention rate of BMMNC was as low as approximately 20% irrespective of donor cell doses injected (1×106, 8×106, 4×107). Quantitative cell-size assessment revealed a positive relationship between the size of BMMNC and retention ratio; larger subpopulations of BMMNC were more preferentially retained compared to smaller ones. Furthermore, a larger cell type-bone marrow-derived mesenchymal stromal cells (median size = 11.5µm versus 7.0µm for BMMNC)-had a markedly increased retention rate (77.5±1.8%). A positive relationship between the cell size and retention ratio was also seen in mesenchymal stromal cells. Flow-cytometric studies showed expression of cell-surface proteins, including integrins and selectin-ligands, was unchanged between pre-injection BMMNC and those exited from the heart, suggesting that biochemical interaction between donor cells and host coronary endothelium is not critical for BMMNC retention. Histological analyses showed that retained BMMNC and mesenchymal stromal cells were entrapped in the coronary vasculature and did not extravasate by 60 minutes after transplantation. Whilst BMMNC did not change coronary flow after intracoronary injection, mesenchymal stromal cells reduced it, suggesting coronary embolism, which was supported by the histological finding of intravascular cell-clump formation. These data indicate that cell-size dependent, passive (mechanical), intravascular entrapment is responsible for the initial donor cell retention after intracoronary injection of BMMNC in the heart having normal vasculatures (at least).

The lung impedance monitoring in treatment of chronic heart failure (the LIMIT-CHF study).

AIMS: To assess the usefulness of intrathoracic impedance monitoring (IIM) alerts in guiding empirical treatment of chronic heart failure (CHF) patients to prevent heart failure (HF) hospitalizations and unplanned HF care. METHODS AND RESULTS: Chronic heart failure patients with OptiVol or CorVue capable implantable cardioverter-defibrillators were randomized to either the active group (IIM alarm turned on and diuretic dose increased by 50% for 1 week in the event of alarm sounding) or the control group (IIM alarm turned off). The primary endpoint was the number of HF hospitalizations per patient at 1 year. The NYHA class, 6MWT, B-type natriuretic peptide (BNP), and MLWHF questionnaire score were collected at baseline and follow-up. Eighty patients were included and 71 reached 1-year follow-up. There were 1.7 ± 1.5 alerts in the active group and 1.1 ± 1.0 in the control group, P = 0.07. In the active group, 61% of alerts led to a diuretic dose increase. There was a total of 11 HF hospitalizations in the active group vs. 6 in the control group without significant differences in the number of episodes per patient (0.3 ± 0.9 vs. 0.2 ± 0.4, P = 0.95). There were no unplanned HF visits in the active group vs. 0.1 ± 0.3 per patient in the control group, P = 0.08. The total MLWHF scores were significantly increased at the final follow-up in the control group, whereas a trend towards reduction was observed in the active group. CONCLUSION: In this study, an empirical HF treatment guided by IIM alerts did not reduce emergency treatment of HF. However, it seems to have a positive impact on quality of life. CLINICAL TRIAL REGISTRATIONURL: http://www.clinicaltrials.gov. Unique identifier: NCT01320007.

A highly effective technique for transseptal endocardial left ventricular lead placement for delivery of cardiac resynchronization therapy.

BACKGROUND: Implantation of a left ventricular (LV) lead fails in 5% to 10% of patients in whom cardiac resynchronization therapy (CRT) is attempted. Alternatives for delivery of CRT are surgical epicardial and endocardial transvenous leads. Endocardial transseptal LV lead delivery is challenging because of the absence of dedicated equipment designed for this procedure. OBJECTIVE: The purpose of this study was to describe a new technique for delivery of a transseptal LV lead. METHODS: This dual approach from the right femoral vein and left subclavian vein involves use of an Endrys transseptal needle and Mullins sheath to deliver a gooseneck snare from the left subclavian vein into the right atrium that can then be used to deliver a deflectable sheath into the left atrium. An active fixation lead is advanced into the LV through the sheath and screwed into the lateral wall. RESULTS: The procedure was performed successfully in 12 patients in whom transvenous LV lead implantation had previously failed. The Endrys transseptal needle, ideally suited for this technique, facilitated passage of the gooseneck snare into the left atrium with no difficulty. Median procedure time was 148 minutes (interquartile range [IQR] 113-176 minutes), and median fluoroscopy time was 16 minutes (IQR 10-19 minutes). There was no need for repeat procedures after median follow-up of 97 days (IQR 36-313 days). CONCLUSION: This approach using an Endrys needle and a gooseneck snare provides a reliable and effective alternative technique for delivery of an endocardial LV lead that is delivered easily through a deflectable sheath inserted transseptally into the LV.

Predictors of new onset atrial fibrillation in patients with heart failure.

INTRODUCTION: Stroke associated with atrial fibrillation (AF) is more frequent in heart failure. It is unknown what variables predict future AF in these patients and how AF might evolve over time. We investigated this in patients with implantable cardiac defibrillators (ICD) where AF detection is optimal. METHODS: Single centre, retrospective, observational cohort study. All ischaemic cardiomyopathy patients with dual chamber, primary prevention ICD implants between Aug 2003 and Dec 2009 were screened and included if at implant, they had no known AF history. Nine variables were analysed. AF was defined as any atrial tachyarrhythmia ≥180 bpm and ≥30 s. Multivariable, binary logistic regression models were built by adding variables significant in the univariate models. Variables were retained in the final multivariate models if p<0.05. RESULTS: n=197 met the inclusion criteria (85.8% male, median age: 66.8 years). After median follow-up for 2.8 years, 44.2% developed AF. After univariate analysis, the baseline variables associated with AF after implant were age, NYHA class and renal impairment (RI, defined eGFR<60 ml/min/1.73 m2) (p<0.05). After multivariable analysis, the only variable which was associated with AF was RI (HR: 2.04 (CI: 1.10-3.79)). Two baseline variables were independently associated with all-cause mortality: RI (HR: 2.42 (1.14-5.12)) and non-white ethnicity. CONCLUSION: RI at time of implant was independently associated with both future AF and all-cause mortality during long-term follow-up. RI was a stronger predictor of AF than age. Those patients with heart failure and RI should be regularly screened for asymptomatic AF, regardless of age, to ensure that stroke prophylaxis may be initiated.

Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study.

Transplantation of bone marrow mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure. We have reported that epicardial placement of MSC-sheets generated using temperature-responsive dishes markedly increases donor MSC survival and augments therapeutic effects in an acute myocardial infarction (MI) model, compared to intramyocardial (IM) injection. This study aims to expand this knowledge for the treatment of ischemic cardiomyopathy, which is likely to be more difficult to treat due to mature fibrosis and chronically stressed myocardium. Four weeks after MI, rats underwent either epicardial MSC-sheet placement, IM MSC injection, or sham treatment. At day 28 after treatment, the cell-sheet group showed augmented cardiac function improvement, which was associated with over 11-fold increased donor cell survival at both days 3 and 28 compared to IM injection. Moreover, the cell-sheet group showed improved myocardial repair, in conjunction with amplified upregulation of a group of reparative factors. Furthermore, by comparing with our own previous data, this study highlighted similar dynamics and behavior of epicardially placed MSCs in acute and chronic stages after MI, while the acute-phase myocardium may be more responsive to the stimuli from donor MSCs. These proof-of-concept data encourage further development of the MSC-sheet therapy for ischemic cardiomyopathy toward clinical application.

The use of scaffold-free cell sheet technique to refine mesenchymal stromal cell-based therapy for heart failure.

Transplantation of bone marrow-derived mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure based on their secretion-mediated "paracrine effects". Feasibility of the scaffoldless cell sheet technique to enhance the outcome of cell transplantation has been reported using other cell types, though the mechanism underpinning the enhancement remains uncertain. We here investigated the role of this innovative technique to amplify the effects of MSC transplantation with a focus on the underlying factors. After coronary artery ligation in rats, syngeneic MSCs were grafted by either epicardial placement of MSC sheets generated using temperature-responsive dishes or intramyocardial (IM) injection. Markedly increased initial retention boosted the presence of donor MSCs persistently after MSC sheet placement although the donor survival was not improved. Most of the MSCs grafted by the cell sheet technique remained resided on the epicardial surface, but the epicardium quickly regressed and new vessels sprouted into the sheets, assuring the permeation of paracrine mediators from MSCs into the host myocardium. In fact, there was augmented upregulation of various paracrine effect-related genes and signaling pathways in the early phase after MSC sheet therapy. Correspondingly, more extensive paracrine effects and resultant cardiac function recovery were achieved by MSC sheet therapy. Further development of this approach towards clinical application is encouraged.

The use of cell-sheet technique eliminates arrhythmogenicity of skeletal myoblast-based therapy to the heart with enhanced therapeutic effects.

BACKGROUND: Clinical application of skeletal myoblast transplantation has been curtailed due to arrhythmogenicity and inconsistent therapeutic benefits observed in previous studies. However, these issues may be solved by the use of a new cell-delivery mode. It is now possible to generate "cell-sheets" using temperature-responsive dishes without artificial scaffolds. This study aimed to validate the safety and efficacy of epicardial placement of myoblast-sheets (myoblast-sheet therapy) in treating heart failure. METHODS AND RESULTS: After coronary artery ligation in rats, the same numbers of syngeneic myoblasts were transplanted by intramyocardial injection or cell-sheet placement. Continuous radio-telemetry monitoring detected increased ventricular arrhythmias, including ventricular tachycardia, after intramyocardial injection compared to the sham-control, while these were abolished in myoblast-sheet therapy. This effect was conjunct with avoidance of islet-like cell-cluster formation that disrupts electrical conduction, and with prevention of increased arrhythmogenic substrates due to exaggerated inflammation. Persistent ectopic donor cells were found in the lung only after intramyocardial injection, strengthening the improved safety of myoblast-sheet therapy. In addition, myoblast-sheet therapy enhanced cardiac function, corresponding to a 9.2-fold increase in donor cell survival, compared to intramyocardial injection. Both methods achieved reduced infarct size, decreased fibrosis, attenuated cardiomyocyte hypertrophy, and increased neovascular formation, in association with myocardial upregulation of a group of relevant molecules. The pattern of these beneficial changes was similar between two methods, but the degree was more substantial after myoblast-sheet therapy. CONCLUSION: The cell-sheet technique enhanced safety and therapeutic efficacy of myoblast-based therapy, compared to the current method, thereby paving the way for clinical application.

Cell delivery routes for stem cell therapy to the heart: current and future approaches.

An important factor to determine the success of stem cell therapy to the heart is the choice of cell delivery route. This will affect the fate of donor cells and subsequently influence the outcome of treatment; however, there is currently no optimum cell delivery route appropriate for every disease condition or every donor cell type. This review summarises currently available approaches for administering cells to the heart, with a particular focus on cell retention/survival and the therapeutic benefits seen in preclinical and clinical studies. Two major approaches are intracoronary and intramyocardial injection, which have been widely used for the delivery of various types of cells. Although there are advantages to both approaches, donor cell retention and survival are poor using these methods, potentially limiting therapeutic effects. Various attempts to improve current approaches, along with the development of emerging new approaches, are also described and discussed in this review.