Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Patient Characteristics, Outcomes, and Effects of Dapagliflozin According to the Duration of Heart Failure: A Prespecified Analysis of the DELIVER Trial.

BACKGROUND: How patient characteristics and outcomes vary according to the duration of heart failure (HF) is unknown in individuals with mildly reduced or preserved ejection fraction. We compared these, and the efficacy and safety of dapagliflozin, according to the time from diagnosis of HF in a prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). METHODS: HF duration was categorized as ≤6 months, >6 to 12 months, >1 to 2 years, >2 to 5 years, or >5 years. The primary outcome was the composite of worsening HF or cardiovascular death. The effect of treatment was examined by HF duration category. RESULTS: The number of patients in each category was as follows: 1160 (≤6 months), 842 (>6 to 12 months), 995 (>1 to 2 years), 1569 (>2 to 5 years), and 1692 (>5 years). Patients with longer-duration HF were older and had more comorbidities with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: ≤6 months, 7.3 (95% CI, 6.3 to 8.4); >6 to 12 months, 7.1 (6.0 to 8.5); >1 to 2 years, 8.4 (7.2 to 9.7); >2 to 5 years, 8.9 (7.9 to 9.9); and >5 years, 10.6 (9.5 to 11.7). Similar trends were seen for other outcomes. The benefit of dapagliflozin was consistent across HF duration category: the hazard ratio for the primary outcome in the ≤6-month group was 0.67 (95% CI, 0.50 to 0.91); >6 to 12 months, 0.78 (0.55 to 1.12); >1 to 2 years, 0.81 (0.60 to 1.09); >2 to 5 years, 0.97 (0.77 to 1.22); and >5 years, 0.78 (0.64 to 0.96; Pinteraction=0.41). The absolute benefit was greatest in longest-duration HF; the number needed to treat for HF >5 years was 24 versus 32 for ≤6 months. CONCLUSIONS: Patients with longer-duration HF were older, had more comorbidities and symptoms, and had higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. Even patients with long-standing HF and generally mild symptoms are not stable, and it is not too late for such patients to benefit from a sodium-glucose cotransporter 2 inhibitor. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03619213.

Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

Call for Action to Target Interhospital Variation in Cardiovascular Mortality, Readmissions, and Length-of-Stay: Results of a National Population Analysis.

BACKGROUND: Excessive interhospital variation threatens healthcare quality. Data on variation in patient outcomes across the whole cardiovascular spectrum are lacking. We aimed to examine interhospital variability for 28 cardiovascular All Patient Refined-Diagnosis-related Groups (APR-DRGs). METHODS: We studied 103,299 cardiovascular admissions in 99 (98%) Belgian acute-care hospitals between 2012 and 2018. Using generalized linear mixed models, we estimated hospital-specific and APR-DRG-specific risk-standardized rates for in-hospital mortality, 30-day readmissions, and length-of-stay above the APR-DRG-specific 90th percentile. Interhospital variation was assessed based on estimated variance components and time trends between the 2012-2014 and 2016-2018 periods were examined. RESULTS: There was strong evidence of interhospital variation, with statistically significant variation across the 3 outcomes for 5 APR-DRGs after accounting for patient and hospital factors: percutaneous cardiovascular procedures with acute myocardial infarction, heart failure, hypertension, angina pectoris, and arrhythmia. Medical diagnoses, with in particular hypertension, heart failure, angina pectoris, and cardiac arrest, showed strongest variability, with hypertension displaying the largest median odds ratio for mortality (2.51). Overall, hospitals performing at the upper-quartile level should achieve improvements to the median level, and an annual 633 deaths, 322 readmissions, and 1578 extended hospital stays could potentially be avoided. CONCLUSIONS: Analysis of interhospital variation highlights important outcome differences that are not explained by known patient or hospital characteristics. Targeting variation is therefore a promising strategy to improve cardiovascular care. Considering their treatment in multidisciplinary teams, policy makers, and managers should prioritize heart failure, hypertension, cardiac arrest, and angina pectoris improvements by targeting guideline implementation outside the cardiology department.

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study.

BACKGROUND: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. METHODS: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. RESULTS: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). CONCLUSIONS: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.

Community pharmacists' perceptions on multidisciplinary heart failure care: an exploratory qualitative study.

BACKGROUND: Heart failure (HF) is an important health problem and guidelines recommend multidisciplinary management. The pharmacist is an important member of the multidisciplinary heart failure team, both in the hospital and community setting. This study aims to explore the perceptions of community pharmacists on their role in HF care. METHODS: We conducted a qualitative study based on face-to-face semi-structured interviews with 13 Belgian community pharmacists between September 2020 and December 2020. We used the Qualitative Analysis Guide of Leuven (QUAGOL) method as guidance for data analysis until data saturation was reached. We structured interview content into a thematic matrix. RESULTS: We identified two major themes: heart failure management and multidisciplinary management. Pharmacists feel responsible for the pharmacological and non-pharmacological management of heart failure, citing easy access and pharmacological expertise as important assets. Diagnostic uncertainty, lack of knowledge and time, disease complexity and difficulties in communication with patients and informal care providers are barriers to optimal management. General practitioners are the most important partners in multidisciplinary community heart failure management, although pharmacists perceive a lack of appreciation and cooperation and deplore communication difficulties. They feel intrinsically motivated to provide extended pharmaceutical care in HF but cite the lack of financial viability and information sharing structures as important barriers. CONCLUSION: The importance of pharmacist involvement in multidisciplinary heart failure teams is undisputed by Belgian pharmacists, who cite easy access and pharmacological expertise as important assets. They point out several barriers impeding evidence-based pharmacist care for outpatients with heart failure: diagnostic uncertainty and disease complexity, lack of multidisciplinary information technology and insufficient resources. We recommend that future policy should focus on improved medical data exchanges between primary and secondary care electronic health records as well as the reinforcement of interprofessional relationships between locally affiliated pharmacists and general practitioners.

Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

AIMS: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. METHODS AND RESULTS: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated. CONCLUSION: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.

Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction.

BACKGROUND: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function. METHODS: Collagen1α1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing. RESULTS: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-ß signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. CONCLUSIONS: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies CTHRC1 as a novel regulator of the healing scar process and a target for future translational studies.

AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. METHODS: Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism. RESULTS: Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. CONCLUSION: In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Exercise capacity, muscle strength and objectively measured physical activity in patients after heart transplantation.

Maximal exercise capacity of patients after heart transplantation (HTX) remains limited, affecting their quality of life. Evidence on the evolution of muscle strength and physical activity (PA) post-HTX is lacking, but a prerequisite to tailor cardiac rehabilitation programmes. Forty-five consecutive patients were evaluated every 3 months during the first year post-HTX. Functional exercise capacity (Six minutes walking distance test (6MWD)), peripheral (Quadriceps strength (QF)) and respiratory (Maximal inspiratory strength (MIP)) muscle strength were evaluated. PA (number of steps (PAsteps), active time (PAactive) and sedentary time (PAsed)) was objectively measured. 6MWD, QF, MIP, PAsteps and PAactive significantly improved over time (P < 0.001). No change in PAsed was noticed (P = 0.129). Despite improvements in 6MWD and QF, results remained substantially below those of age-and gender-matched healthy subjects. One year post-HTX, 30% of patients presented with peripheral muscle weakness. Baseline levels of 6MWD and QF were significantly higher in patients with pretransplant LVAD-implantation and this difference was maintained during follow-up. cardiac rehabilitation, combining aerobic exercise training and peripheral muscle strength training, is mandatory in patients post-HTX. Inspiratory muscle training should be implemented when respiratory muscle weakness is present. Programmes improving physical activity and reducing sedentary time post-HTX are essential.

Cardiologists' perceptions on multidisciplinary collaboration in heart failure care - a qualitative study.

BACKGROUND: Cardiologists play a key role in multidisciplinary care by guiding heart failure (HF) management in the hospital and in the community. Regional implementation of multidisciplinary health care interventions depends on how they perceive collaboration with other health care disciplines, yet research on this topic is limited. This study aimed to explore the views and opinions of cardiologists on multidisciplinary collaboration in HF care. METHODS: We conducted a qualitative study based on face-to-face semi-structured interviews with 11 Belgian cardiologists between September 2019 and February 2020. We used the Qualitative Analysis Guide of Leuven (QUAGOL) method as guidance for data analysis until data saturation was reached. RESULTS: Cardiologists consider the general practitioner (GP) and HF nurse as the most important partners in HF management. Cardiologists identified four problems in current multidisciplinary collaboration: the communication of a HF diagnosis to the patient, advanced care planning, titration of HF medication by the GP and electronic data exchange and communication. Three themes emerged as ideas for improvement of HF care: 1) expansion of the role of the HF nurse, 2) implementation of a structured, patient-centered, and flexible model of disease management program and 3) integrated data approaches. CONCLUSION: Cardiologists value close cooperation with GPs in HF management. They advocate an expanded future role for the HF nurse, increased eHealth, and structured disease management to optimize current HF care.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

AIMS: Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. METHODS AND RESULTS: Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. CONCLUSIONS: Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction.

RATIONALE: Allogeneic cardiac stem cells (AlloCSC-01) have shown protective, immunoregulatory, and regenerative properties with a robust safety profile in large animal models of heart disease. OBJECTIVE: To investigate the safety and feasibility of early administration of AlloCSC-01 in patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS: CAREMI (Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With STEMI and Left Ventricular Dysfunction) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial in patients with ST-segment-elevation myocardial infarction, left ventricular ejection fraction ≤45%, and infarct size ≥25% of left ventricular mass by cardiac magnetic resonance, who were randomized (2:1) to receive AlloCSC-01 or placebo through the intracoronary route at days 5 to 7. The primary end point was safety and included all-cause death and major adverse cardiac events at 30 days (all-cause death, reinfarction, hospitalization because of heart failure, sustained ventricular tachycardia, ventricular fibrillation, and stroke). Secondary safety end points included major adverse cardiac events at 6 and 12 months, adverse events, and immunologic surveillance. Secondary exploratory efficacy end points were changes in infarct size (percentage of left ventricular mass) and indices of ventricular remodeling by magnetic resonance at 12 months. Forty-nine patients were included (92% male, 55±11 years), 33 randomized to AlloCSC-01 and 16 to placebo. No deaths or major adverse cardiac events were reported at 12 months. One severe adverse events in each group was considered possibly related to study treatment (allergic dermatitis and rash). AlloCSC-01 elicited low levels of donor-specific antibodies in 2 patients. No immune-related adverse events were found, and no differences between groups were observed in magnetic resonance-based efficacy parameters at 12 months. The estimated treatment effect of AlloCSC-01 on the absolute change from baseline in infarct size was -2.3% (95% confidence interval, -6.5% to 1.9%). CONCLUSIONS: AlloCSC-01 can be safely administered in ST-segment-elevation myocardial infarction patients with left ventricular dysfunction early after revascularization. Low immunogenicity and absence of immune-mediated events will facilitate adequately powered studies to demonstrate their clinical efficacy in this setting. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.

Qualitative and quantitative analysis of diffusion-weighted brain MR imaging in comatose survivors after cardiac arrest.

PURPOSE: The aim of this study is to compare a qualitative and a quantitative assessment of brain diffusion-weighted imaging (DWI) in predicting outcome of comatose patients after cardiac arrest (CA). METHODS: Two observers used a scoring template to analyze the DWI of 75 patients. A total of 13 regions were scored from 0 to 3 (0 = normal, 1 = probably normal, 2 = probably abnormal, 3 = definitely abnormal). The total cerebral cortex (TCC), the total deep grey nuclei (TDGN), the total brain stem, the total cerebellum, and the total brain score were calculated. Intra- and inter-observer variability were tested. The mean whole brain apparent diffusion coefficient (ADC) values and percentage of voxels below a specific ADC value cut-off were calculated. The data were correlated with clinical outcome (cerebral performance category score after 180 days, dichotomized in a score 1-2 with favorable outcome and score 3-5 with unfavorable outcome) using ROC analysis. RESULTS: Intra-observer variability was excellent for the TCC score (ICC 0.95 and 0.86) and the TDGN score (ICC 0.89 and 0.75). Inter-observer variability was good to excellent for total cerebral cortex score and total deep grey nuclei score in both the first (ICC 0.78 and 0.69) and third (ICC 0.86 and 0.83) image assessment. TCC and TDGN score show the best correlation with clinical outcome (highest AUC values 0.87 and 0.87). Quantitative parameters did not show good correlation with clinical outcome (AUC values 0.57 and 0.60). CONCLUSION: A qualitative assessment of brain DWI using a scoring template provides useful data regarding patient outcome while quantitative data appeared less reliable.

Early goal-directed haemodynamic optimization of cerebral oxygenation in comatose survivors after cardiac arrest: the Neuroprotect post-cardiac arrest trial.

AIMS: During the first 6-12 h of intensive care unit (ICU) stay, post-cardiac arrest (CA) patients treated with a mean arterial pressure (MAP) 65 mmHg target experience a drop of the cerebral oxygenation that may cause additional cerebral damage. Therefore, we investigated whether an early goal directed haemodynamic optimization strategy (EGDHO) (MAP 85-100 mmHg, SVO2 65-75%) is safe and could improve cerebral oxygenation, reduce anoxic brain damage, and improve outcome when compared with a MAP 65 mmHg strategy. METHODS AND RESULTS: A total of 112 out-of-hospital CA patients were randomly assigned to EGDHO or MAP 65 mmHg strategies during the first 36 h of ICU stay. The primary outcome was the extent of anoxic brain damage as quantified by the percentage of voxels below an apparent diffusion coefficient (ADC) score of 650.10-6 mm2/s on diffusion weighted magnetic resonance imaging (at day 5 ± 2 post-CA). Main secondary outcome was favourable neurological outcome (CPC score 1-2) at 180 days. In patients assigned to EGDHO, MAP (P < 0.001), and cerebral oxygenation during the first 12 h of ICU stay (P = 0.04) were higher. However, the percentage of voxels below an ADC score of 650.10-6 mm2/s did not differ between both groups [16% vs. 12%, odds ratio 1.37, 95% confidence interval (CI) 0.95-0.98; P = 0.09]. Also, the number of patients with favourable neurological outcome at 180 days was similar (40% vs. 38%, odds ratio 0.98, 95% CI 0.41-2.33; P = 0.96). The number of serious adverse events was lower in patients assigned to EGDHO (P = 0.02). CONCLUSION: Targeting a higher MAP in post-CA patients was safe and improved cerebral oxygenation but did not improve the extent of anoxic brain damage or neurological outcome.

Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction).

RATIONALE: Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. OBJECTIVE: In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. METHODS AND RESULTS: With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. CONCLUSIONS: This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging-based efficacy end points. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439398.

Urinary peptidomic biomarkers of renal function in heart transplant recipients.

BACKGROUND: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). METHODS: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. RESULTS: In multivariable Bonferroni-corrected analyses of the baseline data, a 1-SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable-adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit α (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. CONCLUSIONS: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction.

General practitioners' perceptions about their role in current and future heart failure care: an exploratory qualitative study.

BACKGROUND: A comprehensive disease management programme (DMP) with a central role for general practitioners (GPs) is needed to improve heart failure (HF) care. However, previous research has shown that GPs have mixed experiences with multidisciplinary HF care. Therefore, in this study, we explore the perceptions that GPs have regarding their role in current and future HF care, prior to the design of an HF disease management programme. METHODS: This was a qualitative semi-structured interview study with Belgian GPs until data saturation was reached. The QUAGOL method was used for data analysis. RESULTS: In general, GPs wanted to assume a central role in HF care. Current interdisciplinary collaboration with cardiologists was perceived as smooth, partly because of the ease of access. In contrast, due to less well-established communication and the variable knowledge of nurses regarding HF care, collaboration with home care nurses was perceived as suboptimal. With regard to the future organization of HF care, all GPs confirmed the need for a structured chronic care approach and envisioned this as a multidisciplinary care pathway: flexible, patient-centred, without additional administration and with appropriate delegation of some critical tasks, including education and monitoring. GPs considered all-round general practice nurses as the preferred partner to delegate tasks to in HF care and reported limited experience in collaborating with specialist HF nurses. CONCLUSION: GPs expressed the need for a protocol-driven care pathway in chronic HF care. However, in contrast to the existing care trajectories, this pathway should be flexible, without additional administrative burdens and with a central role for GPs.