Efficacy and safety of angiotensin II in cardiogenic shock: A systematic review.

BACKGROUND: Cardiogenic shock (CS) is associated with high morbidity and mortality. In recent times, there is increasing interest in the role of angiotensin II in CS. We sought to systematically review the current literature on the use of angiotensin II in CS. METHODS: PubMed, EMBASE, Medline, Web of Science, PubMed Central, and CINAHL databases were systematically searched for studies that evaluated the efficacy of angiotensin II in patients with CS during 01/01/2010-07/07/2022. Outcomes of interest included change in mean arterial pressure (MAP), vasoactive medication requirements (percent change in norepinephrine equivalent [NEE] dose), all-cause mortality, and adverse events. RESULTS: Of the total 2,402 search results, 15 studies comprising 195 patients were included of which 156 (80%) received angiotensin II. Eleven patients (84.6%) in case reports and case series with reported MAP data at hour 12 noted an increase in MAP. Two studies noted a positive hemodynamic response (defined a priori) in eight (88.9%) and five (35.7%) patients. Eight studies reported a reduction in NEE dose at hour 12 after angiotensin II administration and one study noted a 100% reduction in NEE dose. Out of 47 patients with documented information, 13 patients had adverse outcomes which included hepatic injury (2), digital ischemia (1), ischemic optic neuropathy (1), ischemic colitis (2), agitated delirium (1), and thrombotic events (2). CONCLUSIONS: In this first systematic review of angiotensin II in CS, we note the early clinical experience. Angiotensin II was associated with improvements in MAP, decrease in vasopressor requirements, and minimal reported adverse events.

Impact of prior coronary artery bypass grafting on periprocedural and short-term outcomes of patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis.

BACKGROUND: The effect of prior coronary artery bypass graft (CABG) on the outcomes of transcatheter aortic valve replacement (TAVR) remains incompletely characterized. In this meta-analysis, we investigated the impact of prior CABG on TAVR outcomes. METHODS: A systematic search was conducted in PubMed, Google Scholar, and Cochrane databases from inception to 24 July 2022, using the search terms 'TAVR', 'CABG', 'peri-procedural complications', and 'mortality'. The major outcomes were peri-procedural complications, intraprocedural mortality, 30-day mortality, and 30-day cardiac mortality. We used random-effects models to aggregate data and to calculate pooled incidence and risk ratios with 95% confidence intervals (CIs). RESULTS: Among 116 results from the systematic search, a total of 8 studies (5952 patients) were included. Compared to patients without previous CABG, patients with prior CABG undergoing TAVR were younger, predominantly male sex, had more comorbidities, higher rates of peri-procedural myocardial infarction (MI) [relative risk (RR) 1.93; 95% CI, 1.09-3.43; P = 0.03], but lower rates of stroke (RR 0.71; 95% CI, 0.51-0.99; P = 0.04), major vascular complications (RR 0.70; 95% CI, 0.51-0.95; P = 0.02), and major bleeding (RR 0.70; 95% CI, 0.56-0.88; P = 0.002). There were no significant differences between the two cohorts in rates of pacemaker implantation, cardiac tamponade, acute kidney injury, intra-procedural mortality, 30-day mortality, and 30-day cardiac mortality. CONCLUSION: Among patients undergoing TAVR, a history of prior CABG was not associated with an increased risk of periprocedural complications (except for acute MI) or short-term mortality compared to those without CABG.

Impact of concomitant aortic stenosis on the management and outcomes of acute myocardial infarction hospitalizations in the United States.

Objective: To evaluate the prevalence, management and outcomes of concomitant aortic stenosis (AS) in admissions with acute myocardial infarction (AMI). Methods: We used the HCUP-NIS database (2000-2017) to identify adult AMI admissions with concomitant AS. Outcomes of interest included prevalence of AS, in-hospital mortality, use of cardiac procedures, hospitalization costs, length of stay, and discharge disposition. Results: Among a total of 11,622,528 AMI admissions, 513,688 (4.4 %) were identified with concomitant AS. Adjusted temporal trends revealed an increase in STEMI and NSTEMI hospitalizations with concomitant AS. Compared to admissions without AS, those with AS were on average older, of female sex, had higher comorbidity, higher rates of NSTEMI (78.9 % vs 62.1 %), acute non-cardiac organ failure, and cardiogenic shock. Concomitant AS was associated with significantly lower use of coronary angiography (45.5 % vs 64.4 %), percutaneous coronary intervention (20.1 % vs 42.5 %), coronary atherectomy (1.7 % vs. 2.8 %) and mechanical circulatory support (3.5 % vs 4.8 %) (all p < 0.001). Admissions with AS had higher rates of coronary artery bypass surgery and surgical aortic valve replacement (5.9 % vs 0.1 %) compared to those without AS. Admissions with AMI and AS had higher in-hospital mortality (9.2 % vs. 6.0 %; adjusted OR 1.12 [95 % CI 1.10-1.13]; p <0.001). Concomitant AS was associated with longer hospital stay, more frequent palliative care consultations and less frequent discharges to home. Conclusions: In this 18-year study, an increase in prevalence of AS in AMI hospitalization was noted. Concomitant AS was associated with lower use of guideline-directed therapies and worse clinical outcomes among AMI admissions.

Newer P2Y12 Inhibitors vs Clopidogrel in Acute Myocardial Infarction With Cardiac Arrest or Cardiogenic Shock: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the outcomes, safety, and efficacy of dual antiplatelet therapy (DAPT) with newer P2Y12 inhibitors compared with clopidogrel in patients with acute myocardial infarction (AMI) complicated by cardiac arrest (CA) or cardiogenic shock (CS). PATIENTS AND METHODS: MEDLINE, EMBASE, and the Cochrane Library were queried systematically from inception to January 2021 for comparative studies of adults (≥18 years) with AMI-CA/CS receiving DAPT with newer P2Y12 inhibitors as opposed to clopidogrel. We compared outcomes (30-day or in-hospital and 1-year all-cause mortality, major bleeding, and definite stent thrombosis) of newer P2Y12 inhibitors and clopidogrel in patients with AMI-CA/CS. RESULTS: Eight studies (1 randomized trial and 7 cohort studies) comprising 1100 patients (695 [63.2%] receiving clopidogrel and 405 [36.8%] receiving ticagrelor or prasugrel) were included. The population was mostly male (68.5%-86.7%). Risk of bias was low for these studies, with between-study heterogeneity and subgroup differences not statistically significant. Compared with the clopidogrel cohort, the newer P2Y12 cohort had lower rates of early mortality (odds ratio [OR], 0.60; 95% CI, 0.45 to 0.81; P=.001) (7 studies) and 1-year mortality (OR, 0.51; 95% CI, 0.36 to 0.71; P<.001) (3 studies). We did not find a significant difference in major bleeding (OR, 1.21; 95% CI, 0.71 to 2.06; P=.48) (6 studies) or definite stent thrombosis (OR, 2.01; 95% CI, 0.63 to 6.45; P=.24) (7 studies). CONCLUSION: In patients with AMI-CA/CS receiving DAPT, compared with clopidogrel, newer P2Y12 inhibitors were associated with lower rates of early and 1-year mortality. Data on major bleeding and stent thrombosis were inconclusive.

Redo-aortic valve replacement in prior stentless prosthetic aortic valves: Transcatheter versus surgical approach.

OBJECTIVES: The objective was to compare outcomes of redo-aortic valve replacement (AVR) via surgical or transcatheter approach in prior surgical AVR with large percentage of prior stentless surgical AVR. BACKGROUND: With the introduction of transcatheter aortic valve replacement (TAVR), patients with increased surgical risks now have an alternative to redo surgical AVR (SAVR), known as valve-in-valve (ViV) TAVR. Stentless prosthetic aortic valves present a more challenging implantation for ViV-TAVR given the lack of structural frame. METHODS: We performed a retrospective study of 173 subjects who have undergone SAVR (N = 100) or ViV-TAVR (N = 73) in patients with prior surgical AVR at Wake Forest Baptist Medical Center from 2009 to 2019. Our study received the proper ethical oversight. RESULTS: The average ages in redo-SAVR and ViV-TAVR groups were 58.03 ± 13.86 and 66.57 ± 13.44 years, respectively (p < 0.0001). The redo-SAVR had significantly lower STS (2.78 ± 2.09 and 4.68 ± 5.51, p < 0.01) and Euroscores (4.32 ± 2.98 and 7.51 ± 8.24, p < 0.05). The redo-SAVR group had higher percentage requiring mechanical support (8% vs. 0%, p < 0.05) and vasopressors (53% vs. 0%, p < 0.0001), longer length of stay (13.65 ± 11.23 vs. 5.68 ± 7.64 days, p < 0.0001), and inpatient mortality (16% vs. 2.78%, p < 0.005). At 30-day follow-up, redo-SAVR group had higher rates of acute kidney injury (10% vs. 0%, p < 0.01), however ViV-TAVR group had more new left bundle branch blocks (6.85% vs. 0%, p < 0.05). No significant differences regarding re-hospitalization rates, stroke, or death up to 1-year. CONCLUSION: Although the ViV-TAVR group had higher risk patients, there were significantly fewer procedural complications, shorter length of stay, and similar mortality outcomes up to 1-year follow-up.

A novel technique for postclosure of large-bore sheaths using two Perclose devices.

OBJECTIVES: This study aimed to assess the feasibility, efficacy, and safety of a novel percutaneous postprocedure closure technique for large arterial sheath removal with the use of two Perclose ProGlide (Abbott Vascular Devices, Redwood City, CA) devices. BACKGROUND: Postprocedural closing of large-bore arteriotomies using the Perclose system can be difficult given the subsequent inability of the device to capture sufficient wall tissue. METHODS: Our study was a single-center retrospective analysis of 22 consecutive patients who underwent large arteriotomy closure via the postclosure technique with a 12-16-Fr sheath. Efficacy endpoints included successful deployment of the system and hemostasis. Safety endpoints included the incidence of major or minor vascular complications as defined by the Vascular Academic Research Consortium-2 (VARC-2) definitions at 30-day follow-up. RESULTS: The postclosure technique resulted in 100% technical success rate and no postprocedural bleeding or vascular complications. CONCLUSION: Postclosure technique is a safe, highly effective, and feasible percutaneous method to achieve large-bore arteriotomy hemostasis with low rates of major bleeding or vascular complications and favorable early outcome.

Endothelial Hypoxia-Inducible Factor-1α Is Required for Vascular Repair and Resolution of Inflammatory Lung Injury through Forkhead Box Protein M1.

Endothelial barrier dysfunction is a central factor in the pathogenesis of persistent lung inflammation and protein-rich edema formation, the hallmarks of acute respiratory distress syndrome. However, little is known about the molecular mechanisms that are responsible for vascular repair and resolution of inflammatory injury after sepsis challenge. Herein, we show that hypoxia-inducible factor-1α (HIF-1α), expressed in endothelial cells (ECs), is the critical transcriptional factor mediating vascular repair and resolution of inflammatory lung injury. After sepsis challenge, HIF-1α but not HIF-2α expression was rapidly induced in lung vascular ECs, and mice with EC-restricted disruption of Hif1α (Hif1af/f/Tie2Cre+) exhibited defective vascular repair, persistent inflammation, and increased mortality in contrast with the wild-type littermates after polymicrobial sepsis or endotoxemia challenge. Hif1af/f/Tie2Cre+ lungs exhibited marked decrease of EC proliferation during recovery after sepsis challenge, which was associated with inhibited expression of forkhead box protein M1 (Foxm1), a reparative transcription factor. Therapeutic restoration of endothelial Foxm1 expression, via liposomal delivery of Foxm1 plasmid DNA to Hif1af/f/Tie2Cre+ mice, resulted in reactivation of the vascular repair program and improved survival. Together, our studies, for the first time, delineate the essential role of endothelial HIF-1α in driving the vascular repair program. Thus, therapeutic activation of HIF-1α-dependent vascular repair may represent a novel and effective therapy to treat inflammatory vascular diseases, such as sepsis and acute respiratory distress syndrome.

Comparison of outcomes with surgical cut-down versus percutaneous transfemoral transcatheter aortic valve replacement: TAVR transfemoral access comparisons between surgical cut-down and percutaneous approach.

OBJECTIVES: The objective is to compare the short-term (30 days) and late (12 months) vascular adverse events in patients undergoing transfemoral (TF)-transcatheter aortic valve replacement (TAVR) by surgical cut-down (SC) vs. percutaneous (PC) approaches. BACKGROUND: Programs continue to utilize both approaches in TF-TAVR. There are limited data comparing outcomes by SC vs. PC approaches and long-term effects of endovascular intervention facilitated hemostasis on late vascular adverse events. METHODS: A total of 146 men and women aged 79.7 ± 10.0 years with severe aortic stenosis deemed extreme or high risk for surgery underwent TAVR via TF access. 61 had SC and 85 had PC approaches. Valve Academic Research Consortium (VARC-2) outcomes were assessed at an average of 12.1 months after TAVR. RESULTS: Hospital length of stay (LOS) post-TAVR was shorter for the PC group compared to the SC group (5.1 ± 3.9 vs. 8.2 ± 6.6 days; P < 0.001). More patients were discharged directly to home in the PC than the SC group (85.9% vs. 68.9%, P < 0.05). At 30 days, there were 13/61 (21.3%) and 16/85 (18.8%; P < 0.05) of any vascular events, and 2/61 (3.3%) and 2/85 (2.4%; P = 0.73) major vascular events in the SC and PC groups, respectively. There was no difference in all-cause mortality between the SC (14/61; 23%) and PC groups [17/85 (20%); P = 0.34]. There was no difference in any [4/33 (12%) vs. 3/43 (7%); P = 0.84] or major vascular adverse events [1/33 (3%) vs. 1/43 (2%); P = 0.79] in subjects that underwent adjunctive endovascular intervention compared to those who did not, respectively. There were no statistically significant univariate or multivariate predictors of any vascular event at 12 months when comparing SC to PC groups. CONCLUSION: For TF TAVR, the PC approach, when compared to the SC approach, is associated with a shorter hospital LOS and higher rate of direct discharge to home with similar risk of vascular complications, late vascular adverse events, and all-cause mortality at 12 months.

TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis.

RATIONALE: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function. OBJECTIVE: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. METHODS AND RESULTS: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). CONCLUSIONS: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment-elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial.

BACKGROUND: Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function. METHODS: To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial. RESULTS: In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays. CONCLUSIONS: In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.

Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial.

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

Bone marrow characteristics associated with changes in infarct size after STEMI: a biorepository evaluation from the CCTRN TIME trial.

RATIONALE: Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, selected patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. OBJECTIVE: The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size after ST-segment-elevation-myocardial infarction. METHODS AND RESULTS: This prospective study comprised patients consecutively enrolled in the CCTRN TIME (Cardiovascular Cell Therapy Research Network Timing in Myocardial Infarction Evaluation) trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac MRI. Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cardiac MRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31(+) BMCs (P=0.046) and in those with faster BMC growth rates in colony-forming unit Hill and endothelial-colony forming cell functional assays (P=0.033 and P=0.032, respectively). CONCLUSIONS: This study identified BMC characteristics associated with a better clinical outcome in patients with segment-elevation-myocardial infarction and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these patients with segment-elevation-myocardial infarction, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. CLINICAL TRIAL REGISTRATION INFORMATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes.

RATIONALE: Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). OBJECTIVE: To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. METHODS AND RESULTS: BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%-2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b(+) cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus -0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34(+) percentage in patients with chronic IHD correlated with decrement in LVEF (-2.9% versus +0.7%; P=0.0355). CONCLUSIONS: In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. CLINICAL TRIAL REGISTRATIONS URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005.

Comparison of 30-day outcomes of coronary artery bypass grafting surgery verus hybrid coronary revascularization stratified by SYNTAX and euroSCORE.

OBJECTIVE: The optimal treatment of multivessel coronary artery disease is not well established. Hybrid coronary revascularization by combining the left internal mammary artery-left anterior descending artery graft and drug-eluting stents in non-left anterior descending artery territories might offer superior results compared with sole coronary artery bypass grafting or sole percutaneous coronary intervention. METHODS: We retrospectively analyzed the 30-day outcomes of 381 consecutive patients undergoing coronary artery bypass grafting (n = 301) vs hybrid coronary revascularization (n = 80). In a 2 × 2 matrix, the 2 groups were stratified by the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score (≤32 vs ≥33) and the European System for Cardiac Operative Risk Evaluation (euroSCORE) (<5 vs ≥5). The composite endpoint (death from any cause, stroke, myocardial infarction, low cardiac output syndrome) and secondary endpoints (worsening postprocedural renal function and bleeding) were determined. RESULTS: After stratification using the SYNTAX and the euroSCORE, the preoperative characteristics were similar within the 4 groups, except for the ≥33 SYNTAX/>5 euroSCORE. The hybrid coronary revascularization patients were older (77 vs 65 years, P = .001). The postoperative outcomes using combined SYNTAX and the euroSCORE stratification showed a similar rate of the composite endpoint for all groups except for patients with ≥33 SYNTAX/>5 euroSCORE (0% for the coronary artery bypass grafting group vs 33% for the hybrid coronary revascularization group, P = .001). An analysis of the secondary endpoint showed similar results across all groups, except for in the ≥33 SYNTAX/>5 euroSCORE group, in which bleeding (re-exploration for bleeding and transfusion >3 packed red blood cell units per patient) was 44% in the hybrid coronary revascularization group vs 11% in the coronary artery bypass grafting group (P = .05). CONCLUSIONS: Hybrid coronary revascularization is a safe alternative to coronary artery bypass grafting in many patients with multivessel coronary artery disease. However, in high-risk patients with complex coronary artery disease (≥33 SYNTAX/>5 euroSCORE), coronary artery bypass grafting is superior to hybrid coronary revascularization.

Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial.

CONTEXT: While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. OBJECTIVES: To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. DESIGN, SETTING, AND PATIENTS: A randomized, 2 × 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] ≤ 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. INTERVENTIONS: Intracoronary infusion of 150 × 106 BMCs or placebo (randomized 2:1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1:1) after treatment with PCI. MAIN OUTCOME MEASURES: The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. RESULTS: The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P = .96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (−0.9% [95% CI, −6.6% to 4.9%], P = .76) or day 7 (1.1% [95% CI, −4.7% to 6.9%], P = .70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. CONCLUSION: Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00684021.

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT: Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE: To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS: A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION: Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES: Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS: Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION: Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00824005.