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Background Patients with refractory angina (RA) have poor quality of life and new therapies are needed. XC001 is a novel adenoviral vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) promoting an enhanced local angiogenic effect. Methods The E picardial Delivery of X C001 Gene Therapy for Refractory A ngina C oronary T reatment (EXACT) trial is a 6-month (with 6-month extension) phase 1/2, first-in-human, multicenter, open-label, single-arm, dose-escalation study to evaluate the safety, tolerability, and preliminary efficacy of XC001 in patients with RA. The trial will enroll 33 patients in an initial (n = 12) ascending dose-escalation phase (1 × 109, 1 × 1010, 4 × 1010, and 1 × 1011 viral particles), followed by phase 2 (n = 21) assessing the highest tolerated dose. Patients must have stable Canadian Cardiovascular Society (CCS) class II–IV angina on maximally tolerated medical therapy without options for conventional revascularization, demonstrable ischemia on stress testing, and angina limiting exercise tolerance. XC001 will be delivered directly to ischemic myocardium via surgical transthoracic epi c ardial access. The primary outcome is safety via adverse event monitoring through 6 months. Efficacy assessments include difference from baseline to month 6 in time to 1 mm of ST segment depression, time to angina, and total exercise duration; myocardial blood flow at rest, and stress and coronary flow reserve by positron emission tomography; quality of life; CCS functional class; and angina frequency. Conclusions The EXACT trial will determine whether direct intramyocardial administration of XC001 in patients with RA is safe and evaluate its effect on exercise tolerance, myocardial perfusion, angina and physical activity, informing future clinical investigation. Clinical trial registration NCT04125732

The outcomes of patients with previous coronary bypass graft surgery (CABG) presenting with ST-segment elevation acute myocardial infarction (STEMI) have received limited study. We compared the clinical and procedural characteristics and outcomes of STEMI patients with and without previous CABG in a contemporary multicenter STEMI registry between 2003 and 2020. The primary outcomes of the study were mortality and major cardiac adverse events (MACE: death, MI or stroke). Survival curves were derived using the Kaplan-Meier method and compared with the log-rank test. Of the 13,893 patients included in the analyses, 7.2% had previous CABG. Mean age was 62.4 ± 13.6 years, most patients (71%) were men and 22% had diabetes. Previous CABG patients were older (69.0 ± 11.7 vs 61.9 ± 13.6 years, p0.001) and more likely to have diabetes (40% vs 21%, p0.001) compared with patients without previous CABG. Previous CABG patients had higher mortality and MACE at 5 years (p0.001). Outcomes were similar with saphenous vein graft vs native coronary culprits. Previous CABG remained associated with mortality from discharge to 18 months (p = 0.044) and from 18 months to 5 years (p0.001) after adjusting for baseline characteristics. Long term outcomes after STEMI were worse among patients with previous CABG compared with patients without previous CABG, even after adjustment for baseline characteristics.

AIMS CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. METHODS AND RESULTS Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. CONCLUSIONS This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Aim Heart failure following myocardial infarction (MI) is a potentially lethal problem with a staggering incidence. The CardiAMP Heart Failure trial represents the first attempt to personalize marrow-derived cell-based therapy to individuals with cell characteristics associated with beneficial responses in prior trials. Before the initiation of the randomized pivotal trial, an open-label “roll-in cohort” was completed to ensure the feasibility of the protocol's procedures. Methods Patients with chronic post-MI heart failure (NYHA class II-III) receiving stable, guideline-directed medical therapy with a left ventricular ejection fraction between 20 and 40% were eligible. Two weeks prior to treatment, a ~ 5 mL bone marrow aspiration was performed to examine “cell potency”. On treatment day, a 60 mL bone marrow aspiration, bone marrow mononuclear cell (BM MNC) enrichment and transendocardial injection of 200 million BM MNC's was performed in a single, point of care encounter. Patients were then followed to assess clinical outcomes. Results The cell potency small volume bone marrow aspirate, the 60 mL bone marrow aspirate, and transendocardial injections were well tolerated in 10 patients enrolled. There were no serious adverse events related to bone marrow aspiration or cell delivery. Improvement in 6-min walk distance was observed at 6 months (+47.8 m, P = 0.01) and trended to improvement at 12 months (+46.4, P = 0.06). Similarly, trends to improved NYHA heart failure functional class, quality of life, left ventricular ejection fraction and recruitment of previously akinetic left ventricular wall segments were observed. Conclusion All CardiAMP HF protocol procedures were feasible and well tolerated. Favorable functional, echo and quality of life trends suggest this approach may offer promise for patients with post MI heart failure. The randomized CardiAMP Heart Failure pivotal trial is underway to confirm the efficacy of this approach. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT02438306

Background Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marr...

Objectives: Veno-arterial extracorporeal membrane oxygenation (VA ECMO) has been increasingly used in cardiopulmonary resuscitation (ECPR) in select patients. Few centers have published their experience or outcomes with ECPR. The aim of our study was to evaluate outcomes of adult patients in cardiac arrest placed on VA ECMO in the catheterization laboratory. Methods: We performed a retrospective analysis of adult patients in refractory cardiac arrest who underwent ECPR at the Minneapolis Heart Institute (MHI) at Abbott Northwestern Hospital from January 2012 to December 2017. Relevant data were obtained from electronic medical records, including arrest to ECMO flow time, total ECMO support time, and outcomes. Results: Twenty-six adult patients underwent ECPR at the study site during the defined time period. Seven patients (27%) sustained cardiac arrest out of hospital, 19 patients arrested in-hospital with eight of those occurring in the catheterization laboratory. Seventeen (65%) patients had initial rhythm of ventricular fibrillation or tachycardia (VF/VT). All patients underwent mechanical CPR with LUCAS device. Overall 30 day and 6 month survival was 69%. Median time from arrest to ECMO flow was 46 mins (21,68) vs 61 mins (36,71) in survivors and non-survivors, respectively. Sixteen of 18 survivors discharged with a CPC score of 1 or 2. Conclusions: We demonstrate that adult patients in cardiac arrest initiated on VA ECMO in the cardiac catheterization laboratory and cared for by a multidisciplinary shock team in the critical care unit have superior long-term survival and functionally favorable neurologic recovery when compared to current literature.

Aims Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. Methods and results We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. Conclusion Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. Trial registration Clinicaltrials.gov identifier: NCT01458405.

Ranolazine is approved for patients with chronic stable angina but has not been formally studied in patients with refractory angina pectoris (RAP). Patients with RAP have limited therapeutic options and significant limitations in their quality of life. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness of ranolazine in RAP patients in order to expand treatment options for this challenging patient population. Using an extensive prospective database, we enrolled 158 consecutive patients evaluated in a dedicated RAP clinic. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 12, 24, and 36 months. At 3 years, 95 (60%) patients remained on ranolazine. A ≥2 class improvement in angina was seen in 48% (38 of 80 patients with known Canadian Cardiovascular Society class) of those who remained on ranolazine. Discontinuation due to side effects, ineffectiveness, cost, and progression of disease were the principle reasons for discontinuation, but primarily occurred within the first year. In conclusion, ranolazine is an effective antianginal therapy at 3-year follow-up in patients with RAP and may reduce cardiac readmission.

This study sought to compare the clinical characteristics and long-term outcomes of patients with ST-segment elevation myocardial infarction (STEMI) with and without cardiogenic shock (CS) or cardiac arrest (CA) before percutaneous coronary intervention (PCI).Patients with STEMI complicated by CS or CA are underrepresented in STEMI registries.Consecutive patients with STEMI or new left bundle branch block within 24 h of symptom onset were included in a regional STEMI program comprising a PCI center (Minneapolis Heart Institute at Abbott Northwestern Hospital), 11 hospitals 60 miles from PCI center (zone 1), and 19 hospitals 60 to 210 miles from PCI center (zone 2). No patients were excluded. Patients were stratified based on the presence (+) or absence (-) of CS or CA before PCI. Patients with CA were further classified based on initial rhythm. Primary outcomes were in-hospital and 5-year mortality.Between March 2003 and December 2014, 4,511 STEMI patients were included in the regional program, including 398 (9%) with CS and 499 (11%) with CA. Hospital mortality was: CS+ and CA+, 44%; CS+ and CA-, 23%; CS- and CA+, 19%; and CS- and CA-, 2% (p 0.001). The 5-year survival probability for CS+ and CA+ patients was 0.69 (95% confidence interval: 0.61 to 0.76) and 0.89 (95% confidence interval: 0.84 to 0.93), respectively (p 0.01). Compared with patients with shockable rhythms, CA patients with nonshockable rhythms had significantly lower odds of survival at hospital discharge and at 5 years (both p 0.001).The combination of CS and CA significantly increases short-term mortality in patients with STEMI. After 5 years of follow-up, CS patients remained at high risk of fatal events, whereas the prognosis of CA patients was determined by initial rhythm at presentation.

Cell therapy trials for heart failure (HF) have shown modest improvement; however, the mechanisms underlying improvement in some patients but not others are not well understood. Although immune cells are important in the course of HF, our understanding of the immune processes in HF is limited. The objective of this study was to evaluate associations between temporal changes in peripheral blood (PB) cell subpopulations and improved outcome in patients with chronic ischemic cardiomyopathy after bone marrow-derived mononuclear cell therapy or placebo in the FOCUS-CCTRN trial. Peripheral blood was collected at days 0, 1, 30, 90, and 180 from consented participants. We used flow cytometry to compare PB populations in patients with the best (cohort 1) or worst functional outcome (cohort 2) in three primary endpoints: left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption (VO2 max). A linear mixed model was used to assess changes over time in 32 cell populations. The difference between each time point and baseline was calculated as linear contrast. Compared with cohort 2, patients who improved (cohort 1) had a higher frequency of CD45+CD19+ B cells at days 0, 1, 90, and 180. CD11B+ cells increased over baseline at day 1 in both cohorts and remained higher in cohort 2 until day 30. CD45+CD133+ progenitor cells decreased over baseline at day 30 in cohort 1. We identified specific cell subpopulations associated with improved cardiac function in patients with chronic LV dysfunction. These findings may improve patient selection and prediction of outcomes in cell therapy trials.

Visual Abstract, Highlights • A first-in-man clinical trial was completed with VentriGel, an extracellular matrix hydrogel derived from decellularized porcine myocardium, in post–MI patients. • Results from the trial support the safety and feasibility of transendocardial injection of VentriGel in post–MI patients with left ventricular dysfunction. • Although the study was not designed to evaluate efficacy, there were suggestions of improvements including increases in 6-min walk test distance and decreases in New York Heart Association functional class across the entire cohort of patients. • Improvements in left ventricular remodeling were mainly observed in patients who were treated >1-year post–MI as opposed to, Summary This study evaluated the safety and feasibility of transendocardial injections of VentriGel, a cardiac extracellular matrix hydrogel, in early and late post–myocardial infarction (MI) patients with left ventricular (LV) dysfunction. VentriGel was delivered in 15 patients with moderate LV dysfunction (25% ≤ LV ejection fraction ≤ 45%) who were between 60 days to 3 years post-MI and were revascularized by percutaneous coronary intervention. The primary endpoints were incidence of adverse events and abnormal clinical laboratory results. This first-in-man study established the safety and feasibility of delivering VentriGel in post-MI patients, thus warranting further evaluation in larger, randomized clinical trials.

Rationale: Postconditioning at the time of primary percutaneous coronary intervention (PCI) for ST-segment–elevation myocardial infarction may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit. Objective: We performed the first National Heart, Lung, and Blood Institute–sponsored trial of postconditioning in the United States using strict enrollment criteria to optimize the early benefits of postconditioning and assess its long-term effects on left ventricular (LV) function. Methods and Results: We randomized 122 ST-segment–elevation myocardial infarction patients to postconditioning (4, 30 seconds PTCA [percutaneous transluminal coronary angioplasty] inflations/deflations)+PCI (n=65) versus routine PCI (n=57). All subjects had an occluded major epicardial artery (thrombolysis in myocardial infarction=0) with ischemic times between 1 and 6 hours with no evidence of preinfarction angina or collateral blood flow. Cardiac magnetic resonance imaging measured at 2 days post-PCI showed no difference between the postconditioning group and control in regards to infarct size (22.5±14.5 versus 24.0±18.5 g), myocardial salvage index (30.3±15.6% versus 31.5±23.6%), or mean LV ejection fraction. Magnetic resonance imaging at 12 months showed a significant recovery of LV ejection fraction in both groups (61.0±11.4% and 61.4±9.1%; P P P =0.05) on baseline magnetic resonance imaging and significantly less adverse LV remodeling compared with control subjects with microvascular obstruction ( P Conclusions: We found no early benefit of postconditioning on infarct size, myocardial salvage index, and LV function compared with routine PCI. However, postconditioning was associated with improved LV remodeling at 1 year of follow-up, especially in subjects with microvascular obstruction. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01324453.

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

Introduction: The development of microvascular obstruction (MVO) in the setting of ST-Elevation Myocardial Infarction (STEMI) is a powerful predictor of reduced left-ventricular (LV) function, adverse LV remodeling and increased mortality. Although MVO is associated with increasing infarct size and ischemic duration, additional causes of MVO have not been clearly identified. Although MVO may arise from intravascular obstruction from embolization of thrombus, it may also arise from compression of the microvasculature due to increased myocardial edema and extravascular compressive forces. Hypothesis: Because left-ventricular hypertrophy (LVH) is associated with increased extravascular compressive forces, we hypothesized that patients with greater LV mass may be more susceptible to the development of MVO during STEMI. Methods: We measured MVO in 385 patients (59.4 + 12.3 years; 77% male) admitted to our Institution with STEMI who underwent cardiac MRI for measurement of LV function and infarct size following successful primary PCI. A total of 219 patients (57%) had MVO on cardiac MRI measured 1-3 days following PCI of which 172 patients had paired measurements of LV mass. Results: Patients with MVO (13.7 + 13.9 grams) had significantly greater infarct size (54 vs. 31 g; p < 0.001) and LV mass (151 vs 140 g; p Conclusions: MVO increases with increasing LV mass and may contribute to the known adverse effects of LVH in STEMI.

Introduction: Cell therapy failed to improve global LV ejection fraction (LVEF) in most trials of post-MI LV dysfunction. LVEF does not consider the effect of cell therapy on different segments of the myocardium, which may be heterogeneous across different myocardial regions in patients with regional MI. Hypothesis: Allogeneic cardiosphere-derived cells (CDCs) improve segmental (but not global) myocardial function indexed as circumferential strain by MRI. Methods: In this randomized double-blind trial, 142 post-MI patients with LVEF Results: In total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3(10.8) and 108 (87.1%) males). Segmental Ecc improvement was significantly greater in patients receiving CDC (-0.5%(4.0)) compared to placebo (0.2%(3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of -0.7% (3.5) in patients receiving CDC vs. 0.04% (3.7) in the placebo group, p=0.04). The beneficial effect of CDCs for improving segmental Ecc was greater in patients with LV ejection fraction18.8% or LV end-diastolic volume index>100 [mixed effect regression coefficients of -0.92(p=0.02),-0.78(p=0.03), and -1.16(p=0.004) respectively versus -0.58(p=0.05) for the entire cohort]. Conclusions: In patients with post-MI LV dysfunction, allogeneic CDC administration resulted in improved segmental myocardial function. This CDC induced improvement in segmental myocardial function was greater in patients with severe LV dysfunction, dilated LV and greater infarct size. (clinicaltrials.gov Identifier: NCT01458405).

Introduction: Incomplete revascularization following coronary artery bypass surgery (CABG) is associated with increased repeat revascularization, myocardial infarction and death. However, whether the rate of incomplete revascularization is increasing over time has not been previously described. Methods: We performed a retrospective review of consecutive patients who underwent elective and isolated CABG for multi-vessel coronary artery disease in 2007 (n=291) and in 2017 (n=290) at a single Institution. All coronary angiograms and CABG operative reports were reviewed and a Revascularization Index Score (RIS) was created to compare rates of incomplete revascularization between the two time periods based on the coronary anatomy and degree of stenosis. Thus a patient with complete revascularization will have an RIS score of 1.0 while a patient who has 3 of 4 eligible vessels bypassed will have an RIS score of 0.75. Results: Over a 10 year period, the rate of incomplete revascularization increased from 17.9% to 28.3% (p = 0.003) and was accompanied by a decline in the RIS score from 0.73 to 0.67 (p= 0.005). Mortality significantly increased over time with incomplete compared to complete revascularization in the 2007 cohort. Conclusions: The incidence of incomplete revascularization following CABG significantly increased over a 10-year time period between 2007 and 2017. These differences may be attributable to patient factors including more severe coronary artery disease associated with older age, greater incidence of smoking and previous PCI. In line with previous. meta-analyses, the incidence of mortality over time was higher in those patients with incomplete compared to those with complete revascularization. These results suggest that patients with incomplete revascularization represents an important target for the development of novel therapies.

Introduction: The outcomes of ST elevation myocardial infarction (STEMI) patients with prior coronary bypass graft (CABG) surgery have received limited study. Methods: We compared the clinical and procedural characteristics and outcomes of STEMI patients with and without prior CABG surgery in a contemporary STEMI registry of consecutive STEMI patients with STEMI or new left bundle-branch block within 24 hours of symptom onset presenting between March 2003 and April 2020. Morality and major cardiac adverse events (MACE: death, MI or stroke) were the primary outcomes of the study. Survival curves are depicted using the Kaplan-Meier method and compared with log-rank test. Results: Of the 6,311 patients included in the analyses, 6.9% had history of prior CABG. Mean age was 63.4 ± 13.9 years and most of the patients were men (71%), 21% had prior MI and 19% had diabetes mellitus. Prior CABG patients were older (70.4±11.7 vs. 62.9±13.9 years, p Conclusions: Patients with STEMI and previous CABG represent a higher risk cohort with worse in-hospital and long-term outcomes compared to those without previous CABG.

Incomplete revascularization following coronary artery bypass grafting (CABG) is associated with increased repeat revascularization, myocardial infarction and death. Whether the rate of incomplete revascularization is increasing over time has not been previously described. All patients with multivessel coronary artery disease who underwent isolated and elective CABG at our Institution in 2007 (n = 291) were compared to patients who underwent CABG in 2017 (n = 290). A Revascularization Index Score was created to compare rates of incomplete revascularization between the 2 years based on the coronary anatomy and degree of stenosis. Comparison of the 2 years disclose that the rate of incomplete revascularization increased from 17.9% in 2007 to 28.3% in 2017 (p = 0.003) and was accompanied by a decline in the Revascularization Index Score from 0.73 to 0.67 (p = 0.005). Left ventricular function improved in both groups following CABG. Two-year cardiovascular mortality was significantly higher in the 2017 cohort compared to the 2007 cohort. These differences may be attributable to patient factors including more severe coronary artery disease associated with older age, greater incidence of smoking and previous percutaneous coronary intervention. In conclusion, the rate of incomplete revascularization following CABG significantly increased in 2017 compared to 2007 and was associated with higher cardiovascular mortality.

Objective To examine the outcomes with intravascular brachytherapy (IVBT) in recurrent in-stent restenosis (ISR). Background Recurrent ISR can be challenging to treat and IVBT can be used for recurrent ISR but has received limited study. Methods We performed a systematic review and meta-analysis of five observational studies, including 917 patients (1014 lesions) with recurrent ISR, defined as having at least two prior ISR episodes with previous treatment with a stent, who underwent treatment with IVBT. Outcomes of interest included target vessel revascularization (TVR), myocardial infarction (MI), and all-cause mortality. Results During a mean follow-up of 24 ± 7 months, the incidence of TVR was 29.2% (95% CI 18.0–40.4%). The incidence of MI and all-cause mortality were 4.3% (95% CI 1.7%–6.9%) and 7.3% (95% CI 3.2–11.5%), respectively. At one- and two-years after PCI the incidence of TVR was 17.5% (95% CI 13.6%–21.4%) and 26.7% (95% CI 16.6%–36.9%), respectively and the incidence of MI was 3.1% (95% CI 2–4.2%) and 3.9% (95% CI 1–6.8%), respectively. Conclusion Intravascular brachytherapy can be used to treat recurrent ISR, although TVR is needed in approximately one of four patients at two years.

Background Recurrent drug-eluting stents (DES) in-stent restenosis (ISR) can be challenging to treat. The combined use of excimer laser atherectomy (ELCA) and vascular brachytherapy (VBT) for this indication has received limited study. Methods We report the long-term outcomes of patients with recurrent DES ISR treated with combined VBT and ELCA from January 2014 to September 2018 at a single institution. Outcomes included target lesion failure (TLF), defined as the composite of clinically driven target lesion revascularization (TLR), target lesion myocardial infarction (MI), and target lesion-related cardiac death. Results During the study period, 116 patients (143 lesions) underwent VBT, of which 19 patients (19 lesions) underwent combined laser atherectomy and VBT. All procedures were successful without no-reflow or dissection. Two propensity-score matched cohorts (ELCA + VBT (n = 18) vs. VBT only (n = 18)) were compared. During a median follow-up of 25.5 (14.5–40) months, there was no difference in the incidence of TLF (38.9% vs. 38.9%, log-rank p = 0.688), target-lesion MI (5.6% vs. 5.6%, log-rank p = 0.915), or TLR (38.9% vs. 33.3%, log-rank p = 0.933) between both groups. There was no cardiac death related to the target lesion. Conclusions When compared with VBT alone for the treatment of resistant DES ISR, combined use of ELCA and brachytherapy is associated with comparable long-term outcomes. ELCA should be considered in ISR lesions due to stent underexpansion.

BACKGROUND We sought to describe changes in demographic variables, process of care measures, and outcomes of patients treated in a regional ST-segment elevation myocardial infarction (STEMI) program over the last 15 years. METHODS We describe demographic variables, process of care measures, and outcomes of patients treated in the program in various 5-year time periods: 2003-2007 (n = 1,821), 2008-2012 (n = 1,968), and 2013-2018 (n = 2,223). The primary outcome measures were in-hospital and 30-day mortality. RESULTS Among 6,012 STEMI patients treated from 2003 to 2018 we observed a significant increase in mean age at presentation (62 ± 14 to 64 ± 13 years) and diabetes (14-22%, p

As the mortality of coronary artery disease improves and the population ages, an increasing number of patients with refractory angina are not candidates for percutaneous or surgical revascularization. We evaluated the impact of a dedicated refractory angina clinic on quality of life. In 76 patients who completed the Medical Outcomes Study 36-Item Short-Form Health Survey and Seattle Angina Questionnaire at baseline and 1 year, the Medical Outcomes Study results showed the proportion of patients who rated their health as “good” or “excellent” more than doubled from baseline to 1 year (15.8% vs. 42.2%; P < .001). Similarly, the Seattle Angina Questionnaire score was significantly improved at 1 year compared to baseline (P = .025), as were angina stability (P = 0.017) and angina frequency (P = .010). In conclusion, treatment in a dedicated clinic is associated with improved quality of life in patients with refractory angina.

Introduction: Coronary artery perforations are more likely to occur during percutaneous coronary intervention of complex coronary lesions, such as heavily calcified lesions and chronic total occlusions.Areas covered: Authors provide an update on the management of coronary perforations by performing a critical review of the related, recently published literature.Expert commentary: Meticulous attention to guidewire position and to device selection is critical for minimizing the risk for coronary perforation. If a perforation occurs, following a structured, algorithmic approach can maximize the likelihood of a successful outcome.

BACKGROUND A significant proportion of patients with complex, advanced coronary artery disease have refractory angina (RA) despite maximal pharmacological therapy and are deemed suboptimal candidates for revascularization. These patients are frequently termed "no-option" patients. However, despite this designation, many subsequently undergo coronary revascularization. We sought to determine the incidence, etiology and outcome of revascularization in "no-option" patients. METHODS AND RESULTS We examined a comprehensive, prospective RA database to identify 342 of 1363 (25.1%) patients who subsequently underwent revascularization after a median interval of 2.2 years from the "no-option" diagnosis. Coronary revascularization was achieved by percutaneous coronary intervention (PCI) (n = 274, 20.1%), coronary bypass graft surgery (n = 44, 3.2%) or both (n = 24, 1.8%). During a median follow-up of 5.1 years, patients who underwent revascularization had lower annual mortality (2% vs. 4.4%, P

Obtaining femoral and radial arterial access in the cardiac catheterization laboratory using state-of-the-art techniques is essential to optimize outcomes, patient satisfaction, and procedural efficiency. Although transradial access is increasingly used for coronary angiography and percutaneous coronary intervention, femoral access remains necessary for numerous procedures, many requiring large-bore access, including complex high-risk coronary interventions, structural procedures, and procedures involving mechanical circulatory support. For femoral access, contemporary access techniques should combine the use of fluoroscopy, ultrasound, micropuncture needle, femoral angiography, and vascular closure devices, when feasible. For radial access, ultrasound may reveal important anatomic features and expedite access. Despite randomized controlled trials supporting use of routine ultrasound guidance for femoral and/or radial arterial access, ultrasound remains underused in cardiac catheterization laboratories. This article reviews contemporary techniques to achieve optimal arterial access in the cardiac catheterization laboratory.

Rationale: Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. Objective: To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI. Methods and Results: BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony–forming cell colony maximum in the BM of patients with AMI (estimate±SE, −0.13±0.05; P =0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony–forming cell colony outgrowth in the presence of exogenous IL-1β or IL-6 ( P P P =0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P Conclusions: Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI. Clinical Trial Registrations: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00684060.

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

Objectives To examine the outcomes of vascular brachytherapy (VBT) for recurrent drug-eluting stents (DES) in-stent restenosis (ISR). Background Recurrent DES-ISR can be challenging to treat. VBT has been used with encouraging results. Methods We report the long-term outcomes of patients with recurrent DES-ISR treated with VBT between January 2014 and September 2018 at a tertiary care institution. The main outcome was target lesion failure (TLF), defined as the composite of clinically driven target lesion revascularization (TLR), target lesion myocardial infarction (MI), and target lesion-related cardiac death. Cox proportional hazards analysis was performed to identify variables associated with recurrent TLF. Results During the study period, 116 patients (143 lesions) underwent VBT. Median follow-up was 24.7 (14.5-35.4) months. The incidence of TLR, target-lesion MI, and TLF was 18.9%, 5.6%,and 20.1% at 1 year, and 29.4%, 10.5%, and 32.9% at 2 years.Initial presentation with acute coronary syndrome (ACS) was independently associated with TLF (hazard ratio = 1.975, 95% CI [1.120, 3.485], p = .019). Lesions treated with intravascular ultrasound (IVUS) guidance had a lower incidence of TLR (14.3% vs. 39.6%, log-rank p = .038), and a trend toward lower incidence of TLF (19% vs. 42.6%, log-rank p = .086). Conclusions VBT can improve the treatment of recurrent DES-ISR, but TLF occurs in approximately one in three patients at 2 years. Initial presentation with ACS was associated with higher TLF and the use of IVUS with a trend for lower incidence of TLF.

Implantation of bone marrow-derived cells (BMCs) into mouse hearts post-myocardial infarction (MI) limits cardiac functional decline. However, clinical trials of post-MI BMC therapy have yielded conflicting results. While most laboratory experiments use healthy BMC donor mice, clinical trials use post-MI autologous BMCs. Post-MI mouse BMCs are therapeutically impaired, due to inflammatory changes in BMC composition. Thus, therapeutic efficacy of the BMCs progressively worsens after MI but recovers as donor inflammatory response resolves. The availability of post-MI patient BM mononuclear cells (MNCs) from the TIME and LateTIME clinical trials enabled us to test if human post-MI MNCs undergo a similar period of impaired efficacy. We hypothesized that MNCs from TIME trial patients would be less therapeutic than healthy human donor MNCs when implanted into post-MI mouse hearts, and that therapeutic properties would be restored in MNCs from LateTIME trial patients. Post-MI SCID mice received MNCs from healthy donors, TIME patients, or LateTIME patients. Cardiac function improved considerably in the healthy donor group, but neither the TIME nor LateTIME group showed therapeutic effect. Conclusion: post-MI human MNCs lack therapeutic benefits possessed by healthy MNCs, which may partially explain why BMC clinical trials have been less successful than mouse studies.

BACKGROUND: Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret due to small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design. METHODS: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size (IS) from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), BNP/NT-proBNP, 6-minute walk test (6MWT), NYHA class and MACE incidences were considered secondary outcomes. RESULTS: In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59 to 2.83; P < 0.001; I(2) = 32%) and 6.01% (95% CI 4.45 to 7.57; P < 0.001; I(2) = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy (ICM) studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced LVESV; however, infarct size (IS), 6MWT, NYHA class, and MACE rates were comparable. CONCLUSION: MNC therapy may convey a modest but sustained increase in LVEF in ICM patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.

> Good judgment seeks balance and progress; lack of it eventually finds imbalance and frustration. > > —President Dwight D. Eisenhower, January 1961 speech on the growing military-industrial complex. The increasing regulatory burden and cost of doing clinical trials in cardiac emergencies has greatly impacted the development of novel therapies resulting in increased morbidity and mortality of patients. A new regulatory framework is required. Over the past 2 decades, great progress has been made in the treatment of ST-segment–elevation myocardial infarction (STEMI). The development of regional systems of care for delivery of primary percutaneous coronary intervention,1 advances in pharmacotherapy and public education have significantly reduced the time to reperfusion. Although the rapid restoration of coronary blood flow is the most effective means of reducing infarct size and preserving left ventricular function, it is not without consequence as reperfusion may also be associated with further injury to the myocardium and vasculature. Reperfusion injury may increase infarct size to a degree that is similar to the initial ischemic insult2 by increasing myocyte cell death, activating apoptosis, and promoting endothelial dysfunction. Improvements in reducing ischemia–reperfusion (I/R) injury are urgently needed as this represent the largest remaining target available to reduce infarct size. This achievement could significantly improve patient’s quality of life and reduce the great expenditures associated with the development of congestive heart failure. Unfortunately, efforts at reducing I/R injury by methods successful in animal models have largely been unsuccessful in clinical trials.3 To date, clinical trials to limit reperfusion injury have targeted many areas including reactive oxygen species, reductions in calcium overload, inflammation, mitochondrial permeability transition pore to name just a few. The reasons for disappointing results in the majority of trials may include the frequently longer duration of ischemia and comorbidities in humans with STEMI compared with animals, the frequent inability …

Objective To assess safety and feasibility of autologous adipose-derived regenerative cells (ADRCs), for treatment of chronic ischemic cardiomyopathy patients. Background Preclinical and early clinical trials suggest ADRCs have excellent potential for ischemic conditions. Methods The Athena program consisted of two parallel, prospective, randomized (2:1, active: placebo), double-blind trials assessing intramyocardial (IM) ADRC delivery [40-million, n = 28 (ATHENA) and 80-million (ATHENA II) cells, n = 3]). Patients with an EF ≥20% but ≤45%, multivessel coronary artery disease (CAD) not amenable to revascularization, inducible ischemia, and symptoms of either angina (CCS II–IV) or heart failure (NYHA Class II–III) on maximal medical therapy were enrolled. All patients underwent fat harvest procedure (≤450 mL adipose), on-site cell processing (Celution® System, Cytori Therapeutics), electromechanical mapping, and IM delivery of ADRCs or placebo. Results Enrollment was terminated prematurely due to non-ADRC-related adverse events and subsequent prolonged enrollment time. Thirty-one patients (17-ADRCs, 14-placebo) mean age 65 ± 8 years, baseline LVEF(%) 31.1 ± 8.7 (ADRC), 31.8 ± 7.7 (placebo) were enrolled. Change in V02 max favored ADRCs (+45.4 ± 222 vs. −9.5 ± 137 mL/min) but there was no difference in left ventricular function or volumes. At 12-months, heart failure hospitalizations occurred in 2/17 (11.7%) [ADRC] and 3/14 (21.4%) [placebo]. Differences in NYHA and CCS classes favored ADRCs at 12-months with significant improvement in MLHFQ (−21.6 + 13.9 vs. −5.5 + 23.8, P = 0.038). Conclusions A small volume fat harvest, automated local processing, and IM delivery of autologous ADRCs is feasible with suggestion of benefit in “no option” CAD patients. Although the sample size is limited, the findings support feasibility and scalability for treatment of ischemic cardiomyopathy with ADRCs. © 2016 Wiley Periodicals, Inc.

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34 + stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI ( N = 167), patients treated with autologous CD34 + stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10 5 CD34/kg body weight), and high dose (5 × 10 5 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA ® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III–IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency ( p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time ( p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34 + cells had significant reduction in angina frequency ( p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose ( p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively ( p = 0.08). Autologous CD34 + cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34 + cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. Background IM administration of autologous CD34 + cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34 + administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34 + cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34 + ]). Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34 + Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)

Background Anthracycline-induced cardiomyopathy (AIC) can be irreversible with a poor prognosis, and disproportionately affects women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure treatment. Allo-MSCs are known to favorably affect fibrosis, apoptosis, and inflammation, which are key features of AIC. Methods This phase I study evaluated 37 adult cancer survivors (68% female) with left ventricular dysfunction secondary to chronic AIC. The study included a six-subject open-label, lead-in phase followed by 31 subjects randomized 1:1 to receive 1 × 108 allo-MSCs or vehicle via 20 transendocardial injections. Subjects were followed for 1 year to assess safety and feasibility (Fisher's test). Secondary efficacy measures included cardiac function/structure measured by magnetic resonance imaging (MRI), functional capacity, quality of life (MLHFQ), and biomarkers. These were assessed by ANCOVA adjusting for baseline values. Results Ninety-seven percent of subjects underwent successful study product injections, all allo-MSC-assigned subjects received the target dose. Follow-up visits were well attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-MRI compatible devices, MRI endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes including major adverse cardiac events, other significant adverse events, and days alive and out of the hospital. Ten of the 13 efficacy measures numerically favored the allo-MSC group including a lower MLHFQ score (p = .048). Conclusion In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible and MRI was successfully performed in the majority of patients with devices. This study provides crucial information for designing Phase II trials aimed at assessing efficacy of cell therapy in patients with AIC.

Recurrent drug-eluting stent restenosis (DES ISR) can be challenging to treat. Vascular brachytherapy (VBT) has been used with encouraging results. We report the long-term outcomes of patients with recurrent DES ISR treated with VBT from January 2014 to September 2018 [target lesion failure (TLF)

Cardiogenic shock develops in up to 10% of patients with acute myocardial infarction and continues to have high mortality. Early invasive treatment is the default therapeutic approach in these patients. On the basis of the results of the CULPRIT-SHOCK trial, culprit-only revascularization during the acute phase is preferred over multivessel revascularization. Routine use of intra-aortic balloon pump (IABP) is not recommended; however, the use of mechanical circulatory support has been increasing despite limited observational data to support its use. Several studies support multivessel revascularization in patients with uncomplicated ST-segment elevation acute myocardial infarction and simple nonculprit lesions to improve subsequent clinical outcomes. Keywords: Multivessel coronary artery disease, Cardiogenic shock, Acute coronary syndromes, STEMI, Non-STEMI

OBJECTIVES We examined the contemporary incidence, types, predictors, angiographic characteristics, management and outcomes of coronary perforation. BACKGROUND Coronary perforation is a rare, but important, complication of percutaneous coronary intervention (PCI). There is lack of data on perforations stratified as large and distal vessel perforations. METHODS Retrospective, observational cohort study of all patients who underwent PCI at a high volume, tertiary hospital between the years 2009 and 2016. Angiograms of all coronary perforation cases were reviewed to determine the mechanism, type, and management of perforation. Risk-adjusted periprocedural complication rates were compared between patients with and without coronary perforation. One-year mortality outcomes of patients with large vessel vs. distal vessel perforation were also examined. RESULTS Coronary perforation occurred in 68 of 13,339 PCIs (0.51%) performed during the study period: 51 (75%) were large vessel perforations and 17 (25%) distal vessel perforations. Most (67%) large vessel perforations were due to balloon/stent inflation, whereas most (94%) distal vessel perforations were due to guidewire exit. Patients with coronary perforations had significantly higher risk for periprocedural complications (adjusted odds ratio 7.57; 95% CI: 4.22-13.50; P