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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.

Patients with STEMI ( n = 385) had cardiac MRIs 2 to 3 days following reperfusion with primary PCI to determine the relationship between myocardial edema, LV mass, and MVO. We observed that MVO increased linearly with LV mass and that myocardial edema measured by T2-imaging also increased linearly with LV mass. Patients with MVO had greater edema and LVEDP than subjects without MVO. These findings suggest that myocardial edema which arises from ischemia-reperfusion injury may result in extravascular compression of the microcirculation manifested as MVO on cardiac MRI.

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

To examine the incidence, treatment and outcomes of perforation during percutaneous coronary intervention (PCI).Coronary perforation is a potentially life-threatening PCI complication.We examined the clinical, angiographic, and procedural characteristics, management, and outcomes of coronary perforation at a tertiary care institution.Between 2014 and 2019, perforation occurred in 70 of 10,278 PCIs (0.7%). Patient age was 71 ± 12 years, 66% were men, and 30% had prior coronary artery bypass graft surgery. Among perforation cases, the prevalence of chronic total occlusions was 33%, moderate/severe calcification was 66% and moderate/severe tortuosity was 41%. The frequency of Ellis class 1, 2, and 3 perforations was 14%, 50%, and 36%, respectively. Most (n = 51; 73%) were large vessel perforations, 16 (23%) were distal vessel perforations and 3 (4%) were collateral vessel perforations (1 septal and 2 epicardial). Hypotension occurred in 26%, pericardial effusion in 36% and tamponade in 13%; 47% of perforations did not have clinical consequences. Perforations were most often treated with prolonged balloon inflation (63%), reversal of anticoagulation (39%), and covered stent implantation (33%). Technical and procedural success were 73% and 60%, respectively, and major periprocedural adverse cardiac events occurred in 21% of the patients. Three patients (4%) required emergent CABG surgery and four (6%) died.Coronary perforation is an infrequent complication of PCI. Most perforations are large vessel perforations and often require further intervention. The incidence of death or emergent cardiac surgery is low.

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.

Microvascular obstruction (MVO) contributes significantly to adverse left-ventricular remodeling and mortality following ST-segment elevation myocardial infarction (STEMI). Because circadian processes contribute significantly to the timing and degree of ischemic injury in STEMI we hypothesized that the occurrence of MVO may also exhibit circadian behavior.A single center cohort trial of 336 STEMI patients (273 M 63 F) with their first STEMI who were reperfused with primary percutaneous coronary intervention (PCI) and referred for cardiac MRI prior to discharge. The time of onset of chest pain was recorded from the patients chart and used to stratify patients with MVO over a 24-h cycle to analyze for circadian behavior. Subjects with MVO (n = 200) had greater infarct size by cMRI (45 vs. 20 g; p 0.001), had reduced ejection fraction (LVEF = 50 vs 45%; p = 0.008) and significantly greater LV end-diastolic (LVEDVI) and end-systolic (LVESVI) volume index compared to subject without MVO (n = 136). The frequency of patients with MVO was compared against the frequency of patients without MVO at each 1-h and 3-h period over a 24-h cycle. A clear peak in patients with MVO (MVO + / MVO -) was seen at the 0700 h interval where 26 out of 27 patients had MVO (p = 0.0038) although MVO mass was not increased. This observation remained significant at the 06-09 time interval when 3-h segments were analyzed. Through 2021, mortality in patients with MVO was significantly greater compared to patients without MVO (n = 20 vs. 5, p 0.03).This analysis reveals for the first time a circadian dependence of the frequency of MVO in the setting of STEMI which could explain in part, the wide variation in MVO seen in STEMI patients with similar ischemic times and infarct size.

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.

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.

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.

The concept that cell‐based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.

Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term ‘stem cell therapy’ is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

Introduction: Although preclinical studies of cell delivery in models of ischemic heart failure (HF) suggest a beneficial interaction between mesenchymal stromal cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) resulting in additive therapeutic effects, no clinical trial has examined a combination of different cell types in ischemic HF. Furthermore, comparative studies of different cell products in humans are rare. CONCERT-HF (NCT02501811) is an NHLBI-sponsored, randomized, double-blind, placebo-controlled, Phase II trial of the Cardiovascular Cell Therapy Research Network (CCTRN) investigating feasibility, safety, and efficacy of MSCs and CPCs, alone and in combination, in patients with chronic ischemic HF. Objectives: To address the following questions: Is combined treatment with MSCs and CPCs feasible and safe in patients with ischemic HF? Do MSCs and CPCs, given alone or in combination, alleviate LV dysfunction, reduce scar size, improve quality of life, and/or augment functional capacity? Is either cell type more effective than the other? Is the combination of MSCs and CPCs more efficacious than MSCs alone or CPCs alone? Methods: Patients were randomized (1:1:1:1) to receive i) the combination of autologous bone marrow-derived MSCs and autologous CPCs, ii) MSCs alone, iii) CPCs alone, or iv) placebo. Target doses were 150 x 10 6 MSCs and 5 x 10 6 CPCs. All patients underwent bone marrow aspiration and right heart catheterization. Endomyocardial biopsy was performed only in the MSC + CPC and CPC alone groups; a “sham biopsy” was performed in the MSC alone and placebo groups. All patients underwent study product injection using the NOGA ® XP Mapping System and were followed for 12 months. Results: A total of 125 patients (116 M, 9 F), 62.5 ± 8.9 years old, were enrolled at 7 CCTRN centers between Nov 2016 and Oct 2018. Baseline LVEF (cardiac MRI) was 28.6 ± 6.1% with a mean scar size of 31.8 ± 10.9 g and NYHA class II (80%) or class III (15.2%). Conclusions: CONCERT-HF is the first cell therapy trial to assess a combination of different cell types and to directly compare two different cell products in patients with HF. All patients will complete follow-up by the end of June and final primary (12-month) safety and outcomes data will be available in August 2020.

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

Summary Background Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. Methods In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT02439749 . Findings From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was −3·9 mm Hg (Bayesian 95% credible interval −6·2 to −1·6) and for office systolic blood pressure the difference was −6·5 mm Hg (−9·6 to −3·5). No major device-related or procedural-related safety events occurred up to 3 months. Interpretation SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. Funding Medtronic.

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.

This perspective focuses on the development of tissue engineered (TE) cell-based therapies to treat left ventricular (LV) dysfunction and chronic heart failure (CHF). The development of induced pluripotent stem cells enabled investigators to seed or co-culture human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) alone and in combination with other cells onto bioengineered scaffolds applied to the epicardial surface of the damaged left ventricle. Using our work as an example, we show how a xenograft implant of a bioengineered scaffold embedded with human neonatal fibroblasts and seeded with hiPSC-CMs partially reversed maladaptive LV remodeling and improved LV systolic/diastolic function in an immune-competent rat model of CHF. The fibroblasts lay down an extracellular matrix and secrete growth factors that increase myocardial blood flow. This approach provides an improved cell payload that covers a larger area of the damaged left ventricle as opposed to direct cell injections into the heart or down the coronary arteries. These studies combined with ongoing studies in immune-competent Yucatan mini swine treated with the same xenograft led to the preliminary design of a proposed Phase I clinical trial that will be presented to the Federal Drug Administration. For the proposed Phase I clinical, this TE patch will be implanted onto the epicardial surface of non-immunosuppressed patients undergoing elective Coronary Artery Bypass Grafting with Ejection Fractions ≥ 20% and ≤ 45%. The primary endpoints will be adverse events/severe adverse events associated with placing the TE patch on the heart. While Phase I trials are primarily safety trials, this proposed trial is designed to obtain some potential efficacy endpoints to help with the design of future Phase II/III clinical trials. These endpoints include changes in LV remodeling that were seen in the pre-clinical animal models as well as including endpoints that focus on patient well-being.

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.