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Background Most 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.Methods In this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF

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.

ST-elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality in the United States. Timely reperfusion with primary percutaneous coronary intervention is associated with improved outcomes. The Society for Cardiovascular Angiography & Interventions puts forth this expert consensus document regarding best practices for cardiac catheterization laboratory team readiness, arterial access with an algorithm to help determine proper arterial access in STEMI, and diagnostic angiography. This consensus statement highlights the strengths and limitations of various diagnostic and therapeutic interventions to access and treat a patient with STEMI in the catheterization laboratory, reviews different options to manage large thrombus burden during STEMI, and reviews the management of STEMI across the spectrum of various anatomical and clinical circumstances.

Abstract Aims Age is an important risk factor for mortality among patients with cardiogenic shock and heart failure (HF). We sought to assess the extent to which age modified the performance of the Society for Cardiovascular Angiography and Interventions (SCAI) shock stage for in‐hospital and 1 year mortality in cardiac intensive care unit (CICU) patients with and without HF. Methods and results We retrospectively reviewed unique admissions to the Mayo Clinic CICU during 2007–2015 and stratified patients by age and SCAI shock stage. The association between age and in‐hospital mortality was analysed using multivariable logistic regression, and 1 year mortality was analysed using Cox proportional hazards analysis, both in the entire cohort and among patients with an admission diagnosis of HF or acute coronary syndrome (ACS). The final study population included 10 004 unique patients with a mean age of 67 ± 15 years, including 46.1% with HF and 43.1% with ACS. Older patients more frequently had HF and had more extensive co‐morbidities, higher illness severity, more organ failure, and differential use of critical care therapies. The percentage of patients with SCAI shock stages A, B, C, D, and E were 46%, 30%, 16%, 7%, and 1%, respectively. Patients with HF were older, had greater severity of illness and higher SCAI shock stage, and had higher rates of death at all time points. In‐hospital mortality occurred in 908 (9%) patients, including 549 (12%) patients with HF (61% of all hospital deaths). Age was independently associated with hospital mortality (adjusted odds ratio per 10 years 1.3, 95% confidence interval 1.2–1.4, P

Abstract Patients with refractory angina who are suboptimal candidates for further revascularization have improved exercise time, decreased angina frequency, and reduced major adverse cardiac events with intramyocardial delivery of CD34+ cells. However, the effect of CD34+ cell therapy on health care expenditures before and after treatment is unknown. We determined the effect of CD34+ cell therapy on cardiac‐related hospital visits and costs during the 12 months following stem cell injection compared with the 12 months prior to injection. Cardiac‐related hospital admissions and procedures were retrospectively tabulated for patients enrolled at one site in one of three double‐blinded, placebo‐controlled CD34+ trials in the 12 months before and after intramyocardial injections of CD34+ cells vs placebo. Fifty‐six patients were randomized to CD34+ cell therapy (n = 37) vs placebo (n = 19). Patients randomized to cell therapy experienced 1.57 ± 1.39 cardiac‐related hospital visits 12 months before injection, compared with 0.78 ± 1.90 hospital visits 12 months after injection, which was associated with a 62% cost reduction translating to an average savings of $5500 per cell therapy patient. Patients in the placebo group also demonstrated a reduction in cardiac‐related hospital events and costs, although to a lesser degree than the CD34+ group. Through 1 January 2019, 24% of CD34+ subjects died at an average of 6.5 ± 2.4 years after enrollment, whereas 47% of placebo patients died at an average of 3.7 ± 1.9 years after enrollment. In conclusion, CD34+ cell therapy for subjects with refractory angina is associated with improved mortality and a reduction in hospital visits and expenditures for cardiac procedures in the year following treatment.

Tremendous progress has been made in the treatment of ST-segment elevation myocardial infarction (STEMI), the most severe and time-sensitive acute coronary syndrome. Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion, which has stimulated the development of regional STEMI systems of care with standardized protocols designed to optimize care. However, challenges remain for patients with cardiogenic shock, out-of-hospital cardiac arrest, an expected delay to reperfusion (>120 min), in-hospital STEMI, and more recently, those with Covid-19 infection. Ultimately, the goal is to provide timely reperfusion with primary PCI coupled with the optimal antiplatelet and anticoagulant therapies. We review the challenges and provide insights into the remaining knowledge gaps for contemporary STEMI care.

Our previous research found seven specific factors that cause system delays in ST-elevation Myocardial infarction management in developing countries. These delays, in conjunction with a lack of organized STEMI systems of care, result in inefficient processes to treat AMI in developing countries. In our present opinion paper, we have specifically explored the three most pertinent causes that afflict the seven specific factors responsible for system delays. In doing so, we incorporated a unique strategy of global STEMI expertise. With this methodology, the recommendations were provided by expert Indian cardiologist and final guidelines were drafted after comprehensive discussions by the entire group of submitting authors. We expect these recommendations to be utilitarian in improving STEMI care in developing countries.

Abstract Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76–94% elevated) than non-responders. Several biomarkers had values that differed significantly (P 0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

Background Little is known regarding use of cardiac therapies and clinical outcomes among older myocardial infarction (MI) patients with cognitive impairment. Methods and Results Patients ≥65 years old with MI in the NCDR (National Cardiovascular Data Registry) Chest Pain–MI Registry between January 2015 and December 2016 were categorized by presence and degree of chart‐documented cognitive impairment. We evaluated whether cognitive impairment was associated with all‐cause in‐hospital mortality after adjusting for known prognosticators. Among 43 812 ST‐segment–elevation myocardial infarction (STEMI) patients, 3.9% had mild and 2.0% had moderate/severe cognitive impairment; among 90 904 non–ST‐segment–elevation myocardial infarction (NSTEMI patients, 5.7% had mild and 2.6% had moderate/severe cognitive impairment. A statistically significant but numerically small difference in the use of primary percutaneous coronary intervention was observed between patients with STEMI with and without cognitive impairment (none, 92.1% versus mild, 92.8% versus moderate/severe, 90.4%; P=0.03); use of fibrinolysis was lower among patients with cognitive impairment (none, 40.9% versus mild, 27.4% versus moderate/severe, 24.2%; P

Background Hypertension remains one of the most important, modifiable cardiovascular risk factors. Yet, the largest minority ethnic group (Hispanics/Latinos) often have different health outcomes and behavior, making hypertension management more difficult. We explored the effects of an American Heart Association–sponsored population health intervention aimed at modifying behavior of Latinos living in Texas. Methods and Results We enrolled 8071 patients, and 5714 (65.7%) completed the 90‐day program (58.5 years ±11.7; 59% female) from July 2016 to June 2018. Navigators identified patients with risk factors; initial and final blood pressure (BP) readings were performed in the physician's office; and interim home measurements were recorded telephonically. The intervention incorporated home BP monitoring, fitness and nutritional counseling, and regular follow‐up. Primary outcomes were change in systolic BP and health‐related quality of life. Using a univariate paired‐samples pre–post design, we found an average 5.5% (7.6‐mm Hg) improvement in systolic BP (139.1 versus 131.5, t=10.32, P

Autologous cardiosphere-derived cells (CDCs) were the first therapeutic modality to demonstrate myocardial regeneration with a decrease in scar size and an increase in viable, functional tissue. Widespread applicability of autologous CDC therapy is limited by the need for patient-specific myocardial biopsy, cell processing, and quality control, resulting in delays to therapy and inherent logistical and economic constraints. Preclinical data had demonstrated equivalent efficiency of allogeneic to autologous CDCs. The ALLogeneic Heart STem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial is a multicenter randomized, double-blind, placebo-controlled phase 1/2 safety and efficacy trial of intracoronary delivery of allogeneic CDCs (CAP-1002) in patients with myocardial infarction (MI) and ischemic left ventricular dysfunction. The phase 1 safety cohort enrolled 14 patients in an open-label, nonrandomized, dose-escalation safety trial. The phase 2 trial is a doubleblind, randomized, placebo-controlled trial that will compare intracoronary CDCs to placebo in a 2:1 allocation and will enroll up to 120 patients. The primary endpoint for both phases is safety at 1 month. For phase 2, the primary efficacy endpoint is relative change from baseline in infarct size at 12 months, as assessed by magnetic resonance imaging. The ALLSTAR trial employs a “seamless” WOVE 1 design that enables continuous enrollment from phase 1 to phase 2 and will evaluate the safety of intracoronary administration of allogeneic CDCs and its efficacy in decreasing infarct size in post-MI patients.

Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient's own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90 + mesenchymal stem cells (MSCs), and CD45 + CD14 + autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM). This ongoing randomized, double-blinded, placebo-controlled phase 2b trial (ixCELL-DCM) was designed to assess the efficacy, safety, and tolerability of catheter-based transendocardial injection of ixmyelocel-T in patients with heart failure due to IDCM. Patients ( N = 114) with New York Heart Association class III or IV symptomatic heart failure due to IDCM, who have left ventricular ejection fraction ≤35% and an automatic implantable cardioverter defibrillator, but are ineligible for revascularization procedures, were randomly assigned (1:1 ratio) to ixmyelocel-T or placebo (vehicle control). The primary efficacy endpoint is a composite of the total number of deaths, cardiovascular hospitalizations, or unplanned clinic visits to treat acutely decompensated heart failure during the 12 months following treatment administration. Secondary endpoints include the win ratio analysis for hierarchical occurrences of clinical events in the primary endpoint, total numbers of clinical events, left ventricular structure and function, and quality-of-life assessments. ixCELL-DCM is one of the largest cell therapy trials in heart failure patients to date and the first double-blinded, placebo-controlled study of ixmyelocel-T administered via transendocardial catheter-based injections in patients with heart failure secondary to IDCM.

Approximately 31% of patients previously infected with SARS-CoV-2 are living with symptoms of long COVID in the United States. Long COVID significantly reduces quality of life and increases morbidity and disability; however, treatment options are limited. Enhanced External Counterpulsation (EECP) is an FDA-approved, non-invasive treatment for the management of cardiovascular symptoms with a mechanism of action which stimulates pathways that induce endothelial homeostasis, improving microvascular function, inflammation, and immune regulation, thereby potentially targeting the underlying etiology of long COVID. We recently reported that EECP improved symptoms in 231 patients with long COVID. Previous studies assessing the effects of EECP for long COVID have lacked a control group. As such, this analysis is the first comparing outcomes in patients with long COVID undergoing EECP (n = 33) to a non-treated group (control, n = 33). The patients were matched for baseline characteristics, and all patients completed patient-reported outcome assessments, including PROMIS Fatigue, the Duke Activity Status Index (DASI), and the Rose Dyspnea Scale (RDS), two times within a specified time interval. When comparing the average change from baseline in both groups, the EECP-treated patients’ improvement was significantly greater than the improvement in the control group across all measured endpoints, including PROMIS Fatigue (−15.0 ± 8.9 vs. −2.8 ± 5.9, p < 0.001) and DASI (+17.8 (11.8, 26.8) vs. +1.8 (−3.5, 5.5), p < 0.001), and there was an improvement of ≥1 in the RDS class (75.8% vs. 33.3%, p < 0.001). This study’s limitations include the small sample size and lack of information regarding concurrent treatments or interventions in the non-treated group; however, these preliminary data support EECP as a potential low-risk treatment option for patients with long COVID.

Background: In patients with angina and non-obstructive coronary artery disease (ANOCA), diagnosis of coronary microvascular dysfunction (CMD) remains an unmet need. Magnetocardiography (MCG), is a rest-based, non-invasive scan that can detect weak electrophysiological changes that occur at the early phase of ischemia. Objective: This study assessed the ability of MCG to detect CMD in ANOCA patients as compared to reference standard, invasive coronary flow reserve (CFR). Methods: Patients with ANOCA and invasive coronary physiologic assessment using intracoronary flow measurements with Doppler and thermodilution methods were enrolled. CMD was defined dichotomously as an invasive CFR

Background One‐time assessment of the Society for Cardiovascular Angiography and Interventions (SCAI) shock classification robustly predicts mortality in the cardiac intensive care unit (CICU). We sought to determine whether serial SCAI shock classification could improve risk stratification. Methods and Results Unique admissions to a single academic level 1 CICU from 2015 to 2018 were included in this retrospective cohort study. Electronic health record data were used to assign the SCAI shock stage during 4‐hour blocks of the first 24 hours of CICU admission. Shock was defined as hypoperfusion (SCAI shock stage C, D, or E). In‐hospital death was evaluated using logistic regression. Among 2918 unique CICU patients, 1537 (52.7%) met criteria for shock during ≥1 block, and 266 (9.1%) died in the hospital. The SCAI shock stage on admission was: A, 37.6%; B, 31.5%; C, 25.9%; D, 1.8%; and E, 3.3%. Patients who met SCAI criteria for shock on admission (first 4 hours) and those with worsening SCAI shock stage after admission were at higher risk for in‐hospital death. Each higher admission (adjusted odds ratio, 1.36 [95% CI, 1.18–1.56]; area under the receiver operating characteristic curve, 0.70), maximum (adjusted odds ratio, 1.59 [95% CI, 1.37–1.85]; area under the receiver operating characteristic curve, 0.73) and mean (adjusted odds ratio, 2.42 [95% CI, 1.99–2.95]; area under the receiver operating characteristic curve, 0.78) SCAI shock stage was incrementally associated with a higher in‐hospital mortality rate. Discrimination was highest for the mean SCAI shock stage (P

Angina or ischemia with no obstructive coronary disease (ANOCA/INOCA) is a common but under-treated condition due to poorly understood pathophysiologic mechanisms, limited diagnostic tools, and lack of proven targeted therapy. Coronary microvascular dysfunction (CMD) occurs when the microvasculature inadequately perfuses the myocardium under stress, or at rest in the case of microvascular spasm resulting in ANOCA/INOCA. Coronary functional angiography (CFA) measures endothelial independent microvascular dysfunction (coronary flow reduction

Although there is an established association between elevated triglyceride (eTG, ≥175 mg/dl) levels and adverse cardiovascular events, some studies have suggested that eTG levels may be linked to neutral or even improved clinical outcomes, particularly among patients with acute myocardial infarction. However, these studies had certain limitations, including small sample sizes, heterogeneous study populations, and inadequate statistical adjustments. To address these limitations, we conducted an analysis of 5347 patients with ST-segment elevation myocardial infarction (STEMI) between March 2003 and December 2020, using a prospective registry-based cohort from two large, regional STEMI centers. We used a triglyceride level of 175 mg/dl as the cutoff point for eTG levels. Of the study participants, 24.5% (n = 1312) had eTG levels. These patients were more likely to be younger, male, and have a higher number of cardiovascular risk factors compared to those with low TG levels. Despite these unfavorable cardiovascular risk profiles, patients with eTG levels had lower unadjusted risks of 1-year major adverse cardiac events (MACE) -a composite of myocardial infarction, stroke, and death- than those with low TG levels (8.8% vs. 11%, p = 0.034). However, after adjusting for certain clinical factors and lipid profile, eTG levels were not associated with a lower 1-year MACE (aHR: 1.10 (0.71–1.70), p = 0.7). In conclusion, a quarter of STEMI patients had eTG levels and these patients had comparable long-term cardiovascular outcomes compared to those with low TG levels after controlling for clinical factors and lipid profile.

Background Diabetes mellitus and high platelet reactivity (HPR) on clopidogrel are both associated with increased risk of ischemic events after percutaneous coronary intervention, but whether the HPR‐associated risk of adverse ischemic events differs by diabetes mellitus status is unknown. Methods and Results ADAPT‐DES (Assessment of Dual Antiplatelet Therapy With Drug‐Eluting Stents) was a prospective, multicenter registry of patients treated with coronary drug‐eluting stents. HPR was defined as P2Y12 reaction units >208 by the VerifyNow point‐of‐care assay. Cox multivariable analysis was used to assess whether HPR‐associated risk of major adverse cardiac events (MACE; cardiac death, myocardial infarction, or stent thrombosis) varied for patients with insulin‐treated diabetes mellitus (ITDM), non–ITDM, and no diabetes mellitus. Diabetes mellitus and HPR were included in an interaction analysis. Of 8582 patients enrolled, 2429 (28.3%) had diabetes mellitus, of whom 998 (41.1%) had ITDM. Mean P2Y12 reaction units were higher in patients with diabetes mellitus versus without diabetes mellitus, and HPR was more frequent in patients with diabetes mellitus. HPR was associated with consistently increased 2‐year rates of MACE in patients with and without diabetes mellitus (Pinteraction=0.36). A significant interaction was present between HPR and non–insulin‐treated diabetes mellitus versus ITDM for 2‐year MACE (adjusted hazard ratio [HR] for non–ITDM, 2.28 [95% CI, 1.39–3.73] versus adjusted HR for ITDM, 1.02 [95% CI, 0.70–1.50]; Pinteraction=0.01). Conclusions HPR was more common in patients with diabetes mellitus and was associated with an increased risk of MACE in both patients with and without diabetes mellitus. In patients with diabetes mellitus, a more pronounced effect of HPR on MACE was present in lower‐risk non–ITDM patients than in higher‐risk patients with ITDM. Registration URL: https://clinicaltrials.gov/ct2/show/NCT00638794; Unique identifier: NCT00638794. ADAPT‐DES (Assessment of Dual Antiplatelet Therapy With Drug‐Eluting Stents).

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is evident in up to 15% of all acute myocardial infarctions (AMI) and disproportionally affects females. Despite younger age, female predominance, and fewer cardiovascular risk factors, MINOCA patients have a worse prognosis than patients without cardiovascular disease and a similar prognosis compared to patients with MI and obstructive coronary artery disease (CAD). MINOCA is a syndrome with a broad differential diagnosis that includes both ischemic [coronary artery plaque disruption, coronary vasospasm, coronary microvascular dysfunction, spontaneous coronary artery dissection (SCAD), and coronary embolism/thrombosis] and non-ischemic mechanisms (Takotsubo cardiomyopathy, myocarditis, and non-ischemic cardiomyopathy)—the latter called MINOCA mimickers. Therefore, a standardized approach that includes multimodality imaging, such as coronary intravascular imaging, cardiac magnetic resonance, and in selected cases, coronary reactivity testing, including provocation testing for coronary vasospasm, is necessary to determine underlying etiology and direct treatment. Herein, we review the prevalence, characteristics, prognosis, diagnosis, and treatment of MINOCA -a syndrome often overlooked.

Background Persistence to P2Y12 inhibitors after myocardial infarction (MI) remains low. Out‐of‐pocket cost is cited as a factor affecting medication compliance. We examined whether a copayment intervention affected 1‐year persistence to P2Y12 inhibitors and clinical outcomes. Methods and Results In an analysis of ARTEMIS (Affordability and Real‐World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study), patients with MI discharged on a P2Y12 inhibitor were stratified by baseline out‐of‐pocket medication burden: low ($0–$49 per month), intermediate ($50–$149 per month), and high (≥$150 per month). The impact of the voucher intervention on 1‐year P2Y12 inhibitor persistence was examined using a logistic regression model with generalized estimating equations. We assessed the rates of major adverse cardiovascular events among the groups using a Kaplan–Meier estimator. Among 7351 MI‐treated patients at 282 hospitals, 54.2% patients were in the low copay group, 32.0% in the middle copay group, and 13.8% in the high copay group. Patients in higher copay groups were more likely to have a history of prior MI, heart failure, and diabetes compared with the low copay group (all P

Abstract 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.

Abstract Aims This study aims to explore long‐term clinical outcomes of cardiopoiesis‐guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART‐1) trial. Methods and results CHART‐1 is a multinational, randomized, and double‐blind trial conducted in 39 centres in heart failure patients (n = 315) on standard‐of‐care therapy. The ‘active’ group received cardiopoietic stem cells delivered intramyocardially using a retention‐enhanced catheter. The ‘control’ group underwent patient‐level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann–Whitney estimator 0.52, 95% confidence interval (CI) 0.45–0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow‐up, patients with left ventricular end‐diastolic volume of 200–370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16–0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09–0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. Conclusions Longitudinal follow‐up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long‐term clinical follow‐up thus offers guidance for future targeted trials.

Clinical trials of cell-based therapies for heart failure have resulted in significant strides forward in our understanding of the potential the failing heart has for regeneration and repair. Yet, two decades on, the need for novel cell-based therapies for heart failure has never been greater. The DREAM-HF trial, which was presented as a late-breaking trial at the American Heart Association Scientific Sessions 2021 did not meet the primary heart failure outcome, but did show a large, clinically significant reduction in major adverse cardiovascular events (MACE) in patients receiving cells, an effect that was most pronounced in patients with evidence of maladaptive inflammation. These results represent an important step forward in our understanding of how cell-based therapies can exert beneficial effects in patients with heart failure and should serve as a guide for future clinical efforts. In light of the results of DREAM-HF, this review serves to provide an understanding of the current state of cell-based therapies for heart failure, as well as to highlight major knowledge gaps and suggest guiding principles for clinical trials of cell therapy going forward. Using the knowledge gained from DREAM-HF along with the trials that preceded it, the potential for breakthrough cell-based therapies for heart failure in the coming decade is immense.

Study objective: Since the 1990s, national guidelines have recommended hospitals develop STEMI treatment protocols and monitor quality. A 2003 survey of Minnesota hospitals without cardiac catheterization laboratories (CCL) found

Background Contemporary real‐world data on stroke in patients presenting with ST‐segment–elevation myocardial infarction (STEMI) are scarce. Methods and Results We evaluated the incidence, trends, cause, and predictors of stroke from 2003 to 2019 in 4 large regional STEMI programs in the upper Midwest that use similar transfer and treatment protocols. We also evaluated the long‐term impact of stroke on 5‐year mortality. Multivariate logistic and Cox regression analysis was used to identify variables independently associated with stroke in patients presenting with STEMI and identify variables associated with 5‐year mortality. A total of 12 868 patients presented with STEMI during the study period. Stroke occurred in 98 patients (0.76%). The incidence of stroke remained stable over time (0.5% in 2003, 1.2% in 2019; P‐trend=0.22). Most (75%) of strokes were ischemic, with a median time to stroke symptoms of 14 hours after primary percutaneous coronary intervention (interquartile range, 4–72 hours), which led to a small minority (3%) receiving endovascular treatment and high in‐hospital mortality (18%). On multivariate regression analysis, age (increment of 10 years) (odds ratio [OR], 1.32; 95% CI, 1.10–1.58; P‐value=0.003) and preintervention cardiogenic shock (OR, 2.03; (95% CI, 1.03–3.78; P=0.032)) were associated with a higher risk of in‐hospital stroke. In‐hospital stroke was independently associated with increased risk of 5‐year mortality (hazard ratio, 2.01; 95% CI, 1.13–3.57; P=0.02). Conclusions In patients presenting with STEMI, the risk of stroke is low (0.76%). A stroke in patients presenting with STEMI is associated with significantly higher in‐hospital (18%) and long‐term mortality (35% at 5 years). Stroke was associated with double the risk of 5‐year death.

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. Key Words: biomaterial, catheter, heart failure, injectable, myocardial infarction

Background Hospitals commonly provide a short‐term supply of free P2Y12 inhibitors at discharge after myocardial infarction, but it is unclear if these programs improve medication persistence and outcomes. The ARTEMIS (Affordability and Real‐World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) trial randomized hospitals to usual care versus waived P2Y12 inhibitor copayment costs for 1‐year post‐myocardial infarction. Whether the impact of this intervention differed between hospitals with and without pre‐existing medication assistance programs is unknown. Methods and Results In this post hoc analysis of the ARTEMIS trial, we examined the associations of pre‐study free medication programs and the randomized copayment voucher intervention with P2Y12 inhibitor persistence (measured by pharmacy fills and patient report) and major adverse cardiovascular events using logistic regression models including a propensity score. Among 262 hospitals, 129 (49%) offered pre‐study free medication assistance. One‐year P2Y12 inhibitor persistence and major adverse cardiovascular events risks were similar between patients treated at hospitals with and without free medication programs (adjusted odds ratio 0.93, 95% CI, 0.82–1.05 and hazard ratio 0.92, 95% CI, 0.80–1.07, respectively). The randomized copayment voucher intervention improved persistence, assessed by pharmacy fills, in both hospitals with (53.6% versus 44.0%, adjusted odds ratio 1.45, 95% CI, 1.20–1.75) and without (59.0% versus 48.3%, adjusted odds ratio 1.46, 95% CI, 1.25–1.70) free medication programs (Pinteraction=0.71). Differences in patient‐reported persistence were not significant after adjustment. Conclusions While hospitals commonly report the ability to provide free short‐term P2Y12 inhibitors, we did not find association of this with medication persistence or major adverse cardiovascular events among patients with insurance coverage for prescription medication enrolled in the ARTEMIS trial. An intervention that provided copayment assistance vouchers for 1 year was successful in improving medication persistence in hospitals with and without pre‐existing short‐term medication programs. Registration URL: https://www.clini​caltr​ials.gov/. Unique identifier: NCT02406677.

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve + cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34+ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial.

Background We aimed to determine the change in treatment strategies and times to treatment over the first 5 years of the Mission: Lifeline program. Methods and Results We assessed pre‐ and in‐hospital care and outcomes from 2008 to 2012 for patients with ST‐segment–elevation myocardial infarction at US hospitals, using data from the National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry—Get With The Guidelines Registry. In‐hospital adjusted mortality was calculated including and excluding cardiac arrest as a reason for primary percutaneous coronary intervention delay. A total of 147 466 patients from 485 hospitals were analyzed. There was a decrease in the proportion of eligible patients not treated with reperfusion (6.2% versus 3.3%) and treated with fibrinolytic therapy (13.4% versus 7.0%). Median time from symptom onset to first medical contact was unchanged (≈50 minutes). Use of prehospital ECGs increased (45% versus 71%). All major reperfusion times improved: median first medical contact‐to‐device for emergency medical systems transport to percutaneous coronary intervention–capable hospitals (93 to 84 minutes), first door‐to‐device for transfers for primary percutaneous coronary intervention (130 to 112 minutes), and door‐in–door‐out at non–percutaneous coronary intervention–capable hospitals (76 to 62 minutes) (all P

BackgroundGuidelines recommend P2Y12 inhibitor therapy for 1 year after myocardial infarction (MI), yet little guidance is provided on antiplatelet management for patients with recurrent ischemic events during that year. We describe changes in P2Y12 inhibitor type among patients with recurrent ischemic events in the first year after MI. Methods and ResultsThe TRANSLATE‐ACS (Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study enrolled 12 365 patients with MI treated with percutaneous coronary intervention. We examined whether P2Y12 inhibitor choice changed among patients with recurrent MI, stent thrombosis, and/or unplanned revascularization during the first year after MI, and modeled factors associated with P2Y12 inhibitor intensification (changing clopidogrel to prasugrel or ticagrelor). In the first year after MI, 1414 patients (11%) had a total of 1740 recurrent ischemic events (771 recurrent MIs, 969 unplanned revascularizations, and 165 stent thromboses). Median time to the first recurrent ischemic event was 154 days (25th–75th percentiles, 55–287 days). Of those with recurrent ischemic events, 101 of 1092 (9.3%) occurring in clopidogrel‐treated patients led to P2Y12 inhibitor intensification. Recurrent events involving stent thrombosis or MI were the strongest factors associated with P2Y12 inhibitor intensification, yet only 40% of patients with stent thrombosis and 14% of patients with recurrent MI had P2Y12 inhibitor intensification. Increasing age and longer time from the index MI were associated with lower likelihood for intensification. ConclusionsFew patients after MI with a recurrent ischemic event who were taking clopidogrel switched to a more potent P2Y12 inhibitor, even after stent thrombosis events. Specific guidance is needed for patients who have recurrent ischemic events, particularly when closely spaced. Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01088503.

BackgroundThe impact of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines on statin eligibility in individuals otherwise destined to experience cardiovascular disease (CVD) events is unclear. Methods and ResultsWe analyzed a prospective cohort of consecutive ST‐segment elevation myocardial infarction (STEMI) patients from a regional STEMI system with data on patient demographics, low‐density lipoprotein cholesterol levels, CVD risk factors, medication use, and outpatient visits over the 2 years prior to STEMI. We determined pre‐STEMI eligibility according to American College of Cardiology/American Heart Association guidelines and the prior Third Report of the Adult Treatment Panel guidelines. Our sample included 1062 patients with a mean age of 63.7 (13.0) years (72.5% male), and 761 (71.7%) did not have known CVD prior to STEMI. Only 62.5% and 19.3% of individuals with and without prior CVD were taking a statin before STEMI, respectively. In individuals not taking a statin, median (interquartile range) low‐density lipoprotein cholesterol levels in those with and without known CVD were low (108 [83, 138] mg/dL and 110 [87, 133] mg/dL). For individuals not taking a statin, only 38.7% were statin eligible by ATP III guidelines. Conversely, 79.0% would have been statin eligible according to American College of Cardiology/American Heart Association guidelines. Less than half of individuals with (49.2%) and without (41.1%) prior CVD had seen a primary care provider during the 2 years prior to STEMI. ConclusionsIn a large cohort of STEMI patients, application of American College of Cardiology/American Heart Association guidelines more than doubled pre‐STEMI statin eligibility compared with Third Report of the Adult Treatment Panel guidelines. However, access to and utilization of health care, a necessity for guideline implementation, was suboptimal prior to STEMI.

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.

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