Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

The changing landscape of cardiac co-morbidities and in-hospital cardiac complications mediating Covid-19 mortality between 2020 and 2021.

Background: Cardiac co-morbidities and in-hospital cardiac complications significantly contribute to COVID-19 mortality. However, their influence on mortality between 2021 and 2020 may differ due to the availability of vaccines, different viral strains, and therapeutic advancements. Methods: We performed a retrospective chart review and individual patient analysis of all COVID-19 associated in-patient deaths in 2020 (n = 346) and 2021(n = 527) in a large Minneapolis health system. Cause of death was adjudicated by at least two health care providers, including one cardiologist. Results: Patients who died in 2021 were younger, of similar race/ethnicity, and body mass index compared to 2020. In 2021, 24 % of the cohort was full or partially vaccinated, while none were vaccinated in 2020. Patients who died in 2021 had significantly fewer cardiovascular co-morbidities and major adverse cardiovascular events prior to COVID-19 infection, resulting in significantly fewer in-hospital cardiac adverse events compared to patients who died in 2020, including myocardial infarction, stroke, and atrial fibrillation. In contrast, patients in 2021 had significantly higher rates of venous thromboembolic events. Conclusion: Patients who died from COVID-19 in 2021 had significantly fewer cardiovascular co-morbidities and in-hospital cardiovascular complications compared to patients who died in 2020. Sixteen percent of patients stipulated as dying from COVID-19 actually die from other causes.

Incidence, treatment and outcomes of coronary artery dissection during percutaneous coronary intervention.

BACKGROUND: Coronary artery dissection is a feared and potentially life-threatening complication of percutaneous coronary intervention (PCI). METHODS: We examined the clinical, angiographic, and procedural characteristics, and outcomes of coronary dissection at a tertiary care institution. RESULTS: Between 2014 and 2019, unplanned coronary dissection occurred in 141 of 10,278 PCIs (1.4%). Median patient age was 68 (60, 78) years, 68% were men, and 83% had hypertension. The prevalence of diabetes (29%), and prior PCI (37%) was high. Most target vessels were significantly diseased: 48% had moderate/severe tortuosity and 62% had moderate/severe calcification. The most common cause of dissection was guidewire advancement (30%), followed by stenting (22%), balloon angioplasty (20%), and guide-catheter engagement (18%). TIMI flow was 0 in 33% and 1-2 in 41% of cases. Intravascular imaging was used in 17% of the cases. Stenting was used to treat the dissection in 73% of patients. There was no consequence of dissection in 43% of patients. Technical and procedural success was 65% and 55%, respectively. In-hospital major adverse cardiovascular events occurred in 23% of patients: 13 (9%) had an acute myocardial infarction (MI), 3 (2%) had emergency coronary artery bypass graft surgery, and 10 (7%) died. During a mean follow up of 1612 days, 28 (20%) patients died, and the rate of target lesion revascularization was 11.3% (n=16). CONCLUSION: Coronary artery dissection is an infrequent complication of PCI, but is associated with adverse clinical outcomes, such as death and acute MI.

EXACT Trial: Results of the Phase 1 Dose-Escalation Study.

BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown. METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses. CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04125732.

Microvascular obstruction identifies a subgroup of patients who benefit from stem cell therapy following ST-elevation myocardial infarction.

BACKGROUND: Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. METHODS AND RESULTS: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multicenter French BONAMI trial and SWISS-AMI trials. A total of 327 patients had paired imaging data at 1 year. All patients received 100 to 150 million intracoronary autologous BMCs or placebo / control 3 to 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n = 210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n = 146) (P < .01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; P < .05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo. CONCLUSIONS: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

Frequency and outcomes of STEMI patients presenting between 12 and 24 h after symptom onset: Late-presenting STEMI.

OBJECTIVES: To assess the characteristics and prognosis of ST-elevation myocardial infarction (STEMI) patients, presenting between 12 and 24 h after symptom onset, in contemporary regional STEMI systems of care in the United States. BACKGROUND: Previous observational studies have been inconsistent regarding the benefit of primary percutaneous coronary intervention (PCI) compared with conservative management for late-presenting STEMI patients and the majority of randomized trials are from the fibrinolytic era. METHODS: Using a two-center registry-based cohort from March 2003 to December 2020, we evaluated the frequency, clinical characteristics, and outcomes of STEMI patients, stratified by symptom onset to balloon time: <3, 3-6, 6-12, and 12-24 h (late presenters). RESULTS: Among 5427 STEMI patients with available symptom onset time, 6.2% were late presenters, which increased to 11% during the early phase of the Covid-19 pandemic. As symptom onset to balloon time increased, patients were more likely to be older, female, and have a history of hypertension and diabetes mellitus. Late presenters with an identifiable culprit lesion were less likely to be revascularized with PCI (96%, 96%, 95%, and 92%; p for trend = 0.004) and had a longer median door-to-balloon time (82, 109, 107, and 117 min; p for trend < 0.001). In-hospital and 1-year death risks were comparable between late and earlier presenters. CONCLUSION: Despite the unfavorable risk profile and longer door-to-balloon time, clinical outcomes of late presenters were similar to those presenting within 12 h of symptom onset.

Outcomes and challenges of the provisional stenting technique: Insights from the PROGRESS-BIFURCATION registry.

BACKGROUND: Provisional stenting is the most commonly used coronary bifurcation stenting strategy. METHODS: We examined the clinical and angiographic characteristics, challenges encountered, and procedural outcomes with the provisional bifurcation stenting strategy in the Prospective Global Registry of Percutaneous Coronary Intervention (PCI) in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). RESULTS: Provisional stenting was used in 334 of 430 bifurcation interventions (78%). Technical success was lower (95% vs. 100%, p = 0.017) in provisional, but procedural success (90% vs. 95%, p = 0.095) and incidence of in-hospital major adverse cardiovascular events were similar (5% vs. 5%, p = 0.945) compared with two-stent strategies. Provisional was less often preferred in left main/left anterior descending involvement (47% vs. 73%, p < 0.001). Provisional stenting cases had smaller side branch (SB) diameter (2.4 ± 0.5 vs. 2.7 ± 0.6 mm, p < 0.001), shorter SB lesion length (5 [3-8] vs. 10 [5-10] mm, p < 0.001), less SB diameter stenosis (46 ± 35 vs. 81 ± 20%, p < 0.001), and were less likely to be Medina 1,1,1 (34% vs. 73%, p < 0.001). PCI challenges were less common (30% vs. 58%, p < 0.001) with provisional stenting: (1) rewiring difficulty (43%) that was overcome with use of a different wire (74%) or microcatheter (46%); (2) inability to deliver a stent (22%) or balloon (9%) that was overcome with use of a smaller balloon (88%), rewiring (25%), or increased support/microcatheter (25%). CONCLUSIONS: Provisional bifurcation stenting was more often performed in distal lesions with less SB involvement and had lower technical success, but similar procedural success and complications compared with two-stent strategies.

Increasing myocardial edema is associated with greater microvascular obstruction in ST-segment elevation myocardial infarction.

Microvascular obstruction (MVO) frequently develops after ST-elevation myocardial infarction (STEMI) and is associated with increased mortality and adverse left ventricular remodeling. We hypothesized that increased extravascular compressive forces in the myocardium that arise from the development of myocardial edema because of ischemia-reperfusion injury would contribute to the development of MVO. We measured MVO, infarct size, and left ventricular mass in patients with STEMI (n = 385) using cardiac MRI 2 to 3 days following successful percutaneous coronary intervention and stenting. MVO was found in 57% of patients with STEMI. The average infarct size was 45 ± 29 g. Patients with MVO had significantly greater infarct size and reduced left ventricular (LV) function (P < 0.01) compared with patients without MVO. Patients with MVO had significantly greater LV mass than patients without MVO and there was a linear increase in MVO with increasing LV mass (P < 0.001). Myocardial edema by T2-weighted imaging increased with increasing LV mass and patients with MVO had significantly greater myocardial edema than patients without MVO (P < 0.01). Patients with MVO had significantly greater left ventricular end-diastolic pressure (LVEDP) than patients without MVO (P < 0.05). In a cohort of patients with STEMI who underwent primary percutaneous intervention, we observed that MVO increased linearly with increasing LV mass and was associated with increased myocardial edema and higher LVEDP. These observations support the concept that extravascular compressive forces in the left ventricle may increase with increasing ischemic injury and contribute to the development of MVO.NEW & NOTEWORTHY 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.

Circadian dependence of microvascular obstruction during ST-segment elevation myocardial infarction.

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Incidence, Treatment, and Outcomes of Coronary Artery Perforation During Percutaneous Coronary Intervention.

OBJECTIVES: To examine the incidence, treatment and outcomes of perforation during percutaneous coronary intervention (PCI). BACKGROUND: Coronary perforation is a potentially life-threatening PCI complication. METHODS: We examined the clinical, angiographic, and procedural characteristics, management, and outcomes of coronary perforation at a tertiary care institution. RESULTS: 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. CONCLUSIONS: 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.

Challenges and outcomes of the double kissing crush stenting technique: Insights from the PROGRESS-BIFURCATION registry.

BACKGROUND: Although the double kissing (DK) crush stenting technique can provide excellent outcomes in percutaneous coronary intervention (PCI) of bifurcation lesions, it can be challenging to perform. METHODS: We examined the clinical and angiographic characteristics, challenges encountered, and procedural outcomes of bifurcation PCI with DK crush in Prospective Global Registry of Percutaneous Coronary Intervention in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). RESULTS: DK crush was used in 48 of 435 bifurcation lesions (11%). Technical success was 100%, procedural success was 96%, and the incidence of in-hospital major adverse cardiovascular events was 4%. Challenges while performing DK crush were encountered in 26 lesions (54%): (1) difficulty in side branch (SB) first rewiring (38%) that was overcome with the use of a new guidewire (30%) or a microcatheter (15%); (2) inability to deliver balloon to an SB for the first kiss (54%) that was overcome with the use of a smaller balloon (86%), rewiring (29%), microcatheter (14%), and increased support 7%; (3) difficulty in SB second rewiring (19%) that was overcome with the use of a new guidewire (80%) and/or microcatheter (60%). DK crush was more often performed in left main and proximal left anterior descending artery lesions (70% vs. 50%, p = 0.014). DK crush cases required more contrast (198 ± 84 ml vs. 163 ± 70 ml, p = 0.003), fluoroscopy time (35 ± 20 min vs. 25 ± 21 min, p = 0.004), and lasted longer (137 ± 69 min vs. 99 ± 66 min, p = 0.001) compared with non-DK crush techniques. CONCLUSIONS: While challenges are common when performing DK crush bifurcation stenting, success rates are high and complication rates are low.

Recommendations for nomenclature and definition of cell products intended for human cardiovascular use.

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.

Dare to dream? Cell-based therapies for heart failure after DREAM-HF: Review and roadmap for future clinical study.

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.

Peripheral Blood Biomarkers Associated With Improved Functional Outcome in Patients With Chronic Left Ventricular Dysfunction: A Biorepository Evaluation of the FOCUS-CCTRN Trial.

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.

Epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (The EXACT Trial): Rationale, design, and clinical considerations.

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 Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (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 epicardial 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.

Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial.

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 <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups. RESULTS: In 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). CONCLUSIONS: In 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 NUMBER: NCT01458405.

Comparison of Outcomes of Patients with vs without Previous Coronary Artery Bypass Graft Surgery Presenting with ST-Segment Elevation Acute Myocardial Infarction.

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, p <0.001) and more likely to have diabetes (40% vs 21%, p <0.001) compared with patients without previous CABG. Previous CABG patients had higher mortality and MACE at 5 years (p <0.001). 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 (p <0.001) 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.