Understanding triple negative myeloproliferative neoplasms: pathogenesis, clinical features, and management.

ABSTRACTMyeloproliferative neoplasms (MPNs) that lack the classical "driver mutations," termed triple negative MPNs, remain a poorly understood entity. Despite considerable progress toward understanding MPN pathobiology, the mechanisms leading to the development of these MPNs remains inadequately elucidated. While triple negative primary myelofibrosis (TN-PMF) portends a poor prognosis, triple negative essential thrombocythemia (TN-ET) is more favorable as compared with JAK2 mutated ET. In this review, we summarize the clinical features and prognosis of TN-PMF and -ET as well as diagnostic challenges including identification of non-canonical driver mutations. We also discuss additional molecular drivers to better understand possible pathogenic mechanisms underlying triple negative MPNs. Finally, we highlight current therapeutic approaches as well as novel targets, particularly in the difficult to treat TN-PMF population.

Body temperature as a predictor of mortality in COVID-19.

It remains uncertain if body temperature (BT) is a useful prognostic indicator in coronavirus disease 2019 (COVID-19). We investigated the relationship between BT and mortality in COVID-19 patients. We used a de-identified database that prospectively collected information from patients screened for COVID-19 at the Mount Sinai facilities from February 28, 2020 to July 28, 2021. All patients diagnosed with COVID-19 that had BT data were included. BT at initial presentation, maximum BT during hospitalization, comorbidity, and vaccination status data were extracted. Mortality rate was assessed as a primary outcome. Among 24,293 cases, patients with initial BT below 36 °C had higher mortality than those with BT of 36-37 °C (p < 0.001, odds ratio 2.82). Initial BT > 38 °C was associated with high mortality with an incremental trend at higher BT. In 10,503 in-patient cases, a positive association was observed between mortality and maximum BT except in patients with BT < 36 °C. Multiple logistic regression analyses including the comorbidities revealed that maximum BT was an independent predictor of mortality. While vaccination did not change the distribution of maximum BT, mortality was decreased in vaccinated patients. Our retrospective cohort study suggests that high maximum BT is an independent predictor of higher mortality in COVID-19 patients.

T1 Gastric Cancer Is Associated With a High Incidence of Regional Lymph Node Metastases.

INTRODUCTION: Early stage gastric cancer, particularly T1 disease, is associated with high recurrence-free and overall survival rates following resection with curative intent. However, rare cases of T1 gastric cancer have nodal metastasis and this is associated with poor outcomes. METHODS: Data from gastric cancer patients treated with surgical resection and D2 lymph node (LN) dissection at a single tertiary care institution from 2010 to 2020 were analyzed. Patients with early stage (T1) tumors were assessed in detail to identify variables associated with regional LN metastasis including histologic differentiation, signet ring cells, demographics, smoking history, neoadjuvant therapy, and clinical staging by endoscopic ultrasound (EUS). We used standard statistical techniques including Mann-Whitney U and Chi-squared tests. RESULTS: Of 426 patients undergoing surgery for gastric cancer, 34% (n = 146) were diagnosed with T1 disease on surgical pathology. Among 146 T1 (T1a, T1b) gastric cancers, 24 patients [(17%) T1a (n = 4), T1b (n = 20)] had histologically confirmed regional LN metastases. The age at diagnosis ranged between 19 and 91 y and 54.8% were male. Prior smoking status was not associated with nodal positivity (P = 0.650). Of the 24 patients with positive LN on final pathology, seven patients received neoadjuvant chemotherapy. EUS was performed on 98 (67%) of the 146 T1 patients. Of these patients, 12 (13.2%) had positive LN on final pathology; however, none (0/12) were detected on preoperative EUS. There was no association between node status on EUS and node status on final pathology (P = 0.113). The sensitivity of EUS for N status was 0%, specificity was 84.4%, negative predictive value was 82.2% and positive predictive value was 0%. Signet ring cells were identified in 42% of node negative T1 tumors and 64% of node positive T1 tumors (P = 0.063). For LN positive cases on surgical pathology, 37.5% had poor differentiation, 42% had lymphovascular invasion, and regional nodal metastases were associated with increasing T stage (P = 0.003). CONCLUSIONS: T1 gastric cancer is associated with a substantial risk (17%) of regional LN metastasis, when pathologically staged following surgical resection and D2 lymphadenectomy. Clinically staged N+ disease by EUS was not significantly associated with pathologically staged N+ disease in these patients.

Natural history of bicuspid aortic valves and ascending aortic aneurysms: Aortic center experience.

BACKGROUND AND AIM: The American Association of Thoracic Surgery published guidelines in 2018 encouraging regular surveillance rather than surgical intervention for ascending aortic aneurysms under 5.5 cm in both bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients. Since then, there have been limited studies reporting outcomes, especially by valve type. We aimed to analyze clinical outcomes including survival and aortic events in a cohort of BAV and TAV patients with ascending aortic aneurisms followed conservatively with routine computerized tomography  (CT) surveillance per current guidelines. METHODS: We followed 188 patients in our clinic between 2016 and 2019; 147 had two or more CT scans which allowed measurement of aortic growth. Echocardiogram data was evaluated for each patient. We identified similar cohorts of BAV (n = 32) and TAV (n = 64) patients matched by age, sex, hypertension, smoking history, family history of aortic disease, coronary artery disease, and hyperlipidemia. Univariate and multivariate analyses of the unmatched cohorts were performed. RESULTS: The mean aneurysm size was 4.3 ± 0.58 cm with 95% confidence interval (3.14, 5.46). This did not differ between BAV and TAV patients, nor did aneurysm growth rates. Overall adverse event rate (dissection, rupture, and death) was low for the entire cohort (BAV group, 3% and TAV group, 3.5%). Survival at 10 years for the entire cohort was 90 ± 32%. CONCLUSIONS: Regardless of aortic valve type, there was a similar natural history and low adverse event rate. In the absence of risk factors, conservative management can be accomplished with minimal risk to the patient.

Endobronchial Aerosolized AAV1.SERCA2a Gene Therapy in a Pulmonary Hypertension Pig Model: Addressing the Lung Delivery Bottleneck.

A disappointing number of new therapies for pulmonary hypertension (PH) have been successfully translated to the clinic. Adeno-associated viral (AAV) gene therapy has the potential to treat the underlying pathology of PH, but the challenge remains in efficient and safe delivery. The aims of this study were (1) to test the efficacy of endobronchial aerosolization delivery for AAV1-mediated sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) gene therapy in a PH pig model and (2) to identify the most efficient airway administration modality for in-lung gene therapy in PH. We hypothesized that delivery to the distal bronchi increases lung viral uptake and avoids virus loss in off-target compartments. In part 1 of the study, PH was induced in pigs by surgically banding the pulmonary veins. Two months postsurgery, 1 × 1013 viral genomes (vg) of AAV1.SERCA2a or saline was endobronchially aerosolized using a bronchoscope. Two months after aerosolization, high vg copies (vgc) were detected in the lungs, accompanied by functional and morphometrical amelioration of PH. In part 2 of the study, we directly compared the endobronchial aerosolization gene delivery to the intratracheal aerosolization in PH pigs. Endobronchial delivery demonstrated higher viral expression (6,719 ± 927 vs. 1,444 ± 402 vgc/100 ng DNA, p = 0.0017), suggesting this delivery modality is a promising method for clinical AAV gene therapy for PH.

Pan-cancer proteogenomic investigations identify post-transcriptional kinase targets.

Identifying genomic alterations of cancer proteins has guided the development of targeted therapies, but proteomic analyses are required to validate and reveal new treatment opportunities. Herein, we develop a new algorithm, OPPTI, to discover overexpressed kinase proteins across 10 cancer types using global mass spectrometry proteomics data of 1,071 cases. OPPTI outperforms existing methods by leveraging multiple co-expressed markers to identify targets overexpressed in a subset of tumors. OPPTI-identified overexpression of ERBB2 and EGFR proteins correlates with genomic amplifications, while CDK4/6, PDK1, and MET protein overexpression frequently occur without corresponding DNA- and RNA-level alterations. Analyzing CRISPR screen data, we confirm expression-driven dependencies of multiple currently-druggable and new target kinases whose expressions are validated by immunochemistry. Identified kinases are further associated with up-regulated phosphorylation levels of corresponding signaling pathways. Collectively, our results reveal protein-level aberrations-sometimes not observed by genomics-represent cancer vulnerabilities that may be targeted in precision oncology.

Secondary Invasive Breast Events among Patients with Hormone-Positive Breast Cancer and High-Risk Oncotype DX Recurrence Scores 26-30 and ≥31.

BACKGROUND: The Oncotype DX Recurrence Score (ODx RS) is the most widely adopted genomic assay used to guide treatment for patients with early-stage, hormone-positive (HR+) breast cancer (BC), with higher scores predicting greater risk of recurrence and benefit from chemotherapy. Patients with ODx RS >25 typically recieve adjuvant chemotherapy; however, data regarding efficacy of chemotherapy for reducing recurrence in this population have been mixed. OBJECTIVES: This study aimed to evaluate outcomes of patients with early-stage HR+ BC with high-risk ODx RS (26-30 and ≥31) in order to assess treatment patterns and outcomes. We hypothesized that the benefit of chemotherapy in these groups may be minimal and that select patients may forgo chemotherapy in favor of more aggressive endocrine therapy and ovarian suppression. METHODS: We performed a retrospective analysis of 515 patients with early-stage, HR+ BC with high-risk ODx RS 26-30 and ≥31 treated between 2006 and 2018. Patients were stratified by RS: low-risk (≤10), intermediate-risk (11-25), and high-risk (≥26). The Kaplan-Meier method was used to estimate the time to secondary invasive breast events (SIBE) or distributions overall and among different RS groups with the log rank test used to compare distributions between groups. RESULTS: Rates of chemotherapy administration were 7% among the low-risk group, 18% among the intermediate-risk group, and 83% among high-risk patients with 41 SIBE (8%) reported. When stratified by ODx RS, 5-year rates of SIBE were 4%, 6%, and 16% for low-risk, intermediate-risk, and high-risk RS, respectively. Among the 27 lymph node (LN)-negative patients with ODx RS 26-30, 74% received chemotherapy. The 5-year rate of SIBE was 25% among patients who received chemotherapy and 33% among those who did not (p = 0.5489). Among the 23 LN-negative patients with ODx RS ≥31, 91% of patients received chemotherapy. The 5-year rate of SIBE was 0% both with and without chemotherapy. CONCLUSIONS: There was no statistically significant difference in SIBE for patients with high-risk ODx RS based on chemotherapy treatment. More aggressive endocrine therapy with ovarian suppression has become an alternative to chemotherapy among patients with intermediate-risk ODx RS (16-25). This approach may be useful among patients with high-risk ODx RS, with additional studies needed in this patient population.

Corrigendum: Novel Porcine Model of Coronary Dissection Reveals the Impact of Impella on Dissected Coronary Arterial Hemodynamics.

[This corrects the article DOI: 10.3389/fcvm.2020.00162.].

The impact of the globalization of cancer clinical trials on the enrollment of Black patients.

BACKGROUND: The enrollment of Black patients in cancer clinical trials continues to trend far below the true prevalence of disease in Black patients in the United States, limiting the generalizability of trial results. A potentially overlooked contributor to the underenrollment of Black patients may be the increasing enrollment of cancer trials in countries outside the United States. However, the impact of the globalization of cancer clinical trials on recruitment of racial minority patients has been understudied. METHODS: In this study, race and accrual location data for all cancer drugs approved by the US Food and Drug Administration (FDA) between 2015 and 2018 were analyzed. A disparity score was calculated for each approval, a metric comparing Black enrollment in clinical trials with the estimated burden of disease in Black patients. RESULTS: Of 49 global clinical trials supporting 35 FDA drug approvals with race data available, Black patients accounted for 2.5% of enrollment (range, 0%-10%), with a median disparity score of 0.19 (range, 0.01-0.98). In 21 clinical trials supporting 18 FDA drug approvals with both race and accrual location data available, 64% patients were enrolled outside the United States (range, 0%-100%). Black patients accounted for 3.2% of enrollment (range, 0.2%-10%), and the median disparity score was 0.23 (range, 0.01-0.98). There was a significant inverse correlation between the proportion of trial patients enrolled outside the United States and the disparity score (Pearson correlation, -0.61; P = .007). CONCLUSIONS: The globalization of cancer clinical trials is associated with a widening racial enrollment disparity gap in the United States. The impact of global trials on domestic clinical trial generalizability warrants further consideration from a regulatory and policy standpoint. LAY SUMMARY: Black patients continue to be underrepresented in cancer clinical trials; this disparity has worsened in recent years perhaps because of the globalization of cancer clinical trials. In an analysis of demographic information from 21 cancer clinical trials leading to US Food and Drug Administration approvals between 2015 and 2018, clinical trials conducted primarily outside the United States were 2-fold less likely to enroll Black participants than US clinical trials. Thus, the globalization of cancer clinical trials may have the unintended consequence of further exacerbating existing racial disparities in cancer clinical trial representation and ultimately the generalizability of trial results.

Left Ventricular Assist Devices for Acute Myocardial Infarct Size Reduction: Meta-analysis.

We conducted a meta-analysis of preclinical studies that tested left ventricular assist device (LVAD) therapy for reducing myocardial infarct size in experimental acute myocardial infarction (AMI). Twenty-six articles were included with a total of 488 experimental animal subjects. The meta-analysis showed that infarct size was significantly decreased by LVAD support compared to control animals (SDM, - 2.19; 95% CI, - 2.70 to - 1.69; P < 0.001). The meta-regression analysis demonstrated a high degree of heterogeneity associated with time from coronary artery occlusion to LVAD support, which correlated positively with infarct size. Subgroup analysis suggested smaller infarct size in LVAD therapies that withdrew blood from left heart than those from right heart. The proportion of left ventricular support relative to total cardiac output was positively correlated with infarct size reduction in Impella studies. Thus, early initiation of LVAD after ischemia and effective left ventricular venting may be important factors to reduce infarct size in AMI.

Impaired left ventricular global longitudinal strain is associated with elevated left ventricular filling pressure after myocardial infarction.

Left ventricular (LV) global longitudinal strain (GLS) has emerged as a significant prognostic marker in patients after myocardial infarction (MI). Although elevated LV filling pressure after MI might alter GLS, direct evidence for this is lacking. This study aimed to clarify the association between GLS and LV filling pressure in a large animal MI model. A total of 104 Yorkshire pigs underwent both echocardiographic and hemodynamic assessments 1-4 wk after induction of large anterior MI. GLS was measured in the apical four-chamber view using a semiautomated speckle-tracking software. LV pressure-volume relationship was invasively measured using a high-fidelity pressure-volume catheter. GLS >-14% was considered impaired. Compared with pigs with LV ejection fraction (LVEF) >40% and preserved GLS (n = 29), those with LVEF >40% and impaired GLS (n = 37) and those with LVEF ≤40% (n = 38) had significantly higher LV end-diastolic pressure (15.5 ± 5.5 vs. 19.7 ± 5.8 and 19.6 ± 6.6 mmHg; P = 0.008 and P = 0.026, respectively) and higher LV mean diastolic pressure (7.1 ± 2.9 vs. 10.4 ± 4.5 and 11.1 ± 5.4 mmHg; P = 0.013 and P = 0.002, respectively). GLS was modestly correlated with τ (r = 0.21, P = 0.039) and slope of LV end-diastolic pressure-volume relationship (r = 0.43, P < 0.001). Impaired GLS was associated with higher LV end-diastolic and mean-diastolic pressures after adjusting for LVEF and baseline characteristics (P = 0.026 and P = 0.001, respectively). Impaired GLS assessed by speckle-tracking echocardiography was associated with elevated LV filling pressure after MI. GLS has an incremental diagnostic value for detecting elevated LV filling pressure and may be particularly useful for evaluating post-MI patients with preserved LVEF.NEW & NOTEWORTHY Strain analysis was performed in 104 pigs after MI, and its relationship to invasive hemodynamic measurements was studied. Impaired longitudinal strain was associated with high ventricular filling pressure independent of LVEF in post-MI setting. Global longitudinal strain is a potential prognostic marker after MI.

Novel Porcine Model of Coronary Dissection Reveals the Impact of Impella on Dissected Coronary Arterial Hemodynamics.

Background: Coronary artery dissection (CAD) sometimes accompanies unstable hemodynamics and requires mechanical cardiac support. Meanwhile, mechanical cardiac support may influence coronary hemodynamics in CAD. No study has examined the impact of Impella left ventricular (LV) support on CAD. Materials and Methods: CAD was induced in eight Yorkshire pigs by injuring the left anterior descending artery (LAD) using a 0.018-in. stiff guidewire and/or deep engagement of a blunt-cut coronary guiding catheter. After the creation of CAD, hemodynamic parameters, coronary pressure, and flow as well as coronary angiograms were acquired before and after maximum LV support using the Impella CP. Result: CADs with a large flap were successfully created by deep engagement of a blunt-tip guiding catheter with forceful contrast injection. One animal (#8) exhibited thrombolysis in myocardial infarction (TIMI)-1 flow, while the others (animals #1-#7) showed TIMI-2/3 flow. In TIMI-2/3 animals, maximal Impella support increased mean coronary pressure (108.4 ± 22.5 to 124.7 ± 28.0 mmHg, P < 0.001) with unchanged mean coronary flow velocity (63.50 ± 28.66 to 48.32 ± 13.30 cm/s, P = 0.17) of the LAD distal to the dissection. The LV end-diastolic pressure (20.6 ± 6.6 vs. 12.0 ± 3.4 mmHg, P = 0.032), LV end-diastolic volume (127 ± 32 vs. 97 ± 26 ml, P = 0.015), stroke volume (68 ± 16 vs. 48 ± 14 ml, P = 0.003), stroke work (5,744 ± 1,866 vs. 4,424 ± 1,650 mmHg·ml, P = 0.003), and heart rate (71.4 ± 6.6 vs. 64.9 ± 9.3/min, P = 0.014) were all significantly reduced by Impella support, indicating effective unloading of the LV. In the TIMI-1 animal (animal #8), maximal Impella support resulted in further delay in angiographic coronary flow and reduced distal coronary pressure (22.9-17.1 mmHg), together with increased false-lumen pressure. Conclusion: Impella support effectively unloaded the LV and maintained the hemodynamics in a novel porcine model of CAD. Coronary pressure distal to the dissection was increased in TIMI-2/3 animals after Impella support but decreased in the animal with initial TIMI-1 flow.

Consideration of clinical translation of cardiac AAV gene therapy.

Advancements in conventional cardiac care have significantly reduced mortality from coronary heart disease and acute myocardial infarction. However, the prevalence of heart failure continues to increase in an aging population with profound social and economic consequences. Cardiac gene therapy with adeno-associated virus (AAV) vectors is emerging as a potential modality for addressing this desperate clinical need. After showing initial promise in extensive preclinical studies and an early clinical trial, disappointing results of large-scale clinical trial derailed the progress of AAV-mediated cardiac gene therapy. However, it appears that knowledge gained from previous failures coupled with developments in targeted gene delivery have set the stage for a new frontier in cardiac AAV gene therapy.

Diabetes and Metformin Association with Recurrence Score in a Large Oncotype Database of Breast Cancer Patients.

BACKGROUND: The Oncotype DX® (ODX) is a genomic assay that provides clinicians with a prediction of benefit of chemotherapy in node-negative, tamoxifen-treated breast cancer. However, the relationship between ODX recurrence score (RS) and diabetes, a common comorbidity in breast cancer patients, has been inadequately described in the literature. Specifically, the association of diabetes treatment with metformin and RS is inconclusive, with different studies reporting conflicting results. Because diabetes has been associated with higher RS, it has been suggested that management of diabetes with metformin in breast cancer patients may be associated with a lower RS. OBJECTIVES: We studied a large cohort of early-stage, hormone-positive breast cancer patients to determine if there is an association between RS and metformin treatment. METHODS: In this study, we retrospectively examined the medical records of 514 early-stage, hormone-positive breast cancer patients who had oncotype testing performed between 2007 and 2017. Number (%) or median were used to describe the patients' characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Of this cohort, 67 (13%) had a diabetes diagnosis at the time of breast cancer diagnosis, including both diabetes mellitus and pre-diabetes. The median RS for non-diabetic patients was 16 and the median RS for diabetic patients was 15. This difference was not significant, nor was there a statistical difference in RS between diabetic patients taking metformin (median RS = 15) and diabetic patients not taking metformin (median RS = 15). These results held true even when controlling for BMI. CONCLUSIONS: We conclude that neither diabetes diagnosis nor metformin use is associated with a difference in oncotype RS in this population of diabetic patients.

BRCA Mutation Association with Recurrence Score and Discordance in a Large Oncotype Database.

BACKGROUND: The Oncotype DX Breast Cancer Assay is a 21-gene assay used to predict the likelihood of distant recurrence and the benefit of chemotherapy in patients with node-negative, tamoxifen-treated breast cancer. Prior studies demonstrated 7-19% discordance, or a difference between the recurrence score (RS) and tumor grade (TG) in breast cancer patients. BRCA mutated tumors (BRCA+) have been shown to be associated with higher RS as compared to BRCA-negative patients (BRCA-). OBJECTIVES: We developed a large Oncotype RS database to determine if the BRCA mutation status is associated with discordance. METHODS: We identified 723 patients (32 [4%] mutation-positive and 691 [96%] mutation-negative patients) with early-stage, hormone-positive breast cancer treated between 2006 and 2018, with tumor characteristics available for analysis. Discordance was defined as one- or two-step difference between RS (low, intermediate, high risk) and TG (well [WD], moderately [MD], and poorly [PD] differentiated). Mutation positive was defined as BRCA1 deleterious mutation, BRCA2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation (classified as other VUS). Number (%) or median were used to describe patient characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Among these patients, there were 32 (4% of total) who were identified as mutation-positive. Of those patients, 16% had a documented deleterious mutation in BRCA1, 22% in BRCA2, 6% had a BRCA mutation of unknown type (either 1 or 2), 25% were BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM). The median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) versus 16 in patients in the BRCA-negative database, which was statistically significant (p < 0.01). One- and two-step discordance was present in 46 and 8%, respectively, of patients with deleterious BRCA mutations versus 53 and 11%, respectively, in the BRCA-negative database. CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA-negative patients. We further demonstrated that patients with BRCA-positive tumors display higher RS than patients with BRCA-negative tumors.

A Novel Large Animal Model of Thrombogenic Coronary Microembolization.

Coronary microembolization is one of the main causes of the "no-reflow" phenomenon, which commonly occurs after reperfusion of an occluded coronary artery. Given its high incidence and the fact that it has been proven to be an independent predictor of cardiac morbidity and mortality, there is an imperative need to study its underlying mechanisms and pathophysiology. Large animal models are essential to perform translational studies. Currently there is no animal model that recapitulates a clinical scenario of thrombogenic microembolism with preceding myocardial ischemia. Therefore, the goal of this study was to develop and characterize a novel pig model of coronary microembolization using autologous thrombus injection (CMET). Twenty-three pigs underwent myocardial infarction through percutaneous balloon occlusion of the left anterior descending artery (LAD). Each animal was enrolled in one of two groups: (1) the CMET group, in which the LAD occlusion was followed by delivery of autologous clotted blood in the LAD (distal to the balloon occlusion) and reperfusion; (2) the ischemic reperfusion (I/R) group, in which the LAD ischemia was followed by reperfusion. Surviving animals underwent functional and morphological characterization at 1-week post-procedure. Three sham operated animals were used as a control. CMET resulted in impaired left ventricular function compared to I/R pigs at 1 week. Three-dimensional echocardiography demonstrated reduced ejection fraction in the CMET group (CMET vs. I/R: 35.6 ± 4.2% vs. 47.6 ± 2.4%, p = 0.028). Invasive hemodynamic measurements by Swan-Ganz and left ventricular pressure-volume catheters revealed that CMET impaired left ventricular contractility and diastolic function. This was confirmed by both load-dependent indices including cardiac output (CMET vs. I/R: 2.7 ± 0.2 l/min, vs. 4.0 ± 0.1 l/min, p = 0.002) and load independent indices including preload-recruitable stroke work (CMET vs. I/R: 25.8 ± 4.0 vs. 47.5 ± 6.5 mmHg, p = 0.05) and end-diastolic pressure-volume relationship (slope, 0.68 ± 0.07 vs. 0.40 ± 0.11 mmHg/ml, p = 0.01). Our unique closed-chest model of coronary microembolization using autologous thrombus injection resembles the clinical condition of thrombogenic coronary microembolization in I/R injury. This model offers opportunities to conduct translational studies for understanding and treating coronary microembolization in myocardial infarction.