Microvascular Obstruction and Intramyocardial Hemorrhage in Reperfused Myocardial Infarctions: Pathophysiology and Clinical Insights From Imaging.

Microvascular injury immediately following reperfusion therapy in acute myocardial infarction (MI) has emerged as a driving force behind major adverse cardiovascular events in the postinfarction period. Although postmortem investigations and animal models have aided in developing early understanding of microvascular injury following reperfusion, imaging, particularly serial noninvasive imaging, has played a central role in cultivating critical knowledge of progressive damage to the myocardium from the onset of microvascular injury to months and years after in acute MI patients. This review summarizes the pathophysiological features of microvascular injury and downstream consequences, and the contributions noninvasive imaging has imparted in the development of this understanding. It also highlights the interventional trials that aim to mitigate the adverse consequences of microvascular injury based on imaging, identifies potential future directions of investigations to enable improved detection of disease, and demonstrates how imaging stands to play a major role in the development of novel therapies for improved management of acute MI patients.

Stress Perfusion Cardiac Magnetic Resonance vs SPECT Imaging for Detection of Coronary Artery Disease.

BACKGROUND: GadaCAD2 was 1 of 2 international, multicenter, prospective, Phase 3 clinical trials that led to U.S. Food and Drug Administration approval of gadobutrol to assess myocardial perfusion and late gadolinium enhancement (LGE) in adults with known or suspected coronary artery disease (CAD). OBJECTIVES: A prespecified secondary objective was to determine if stress perfusion cardiovascular magnetic resonance (CMR) was noninferior to single-photon emission computed tomography (SPECT) for detecting significant CAD and for excluding significant CAD. METHODS: Participants with known or suspected CAD underwent a research rest and stress perfusion CMR that was compared with a gated SPECT performed using standard clinical protocols. For CMR, adenosine or regadenoson served as vasodilators. The total dose of gadobutrol was 0.1 mmol/kg body weight. The standard of reference was a 70% stenosis defined by quantitative coronary angiography (QCA). A negative coronary computed tomography angiography could exclude CAD. Analysis was per patient. CMR, SPECT, and QCA were evaluated by independent central core lab readers blinded to clinical information. RESULTS: Participants were predominantly male (61.4% male; mean age 58.9 ± 10.2 years) and were recruited from the United States (75.0%), Australia (14.7%), Singapore (5.7%), and Canada (4.6%). The prevalence of significant CAD was 24.5% (n = 72 of 294). Stress perfusion CMR was statistically superior to gated SPECT for specificity (P = 0.002), area under the receiver operating characteristic curve (P < 0.001), accuracy (P = 0.003), positive predictive value (P < 0.001), and negative predictive value (P = 0.041). The sensitivity of CMR for a 70% QCA stenosis was noninferior and nonsuperior to gated SPECT. CONCLUSIONS: Vasodilator stress perfusion CMR, as performed with gadobutrol 0.1 mmol/kg body weight, had superior diagnostic accuracy for diagnosis and exclusion of significant CAD vs gated SPECT.

Worldwide variation in cardiovascular magnetic resonance practice models.

INTRODUCTION: The use of cardiovascular magnetic resonance (CMR) for diagnosis and management of a broad range of cardiac and vascular conditions has quickly expanded worldwide. It is essential to understand how CMR is utilized in different regions around the world and the potential practice differences between high-volume and low-volume centers. METHODS: CMR practitioners and developers from around the world were electronically surveyed by the Society for Cardiovascular Magnetic Resonance (SCMR) twice, requesting data from 2017. Both surveys were carefully merged, and the data were curated professionally by a data expert using cross-references in key questions and the specific media access control IP address. According to the United Nations classification, responses were analyzed by region and country and interpreted in the context of practice volumes and demography. RESULTS: From 70 countries and regions, 1092 individual responses were included. CMR was performed more often in academic (695/1014, 69%) and hospital settings (522/606, 86%), with adult cardiologists being the primary referring providers (680/818, 83%). Evaluation of cardiomyopathy was the top indication in high-volume and low-volume centers (p = 0.06). High-volume centers were significantly more likely to list evaluation of ischemic heart disease (e.g., stress CMR) as a primary indicator compared to low-volume centers (p < 0.001), while viability assessment was more commonly listed as a primary referral reason in low-volume centers (p = 0.001). Both developed and developing countries noted cost and competing technologies as top barriers to CMR growth. Access to scanners was listed as the most common barrier in developed countries (30% of responders), while lack of training (22% of responders) was the most common barrier in developing countries. CONCLUSION: This is the most extensive global assessment of CMR practice to date and provides insights from different regions worldwide. We identified CMR as heavily hospital-based, with referral volumes driven primarily by adult cardiology. Indications for CMR utilization varied by center volume. Efforts to improve the adoption and utilization of CMR should include growth beyond the traditional academic, hospital-based location and an emphasis on cardiomyopathy and viability assessment in community centers.

Cardiac Magnetic Resonance Imaging Versus Invasive-Based Strategies in Patients With Chest Pain and Detectable to Mildly Elevated Serum Troponin: A Randomized Clinical Trial.

BACKGROUND: The optimal diagnostic strategy for patients with chest pain and detectable to mildly elevated serum troponin is not known. The objective was to compare clinical outcomes among an early decision for a noninvasive versus an invasive-based care pathway. METHODS: The CMR-IMPACT trial (Cardiac Magnetic Resonance Imaging Strategy for the Management of Patients with Acute Chest Pain and Detectable to Elevated Troponin) was conducted at 4 United States tertiary care hospitals from September 2013 to July 2018. A convenience sample of 312 participants with acute chest pain symptoms and a contemporary troponin between detectable and 1.0 ng/mL were randomized early in their care to 1 of 2 care pathways: invasive-based (n=156) or cardiac magnetic resonance (CMR)-based (n=156) with modification allowed as the patient condition evolved. The primary outcome was a composite including death, myocardial infarction, and cardiac-related hospital readmission or emergency visits. RESULTS: Participants (N=312, mean age, 60.6 years, SD 11.3; 125 women [59.9%]), were followed over a median of 2.6 years (95% CI, 2.4-2.9). Early assigned testing was initiated in 102 out of 156 (65.3%) CMR-based and 110 out of 156 (70.5%) invasive-based participants. The primary outcome (CMR-based versus invasive-based) occurred in 59% versus 52% (hazard ratio, 1.17 [95% CI, 0.86-1.57]), acute coronary syndrome after discharge 23% versus 22% (hazard ratio, 1.07 [95% CI, 0.67-1.71]), and invasive angiography at any time 52% versus 74% (hazard ratio, 0.66 [95% CI, 0.49-0.87]). Among patients completing CMR imaging, 55 out of 95 (58%) were safely identified for discharge based on a negative CMR and did not have angiography or revascularization within 90 days. Therapeutic yield of angiography was higher in the CMR-based arm (52 interventions in 81 angiographies [64.2%] versus 46 interventions in 115 angiographies [40.0%] in the invasive-based arm [P=0.001]). CONCLUSIONS: Initial management with CMR or invasive-based care pathways resulted in no detectable difference in clinical and safety event rates. The CMR-based pathway facilitated safe discharge, enriched the therapeutic yield of angiography, and reduced invasive angiography utilization over long-term follow-up. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01931852.

Sex-Specific Stress Perfusion Cardiac Magnetic Resonance Imaging in Suspected Ischemic Heart Disease: Insights From SPINS Retrospective Registry.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of mortality in women, but current noninvasive cardiac imaging techniques have sex-specific limitations. OBJECTIVES: In this study, the authors sought to investigate the effect of sex on the prognostic utility and downstream invasive revascularization and costs of stress perfusion cardiac magnetic resonance (CMR) for suspected CVD. METHODS: Sex-specific prognostic performance was evaluated in a 2,349-patient multicenter SPINS (Stress CMR Perfusion Imaging in the United States [SPINS] Study) Registry. The primary outcome measure was a composite of cardiovascular death and nonfatal myocardial infarction; secondary outcomes were hospitalization for unstable angina or heart failure, and late unplanned coronary artery bypass grafting. RESULTS: SPINS included 1,104 women (47% of cohort); women had higher prevalence of chest pain (62% vs 50%; P < 0.0001) but lower use of medical therapies. At the 5.4-year median follow-up, women with normal stress CMR had a low annualized rate of primary composite outcome similar to men (0.54%/y vs 0.75%/y, respectively; P = NS). In contrast, women with abnormal CMR were at higher risk for both primary (3.74%/y vs 0.54%/y; P < 0.0001) and secondary (9.8%/y vs 1.6%/y; P < 0.0001) outcomes compared with women with normal CMR. Abnormal stress CMR was an independent predictor for the primary (HR: 2.64 [95% CI: 1.20-5.90]; P = 0.02) and secondary (HR: 2.09 [95% CI: 1.43-3.08]; P < 0.0001) outcome measures. There was no effect modification for sex. Women had lower rates of invasive coronary angiography (3.6% vs 7.3%; P = 0.0001) and downstream costs ($114 vs $171; P = 0.001) at 90 days following CMR. There was no effect of sex on diagnostic image quality. CONCLUSIONS: Stress CMR demonstrated excellent prognostic performance with lower rates of invasive coronary angiography referral in women. Stress CMR should be considered as a first-line noninvasive imaging tool for the evaluation of women. (Stress CMR Perfusion Imaging in the United States [SPINS] Study [SPINS]; NCT03192891).

The role of coronary computed tomography angiography in low- and intermediate-risk patients with chest pain: a paradigm shift in modern cardiology.

Chest pain is a common complaint among patients presenting to primary care physicians. The management of chest pain secondary to coronary artery disease is rapidly changing as new evidence increase our knowledge of this complex clinical problem. The 2021 multisociety guidelines developed by the American College of Cardiology and the American Heart Association along with other organizations and imaging societies represent the first international guidelines for the evaluation and diagnosis of patients with acute or stable chest pain. This review will discuss in details the evaluation of low- and intermediate risk subjects presenting with acute and stable chest pain both in the emergency and office settings, providing a practical approach, supported by contemporary evidence, for the management of this important clinical problem leveraging on the central role played by coronary computed tomography angiography as documented by current clinical guidelines and available scientific literature.

Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity.

Importance: Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown. Objective: To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity. Design, Setting, and Participants: This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry. Exposures: Ibrutinib treatment for cancer control. Main Outcomes and Measures: The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk-matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE. Results: Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P < .001, P = .01, and P < .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P < .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE. Conclusions and Relevance: In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.

Integrating Coronary Atherosclerosis Burden and Progression with Coronary Artery Disease Risk Factors to Guide Therapeutic Decision Making.

IMPORTANCE: Although atherosclerosis represents the primary driver of coronary artery disease, evaluation and treatment approaches have historically relied upon indirect markers of atherosclerosis that include surrogates (cholesterol), signs (angina), and sequelae (ischemia) of atherosclerosis. Direct quantification and characterization of atherosclerosis may encourage a precision heart care paradigm that improves diagnosis, risk stratification, therapeutic decision-making, and longitudinal disease tracking in a personalized fashion. OBSERVATIONS: The American College of Cardiology Innovations in Prevention Working Group introduce the Atherosclerosis Treatment Algorithms that personalize medical interventions based upon atherosclerosis findings from coronary computed tomography angiography (CTA) and cardiovascular risk factors. Through integration of coronary CTA-based atherosclerosis evaluation, clinical practice guidelines, and contemporary randomized controlled trial evidence, the Atherosclerosis Treatment Algorithms leverage patient-specific atherosclerosis burden and progression as primary targets for therapeutic intervention. After defining stages of atherosclerosis severity by coronary CTA, Atherosclerosis Treatment Algorithms are described for worsening stages of atherosclerosis for patients with lipid disorders, diabetes, hypertension, obesity, and tobacco use. The authors anticipate a rapid pace of research in the field, and conclude by providing perspectives on future needs that may improve efforts to optimize precision prevention of coronary artery disease. Importantly, the Atherosclerosis Treatment Algorithms are not endorsed by the American College of Cardiology, and should not be interpreted as a statement of American College of Cardiology policy. CONCLUSIONS AND RELEVANCE: We describe a precision heart care approach that emphasizes atherosclerosis as the primary disease target for evaluation and treatment. To our knowledge, this is the first proposal to use coronary atherosclerosis burden and progression to personalize therapy selection and therapy changes, respectively. DISCLOSURE: The American College of Cardiology Foundation has made an investment in Cleerly, Inc., makers of a software solution that utilizes coronary CT angiography findings to evaluate coronary artery disease.

Cannabis Use and Heart Transplantation: Disparities and Opportunities to Improve Outcomes.

Heart transplantation (HT) remains the optimal therapy for many patients with advanced heart failure. Use of substances of potential abuse has historically been a contraindication to HT. Decriminalization of cannabis, increasing cannabis use, clinician biases, and lack of consensus for evaluating patients with heart failure who use cannabis all have the potential to exacerbate racial and ethnic and regional disparities in HT listing and organ allocation. Here' we review pertinent pre-HT and post-HT considerations related to cannabis use' and relative attitudes between opiates and cannabis are offered for context. We conclude with identifying unmet research needs pertaining to the use of cannabis in HT that can inform a standardized evaluation process.

Highlights of the Virtual Society for Cardiovascular Magnetic Resonance 2022 Scientific Conference: CMR: improving cardiovascular care around the world.

The 25th Society for Cardiovascular Magnetic Resonance (SCMR) Annual Scientific Sessions saw 1524 registered participants from more than 50 countries attending the meeting virtually. Supporting the theme "CMR: Improving Cardiovascular Care Around the World", the meeting included 179 invited talks, 52 sessions including 3 plenary sessions, 2 keynote talks, and a total of 93 cases and 416 posters. The sessions were designed so as to showcase the multifaceted role of cardiovascular magnetic resonance (CMR) in identifying and prognosticating various myocardial pathologies. Additionally, various social networking sessions as well as fun activities were organized. The major areas of focus for the future are likely to be rapid efficient and high value CMR exams, automated and quantitative acquisition and post-processing using artificial intelligence and machine learning, multi-contrast imaging and advanced vascular imaging including 4D flow.

Transferrin predicts trimethylamine-N-oxide levels and is a potential biomarker of cardiovascular disease.

INTRODUCTION: Trimethylamine-N-oxide (TMAO) is a circulating biomarker associated with cardiovascular disease (CVD). Production of TMAO is facilitated by gut microbiota and dependent on micronutrients such as choline, betaine, and L-carnitine, present in foods such as red meat and eggs. HYPOTHESIS: We sought to predict serum TMAO quartile levels among healthy individuals at increased risk of CVD using clinical data via an ordinal logistic model. METHODS: Data from participants (n = 127) enrolled in a longitudinal observational study on CVD were used to build a predictive model for TMAO using ordinal logistic regression with demographic variables and 40 other variables considered related to CVD risk. First, univariate models for each covariate were tested (with serum TMAO quartiles as the dependent variable), and only variables with P < 0.30 were evaluated further. Second, demographic variables (age, gender, white vs. non-white race) were included in a multivariable model with each previously identified independent variable controlling for potential confounding. Last, the final model included fixed demographics and candidates from the confounder-adjusted model with P < 0.10. RESULTS: Eight candidate variables were included in the final model, with only transferrin, high-density lipoprotein cholesterol (HDL-C) and race (white vs. non-white) showing significant associations with TMAO. Participants had 0.16 (Q2), 0.31 (Q3), and 0.20 (Q4) odds of being in a higher TMAO quartile compared with participants in the lowest transferrin quartile. Non-white participants had 2.92 times higher odds of being in the highest TMAO quartile compared to white individuals. Participants in the second quartile of HDL-C had 2.68 times higher odds of being in a higher TMAO quartile compared with participants in the lowest HDL-C quartile. CONCLUSIONS: Transferrin demonstrated a significant predictive association with TMAO and may represent a novel potential biomarker of increased CVD risk worthy of further study. These results warrant further examination of iron, metabolism, homeostasis, and gut microbiome to better understand and mitigate known increased CVD risk.

Coronary CTA plaque volume severity stages according to invasive coronary angiography and FFR.

BACKGROUND: Atherosclerotic plaque characterization by coronary computed tomography angiography (CCTA) enables quantification of coronary artery disease (CAD) burden and type, which has been demonstrated as the strongest discriminant of future risk of major adverse cardiac events (MACE). To date, there are no clinically useful thresholds to assist with understanding a patient's disease burden and guide diagnosis and management, as there exists with coronary artery calcium (CAC) scoring. The purpose of this manuscript is to establish clinically relevant plaque stages and thresholds based on evidence from invasive angiographic stenosis (ICA) and fractional flow reserve (FFR) data. METHODS: 303 patients underwent CCTA prior to ICA and FFR for an AHA/ACC clinical indication. Quantitative computed tomography (QCT) was performed for total plaque volume (TPV, mm3) and percent atheroma volume (PAV, %). We segmented atherosclerosis by composition for low-density non-calcified plaque (LD-NCP), non-calcified plaque (NCP), and calcified plaque (CP). ICAs were evaluated by quantitative coronary angiography (QCA) for all coronary segments for % diameter stenosis. The relationship of atherosclerotic plaque burden and composition by QCT to ICA stenosis extent and severity by QCA and presence of ischemia by FFR was assessed to develop 4 distinct disease stages. RESULTS: The mean age of the patients was 64.4 â€‹± â€‹10.2 years; 71% male. At the 50% QCA stenosis threshold, QCT revealed a mean PAV of 9.7 (±8.2)% and TPV of 436 (±444.9)mm3 for those with non-obstructive CAD; PAV of 11.7 (±8.0)% and TPV of 549.3 (±408.3) mm3 for 1 vessel disease (1VD), PAV of 17.8 (±9.8)% and TPV of 838.9 (±550.7) mm3 for 2VD, and PAV of 19.2 (±8.2)% and TPV of 799.9 (±357.4) mm3 for 3VD/left main disease (LMD). Non-ischemic patients (FFR >0.8) had a mean PAV of 9.2 (±7.3) % and TPV of 422.9 (±387.9 â€‹mm3) while patients with at least one vessel ischemia (FFR ≤0.8) had a PAV of 15.2 (±9.5)% and TPV of 694.6 (±485.1). Definition of plaque stage thresholds of 0, 250, 750 â€‹mm3 and 0, 5, and 15% PAV resulted in 4 clinically distinct stages in which patients with no, nonobstructive, single VD and multi-vessel disease were optimally distributed. CONCLUSION: Atherosclerotic plaque burden by QCT is related to stenosis severity and extent as well as ischemia. We propose staging of CAD atherosclerotic plaque burden using the following definitions: Stage 0 (Normal, 0% PAV, 0 â€‹mm3 TPV), Stage 1 (Mild, >0-5% PAV or >0-250 â€‹mm3 TPV), Stage 2 (Moderate, >5-15% PAV or >250-750 â€‹mm3 TPV) and Stage 3 (Severe, >15% PAV or >750 mm3 TPV).

30-minute CMR for common clinical indications: a Society for Cardiovascular Magnetic Resonance white paper.

BACKGROUND: Despite decades of accruing evidence supporting the clinical utility of cardiovascular magnetic resonance (CMR), adoption of CMR in routine cardiovascular practice remains limited in many regions of the world. Persistent use of long scan times of 60 min or more contributes to limited adoption, though techniques available on most scanners afford routine CMR examination within 30 min. Incorporating such techniques into standardize protocols can answer common clinical questions in daily practice, including those related to heart failure, cardiomyopathy, ventricular arrhythmia, ischemic heart disease, and non-ischemic myocardial injury. BODY: In this white paper, we describe CMR protocols of 30 min or shorter duration with routine techniques with or without stress perfusion, plus specific approaches in patient and scanner room preparation for efficiency. Minimum requirements for the scanner gradient system, coil hardware and pulse sequences are detailed. Recent advances such as quantitative myocardial mapping and other add-on acquisitions can be incorporated into the proposed protocols without significant extension of scan duration for most patients. CONCLUSION: Common questions in clinical cardiovascular practice can be answered in routine CMR protocols under 30 min; their incorporation warrants consideration to facilitate increased access to CMR worldwide.

Evidence-based cardiovascular magnetic resonance cost-effectiveness calculator for the detection of significant coronary artery disease.

BACKGROUND: Although prior reports have evaluated the clinical and cost impacts of cardiovascular magnetic resonance (CMR) for low-to-intermediate-risk patients with suspected significant coronary artery disease (CAD), the cost-effectiveness of CMR compared to relevant comparators remains poorly understood. We aimed to summarize the cost-effectiveness literature on CMR for CAD and create a cost-effectiveness calculator, useable worldwide, to approximate the cost-per-quality-adjusted-life-year (QALY) of CMR and relevant comparators with context-specific patient-level and system-level inputs. METHODS: We searched the Tufts Cost-Effectiveness Analysis Registry and PubMed for cost-per-QALY or cost-per-life-year-saved studies of CMR to detect significant CAD. We also developed a linear regression meta-model (CMR Cost-Effectiveness Calculator) based on a larger CMR cost-effectiveness simulation model that can approximate CMR lifetime discount cost, QALY, and cost effectiveness compared to relevant comparators [such as single-photon emission computed tomography (SPECT), coronary computed tomography angiography (CCTA)] or invasive coronary angiography. RESULTS: CMR was cost-effective for evaluation of significant CAD (either health-improving and cost saving or having a cost-per-QALY or cost-per-life-year result lower than the cost-effectiveness threshold) versus its relevant comparator in 10 out of 15 studies, with 3 studies reporting uncertain cost effectiveness, and 2 studies showing CCTA was optimal. Our cost-effectiveness calculator showed that CCTA was not cost-effective in the US compared to CMR when the most recent publications on imaging performance were included in the model. CONCLUSIONS: Based on current world-wide evidence in the literature, CMR usually represents a cost-effective option compared to relevant comparators to assess for significant CAD.

MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4.

BACKGROUND: MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction-associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. METHODS: We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. RESULTS: Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4. CONCLUSIONS: Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.