Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]).

BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging-assessed infarct size. Secondary end points included cardiac magnetic resonance-determined myocardial salvage and creatine kinase kinetics. RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU·h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000.

Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a puzzling clinical entity with no previous evaluation of the literature. This systematic review aims to (1) quantify the prevalence, risk factors, and 12-month prognosis in patients with MINOCA, and (2) evaluate potential pathophysiological mechanisms underlying this disorder. METHODS AND RESULTS: Quantitative assessment of 28 publications using a meta-analytic approach evaluated the prevalence, clinical features, and prognosis of MINOCA. The prevalence of MINOCA was 6% [95% confidence interval, 5%-7%] with a median patient age of 55 years (95% confidence interval, 51-59 years) and 40% women. However, in comparison with those with myocardial infarction associated with obstructive coronary artery disease, the patients with MINOCA were more likely to be younger and female but less likely to have hyperlipidemia, although other cardiovascular risk factors were similar. All-cause mortality at 12 months was lower in MINOCA (4.7%; 95% confidence interval, 2.6%-6.9%) compared with myocardial infarction associated with obstructive coronary artery disease (6.7%, 95% confidence interval, 4.3%-9.0%). Qualitative assessment of 46 publications evaluating the underlying pathophysiology responsible for MINOCA revealed the presence of a typical myocardial infarct on cardiac magnetic resonance imaging in only 24% of patients, with myocarditis occurring in 33% and no significant abnormality in 26%. Coronary artery spasm was inducible in 27% of MINOCA patients, and thrombophilia disorders were detected in 14%. CONCLUSIONS: MINOCA should be considered as a working diagnosis with multiple potential causes that require evaluation so that directed therapies may improve its guarded prognosis.

The What, When, Who, Why, How and Where of Myocardial Infarction With Non-Obstructive Coronary Arteries (MINOCA).

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is an intriguing clinical entity that is being increasingly recognized with the more common use of coronary angiography during acute myocardial infarction. This review systematically addresses the contemporary understanding of MINOCA, including, (1) what are the diagnostic criteria, (2) when the diagnosis should be considered, (3) who is at risk, (4) why this new syndrome should be diagnosed, (5) how these patients should be managed, and (6) where to next?

Anti-Anginal Efficacy of Zibotentan in the Coronary Slow-Flow Phenomenon.

BACKGROUND: Patients with coronary microvascular disorders often experience recurrent angina for which there are limited evidence-based therapies. These patients have been found to exhibit increased plasma levels of endothelin; thus, selective endothelin-A (Et-A) receptor blockers such as zibotentan may be an effective anti-anginal therapy in these patients. The study evaluated the impact of a 10 mg daily dose of zibotentan on spontaneous angina episodes in patients with the coronary slow-flow phenomenon who had refractory angina (i.e., experiencing angina at least three times/week despite current anti-anginal therapy). METHODS: Using a randomized, double-blind, placebo-controlled, crossover trial design with 4-week treatment periods, 18 patients (63.2 ± 9.9 years, 33% females) were recruited. The primary endpoint was angina frequency as measured by an angina diary, with secondary endpoints including nitrate consumption, angina duration/severity and the Seattle Angina Questionnaire (SAQ) domains. RESULTS: During the 4 weeks of therapy, angina frequency significantly improved with zibotentan therapy (placebo 41.4 (58.5) vs. zibotentan 29.2 (31.6), p < 0.05), and sublingual nitrate consumption significantly reduced (placebo 11.8 (15.2) vs. zibotentan 8.8 (12.9), p < 0.05. CONCLUSIONS: Zibotentan improved the frequency of spontaneous angina episodes and reduced sublingual nitrate consumption in patients unresponsive to standard anti-anginal therapy.

Randomised Placebo-Controlled Pilot Trial Evaluating the Anti-Anginal Efficacy of Ticagrelor in Patients with Angina with Nonobstructive Coronary Arteries and Coronary Slow Flow Phenomenon.

Background: The coronary slow flow phenomenon (CSFP) is an angiographic finding characterised by the delayed passage of contrast through the coronary arteries, despite the absence of obstructive coronary artery disease (defined as less than 50% narrowing of the vessel lumen). Patients with the CSFP experience recurrent angina, for which there are limited evidence-based therapies. Ticagrelor may serve as an effective anti-anginal therapy for these patients by increasing adenosine levels, which could alleviate coronary microvascular dysfunction and its associated angina due to its vasodilatory properties. This study aimed to determine the anti-anginal efficacy of ticagrelor 90 mg taken twice daily on spontaneous angina episodes in patients with refractory angina (i.e., episodes ≥3/week despite two anti-anginals) and documented CSFP. Methods: In a randomised, double-blind, placebo-controlled, cross-over trial, the anti-anginal efficacy of a 4-week ticagrelor therapy regimen was evaluated in 20 patients with refractory angina (mean age 61.5 ± 10.5 years; 40% women) who had documented slow coronary flow. The primary endpoint was the frequency of angina episodes, recorded using an angina diary. Secondary endpoints included the duration and severity of angina episodes, consumption of short-acting nitrates, and health status evaluations using the Seattle Angina Questionnaire (SAQ) and the Short Form-36 (SF-36) indices. Results: During the four weeks of therapy, ticagrelor did not significantly improve angina symptoms compared to the placebo (placebo 25.7 (16.7)) vs. ticagrelor 19.8 (18.1), p > 0.05). Furthermore, it did not impact other patient-related outcome measures, including angina severity, duration, frequency of prolonged angina episodes, nitrate consumption, or the SAQ/SF-36 health outcome indices. No serious adverse events related to the study drug were observed. Conclusions: In patients with documented CSFP who were unresponsive to standard anti-anginal therapy, ticagrelor did not reduce the frequency of spontaneous angina episodes or the consumption of nitrates. Further confirmation of the potential benefits of this therapy may be obtained through a larger clinical trial.

Angina and Non-Obstructive Coronary Artery (ANOCA) Patients with Coronary Vasomotor Disorders.

Angina and Non-Obstructive Coronary Artery (ANOCA) patients often lack a clear explanation for their symptoms, and are frequently discharged with the label of "unspecified chest pain", despite the availability of functional coronary angiography (provocative spasm and microvascular function testing) to identify potential underlying coronary vasomotor disorders. This study compared the outcomes of ANOCA patients with a coronary vasomotor disorder diagnosis post elective coronary angiography to patients discharged with unspecified chest pain. Using the CADOSA (Coronary Angiogram Database of South Australia) registry, consecutive symptomatic patients (n = 7555) from 2012 to 2018 underwent elective angiography; 30% had ANOCA (stenosis <50%). Of this cohort, 9% had documented coronary vasomotor disorders diagnosed, and 91% had unspecified chest pain. Patients with coronary vasomotor disorders were younger and had a similar female prevalence compared with those with unspecified chest pain. New prescriptions of calcium channel blockers and long-acting nitrates were more common for the coronary vasomotor cohort at discharge. In the 3 years following angiography, both groups had similar all-cause mortality rates. However, those with coronary vasomotor disorders had higher rates of emergency department visits for chest pain (39% vs. 15%, p < 0.001) and readmissions for chest pain (30% vs. 10%, p < 0.001) compared with those with unspecified chest pain. This real-world study emphasizes the importance of identifying high-risk ANOCA patients for personalized management to effectively address their symptoms.

Do Chest Pain Characteristics in Patients with Acute Myocardial Infarction Differ between Those with and without Obstructive Coronary Artery Disease?

The universal definition of acute myocardial infarction (MI) requires both evidence of myocardial injury and myocardial ischaemia. In MINOCA (MI with non-obstructive coronary arteries), patients must fulfil this MI criteria, but is their chest pain similar to those who have MI with obstructive CAD (MICAD)? This study compares prospectively collected chest pain features between patients with MINOCA and MICAD. Utilising the Coronary Angiogram Database of South Australia (CADOSA), consecutive MI patients were categorized as MINOCA or MICAD based on angiographic findings. Chest pain data were collected via direct patient interviews by trained staff members. Of 6811 consecutive patients fulfilling a clinical MI diagnosis, 411 (6.0%) were MINOCA, and 5948 MICAD. The MINOCA patients were younger, more often female and had less cardiovascular risk factors than those with MICAD. There were no significant differences in chest pain characteristics between the MINOCA and MICAD cohorts in relation to pain location, quality, associated symptoms, or duration. In conclusion, MINOCA patients have chest pain characteristics that are indistinguishable from MICAD patients, suggesting that their pain is ischaemic in nature. Thus, in the presence of positive myocardial injury markers, ischaemic chest pain fulfils the universal criteria for MI, despite the absence of obstructive coronary artery disease.

Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment for Post Infarct Angina in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries: A MINOCA-BAT Sub Study Rationale and Design.

Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients-The MINOCA BAT post infarct angina sub study. Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months. Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years. Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.

Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries: A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration.

BACKGROUND: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms "MI," "nonobstructive," "angiography," and "prognosis" were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran's Q and I2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI. RESULTS: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%-4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%-3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%-4.1%] versus 5.6% [95% CI, 4.1%-7.0%]; odds ratio, 0.60 [95% CI, 0.52-0.70], P<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%-5.9%]) compared with No-MI (0.7% [95% CI, 0.1%-1.3%]; odds ratio, 3.71 [95% CI, 0.58-23.61], P=0.09). CONCLUSIONS: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020145356.

Validation of contemporary electrocardiographic indices of area at risk and infarct size in acute ST elevation myocardial infarction (STEMI).

BACKGROUND: Electrocardiographic (ECG) methods to assess area at risk (AAR) and infarct size (IS) in patients with ST-elevation myocardial infarction (STEMI) have been previously established but not validated against contemporary benchmark Cardiac Magnetic Resonance (CMR) measures. We compared ECG-determined and CMR-determined measures for (a) AAR, (b) IS, and (c) myocardial salvage. METHODS: Sixty patients with ECG evidence of STEMI and CMR imaging performed within 13 days were included. The ECG-determined (a) AAR scores (Aldrich and Wilkins), (b) IS (Selvester score), and (c) myocardial salvage (i.e. [AAR-IS] / AAR × 100%), were compared with CMR-determined measures. RESULTS: Compared with CMR-determined AAR, both the Wilkins & Aldrich scores underestimated AAR, although the Wilkins (r = 0.72, p < 0.001) showed a better correlation than the Aldrich (r = 0.54, p < 0.001). Bland-Altman analysis revealed a bias of 2.6% (95% limits of agreement: 18.5%, -13.3%) for the Wilkins and 5.9% (95% limits of agreement: 25.6%, -13.8%) for the Aldrich. Estimation of IS was similar between the Selvester score and CMR, with good correlation (r = 0.77, p < 0.001) and agreement (fixed bias 0.4%, 95% limits of agreement 20.8%, -15.5%). However, ECG-determined myocardial salvage significantly underestimated CMR-determined myocardial salvage, with an inverse correlation (r = -0.33, p = 0.01). CONCLUSIONS: The Wilkins score is superior to Aldrich score as an ECG-AAR index, Selvester score is a reasonable ECG estimate of infarct size, though ECG derived myocardial salvage does not have enough accuracy to be used in the clinical setting; it may be an inexpensive surrogate for myocardial salvage in large research studies. Further validation and prognostic studies are required.

ST-segment elevation and cardiac magnetic resonance imaging findings in myocardial infarction with non-obstructive coronary arteries.

PURPOSE: Patients with myocardial infarction and non-obstructive coronary arteries (MINOCA) may present with or without ST-elevation (STE) on the electrocardiogram (ECG). Previous studies have shown that STE was associated with higher risk of early mortality and long-term major adverse coronary events, and that cardiac magnetic resonance imaging (CMR) can help to determine whether the cause of a MINOCA presentation is ischemic or non-ischemic. We set out to determine the relationship between STE and CMR findings in patients presenting with MINOCA. DESIGN: Patients who underwent CMR based on a provisional diagnosis of MINOCA were pooled from three prospective cohort studies: the multicenter Stockholm Myocardial Infarction with Normal Coronaries, a prospective University of Adelaide study, and a prospective NYU School of Medicine diagnostic imaging study. STE was defined as ≥1 mm in ≥2 contiguous leads. RESULTS: Among 292 patients, average age was 57.0 years (±11.9), and 68% were female. Fifty-seven had STE, 231 had no STE and four had left bundle branch block. There was no difference between patients with vs. without STE in the likelihood of the CMR findings of infarction (21% vs. 18%), myocarditis (10% vs. 14%), left ventricular wall motion pattern consistent with takotsubo syndrome on CMR (16% vs. 14%). CONCLUSION: STE on the presenting ECG was not associated with CMR findings in patients with a provisional diagnosis of MINOCA. Based on these findings, increased risk among MINOCA patients with STE does not appear to be related to variation in these CMR findings.

Risk of Thrombosis in Patients Presenting with Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA).

Patients presenting with myocardial infarction (MI) in the absence of obstructive coronary artery disease (CAD) is termed MI with nonobstructive coronary arteries (MINOCA). The underlying pathophysiology of MINOCA is multifactorial and in situ formation and subsequent spontaneous lysis of a coronary thrombus is often hypothesized as one of the mechanisms. The objective of this study is to determine whether MINOCA patients had a greater prothrombotic tendency in comparison to MI patients with obstructive CAD (MICAD). Prospectively, blood samples of 25 consecutive MINOCA patients (58 (interquartile range [IQR]: 48, 75) years, 48% women) and 25 age-/gender-matched MICAD patients (58 (IQR: 50, 66) years, 48% women) were obtained at 1 month after the initial presentation and overall thrombin generation potential and congenital/acquired thrombophilia states were assessed. As regard to results, overall thrombin generation parameters were similar ( p > 0.05) between the MINOCA and MICAD groups, highlighting similar endogenous thrombin potential (1,590 nM/min; IQR: 1,380, 2,000 vs. 1,750 nM/min; IQR: 1,500, 2,040, respectively). There were no significant differences between MINOCA and MICAD, respectively, in respect to the numbers of patients with congenital thrombophilia states including factor V Leiden (0 vs. 4%) and prothrombin gene mutation (8 vs. 4%), decreased antithrombin (8 vs. 0%), protein C (0 vs. 0%), and protein S (4 vs. 0%). None of the patients demonstrated presence of lupus anticoagulant and anticardiolipin antibodies. Although MINOCA patients revealed thrombotic characteristics that are similar to those with MICAD, the results from this study are inconclusive and a larger study with healthy control subjects is required to assess the risk of thrombosis in MINOCA.

Myocardial Infarction With Non-obstructive Coronary Arteries - Diagnosis and Management.

MI with non-obstructive coronary arteries (MINOCA) is an enigma that is being increasingly recognised with the frequent use of angiography following acute MI. To diagnose this condition, it is important to determine the multiple potential underlying mechanisms that may be responsible, many of which require different treatments. This review evaluates the contemporary diagnosis and management of MINOCA.