A 3-year evaluation of preclinicaltrials.eu reveals room for improvement in preregistration of animal studies.

In 2018, the first registry dedicated to preregistration of animal study protocols was launched. Despite international support, the overall number of (pre)registered protocols is still low, illustrating the need for pushing the preregistration agenda among researchers and policymakers.

Digital Solutions to Optimize Guideline-Directed Medical Therapy Prescriptions in Heart Failure Patients: Current Applications and Future Directions.

PURPOSEOF REVIEW: Guideline-directed medical therapy (GDMT) underuse is common in heart failure (HF) patients. Digital solutions have the potential to support medical professionals to optimize GDMT prescriptions in a growing HF population. We aimed to review current literature on the effectiveness of digital solutions on optimization of GDMT prescriptions in patients with HF. RECENT FINDINGS: We report on the efficacy, characteristics of the study, and population of published digital solutions for GDMT optimization. The following digital solutions are discussed: teleconsultation, telemonitoring, cardiac implantable electronic devices, clinical decision support embedded within electronic health records, and multifaceted interventions. Effect of digital solutions is reported in dedicated studies, retrospective studies, or larger studies with another focus that also commented on GDMT use. Overall, we see more studies on digital solutions that report a significant increase in GDMT use. However, there is a large heterogeneity in study design, outcomes used, and populations studied, which hampers comparison of the different digital solutions. Barriers, facilitators, study designs, and future directions are discussed. There remains a need for well-designed evaluation studies to determine safety and effectiveness of digital solutions for GDMT optimization in patients with HF. Based on this review, measuring and controlling vital signs in telemedicine studies should be encouraged, professionals should be actively alerted about suboptimal GDMT, the researchers should consider employing multifaceted digital solutions to optimize effectiveness, and use study designs that fit the unique sociotechnical aspects of digital solutions. Future directions are expected to include artificial intelligence solutions to handle larger datasets and relieve medical professional's workload.

Current State and Future Perspectives of Artificial Intelligence for Automated Coronary Angiography Imaging Analysis in Patients with Ischemic Heart Disease.

PURPOSE OF REVIEW: Artificial intelligence (AI) applications in (interventional) cardiology continue to emerge. This review summarizes the current state and future perspectives of AI for automated imaging analysis in invasive coronary angiography (ICA). RECENT FINDINGS: Recently, 12 studies on AI for automated imaging analysis In ICA have been published. In these studies, machine learning (ML) models have been developed for frame selection, segmentation, lesion assessment, and functional assessment of coronary flow. These ML models have been developed on monocenter datasets (in range 31-14,509 patients) and showed moderate to good performance. However, only three ML models were externally validated. Given the current pace of AI developments for the analysis of ICA, less-invasive, objective, and automated diagnosis of CAD can be expected in the near future. Further research on this technology in the catheterization laboratory may assist and improve treatment allocation, risk stratification, and cath lab logistics by integrating ICA analysis with other clinical characteristics.

Marfan syndrome resulting from a rare pathogenic FBN1 variant, ascertained through a proband with IgG4-related arteriopathy.

A 57-year-old man with a family history of aortic aneurysm was found, during assessment of unexplained fever, to have an infrarenal aortic aneurysm requiring immediate repair. Dilatation of popliteal and iliac arteries was also present. Progressive aortic root dilatation with aortic regurgitation was documented from 70 years leading to valve-sparing aortic root replacement at 77 years, at which time genetic studies identified a likely pathogenic FBN1 missense variant c.6916C > T (p.Arg2306Cys) in exon 56. The proband's lenses were normally positioned and the Marfan syndrome (MFS) systemic score was 0/20. Cascade genetic testing identified 15 other family members with the FBN1 variant, several of whom had unsuspected aortic root dilatation; none had ectopia lentis or MFS systemic score ≥ 7. Segregation analysis resulted in reclassification of the FBN1 variant as pathogenic. The combination of thoracic aortic aneurysm and dissection (TAAD) and a pathogenic FBN1 variant in multiple family members allowed a diagnosis of MFS using the revised Ghent criteria. At 82 years, the proband's presenting abdominal aortic aneurysm was diagnosed retrospectively to have resulted from IgG4-related inflammatory aortopathy.

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift.

The international consortium TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) has recently addressed key priorities in the field of cell-based therapy for cardiac repair, identifying the efficacy of translational research as one of the main challenges to ultimately improve the quality of life of patients with ischemic disease. Much of the controversy and confusion surrounding cardiac regenerative therapy stems from insufficient rigor in the conduct of preclinical studies, and there is an increasing recognition of a number of problems that undermine its quality that may contribute to translational failure. Here, we introduce well defined stages for preclinical research, and put forth proposals that should promote more rigorous preclinical work, in an effort to improve its quality and translatability. To augment the utility of preclinical research and its translation, it is necessary to (1) improve the quality of preclinical research, (2) promote collaborative efforts, and (3) enhance the sharing of knowledge and protocols. In particular, confirmatory (stage III) preclinical studies should be considered as a preamble to clinical studies and therefore must adhere to their standards of quality (including internal validity, standardization of protocols, and multicenter design). To increase transparency and minimize bias, these studies should be prospectively registered in an independent, open database. Ultimately, these recommendations should be implemented in the daily routine of investigators and in the policies of institutions, journals, and funding agencies.

Cardiac Stem Cell Treatment in Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Studies.

RATIONALE: Cardiac stem cells (CSC) therapy has been clinically introduced for cardiac repair after myocardial infarction (MI). To date, there has been no systematic overview and meta-analysis of studies using CSC therapy for MI. OBJECTIVE: Here, we used meta-analysis to establish the overall effect of CSCs in preclinical studies and assessed translational differences between and within large and small animals in the CSC therapy field. In addition, we explored the effect of CSC type and other clinically relevant parameters on functional outcome to better predict and design future (pre)clinical studies using CSCs for MI. METHODS AND RESULTS: A systematic search was performed, yielding 80 studies. We determined the overall effect of CSC therapy on left ventricular ejection fraction and performed meta-regression to investigate clinically relevant parameters. We also assessed the quality of included studies and possible bias. The overall effect observed in CSC-treated animals was 10.7% (95% confidence interval 9.4-12.1; P<0.001) improvement in ejection fraction compared with placebo controls. Interestingly, CSC therapy had a greater effect in small animals compared with large animals (P<0.001). Meta-regression indicated that cell type was a significant predictor for ejection fraction improvement in small animals. Minor publication bias was observed in small animal studies. CONCLUSIONS: CSC treatment resulted in significant improvement of ejection fraction in preclinical animal models of MI compared with placebo. There was a reduction in the magnitude of effect in large compared with small animal models. Although different CSC types have overlapping culture characteristics, we observed a significant difference in their effect in post-MI animal studies.

Endogenous assessment of diffuse myocardial fibrosis in patients with T1ρ -mapping.

PURPOSE: Recently, it was shown that a significantly higher T1ρ is found in compact myocardial fibrosis after chronic myocardial infarction. In this study, we investigated the feasibility of native T1ρ -mapping for the detection of diffuse myocardial fibrosis in patients with dilated cardiomyopathy (DCM). MATERIALS AND METHODS: T1ρ -mapping was performed on three explanted hearts from DCM patients at 3 Tesla (T). Histological fibrosis quantification was performed, and compared with the T1ρ -relaxation times in the heart. Furthermore, twenty DCM patients underwent an MRI at 1.5T. Native T1ρ -maps, native T1 -maps, and extracellular volume (ECV)-maps were acquired. Additionally, eight healthy volunteers were scanned for reference values. RESULTS: A significant correlation (Pearson r = 0.49; P = 0.005) was found between ex vivo T1ρ -values and fibrosis fraction from histology. Additionally, a significantly higher T1ρ -relaxation time (55.2 ± 2.7 ms) was found in DCM patients compared with healthy control subjects (51.5 ± 1.2 ms) (P = 0.0024). The relation between in vivo T1ρ -values and ECV-values was significant (Pearson r = 0.66). No significant relation was found between native T1 - and ECV-values in this study (P = 0.89). CONCLUSION: This study showed proof of principle for the endogenous detection of diffuse myocardial fibrosis with T1ρ -MRI. Ex vivo and in vivo experiments showed promising results that T1ρ -MRI can be used to measure the extent of diffuse myocardial fibrosis in the myocardium. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:132-138.

An easy-to-use scoring index to determine severity of mitral regurgitation by 2D echocardiography in clinical practice.

PURPOSE: Mitral regurgitation (MR) grading by two-dimensional transthoracic echocardiography is challenging, but important to determine the best treatment strategy in patients with MR. Current guidelines advocate an integrative approach, although no recommendation is provided on how to do so. An easy-to-use index will be helpful for standardized and reproducible MR grading. METHODS: Eleven echocardiographic parameters were retrospectively evaluated in 145 patients with moderate or severe MR. Parameters were scored positive or negative for severe MR, where expert panel consensus reading was considered as the reference standard. Logistic regression was performed, and adjusted coefficients were used to create a risk score for severe MR per patient (ROSE-index). The best cutoff with corresponding predictive values was determined. RESULTS: Eighty-two percent of all parameters could be determined. Multivariable analysis revealed five parameters that remained significant predictors for severe MR: morphology, jet characteristics, vena contracta, systolic reversal, and left ventricular dimensions. With different weighing, a total score of 8 could be obtained. Median total ROSE-index score for moderate (2.0) and severe MR (5.0) did significantly differ. The cutoff score (≥4) revealed sensitivity 0.84 and specificity 0.83 to diagnose severe MR. Negative predictive value was 100% for score 0 and 1; score 6-8 showed a 100% positive predictive value. Inter- and intra-observer agreements were excellent (K-values >0.80). CONCLUSION: Here, we propose an easy-to-use tool for integrated analysis of guideline parameters to assess MR severity. Using this so-called ROSE-index revealed reliable and reproducible assessment of severe MR (cutoff≥4) that may be helpful for clinical decision making.

Baseline MDCT findings after prosthetic heart valve implantation provide important complementary information to echocardiography for follow-up purposes.

OBJECTIVES: Recent studies have proposed additional multidetector-row CT (MDCT) for prosthetic heart valve (PHV) dysfunction. References to discriminate physiological from pathological conditions early after implantation are lacking. We present baseline MDCT findings of PHVs 6 weeks post implantation. METHODS: Patients were prospectively enrolled and TTE was performed according to clinical guidelines. 256-MDCT images were systematically assessed for leaflet excursions, image quality, valve-related artefacts, and pathological and additional findings. RESULTS: Forty-six patients were included comprising 33 mechanical and 16 biological PHVs. Overall, MDCT image quality was good and relevant regions remained reliably assessable despite mild-moderate PHV-artefacts. MDCT detected three unexpected valve-related pathology cases: (1) prominent subprosthetic tissue, (2) pseudoaneurysm and (3) extensive pseudoaneurysms and valve dehiscence. The latter patient required valve surgery to be redone. TTE only showed trace periprosthetic regurgitation, and no abnormalities in the other cases. Additional findings were: tilted aortic PHV position (n = 3), pericardial haematoma (n = 3) and pericardial effusion (n = 3). Periaortic induration was present in 33/40 (83 %) aortic valve patients. CONCLUSIONS: MDCT allowed evaluation of relevant PHV regions in all valves, revealed baseline postsurgical findings and, despite normal TTE findings, detected three cases of unexpected, clinically relevant pathology. KEY POINTS: • Postoperative MDCT presents baseline morphology relevant for prosthetic valve follow-up. • 83 % of patients show periaortic induration 6 weeks after aortic valve replacement. • MDCT detected three cases of clinically relevant pathology not found with TTE. • Valve dehiscence detection by MDCT required redo valve surgery in one patient. • MDCT is a suitable and complementary imaging tool for follow-up purposes.

Necrostatin-1 alleviates reperfusion injury following acute myocardial infarction in pigs.

BACKGROUND: In rodents, it has previously been shown that necrostatin-1 (Nec-1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec-1 in a large animal model, we assessed the effects of Nec-1 in a porcine I/R model, relevant to human disease. MATERIALS AND METHODS: In Dalland landrace pigs (69 ± 3 kg), I/R injury was induced by a 75-min surgical ligation of the left circumflex coronary artery (LCx). Ten minutes prior to reperfusion, pigs were randomly allocated to different Nec-1 doses (1.0 mg/kg or 3.3 mg/kg) or vehicle treatment (control, CTRL). Functional endpoints and immunohistological analyses were performed 24 h after reperfusion. RESULTS: Nec-1 3.3 mg/kg significantly reduced IS (n = 6; 24.4 ± 15.6%) compared to Nec-1 1.0 mg/kg (n = 5; 54.8 ± 16.9%) or CTRLs (n = 6; 62.1 ± 26.6%; P = 0.016). In line, LV ejection fraction (LVEF) was significantly higher in Nec-1 3.3 mg/kg, copared to Nec-1 1.0 mg/kg or CTRL treated animals (50.0 ± 12.0% vs. 32.5 ± 12.9% vs. 31.9 ± 6.6%, respectively, P = 0.015). Hemodynamically, a preserved contractility was observed [end-systolic volume at 100 mmHg (ESV100 )] at 24-h follow-up (87.6 ± 17.3 mL vs. 74.5 ± 41.1 mL vs. 56.8 ± 11.8 mL, respectively, P = 0.032), reflecting improved cardiac function. CONCLUSIONS: In the pig model of I/R injury, intravenous administration of Nec-1 prior to reperfusion was an effective and above all practical therapeutic strategy that significantly reduced IS and preserved left ventricular function. These data highlight the potential of cardioprotection as a promising adjuvant therapy in the setting of early reperfusion following I/R injury.

Endogenous contrast MRI of cardiac fibrosis: beyond late gadolinium enhancement.

The aim of this review is to provide an overview of detection of cardiac fibrosis with MRI using current standards and novel endogenous MRI techniques. Assessment of cardiac fibrosis is important for diagnosis, prediction of prognosis and follow-up after therapy. During the past years, progress has been made in fibrosis detection using MRI. Cardiac infarct size can be assessed noninvasively with late gadolinium enhancement. Several methods for fibrosis detection using endogenous contrast have been developed, such as native T1 -mapping, T1ρ -mapping, Magnetization transfer imaging, and T2 *-mapping. Each of these methods will be described, providing the basic methodology, showing potential applications from applied studies, and discussing the potential and challenges or pitfalls. We will also identify future steps and developments that are needed for bringing these methods to the clinical practice.

Are novel non-invasive imaging techniques needed in patients with suspected prosthetic heart valve endocarditis? A systematic review and meta-analysis.

OBJECTIVES: Multimodal non-invasive imaging plays a key role in establishing a diagnosis of PHV endocarditis. The objective of this study was to provide a systematic review of the literature and meta-analysis of the diagnostic accuracy of TTE, TEE, and MDCT in patients with (suspected) PHV endocarditis. METHODS: Studies published between 1985 and 2013 were identified via search and cross-reference of PubMed/Embase databases. Studies were included if (1) they reported on the non-invasive index tests TTE, TEE, or MDCT; (2) data was provided on PHV endocarditis as the condition of interest; and (3) imaging results were verified against either surgical inspection/autopsy or clinical follow-up reference standards, thereby enabling the extraction of 2-by-2 tables. RESULTS: Twenty articles (including 496 patients) met the inclusion criteria for PHV endocarditis. TTE, TEE, and MDCT + TEE had a pooled sensitivity/specificity for vegetations of 29/100%; 82/95%, and 88/94%, respectively. The pooled sensitivity/specificity of TTE, TEE, and MDCT + TEE for periannular complications was 36/93%, 86/98%, and 100/94%, respectively. CONCLUSIONS: TEE showed good sensitivity and specificity for establishing a diagnosis of PHV endocarditis. Although MDCT data are limited, this review showed that MDCT in addition to TEE may improve sensitivity in detecting life-threatening periannular complications. KEY POINTS: • Multimodal imaging is an important ingredient of diagnostic workup for PHV endocarditis. • Transthoracic and transesophageal echography may miss life-threatening periannular complications. • MDCT can improve sensitivity for the detection of life-threatening periannular complications.

Endogenous assessment of chronic myocardial infarction with T(1ρ)-mapping in patients.

BACKGROUND: Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T(1ρ) is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T(1ρ)-mapping. In this study we aimed to translate and validate T(1ρ)-mapping for endogenous detection of chronic MI in patients. METHODS: We first performed a study in a porcine animal model of chronic MI to validate the implementation of T(1ρ)-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T(1ρ)-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T(1ρ)-map was calculated. The resulting T(1ρ)-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model. RESULTS: In the animal model (n = 9) a significantly higher T(1ρ) relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T(1ρ) relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T(1ρ)-maps was 74%. CONCLUSION: We have shown the feasibility of native T(1ρ)-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T(1ρ)-mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.

Multidetector-row computed tomography allows accurate measurement of mechanical prosthetic heart valve leaflet closing angles compared with fluoroscopy.

PURPOSE: The purpose of this study was to compare multidetector-row computed tomography (MDCT) leaflet restriction measurements with fluoroscopy measurements in commonly used mechanical prosthetic heart valves (PHVs). METHODS: Four mechanical PHVs (ON-X, Carbomedics, St. Jude, and Medtronic Hall) were imaged in a pulsatile model using fluoroscopy and 64-detector-row computed tomography. Five image acquisitions of each PHV without (1) and with (4) restricted leaflet closure were made. Three observers measured closure angles on fluoroscopy and MDCT. Data were analyzed using intraclass correlation coefficient (ICC) and Bland-Altman plots. RESULTS: Interobserver agreement was high in restricted and non-restricted leaflets on both modalities (ICCs >0.995). MDCT and fluoroscopy showed high agreements (ICCs >0.989). Median MDCT closure angle measurements differed at most -2 to +2 degrees from fluoroscopy in the restricted and -1 to +2 degrees in the non-restricted leaflets. CONCLUSIONS: MDCT allows measurement of leaflet motion with a maximal median discrepancy of 2 degrees. Both MDCT and fluoroscopy detect restricted leaflet closure with great accuracy.

Explainable machine learning using echocardiography to improve risk prediction in patients with chronic coronary syndrome.

Aims: The European Society of Cardiology guidelines recommend risk stratification with limited clinical parameters such as left ventricular (LV) function in patients with chronic coronary syndrome (CCS). Machine learning (ML) methods enable an analysis of complex datasets including transthoracic echocardiography (TTE) studies. We aimed to evaluate the accuracy of ML using clinical and TTE data to predict all-cause 5-year mortality in patients with CCS and to compare its performance with traditional risk stratification scores. Methods and results: Data of consecutive patients with CCS were retrospectively collected if they attended the outpatient clinic of Amsterdam UMC location AMC between 2015 and 2017 and had a TTE assessment of the LV function. An eXtreme Gradient Boosting (XGBoost) model was trained to predict all-cause 5-year mortality. The performance of this ML model was evaluated using data from the Amsterdam UMC location VUmc and compared with the reference standard of traditional risk scores. A total of 1253 patients (775 training set and 478 testing set) were included, of which 176 patients (105 training set and 71 testing set) died during the 5-year follow-up period. The ML model demonstrated a superior performance [area under the receiver operating characteristic curve (AUC) 0.79] compared with traditional risk stratification tools (AUC 0.62-0.76) and showed good external performance. The most important TTE risk predictors included in the ML model were LV dysfunction and significant tricuspid regurgitation. Conclusion: This study demonstrates that an explainable ML model using TTE and clinical data can accurately identify high-risk CCS patients, with a prognostic value superior to traditional risk scores.

Comparison of the Diagnostic Yield of Intracoronary Acetylcholine Infusion and Acetylcholine Bolus Injection Protocols During Invasive Coronary Function Testing.

Coronary endothelial dysfunction (CED) and coronary artery spasm (CAS) are causes of angina with no obstructive coronary arteries in patients. Both can be diagnosed by invasive coronary function testing (ICFT) using acetylcholine (ACh). This study aimed to evaluate the diagnostic yield of a 3-minute ACh infusion as compared with a 1-minute ACh bolus injection protocol in testing CED and CAS. We evaluated 220 consecutive patients with angina and no obstructive coronary arteries who underwent ICFT using continuous Doppler flow measurements. Per protocol, 110 patients were tested using 3-minute infusion, and thereafter 110 patients using 1-minute bolus injections, because of a protocol change. CED was defined as a <50% increase in coronary blood flow or any epicardial vasoconstriction in reaction to low-dose ACh and CAS according to the Coronary Vasomotor Disorders International Study Group (COVADIS) criteria, both with and without T-wave abnormalities, in reaction to high dose ACh. The prevalence of CED was equal in both protocols (78% vs 79%, p = 0.869). Regarding the endotypes of CAS according to COVADIS, the equivocal endotype was diagnosed less often in the 3 vs 1-minute protocol (24% vs 44%, p = 0.004). Including T-wave abnormalities in the COVADIS criteria resulted in a similar diagnostic yield of both protocols. Hemodynamic changes from baseline to the low or high ACh doses were comparable between the protocols for each endotype. In conclusion, ICFT using 3-minute infusion or 1-minute bolus injections of ACh showed a similar diagnostic yield of CED. When using the COVADIS criteria, a difference in the equivocal diagnosis was observed. Including T-wave abnormalities as a diagnostic criterion reclassified equivocal test results into CAS and decreased this difference. For clinical practice, we recommend the inclusion of T-wave abnormalities as a diagnostic criterion for CAS and the 1-minute bolus protocol for practicality.

Digital consults to optimize guideline-directed therapy: design of a pragmatic multicenter randomized controlled trial.

AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization.

Impact of sex on the assessment of the microvascular resistance reserve.

BACKGROUND: The microvascular resistance reserve (MRR) is an innovative index to assess the vasodilatory capacity of the coronary circulation while accounting for the presence of concomitant epicardial disease. The MRR has shown to be a valuable diagnostic and prognostic tool in the general coronary artery disease (CAD) population. However, considering the fundamental aspects of its assessment and the unique hemodynamic characteristics of women, it is crucial to provide additional considerations for evaluating the MRR specifically in women. AIM: The aim of this study was to assess the diagnostic and prognostic applicability of the MRR in women and assess the potential differences across different sexes. METHODS: From the ILIAS Registry, we enrolled all patients with a stable indication for invasive coronary angiography, ensuring complete physiological and follow-up data. We analyzed the diagnostic value by comparing differences between sexes and evaluated the prognostic value of the MRR specifically in women, comparing it to that in men. RESULTS: A total of 1494 patients were included of which 26% were women. The correlation between MRR and CFR was good and similar between women (r = 0.80, p < 0.005) and men (r = 0.81, p < 0.005). The MRR was an independent and important predictor of MACE in both women (HR 0.67, 0.47-0.96, p = 0.027) and men (HR 0.84, 0.74-0.95, p = 0.007). The optimal cut-off value for MRR in women was 2.8 and 3.2 in men. An abnormal MRR similarly predicted MACE at 5-year follow-up in both women and men. CONCLUSION: The MRR seems to be equally applicable in both women and men with stable coronary artery disease.