Cardio-Oncology: A New Discipline in Medicine and Its Relevance to Hematology.

Cardio-oncology, a burgeoning subspecialty, addresses the complex interplay between cardiology and oncology, particularly in light of increased cardiovascular (CV) disease mortality in cancer patients. This review provides a comprehensive overview of cardio-oncology with a focus on the therapies used in hematological malignancies. We explore the bidirectional relationship between heart failure and cancer, emphasizing the need for collaborative care. The review discusses risk stratification, highlighting the importance of baseline CV risk assessment and personalized surveillance regimens. Primary and secondary prevention strategies, including pharmacological interventions, are outlined. The review also delves into the cardiotoxicity associated with hematological cancer therapies, focusing on anthracyclines, Bruton kinase inhibitors, BCR-ABL tyrosine kinase inhibitors, CAR-T cell therapy, immune checkpoint inhibitors, multiple myeloma treatments, and hematopoietic stem cell transplantation. We then highlight the high risk of venous and arterial thromboembolisms in cancer patients and the challenges of anticoagulation management in cardio-oncology. Finally, the review touches on the importance of long-term follow-up and appropriate screening in cancer survivors at high risk of CV morbidity and mortality, based on their CV risk profile and the type and dose of cardiotoxic therapies they received such as anthracyclines or high radiation doses.

Risk Profiles and Treatment Patterns in Atrial Fibrillation Patients with Chronic Kidney Disease Receiving or not Receiving Anticoagulation Therapy.

Background Patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are at high risk for both thromboembolism and bleeding events. The latter induces a potential reason for withholding oral anticoagulation (OAC) despite an indication for prophylaxis of thromboembolic events. Methods AF patients with CKD (estimated glomerular filtration [eGFR] rate between 15 and 49 mL/min per 1.73 m 2 ) were included in a prospective international registry in Europe between 2016 and 2020, that is, XARENO (factor XA inhibition in renal patients with nonvalvular atrial fibrillation observational registry). The study enrolled adult patients treated at the discretion of physicians with rivaroxaban, vitamin K antagonists (VKA), or without OAC (w/oOAC). Here, we report a prespecified explorative baseline comparison between patients receiving OAC or no OAC within XARENO. Results In total, 1,544 patients (mean age: 78.2 years, mean eGFR: 36.2 mL/min) were studied (rivaroxaban n = 764, VKA n = 691, w/oOAC n = 89). Patients in the w/oOAC group were older and had a similar stroke (mean CHA 2 DS 2 -VASc score 4.0) but higher bleeding risk (mean modified Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly score 2.5 vs. 1.8) compared with the OAC groups. The distribution of comorbidities including hypertension, diabetes, and heart failure was similar. Treatment with antiplatelet drugs was fivefold more frequent in the w/oOAC group. Conclusion Only 5.8% of the overall population of AF patients with advanced CKD received no OAC. These patients were older and had a higher bleeding risk, which might explain this decision, but which contrasts with the more frequent use of antiplatelet drugs in this vulnerable group of patients.

Amyloid Burden Correlates with Electrocardiographic Findings in Patients with Cardiac Amyloidosis-Insights from Histology and Cardiac Magnetic Resonance Imaging.

Cardiac amyloidosis (CA) is associated with several distinct electrocardiographic (ECG) changes. However, the impact of amyloid depositions on ECG parameters is not well investigated. We therefore aimed to assess the correlation of amyloid burden with ECG and test the prognostic power of ECG findings on outcomes in patients with CA. Consecutive CA patients underwent ECG assessment and cardiac magnetic resonance imaging (CMR), including the quantification of extracellular volume (ECV) with T1 mapping. Moreover, seven patients underwent additional amyloid quantification using immunohistochemistry staining of endomyocardial biopsies. A total of 105 CA patients (wild-type transthyretin: 74.3%, variant transthyretin: 8.6%, light chain: 17.1%) were analyzed for this study. We detected correlations of total QRS voltage with histologically quantified amyloid burden (r = -0.780, p = 0.039) and ECV (r = -0.266, p = 0.006). In patients above the ECV median (43.9%), PR intervals were significantly longer (p = 0.016) and left anterior fascicular blocks were more prevalent (p = 0.025). In our survival analysis, neither Kaplan-Meier curves (p = 0.996) nor Cox regression analysis detected associations of QRS voltage with adverse patient outcomes (hazard ratio: 0.995, p = 0.265). The present study demonstrated that an increased amyloid burden is associated with lower voltages in CA patients. However, baseline ECG findings, including QRS voltage, were not associated with adverse outcomes.

Antithrombotic Usage, Including Three-Year Outcomes With Dabigatran and Vitamin K Antagonists for Atrial Fibrillation, in Eastern Europe: A Descriptive Analysis From Phase 3 of the GLORIA-AF Registry.

BACKGROUND: Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients. STUDY QUESTION: Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA? STUDY DESIGN: Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe). MEASURES AND OUTCOMES: Three-year outcomes with dabigatran and VKA. RESULTS: In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%). CONCLUSIONS: Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.

Reduction in 99mTc-DPD myocardial uptake with therapy of ATTR cardiomyopathy.

Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). We aimed to determine the impact of RNAi therapeutics on myocardial amyloid load using quantitative single photon emission computed tomography/computed tomography (SPECT/CT) imaging in patients with ATTRv-related cardiomyopathy (ATTRv-CM). We furthermore compared them with wild-type ATTR-CM (ATTRwt-CM) patients treated with tafamidis.Methods and results: ATTRv-CM patients underwent [99mTc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy and quantitative SPECT/CT imaging before and after 12 months (IQR: 11.0-12.0) of treatment with RNAi therapeutics (patisiran: n = 5, inotersen: n = 4). RNAi treatment significantly reduced quantitative myocardial uptake as measured by standardised uptake value (SUV) retention index (baseline: 5.09 g/mL vs. follow-up: 3.19 g/mL, p = .028) in ATTRv-CM patients without significant improvement in cardiac function. Tafamidis treatment resulted in a significant reduction in SUV retention index (4.96 g/mL vs. 3.27 g/mL, p < .001) in ATTRwt-CM patients (historical control cohort: n = 40) at follow-up [9.0 months (IQR: 7.0-10.0)] without beneficial impact on cardiac function.Conclusions: RNAi therapeutics significantly reduce quantitative myocardial uptake in ATTRv-CM patients, comparable to tafamidis treatment in ATTRwt-CM patients, without impact on cardiac function. Serial 99mTc-DPD SPECT/CT imaging may be a valuable tool to quantify and monitor response to disease-specific therapies in both ATTRv-CM and ATTRwt-CM.

European Society of Cardiology Core Curriculum for cardio-oncology.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists.

Improvement of Symptoms and Cardiac Magnetic Resonance Abnormalities in Patients with Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome (PASC-CVS) after Guideline-Oriented Therapy.

Cardiac magnetic resonance (CMR) studies reported CMR abnormalities in patients with mild-moderate SARS-CoV-2 infection, suggesting ongoing myocardial inflammation. Patients (n = 278, 43 ± 13 years, 70.5% female) with post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) were included prospectively into the Vienna POSTCOV Registry between March 2021 and March 2023 (clinicaltrials.gov NCT05398952). Clinical, laboratory, and CMR findings were recorded. Patients with abnormal CMR results were classified into isolated chronic pericardial (with/without pleural) effusion, isolated cardiac function impairment, or both (myopericarditis) groups. Medical treatment included a nonsteroidal anti-inflammatory agent (NSAID) for pericardial effusion and a condition-adapted maximal dose of heart failure (HF) treatment. Three months after medical therapy, clinical assessment and CMR were repeated in 82 patients. Laboratory analyses revealed normal hematological, inflammatory, coagulation, and cardiac biomarkers. CMR abnormalities were found in 155 patients (55.8%). Condition-adapted HF treatment led to a significant increase in the left ventricular ejection fraction (LVEF) in patients with initially reduced LVEF (from 49 ± 5% to 56 ± 4%, p = 0.009, n = 25). Low-moderate doses of NSAIDs for 3 months significantly reduced pericardial effusion (from 4/3;5.75/mm to 2/0;3/mm, median/interquartile ranges/p < 0.001, n = 51). Clinical symptoms improved markedly with a decrease in CMR abnormalities, which might be attributed to the maintenance of NSAID and HF medical treatment for PASC-CVS.

A CircRNA-miRNA-mRNA Network for Exploring Doxorubicin- and Myocet-Induced Cardiotoxicity in a Translational Porcine Model.

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA-miRNA-mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA-miRNA-mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA-miRNA-mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Effect of monovalent COVID-19 vaccines on viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome.

Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms, but reactivation of other viruses as a factor has received less attention. Here we evaluated the reactivation of parvovirus-B19 and several members of the Herpesviridae family (DNA viruses) in patients with long-COVID syndrome. We hypothesized that monovalent COVID-19 vaccines inhibit viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome, thereby reducing clinical symptoms. Clinical and laboratory data for 252 consecutive patients with PCR-verified past SARS-CoV-2 infection and long-COVID syndrome (155 vaccinated and 97 non-vaccinated) were recorded during April 2021-May 2022 (median 243 days post-COVID-19 infection). DNA virus-related IgG and IgM titers were compared between vaccinated and non-vaccinated long-COVID patients and with age- and sex-matched non-infected, unvaccinated (pan-negative for spike-antibody) controls. Vaccination with monovalent COVID-19 vaccines was associated with significantly less frequent fatigue and multiorgan symptoms (p < 0.001), significantly less cumulative DNA virus-related IgM positivity, significantly lower levels of plasma IgG subfractions 2 and 4, and significantly lower quantitative cytomegalovirus IgG and IgM and EBV IgM titers. These results indicate that anti-SARS-CoV-2 vaccination may interrupt viral cross-talk in patients with long-COVID syndrome (ClinicalTrials.gov Identifier: NCT05398952).

Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.

Cardiac Amyloidosis and Valvular Heart Disease.

Growing interest has accrued in the co-existence of cardiac amyloidosis and valvular heart disease. Amyloid infiltration from either transthyretin (ATTR) or of light chain (AL) origin may affect any structure of the heart, including the valves. The recent literature has mainly focused on aortic stenosis and cardiac amyloidosis, improving our understanding of the epidemiology, diagnosis, treatment and prognosis of this dual pathology. Despite being of high clinical relevance, data on mitral/tricuspid regurgitation and cardiac amyloidosis are rather scarce and mostly limited to case reports and small cases series. It is the aim of this review article to summarize the current evidence of concomitant valvular heart disease and cardiac amyloidosis by including studies on epidemiology, diagnostic approaches, screening possibilities, therapeutic management, and prognostic implications.

Evaluation and management of cancer patients presenting with acute cardiovascular disease: a Clinical Consensus Statement of the Acute CardioVascular Care Association (ACVC) and the ESC council of Cardio-Oncology-part 2: acute heart failure, acute myocardial diseases, acute venous thromboembolic diseases, and acute arrhythmias.

Advances in treatment, common cardiovascular (CV) risk factors and the ageing of the population have led to an increasing number of cancer patients presenting with acute CV diseases. These events may be related to cancer itself or cancer treatment. Acute cardiac care specialists must be aware of these acute CV complications and be able to manage them. This may require an individualized and multidisciplinary approach. The management of acute coronary syndromes and acute pericardial diseases in cancer patients was covered in part 1 of a clinical consensus document. This second part focusses on acute heart failure, acute myocardial diseases, venous thromboembolic diseases and acute arrhythmias.

Comparison of High-Sensitivity C-Reactive Protein vs C-reactive Protein for Cardiovascular Risk Prediction in Chronic Cardiac Disease.

BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) is a biomarker used for risk prediction for cardiovascular disease by assessing low concentration of inflammation. Measurements of regular CRP have become very sensitive with a lower detection limit of 0.3 mg/L. This study aimed to compare and explore the association between CRP and hs-CRP. METHODS: Data from 607 consecutive patients referred for cardiovascular risk assessment with hs-CRP were reviewed retrospectively. In total, 570 patients were included in the analysis and classified into 3 (low-, medium-, and high-risk) groups (hs-CRP cutoff: <1, 1-3, >3 mg/L). Correlation between hs-CRP and CRP was assessed with the kappa statistic and visualized with a Bland-Altman plot. The association between hs-CRP and occurrence of the composite outcome (acute myocardial infarction, stroke, coronary intervention [percutaneous coronary intervention or bypass surgery], or death) was determined with Cox regression analysis and visualized with Kaplan-Meier curves. RESULTS: A total number reclassification occurred in 8.6% of the cases for CRP risk groups, which demonstrates an agreement of 91.4% (kappa 0.87; P < 0.001). The correlation between CRP and hs-CRP was significant (P < 0.001), Spearman regression R2 = 0.98. A Bland-Altman plot displayed an average difference of 0.19 mg/L (95%CI, 0.17 to 0.23) between the CRP and hs-CRP. Cardiovascular events were more likely to occur in patients who were older, with hs-CRP or CRP >3 mg/L and a history of coronary artery disease. CONCLUSIONS: The usual laboratory tests for CRP values in the lower range highly correlate with the hs-CRP tests and can therefore replace the costlier hs-CRP measurements.

Comprehensive myocardial characterization using cardiac magnetic resonance associates with outcomes in low gradient severe aortic stenosis.

AIMS: This study sought to compare cardiac magnetic resonance (CMR) characteristics according to different flow/gradient patterns of aortic stenosis (AS) and to evaluate their prognostic value in patients with low-gradient AS. METHODS AND RESULTS: This international prospective multicentric study included 147 patients with low-gradient moderate to severe AS who underwent comprehensive CMR evaluation of left ventricular global longitudinal strain (LVGLS), extracellular volume fraction (ECV), and late gadolinium enhancement (LGE). All patients were classified as followings: classical low-flow low-gradient (LFLG) [mean gradient (MG) < 40 mmHg and left ventricular ejection fraction (LVEF) < 50%]; paradoxical LFLG [MG < 40 mmHg, LVEF ≥ 50%, and stroke volume index (SVi) < 35 ml/m2]; and normal-flow low-gradient (MG < 40 mmHg, LVEF ≥ 50%, and SVi ≥ 35 ml/m2). Patients with classical LFLG (n = 90) had more LV adverse remodelling including higher ECV, and higher LGE and volume, and worst LVGLS. Over a median follow-up of 2 years, 43 deaths and 48 composite outcomes of death or heart failure hospitalizations occurred. Risks of adverse events increased per tertile of LVGLS: hazard ratio (HR) = 1.50 [95% CI, 1.02-2.20]; P = 0.04 for mortality; HR = 1.45 [1.01-2.09]; P < 0.05 for composite outcome; per tertile of ECV, HR = 1.63 [1.07-2.49]; P = 0.02 for mortality; HR = 1.54 [1.02-2.33]; P = 0.04 for composite outcome. LGE presence also associated with higher mortality, HR = 2.27 [1.01-5.11]; P < 0.05 and composite outcome, HR = 3.00 [1.16-7.73]; P = 0.02. The risk of mortality and the composite outcome increased in proportion to the number of impaired components (i.e. LVGLS, ECV, and LGE) with multivariate adjustment. CONCLUSIONS: In this international prospective multicentric study of low-gradient AS, comprehensive CMR assessment provides independent prognostic value that is cumulative and incremental to clinical and echocardiographic characteristics.

Cardio-oncology in Austria: cardiotoxicity and surveillance of anti-cancer therapies : Position paper of the Heart Failure Working Group of the Austrian Society of Cardiology.

Survival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to <50%), or myocardial strain decreases (>15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients.

Clinical Value of Stress Transaortic Flow Rate During Dobutamine Echocardiography in Reduced Left Ventricular Ejection Fraction, Low-Gradient Aortic Stenosis: A Multicenter Study.

BACKGROUND: Low rest transaortic flow rate (FR) has been shown previously to predict mortality in low-gradient aortic stenosis. However limited prognostic data exists on stress FR during low-dose dobutamine stress echocardiography. We aimed to assess the value of stress FR for the detection of aortic valve stenosis (AS) severity and the prediction of mortality. METHODS: This is a multicenter cohort study of patients with reduced left ventricular ejection fraction and low-gradient aortic stenosis (aortic valve area <1 cm2 and mean gradient <40 mm Hg) who underwent low-dose dobutamine stress echocardiography to identify the AS severity and presence of flow reserve. The outcome assessed was all-cause mortality. RESULTS: Of the 287 patients (mean age, 75±10 years; males, 71%; left ventricular ejection fraction, 31±10%) over a mean follow-up of 24±30 months there were 127 (44.3%) deaths and 147 (51.2%) patients underwent aortic valve intervention. Higher stress FR was independently associated with reduced risk of mortality (hazard ratio, 0.97 [95% CI, 0.94-0.99]; P=0.01) after adjusting for age, chronic kidney disease, heart failure symptoms, aortic valve intervention, and rest left ventricular ejection fraction. The minimum cutoff for prediction of mortality was stress FR 210 mL/s. Following adjustment to the same important clinical and echocardiographic parameters, among the three criteria of AS severity during stress, ie, the guideline definition of aortic valve area <1cm2 and aortic valve mean gradient ≥40 mm Hg, or aortic valve mean gradient ≥40 mm Hg, or the novel definition of aortic valve area <1 cm2 at stress FR ≥210 mL/s, only the latter was independently associated with mortality (hazard ratio, 1.72 [95% CI, 1.05-2.82]; P=0.03). Furthermore aortic valve area <1cm2 at stress FR ≥210 mL/s was the only severe aortic stenosis criterion that was associated with improved outcome following aortic valve intervention (P<0.001). Guideline-defined stroke volume flow reserve did not predict mortality. CONCLUSIONS: Stress FR during low-dose dobutamine stress echocardiography was useful for the detection of both AS severity and flow reserve and was associated with improved prediction of outcome following aortic valve intervention.