Practice gaps in the care of mitral valve regurgitation: Insights from the American College of Cardiology mitral regurgitation gap analysis and advisory panel.

BACKGROUND: The revised 2014 American College of Cardiology (ACC)/American Heart Association valvular heart disease guidelines provide evidenced-based recommendations for the management of mitral regurgitation (MR). However, knowledge gaps related to our evolving understanding of critical MR concepts may impede their implementation. METHODS: The ACC conducted a multifaceted needs assessment to characterize gaps, practice patterns, and perceptions related to the diagnosis and treatment of MR. A key project element was a set of surveys distributed to primary care and cardiovascular physicians (cardiologists and cardiothoracic surgeons). Survey and other gap analysis findings were presented to a panel of 10 expert advisors from specialties of general cardiology, cardiac imaging, interventional cardiology, and cardiac surgeons with expertise in valvular heart disease, especially MR, and cardiovascular education. The panel was charged with assessing the relative importance and potential means of remedying identified gaps to improve care for patients with MR. RESULTS: The survey results identified several knowledge and practice gaps that may limit implementation of evidence-based recommendations for MR care. Specifically, half of primary care physicians reported uncertainty regarding timing of intervention for patients with severe primary or functional MR. Physicians in all groups reported that quantitative indices of MR severity were frequently not reported in clinical echocardiographic interpretations, and that these measurements were not consistently reviewed when provided in reports. In the treatment of MR, nearly 30% of primary care physician and general cardiologists did not know the volume of mitral valve repair surgeries by their reference cardiac surgeons and did not have a standard source to obtain this information. After review of the survey results, the expert panel summarized practice gaps into 4 thematic areas and offered proposals to address deficiencies and promote better alignment with the 2014 ACC/American Heart Association valvular disease guidelines. CONCLUSION: Important knowledge and skill gaps exist that may impede optimal care of the patient with MR. Focused educational and practice interventions should be developed to reduce these gaps.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Closing the Last Mile Gap in Access to Multimodality Imaging in Rural Settings: Design of the Imaging Core of the Risk Underlying Rural Areas Longitudinal Study.

Achieving optimal cardiovascular health in rural populations can be challenging for several reasons including decreased access to care with limited availability of imaging modalities, specialist physicians, and other important health care team members. Therefore, innovative solutions are needed to optimize health care and address cardiovascular health disparities in rural areas. Mobile examination units can bring imaging technology to underserved or remote communities with limited access to health care services. Mobile examination units can be equipped with a wide array of assessment tools and multiple imaging modalities such as computed tomography scanning and echocardiography. The detailed structural assessment of cardiovascular and lung pathology, as well as the detection of extracardiac pathology afforded by computed tomography imaging combined with the functional and hemodynamic assessments acquired by echocardiography, yield deep phenotyping of heart and lung disease for populations historically underrepresented in epidemiological studies. Moreover, by bringing the mobile examination unit to local communities, innovative approaches are now possible including engagement with local professionals to perform these imaging assessments, thereby augmenting local expertise and experience. However, several challenges exist before mobile examination unit-based examinations can be effectively integrated into the rural health care setting including standardizing acquisition protocols, maintaining consistent image quality, and addressing ethical and privacy considerations. Herein, we discuss the potential importance of cardiac multimodality imaging to improve cardiovascular health in rural regions, outline the emerging experience in this field, highlight important current challenges, and offer solutions based on our experience in the RURAL (Risk Underlying Rural Areas Longitudinal) cohort study.

Imaging the mitral valve: a primer for the interventional surgeon.

Transcatheter mitral valve interventions (TMVI) have evolved over the past decade as alternatives to open surgical repair for the therapeutic management of patients with severe mitral regurgitation (MR). Concurrent with the development of these technologies, quality multi-modality cardiac imaging has become essential in patient selection and procedural guidance. The former involves assessments of the pathophysiologic mechanisms of regurgitation, valvular anatomy and morphology, as well as objective quantification of the severity of MR. Both transthoracic and transesophageal echocardiography (TEE) are crucial and serve as the gateway to diagnosis and management of mitral valvular disease. Along with multi-detector computed tomography (CT) and cardiac magnetic resonance imaging (CMR), echocardiography plays an important role for preprocedural planning and evaluation of the spatial relationships of the mitral valvular complex with the coronary sinus, circumflex coronary artery and left ventricular (LV) outflow tract. Procedures that target mitral leaflets (e.g., MitraClip, PASCAL) or annulus (e.g., Cardioband, Carillon), or provide chordal (e.g., NeoChord, Harpoon) or valvular replacement, tend to be guided by TEE and assisted by fluoroscopy. As newer devices become available and outcomes of TMVI improve, cardiac imaging will undoubtedly continue to play an essential role in the success of percutaneous mitral valve repair (MVr) and replacement. The interventional surgeon of the future must therefore have a thorough understanding of the various imaging modalities while synthesizing and integrating novel concepts (e.g., neo-LV outflow tract) as applicable to assessing valvular function and pathology.

Utility of a Deep-Learning Algorithm to Guide Novices to Acquire Echocardiograms for Limited Diagnostic Use.

Importance: Artificial intelligence (AI) has been applied to analysis of medical imaging in recent years, but AI to guide the acquisition of ultrasonography images is a novel area of investigation. A novel deep-learning (DL) algorithm, trained on more than 5 million examples of the outcome of ultrasonographic probe movement on image quality, can provide real-time prescriptive guidance for novice operators to obtain limited diagnostic transthoracic echocardiographic images. Objective: To test whether novice users could obtain 10-view transthoracic echocardiographic studies of diagnostic quality using this DL-based software. Design, Setting, and Participants: This prospective, multicenter diagnostic study was conducted in 2 academic hospitals. A cohort of 8 nurses who had not previously conducted echocardiograms was recruited and trained with AI. Each nurse scanned 30 patients aged at least 18 years who were scheduled to undergo a clinically indicated echocardiogram at Northwestern Memorial Hospital or Minneapolis Heart Institute between March and May 2019. These scans were compared with those of sonographers using the same echocardiographic hardware but without AI guidance. Interventions: Each patient underwent paired limited echocardiograms: one from a nurse without prior echocardiography experience using the DL algorithm and the other from a sonographer without the DL algorithm. Five level 3-trained echocardiographers independently and blindly evaluated each acquisition. Main Outcomes and Measures: Four primary end points were sequentially assessed: qualitative judgement about left ventricular size and function, right ventricular size, and the presence of a pericardial effusion. Secondary end points included 6 other clinical parameters and comparison of scans by nurses vs sonographers. Results: A total of 240 patients (mean [SD] age, 61 [16] years old; 139 men [57.9%]; 79 [32.9%] with body mass indexes >30) completed the study. Eight nurses each scanned 30 patients using the DL algorithm, producing studies judged to be of diagnostic quality for left ventricular size, function, and pericardial effusion in 237 of 240 cases (98.8%) and right ventricular size in 222 of 240 cases (92.5%). For the secondary end points, nurse and sonographer scans were not significantly different for most parameters. Conclusions and Relevance: This DL algorithm allows novices without experience in ultrasonography to obtain diagnostic transthoracic echocardiographic studies for evaluation of left ventricular size and function, right ventricular size, and presence of a nontrivial pericardial effusion, expanding the reach of echocardiography to clinical settings in which immediate interrogation of anatomy and cardiac function is needed and settings with limited resources.

Deep Learning-Based Automated Echocardiographic Quantification of Left Ventricular Ejection Fraction: A Point-of-Care Solution.

BACKGROUND: We have recently tested an automated machine-learning algorithm that quantifies left ventricular (LV) ejection fraction (EF) from guidelines-recommended apical views. However, in the point-of-care (POC) setting, apical 2-chamber views are often difficult to obtain, limiting the usefulness of this approach. Since most POC physicians often rely on visual assessment of apical 4-chamber and parasternal long-axis views, our algorithm was adapted to use either one of these 3 views or any combination. This study aimed to (1) test the accuracy of these automated estimates; (2) determine whether they could be used to accurately classify LV function. METHODS: Reference EF was obtained using conventional biplane measurements by experienced echocardiographers. In protocol 1, we used echocardiographic images from 166 clinical examinations. Both automated and reference EF values were used to categorize LV function as hyperdynamic (EF>73%), normal (53%-73%), mildly-to-moderately (30%-52%), or severely reduced (<30%). Additionally, LV function was visually estimated for each view by 10 experienced physicians. Accuracy of the detection of reduced LV function (EF<53%) by the automated classification and physicians' interpretation was assessed against the reference classification. In protocol 2, we tested the new machine-learning algorithm in the POC setting on images acquired by nurses using a portable imaging system. RESULTS: Protocol 1: the agreement with the reference EF values was good (intraclass correlation, 0.86-0.95), with biases <2%. Machine-learning classification of LV function showed similar accuracy to that by physicians in most views, with only 10% to 15% cases where it was less accurate. Protocol 2: the agreement with the reference values was excellent (intraclass correlation=0.84) with a minimal bias of 2.5±6.4%. CONCLUSIONS: The new machine-learning algorithm allows accurate automated evaluation of LV function from echocardiographic views commonly used in the POC setting. This approach will enable more POC personnel to accurately assess LV function.

Right ventricular function in adult patients with Eisenmenger physiology: insights from quantitative echocardiography.

BACKGROUND: The favorable outcomes of Eisenmenger syndrome (ES) relative to other forms of pulmonary arterial hypertension (PAH) have been partially attributed to a unique adaptation of the right ventricle (RV). However, conventional measures of RV function may not adequately express this adaptation. METHODS: We studied 23 patients with ES (age 43 ± 17 years, 16 women, pulmonary artery systolic pressure [PASP] 93 ± 26 mmHg), 25 patients with PAH (age 44 ± 13 years, 17 women, PASP 92 ± 19 mmHg), and 25 subjects without known structural disease (age 45 ± 16 years, 17 women). We evaluated long- and short-axis function of the RV with two-dimensional strain and anatomical M-mode echocardiography, respectively. RESULTS: Long-axis function of the RV was comparable between patients with ES and PAH although depressed relative to controls (global strain, -15.6 ± 4.7, -14.9 ± 4.3, and -22.4 ± 2.8%, respectively, P < 0.001; global RV systolic strain rate, -0.77 ± 0.26, -0.84 ± 0.24, and -1.11 ± 0.21 1/sec, respectively, P < 0.001). However, short-axis RV function was significantly better in patients with ES versus those with PAH and preserved relative to controls (RV fractional shortening by anatomical M-mode, median [interquartile range], 21%[14-33%], 14%[10-16%], and 26%[22-36%], respectively, P = 0.002 for ES vs. PAH, P = 0.09 for ES vs. controls). This differential was not reflected in conventional measures of RV function (fractional area change, 32 ± 10 vs. 29 ± 8% in ES and PAH, respectively, P = 0.26). CONCLUSION: In patients with ES, the RV is characterized by preserved short-axis function, despite a depressed long-axis function. Thus, conventional assessment of RV function might not be suitable for patients with ES.

Automated Echocardiographic Quantification of Left Ventricular Ejection Fraction Without Volume Measurements Using a Machine Learning Algorithm Mimicking a Human Expert.

BACKGROUND: Echocardiographic quantification of left ventricular (LV) ejection fraction (EF) relies on either manual or automated identification of endocardial boundaries followed by model-based calculation of end-systolic and end-diastolic LV volumes. Recent developments in artificial intelligence resulted in computer algorithms that allow near automated detection of endocardial boundaries and measurement of LV volumes and function. However, boundary identification is still prone to errors limiting accuracy in certain patients. We hypothesized that a fully automated machine learning algorithm could circumvent border detection and instead would estimate the degree of ventricular contraction, similar to a human expert trained on tens of thousands of images. METHODS: Machine learning algorithm was developed and trained to automatically estimate LVEF on a database of >50 000 echocardiographic studies, including multiple apical 2- and 4-chamber views (AutoEF, BayLabs). Testing was performed on an independent group of 99 patients, whose automated EF values were compared with reference values obtained by averaging measurements by 3 experts using conventional volume-based technique. Inter-technique agreement was assessed using linear regression and Bland-Altman analysis. Consistency was assessed by mean absolute deviation among automated estimates from different combinations of apical views. Finally, sensitivity and specificity of detecting of EF ≤35% were calculated. These metrics were compared side-by-side against the same reference standard to those obtained from conventional EF measurements by clinical readers. RESULTS: Automated estimation of LVEF was feasible in all 99 patients. AutoEF values showed high consistency (mean absolute deviation =2.9%) and excellent agreement with the reference values: r=0.95, bias=1.0%, limits of agreement =±11.8%, with sensitivity 0.90 and specificity 0.92 for detection of EF ≤35%. This was similar to clinicians' measurements: r=0.94, bias=1.4%, limits of agreement =±13.4%, sensitivity 0.93, specificity 0.87. CONCLUSIONS: Machine learning algorithm for volume-independent LVEF estimation is highly feasible and similar in accuracy to conventional volume-based measurements, when compared with reference values provided by an expert panel.

Novel Multiphase Assessment for Predicting Left Ventricular Outflow Tract Obstruction Before Transcatheter Mitral Valve Replacement.

OBJECTIVES: This study proposes a physiologic assessment of left ventricular outflow tract obstruction (LVOTO) that accommodates changes in systolic flow and accounts for the dynamic neo-left ventricular outflow tract (LVOT). BACKGROUND: Patients considered for transcatheter mitral valve replacement trials often screen-fail because of the perceived risk of LVOTO. In the Intrepid Global Pilot Study, assumed risk of LVOTO was based on computed tomography estimates of the neo-LVOT area computed at end-systole. However, this may overestimate actual risk. METHODS: Retrospective analyses were performed for screen-failed patients for potential LVOTO (n = 33) and treated patients (n = 29) with available dynamic computed tomography. A multiphase assessment of the neo-LVOT area was performed and represented as: 1) multiphase average; and 2) early systolic value. Prospective evaluation was performed in 9 patients approved for enrollment with multiphase and early systole methods that would have previously screen-failed with the end-systolic approach. RESULTS: Of 166 patients screened for possible inclusion; 32 were screen-failed for nonanatomical reasons. Screen failure for assumed LVOTO risk occurred in 37 of 134 (27.6%) patients. Retrospective analysis indicated a potential enrollment increase of 11 of 33 (33.3%) and 18 of 33 (54.5%) patients using multiphase and early systolic assessment methods. In the prospective cohort, there were no clinical observations of LVOTO 30 days post-procedure, despite assumed risk based on end-systolic estimates. CONCLUSIONS: Multiphase, and specifically early systolic, assessment of the neo-LVOT may better determine risk of LVOTO with transcatheter mitral valve replacement compared with end-systolic estimates. This novel approach has the potential to significantly increase patient eligibility, with over one-half of patients previously screen-failed now eligible for treatment.

Clinical Implementation of Continuous-Wave Doppler: It Made All the Difference.

Today, Doppler echocardiography is central to our ability to determine cardiovascular hemodynamics, especially in valvular heart diseases, noninvasively. Continuous-wave Doppler (CWD) plays a central diagnostic role in the diagnosis and management of patients with aortic stenosis. The development and use of CWD in aortic stenosis was due to the pioneering work of Dr. Liv Hatle and her outstanding medical and engineering colleagues in Norway. The author was fortunate to be the first to use the early CWD instruments in North America. Therefore, this article highlights key lessons learned: the importance and value of key contributions made by our engineering and young cardiology and sonographer colleagues, the key importance of the independent PEDOF CWD probe as well as use of the audio signal for accurate detection of high-velocity flows, and the value of CWD for the diagnosis and management of other cardiovascular conditions.

Transthoracic dobutamine stress echocardiography in patients undergoing bariatric surgery.

BACKGROUND: The feasibility and value of transthoracic dobutamine stress echocardiography (DSE) in patients scheduled for bariatric surgery has not been investigated. METHODS: We evaluated 611 patients (86.6% female, 42 +/- 10 years, 136 +/- 18 kg, BMI 48.0 +/- 6.1 kg/m2) referred for DSE prior to surgery between February 2000 and July 2005. Mortality and major cardiovascular events (cardiac death, acute coronary syndrome, and urgent revascularization) were recorded 30-days postoperatively and at 6 months. RESULTS: Adequate baseline imaging quality was achieved in 590 patients (96.6%), with use of echocardiographic contrast agents in 426 patients (72.2%); the remaining 21 patients (3.4%) were referred for alternative preoperative testing. There were no serious adverse events during DSE, which was negative in 545 patients (92.4%). The test was inconclusive in 38 patients (6.4%), requiring alternative investigations, and positive in 7 patients (1.2%). Eventually, 595 patients proceeded to surgery: 539 with DSE-based risk stratification and 56 with risk stratification based on alternative testing. Laparoscopic procedures were employed in 77.0% of patients. There were 3 perioperative deaths, all attributed to sepsis (perioperative mortality 0.50%), but no major cardiovascular events at 30-days. One patient (evaluated prior to surgery with alternative testing) experienced an acute coronary syndrome during the following 6 months (event rate 0.17%). CONCLUSION: Transthoracic DSE is feasible and safe in morbidly obese patients undergoing bariatric surgery; implementation of echocardiographic contrast agents allows for adequate imaging quality in the majority of these patients. However, the very low risk of contemporary bariatric procedures questions the need for routine preoperative stress testing in asymptomatic patients.

The use of echocardiography for the evaluation of dyssynchrony.

Tissue Doppler imaging (TDI), is a new imaging tool that allows measurement of dyssynchrony. In several small studies, TDI predicted clinical response and reverse remodeling after cardiac resynchronization therapy (CRT). Moreover, it allowed detection of mechanical dyssynchrony in heart failure patients with narrow QRS. Using TDI, the selection criteria for CRT might be changed to include heart failure patients with narrow QRS. Furthermore, it will help predict responders to this therapy, hence decreasing the percentage of nonresponders and allowing a more cost-effective use of this new technology.

Coronary artery vasospasm during dobutamine stress echocardiography.

Compared with the frequent occurrence of S-T segment depression, the development of S-T segment elevation during dobutamine stress echocardiography is a relatively rare finding, especially in the setting of nonobstructive coronary artery disease. We present two patients who developed chest discomfort with S-T segment elevation during dobutamine stress testing. Both patients had unremarkable baseline echocardiograms and no history suggestive of coronary vasospasm. Subsequent coronary angiography revealed nonobstructive disease. It is speculated that the likely presence of endothelial dysfunction coupled with mild coronary atherosclerosis caused an imbalance between the coronary vasodilatory and vasoconstrictive forces. The inhibition of the vasodilatory effects of beta-adrenergic receptor stimulation and flow-mediated dilation of dobutamine was overcome by the vasoconstrictive effects of dobutamine-stimulated alpha-1 receptor activation; thus, contributing to the development of coronary vasospasm. This condition is important to recognize and appreciate as the initial treatment for this condition favors the use of nitrates over beta-blockade.

Functional tricuspid regurgitation: a need to revise our understanding.

The assessment of the etiology and severity of functional tricuspid regurgitation (FTR) has many limitations, especially when tricuspid regurgitation (TR) is more than severe. Instead of relying solely on TR severity, a new approach not only takes into account the severity of TR, but also pays strict attention to tricuspid annular dilation (size), the mode of tricuspid leaflet coaptation, and tricuspid leaflet tethering-factors often influenced by right ventricular enlargement and dysfunction. To simplify things, we propose a new staging system for functional tricuspid valve pathology using 3 parameters that may more accurately reflect the severity of the disease: TR severity, annular dilation, and mode of leaflet coaptation (extent of tethering). We believe that by utilizing these parameters, cardiologists and cardiac surgeons will be offered a better system for appraisal and decision-making in FTR.

A Summary of the American Society of Echocardiography Foundation Value-Based Healthcare: Summit 2014: The Role of Cardiovascular Ultrasound in the New Paradigm.

Value-Based Healthcare: Summit 2014 clearly achieved the three goals set forth at the beginning of this document. First, the live event informed and educated attendees through a discussion of the evolving value-based healthcare environment, including a collaborative effort to define the important role of cardiovascular ultrasound in that environment. Second, publication of these Summit proceedings in the Journal of the American Society of Echocardiography will inform a wider audience of the important insights gathered. Third, moving forward, the ASE will continue to build a ''living resource'' on its website, http://www.asecho.org, for clinicians, researchers, and administrators to use in advocating for the value of cardiovascular ultrasound in the new value-based healthcare environment. The ASE looks forward to incorporating many of the Summit recommendations as it works with its members, legislators, payers, hospital administrators, and researchers to demonstrate and increase the value of cardiovascular ultrasound. All Summit attendees shared in the infectious enthusiasm generated by this proactive approach to ensuring cardiovascular ultrasound's place as ''The Value Choice'' in cardiac imaging.

Usefulness of the peak velocity difference by tissue Doppler imaging technique as an effective predictor of response to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) improves symptoms and functional status in heart failure patients; however, current selection criteria need improvement. A novel tissue Doppler imaging parameter, the peak velocity difference (PVD), defined as the greatest difference in time to peak velocity between any of 6 left ventricular regions, may better select responders to CRT. Subjects were divided into 2 groups based on the PVD. Clinical and echocardiographic parameters significantly improved in subjects with dyssynchrony by the baseline PVD and had a better overall response to CRT.

Contrast for vascular imaging.

This article discusses the use of standard contrast agents that, when coupled with high-resolution carotid ultrasound, offers the dramatic potential to improve measurement of intimal medial thickness, better defining luminal endothelial surface, improving the determination of plaque ulceration, and offering the dramatic capabilities to visualize directly neovasculature growth of the vasa vasorum. The technique may identify vulnerable plaques and may also show their alterations with therapeutic pharmacologic interventions. In the coronary circulation, use of contrast significantly enhances the ability to image the epicardial coronary arteries to obtain data on coronary flow reserve for the diagnosis of coronary artery disease.

Timing of aortic valve surgery in chronic aortic stenosis and regurgitation.

The correct timing of aortic valve replacement in chronic aortic stenosis or regurgitation is a very important and sometimes difficult task for physicians caring for patients with aortic valve disease. In this review, we will present the current available literature regarding the appropriate management of these patients.

Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab.

OBJECTIVES: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. BACKGROUND: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. METHODS: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. RESULTS: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 µg/l; ΔMPO >422.6 pmol/l). CONCLUSIONS: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.