 Hello, this is B. Cam Balskert, Professor of Medicine from Baylor College of Medicine. It is a great pleasure for me to be speaking at the inaugural Cardiovascular Global Forum. And the title of my presentation is Universal Definition and Classification of Heart Failure. These are my disclosures. The Universal Definition of Heart Failure was a consensus statement developed by the Heart Failure Society of America, the Heart Failure Association, and the Japanese Heart Failure Association, endorsed by a variety of international Heart Failure societies, as represented on this slide, published early last year in the Journal of Cardiac Failure and the European Journal of Heart Failure. And if we examine the existing definitions and classifications of heart failure across the spectrum, there are usually three categories. The first one is the definition of the syndrome, which usually relies on symptoms and signs. These are critically important for the clinicians as well as the researchers. The second one has traditionally been the ejection fraction phenotypic classification. These have been important for targeting guideline directed therapies. And the third classification has been stages of heart failure. These have been important for prognostication, appropriate referral of patients, and being able to prognosticate and provide appropriate communication back to the patients as well as the referring clinicians. Starting from the textbook definition. The textbooks traditionally define heart failure as a clinical syndrome caused by inability of the heart to meet the body's metabolic needs. Though this definition, but the physiologically made sense, was not applicable to most heart failure patients. In this study, when lactate levels were measured as a representation of tissue level hyperperfusion in stage D heart failure patients awaiting ventricular assist device insertion, the levels were found to be normal in 75% of the patients with very advanced heart failure with low cardiac index. Representing that the tissue level hyperperfusion in this study measured by lactate levels will be abnormal only in a small percentage of patients. Thus, the textbook definition does not apply to majority of the heart failure patients. Furthermore, former society guideline definitions differed significantly from the textbooks and they also differed amongst themselves. If we examine the former guidelines, some focus on symptoms and signs, some on the hemodynamic characterization of low cardiac index and elevated feeling pressures and some even focused on the maladaptive mechanisms such as neurohormonal and or circulatory abnormalities which are not easily measurable in most patients. Further complicating the issue, the care coverage and performance have relied on appropriate documentation and coding which at present times reflects a chaotic mixed batch of academic, historic and hemodynamic episodes of care concepts and as can be seen, we have ICD codes such as systolic combined with diastolic, congestive, acute on chronic heart failure driving care. We have no specific codes for most etiologies except for comorbidities and we do not have any codes for pre-heart failure like pre-cancer does. These all underline the necessity to enhance appropriate diagnostic strategies with clarity and standardization as one of the first steps to achieve uniformity of care. It's also critical for us to recognize that despite the guidelines and expansion of evidence, registries with real-world patients over the last 20 years show very disappointing results with no improvement in ACE or ARB or in the corticoid receptor antagonists or beta blockade use as can be seen, the MRA use has been only in 35% of the indicated patients. These all suggest lack of standardization of care. And if we examine the strategies that have existed in research in heart failure, we recognize that research studies traditionally relied on criteria either the Framingham criteria which incorporates symptoms or signs or objective criteria such as elevated naturally peptide levels or hospitalization. And if we examine other disease definitions, most have evolved into incorporation of objective criteria as can be seen, EGFR use in chronic kidney disease definition or hemoglobin A1C use in diabetes definition have made these definitions practical and also treatment targets clear with a definable threshold. There have been formulations that propose use of naturally peptide levels as the central diagnostic criteria even in the absence of symptoms, very similar to cardiac troponin in the myocardial infraction definition. But these approaches, soul reliance on naturally peptide levels have been criticized because naturally peptide levels can be elevated in a variety of abnormalities other than heart failure such as chronic kidney disease, atrial fibrillation or with other cardiac conditions and thus lacks the specificity. And also in patients with heart failure with preserved EF lacks sensitivity. Thus, naturally peptide based diagnostic strategies by themselves were not felt to be adequate. So with these in mind, we recognize the necessity to standardize the overarching definition in a simple and practical way but with adequate sensitivity and specificity to close the gaps in care. Therefore, the universal definition of heart failure incorporates not only symptoms or signs but now has objective markers and can be summarized as, heart failure is a clinical syndrome with current or prior symptoms in our science caused by a structural and or functional cardiac abnormality and corroborated by at least one of the following. Elevated natural to peptide levels or objective evidence of cardiogenic pulmonary or systemic congestion by diagnostic modalities such as imaging or hemodynamic measurement at rest or with provocation. So this is the new universal definition of heart failure. Symptoms or signs attributable to structural or functional abnormality of the heart either with elevated natural to peptide levels or with evidence of elevated filling pressures either by imaging or by hemodynamic characterization. In the universal definition, we also address and revise the stages of heart failure. And these stages though were recognized by specialists were not widely adopted by non clinicians or were not understood by patients. The nomenclature gave the impression that they only went from stages A to D and not vice versa. And furthermore, we now have newer diagnostic strategies for definitions of pre heart failure, especially with incorporation of biomarkers and evolving treatment strategies to prevent heart failure in the pre heart failure stages. With the recognition of the necessity to be able to translate the concepts better to non specialists and to patients and also emphasize ability to recognize the pre heart failure stage, including characterization with biomarkers. We revised the universal definition stages, the stages of heart failure as the following. At risk for heart failure for former stage A, which is defined for patients at risk for heart failure, but without current or prior symptoms or signs of heart failure and without structural functional or biomarker abnormality. Pre heart failure for former stage B, which we define as patients without current or prior symptoms or signs of heart failure, but with either structural, functional cardiac abnormality or elevated natural to peptide levels or elevated cardiac troponin, especially in the setting of exposure to cardiotoxins. Heart failure for former stage C, for patients with current or prior symptoms or signs of heart failure attributed to structural or functional cardiac abnormality. And advanced heart failure for former stage D for patients with advanced severe symptoms requiring advanced therapies. And we also emphasize that advanced heart failure can improve to heart failure state with guideline directed therapies. We also emphasize that the biomarker based diagnostic strategy is incorporated as pre heart failure stage for patients without current symptoms or signs. We also focus on terminologies for clinical trajectories and emphasize the use of persistent heart failure rather than stable heart failure for those patients with symptoms, though they may not be showing active worsening. These individuals should not be termed as stable heart failure because that creates inertia and the false presumption of cure or stability by the patients. And persistent heart failure should trigger the clinicians to optimize guideline directed therapies. We also emphasize to use heart failure in remission rather than recovered heart failure for patients who have resolution of their symptoms in our signs and normalization of their LV dysfunction. This is important because in the TRED-HF trial upon withdrawal of therapy, 40% of the patients relapsed despite having improvement in their LV function and total resolution of their symptoms in our signs. Thus improvement in function and resolution of symptoms represents remission rather than permanent recovery in most of our patients. In the universal definition, we also provided classifications of ejection fraction which are defined as heart failure with reduced EF with EF less than or equal to 40%, milder reduced EF with EF between 41 to 49%, preserved EF with ejection fraction that is greater than or equal to 50% and heart failure with improved EF with the baseline ejection fraction less than or equal to 40% with more than 10% increase from baseline and a subsequent measurement exceeding that of 40%. The reason it was so critical for us to standardize the EF categories was the expanding indications for the life-saving therapies which now includes SGLT2 inhibition along with RAS inhibitors, metablockers and minnequoticoid receptor antagonists. Also with the recognition that the evidence now incorporates minnequoticoid receptor antagonists angiotensin receptor blockers or ARNI. By postdoc analysis, the benefits extend all the way to include heart failure with mildly reduced EF as well as heart failure with reduced EF with these agents and with prospective data, with randomized clinical data, specifically emperor preserved trial, we now have evidence that SGLT2 inhibitors are effective and beneficial in patients with milder reduced EF as well as reduced EF. ESC guidelines have incorporated the ACE inhibitor, ARB, metablockade, MRA and ARNI as class 2B recommendations, which actually emphasize use of these agents with a class 2B indication. The ESC guidelines preceded the release of the emperor preserved trials and will have likely included SGLT2 inhibition as another potential therapy for patients with mildly reduced EF if it were to have been published before the release, after the release of the emperor preserved trials. The 2021 ESC guidelines are harmonized with the universal definition and uses heart failure with reduced EF, mildly reduced EF and preserved EF categories. We recognize that ejection fraction may not be a perfect descriptor for the heart failure, if you know, to be classification and there have been discussions whether EF should be changed to normal and not non-normal in the aftermath of the emperor preserved trial, but normal EF definition is not a standardized concept with not a single threshold and can vary in women versus men in the setting of hypertrophy or changing loading conditions. And non-normal is not a reliable tool for phenotypic classification for higher risk determination or as a tool for guideline directed therapy implementation. Thus the traditional classifications of heart failure with reduced EF, mildly reduced EF, preserved EF and recently added concepts do help with targeting the therapies with different levels of evidence and indications. In the future, EF may evolve into a different conceptualization for LV systolic dysfunction, especially if we can find a modality by which we can capture the presence of LV systolic dysfunction in a reproducible, widely available and practical modality, we could potentially evolve into not only characterization of reduced mildly reduced or improved and preserved EF by echocardiography, but perhaps include LV strain and or volume measurements as further characterization of LV. And but these will require probably further data. And we also need to keep in mind that the target for the therapy matters. EF may not matter if treatment is effective across the whole continuum of phenotypes of EF, especially if it is targeting congestion or other mechanisms by which it is able to demonstrate benefit, such as with SGLT2 inhibition across the whole continuum of phenotypes. But it may matter if a therapy targets the pump, the pump dysfunction as seen on this slide, an agent that targets the contractile performance such as omicamptive, which is a cardiac myosin activator has been shown in the galactic trial to have increased benefit with decreasing ejection fraction. The benefit was highest in the lowest EF quartile. Thus EF will still matter when the treatments target mechanisms implied in more advanced heart failure or when the therapy is targeting the pump dysfunction or the ejection fraction. And EF still matters for device indications. The medical therapies can result in reversal of remodeling. We know this with beta blockade and the newer agents such as SGLT2 inhibition and ARNI also result in improvement in LV function and LV volume suggesting reversal and modeling. Therefore, we will need to be very cognizant of the potential improvement with reversal of remodeling in EF before consideration of the ICD and CRTD therapies. Thus EF by itself is still important for classification and for targeted therapies as well as for device indications. In universal definition, we also emphasize treatment according to specific etiology. As seen on the right panel of this slide, there are a variety of indications that require specific treatment strategies that may be in addition to guideline-directed therapies or beyond guideline-directed therapies such as consideration of the famidis and cardiac amyloidosis or treatment of the underlying tachycardia in the setting of tachycardia and use cardiomyopathy. And these are critical for clinicians to be aware of beyond just phenotypic characterization and treatments targeting phenotypes in heart failure. Our current staging concepts will help us move the needle in terms of earlier treatment strategies from treating very advanced stages to earlier and perhaps even capturing the pre-heart failure state and prevention of heart failure before the symptoms ensue. As to what the clinicians should do, we expect the clinicians to use the universal definition of heart failure to diagnose, confirm and document heart failure, then classify the patient phenotype according to ejection fraction to initiate and optimize guideline-directed therapies and then classify the stages. Again, to initiate the appropriate prevention and treatment strategies and also to be able to communicate the prognosis and appropriately consider referral for advanced heart failure state. In this subsequent encounter, the clinicians should define the trajectory and specify heart failure with terminologies such as persistent heart failure, not stable heart failure to further optimize the therapy and consider heart failure in remission for those who have resolution of their symptoms in our science and not recovered heart failure. EF can be reclassified if symptoms or signs change or there is a new indication for a new echocardiographic or other modality for EF quantification and if there is an improvement, the classification terminology to use will be heart failure with improved EF which requires continuation of guideline-directed therapies. So in summary, the standardization of the heart failure syndrome with the universal definition provides a practical standardized approach with high sensitivity and specificity. The definition which includes symptoms or signs caused by the cardiac abnormality and corroborated by elevated natural peptide levels or elevated filling pressures by imaging and or hemodynamic characterization are the first steps for us to achieve uniformity of care universally. New revised terminologies of classification of heart failure as at-risk, pre-heart failure, heart failure or advanced heart failure will be easier to be understood by our patients and non-specialists and will help us prevent heart failure in the at-risk or pre-heart failure stage as well as during the heart failure and advanced heart failure stages. EF classifications provides clarity for standardization for phenotypic classification and for us to be able to optimize therapies with the appropriate indications across the continuum of EF. Emphasis for trajectories for terminologies for persistent heart failure rather than stable heart failure and heart failure in remission rather than recovered heart failure allow us to continue and optimize guideline directed therapies. Thank you for your attention and the opportunity to present.