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The increasing aging of the population combined with improvements in cancer detection and care has significantly improved the survival and quality of life of cancer patients. These benefits are hampered by the increase of cardiovascular diseases being heart failure the most frequent manifestation of cardiotoxicity and becoming the major cause of morbidity and mortality among cancer survivor. Current strategies to prevent cardiotoxicity involves different approaches such as optimal management of CV risk factors, use of statins and/or neurohormonal medications, and, in some cases, even the use of chelating agents. As a class, SGLT2-i have revolutionized the therapeutic horizon of HF patients independently of their ejection fraction or glycemic status. There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.
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Importance: The associations of sodium glucose cotransporter-2 inhibitors (SGLT2is) with reduction in mortality and hospitalization rates in patients with heart failure (HF) are well established. However, their association with improving functional capacity and quality of life (QOL) has been variably studied and less reported. Objective: To provide evidence on the extent to which SGLT2is are associated with improvement on objective measures of functional capacity and QOL in patients living with HF. Data Sources: The MEDLINE, EMBASE, and Cochrane databases were systematically searched for relevant articles on July 31, 2023. Study Selection: Randomized, placebo-controlled clinical trials reporting the effect of SGLT2i on functional outcomes of exercise capacity (peak oxygen consumption [peak VO2] or 6-minute walk distance [6MWD]) and/or QOL using validated questionnaires for patients with HF were included. Data Extraction and Synthesis: Data were extracted by 2 authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, and a meta-analysis using the restricted maximum likelihood random-effects model was conducted. Main Outcomes and Measures: Outcomes of interest included changes in peak VO2, 6MWD, and Kansas City Cardiomyopathy Questionnaire-12 total symptom score (KCCQ-TSS), clinical summary score (KCCQ-CSS), and overall summary score (KCCQ-OSS). Results: In this meta-analysis of 17 studies, 23â¯523 patients (mean [range] age, 69 [60-75] years) were followed over a period ranging from 12 to 52 weeks. Four studies included peak VO2 as an outcome, 7 studies included 6MWD, and 10 studies reported KCCQ scores. Mean (SD) left ventricular ejection fraction was 43.5% (12.4%). Compared with controls, patients receiving SGLT2i treatment experienced significant increases in peak VO2 (mean difference [MD], 1.61 mL/kg/min; 95% CI, 0.59-2.63 mL/kg/min; P = .002) and 6MWD (MD, 13.09 m; 95% CI, 1.20-24.97 m; P = .03). SGLT2i use was associated with increased KCCQ-TSS (MD, 2.28 points; 95% CI, 1.74-2.81 points; P < .001), KCCQ-CSS (MD, 2.14 points; 95% CI, 1.53-2.74 points; P < .001), and KCCQ-OSS (MD, 1.90 points; 95% CI, 1.41-2.39 points; P < .001) scores. Subgroup analysis and meta-regression demonstrated almost all improvements were consistent across ejection fraction, sex, and the presence of diabetes. Conclusions and Relevance: These findings suggest that in addition to known clinical associations with mortality and hospitalization outcomes, SGLT2i use is associated with improvement in outcomes of interest to patients' everyday lives as measured by objective assessments of maximal exercise capacity and validated QOL questionnaires, regardless of sex or ejection fraction.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Qualidade de Vida , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume Sistólico , Função Ventricular Esquerda , Pessoa de Meia-IdadeRESUMO
Triglycerides play a crucial role in the efficient storage of energy in the body. Mild and moderate hypertriglyceridemia (HTG) is a heterogeneous disorder with significant association with atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction, ischemic stroke, and peripheral artery disease and represents an important component of the residual ASCVD risk in statin treated patients despite optimal low-density lipoprotein cholesterol reduction. Individuals with severe HTG (>1,000 mg/dL) rarely develop atherosclerosis but have an incremental incidence of acute pancreatitis with significant morbidity and mortality. HTG can occur from a combination of genetic (both mono and polygenic) and environmental factors including poor diet, low physical activity, obesity, medications, and diseases like insulin resistance and other endocrine pathologies. HTG represents a potential target for ASCVD risk and pancreatitis risk reduction, however data on ASCVD reduction by treating HTG is still lacking and HTG-associated acute pancreatitis occurs too rarely to effectively demonstrate treatment benefit. In this review, we address the key aspects of HTG pathophysiology and examine the mechanisms and background of current and emerging therapies in the management of HTG.
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Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Transportador 1 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Glicemia/metabolismoRESUMO
We evaluated modifications in the hemostatic balance of different concentrations of apixaban (APIX) in 25 healthy donors and 53 patients treated with aspirin (ASA, n = 21), ASA and clopidogrel (ASA + CLOPI, n = 11), or ASA and ticagrelor (ASA + TICA, n = 21). Blood samples from participants were spiked ex vivo with apixaban 0 (APIX0), 40 (APIX40), and 160 ng/mL (APIX160). We assessed the effects of APIX on (1) clot formation, by ROTEM thromboelastometry; (2) thrombin generation primed by platelets; and (3) platelet and fibrin interactions with a thrombogenic surface, in a microfluidic model with circulating blood. APIX caused dose-related prolongations of clotting time with minimal impact on other ROTEM parameters. Thrombin generation was significantly inhibited by APIX160, with ASA + TICA actions showing the strongest inhibition (p < 0.01 vs APIX0). Microfluidic studies showed that APIX160 was more potent at suppressing platelet and fibrin interactions (p < 0.001 vs. APIX0). APIX40 demonstrated a consistent antithrombotic action but with a favorable protective effect on the structural quality of fibrin. APIX potentiated the antithrombotic effects of current antiplatelet regimens. APIX at 40 ng/mL, enhanced the antithrombotic action of single or dual antiplatelet regimens but was more conservative for hemostasis than the 160 ng/mL concentration.
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Fibrinolíticos , Trombina , Humanos , Fibrinolíticos/farmacologia , Trombina/farmacologia , Aspirina/farmacologia , Plaquetas , Fibrina/farmacologia , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
BACKGROUND: Statins are the cornerstone of lipid-lowering therapy (LLT) for reduction of low-density lipoprotein cholesterol (LDLc) levels and high percentage of patients require LLT combinations or alternative treatments for adequate LDLc control. METHODS: We performed an intention-to-treat meta-analysis of published data of phase III trials evaluating LLT efficacy on major adverse cardiovascular events (MACE). The primary endpoint was MACE incidence, as reported in each trial, and secondary analyses included myocardial infarction, stroke and mortality. RESULTS: Eleven clinical trials and 135,688 patients were included; seven trials tested high intensity LLT and 4 LLT combinations. Intensive LLT reduced MACE risk by 15% (12.03% vs. 13.79%, HR: 0.85 95% CI 0.80-0.90; p<0.001). The number needed to treat was 56 patients. Meta-regression analyses showed a linear correlation between absolute LDLc reductions and the risk of MACE. Significant reductions in myocardial infarction (HR: 0.83, 95% CI 0.80-0.86) and stroke (HR: 0.81, 95% CI 0.75-0.87) were observed. Cardiovascular death rate was 3.32% in LLT treatment arm vs. 3.56% in controls, resulting in a HR: 0.94 (95% CI 0.88-0.99; p = 0.03); no effect on all-cause mortality was observed (HR: 0.97 95% CI 0.93-1.01; p = 0.09). The sensitivity analyses verified the lack of heterogeneity, except for MACE that was mainly driven by the divergent results of the 2 trials. Small study effect was detected for the assessment of mortality. CONCLUSIONS: Current evidence consistently supports the efficacy of available intensity LLT for LDLc decrease on MACE and cardiovascular mortality reduction.
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Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Ensaios Clínicos Fase III como AssuntoRESUMO
Bempedoic acid is a selective inhibitor of the adenosine triphosphate citrate lyase that reduces low-density lipoprotein cholesterol (LDLc) levels by 17% to 28%. Although the Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (CLEAR-OUTCOMES) trials demonstrated the efficacy on cardiovascular outcomes there is a controversy related to the possible net clinical benefit. Thereafter, we performed an intention-to-treat meta-analysis in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The primary outcome of the metanalysis was the incidence of major adverse cardiovascular events, defined by each study protocol. Secondary outcomes for the analyses were myocardial infarction, stroke, myocardial revascularization, cardiovascular death, and all-cause death. Results of 4 clinical trials evaluated contained a total of 17,324 patients; 9,236 received bempedoic acid for a median of 46.6 months. The mean baseline LDLc was 129.4 (22.8) mg/100 ml and treatment was associated with a mean LDLc reduction of 26.0 (12.6) mg/100 ml. Treatment with bempedoic acid significantly reduced the incidence of major adverse cardiovascular events (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.81 to 0.96), myocardial infarction (HR 0.76, 95% CI 0.66 to 0.89) and myocardial revascularization (HR 0.82, 95% CI 0.73 to 0.92); the crude incidence of stroke, cardiovascular or all-cause mortality were lower in patients in the bempedoic acid groups although no significant risk reduction was observed. No heterogeneity was observed in any of the end points. In conclusion, the metanalysis of the 4 clinical trials currently available with bempedoic acid provides reliable evidence of its clinical benefit with no signs of heterogeneity or harm.
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Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/epidemiologiaRESUMO
Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.
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BACKGROUND: SGLT2i (sodium-glucose cotransporter-2 inhibitors) improve clinical outcomes in patients with heart failure, but the mechanisms of action are not completely understood. SGLT2i increases circulating levels of ketone bodies, which has been demonstrated to enhance myocardial energetics and induce reverse ventricular remodeling. However, the role of SGLT2i or ketone bodies on myocardial ischemia reperfusion injury remains in the dark. The objective of this study is to investigate the cardioprotective potential of empagliflozin and ketone bodies during acute myocardial infarction (MI). METHODS: We used a nondiabetic porcine model of ischemia reperfusion using a percutaneous occlusion of proximal left anterior descending artery for 45 minutes. Animals received 1-week pretreatment with either empagliflozin or placebo prior to MI induction. Additionally, a third group received intravenous infusion of the ketone body BOHB (beta-hydroxybutyrate) during the MI induction. Acute effects of the treatments were assessed 4-hour post-MI by cardiac magnetic resonance and histology (thioflavin for area at risk, triphenyltetrazolium chloride staining for MI size). All animals were euthanized immediately postcardiac magnetic resonance, and heart samples were collected. RESULTS: The area at risk was similar in all groups. Empagliflozin treatment increased BOHB levels. Empagliflozin-treated animals showed significantly higher myocardial salvage, smaller MI size (both by cardiac magnetic resonance and histology), less microvascular obstruction, and improved cardiac function (left ventricle ejection fraction and strain). Furthermore, empagliflozin-treated animals demonstrated reduced biomarkers of cardiomyocyte apoptosis and oxidative stress compared with placebo. The BOHB group showed similar results to the empagliflozin group. CONCLUSIONS: One-week pretreatment with empagliflozin ameliorates ischemia reperfusion injury, reduces MI size and microvascular obstruction, increases myocardial salvage, preserves left ventricle systolic function, and lowers apoptosis and oxidative stress. Periprocedural intravenous infusion of BOHB during myocardial ischemia also induces cardioprotection, suggesting a role for BOHB availability as an additional mechanism within the wide spectrum of actions of SGLT2i.
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Infarto do Miocárdio , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Corpos Cetônicos/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , SuínosRESUMO
Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are glycosuric drugs that were originally developed for the treatment of type 2 diabetes mellitus (T2DM). There is a hypothesis that SGLT2i are drugs that are capable of increasing ketone bodies and free fatty acids. The idea is that they could serve as the necessary fuel, instead of glucose, for the purposes of cardiac muscle requirements and could explain antihypertensive effects, which are independent of renal function. The adult heart, under normal conditions, consumes around 60% to 90% of the cardiac energy that is derived from the oxidation of free fatty acids. In addition, a small proportion also comes from other available substrates. In order to meet energy demands with respect to achieving adequate cardiac function, the heart is known to possess metabolic flexibility. This allows it to switch between different available substrates in order to obtain the energy molecule adenosine triphosphate (ATP), thereby rendering it highly adaptive. It must be noted that oxidative phosphorylation in aerobic organisms is the main source of ATP, which is a result of reduced cofactors. These cofactors include nicotine adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2), which are the result of electron transfer and are used as the enzymatic cofactors that are involved in the respiratory chain. When there is an excessive increase in energy nutrients-such as glucose and fatty acids-which occur in the absence of a parallel increase in demand, a state of nutrient surplus (which is better known as an excess in supply) is created. The use of SGLT2i at the renal level has also been shown to generate beneficial metabolic alterations, which are obtained by reducing the glucotoxicity that is induced by glycosuria. Together with the reduction in perivisceral fat in various organs, such alterations also lead to the use of free fatty acids in the initial stages of the affected heart. Subsequently, this results in an increase in production with respect to ketoacids, which are a more available energy fuel at the cellular level. In addition, even though their mechanism is not fully understood, their vast benefits render them of incredible importance for the purposes of further research.
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Diabetes Mellitus Tipo 2 , Glicosúria , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Rim/metabolismo , Glucose/metabolismo , Corpos Cetônicos/metabolismo , Glicosúria/tratamento farmacológico , Trifosfato de Adenosina/metabolismoRESUMO
Results from DELIVER trial and publication of EMPEROR-Preserved with sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF) > 40% represent a significant step forward in the treatment of HF with preserved EF (HFpEF). However, detailed analysis and attenuation of effect at higher EF levels have sparked some doubts about whether empagliflozin is effective across the entire spectrum of EF. HFpEF is no longer considered as one disease entity, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. This heterogeneity suggests that it should not be considered as a single group in terms of treatment goals or clinical approach. Future research at the higher range of EF should ideally tailor investigations for unequivocally preserved EF (> 50%), consider the dynamic nature of EF over time, and use low-variability imaging techniques such as CMR. Furthermore, classifications based on pathophysiology and HF phenotypes beyond the EF construct will shape the design of future trials and help narrow down groups of patients who may respond to personalized treatment.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Transportador 2 de Glucose-SódioRESUMO
Metabolic syndrome (MS) is frequently associated with an increased body mass index (BMI), and related to an adverse cardiovascular prognosis. The purpose of this study is to evaluate the prevalence and association between MS, obesity and subclinical atherosclerosis (SA). This cross-sectional study included healthy adults, allocated to normal weight (NW) when BMI <25 kg/m2, overweight (OW) BMI ≥25 and <30 kg/m2, or obese (OB) BMI ≥30 kg/m2 groups. Presence of MS was defined according to National Cholesterol Education Program (NCEP) criteria. SA was evidenced with vascular ultrasound. Association between SA, obesity and MS, was evaluated by logistic regression models. There were 3,716 patients studied (female 66.7%, mean age 47 ± 17.5 years). According to BMI, NW represented 28.2%, OW 39.4% and OB 32.4%. MS showed a strong correspondence with BMI (NW 4.9%, OW 21.4%, OB 49.7%; p<0.001). SA was more prevalent in each group when MS was present: NW (25.4% vs. 45.1%, p<0.005), OW (43.2% vs. 58.9%, p<0.0001) and OB (44.2% vs. 57.8%, p<0.0001). Logistic-regression models showed an independent association of SA with MS criteria (arterial hypertension p<0.001; high-density lipoprotein [HDL] p<0.05; and triglycerides p<0.005) adjusted by gender, age and BMI. In conclusion, overweight and obesity are frequent and strongly linked with MS and SA. Prevalence of SA is high, and is independently associated with MS components. However, BMI could not retain statistical significance in the multivariate analyses.
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Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure. Obesity is a modifiable risk factor of HFpEF; however, body mass index provides limited information on visceral adiposity and patients with similar anthropometrics can present variable cardiovascular risk. Epicardial adipose tissue (EAT) is the closest fat deposit to the heart and has been proposed as a biomarker of visceral adiposity. EAT may be particularly important for cardiac function, because of its location (under the pericardium) and because it acts as a metabolically active endocrine organ (which can produce both beneficial and detrimental cytokines). In this paper, the authors review the role of EAT in normal and pathologic conditions and discuss the noninvasive imaging modalities that allow its identification. This review highlights EAT implications in HFpEF and discuss new therapies that act on EAT and might also exert beneficial effects on the cardiovascular system.
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Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve clinical outcomes in patients with heart failure (HF), but mechanisms of action are incompletely understood. In the EMPA-TROPISM trial, empagliflozin reversed cardiac remodeling and increased physical capacity in stable non-diabetic patients with systolic HF. Here we explore, post hoc, whether treatment effects in this cohort, comprising patients who had a high prevalence of iron deficiency, were related to iron metabolism. Myocardial iron content estimated by cardiac magnetic resonance T2* quantification increased after initiation of empagliflozin but not placebo (treatment effect: P = 0.01). T2* changes significantly correlated with changes in left ventricular volumes, mass and ejection fraction, peak oxygen consumption and 6-minute walking distance; concomitant changes in red blood cell indices were consistent with augmented hematopoiesis. Exploratory causal mediation analysis findings indicated that changes in myocardial iron content after treatment with empagliflozin may be an important mechanism to explain its beneficial clinical effects in patients with HF.ClinicalTrials.gov: NCT03485222 .
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Compostos Benzidrílicos , Glucosídeos , Insuficiência Cardíaca Sistólica , Ferro , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Masculino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Cardíaca Sistólica/metabolismo , Ferro/metabolismo , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Idoso , Miocárdio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Fatores de Tempo , Tolerância ao Exercício/efeitos dos fármacos , BiomarcadoresRESUMO
Despite major advancements in the development of safer and more effective anticoagulant agents, bleeding complications remain a significant concern in the treatment of thromboembolic diseases. Improvements in our understanding of the coagulation pathways highlights the notion that the contact pathway-specifically factor XI (FXI)-has a greater role in the etiopathogenesis of thrombosis than in physiological hemostasis. As a result, a number of drugs targeting FXI are currently in different stages of testing and development. This article aims to review the different strategies directed towards FXI-inhibition with a brief summation of the agents in clinical development, and to comment on the therapeutic areas that could be explored for potential indications. Therapeutics targeting FXI/FXIa inhibition have the potential to usher in a new era of anticoagulation therapy.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Metabolômica , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
The publication of the EMPEROR-Preserved trial and data on the benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF)> 40% represent a significant step forward in the treatment of HF with preserved EF. Given these results, in February 2022 the US Food and Drug Administration approved the use of empaglifozin in adults with HF with reduced or preserved EF. However, more detailed analysis of the EMPEROR-Preserved trial led to doubts about the effect of empagliflozin in patients with an EF of> 60% this patient group is widely heterogeneous and, probably, a single phenotype cannot be considered in treatment goals or the clinical approach. Moreover, EF occurs on a continuum and classifications of HF according to arbitrary cut-points in EF do not appear consistent with recent evidence, which points to a gradual shift and considerable overlap in underlying mechanisms, phenotypes and treatment response over the spectrum of EF. Enhanced knowledge of pathophysiological mechanisms is essential to establish new therapeutic targets, interpret the results of clinical trials, and develop targeted and effective therapies.