MD, PhD João Pedro Ferreira
email: j.ferreira@chru-nancy.fr

MD Francisco Vasques-Nóvoa

MD Diana Ferrão

PhD Francisca Saraiva

PhD Inês Falcão-Pires

MD, PhD João Sérgio Neves

MD, PhD Abhinav Sharma

MD, PhD Patrick Rossignol

MD, PhD Faiez Zannad

MD, PhD Adelino Leite-Moreira

Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD

Keywords: fenofibrate, heart failure, type 2 diabetes, outcomes

Objectives: Patients with type 2 diabetes (T2D) have a high risk for developing heart failure (HF), which is associated with poor prognosis. Fenofibrate may reduce HF events through multiple mechanisms. To study the effect of fenofibrate (vs. placebo) in HF outcomes among patients with T2D receiving simvastatin enrolled in the ACCORD-Lipid trial.

Research design and Methods: Cox regression analysis with background glucoselowering strategy as stratification variable. The median follow-up was 4.7 years.

Results: A total of 5518 patients were included. The median age was 62 years and 31% were women. A prior HF history was present in 5% of the patients. The composite outcome of HF hospitalization or cardiovascular death occurred in 190 (6.9%) patients in the fenofibrate group vs. 228 (8.3%) in the placebo group: HR 0.82, 95%CI 0.68-1.00, P =0.048. The beneficial effect of fenofibrate to reduce HF hospitalizations or cardiovascular death was present among patients receiving standard glucose-lowering strategy: HR 0.64, 95%CI 0.48-0.85, and not among patients receiving intensive glucose-lowering strategy: HR 1.02, 95%CI 0.79-1.33, interaction P =0.017. A similar pattern was observed for HF hospitalizations alone.

The effect of fenofibrate on blood lipids was not influenced by background glucoselowering therapy in a clinically important manner. Fenofibrate caused more transient worsening eGFR events but slowed the long-term eGFR decline.

Conclusion:

In patients with T2D treated with simvastatin, fenofibrate reduced the composite of HF hospitalizations or cardiovascular mortality, an effect that was seen predominantly in patients with standard background glucose-lowering therapy.

Introduction

Type 2 diabetes (T2D) is a global epidemic affecting around 500 million people worldwide. [START_REF] Saeedi | Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition[END_REF] Patients with type 2 diabetes (T2D) have a high risk for developing heart failure (HF), which, once occurring, is associated with a substantially increased morbidity and mortality. [START_REF] Cas | Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure[END_REF] Therefore, preventive strategies are needed to decrease the HF risk.

Statins are one of the most effective drug-class agents for reducing the risk of cardiovascular events in patients with T2D, [START_REF] Colhoun | Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial[END_REF][START_REF] Collins | MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial[END_REF] including a potential risk reduction in HF hospitalizations. [START_REF] Kishimoto | Intensity of statin therapy and new hospitalizations for heart failure in patients with type 2 diabetes[END_REF] The cardiovascular benefits of fibrates when added on top of guideline-directed statin therapy are less well established in patients with T2D.

Fenofibrate did not reduce mortality in the FIELD (Fenofibrate Intervention and Event

Lowering in Diabetes) trial, but it reduced total cardiovascular events, mainly due to a reduction in non-fatal myocardial infarctions and revascularizations. [START_REF] Keech | Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial[END_REF] More patients in placebo than in fenofibrate group started statins, which might have led to an underestimation of the potential benefits of fenofibrate in the FIELD study. Large observational studies found an association between fenofibrate use and lower incidence of mortality and cardiovascular events. [START_REF] Jo | Fenofibrate Use Is Associated With Lower Mortality and Fewer Cardiovascular Events in Patients With Diabetes: Results of 10,114 Patients From the Korean National Health Insurance Service Cohort[END_REF] In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Lipid trial, the combination of fenofibrate and simvastatin did not reduce the composite of time-to-first of myocardial infarction, stroke, or cardiovascular death compared with simvastatin and placebo. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] However, a 18% reduction in HF events was observed with fenofibrate, albeit not reaching statistical significance (P =0.1). It should be noted that ACCORD had a factorial design with patients randomized to either intensive or standard glucose-lowering strategy in the main study, and then to the blood pressure or lipid substudies. [START_REF] Buse | Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods[END_REF] In the glucose-lowering study, the use of intensive glucose-lowering strategy could have confounded the effect of fenofibrate, particularly regarding HF events which risk may be increased with the more frequent use of certain glucose lowering medications such as insulin and thiazolidinediones. [START_REF] Gerstein | Effects of intensive glucose lowering in type 2 diabetes[END_REF][START_REF] Cosmi | Treatment with insulin is associated with worse outcome in patients with chronic heart failure and diabetes[END_REF][START_REF] Shen | Insulin treatment and clinical outcomes in patients with diabetes and heart failure with preserved ejection fraction[END_REF][START_REF] Wallach | Updating insights into rosiglitazone and cardiovascular risk through shared data: individual patient and summary level meta-analyses[END_REF] Fenofibrate is a peroxisome proliferator-activated receptor alfa (PPARα) activator which can display anti-inflammatory effects beyond its lipid (triglycerides in particular) and uric acid lowering properties. [START_REF] Lee | Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice[END_REF][START_REF] Waldman | Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study[END_REF] It is thus plausible that fenofibrate might have an effect in reducing HF events, and such hypothesis requires further investigation.

In the present analysis, we aim to study the effect of fenofibrate (vs. placebo) in HF events when added on top of simvastatin in patients with T2D enrolled in the ACCORD Lipid trial, and whether the fenofibrate effect could have been modified by background glucose-lowering strategy intensity.

Methods

ACCORD Lipid study design

ACCORD was a multicenter clinical study, sponsored by the National Heart, Lung, and Blood Institute (NHLBI), and conducted in 77 clinical centers in the United States and Canada. ACCORD enrolled patients with T2D and a glycated hemoglobin level of 7.5% or greater and who had evidence of cardiovascular disease or significant atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, current status as a smoker, or obesity).

In the main ACCORD study, a total of 10251 patients were randomly assigned to receive either intensive anti-hyperglycemic therapy targeting a glycated hemoglobin level lower than 6.0% or to receive standard therapy targeting a glycated hemoglobin level of 7.0 to 7.9%. The results of this comparison have been reported previously. [START_REF] Gerstein | Effects of intensive glucose lowering in type 2 diabetes[END_REF] A selected subgroup of patients (n =5518) from the ACCORD study were also enrolled in the ACCORD Lipid trial and underwent randomization, in a 2-by-2 factorial design, to receive either simvastatin plus fenofibrate or simvastatin plus placebo, so that the comparison is fenofibrate vs. placebo. Patients were specifically eligible to participate in the lipid trial if they also had an LDL cholesterol level between 60 and 180 mg/dL, an HDL cholesterol level below 55 mg/dL for women and blacks or below 50 mg/dL for all other groups, and a triglyceride level below 750 mg/dL if they were not receiving lipid-lowering therapy or below 400 mg/dL if receiving lipid-lowering therapy. ACCORD Lipid was conducted between 2001 and 2005, with a median follow-up of 4.7 years, and the primary results have been previously reported. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] The study protocol was approved by the institutional review board or ethics committee at each center, as well as by a review panel at the NHLBI. All patients provided written informed consent to participate in the study.

Outcomes were independently adjudicated by a central committee whose members were unaware of study-group assignments based on predefined criteria. The primary outcome of ACCORD Lipid was the first occurrence of a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. In the present study we used the composite outcome of time-to-first of cardiovascular death or HF hospitalization, HF hospitalization and cardiovascular death alone as the main outcomes of interest. In ACCORD, HF hospitalization required documented clinical and radiologic evidence for adjudication. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] The access to the ACCORD database was provided by the NHLBI/BioLINCC (https://biolincc.nhlbi.nih.gov/studies/accord/) with ethical approval from the Centro Hospitalar Universitário São João (process number #500/2020).

Statistical considerations

In trials with a 2-by-2 factorial design the main analytical issues that may arise relate to the investigation of main effects and the interaction between the interventions in the regression models. The results of factorial trials may be confounded if a significant interaction is observed between the randomized interventions. [START_REF] Montgomery | Design, analysis and presentation of factorial randomised controlled trials[END_REF] In ACCORD Lipid no significant interaction was observed between the lipid and glycemia interventions for the primary outcome (interaction P =0.36); however, secondary outcomes, such as HF, have not been tested for such potential interactions.

In the present study, the outcomes were analyzed by Cox models, according to the intention-to-treat principle, and the results reported as hazard ratios (HR) and 95% confidence intervals (95%CI). The Cox models contain a term representing the lipidlowering treatment assignment (fenofibrate or placebo) plus the glucose-lowering strategy (intensive or standard) as stratification variable. The results are reported for the overall population, and for subgroups of intensive or standard glucose-lowering strategy along with a lipid-by-glucose lowering strategies interaction term. Further subgroup analyses based on sex, atherogenic dyslipidemia, insulin, thiazolidinedione, sulfonylurea therapy, and glycated hemoglobin levels at baseline are also presented. We also performed interaction tests using post-randomization on-treatment use of certain anti-hyperglycemic drugs in time-updated Cox models.

To study the effect of fenofibrate (vs. placebo) on blood lipids and eGFR over time, mixed-effects models were used with the variable of interest as outcome, lipidlowering treatment, baseline blood lipid value or baseline eGFR, study visits and treatment-by-visit interaction as fixed effects, and patients as random effects, with an unstructured covariance matrix allowing the effects to vary freely between patients, and a random slope at the study visit level. Serious adverse events were reported by the investigators to the ACCORD Coordinating Center and were analyzed by means of logistic regression and stratified according to glucose-lowering strategy. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] Worsening eGFR adverse events were defined by a drop in eGFR greater than 40% from the baseline value, assessed by the MDRD formula. [START_REF] Levey | A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group[END_REF] The associations between blood lipids (log2 transformed) and outcomes were studied using Cox models, adjusting for the validated Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM) which includes prior HF, atrial fibrillation, coronary artery disease, estimated glomerular filtration rate, and urine albumin-to-creatinine ratio. [START_REF] Elharram | Prediction of heart failure outcomes in patients with type 2 diabetes mellitus: Validation of the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HF(DM) ) in patients in the ACCORD trial[END_REF] Mediation analyses were performed taking the time-dynamic evolvement of both the potential mediators (eGFR, HDL-cholesterol, and triglycerides) and the outcome cardiovascular death or HF hospitalization into account. [START_REF] Baron | The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations[END_REF] A two-sided P-value of <0.05 was considered statistically significant. No correction for multiple testing was performed due to the exploratory nature of this work. All

Results

Patients' baseline characteristics

A total of 5518 patients were enrolled in the ACCORD Lipid study all of whom were receiving simvastatin, with 2765 randomized fenofibrate and 2753 to placebo.

Regarding the background glucose-lowering strategy, 1370 were receiving standard glucose-lowering and placebo, 1383 were receiving intensive glucose-lowering and placebo, 1391 were receiving standard glucose-lowering and fenofibrate, and 1374 were receiving intensive glucose-lowering and fenofibrate. Supplemental Figure 1 (flow-chart).

The baseline characteristics were well balanced between groups. The median age was 62 years, and around 31% were women. A prior HF history was present in about 5% of the patients and 10% were using loop diuretics. Most patients were treated with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker.

The median estimated glomerular filtration rate was nearly 90 ml/min/1.73m 2 and the glycated hemoglobin 8.1%. Table 1.

Heart failure outcomes by subgroups of glucose-lowering strategies

For the composite outcome of HF hospitalization or cardiovascular death, 228 (8.3%) patients experienced an event in the placebo group vs. 190 (6.9%) in the fenofibrate group, corresponding to an HR of 0.82, 95%CI 0.68-1.00, P =0.048 in favor of fenofibrate. The beneficial effect of fenofibrate to reduce HF hospitalizations or cardiovascular death was only present among patients receiving standard glucoselowering strategy with an HR of 0.64, 95%CI 0.48-0.85 and not among patients receiving intensive glucose-lowering strategy who did not benefit from fibrate therapy HR 1.02, 95%CI 0.79-1.33, interaction P =0.017. Figure 1. A similar pattern was observed for HF hospitalizations alone, where only patients receiving standard glucose-lowering strategy could benefit from fenofibrate: HR 0.60, 95%CI 0.42-0.85 in the standard group and HR 1.05, 95%CI 0.75-1.47 in the intensive group, interaction P =0.025. No between group differences (interactions) were seen for cardiovascular or all-cause mortality, nor for the composite outcome of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Table 2.

For the composite outcome of HF hospitalization or cardiovascular death, and in concordance with the findings above described, an intensive glucose-lowering strategy (compared with a standard strategy) was harmful for patients receiving fenofibrate HR 1.55, 95%CI 1.16-2.07 but not for those receiving placebo HR 0.96, 95%CI 0.74-1.25, interaction P =0.017. In agreement with the main glucose-lowering report, the intensive glucose-lowering strategy increased the risk of mortality regardless of fibrate therapy with an HR of 1.3 in both groups, interaction P =0.78.

Supplemental Table 1.

Treatment-by-sex, atherogenic dyslipidemia, insulin, thiazolidinedione, sulfonylurea therapy, and glycated hemoglobin interaction tests (all at baseline) were statistically non-significant. Supplemental Figure 2.

In the 26324 patient-visits with recorded information, insulin and thiazolidinediones were used more frequently in the intensive anti-hyperglycemic arm than in the standard anti-hyperglycemic arm: 7786 (59%) vs. 5860 (44%) patient-visits and 7078 (54%) vs. 4342 (33%) patient-visits, respectively (P <0.001 for both). No significant differences in the use of insulin and thiazolidinediones were observed between the placebo and the fenofibrate groups. Insulin was used in 6672 (51%) patient-visits in the placebo group and 6786 (51%) patient-visits in the fenofibrate group, P =0.69.

The time-updated treatment effect of fenofibrate (vs. placebo) on the composite of cardiovascular death or HF hospitalization was HR 0.91, 95%CI 0.65-1.29 without insulin use and HR 0.78, 95%CI 0.62-0.98 with insulin use, interaction P =0.42.

Thiazolidinediones were used in 5639 (43%) patient-visits in the placebo group and 5738 (43%) patient-visits in the fenofibrate group, P =0.72. The time-updated treatment effect of fenofibrate (vs. placebo) on the composite of cardiovascular death or HF hospitalization was HR 0.87, 95%CI 0.69-1.10 without thiazolidinedione use and HR 0.73, 95%CI 0.52-1.04 with thiazolidinedione use, interaction P =0.42. The three-way interaction between treatment-insulin-thiazolidinedione use was nonsignificant, interaction P=0.63.

Effect of fenofibrate on blood lipids by subgroups of glucose-lowering strategies

Compared with placebo, throughout the follow-up fenofibrate reduced the blood levels of triglycerides by -28.4 mg/dL, an effect that was statistically (but not clinically) different between patients on a standard vs. intensive anti-hyperglycemic strategy: -31.6 mg/dL on standard vs. -25.1 mg/dL on intensive, interaction P =0.05. 2. The effect of fenofibrate on total (-4.9 mg/dL), VLDL (-5.3 mg/dL), and HDL (+1 mg/dL) cholesterol was less marked and not different between standard and intensive anti-hyperglycemic strategies, interaction P >0.1 for all. A treatment effect interaction was observed for LDL cholesterol, but the effect magnitude on LDL cholesterol was overall small (-0.7 mg/dL) and of uncertain clinical significance. Supplemental Table 2.

Supplemental Table

Prognostic association of blood lipids

After adjustment for the TRS-HFDM score, baseline blood lipids were not significantly associated with the outcome of HF hospitalization or cardiovascular death, except HDL cholesterol where higher concentrations were independently associated with a lower risk of subsequent events: HR 0.62 per doubling HDL concentration, 95%CI 0.45-0.86, P =0.004. Supplemental Table 3.

Adverse events by subgroups of glucose-lowering strategies

Compared with placebo, fenofibrate therapy induced more worsening eGFR events (36.2% vs. 16.1%) irrespective of the glucose lowering-strategy, interaction P =0.15.

Other hypoglycemic and non-hypoglycemic adverse events did not differ between treatment groups, nor by glucose lowering strategy, interaction P >0.1 for all.

Supplemental Table 4.

eGFR slope analysis

From baseline to month 4 fenofibrate induced an eGFR drop of -14.8 (-15.5 to -14.1) ml/min/1.73m 2 , after month 4 fenofibrate slowed the decline in eGFR compared with placebo: annualized eGFR slope in the placebo group = -1.7 (-2.1 to -1.3) ml/min/1.73m 2 vs. -0.3 (-0.8 to +0.1) ml/min/1.73m 2 in the fenofibrate group, corresponding to a difference in slopes of +1.4 (+0.8 to +1.9) ml/min/1.73m 2 per year in favor of fenofibrate (P <0.001), without treatment-by-glucose lowering strategy interaction, interaction P =0.37. Supplemental Figure 3.

Mediation analyses

The effect of fenofibrate to reduce the composite of cardiovascular death or HF hospitalization was not statistically mediated by slope changes in eGFR, HDL-C, or triglyceride, as none of these post-randomization parameters was associated with the composite of HF hospitalization or cardiovascular death: eGFR slope (HR =0.98, 95%CI 0.97-1.00 per 5 ml/min/1.73m 2 /year, P =0.08), triglyceride slope (HR 1.00, 95%CI 0.99-1.01 5 mg/dL/year, P =0.77), HDL slope (HR 0.98, 95%CI 0.93-1.04, P =0.66). Therefore, requirements for a significant mediation effect were not met.

Discussion

Our study shows that fenofibrate reduced the composite of HF hospitalizations or cardiovascular death, an effect that was mainly due to a reduction in HF hospitalizations among patients on a standard glucose-lowering strategy.

While there has been increasing evaluation of SGLT2i and GLP-1RA to reduce the risk of cardiovascular events in patients with T2D, the role of fenofibrates and HF risk has largely been unexplored. Furthermore, an intensive glucose-lowering strategy may have confounded the effect of fenofibrate to reduce HF events due to an excess risk of adverse and fatal events with this strategy. The mechanisms by which fenofibrate reduce HF events are not explained by the lowering of triglyceride levels nor other lipoproteins, which changes were of similar "clinical" magnitude irrespective of the glucose-lowering strategy. However, fenofibrate induced more transient worsening eGFR events, which likely affected the elimination and circulating concentration of anti-hyperglycemic drugs, particularly on the intensive arm, which could have led to an excess of adverse events and hospitalizations among patients randomized to both fenofibrate and an intensive glucose-lowering strategy. On the other hand, the effect of fenofibrate in the standard glucose-lowering strategy group is likely an unconfounded effect. Of course, this effect represents a post-hoc subgroup analysis; still, the strength of effect and biological plausibility warrant further testing of fibrates to reduce HF events among patients with T2D in adequately powered randomized trials. Still, we tested the hypothesis of whether the more frequent on-treatment use of insulin and thiazolidinediones could have modified the effect of fenofibrate. We did not find evidence supporting this hypothesis; however, because both anti-hyperglycemic strategies (intensive or standard) used these therapies and these are post-randomization tests, such hypothesis remains open. In addition, current guidelines recommend treatment goals for T2D that are more similar to the standard glucose-lowering arm than the intensive glucose-lowering arm of ACCORD. [START_REF]Glycemic Targets: Standards of Medical Care in Diabetes-2021[END_REF] Fenofibrate is a PPARα agonist, a factor that is predominantly expressed in tissues that metabolise fatty acids, such as the liver, kidney, heart, and muscle. The activation of PPARα is essential for fatty acid metabolism, cholesterol homeostasis, differentiation of endothelial progenitor cells and anti-inflammation. [START_REF] Staels | Mechanism of action of fibrates on lipid and lipoprotein metabolism[END_REF][START_REF] Willson | The PPARs: from orphan receptors to drug discovery[END_REF] In patients with rheumatoid arthritis (a systemic inflammatory condition), treatment with fenofibrate resulted in a significant decrease in C-reactive protein and interleukin-6 concentrations. [START_REF] Shirinsky | The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study[END_REF] In individuals with metabolic syndrome, treatment with fenofibrate for eight weeks significantly attenuated the development of endothelial dysfunction, reduced vascular inflammation, increased adiponectin levels and insulin sensitivity. [START_REF] Koh | Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia[END_REF] Inflammation and endothelial dysfunction are risk factors for the development and progression of HF; [START_REF] Paulus | A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation[END_REF][START_REF] Ferreira | Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure[END_REF] therefore, the anti-inflammatory effect of fibrates may mitigate the risk of HF. Furthermore, the interleukin-6 pathway and other mechanistically related pathways, are activated in patients with T2D and HF, further enhancing the biologic plausibility of the HF reduction seen with fenofibrate. [START_REF] Tromp | Distinct Pathological Pathways in Patients With Heart Failure and Diabetes[END_REF][START_REF] Verdonschot | Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial[END_REF] Perhaps more important than the anti-inflammatory effects of fibrates, is that PPARα is a key player in the "nutrient deprivation" cascade and autophagy, and also a master controller of cardiac lipid metabolism and cardiac hypertrophy. [START_REF] Planavila | Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation[END_REF] The suppression of PPARα and sirtuin-1 (Sirt1) signalling likely contributes to the diminution of autophagic flux and mitochondrial dysfunction seen in various forms of cardiomyopathy. [START_REF] Caragnano | Autophagy and Inflammasome Activation in Dilated Cardiomyopathy[END_REF] Thus, activation of PPARα (e.g., with fenofibrate) promotes autophagic flux in cardiomyocytes, allowing the maintenance of mitochondrial homeostasis, reducing oxidative stress, and mitigating cardiac injury. [START_REF] Wang | Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice[END_REF][START_REF] Packer | Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors[END_REF] The third player influenced by PPARα/Sirt1 signalling is fibroblast growth factor 21 (FGF21), which is mainly produced by the liver under the control of PPARα. FGF21 is a key player in providing cardiac metabolic flexibility, as it regulates fatty acid oxidation, ketogenesis and insulin resistance. [START_REF] Vernia | The PPARα-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway[END_REF] The activation of PPARα increases FGF21, thereby preventing oxidative stress and improving cardiac energy utilization.

Interestingly, another drug class that is thought to act via the PPARα/Sirt1/FGF21 axis are sodium glucose co-transporter 2 inhibitors (SGLT2i). [START_REF] Packer | Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors[END_REF] In patients with T2D, SGLT2i consistently led to a 30-40% relative reduction of HF events, [START_REF] Zelniker | SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials[END_REF] which is an effect of similar magnitude to that found herein among patients randomized to fenofibrate and a standard glucose-lowering strategy. Further supporting this hypothesis, both fenofibrate and SGLT2i lead to reductions in serum uric acid levels and gout episodes, effects that are thought to be mediated by a reduction in oxidative stress. [START_REF] Waldman | Effect of fenofibrate on uric acid and gout in type 2 diabetes: a post-hoc analysis of the randomised, controlled FIELD study[END_REF][START_REF] Zhao | Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials[END_REF] To further increase the robustness of these results, our findings have been replicated in the Veterans Affairs HDL Intervention Trial (VA-HIT) that included 2531 men with coronary artery disease and low HDL cholesterol levels, of whom 25% had diabetes, randomized to either the fibrate gemfibrozil or placebo. [START_REF] Rubins | Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group[END_REF] In VA-HIT, gemfibrozil led to a 22% relative reduction in HF hospitalizations (P =0.04). The FIELD trial, that included exclusively patients with T2D, does not report HF hospitalizations as an individual endpoint, but fenofibrate led to a 11% reduction in total cardiovascular disease events (P =0.035). [START_REF] Keech | Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial[END_REF] Despite the increased occurrence of a transient worsening eGFR with fenofibrate therapy, the long-term kidney effect of fenofibrate was kidney protective, including a slowing of eGFR decline and a reduction in micro-and macroalbuminuria with fenofibrate compared to placebo. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] A decrease of albuminuria progression was also observed in the Diabetes Atherosclerosis Intervention Study (DAIS) [START_REF] Ansquer | Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). American journal of kidney diseases : the official journal of the National Kidney Foundation[END_REF] and in the FIELD trial. [START_REF] Davis | Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study[END_REF] At the start of the ACCORD Lipid, the dose of fenofibrate was 160 mg/day in all participants which is a high dose for individuals with impaired kidney function and may have led to rise in serum creatinine. During the trial, the protocol was revised and fenofibrate dose was then adjusted according to estimated glomerular filtration rate. [START_REF] Ginsberg | Effects of combination lipid therapy in type 2 diabetes mellitus[END_REF] The rise in serum creatinine with fenofibrate was reversible upon discontinuation of the drug [START_REF] Mychaleckyj | Reversibility of fenofibrate therapyinduced renal function impairment in ACCORD type 2 diabetic participants[END_REF] and was not associated with concomitant increase in urinary biomarkers representing glomerular or tubular injury, inflammation, or fibrosis. [START_REF] Chauhan | The Association of Fenofibrate with Kidney Tubular Injury in a Subgroup of Participants in the ACCORD Trial[END_REF] This suggests that the rise in creatinine was related to hemodynamic causes. A similar pattern of initial increase of serum creatine has also been observed with SGLT2 inhibitors, that are associated with long-term renal and cardiovascular protection. [START_REF] Heerspink | Clinical Implications of an Acute Dip in eGFR after SGLT2 Inhibitor Initiation[END_REF] Several other potential protective effects of fenofibrate have been identified in patients with T2D. In the ACCORD Eye Study and in the FIELD study, fenofibrate reduced diabetic retinopathy progression. [START_REF] Chew | The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study[END_REF][START_REF] Keech | Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial[END_REF] Importantly, the effect of fenofibrate to reduce major adverse cardiovascular events maybe be more pronounced in patients with certain PPARα variants (rs6008845 T/T homozygotes). [START_REF] Morieri | PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid[END_REF] In a prespecified analysis of the FIELD trial, fenofibrate reduced the risk of lower extremity amputations, [START_REF] Rajamani | Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial[END_REF] which may be related to a reduction of peripheral neuropathy. Even in the absence of protection from major atherosclerotic cardiovascular events, fenofibrate may have a relevant role on the prevention of several other relevant complications in T2D. A potential protection from HF is of particular relevance given the high residual risk of HF events when the main risk factors are controlled in T2D. [START_REF] Rawshani | Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes[END_REF] Further randomized trials are needed to confirm the effect of fibrates on HF events in T2D.

Limitations

Some limitations should be acknowledged in our work. This is a post-hoc analysis of a randomized controlled trial and these tests were not corrected for multiplicity; therefore, there is an increased risk of chance findings, and these results should be regarded as hypothesis-generating. However, the strength of the treatment effect seen in patients treated with standard glucose-lowering therapy, the biological plausibility, and external replication in the VA-HIT trial (as above discussed) provide robustness to our analyses. There is a difference of 7 HF hospitalization events between the ACCORD Lipid data we had access to, and the ACCORD Lipid main report; 8 these 7 events do not impact the reported estimates.

Conclusions

In patients with T2D treated with simvastatin, fenofibrate reduced the composite of HF hospitalizations or cardiovascular mortality, an effect that was seen predominantly in patients with standard background glucose-lowering therapy.

Adequately powered prospective randomized controlled trials are needed to confirm these findings.

  analyses were performed using Stata® (StataCorp. 2021. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC).

  Total cholesterol, mg/dL 171.0 (149.0, 197.0) 171.0 (149.0, 197.0) 171.0 (149.0, 196.0) 171.0 (147.0, 196.0) LDL cholesterol, mg/dL 96Triglycerides, mg/dL 161.0 (115.0, 225.0) 161.0 (111.0, 229.0) 162.0 (116.0, 233.0) 163.5 (113.0, 230.0)

Figure 1 .

 1 Figure 1. Time-to-first events of the composite of heart failure hospitalization or cardiovascular death by subgroups of glucose-lowering strategies

Table 1 .

 1 Baseline characteristics of the patients by subgroups of glucose-lowering strategies

	Characteristic	Standard glycemia and placebo	Intensive glycemia and placebo	Standard glycemia and fibrate	Intensive glycemia and fibrate
	N. =5518	1370	1383	1391	1374
	Age, years	62.0 (57.8, 67.1)	62.2 (57.7, 67.4)	61.9 (57.7, 67.0)	61.9 (57.7, 67.2)
	Women, n. (%)	431 (31.5%)	412 (29.8%)	428 (30.8%)	423 (30.8%)
	Race Class: Black, n. (%)	212 (15.5%)	226 (16.3%)	188 (13.5%)	200 (14.6%)
	Hispanic, n. (%)	104 (7.6%)	90 (6.5%)	110 (7.9%)	103 (7.5%)
	Other, n. (%)	164 (12.0%)	168 (12.1%)	180 (12.9%)	161 (11.7%)
	White, n. (%)	890 (65.0%)	899 (65.0%)	913 (65.6%)	910 (66.2%)
	CVD history, n. (%)	497 (36.3%)	511 (36.9%)	502 (36.1%)	506 (36.8%)
	HF history, n. (%)	69 (5.0%)	71 (5.1%)	71 (5.1%)	80 (5.8%)
	Dyslipidemia, n. (%)	963 (70.3%)	959 (69.3%)	981 (70.5%)	958 (69.7%)
	Hypertension, n. (%)	999 (72.9%)	985 (71.2%)	993 (71.4%)	957 (69.7%)
	Smoking, n. (%)	207 (15.1%)	186 (13.4%)	196 (14.1%)	214 (15.6%)
	BMI, Kg/m2	31.9 (28.3, 36.0)	32.1 (28.4, 36.0)	31.7 (28.1, 35.7)	32.0 (28.3, 35.7)
	Amputation lower limb, n. (%)	31 (2.3%)	29 (2.1%)	28 (2.0%)	35 (2.5%)
	SBP, mmHg	133.0 (123.0, 145.0) 132.0 (122.0, 145.0) 133.0 (121.0, 144.0) 132.0 (121.0, 145.0)
	Heart rate, bpm	72.0 (64.0, 81.0)	72.0 (64.0, 80.0)	72.0 (63.0, 80.0)	72.0 (64.0, 80.0)
	HbA1c, %	8.1 (7.6, 8.8)	8.1 (7.5, 8.8)	8.1 (7.6, 8.8)	8.1 (7.6, 8.9)
	eGFR, ml/min	89.8 (76.3, 104.3)	89.2 (73.9, 105.0)	89.1 (73.9, 104.7)	89.6 (76.3, 103.8)
	UACR, mg7g

  CVD, cardiovascular disease; HF, heart failure; BMI, body mas index; SBP, systolic blood pressure; HbA1c, glycated hemoglobin in %, * the corresponding results for HbA1c in mmol/mol are 65 (60-73) mmol/L; eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio; MRAs, mineralocorticoid receptor antagonists; ACEi/ARBs, angiotensin converting enzyme inhibitors/angiotensin receptor blockers; CCBs, calcium channel blockers. HF, heart failure; *The primary outcome was a composite of time-to-first of myocardial infraction, stroke, or cardiovascular death; Event-rate is represented per 100 person-years.

	Loop diuretics, n. (%) Thiazide diuretics, n. (%) MRAs, n. (%) ACEi/ARBs, n. (%) CCBs, n. (%) Beta-blockers, n. (%) Biguanides, n. (%) Sulfonylureas, n. (%) Thiazolidinediones, n. (%) Insulin, n. (%) Anti-platelet, n. (%) Standard anti-hyperglycemic group Intensive anti-hyperglycemic group Legend: Overall population Legend:	139 (10.1%) 353 (25.8%) 35 (2.6%) 941 (68.7%) 262 (19.1%) 441 (32.2%) 909 (66.4%) 766 (55.9%) 273 (19.9%) 462 (33.7%) 786 (57.4%) 221/2753 (8.0) 203 (7.3) 95/1370 (6.9) 91/1391 (6.5) 126/1383 (9.1) 112/1374 (8.2) 1.9 (1.6-2.2) 127 (9.2%) 380 (27.5%) 36 (2.6%) 950 (68.7%) 256 (18.5%) 445 (32.2%) 911 (65.9%) 773 (55.9%) 285 (20.6%) 455 (32.9%) 799 (57.8%) 1.6 (1.4-1.9) 1.4 (1.2-1.7)	128 (9.2%) 375 (27.0%) 36 (2.6%) 942 (67.7%) 263 (18.9%) 476 (34.2%) 918 (66.0%) 758 (54.5%) 265 (19.1%) 476 (34.2%) 815 (58.6%) 1.5 (1.3-1.7) 0.91 (0.75-1.10) 128 (9.3%) 365 (26.6%) 43 (3.1%) 906 (65.9%) 262 (19.1%) 436 (31.7%) 905 (65.9%) 775 (56.4%) 280 (20.4%) 443 (32.2%) 836 (60.8%) 0.35 1.3 (1.1-1.6) 0.94 (0.71-1.25) 1.7 (1.4-2.0) 0.89 (0.69-1.15)	0.78

This study was supported by national funds through FCT Fundação para a Ciência e Tecnologia, I.P., under the scope of the Cardiovascular R&D Center -UnIC (UIDB/00051/2020 and UIDP/00051/2020).

Acknowledgements

Dr. João Pedro Ferreira is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

Availability of data and materials

The ACCORD database can be fully available from NHLBI/BioLINCC upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the institutional review board or ethics committee at each center, as well as by a review panel at the NHLBI. All patients provided written informed consent to participate in the study. The access to the ACCORD database was provided by the NHLBI/BioLINCC with ethical approval from the Centro Hospitalar Universitário São João (process number #500/2020).

Consent for publication

All authors approved the manuscript and consent its publication.

Competing interests

Dr

Authors' contributions

JPF performed the statistical analysis and drafted manuscript and its revisions; all other authors provided critical input.


MD, PhD João Pedro Ferreira

MD Milton Packer

MD ; Javed Butler

MD, PhD Faiez Zannad

Reconsidering the ejection fraction centric view of pharmacologic treatment for heart failure

Keywords: ejection fraction, heart failure, unified definition

For the past two decades, heart failure (HF) has been classified into two phenotypes based on ejection fraction (EF). Inhibitors of the RAAS, neprilysin, , and betablockers represent foundational treatments for patients with a reduced EF (<40%) but have not been considered effective in patients with preserved EF (≥40%).

However, re-examination of the clinical trial evidence has cast considerable doubt about the utility of an EF threshold of 40% as the main decision tool for HF treatment. In CHARM, candesartan reduced the risk of cardiovascular death or HF hospitalization by 24% up to an EF of 50%, with attenuation of the effect on HF hospitalization in patients with EF >55-60%. In RALES and TOPCAT, spironolactone reduced the risk of cardiovascular death or HF hospitalization by 28% up to an EF of 50%, with attenuation of the effect on HF hospitalization in patients with EF >55-60%. In PARADIGM-HF and PARAGON-HF, sacubitril/valsartan reduced total HF hospitalizations by 20% up to an EF of 55-60%, with an attenuated effect in patients with the highest EF. In the EMPEROR trials, empagliflozin reduced the risk of total HF hospitalizations by approximately 30% in patients with EF ranging from <25% to 60%, with an attenuated effect in patients with EF >60-65%. Since patients with an EF >60% represent only 10-15% of all HF patients, we propose that foundational HF treatments should be applied to patients across broad range of EF.

Mail: j.ferreira@chru-nancy.fr or jp7ferreira@hotmail.com

Introduction

In 1628 William Harvey described in detail the mechanisms of the circulatory system, with the heart playing a central role by pumping the blood throughout the entire body while emptying completely during systole. [START_REF] Bruce | Left ventricular residual volume in the intact and denervated dog heart[END_REF] Later in the 19 th century some authors observed that some blood remained in the heart after its contraction, [START_REF] Chauveau | Nouvelles recherches expérimentales sur les mouveménts et les bruits normaux du coeur envisages au point de vue la physiologie medicale[END_REF][START_REF] Roy | Remarks on Failure of the Heart from Overstrain[END_REF] and in 1906 Yandell Henderson estimated that approximately 2/3 of total volume of the left ventricle would be discharged during systole. [START_REF] Henderson | The volume curve of the ventricles of the mammalian heart, and the significance of this curve in respect to the mechanics of the heart-beat and the filling of the ventricles[END_REF] Two decades later, Gustav Nylin proposed that the relation between heart volume and cardiac output per beat (i.e., stroke volume) could be used as a measure of cardiac activity. [START_REF] Nylin | The relation between heart volume and cardiac output per beat as a measure of cardiac activity[END_REF] Since the early 20 th century, heart failure (HF) has been defined as "a condition in which the heart fails to discharge its contents adequately", [START_REF] Lewis | Diseases of the heart[END_REF] and in 1962, Folse and Braunwald showed that the ratio of stroke volume (SV) divided by the end-diastolic volume (EDV) of the left ventriculus could provide relevant information to a hemodynamic analysis of left ventricular function. [START_REF] Folse | Determination of fraction of left ventricular volume ejected per beat and of ventricular end-diastolic and residual volumes. Experimental and clinical observations with a precordial dilution technic[END_REF] A few years later Stuart Bartle proposed the term "ejected fraction" to reflect the ratio of SV to EDV. [START_REF] Bartle | Ejection fraction -an index of myocardial function (abstract)[END_REF] As it became clear that the HF syndrome was accompanied by elevated cardiac filling pressures along with a reduced proportion of ejected left ventricular volume, LVEF became a convenient means to examine ventricular function, despite the fact that it is principally a crude measure of left ventricular volume that is preload and afterload dependent. [START_REF] Cikes | Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure[END_REF] The ratio of SV to EDV is not a measure of myocardial contractility; changes in the ratio do not reflect changes in the degree of myocardial shortening; and measurements relating to the myocardium are not included in determination of the LVEF. [START_REF] Stokke | Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain[END_REF][START_REF] Maurer | How Should Physicians Assess Myocardial Contraction?: Redefining Heart Failure With a Preserved Ejection Fraction[END_REF] Furthermore, LVEF assessment may have poor reproducibility depending on the observer and the used method. [START_REF] Wood | Left ventricular ejection fraction and volumes: it depends on the imaging method[END_REF][START_REF] Thorstensen | Reproducibility in echocardiographic assessment of the left ventricular global and regional function, the HUNT study[END_REF] Nonetheless, despite its major limitations and only moderate reproducibility, the ready availability of LVEF led it to become the leading metric used by clinicians to characterize the left ventricular function of their patients.

Use of ejection fraction in heart failure trials

In the 1980s randomized, controlled, and double-blind trials (RCTs) in HF started to be conducted. [START_REF] Massie | 15 years of heart-failure trials: what have we learned?[END_REF] The first large RCT with a survival endpoint, the Veterans Administration Cooperative Study (V-HeFT-I), [START_REF] Cohn | Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study[END_REF] selected patients taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin, or the combination of hydralazine and isosorbide dinitrate based on evidence of cardiac dilatation (cardiothoracic ratio >0.55 on chest x-ray or a left ventricular internal diameter in diastole >2.7 cm/m 2 on echocardiography) or a radionuclide ejection fraction <45% in association with reduced exercise tolerance. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial randomized patients to enalapril or placebo based on the presence of severe symptoms and a radiologicallydetermined heart size >600 ml/m 2 in men and >550 ml/m 2 in women, without the characterization of ejection fraction. [START_REF] Swedberg | Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)[END_REF] However, in the late 1980s and 1990s, LVEF became a systematic inclusion criterion in HF trials. The Studies of Left Ventricular Dysfunction (SOLVD), [START_REF] Yusuf | Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure[END_REF] the Assessment Trial of Lisinopril and Survival Trial (ATLAS), [START_REF] Packer | Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group[END_REF] the Prospective Randomized Amlodipine Survival Evaluation Study Group (PRAISE), [START_REF] Packer | Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group[END_REF] the Flolan International Randomized Survival Trial (FIRST), [START_REF] Califf | A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST)[END_REF] the U.S. Carvedilol Heart Failure Study, [START_REF] Packer | The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group[END_REF] and the Randomized Aldactone Evaluation Study (RALES) [START_REF] Pitt | The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators[END_REF] trials required patients to have a LVEF ≤25-35%. The use of LVEF as an inclusion criterion in HF trials continued thereafter. [START_REF] Mcmurray | Angiotensin-neprilysin inhibition versus enalapril in heart failure[END_REF][START_REF] Mcmurray | Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction[END_REF][START_REF] Packer | Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure[END_REF]

Classification of heart failure based on ejection fraction

Hemodynamic studies found that some patients had elevated filling pressures without marked increases in ventricular chamber size, and such patients were initially termed "diastolic HF". [START_REF] Zile | Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle[END_REF] Clinically, these patients did not differ from those with systolic dysfunction, and in most such patients, myocardial shortening was impaired, often markedly so. [START_REF] Maurer | How Should Physicians Assess Myocardial Contraction?: Redefining Heart Failure With a Preserved Ejection Fraction[END_REF] The distinguishing feature of these patients was that the depression of contractility was not accompanied by marked left ventricular enlargement, in contrast with those whose ejection fraction were demonstrably low. [START_REF] Maurer | How Should Physicians Assess Myocardial Contraction?: Redefining Heart Failure With a Preserved Ejection Fraction[END_REF] Evidence on how to treat patients with heart failure without a reduced ejection fraction was lacking, because most trials enrolled patients with marked left ventricular enlargement or a severely reduced ejection fraction. [START_REF] Remme | Guidelines for the diagnosis and treatment of chronic heart failure[END_REF] One exception is the Digitalis Investigation Group (DIG) trial, whose ancillary trial enrolled 988 patients (492 assigned to digoxin and 496 assigned to placebo) with a LVEF >45%. The results of this ancillary study were consistent with the findings of the main trial, with a HR of 0.99, 95%CI 0.76 to 1.28) for all-cause mortality and a HR of 0.82, 95%CI, 0.63 to 1.07 for the composite of all-cause death or hospitalization for HF. [START_REF]The effect of digoxin on mortality and morbidity in patients with heart failure[END_REF] Subsequently, the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program included HF patients with both an ejection fraction less than and greater than 40%. The CHARM-Preserved trial included patients with a LVEF ≥40% and HF symptoms to compare candesartan (an angiotensin receptor blocker, ARB) with placebo. [START_REF] Yusuf | Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial[END_REF] The trial investigators proposed to identify a group of patients who had been excluded in prior trials, thus addressing a therapeutic void rather than making a mechanistic distinction. After the publication of CHARM-Preserved, the use of the term "preserved HF or HFpEF" for patients with an ejection fraction ≥40% became widely adopted, and it continues to be used at the present time. [START_REF] Pfeffer | Heart Failure With Preserved Ejection Fraction In Perspective[END_REF] Some further subclassification of HFpEF has evolved over the years. The most popular one is the "mid-range ejection fraction or HFmrEF or mildly reduced ejection fraction" used to characterize patients with LVEF of 41% to 49%. [START_REF] Lam | The middle child in heart failure: heart failure with midrange ejection fraction (40-50%)[END_REF][START_REF] Tromp | Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction[END_REF][START_REF] Mcdonagh | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure[END_REF] Most HF treatments are recommended to patients with a LVEF <40%. [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] Of course, people who take the guidelines literally may not treat a patient in whom they measured a LVEF of 43% while another colleague could have measured 39% in the same patient on the same day. [START_REF] Pellikka | Variability in Ejection Fraction Measured By Echocardiography, Gated Single-Photon Emission Computed Tomography, and Cardiac Magnetic Resonance in Patients With Coronary Artery Disease and Left Ventricular Dysfunction[END_REF] Moreover, patients with a LVEF ≥40% or >50% typically have myocardial contractile "systolic" impairment of the left ventricle when measured by other assessments (e.g., strain analysis or myocardial contraction fraction). [START_REF] Stokke | Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain[END_REF][START_REF] Maurer | How Should Physicians Assess Myocardial Contraction?: Redefining Heart Failure With a Preserved Ejection Fraction[END_REF][START_REF] Halliday | Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial[END_REF][START_REF] Aurigemma | Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy[END_REF][START_REF] Triposkiadis | The continuous heart failure spectrum: moving beyond an ejection fraction classification[END_REF] Interpretation of large RCT in heart failure with preserved ejection fraction Several landmark RCTs have provided robust evidence that angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), sacubitril/valsartan, and the sodium glucose co-transporter 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin significantly improve mortality and morbidity in patients with a LVEF <40%. [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF][START_REF] Zannad | SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials[END_REF][START_REF] Vaduganathan | Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials[END_REF] Most of these treatments have also been tested in patients with a LVEF ≥40% or >45% but, in most cases, with less compelling results when compared with patients with a LVEF <40%.

Angiotensin converting enzyme inhibitors

Perindopril

In the PEP-CHF study, a total of 850 patients aged ≥70 years with a clinical and echocardiographic diagnosis of predominantly mild to moderate HF due to diastolic dysfunction on echocardiography were randomized to either perindopril 4 mg or placebo. [START_REF] Cleland | The perindopril in elderly people with chronic heart failure (PEP-CHF) study[END_REF] Patients with a left ventricular wall motion index of <1.4 (a proxy for HFrEF) were excluded. Many patients withdrew from perindopril (28%) and placebo (26%) after the first year of follow-up and started taking open-label ACEi. At the end of follow-up (median 2.1 years), the composite endpoint of all-cause mortality and HF hospitalization did not differ between groups: HR 0.92, 95%CI 0.70-1.21, P =0.55. However, at 1 year, when most patients were still taking the assigned treatment, perindopril appeared to improve symptoms and exercise tolerance, and reduced HF hospitalizations: HR 0.63, 95%CI 0.41-0.97, P =0.033.

Angiotensin receptor blockers

Candesartan

In the CHARM program, patients with LVEF>40% were allocated to the CHARM-Preserved trial, [START_REF] Yusuf | Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial[END_REF] which included 3023 patients (65% of the patients had a LVEF≥50% and 35% a LVEF >40 and <50%). Compared with placebo, candesartan did not reduce the risk of the primary outcome, a composite of time-to-first of cardiovascular death or HF hospitalization; unadjusted HR 0.86, 95%CI 0.77-1.03, P =0.12. In the prespecified covariate adjusted analysis the hazard ratio was 0.86, 95%CI 0.74-1.00, P =0.051. Fewer patients were hospitalized for HF in the candesartan group (230 vs. 279, P =0.017). Together, these findings support a statistically significant and clinically meaningful effect of candesartan for preventing HF admissions among patients who have HF and a LVEF >40%. [START_REF] Yusuf | Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial[END_REF] Analyzing the effect of candesartan across the continuous spectrum of LVEF showed that the drug reduced the time-to-first cardiovascular death or HF hospitalization by 24% up to a LVEF of 50%, with attenuation of the effect on heart failure hospitalization in patients with EF of 60% or greater. [START_REF] Triposkiadis | The continuous heart failure spectrum: moving beyond an ejection fraction classification[END_REF] Candesartan did not reduce cardiovascular mortality in these patients. [START_REF] Lund | Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum[END_REF]

Irbesartan

The Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) trial tested irbesartan vs. placebo in 4133 patients with a LVEF≥45% who were aged 60 or older. [START_REF] Massie | Irbesartan in patients with heart failure and preserved ejection fraction[END_REF] Irbesartan did not reduce the primary outcome of all-cause mortality or hospitalizations for cardiovascular causes (HR 0.95, 95%CI 0.86-1.05, P =0.35 or HF hospitalizations HR 0.95, 95%CI 0.81-1.10, P =0.50). However, a post-hoc analysis adjusting for baseline variables with prognostic impact, suggested benefit with irbesartan treatment with a 13% reduction in the time-to-first of cardiovascular death or HF hospitalization: HR 0.87, 95%CI 0.77-0.99, p=0.039. [START_REF] Ferreira | Covariate adjusted reanalysis of the I-Preserve trial[END_REF] . Ejection fraction (<60% vs. ≥60%) did not modify the effect of irbesartan on the primary outcome, interaction P =0.28. [START_REF] Massie | Irbesartan in patients with heart failure and preserved ejection fraction[END_REF]

Beta-Blockers

The Beta-blockers in Heart Failure Collaborative Group pooled individual patientlevel data from double-blind RCTs in HF in order to examine the effects of betablockers across the spectrum of LVEF. [START_REF] Cleland | Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials[END_REF] Among 14262 patients in sinus rhythm, beta-blockers improved outcomes among patients with a LVEF up to 50%. It should be noted that only 241 patients had a LVEF >50%, all from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial; [START_REF] Flather | Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS)[END_REF] hence, this subgroup is too small to form the basis of valid conclusions. However, most patients with HFpEF are already receiving betablockers, presumably for other cardiovascular disorders.

Spironolactone

The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial investigated the prognostic effect of spironolactone vs. placebo in 3,445 patients with a LVEF≥45% randomized in North America, South America and Canada i.e., "the Americas" and Russia/Georgia i.e., "Eastern Europe". [START_REF] Pitt | Spironolactone for heart failure with preserved ejection fraction[END_REF] The primary outcome was a composite endpoint of cardiovascular death or HF hospitalization. Spironolactone did not reduce the primary outcome, HR 0.89, 95%CI 0.77-1.04, P =0.14 but did reduce HF hospitalizations: HR 0.83, 95%CI 0.69-0.99, P =0.04. However, marked regional variations were seen in the trial, whereby patients from Eastern Europe had event rates similar to the general population of those countries, raising the likelihood that these patients did not have heart failure. Furthermore, these patients did not experience rises in serum potassium and creatinine with spironolactone; and the analysis of blood spironolactone metabolites confirmed a low treatment adherence in Eastern Europe. [START_REF] Pfeffer | Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial[END_REF][START_REF] De Denus | Spironolactone Metabolites in TOPCAT -New Insights into Regional Variation[END_REF] When the analysis excluded patients from Eastern Europe, spironolactone reduced the primary outcome (HR 0.82, 95%CI 0.69-0.98, P =0.026). Further analysis suggested that ejection fraction influenced the magnitude of the effect of spironolactone, with an attenuated effect in patients with an ejection fraction >55-60%. [START_REF] Solomon | Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction[END_REF]

Sacubitril/Valsartan

The Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction trial (PARAGON-HF) trial examined the efficacy and safety of sacubitril/valsartan vs. valsartan in 4822 patients aged 50 years or older with LVEF ≥45%, structural heart disease, and increased levels of natriuretic peptides. The primary outcome was a composite of total hospitalizations for HF or cardiovascular mortality. [START_REF] Solomon | Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction[END_REF] Compared with valsartan, sacubitril/valsartan exerted a modest effect to reduce the rate of the primary outcome: RR 0.87, 95%CI 0.75-1.01, P =0.06. Subgroup analyses showed that patients with LVEF below the median (of 57%) and women had a greater benefit with sacubitril/valsartan. [START_REF] Mcmurray | Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF[END_REF][START_REF] Solomon | Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure[END_REF][START_REF] Vaduganathan | Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF[END_REF] Additionally, sacubitril/valsartan led to significant improvements in quality-of-life scores and NYHA class, as well as lower rates of renal events and worsening renal function. [START_REF] Jering | Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF[END_REF] Analyses across the continuous spectrum of LVEF showed that sacubitril/valsartan (vs. valsartan) reduced first and recurrent HF hospitalizations up to a LVEF of 55-60%, with an attenuated effect in patients with an ejection fraction of 60% or greater. 55

Sodium-glucose cotransporter 2 inhibitors

The Empagliflozin Outcome trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trial enrolled patients with HF and a LVEF >40%. Compared with placebo, empagliflozin reduced the composite of cardiovascular death or heart failure hospitalizations by 21% (HR 0.79, 95%CI 0.69-0.90, P <0.001) and recurrent HF hospitalizations by 27% (HR 0.73, 95%CI 0.61-0.88, P <0.001) with no treatment effect modification by LVEF for the primary outcome. [START_REF] Anker | Empagliflozin in Heart Failure with a Preserved Ejection Fraction[END_REF] However, the effect of empagliflozin on heart failure hospitalizations became attenuated at an ejection fraction of >60%. [START_REF] Packer | Effect of Empagliflozin on Worsening Heart Failure Events in Patients with Heart Failure and a Preserved Ejection Fraction: The EMPEROR-Preserved Trial[END_REF] The challenges in the interpretation of HFpEF trials are displayed in Table 1, and the LVEF subgroup analysis of HFpEF trials displayed in Table 2.

Totality of evidence

As above stated, ejection fraction reflects the volume rather than the contractility of the heart. Based on the available evidence, most drugs used for the treatment of patients with heart failure (inhibitors of the renin-angiotensin system, sacubitril/valsartan, MRAs and SGLT2i) appears to be beneficial in reducing heart failure hospitalizations across a broad spectrum of ejection fractions, at least, up to 55-60%. Additionally, these drugs reduce cardiovascular mortality in patients with an ejection fraction of 40% or less.

The pathophysiology of patients with heart failure who have an ejection fraction of 60% or greater requires further study. These patients represent one-third of those with HFpEF but only 10-15% of all patients included in heart failure trials and are represented mostly by women with atrial fibrillation (who may require specific treatments for atrial fibrillation). Therefore, we propose that foundational HF treatments should be applied to patients across broad range of EF. * The treatment effect represented for patients with a LVEF between 50 and 60%, represents the effect in the subgroup of patients with LVEF ≥50%; The effect of candesartan vs. placebo across the continuous spectrum of LVEF is represented with "splines" with imprecise results at LVEF >60% due to a small number of patients/events (Lund L et *** In PARAGON-HF the represented cutoffs are: 32.5-42.5%, 42.6-52.5%, 52.6-62.5%, and >62.5% (Solomon SD et al. Circulation 2020; 5, 352-361). **** The effect of spironolactone vs. placebo in the subgroup of patients with a LVEF <40% is taken from the RALES trial where the composite of CV death or HFH represents CV death alone (Pitt B et al. N Engl J Med 1999; 341:709-717); TOPCAT included patients with LVEF ≥45% hence the subgroup of patients with a LVEF 40-

  al. European Journal of Heart Failure 2018; 20, 1230-1239). ** The "active comparator" was enalapril in PARADIGM-HF (McMurray JJV et al. N Engl J Med 2014; 371:993-1004) and valsartan in PARAGON-HF (Solomon SD et al. N Engl J Med 2019; 381:1609-1620).

Table 1 .

 1 Main results of HFpEF trials

	Trial	LVEF	Interpretation	Re-	Re-
		range	issues	analysis	interpretation
	PEF-CHF	LVEF	High rates of	1-year	Perindopril
	(Perindopril vs.	was not	open-label	analysis	reduced HF
	Placebo)	used for	ACEi after 1		hospitalizations
		inclusion	year		and improved HF
					symptoms
	CHARM-	54±9%	Total HFH not		Candesartan
	Preserved		considered	Total (first	reduced first and
	(Candesartan vs.			and	recurrent HFH
	Placebo)			recurrent)	with an
				HFH	attenuation of
					effect at LVEF
					>60%
	I-Preserve	60±9%	Adjustment for	Covariate	Irbesartan
	(Irbesartan vs.		prognostically	adjusted	reduced the
	Placebo)		important		composite of
			variables not		HFH or CV death
			considered
	Beta-blockers in	Most (n	Only 241	Across	Beta-blockers
	Heart Failure	=575)	patients with	LVEF	improved
	Collaborative	patients	LVEF ≥50%	range	prognosis up to
	Group (Beta-	with	(all from the		LVEF of 50% in
	blockers vs.	LVEF 40-	SENIORS trial)		sinus rhythm, but
	Placebo meta-	49%			underpowered
	analysis)				above 50%.
	TOPCAT	56 (51-	Marked	Regional	Spironolactone
	(Spironolactone	61)	regional	analysis	improved
	vs. Placebo)		differences		outcomes in
			with HF		patients enrolled
			diagnosis and		in the Americas
			adherence		but not in Eastern
			issues		Europe
			detected in		The effect of
			Eastern		spironolactone
			Europe		was attenuated at
					LVEF >60%
	PARAGON-HF	58±8%	Treatment	Sex	Sacubitril/Valsart
	(Sacubitril/Valsart		effect more	differences	an improved
	an vs. Valsartan)		pronounced in	and LVEF	outcomes in
			women and	spectrum	women and in
			LVEF below		patients with
			the median of		LVEF below 60%
			57%		The effect of
					sacubitril/valsarta
					n was attenuated

Table 2 .

 2 Treatment effect on the primary endpoint of heart failure hospitalization and cardiovascular death, across the spectrum of ejection fraction

	Outcome/Drug/Trial	LVEF <40% LVEF 40-49% LVEF 50-60% LVEF >60%
	Candesartan vs. Placebo *
	CV death or HFH	0.82 (0.75-0.91)	0.76 (0.61-0.96)	0.95 (0.79-1.14)	-
	Total HFH	0.68 (0.58-0.80)	0.48 (0.33-0.70)	0.78 (0.59-1.03)	-
	Sacubitril/Valsartan vs. Active comparator **
	CV death or HFH ***	0.81	0.89	0.89	1.03
		(0.69-0.94)	(0.73-1.10)	(0.74-1.06)	(0.80-1.32)
	Total HFH ***	0.82	0.77	0.81	1.04
		(0.63-1.06)	(0.58-1.02)	(0.63-1.05)	(0.76-1.44)
	Spironolactone vs. Placebo ****
	CV death or HFH	0.69	0.72	0.85	0.97
		(0.58-0.82)	(0.50-1.05)	(0.61-1.18)	(0.76-1.23)
	First HFH	0.65	0.76	0.70	0.98
		(0.54-0.77)	(0.46-1.27)	(0.47-1.04)	(0.74-1.30)
	Beta-blockers vs. Placebo *****
	CV death or CV hosp.	0.74 (0.62-0.88)	0.83 (0.60-1.13)	0.66 (0.38-1.15)	-
	Empagliflozin vs. Placebo ******
	CV death or HFH	0.75	0.71	0.80	0.87
		(0.65-0.86)	(0.57-0.88)	(0.64-0.99)	(0.69-1.10)
	Total HFH	0.70	0.57	0.66	1.07
		(0.58-0.85)	(0.42-0.79)	(0.48-0.91)	(0.76-1.46)
	Legend: LVEF, left ventricular ejection fraction; HFH, heart failure hospitalization;
	Inter.P, interaction P-value.

Disclosures

JPF reports consulting fees from Boehringer Ingelheim. FZ reports personal fees from Boehringer Ingelheim, Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno pharmacuetical, Applied Therapeutics, Merck, Bayer, and Cellprothera; and other support from CVCT and Cardiorenal. MP reports personal fees from Boehringer Ingelheim, AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and NovoNordisk.


Sascha Fagel
email: sascha.fagel@tu-berlin.de

Frédéric Elisei
email: frederic.elisei]@gipsa-lab.inpg.fr

Gérard Bailly

From 3-D Speaker Cloning to Text-to-Audiovisual-Speech

Keywords: talking head, intelligibility, evaluation

Visible speech movements were motion captured and parameterized. Coarticulated targets were extracted from VCVs and modeled to generate arbitrary German utterances by target interpolation. The system was extended to synthesize English utterances by a mapping to German phonemes. An evaluation by means of a modified rhyme test reveals that the synthetic videos of isolated words increase the recognition scores from 27 % to 47.5 % when added to audio only presentation.

Introduction

Visible speech movements that match audible speech increase the intelligibility [START_REF] Sumby | Visual Contribution to Speech Intelligibility in Noise[END_REF]. This advantage can be reproduced by synthetic video [START_REF] Goff | Realtime Analysis-Synthesis and Intelligibility of Talking Faces[END_REF][START_REF] Fagel | Intelligibility of natural and 3D-cloned German speech[END_REF] although the perceptual relevance of all properties of the visualization are not yet completely understood. A playback of separately generated audio and video synthesis synchronous at phoneme level often leads to reasonable results [START_REF] Beskow | Talking Heads-Models and Applications for Multimodal Speech Synthesis[END_REF].

3-D Speaker Cloning

A native speaker of German was filmed from three views with 398 colored beads glued on the face. The speaker uttered 100 VCVs composed of V={a,i,u,E,O} and C={p,b,t,d,k,g,f, v,s,z,S,Z,C,j,x,R,m,n,N,l}. Additionally the vowels {a,e,i,o, u,2,y,E,I,O,U,6,Y,@} and 9 were uttered in isolation. The six main articulatory parameters were extracted by an iterative PCA from 42 poses of vowels and coarticulated consonants [START_REF] Fagel | Intelligibility of natural and 3D-cloned German speech[END_REF]. The synthetically reproduced VCV sequences have shown to yield ~70 % of the intelligibility provided by the natural face.

Coarticulation modeling and TTavS

The generation of parameter sequences for an utterance to be synthesized is done in two steps: target estimation and transition interpolation. The targets (a set of values of the six articulation parameters) for consonantal segments in asymmetric contexts are linear combinations of the parameters from the two measured context VCVs (or an estimated mixture of the existing data if V≠{a,i,u,E,O}). If consonants occur in clusters the influence of a context vowel decreases linearly with the distance in phones. A symmetric context is assumed if only one context vowel exists due to an utterance boundary. Targets for a vowel segment are taken 1) from the VCVs if the vowel is between two identical consonants, 2) from the vowel measured in isolation in case of pure vocalic context, or 3) an average of both if left context ≠ right context.

The transitions are linear to quadratic interpolations of the targets of each parameter where the exponent (1 to 2) is determined by the degree of coarticulation that occurred in the target estimation of consonants: linear interpolation if the target completely adopts to the neighbors (the parameter value of the consonant in the VCV equals that one of the vowel), quadratic interpolation if the target is not coarticulated at all (the parameter value of a consonant is the same in both contexts).

Evaluation

A modified rhyme test without carrier sentence was carried out as a preliminary evaluation of the system in terms of intelligibility. The English phonemes were mapped to German based on articulatory considerations and the American English voice us1 of the mbrola speech synthesizer were used for the audiovisual synthesis with white noise at 0dB SNR. The test words were taken from [START_REF] House | Articulation-Testing Methods: Consonantal Differentiation with a Closed-Response Set[END_REF]: six lists of 50 monosyllabic words each. 12 subjects with normal hearing and normal or corrected to normal vision participated in the test. All word lists were used in the test but distributed over the subjects. One of the six word lists was presented to a subject audiovisually, another one was presented audio alone (blocked conditions). Hence, a higher intelligibility of audiovisual compared to audio alone presentation -if present -cannot be produced by a possible learning effect. After each presented spoken word the subject was requested to select the most probable one from six alternatives.

Results: 11 of 12 subjects benefit from the additional synthetic visual speech. The overall increase of recognition rate is from 27 % (std. 6.1 %) correct answers in audio alone condition to 47.5 % (std. 12.9 %) in audiovisual condition (at a chance level of 16.7 %). This gain is highly significant (ANOVA, p < .001). The error reduction due to the synthetic face added to the audio presentation -as called "audiovisual benefit" by [START_REF] Sumby | Visual Contribution to Speech Intelligibility in Noise[END_REF] -is 28.1 %.

Conclusions

The speech visualization of the presented TTavS system shows a significantly enhanced intelligibility compared to audio alone presentation in an evaluation experiment of isolated word recognition. The gain in intelligibility (20.5 %) is somewhat below that measured with directly reproduced motion capture data in [START_REF] Fagel | Intelligibility of natural and 3D-cloned German speech[END_REF] (24.5 % to 26.2 % depending on the SNR). However, due to the differing evaluation schemes and the limited transferability to intelligibility of natural speech, the system's performance has to be evaluated further.

Acknowledgements

We thank Christophe Savariaux and Ralf Baumbach for their help with recording and data preparation. The work was partly supported by DAAD (D/0502124) and DFG (FA 795/4-1).


Sascha Fagel
email: sascha.fagel@tu-berlin.de

Gérard Bailly
email: gerard.bailly@gipsa-lab.inpg.fr

From 3-D Speaker Cloning to Text-to-Audiovisual-Speech

Keywords: talking head, intelligibility, evaluation, trajectory generation

Visible speech movements were optically motion captured and parameterized by means of a guided PCA. Co-articulated consonantal targets were extracted from VCVs, vocalic targets were extracted from these VCVs and from sustained vowels. Targets were selected or combined to derive target sequences for phone chains of arbitrary German utterances. Parameter trajectories for these utterances are generated by interpolating targets through linear to quadratic functions that reflect he degree of co-articulatory influence. Videos of test word embedded in a carrier sentence were rendered from parameter trajectories for an evaluation in the form of a rhyme test with carrier sentence in noise. Results show that the synthetic videos -although intelligible only somewhat above chance level when played alone -significantly increase the recognition scores from 45.6% in audio alone presentation to 60.4% in audiovisual presentation.

Introduction

Visible speech movements that match audible speech increase the intelligibility [START_REF] Erber | Interaction of Audition and Vision in the Recognition of Oral Speech Stimuli[END_REF]. This advantage can be reproduced by synthetic video [START_REF] Goff | Real-time Analysis-Synthesis and Intelligibility of Talking Faces[END_REF][START_REF] Fagel | Intelligibility of Natural and 3D-cloned German Speech[END_REF] although the perceptual relevance of all properties of the visualization are not yet completely understood. A playback of separately generated audio and video synthesis synchronous at phoneme level often leads to reasonable results [START_REF] Beskow | Talking Heads-Models and Applications for Multimodal Speech Synthesis[END_REF].

There are several approaches to the synthetic visualization of speech movements. Besides data-based systems that use pre-recorded video images [START_REF] Ezzat | Trainable Videorealistic Speech Animation[END_REF] or sequences [START_REF] Bregler | Video Rewrite: Driving Visual Speech with Audio[END_REF] one major method is the manipulation of a 3-D object that represents the geometric properties of a face or a head. The positions of all vertices has to be defined over the time of the synthesized utterance. Not every vertex is controlled separately but a limited number of parameters is used to control the vertex positions. Of whatever kind these controls are -muscle activations [START_REF] Kähler | Geometry-based Muscle Modeling for Facial Animation[END_REF], purely statistic components [START_REF] Matthews | 2D vs. 3D Deformable Face Models: Representational Power, Construction, and Real-Time Fitting[END_REF] or articulatory motivated parameters [START_REF] Maeda | Face Models Based on a Guided PCA of Motioncapture Data: Speaker Dependent Variability in /s/-/S/ Contrast Production[END_REF] -an adequate series of control values has to be generated for the synthesis of a previously unknown utterance. These control values can be generated by rule [START_REF] Cohen | Modeling Coarticulation in Synthetic Visual Speech[END_REF] [START_REF] Fagel | An Articulation Model for Audiovisual Speech Synthesis -Determination, Adjustment, Evaluation[END_REF], by statistical methods such as HMM [START_REF] Govokhina | Learning Optimal Audiovisual Phasing for a HMM-based Control Model for Facial Animation[END_REF] or data-based. The method proposed here is mainly a member of the latter group.

3-D Speaker Cloning

A native speaker of German was filmed from three views with 398 colored beads glued on the face. The speaker uttered 100 symmetric VCVs composed of V = {a,i,u,E,O} and C = {p,b,t,d,k,g,f,v,s,z,S,Z,C,j,x,R,m,n,N,l}. Additionally the vowels {a,e,i,o,u,2,y,E,I,O,U,6,Y,@} and 9 were uttered short-time sustained in isolation. Six main articulatory parameters were extracted by an iterative modeling procedure -a so-called guided PCA [START_REF] Maeda | Face Models Based on a Guided PCA of Motioncapture Data: Speaker Dependent Variability in /s/-/S/ Contrast Production[END_REF]. Marker positions were taken from the center frames of 42 captured sequences: the 15 sustained vowels and 13 consonants each co-articulated in VCVs with V = {a,i,u} context [START_REF] Fagel | Intelligibility of Natural and 3D-cloned German Speech[END_REF]. These 42 visemes are selected to cover the articulatory space of all captured sequences. By iteratively defining regions of articulators to guide the PCA, the following articulatory parameters result: The synthetically reproduced VCV sequences have shown to yield approx. 70% of the intelligibility provided by the natural face. The error reduction (as known as audiovisual benefit [START_REF] Sumby | Visual Contribution to Speech Intelligibility in Noise[END_REF]) was between 32.6% and 41.6%, depending on the signal-to-noise ratio in the audio channel (SNR = -6dB or SNR = 0dB, respectively). Figure 1 shows a screenshot of the synthetic display used in the evaluation (section 4).

Coarticulation modeling and TTavS

The parameter values to control the face are taken in principle from measurements (i.e. from data). As only VCV sequences and sustained vowels in isolation are used, a set of additional procedures are necessary to fill the missing data when generating parameter trajectories for an arbitrary utterance. The generation of parameter sequences is done in two steps: target estimation and transition interpolation.

For the determination of targets (sets of values of the six articulation parameters) the phonetic contexts were differentiated.

1)

If consonantal segments occur in asymmetric vocalic contexts: the parameters of the consonant in the two measured symmetric VCVs are linearly combined. In case of V≠{a,i,u,E,O}, i.e. the VCV of the consonantal segment and one of the context vowels does not exist in the motion capture database then a manually estimated mixture of the existing data is used (e.g. /I/ is estimated by taking a part of 0.8 from the according consonant appearing in /i/ context and 0.2 of the consonant in /E/ context).

2)

If consonants occur in clusters: the influence of a context vowel decreases linearly with the distance in phones, i.e. given the distance of the consonant to the preceding vowel V n is n and to the subsequent vowel V m is m (where n = m = 1 means direct neighbors), then parameter values of the consonant in V n CV n are taken by m/(n+m) and from V n CV n by n/(n+m). The transitions are linear to quadratic interpolations of the targets of each parameter. Like in the target estimation, consonantal targets are interpolated by regarding the nearest preceding and subsequent vowel. The exponent of the interpolation (1.0 to 2.0) is determined by the degree of coarticulation that occurred in the target estimation of consonants. Linear interpolation is used if the target completely adopts to the neighbors, i.e. if the parameter values of the consonant in the V n CV n an in the V m CV m equals that one of the respective context vowel. The linear interpolation leads to transient targets (a "pass through") and hence no quasi-stationary phase of the articulator in the consonantal segment. Quadratic interpolation is used if the target is not co-articulated at all, i.e. the parameter value of the consonant in one contexts equals that one of the parameter value of the consonant in the other context. Quadratic interpolation leads to a quasi-stationary phase of the articulator in the consonantal segment. The exponent of the interpolation is calculated to range from 1.0 to 2.0 between these extreme cases. Figure 2 shows the original and a synthesized parameter trajectories for the sequence /aba/.

Evaluation

A rhyme test with carrier sentence was carried out as evaluation of the system in terms of intelligibility. Txt2Pho from HADIFIX [START_REF] Portele | Das Sprachsynthesesystem Hadifx[END_REF] was used to generate phone sequences and durations (and f0 contour) from the sentences. The mbrola speech synthesizer [START_REF]The MBROLA Project[END_REF] with the German voice de2 was used for the audio synthesis. White noise at 0dB SNR was added. The test words were taken from Sendlmeier [START_REF] Sendlmeier | Ein Verfahren zur Messung von Fehlleistungen beim Sprachverstehen -Überlegungen und erste Ergebnisse[END_REF]:

The test contains three lists of 40 monosyllabic words each, and one set of five answer alternatives. The words test word initial and word final consonants and medial vowels. The test is phonetically balanced. 12 subjects with normal hearing and normal or corrected to normal vision participated voluntarily in the test. All word lists were used in the test but distributed over the subjects. One of the three word lists was presented to a subject audiovisually, another one was presented audio alone and a the third one visual alone. The test word was masked in the audio channel by white noise at 0dB SNR with 200ms fade in and out before and after the word (during the carrier sentence). In the visual alone condition the carrier sentence was audible and only the test word was cut out of the audio channel. It was assured that the masking and the cutting covered as well the transition to the first phone of the test word and from the last phone of the test word. A black screen was displayed in the audio alone condition. The conditions were blocked, the order of the conditions audiovisual, audio alone and visual alone was varied across subjects (each of the six possible orders was used twice).

After each presented word in carrier sentence the subject was requested to select the most probable word from the five alternatives.

Results

The recognition rate was 26.9% for the face only, which is only somewhat above the chance level of 20%. 10 of the 12 subjects showed an enhanced recognition with the face displayed along with the audio. The overall recognition rate increased from 45.6% in audio alone condition to 60.4% in audiovisual condition. This difference was highly significant (ANOVA: p < .01). Hence, the face causes a reduction of recognition errors (audiovisual benefit, [START_REF] Fagel | Intelligibility of Natural and 3D-cloned German Speech[END_REF]) of 27.2%. When the recognition rates are reduced by chance level, i.e. the percentage above 20% relative to the absolute possible 80% above chance, visual alone recognition is 8.6%, audio alone recognition is 32.0% and audiovisual recognition is 50.5%.

Conclusions and Discussion

The speech visualization of the presented TTavS system shows a significantly enhanced intelligibility in audiovisual condition compared to audio alone presentation in an evaluation experiment of word recognition. The gain in intelligibility measured by error reduction (27.2%) is somewhat below that previously measured with directly reproduced motion capture data [START_REF] Fagel | Intelligibility of Natural and 3D-cloned German Speech[END_REF] (32.6% to 41.6% depending on the SNR). Although the test methods dieffer and hence the results are not directly comparable, it is assumed that the articulation modeling and visualization as described in [START_REF] Fagel | Intelligibility of Natural and 3D-cloned German Speech[END_REF] and the trajectory modeling presented here both decrease the visual intelligibility while preserving part of the benefit of the visible speech movements.

The recognition scores reduced by chance level show a super-additive effect. The recognition scores of audio alone plus video alone presentations are below that one of audiovisual presentation. This is assumed to result from the very low information available in one of the channels, here in the visual alone display, where cross-modal redundancy is nearly not existent and cross-modal synergy effects still occur. Other descriptions of this kind of super-additivity also use nearly unintelligible presentations in one channel that nevertheless leads to enhancement in bimodal presentation: Our results are in line with outcomes of the work of Saldaña and Pisoni [START_REF] Schwartz | Audio-Visual Scene Analysis: Evidence for a "Very-Early" Integration Process in Audio-Visual Speech Perception[END_REF] who use natural video together with hardly intelligible sinewave speech, and Schwartz et al. [19] who use videos of voiced and unvoiced segments that are undistinguishable from each other when played alone but result in a gain of intelligibility when played with audio.

The behavior of the articulatory parameters at utterance boundaries were not extracted from the motion capture database. When using test words embedded in a carrier sentence this drawback does not appear in the evaluation. An appropriate modeling of parameter trajectories at utterance boundaries is an open issue of the presented work.

The next step towards a data-based trajectory generation system following the one that is presented here will be to take a larger database, to use transitions found the database instead of using only targets where possible, and to adapt selection and concatenation methods from diphone synthesis and unit selection. Objective measures such as RMSE of marker positions will be applied besides perceptual evaluation.

Figure 1 :

 1 Figure 1: Synthetic display generated from a mesh of the 398 marker positions and 30 points of an additional lip model, rendered with a static cylindric texture.

3 )

 3 If only one context vowel exists due to an utterance boundary then a symmetric context is assumed and case 1) or 2) applies with V n = V m . 4) Targets for a vowel segment are taken a. from the VCVs if the vowel is between two identical consonants, b. from the vowel measured in isolation in case of pure vocalic context, or c. a balanced average of both if left context ≠ right context.

Figure 2 :

 2 Figure 2: Original (top) and synthesized (bottom) parameter trajectories for the /b/ in the sequence /aba/. Note that the phone timing and accordingly the duration in frames differ as they are naturally produced in the original and generated by the TTS system (which tends to speak faster) in the synthesized version.

Acknowledgements

We thank Frédéric Elisei, Christophe Savariaux and Ralf Baumbach for their help with recording and data preparation. The work was partly supported by DAAD (D/0502124) and DFG (FA 795/4-1).