Assessment and management of heart failure in patients with chronic kidney disease.

Heart failure (HF) and chronic kidney disease (CKD) are two pathological conditions with a high prevalence in the general population. When they coexist in the same patient, a strict interplay between them is observed, such that patients affected require a clinical multidisciplinary and personalized management. The diagnosis of HF and CKD relies on signs and symptoms of the patient but several additional tools, such as blood-based biomarkers and imaging techniques, are needed to clarify and discriminate the main characteristics of these diseases. Improved survival due to new recommended drugs in HF has increasingly challenged physicians to manage patients with multiple diseases, especially in case of CKD. However, the safe administration of these drugs in patients with HF and CKD is often challenging. Knowing up to which values ​​of creatinine or renal clearance each drug can be administered is fundamental. With this review we sought to give an insight on this sizable and complex topic, in order to get clearer ideas and a more precise reference about the diagnostic assessment and therapeutic management of HF and CKD.

Paradigm shift in heart failure treatment: are cardiologists ready to use gliflozins?

Despite recent advances in chronic heart failure (HF) therapy, the prognosis of HF patients remains poor, with high rates of HF rehospitalizations and death in the early months after discharge. This emphasizes the need for incorporating novel HF drugs, beyond the current approach (that of modulating the neurohumoral response). Recently, new antidiabetic oral medications (sodium-glucose cotransporter 2 inhibitors (SGLT2i)) have been shown to improve prognosis in diabetic patients with previous cardiovascular (CV) events or high CV risk profile. Data from DAPA-HF study showed that dapaglifozin is associated with a significant reduction in mortality and HF hospitalization as compared with placebo regardless of diabetes status. Recently, results from EMPEROR-Reduced HF trial were consistent with DAPA-HF trial findings, showing significant beneficial effect associated with empagliflozin use in a high-risk HF population with markedly reduced ejection fraction. Results from the HF with preserved ejection fraction trials using these same agents are eagerly awaited. This review summarizes the evidence for the use of gliflozins in HF treatment.

Vitamin D and cardiovascular disease risk. A literature overview.

BACKGROUND: Atherosclerosis and cerebro and cardiovascular disease associated represent the major cause of morbidity and mortality worldwide. Recently, vitamin D deficiency has been considered a new potential risk factor of these conditions. METHODS AND RESULTS: In this reviw we briefly describe the biological role of vitamin D, analyze the pathophysiological associations between cardiovascular disease and vitamin D, summarize and synthesize the evidence from literature about the association between vitamin D and cardiovascular disease. RESULTS: Vit D is an essential vitamin for bone metabolism and homeostasis. The maintenance of optimal blood levels contributes to the correct homeostasis by influencing different metabolic processes, including those underlying cardiovascular diseases. However, the evidence does not support vitamin D routine administration for the prevention and treatment of cardiovascular disease and intake to achieve specific cardiovascular effects. Evidence shows that maintaining optimal levels of vitamin D, ensures cardiovascular protection.

QTc Interval Prolongation and Life-Threatening Arrhythmias During Hospitalization in Patients With Coronavirus Disease 2019 (COVID-19): Results From a Multicenter Prospective Registry.

BACKGROUND: Prolonged QTc intervals and life-threatening arrhythmias (LTA) are potential drug-induced complications previously reported with antimalarials, antivirals, and antibiotics. Our objective was to evaluate the prevalence and predictors of QTc interval prolongation and incidences of LTA during hospitalization for coronavirus disease 2019 (COVID-19) among patients with normal admission QTc. METHODS: We enrolled 110 consecutive patients in a multicenter international registry. A 12-lead electrocardiograph was performed at admission, after 7, and at 14 days; QTc values were analyzed. RESULTS: After 7 days, 15 (14%) patients developed a prolonged QTc (pQTc; mean QTc increase 66 ± 20 msec; +16%; P < .001); these patients were older and had higher basal heart rates, higher rates of paroxysmal atrial fibrillation, and lower platelet counts. The QTc increase was inversely proportional to the baseline QTc level and leukocyte count and directly proportional to the basal heart rate (P < .01).We conducted a multivariate stepwise analysis including age, male gender, paroxysmal atrial fibrillation, basal QTc values, basal heart rate, and dual antiviral therapy; age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; P < .05), basal heart rate (OR, 1.07; 95% CI, 1.02-1.13; P < .01), and dual antiviral therapy (OR, 12.46; 95% CI, 2.09-74.20; P < .1) were independent predictors of QT prolongation.The incidence rate of LTA during hospitalization was 3.6%. There was 1 patient who experienced cardiac arrest and 3 with nonsustained ventricular tachycardia. LTAs were recorded after a median of 9 days from hospitalization and were associated with 50% of the mortality rate. CONCLUSIONS: After 7 days of hospitalization, 14% of patients with COVID-19 developed pQTc; age, basal heart rate, and dual antiviral therapy were found to be independent predictors of pQTc. Life-threatening arrhythmias have an incidence rate of 3.6%, and were associated with a poor outcome.

Right Ventricular Longitudinal Strain Measures Independently Predict Chronic Heart Failure Mortality.

The assessment of right ventricular (RV) function still remains a challenge. Two-dimensional (2D) speckle tracking has recently been proposed to evaluate right ventricular function by analyzing myocardial deformation. The aim of this study was to evaluate the role of 2D systolic strain measures of RV in predicting mortality in patients with chronic heart failure (HF). We enrolled 332 outpatients in a stable clinical condition and in conventional therapy. A right ventricular-focused four-chamber view was analyzed by 2D speckle tracking to evaluate the global longitudinal strain of RV (RV-GLS) and the strain of RV free wall (RV-fwLS). During a mean follow-up of 36 ± 26 months, 64 patients died. Both RV-GLS and RV-fwLS were associated with all-cause mortality in univariate (HR: 1.16; 95% CI: 1.10-1.23; P < 0.001; C-index: 0.72; and HR: 1.10; 95% CI: 1.06-1.15; P < 0.001; C-index: 0.68, respectively) as well as multivariate analysis (HR: 1.13; 95% CI: 1.05-1.21; P:0.001; C-index: 0.85; and HR: 1.07; 95% CI: 1.02-1.12; P:0.004; C-index: 0.84, respectively). In conclusion, our findings demonstrate the role of RV 2D strain measures to independently predict mortality. These data highlight the clinical usefulness of this echocardiographic approach in the daily management of HF outpatients.

Functional Gain After Inpatient Stroke Rehabilitation: Correlates and Impact on Long-Term Survival.

BACKGROUND AND PURPOSE: Prediction of functional outcome after stroke rehabilitation (SR) is a growing field of interest. The association between SR and survival still remains elusive. We sought to investigate the factors associated with functional outcome after SR and whether the magnitude of functional improvement achieved with rehabilitation is associated with long-term mortality risk. METHODS: The study population consisted of 722 patients admitted for SR within 90 days of stroke onset, with an admission functional independence measure (FIM) score of <80 points. We used univariable and multivariable linear regression analyses to assess the association between baseline variables and FIM gain and univariable and multivariable Cox analyses to assess the association of FIM gain with long-term mortality. RESULTS: Age (P<0.001), marital status (P=0.003), time from stroke onset to rehabilitation admission (P<0.001), National Institutes of Health Stroke Scale score at rehabilitation admission (P<0.001), and aphasia (P=0.021) were independently associated with FIM gain. The R2 of the model was 0.275. During a median follow-up of 6.17 years, 36.9% of the patients died. At multivariable Cox analysis, age (P<0.0001), coronary heart disease (P=0.018), atrial fibrillation (P=0.042), total cholesterol (P=0.015), and total FIM gain (P<0.0001) were independently associated with mortality. The adjusted hazard ratio for death significantly decreased across tertiles of increasing FIM gain. CONCLUSIONS: Several factors are independently associated with functional gain after SR. Our findings strongly suggest that the magnitude of functional improvement is a powerful predictor of long-term mortality in patients admitted for SR.

The Postoperative Paradoxical Septum (POPS): A Comprehensive Review on Physio-Pathological Mechanisms.

The interventricular septum (IVS) is a core myocardial structure involved in biventricular coupling and performance. Physiologically, during systole, it moves symmetrically toward the center of the left ventricle (LV) and opposite during diastole. Several pathological conditions produce a reversal or paradoxical septal motion, such as after uncomplicated cardiac surgery (CS). The postoperative paradoxical septum (POPS) was observed in a high rate of cases, representing a unicum in the panorama of paradoxical septa as it does not induce significant ventricular morpho-functional alterations nor negative clinical impact. Although it was previously considered a postoperative event, evidence suggests that it might also appear during surgery and gradually resolve over time. The mechanism behind this phenomenon is still debated. In this article, we will provide a comprehensive review of the various theories generated over the past fifty years to explain its pathological basis. Finally, we will attempt to give a heuristic interpretation of the biventricular postoperative motion pattern based on the switch of the ventricular anchor points.

[Multidistrict atherosclerotic disease: epidemiological and clinical framework]. / Malattia aterosclerotica polidistrettuale: inquadramento epidemiologico e clinico.

Atherosclerosis is a systemic disease that can involve different arterial districts. Traditionally, the focus of cardiologists has been on the diagnosis and treatment of atherosclerotic coronary artery disease (CAD). However, atherosclerosis localization in other districts is increasingly common and is associated with an increased risk of CAD and, more generally, of adverse cardiovascular events. Although the term peripheral arterial disease (PAD) commonly refers to the localization of atherosclerotic disease in the arterial districts of the lower limbs, in this document, in accordance with the European Society of Cardiology guidelines, the term PAD will be used for all the locations of atherosclerotic disease excluding coronary and aortic ones. The aim of this review is to report updated data on PAD epidemiology, with particular attention to the prevalence and its prognostic impact on patients with CAD. Furthermore, the key points for an appropriate diagnostic framework and a correct pharmacological therapeutic approach are summarized, while surgical/interventional treatment goes beyond the scope of this review.

Independent role of left ventricular global longitudinal strain in predicting prognosis of chronic heart failure patients.

AIMS: To evaluate the independent prognostic role of two-dimensional (2D) strain measures reflecting global longitudinal left ventricular (LV) systolic function in outpatients affected by chronic heart failure (CHF). METHODS AND RESULTS: Global longitudinal LV systolic strain (GLS) was assessed in 308 outpatients affected by CHF, by analyzing standard views with 2D speckle tracking technique. During a mean follow-up of 26 ± 13 months 37 patients died (29 due to cardiovascular causes), 10 patients underwent heart transplantation, and 75 patients experienced at least 1 episode of hospitalization due to acute decompensated heart failure (ADHF). Thirty-one patients without a history of major ventricular arrhythmic events experienced the occurrence of ventricular fibrillation and/or tachycardia or sudden death was observed. Multivariate Cox regression analysis showed that GLS was significantly associated with all-cause mortality (HR: 1.15; 95%CI: 1.02-1.30; P: 0.026), cardiovascular death (HR: 1.20; 95%CI: 1.04-1.39; P: 0.011), cardiovascular death or heart transplantation (HR: 1.24; 95%CI: 1.09-1.41; P: 0.001), ADHF-related hospitalizations (HR: 1.15; 95%CI: 1.05-1.25; P: 0.003), and arrhythmic events (HR: 1.17; 95%CI: 1.03-1.33; P: 0.018). CONCLUSIONS: Quantifying LV longitudinal systolic function in CHF outpatients on the basis of 2D speckle tracking analysis provides a new parameter that independently predicts patient outcome, thus, strengthening its possible role in current clinical practice.

Electrocardiographic Pathological Findings Caused by the SARS-CoV-2 Virus Infection: Evidence from a Retrospective Multicenter International Cohort Longitudinal Pilot Study of 548 Subjects.

COVID-19 has threatened the capability of receiving and allocating patients in emergency departments (EDs) all over the world. This is a retrospective cohort study to explore the role of a simple procedure like an ECG to screen for the severity of COVID-19 on admission to the ED. For this study, 548 consecutive patients were enrolled in a multicenter international registry and stratified upon ECG on admission with a simple distinction between normal vs. abnormal rhythm. Among patients in the abnormal ECG group were those with heart rates higher than 100 beats per minute and/or atrial fibrillation. Survival in patients with normal ECG rhythm was deemed below 75% after 58 days and then stabilized, while survival in patients with abnormal ECG rhythm was deemed below 75% after 11 days and below 50% after 21 days. A multivariate analysis including abnormal rhythm, gender, age, diabetes, obesity, respiratory failure during hospitalization, heart failure during hospitalization, and abnormal rhythm was an independent predictor of death (HR 7.20 95% CI 3.63-14.28, p < 0.01). This finding, if confirmed in large prospective studies, is promising for identifying a cheap and simple procedure for patients in need of a closer look.

Improvement of Left Ventricular Global Longitudinal Strain after 6-Month Therapy with GLP-1RAs Semaglutide and Dulaglutide in Type 2 Diabetes Mellitus: A Pilot Study.

(1) Background: Glucagone-Like Peptide-1 Receptor Agonists (GLP-1 RAs) (GLP-1 RAs) are incretine-based medications recommended in the treatment of type 2 Diabetes Mellitus (DM2) with atherosclerotic cardiovascular disease (ASCVD) or high or very high cardiovascular (CV) risk. However, knowledge of the direct mechanism of GLP-1 RAs on cardiac function is modest and not yet fully elucidated. Left ventricular (LV) Global Longitudinal Strain (GLS) with Speckle Tracking Echocardiography (STE) represents an innovative technique for the evaluation of myocardial contractility. (2) Methods: an observational, perspective, monocentric study was conducted in a cohort of 22 consecutive patients with DM2 and ASCVD or high/very high CV risk, enrolled between December 2019 and March 2020 and treated with GLP-1 RAs dulaglutide or semaglutide. The echocardiographic parameters of diastolic and systolic function were recorded at baseline and after six months of treatment. (3) Results: the mean age of the sample was 65 ± 10 years with a prevalence of the male sex (64%). A significant improvement in the LV GLS (mean difference: -1.4 ± 1.1%; p value < 0.001) was observed after six months of treatment with GLP-1 RAs dulaglutide or semaglutide. No relevant changes were seen in the other echocardiographic parameters. (4) Conclusions: six months of treatment with GLP-1 RAs dulaglutide or semaglutide leads to an improvement in the LV GLS in subjects with DM2 with and high/very high risk for ASCVD or with ASCVD. Further studies on larger populations and with a longer follow-up are warranted to confirm these preliminary results.

Rationale and design of the Biventricular Evaluation of Gliflozins effects In chroNic Heart Failure: BEGIN-HF study.

AIMS: Sodium-glucose cotransporter type 2 inhibitors (SGLT-2i) represent a unique class of anti-hyperglycaemic agents for type 2 diabetes mellitus that selectively inhibit renal glucose reabsorption, thereby increasing urinary excretion of glucose. Several studies have demonstrated the cardioprotective effects of SGLT-2i in patients with heart failure (HF), unrelated to its glucosuric effect. It is unclear whether the benefits of SGLT-2i therapy also rely on the improvement of left ventricular (LV) and/or right ventricular (RV) function in patients with HF. This study aimed to evaluate the effect of SGLT-2i on LV and RV function through conventional and advanced echocardiographic parameters with a special focus on RV function in patients with HF. METHODS AND RESULTS: The Biventricular Evaluation of Gliflozins effects In chroNic Heart Failure (BEGIN-HF) study is an international multicentre, prospective study that will evaluate the effect of SGLT-2i on echocardiographic parameters of myocardial function in patients with chronic stable HF across the left ventricular ejection fraction (LVEF) spectrum. Patients with New York Heart Association Class II/III symptoms, estimated glomerular filtration rate > 25 mL/min/1.73 m2 , age > 18 years, and those who were not previously treated with SGLT-2i will be included. All patients will undergo conventional, tissue-derived imaging (TDI), and strain echocardiography in an ambulatory setting, at time of enrolment and after 6 months of SGLT-2i therapy. The primary endpoint is the change in LV function as assessed by conventional, TDI, and myocardial deformation speckle tracking parameters. Secondary outcomes include changes in RV and left atrial function as assessed by conventional and deformation speckle tracking echocardiography. Univariate and multivariate analyses will be performed to identify predictors associated with primary and secondary endpoints. CONCLUSIONS: The BEGIN-HF will determine whether SGLT-2i therapy improves LV and/or RV function by conventional and advanced echocardiography in patients with HF irrespective of LVEF.

Advances in Multimodality Cardiovascular Imaging in the Diagnosis of Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome defined by the presence of heart failure symptoms and increased levels of circulating natriuretic peptide (NP) in patients with preserved left ventricular ejection fraction and various degrees of diastolic dysfunction (DD). HFpEF is a complex condition that encompasses a wide range of different etiologies. Cardiovascular imaging plays a pivotal role in diagnosing HFpEF, in identifying specific underlying etiologies, in prognostic stratification, and in therapeutic individualization. Echocardiography is the first line imaging modality with its wide availability; it has high spatial and temporal resolution and can reliably assess systolic and diastolic function. Cardiovascular magnetic resonance (CMR) is the gold standard for cardiac morphology and function assessment, and has superior contrast resolution to look in depth into tissue changes and help to identify specific HFpEF etiologies. Differently, the most important role of nuclear imaging [i.e., planar scintigraphy and/or single photon emission CT (SPECT)] consists in the screening and diagnosis of cardiac transthyretin amyloidosis (ATTR) in patients with HFpEF. Cardiac CT can accurately evaluate coronary artery disease both from an anatomical and functional point of view, but tissue characterization methods have also been developed. The aim of this review is to critically summarize the current uses and future perspectives of echocardiography, nuclear imaging, CT, and CMR in patients with HFpEF.

Altered two-dimensional strain measures of the right ventricle in patients with Brugada syndrome and arrhythmogenic right ventricular dysplasia/cardiomyopathy.

AIMS: Brugada syndrome (BrS) is an inherited channelopathy that can be characterized by mild right ventricular (RV) abnormalities that are not detectable with conventional echocardiography. The aim of this study was to evaluate the presence of RV abnormalities in BrS patients when compared with controls and a group of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using two-dimensional (2D) strain analysis. METHODS AND RESULTS: We enrolled 25 BrS, 15 ARVD/C patients, and 25 controls. Right and left ventricular dimension and systo-diastolic function were evaluated by conventional echocardiography. Longitudinal systolic strain (sS) peak, systolic and early diastolic strain rate of lateral RV segments were evaluated by 2D speckle tracking analysis. Left ventricle global and segmental strain measures were also evaluated. A reduced basal or mid-RV lateral sS were the parameters mostly associated with both BrS and ARVD/C. In BrS patients the minimum sS observed in these segments was significantly lower than that of controls (-28.9±3.2% vs. -32.3±3.2%, P: 0.002) but significantly greater than that evaluated in ARVD/C patients (-24.6±6.7%, P<0.001 both vs. BrS and controls). No differences were found between the BrS and the control group when left ventricular strain measures were analysed. CONCLUSION: By 2D strain technique it is possible to observe mild abnormalities in RV systolic and diastolic function of BrS patients that are less pronounced than those observed in ARVD/C patients. These results help to better define the phenotypic characteristics of BrS patients and represent the basis for future studies aimed at testing their clinical usefulness in BrS patients.

Local peribulbar anesthesia before glaucoma filtering surgery in a patient with Brugada syndrome.

We report anesthetic management in a patient with Brugada syndrome, an inherited syndrome characterized by normal QT interval, typical ST-segment-elevation in the right precordial leads, and increased risk of sudden cardiac death in the absence of myocardial ischemia or structural heart disease. A 69-year-old man scheduled for glaucoma filtering surgery underwent local peribulbar anesthesia using 5 mL of lidocaine 20 mg/mL solution that was slowly injected into two different sites approximately 10 min prior to the surgical procedure. The surgery proceeded uneventful and data of patient's blood pressure, heart rate, oxygen saturation were collected. Continuous electrocardiography monitoring before, during, and up to 6 h after surgery did not reveal any arrhythmia or tachycardia. A certain number of drugs should be avoided in patients with Brugada syndrome because of their potential risk to trigger an arrhythmia. Among them there are some anesthetics and in particular those that are sodium channel blockers. Ropivacaine and bupivacaine, commonly used for peribulbar block, have been associated with onset of severe arrhythmias. Contrarily, the use of class IB drugs mexiletine and lidocaine is generally considered safe. Local anesthetic agent should be carefully chosen, and anesthesia should be obtained using the minimal necessary drug dose.

Mid-Diastolic Events (L Events): A Critical Review.

Mid-diastolic events (L events) include three phenomena appreciable on echocardiography occurring during diastasis: mid-diastolic transmitral flow velocity (L wave), mid-diastolic mitral valve motion (L motion), and mid-diastolic mitral annular velocity (L' wave). L wave is a known marker of advanced diastolic dysfunction in different pathological clinical settings such as left ventricle and atrial remodeling, overloaded states, and cardiomyopathies. Patients with L events have poor outcomes with a higher risk of developing heart failure symptoms and arrhythmic complications, including sudden cardiac death. The exact mechanism underlying the genesis of mid-diastolic events is not fully understood, just as the significance of these events in healthy young people or their presence at the tricuspid valve level. We also report an explicative case of a patient with L events studied using speckle tracking imaging of the left atrium and ventricle at the same reference heartbeat supporting the hypothesis of a post-early diastolic relaxation or a "two-step" ventricular relaxation for L wave genesis. Our paper seeks to extend knowledge about the pathophysiological mechanisms on mid-diastolic events and summarizes the current knowledge.

Right Ventricular Function in Chronic Heart Failure: From the Diagnosis to the Therapeutic Approach.

There is growing attention for the study of the right ventricle in cardiovascular disease and in particular in heart failure. In this clinical setting, right ventricle dysfunction is a significant marker of poor prognosis, regardless of the degree of left ventricular dysfunction. Novel echocardiographic methods allow for obtaining a more complete evaluation of the right ventricle anatomy and function as well as of the related abnormalities in filling pressures. Specific and effective therapies for the right ventricle dysfunction are still not well defined and this represents the most difficult and important challenge. This article focuses on available diagnostic techniques for studying right ventricle dysfunction as well as on the therapies for right ventricle dysfunction.

Renal Venous Pattern: A New Parameter for Predicting Prognosis in Heart Failure Outpatients.

AIM OF THE STUDY: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. METHODS: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. RESULTS: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04; 95% CI: 2.14⁻7.65; p < 0.001), pattern D (HR 7.16; 95% CI: 3.69⁻13.9; p < 0.001) and pattern E (HR 8.94; 95% CI: 4.65⁻17.2; p < 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79; 95% CI: 1.09⁻2.97; p: 0) and of pattern D or E (HR: 1.90; 95% CI: 1.16⁻3.12; p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46; 95% CI 0.24⁻0.68; p < 0.001). CONCLUSIONS: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome.

A new educational program in heart failure drug development: the Brescia international master program.

: Despite recent advances in chronic heart failure treatment, prognosis of acute heart failure patients remains poor with a heart failure rehospitalization rate or death reaching approximately 25% during the first 6 months after discharge. In addition, about half of these patients have preserved ejection fraction for which there are no evidence-based therapies. Disappointing results from heart failure clinical trials over the past 20 years emphasize the need for developing novel approaches and pathways for testing new heart failure drugs and devices. Indeed, many trials are being conducted without matching the mechanism and action of the drug with the clinical event. The implementation of these novel approaches should be coupled with the training of a new generation of heart failure physicians and scientists in the art and science of clinical trials. Currently, drug development is led by opinion leaders and experts who, despite their huge personal experience, were never trained systematically on drug development. The aim of this article is to propose a training program of 'drug development in Heart Failure'. A physician attending this course would have to be trained with a major emphasis on heart failure pathophysiology to better match mechanisms of death and rehospitalization with mechanism of action of the drug. Applicants will have to prove their qualifications and special interest in heart failure drug development before enrollment. This article should serve as a roadmap on how to apply emerging general principles in an innovative drug-development-in-heart-failure-process as well as the introduction of a new educational and mentorship program focusing on younger generations of researchers.