Precision Cardiology: Phenotype-targeted Therapies for HFmrEF and HFpEF.

Heart failure with mid-range ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) represent over half of heart failure cases but lack proven effective therapies beyond sodium-glucose cotransporter 2 inhibitor and diuretics. HFmrEF and HFpEF are heterogeneous conditions requiring precision phenotyping to enable tailored therapies. This review covers concepts on precision medicine approaches for HFmrEF and HFpEF. Areas discussed include HFmrEF mechanisms, anti-inflammatory and antifibrotic treatments for obesity-related HFpEF, If inhibition for HFpEF with atrial fibrillation, and mineralocorticoid receptor antagonism for chronic kidney disease-HFpEF. Incorporating precision phenotyping and matched interventions in HFmrEF and HFpEF trials will further advance therapy compared to blanket approaches.

Frailty according to the 2019 HFA-ESC definition in patients at risk for advanced heart failure: Insights from the HELP-HF registry.

AIMS: Frailty is highly prevalent in patients with heart failure (HF), but a concordant definition of this condition is lacking. The Heart Failure Association of the European Society of Cardiology (HFA-ESC) proposed in 2019 a new multi-domain definition of frailty, but it has never been validated. METHODS AND RESULTS: Patients from the HELP-HF registry were stratified according to the number of HFA-ESC frailty domains fulfilled and to the cumulative deficits frailty index (FI) quintiles. Prevalence of frailty and of each domain was reported, as well as the rate of the composite of all-cause death and HF hospitalization, its single components, and cardiovascular death in each group and quintile. Among 854 included patients, 37 (4.3%), 206 (24.1%), 365 (42.8%), 217 (25.4%), and 29 (3.4%) patients fulfilled zero, one, two, three, or four domains, respectively, while 179 patients had a FI < 0.21 and were considered not frail. The 1-year risk of adverse events increased proportionally to the number of domains fulfilled (for each criterion increase, all-cause death or HF hospitalization: hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.27-1.62; all-cause death: HR 1.72, 95% CI 1.46-2.02, HF hospitalizations: subHR 1.21, 95% CI 1.04-1.31; cardiovascular death: HR 1.77, 95% CI 1.45-2.15). Consistent results were found stratifying the cohort for FI quintiles. The FI as a continuous variable demonstrated higher discriminative ability than the number of domains fulfilled (area under the curve = 0.68 vs. 0.64, p = 0.004). CONCLUSION: Frailty in patients at risk for advanced HF, assessed via a multi-domain approach and the FI, is highly prevalent and identifies those at increased risk of adverse events. The FI was found to be slightly more effective in identifying patients at increased risk of mortality.

How to tackle therapeutic inertia in heart failure with reduced ejection fraction. A scientific statement of the Heart Failure Association of the ESC.

Guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF) reduces morbidity and mortality, but its implementation is often poor in daily clinical practice. Barriers to implementation include clinical and organizational factors that might contribute to clinical inertia, i.e. avoidance/delay of recommended treatment initiation/optimization. The spectrum of strategies that might be applied to foster GDMT implementation is wide, and involves the organizational set-up of heart failure care pathways, tailored drug initiation/optimization strategies increasing the chance of successful implementation, digital tools/telehealth interventions, educational activities and strategies targeting patient/physician awareness, and use of quality registries. This scientific statement by the Heart Failure Association of the ESC provides an overview of the current state of GDMT implementation in HFrEF, clinical and organizational barriers to implementation, and aims at suggesting a comprehensive framework on how to overcome clinical inertia and ultimately improve implementation of GDMT in HFrEF based on up-to-date evidence.

Differences in presentation, diagnosis and management of heart failure in women. A scientific statement of the Heart Failure Association of the ESC.

Despite the progress in the care of individuals with heart failure (HF), important sex disparities in knowledge and management remain, covering all the aspects of the syndrome, from aetiology and pathophysiology to treatment. Important distinctions in phenotypic presentation are widely known, but the mechanisms behind these differences are only partially defined. The impact of sex-specific conditions in the predisposition to HF has gained progressive interest in the HF community. Under-recruitment of women in large randomized clinical trials has continued in the more recent studies despite epidemiological data no longer reporting any substantial difference in the lifetime risk and prognosis between sexes. Target dose of medications and criteria for device eligibility are derived from studies with a large predominance of men, whereas specific information in women is lacking. The present scientific statement encompasses the whole scenario of available evidence on sex-disparities in HF and aims to define the most challenging and urgent residual gaps in the evidence for the scientific and clinical HF communities.

Multidisciplinary care of peripartum heart failure: A scientific statement of the Heart Failure Association of the ESC.

Heart failure is the most common cardiovascular complication during pregnancy and the postpartum period. It is associated with increased risk of maternal morbidity and mortality as well as potentially life-threatening foetal pathology. Management of heart failure in pregnancy requires expert knowledge of cardiovascular disease as well as obstetrics which underscores the importance of multidisciplinary cardio-obstetrics teams in order to optimize diagnosis, treatment and outcome. This includes counselling of women at risk before and during the course of pregnancy in order to strengthen the relationship between medical specialists and patients, as well as to allow patient-centred delivery of care and improve quality of life.

The role of multimorbidity in patients with heart failure across the left ventricular ejection fraction spectrum: Data from the Swedish Heart Failure Registry.

AIMS: The aim of this analysis was to provide data on the overall comorbidity burden, both cardiovascular (CV) and non-CV, in a large real-world heart failure (HF) population across the ejection fraction (EF). METHODS AND RESULTS: Patients with HF from the Swedish HF Registry between 2000 and 2021 were included. Of 91 463 patients (median age 76 years [interquartile range 67-82]), 98% had at least one among the 17 explored comorbidities (94% at least one CV and 85% at least one non-CV comorbidity). All comorbidities, except for coronary artery disease (CAD), were more frequent in HF with preserved EF (HFpEF). Patients with multiple comorbidities were older, more likely female, inpatients, with HFpEF, worse New York Heart Association class and higher N-terminal pro-B-type natriuretic peptide levels. In a multivariable Cox model, 12 comorbidities were independently associated with a higher risk of death from any cause. The highest risk was associated with dementia (hazard ratio [HR] 1.55, 95% confidence interval [CI] 1.45-1.65), chronic kidney disease (HR 1.37, 95% CI 1.34-1.41), chronic obstructive pulmonary disease (HR 1.32, 95% CI 1.28-1.35). Obesity was associated with a lower risk of all-cause death (HR 0.81, 95% CI 0.79-0.84). CAD and valvular heart disease were associated with a higher risk of all-cause and CV mortality, but not non-CV mortality, whereas cancer and musculo-skeletal disease increased the risk of non-CV mortality. A significant interaction with EF was observed for several comorbidities. Occurrence of CV and non-CV outcomes was related to the number of CV and non-CV comorbidities, respectively. CONCLUSION: The burden of both CV and non-CV comorbidities was high in HF regardless of EF, but overall higher in HFpEF. Multimorbidity was associated with a high risk of death with a different burden on CV or non-CV outcomes.

Intravenous ferric carboxymaltose for iron repletion following acute heart failure in patients with and without diabetes: a subgroup analysis of the randomized AFFIRM-AHF trial.

BACKGROUND: In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. METHODS: Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. RESULTS: Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM: 327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100 patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58-1.81) and 51.3 vs 66.9 in patients without diabetes (RR: 0.77, 95% CI 0.55-1.07), with no significant interaction between diabetes status and treatment effect (pinteraction = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. CONCLUSIONS: The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016).

Pre-discharge and early post-discharge management of patients hospitalized for acute heart failure: A scientific statement by the Heart Failure Association of the ESC.

Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post-discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre-discharge and titration to target doses in the early post-discharge period, of guideline-directed medical therapy may improve both short- and long-term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre-discharge and the early post-discharge phase after a hospitalization for acute heart failure.

Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology.

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline-recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice.

Roadmap for the management of heart failure patients during the vulnerable phase after heart failure hospitalizations: how to implement excellence in clinical practice.

Patients discharged after an episode of acute heart failure have an increased risk of hospitalizations and deaths within the subsequent 3 months. This phase is commonly called the 'vulnerable period' and it represents a window of opportunity of intervention in order to improve longer term outcomes. Prompt identification of signs of residual haemodynamic congestion is a priority in planning for the out-of-hospital management strategies. Patients will also need to be screened for frailty and have a prioritization of the management of their comorbidities. Life-saving medications should be started together or in a short time and up-titrated (when needed) according to blood pressure, heart rate and concomitant comorbidities. Ideally, patients should be assessed by their general practitioner within 1 week of discharge and have a hospital/clinic follow-up within 4 weeks of discharge. Patients should progressively resume physical activities and adhere to an educational programme with appropriate lifestyle adjustments best implemented during a cardiac rehabilitation programme.

Interdisciplinary assessment and diagnostic algorithm: The role of the cardiologist.

Patients with diabetes have an increased risk of developing heart failure and those with heart failure are at higher risk of developing diabetes. In patients with diabetes antidiabetic medications and the metabolic alterations of diabetes increase the risk of developing heart failure. In diabetic patients with heart failure and in those with an increased likelihood of developing the disease a stepwise approach based on the use of natriuretic peptides and echocardiography to rule out the presence of heart failure should be used. Once the diagnosis of heart failure is established it will be important to define the phenotype according to the left ventricular function and, where appropriate, use additional tests to identify possible additional underlying causes of heart failure like coronary artery disease. A multidisciplinary heart failure management programs is recommended in all patients with diabetes mellitus and heart failure to enable appropriate investigations, accurate diagnosis, and appropriate agreed evidence-based therapy and care plan. The implementation of a multidisciplinary heart failure management program requires a multidisciplinary team that will have to follow the patients throughout the whole heart failure trajectory and that should consider a holistic approach to the diabetic patient with heart failure rather than focussing merely on either heart failure or diabetes.

Needs of standardisation in reporting a venous lower limb ultrasound exam for the assessment of varicose veins.

Duplex ultrasound is an important tool in the assessment and management of patients with varicose veins. Over the past two decades several minimally-invasive therapeutic options have become available for the treatment of these patients. Consequently, the ultrasonographic assessment and the parameters to consider have changed accordingly. Ultrasound parameters, such as the diameter of superficial incompetent veins or their depth from the skin surface amongst others, have become of paramount importance for planning a tailored either operative or non-operative treatment. However, in daily practice there is a wide variety of ultrasound parameters described in the report. This variety can be explained by several factors, such as the background of the healthcare professional performing the exam or the available treatments as per the local national healthcare service guidelines or insurance reimbursement plans. The standardisation of the reporting of the ultrasound findings in patients with varicose veins will improve communication between healthcare professionals and the management of these patients.

Frailty and the risk of all-cause mortality and hospitalization in chronic heart failure: a meta-analysis.

To estimate the risk of all-cause mortality and hospitalization in frail patients with chronic heart failure (HF), a systematic search and meta-analysis was carried out to identify all prospective cohort studies conducted among adults with HF where frailty was quantified and related to the primary endpoints of all-cause mortality and/or hospitalization. Twenty-nine studies reporting the link between frailty and all-cause mortality in 18 757 patients were available for the meta-analysis, along with 11 studies, with 13 525 patients, reporting the association between frailty and hospitalization. Frailty was a predictor of all-cause mortality and hospitalization with summary hazard ratios (HRs) of 1.48 [95% confidence interval (CI): 1.31-1.65, P < 0.001] and 1.40 (95% CI: 1.27-1.54, P < 0.001), respectively. Summary HRs for all-cause mortality among frail inpatients undergoing ventricular assist device implantation, inpatients hospitalized for HF, and outpatients were 1.46 (95% CI: 1.18-1.73, P < 0.001), 1.58 (95% CI: 0.94-2.22, P = not significant), and 1.53 (95% CI: 1.28-1.78, P < 0.001), respectively. Summary HRs for all-cause mortality and frailty based on Fried's phenotype were 1.48 (95% CI: 1.03-1.93, P < 0.001) and 1.42 (95% CI: 1.05-1.79, P < 0.001) for inpatients and outpatients, respectively, and based on other frailty measures were 1.42 (95% CI: 1.12-1.72, P < 0.001) and 1.60 (95% CI: 1.43-1.77, P < 0.001) for inpatients and outpatients, respectively. Across clinical contexts, frailty in chronic HF is associated with an average of 48% and 40% increase in the hazard of all-cause mortality and hospitalization, respectively. The relationship between frailty and all-cause mortality is similar across clinical settings and comparing measurement using Fried's phenotype or other measures.

Frailty and COVID-19: A Systematic Scoping Review.

Older people have paid a huge toll in terms of mortality during the coronavirus disease-19 (COVID-19) pandemic. Frailty may have contributed to the vulnerability of older people to more severe clinical presentation. We aimed at reviewing available evidence about frailty and COVID-19. We searched PUBMED, Web of Science, and EMBASE from 1 December 2019 to 29 May 2020. Study selection and data extraction were performed by three independent reviewers. Qualitative synthesis was conducted and quantitative data extracted when available. Forty papers were included: 13 editorials, 15 recommendations/guidelines, 3 reviews, 1 clinical trial, 6 observational studies, 2 case reports. Editorials and reviews underlined the potential clinical relevance of assessing frailty among older patients with COVID-19. However, frailty was only investigated in regards to its association with overall mortality, hospital contagion, intensive care unit admission rates, and disease phenotypes in the few observational studies retrieved. Specific interventions in relation to frailty or its impact on COVID-19 treatments have not been evaluated yet. Even with such limited evidence, clinical recommendations on the use of frailty tools have been proposed to support decision making about escalation plan. Ongoing initiatives are expected to improve knowledge of COVID-19 interaction with frailty and to promote patient-centered approaches.

Multidimensional Approach to Frailty.

The concept of frailty syndrome (FS) was first described in the scientific literature three decades ago. For a very long time, we understood it as a geriatric problem, recently becoming one of the dominant concepts in cardiology. It identifies symptoms of FS in one in 10 elderly people. It is estimated that in Europe, 17% of elderly people have FS. The changes in FS resemble and often overlap with changes associated with the physiological aging process of the body. Although there are numerous scientific reports confirming that FS is age correlated, it is not an unavoidable part of the aging process and does not apply only to the elderly. FS is a reversible clinical condition. To maximize benefits of frailty-reversing activities for patient with frailty, identification of its determinants appears to be fundamental. Many of the determinants of the FS have already been known: reduction in physical activity, malnutrition, sarcopenia, polypharmacy, depressive symptom, cognitive disorders, and lack of social support. This review shows that insight into FS determinants is the starting point for building both the comprehensive definition of FS and the adoption of the assessment method of FS, and then successful clinical management.

Antidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease: A Real-Life Investigation From Italy.

PURPOSE: The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. METHODS: A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. FINDINGS: Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. IMPLICATIONS: Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.