Correspondence to: Marco Metra, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Piazzale Spedali Civili 1, Brescia 25123, Italy. Tel: 030 307221; Fax: 030 3700359. Email: [email protected]
Correspondence to: Marco Metra, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Piazzale Spedali Civili 1, Brescia 25123, Italy. Tel: 030 307221; Fax: 030 3700359. Email: [email protected]
Research about heart failure (HF) has made major progress in the last years. We give here an update on the most recent findings. Landmark trials have established new treatments for HF with reduced ejection fraction. Sacubitril/valsartan was superior to enalapril in PARADIGM-HF trial, and its initiation during hospitalization for acute HF or early after discharge can now be considered. More recently, new therapeutic pathways have been developed. In the DAPA-HF and EMPEROR-Reduced trials, dapagliflozin and empagliflozin reduced the risk of the primary composite endpoint, compared with placebo [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.65–0.85; P < 0.001 and HR 0.75; 95% CI 0.65–0.86; P < 0.001, respectively]. Second, vericiguat, an oral soluble guanylate cyclase stimulator, reduced the composite endpoint of cardiovascular death or HF hospitalization vs. placebo (HR 0.90; 95% CI 0.82–0.98; P = 0.02). On the other hand, both the diagnosis and treatment of HF with preserved ejection fraction, as well as management of advanced HF and acute HF, remain challenging. A better phenotyping of patients with HF would be helpful for prognostic stratification and treatment selection. Further aspects, such as the use of devices, treatment of arrhythmias, and percutaneous treatment of valvular heart disease in patients with HF, are also discussed and reviewed in this article.
Introduction
Heart failure (HF) is a major health and economic burden worldwide.1-5 Because mortality remains high and the quality of life is poor, it is an area of active research.6-10 In this article, we update recent published data and findings.
Epidemiology: geographic and temporal trends
Data concerning the epidemiology of HF remain insufficient.11-13 The Heart Failure Association (HFA) Atlas is a novel European HF data set with a major aim to provide information about HF epidemiology, resource, and reimbursement policies for HF management.14
In a recent meta-analysis, Jones et al. presented long-term outcomes in 1.5 million ambulatory patients with chronic HF, including 60 non-interventional studies. Despite an improvement in 5 year survival rates between 1970–1979 and 2000–2009 from 29.1% to 59.7%, mortality rates remain unacceptably high and larger than for most types of cancer (Figure1).11, 15 Trends in HF hospitalizations from 2000 to 2014 were examined in Norway. Age-standardized rates of incident HF hospitalization declined on average 1.9% and 1.8% per year for men and women, respectively. Although mortality was reduced, HF rehospitalizations increased.16
Combined survival rates for people with heart failure over time. Adapted from Jones et al.11
Several studies have highlighted the regional heterogeneity of HF populations, patients' characteristics, and outcomes, with important implications for global trial design.12, 17 Dewan et al. compared heart failure with reduced ejection fraction (HFrEF) patients enrolled in different continents in two large trials: Prospective comparison of angiotensin receptor neprilysin inhibitors (ARNI) with angiotensin-converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in HF (PARADIGM-HF) and Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE). They found that Asian patients were younger (55.0–63.9 years) than those in Western Europe (67.9 years) and North America (66.6 years). The adjusted risk of cardiovascular (CV) death was higher in many Asian countries, except Japan. Using Western Europe as the reference group, the adjusted hazard ratio (HR) for China, India, Thailand, and Japan was 1.89 (1.58–2.27), 1.76 (1.49–2.09), 1.87 (1.18–2.96), and 0.77 (0.53–1.12), respectively.18
Prospective multinational data from Asia showed that heart failure with preserved ejection fraction (HFpEF) affects relatively young patients with high prevalence of co-morbidities, most commonly hypertension, anaemia, chronic kidney disease, diabetes, coronary heart disease, and atrial fibrillation (AF).12 Gender may also impact these international differences in HFrEF.19 Similar risk factors for incident HF were reported in the UK population.20 Novel risk factors for worse status continue to be discovered, including nutritional deficiencies even in the developed world.21
Because outcomes are different worldwide, designing a risk prediction model remains challenging and might underestimate or overestimate mortality in some countries.22
Specific phenotypes
Among the specific causes of HF, cardiomyopathies are a heterogeneous group of heart muscle diseases.23-26 Current knowledge regarding the incidence and prevalence of cardiomyopathies and HF has been summarized in a recent position paper by the HFA of the European Society of Cardiology (ESC).27 Genetic phenotyping of cardiomyopathies is helpful to understand the clinical course of the disease and to address aetiology-based therapy.28-30 Desmoglein-2 mutation carriers were found to be at high risk of end-stage HF compared with plakophilin-2 mutation carriers in arrhythmogenic right ventricular (RV) cardiomyopathy.31, 32
A specific phenotype of HF is that caused by amyloidosis. Cardiac amyloidosis is a peculiar cardiomyopathy, characterized by extracellular deposition of misfolded proteins that leads to increased biventricular wall thickness and increased myocardial stiffness.33, 34 Different types of protein deposition cause different types of amyloidosis: light-chain amyloidosis and transthyretin amyloidosis are the most frequent, and the transthyretin stabilizer tafamidis has recently been introduced to improve the prognosis of affected patients.35 Amyloidosis may be a major cause of severe symptoms and poor outcomes.33, 36, 37 Transthyretin amyloidosis is an underdiagnosed cause of HF, especially in HFpEF, hypertrophic or restrictive cardiomyopathy, and aortic stenosis. Compared with wild-type transthyretin amyloidosis, transthyretin-related hereditary amyloidosis more often affects men and is characterized by an early onset with concomitant neurological involvement.38 Such patients need to be screened, and specific treatments can be considered.39
Much recent interest has also focused on other cardiomyopathies including peripartum cardiomyopathy.40
Co-morbidities
Co-morbidities play a major role in the clinical presentation and outcomes of HF.41-43 More than 70% of patients with HF are burdened by co-morbidities, and they have an independent effect on mortality.44, 45
Type 2 diabetes mellitus confers a greater risk of new onset HF, HF rehospitalization, and CV and all-cause mortality, particularly when patients require insulin treatment and/or have concomitant conditions.46-51
Further common co-morbidities associated with HF are chronic kidney disease,52, 53 chronic obstructive pulmonary disease,54 central nervous system abnormalities,55, 56 sleep disordered breathing,57 iron deficiency, cancer,58-61 cachexia,62-64 muscle wasting (sarcopenia),51, 65-69 and frailty.70-73 The prevalence of frailty is increased in HF and is associated with worse outcome.74 Its relation with outcome is independent from other variables in most of the studies. Frailty seems to be more common in HFpEF patients than in HFrEF due to the greater burden in cardiac and non-cardiac co-morbidities in the second condition.75, 76 Recently, a new Frailty Score was developed by the HFA. It considers four main domains: clinical, physical–functional, cognitive–psychological, and social. Each domain covers different variables, including co-morbidities (clinical domain); cognitive impairment and mood disturbances, such as depression (cognitive–psychological); physical impairment, sarcopenia, or cachexia (functional); and isolation or the absence of a caregiver (social). This score should identify high-risk patients (Figure2).72 The prognostic role of social and economic factors has been shown in recent studies,20, 77 and also, sex differences are important to consider in the treatment of patients.78-83
The four main domains—clinical, physical–functional, cognitive–psychological, and social—defining Heart Failure Association Frailty Score. Reversible and/or treatable variables are identified by asterisks. ADL, activities of daily living; HF, heart failure; IADL, instrumental activities of daily living. From Vitale et al.72
Heart failure and cancer
There is a complex and intriguing relationship between HF and cancer.70, 84-87 On one hand, patients with HF have a higher occurrence of malignancy due to a combination of underlying shared mechanisms and risk factors.58, 59, 88 On the other hand, cancer patients frequently develop HF, due to cardiotoxicity.60, 89-93 In breast cancer patients, increased levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and impaired global longitudinal strain (GLS) were found in 34% and 23% of the patients, respectively. GLS and left ventricular ejection fraction (LVEF) declined with increasing cumulative anthracycline dose.94 Both left ventricular (LV) and RV GLS impairment predicted cardiotoxicity also in patients receiving trastuzumab.95 Also, plasma troponin levels may identify patients at higher risk of CV complications.96 In a recent experimental model, the protective effect of phenylalanine-butyramide against doxorubicin-induced cardiotoxicity has been shown.97
Diagnosis and prognosis
New scores and risk prediction models are continuously developed to stratify risk in HF patients.98-101
Clinical signs
Clinical signs have important prognostic value. Low systolic blood pressure and elevated heart rate are associated with poorer outcomes.102, 103 The role of heart rate is controversial in patients with concomitant AF. No relation with outcomes was shown in one meta-analysis.104 A study by Sartipy et al., including HFpEF patients from the Swedish Heart Failure Registry, showed that in those with concomitant AF, higher heart rates were associated with poorer outcomes at short term (1 year) but had no prognostic value in the long term.105
Biomarkers
Plasma levels of natriuretic peptides (NPs) are related with LV wall stress and are surrogates for intracardiac filling pressures. They are useful to discriminate HF from non-cardiac breathlessness in patients presenting to the emergency department. Lower levels of NPs have a very high negative predictive value for the diagnosis of HF. In patients with chronic HF, NPs may be persistently elevated, and an increase of 100% or more may suggest an acute decompensation.106, 107 Moreover, sex and several co-morbidities may influence NP levels, requiring adjusted cut-off: for instance, obese patients have lower values of NT-proBNP.108 NPs, along with troponin, are the most useful biomarkers to predict outcomes in both chronic and acute HF to date.109-112 NT-proBNP is also predictive for non-CV death.113 The role of mid-regional pro-atrial natriuretic peptide has been recently investigated not only in the acute setting but also in chronic HF, and it has a diagnostic value similar to NT-proBNP.114
An analysis of the Aliskiren Trial on Acute Heart Failure Outcome (ASTRONAUT) failed to show a role of plasma renin activity for the selection of patients with the highest likelihood to respond to aliskiren, even if it has a negative prognostic value.115, 116 In PARADIGM-HF, elevated levels of growth factor 15 were associated with mortality and CV outcomes, though they were not changed by assigned treatment.117
Given the central role of inflammation in the pathophysiology of HF, pro-inflammatory cytokines, including interleukin 6 (IL-6), raised interest in the scientific community.118-121 Over 50% of the patients with HFrEF in A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) had elevated IL-6 levels, associated with iron deficiency, AF, and poorer clinical outcome. IL-6 could become a potential therapeutic target, despite trials targeting another marker of inflammation, tumour necrosis factor alpha, were largely unsuccessful.122
Circulating microRNAs continue to be of major interest. Different levels of plasma microRNAs could help in discriminating the aetiology behind HF (ischaemic vs. non-ischaemic).123 Such levels might change after treatment and could represent a tool to monitor patients' clinical status, although evidence is lacking and further research is needed.124-126
There is also increasing interest in biomarkers that may simultaneously be markers, disease process mediators, and therapeutic targets.127-129
The role of imaging, exercise testing, and invasive haemodynamic measurement
Echocardiography allows the assessment of LV volumes and LVEF as well as an estimate of LV filling pressure, RV size and function, valvular disease, and pulmonary artery pressure.130, 131 LV systolic ejection time (SET) is shorter in HF and is an independent predictor of incident HF (HR 1.07; 95% CI 1.02–1.14, per 10 ms decrease).132 Interestingly, a longer SET was associated with improved outcomes among HFrEF but not HFpEF patients. Hence, an increase in SET seems a promising pathway to improve systolic function in these patients.133
Another major area of research regards the left atrium. Left atrial structure and function has been shown to predict outcomes in patients with HF and AF.134 Left atrial strain provided better diagnostic accuracy than conventional echocardiographic measures to discriminate HFpEF from non-cardiac causes of dyspnoea135 and was associated with impaired haemodynamics both at rest and during exercise.136, 137
Cardiac magnetic resonance (CMR) may be helpful in tissue characterization, detection, and quantification of myocardial fibrosis and adipose tissue, which are associated with HF development and progression.138, 139 Myocardial adipose deposition and epicardial fat, both of which can be carefully measured by CMR, may play a major role in the development of HFpEF.139, 140
The 6 min walk test is a valid tool to assess exercise capacity. In BIOSTAT-CHF, both a reduced walked distance at baseline and a decline at 9 month follow-up were associated with a worse prognosis and were not modified by the up-titration of drugs.141
Cardiopulmonary exercise test-derived parameters, such as peak exercise oxygen uptake (peak VO2) and minute ventilation/carbon dioxide relationship slope (VE/VCO2 slope), have a major role for the assessment of the patients with advanced HF and a possible indication to heart transplantation.43 HF prognosis has improved in the last years, suggesting the need of update prognostic threshold of these parameters. Paolillo et al. analysed the metabolic exercise cardiac kidney index (MECKI) score database and divided patients in four groups by enrolment year: Group 1 1993–2000, Group 2 2001–2005, Group 3 2006–2010, and Group 4 2011–2015. In Groups 1, 2, 3, and 4, a 20% overall risk [CV death, urgent heart transplantation, or left ventricular assist device (LVAD) implantation] was observed for peak VO2: 15 mL/min/kg (95% CI 16–13), 9 (11–8), 4 (4–2), and 5 (7–4), respectively. The VE/VCO2 slope value for a 20% risk was 32 (37–29), 47 (51–43), 59 (64–55), and 57 (63–52), respectively.142 Exercise oscillatory ventilation is another pivotal parameter in cardiopulmonary exercise test, and it has a similar prognostic value in both HFrEF and heart failure with mid-range ejection fraction patients.143
Right heart catheterization maintains a major role for the prognostic stratification of patients with severe symptoms.43 It discriminates between patients with isolated postcapillary pulmonary hypertension and those with combined postcapillary and precapillary pulmonary hypertension who have worse outcomes both in HFrEF and valve disease.144-146
Medical treatment of heart failure with reduced ejection fraction
Neurohormonal antagonists
Neurohormonal antagonists, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists, play a pivotal role in the treatment of HFrEF, improving the clinical course of the disease.147-149 In the more recent PARADIGM-HF trial, sacubitril/valsartan was superior to enalapril in reducing the risks of death and of hospitalization for HF.150, 151 A similar efficacy was shown in the reduction of recurrent events (Wei, Lin, and Weissfeld HR in the sacubitril/valsartan group 0.79; 95% CI 0.71–0.89).152 Moreover, treatment with sacubitril/valsartan allows a greater reduction in loop diuretic doses compared with enalapril.153 Results from the Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION) study suggest that initiation of ARNI in HFrEF patients stabilized after an acute HF event, either in hospital or shortly after discharge, is feasible.154De novo HFrEF patients had also major benefits compared with those with prior diagnosis, showing faster and greater decreases in NT-proBNP and high-sensitivity troponin T and lower rates of HF and all-cause rehospitalization.155
In the ESC-EORP-HFA Heart Failure Long-Term Registry, 84% of outpatients were eligible for sacubitril/valsartan based on European Medicines Agency/Food and Drug Administration label, but only 12–28% met the criteria used in guidelines.156 Data from Germany showed a still insufficient rate of initiation and dose up-titration of this agent.157 Reasons behind this under-prescription must be explored to ensure guideline-directed medical therapy (GDMT). Indeed, physicians and patients' adherence to GDMT is associated with improved outcomes over both the short term and longer term.158, 159 Many factors, including older age, hypotension, and impaired renal function, may contribute to underuse of GDMT.160-162 A slow titration of ARNI is associated with better treatment success also in patients with slow systolic blood pressure.163 In EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), renal function did not influence beneficial effects of eplerenone, even if patients with impaired renal function were more susceptible to adverse events (hyperkalaemia and renal failure events) and drug discontinuation.164 Hyperkalaemia represents another limiting factor in the prescription of renin–angiotensin–aldosterone system inhibitors.165-167 Novel potassium-lowering agents, such as patiromer and sodium zirconium cyclosilicate, may be helpful in achieving optimization of therapy, but further studies are needed.39
Sodium–glucose co-transporter 2 inhibitors
In the last years, major advances occurred concerning antidiabetic drugs and CV risk, and a new pathway of HF treatment—different from the neurohormonal one—has been opened (Figure3).168, 169
Positive trials in the treatment of heart failure with reduced ejection fraction from 1986 to 2020. Modified from McMurray.168
Sodium–glucose co-transporter 2 (SGLT-2) inhibitors—empagliflozin, canagliflozin, and dapagliflozin—have consistently shown a reduced risk of HF hospitalization or CV death in diabetic patients regardless of baseline CV disease and previous history of HF.170, 171 Dapagliflozin And Prevention of Adverse outcome in Heart Failure (DAPA-HF) is the first trial proving a significant benefit of an SGLT-2 inhibitor—dapagliflozin—with a reduction in the risk of the composite endpoint of CV death or worsening HF (hospitalization or an urgent visit requiring intravenous therapy for HF) in HFrEF patients with or without diabetes (HR 0.74; 95% CI 0.65–0.85). Each of the three components of the composite outcome was less frequent in the dapagliflozin group.172, 173 The baseline characteristics of DAPA-HF patients were similar to those in contemporary HFrEF registries and trials.174 The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) included patients with a more severe LV systolic dysfunction, higher levels of NPs, and lower estimated glomerular filtration rate, as compared with the patients in the DAPA-HF trial. Empagliflozin reduced the combined risk for CV death or hospitalization for HF compared with placebo (HR 0.75; 95% CI 0.65–0.86; P < 0.001), a difference that was primarily related to a reduction in hospitalization for HF. Indeed, CV death was not significantly reduced probably because EMPEROR-Reduced trial had less statistical power than DAPA-HF (less number of events in a smaller size of the trial and shorter follow-up). The beneficial effects of empagliflozin were consistent in subgroup analyses (diabetes vs. non-diabetes; ARNI treatment vs. no ARNI treatment). Furthermore, empagliflozin was associated with a slower rate of decline in the estimated glomerular filtration rate and with a lower risk of serious renal outcomes. Thus, the EMPEROR-Reduced trial extends the benefits of SGLT-2 inhibitors in stable, more advanced HF population.175, 176 In the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial, sotagliflozin showed beneficial effects in patients with diabetes and recent worsening HF.177 Further studies will assess the efficacy of SGLT-2 inhibitors in other settings (i.e. HFpEF or acute HF).178, 179
The mechanisms behind the beneficial effects of SGLT-2 inhibitors are largely unknown. Besides glycosuric and natriuretic effects, empagliflozin seems to have a direct pleiotropic effect on cardiomyocytes. It improves adenosine triphosphate production and myocardium metabolism, diastolic function, and cardiac remodelling and has favourable effects.180-183
Treatment of iron deficiency
Iron deficiency is common in HF patients and is associated with poor exercise capacity, directly affecting mitochondrial respiration and the function of skeletal muscle and cardiomyocytes.184-188 Indeed, cellular oxidative metabolism relies largely on iron availability in skeletal muscle.189-192 Iron depletion is also associated with reduced quality of life and survival. Treatment with intravenous ferric carboxymaltose (FCM) has been shown to lead to improvements of functional capacity, symptoms, and quality of life in chronic HF patients.193 A recent meta-analysis including four major randomized trials showed a reduction of HF hospitalizations and CV mortality in iron deficiency patients treated with FCM.194 AFFIRM-AHF (Study to Compare Ferric Carboxymaltose with Placebo in Patients with Acute Heart Failure and Iron Deficiency) evaluated the effects of intravenous FCM in patients hospitalized for acute heart failure.195 It showed that treatment with FCM was safe and reduced the risk of HF hospitalisations.196
Other options
Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) was a randomized, placebo-controlled trial evaluating safety and efficacy of vericiguat in HFrEF patients with recent worsening HF. Vericiguat was superior to placebo in the reduction of composite endpoint of CV death or HF hospitalization (HR 0.90; 95% CI 0.82–0.98; P = 0.02).197 Baseline characteristics of VICTORIA-enrolled subjects showed a high-risk population when compared with PARADIGM-HF. The median MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score was 23 (interquartile range 18–27) in VICTORIA vs. 20 (interquartile range 16–24) in PARADIGM-HF trial.198 In the GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial, the selective cardiac myosin activator omecamtiv mecarbil showed a reduction in the primary composite endpoint of a first HF event or death from CV causes.199
Neladenoson bialanate, a partial adenosine A1 receptor agonist, failed to demonstrate favourable changes in NT-proBNP, LVEF, high-sensitivity troponin T, or CV mortality and HF hospitalization in PANTHEON trial. On the other hand, a decrease in renal function was observed.200
Standard treatment of advanced HF remains unsatisfactory. Positive inotropes may be used as bridge strategy and palliative care,43 while no positive inotrope is currently approved for long-term treatment in chronic HF.201 However, intermittent administration of levosimendan in ambulatory patients has been associated with reduction in NT-proBNP levels and HF hospitalization.202
The DIGIT-HF (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure) trial has been designed to demonstrate a role of digitoxin on the top of standard care in improving mortality and morbidity in advanced HFrEF.203
Devices
Cardiac resynchronization therapy
Cardiac resynchronization therapy (CRT) is less frequently used than expected, even when indicated by guidelines.204-207
In an individual patient data meta-analysis of five randomized controlled trials, QRS duration was the only independent predictor of CRT benefit on mortality. Along with QRS duration, lower height but not sex played a role in the composite endpoint of all-cause mortality or first hospitalization for HF.208 In another study, body mass index was associated with outcome: overweight or obese patients receiving CRT with defibrillator were at a lower risk of death compared with underweight subjects.209
According to an analysis from the ESC CRT Survey II, the benefit and complication rates from CRT upgrading, in implantable cardioverter defibrillator (ICD) or pacemaker carriers, are the same as for de novo CRT patients.210 Therefore, patients with a pacing-induced cardiomyopathy must be closely monitored, and an upgrade to CRT or His bundle pacing device might be considered.211
Cardiac resynchronization therapy may be less effective in patients with AF because both atrioventricular (AV) and biventricular resynchronization are required. However, AV junction ablation might represent a safe option: in a small trial, CRT with defibrillator patients with permanent AF, who underwent AV junction ablation, experienced less ICD shocks and a lower incidence of HF hospitalization, compared with patients with AF medical therapy alone.212
A study on neonatal rat ventricular cardiomyocytes showed that irregular pacing induces pro-fibrotic signalling with paracrine effects and oxidative stress, eventually leading to a remodelling process. A similar mechanism might be involved in AF-related HF with arrhythmic ventricular contractions and increased morbidity and mortality.213
Implantable cardioverter defibrillator
The selection of patients who might benefit from ICD implantation is often challenging.214, 215 Myocardial infarction survivors with LVEF > 35% burdened by diabetes and/or kidney dysfunction have a high risk of sudden cardiac death (SCD), but the risk of a non-SCD event is even higher, suggesting that the extension of ICD implantation in such patients might not be worthwhile.52 A combined analysis of four major primary prevention trials in HFrEF patients assessed the effects of ICD implantation in diabetic vs. non-diabetic patients. The use of ICD was associated with a reduced risk of mortality in non-diabetic patients (HR 0.56; 95% CI 0.46–0.67) but not among those with diabetes.216
Percutaneous treatment of mitral and tricuspid regurgitation
Transcatheter mitral valve interventions are spreading as treatment options in patients with HF and severe secondary mitral regurgitation.39, 217, 218 Two randomized controlled trials investigated the prognostic impact of percutaneous edge-to-edge mitral valve repair by MitraClip in HF patients. Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) showed no reduction in HF hospitalizations or mortality in patients undergoing MitraClip compared with those receiving conservative management up to 2 year follow-up.219 On the other hand, Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) demonstrated an impressive reduction in both 2 year HF hospitalizations, which was the primary endpoint, and 2 year all-cause death. Such a discrepancy might be due to the different characteristics of the patients included, suggesting that only carefully selected patients may derive a prognostic benefit from secondary mitral regurgitation correction.39, 220 Further data, coming from observational studies, showed safety and efficacy of MitraClip in improving symptoms and clinical status also in patients with advanced HF, such as those with low ejection fraction (EF) and pulmonary hypertension.146, 221
Orban et al. showed a significant improvement in New York Heart Association class, 6 min walk test distance, and quality of life in 50 patients undergoing percutaneous edge-to-edge repair on the tricuspid valve.222 Schlotter et al. reported outcomes of 159 patients with severe functional tricuspid regurgitation, who underwent transcatheter tricuspid valve repair. Patients were stratified into four aetiology-based clinical scenarios: patients receiving chronic haemodialysis, patients with significant mitral regurgitation, patients with severe pulmonary hypertension, and patients with a history of AF/flutter. Patients with pulmonary hypertension had the highest rates of the primary composite endpoint (death, HF hospitalization, or reintervention), while the highest mortality rate was observed in haemodialysis patients (33.3%).223
Mechanical circulatory support
Left ventricular assist device is a promising option for patients with advanced HF, either as a bridge to transplant or as a lifelong treatment.224-226 In a Spanish retrospective study, 291 patients waiting for cardiac transplant received LVAD. They had a better outcome, compared with those undergoing temporary biventricular assist devices or extracorporeal membrane oxygenation as bridge to heart transplantation.227 LVAD implantation may also favour a recovery of LV function especially when associated with administration of neurohormonal antagonists.228 Data from the Postgraduate Course in Heart Failure (PCHF)-VAD registry showed a better survival in LVAD patients who also received a cardiac implantable electronic device with a defibrillator component (HR 0.64; 95% CI 0.46–0.91; P = 0.012) compared with those who only had LVAD support.229 Also, exercise training may provide incremental benefits in LVAD carriers. The rationale behind the Exercise training in patients with a LVAD (Ex-VAD) trial is to assess if a 12 week supervised exercise training could improve the quality of life and the functional capacity in LVAD patients.230 However, among patients with a reduced EF and New York Heart Association Classes III–IV eligible for heart transplantation or LVAD, more than half declines the indication.231 Infections, as well as bleeding and thrombo-embolic events, are the most common and severe complications of LVAD. The platelet activity state may predict the risk of thrombo-embolic complications after LVAD.232 LVAD design continues to improve and will be subject to ongoing evaluation.233
Telemedicine and disease management
Home telemonitoring is a useful tool for the management of HF patients.39 TIM-HF2 (Telemedical Interventional Management in Heart Failure II study) trial showed a positive impact of telemedicine on unplanned CV hospitalization and mortality.234-236 The HOME-HF study was designed to assess the feasibility and efficacy of BNP home measurement in reduction of HF-related events. It was early interrupted because of slow enrolment, low event rate, and the need of standardize BNP spontaneous fluctuation.237 The HFA has developed a well-visited tool to assist in patient communication and education, a crucial part of ongoing disease management,238 which the development of e-health strategies will likely accelerate,239 as will better mechanisms to enhance dosing choices in guideline-directed HF medication.240, 241
Novel perspectives
New therapeutic strategies are emerging for patients with HF of ischaemic aetiology.
BioVentrix Revivent TC System is a transcatheter technique that aims at limiting myocardial scar on the beating heart of HF patients. At 12 month follow-up, symptomatic patients with previous anterior myocardial infarction who received this treatment had an improvement of LV function, symptoms, and quality of life.242
The Autologous Mesenchymal Stromal Cell Therapy in Heart Failure (MSC-HF) trial randomized patients with ischaemic HF to receive either intramyocardial injections of bone marrow-derived mesenchymal stromal cells or placebo. At 4 year follow-up, patients experienced improved myocardial function and myocardial mass.243 The Stem Cell therapy in IschaEmic Non-treatable Cardiac disease (SCIENCE) trial will assess the efficacy and safety of intramyocardial cell therapy of adipose-derived stromal cells from healthy donors (allogeneic donation) in patients with ischaemic HF.244 Cardiac contractility modulation has been shown to have the potential to improve functional capacity, especially in those with HF and mildly reduced LVEF (25–45%).245
Central sleep apnoea (CSA) is a predictor of CV morbidity and mortality in HF patients. The Treatment of Predominant Central Sleep Apnoea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial compared adaptive servo-ventilation and medical therapy in patients with HF and CSA. The primary endpoint, changes in LVEF at 1 year, was similar between the two groups. However, CV mortality was higher in the adaptive servo-ventilation vs. control arm. Furthermore, other endpoints, such as changes in LV dimensions and cardiac biomarkers, were not affected by the adaptive servo-ventilation.246
A post hoc analysis from the remedē System Pivotal Trial including patients with CSA and baseline HF showed an improvement in the quality of life and a reduction in HF hospitalizations in patients undergoing phrenic nerve stimulation compared with control group (inactive system).247
Epigenetic processes and aberrant gene expression are important mechanisms in HF. A study by Berulava et al. showed that the methylation of m6A RNA can modify the physiological processes leading to HF. Thus, epitranscriptomic pathways could be potential therapeutic targets.248 Proteomic processes also represent a field of interest and could be targets for the future. A recent study demonstrated that glutathione, arginine and proline, and pyruvate pathways were activated in HF patients who died or were rehospitalized.249 The ubiquitous lysosomal protease cathepsin D is secreted as a response to oxidative stress, but its role in HF was unknown. It has been recently discovered that elevated levels of cathepsin D are associated with HF severity and poor outcome.250
Heart failure with preserved ejection fraction
Clinical phenotypes and pathophysiology
Heart failure with preserved ejection fraction is a heterogeneous syndrome with several clinical manifestations.251-253
Using a machine learning-based cluster analysis, Segar et al. identified three phenogroups of patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) trial. Patients in the first phenogroup had a higher burden of co-morbidities, increased levels of NPs, and LV impairment; the second phenogroup had less co-morbidities but a worst diastolic dysfunction; the third phenogroup had lower levels of NPs, intermediate co-morbidities, and the most favourable diastolic profile. Phenogroup 1 had higher rates of HF rehospitalizations and mortality, when compared with Phenogroup 3. Phenogroups 2 and 3 shared the same risk of mortality. A greater risk of rehospitalization was observed in Phenogroup 2 vs. 3,254 a feature also seen with the increased risk associated with co-morbid pulmonary disease in this syndrome.255
The pathophysiology of HFpEF remains largely unknown. Coronary microvascular dysfunction might play a central role in the development of HFpEF. It can be equally caused by both endothelium-based and endothelium-independent mechanisms. When the microvascular dysfunction is not endothelium related, patients show a worse diastolic function and prognosis.256
Another possible mechanism is the systemic and intramyocardial inflammation.119 Obesity and type 2 diabetes mellitus are common in HFpEF patients and often coexist. They both cause inflammation and expansion of epicardial adipose tissue, leading to atrial damage and LV fibrosis/stiffness.257, 258 AF often represents the first manifestation of HFpEF and can be a consequence of atrial myopathy.258
A study by Wu et al. investigated the role of myocardial steatosis in diastolic dysfunction. Intramyocardial fat deposition was measured using CMR in 305 subjects (34 patients with HFrEF, 163 with HFpEF, and 108 non-HF controls). HFpEF patients display a more pronounced intramyocardial fat deposition, when compared with HFrEF patients or controls, leading to diastolic impairment.139 Such phenomenon is—once again—more clear in patients burdened by obesity and metabolic syndrome, in whom adiposity is greater and is associated with myocardial injury and AF.140 Differences between Asia and western countries are also seen in the presentation of HFpEF.259
Diagnosis and prognosis: a challenge for the medical community
The diagnosis of HFpEF remains challenging. Recently, two independently derived algorithms for the HFpEF diagnosis have been published: the H2FPEF score from the Mayo Clinic (Rochester, MN, USA) and the European HFA-PEFF 4-step algorithm.260, 261 The American H2FPEF score was based on clinical and echocardiographic characteristics and validated with invasive haemodynamic testing as gold standard. It identified six variables as HFpEF predictors: obesity (body mass index > 30 kg/m2), AF, age > 60 years, treatment with two or more antihypertensive drugs, E/e' > 9, and pulmonary artery systolic pressure > 35 mmHg. The resultant total H2FPEF score ranged from 0 to 9, with the scores <2 suggesting a low likelihood and scores ≥6 reflecting a high likelihood of HFpEF. The European HFA-PEFF 4-step algorithm is a new stepwise diagnostic tool. It starts from pretest assessment (based on signs, symptoms, electrocardiographic alterations, and laboratory tests), going through risk stratification with rest imaging, analysing specific functional and morphological echocardiographic parameters. The HFA-PEFF score is the sum of points from functional, morphological, and biomarker domains (2 points for each major criteria and 1 for each minor criteria). A total score ≥5 is considered diagnostic for HFpEF, while a total score <1 determines a very low probability of HFpEF. The intermediate values will need further investigation, with stress echocardiography and invasive haemodynamics. The diagnostic pathway could be finally completed with aetiological workup. Barandiarán Aizpurua et al. tried to validate the second step of the HFA-PEFF algorithm, based on echocardiographic findings and NPs.262 However, these results might be overestimated due to the high HFpEF case–control ratio and to the low diagnostic support with invasive measurements.
Diagnostic tools aiming to assess tolerance to exercise are mandatory in HFpEF patients.263-265 However, co-morbidities could limit exercise capacity. Elderly patients with elevated left atrial pressure and impaired reservoir present an abnormal exercise haemodynamics.136 The evaluation of left atrial reservoir strain could be helpful to discriminate HFpEF from non-cardiac dyspnoea.135 In patients who are capable of performing exercise, oxygen consumption trajectory has been suggested as a predictor of disease severity.266 Estimated plasma volume status has been also proposed as a tool for the prediction of long-term outcome in HFpEF patients.267
Treatment: lack of favourable results
Despite the growing impact of HFpEF, there is still no established pharmacological therapy. In the Prospective comparison of ARNI with angiotensin receptor blockers Global Outcomes in HFpEF (PARAGON-HF) trial, sacubitril/valsartan did not reduce the incidence of HF hospitalizations or CV death. However, the subgroup analysis showed that women and patients with lower EF should have a benefit from the treatment.268
In obesity-related HFpEF, underlying pathophysiological abnormalities may be related to derangements in beta-adrenergic drive and to increased aldosterone and neprylisin activity.120, 180 Thus, drugs acting against these pathways could be beneficial.269
In patients with HFpEF and diabetes, insulin treatment is associated with poor outcome.270 Moreover, neither furosemide nor torasemide was associated with effect on myocardial fibrosis in these patients.271 Given their anti-inflammatory and anti-fibrotic actions, SGLT-2 inhibitors might ameliorate cardiac remodelling also in HFpEF patients. Ongoing trials will assess whether such drugs will be extended to HFpEF.178
Novel specific Na+/Ca2+ exchanger inhibitor ORM-11035 is able to reduce cardiac remodelling and diastolic dysfunction with no effects on systemic blood pressure in rats. Considering the promising results, future trials are needed to evaluate the feasibility of such treatment also in humans.272
Acute heart failure
Epidemiology
Several precipitating factors may lead to acute HF, namely, arrhythmia, respiratory infections, and other non-CV factors.273 Worsening HF may develop in an outpatient or an inpatient setting, with a similar drastic increase in event rates.274, 275 The Heart Failure Registry of Patient Outcomes (HERO) study is a prospective, longitudinal multicentre registry including patients hospitalized with acute HF in China. In-hospital or 3 day post-discharge mortality was 3.2%. Death or readmission rate from the 4th day post-discharge to first follow-up was 22.4%.276 In the first 30 days after admission for acute HF, 2% of patients experience SCD or resuscitated SCD or ventricular tachycardia/fibrillation.277 In an Italian series, the 1 year mortality rate was 20%, with the highest risk of death during the index hospitalization.278 The admission department seems to play a role in the natural history of HF, with the general medicine department associated with a poor prognosis, probably due to different characteristics of patients (older age and several co-morbidities).278, 279
Management
Clinical signs, biomarkers, and imaging are essential in the diagnostic process, in-hospital monitoring, and pre-discharge evaluation of acute HF.280 The clinical classification of acute HF into four different profiles, defined by the presence of congestion and/or peripheral hypoperfusion,147 provides information on both early and long-term outcomes.281, 282 Signs and symptoms of congestion represent the major cause of HF hospitalization both in HFrEF and in HFpEF patients.283 Clinical residual congestion at discharge was detected in 30.9% of patients in the ESC-EORP-HFA Heart Failure Long-Term Registry, and it was associated with increased 1 year mortality (Figure4).281 The Reprieve System, a device that continuously measures urine output and supplies intravenous fluid to maintain fluid balance, may represent a useful tool to control decongestion.284
Classification based on congestion/hypoperfusion status assessed by clinical examination performed at admission and discharge. Classification at discharge was used in 7448 patients discharged alive. From Chioncel et al.281
The serial assessment of spot urine sodium predicts effectiveness of decongestion and outcome,285 as well as decrease in NT-proBNP levels.286, 287 Higher levels of mid-regional pro-adrenomedullin and its active form, bio-adrenomedullin, were observed in the presence of volume overload and have been proposed as markers of congestion.288 Mid-regional pro-adrenomedullin and bio-adrenomedullin provide a great accuracy in diagnosis of acute HF and detection of residual congestion.289, 290 Elevated levels of blood lactate, associated with hypoperfusion, and markers of multi-organ injury/dysfunction are predictors of poorer outcomes.291-293 Worsening renal function is only associated with adverse events in patients without decreased BNP.286 We are seeing the importance of assessing adequacy of the decongestive therapies in acute HF.294
Echocardiography estimates LV and RV filling pressure. Higher inferior vena cava diameter and lower jugular venous ratio are independently associated with poorer outcome also in outpatients.287 Lung ultrasound, through the assessment of B-lines, ensures an accurate tool for differential diagnosis of acute dyspnoea,295-297 has a prognostic value,287, 298 and has been proposed to guide diuretic treatment in outpatients with benefits.299 A recent expert consensus aims at standardizing approach in image acquisition methods and B-line quantification.300
Medical therapy
Treatment of acute HF may be divided into three phases—initial stabilization, after initial stabilization, and pre-discharge and post-discharge period.301 Decongestion is the main goal of acute HF therapy. Loop diuretics are the first choice in order to achieve euvolaemia, and diuretic resistance is associated with poorer outcomes.302 In patients at high risk for diuretic resistance, addition of acetazolamide may be useful.303, 304
Treatment of the acute phase failed to improve outcomes so far. Vasodilators seem to be neutral, although an excessive pressure drop is associated with kidney impairment and worse outcome.305 Inotropes and/or vasopressors are associated with an increased risk of all-cause death. Despite the neutral results of the second RELAX in Acute Heart Failure (RELAX-AHF-2) trial,306 a recent meta-analysis including serelaxin trials has shown that serelaxin reduces the risk of 5 day worsening HF and has beneficial effects on markers of renal function and cardiac damage.307 Furthermore, in the RELAX-AHF-EU study, serelaxin showed a reduction of worsening HF and all-cause death through Day 5 when added to standard of care therapy.308 Ongoing studies will assess tolerability and efficacy of BMS-986231, a novel nitroxyl donor with potential benefits on haemodynamics.309
Meanwhile, the optimization of oral treatment in the pre-discharge and post-discharge period plays a pivotal role in improving survival.310 Early initiation of sacubitril/valsartan before or shortly after discharge is safe and beneficial.154, 155 The STRONG-HF (Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies) trial will assess whether fast up-titration of GDMT can be a safe and feasible option in patients discharged after acute HF.311
Conclusions
We have summarized the most recent findings in HF discussing many aspects such as epidemiology, diagnosis, co-morbidities, and treatment. Despite improvements in treatment of HFrEF, HF is still a major cause of poor quality of life, morbidity, and mortality worldwide. However, major advances have been achieved recently in the medical management of HFrEF with the discovery of new therapeutic pathways, namely, SGLT-2 inhibitors, and with better treatment of co-morbidities. New devices are emerging for specific conditions such as sleep apnoea, and percutaneous treatment of mitral and tricuspid regurgitation may have a major impact on symptoms and clinical outcomes. HFpEF remains an unsolved issue, particularly in terms of diagnosis and treatment. Better patient phenotyping seems the next promising step. However, this hypothesis needs testing in properly designed clinical studies.
Conflict of interest
D.T. and M.A. declare that they have no conflict of interest. M.S.A. has received personal fees from Servier, outside the submitted work. SvH has been a paid consultant for and/or received honoraria payments from Bayer, Boehringer Ingelheim, BRAHMS, Chugai, Grünenthal, Helsinn, Hexal, Novartis, Pharmacosmos, Respicardia, Roche, Sorin, and Vifor. SvH owns shares in Actimed. SvH reports research support from IMI and the German Center for Cardiovascular Research (DZHK). M.M. has received in the last 3 years personal honoraria from Abbott Vascular, Actelion, Amgen, AstraZeneca, Bayer, LivaNova, Servier, Vifor Pharma, and Windtree Therapeutics for participation to trials' committees or advisory boards and speaker honoraria from Abbott Vascular, Edwards Therapeutics, and Servier.
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