A year in heart failure: an update of recent findings

Introduction

Heart failure (HF) remains a major cause of morbidity and mortality worldwide, with a 5 year mortality rate close to 50%.1-3 Progress has occurred in its management with major randomized controlled trials finally showing positive findings.4 This article aims to providing an update of the most recent findings.

Epidemiology

Data about epidemiology of HF are still limited. The overall prevalence of HF ranges from about 1.5% to 4% in developed countries (Figure 1).2, 3, 5, 6 It has been growing in the last years likely because of ageing of the population and the improvement in HF treatment.2, 7 No major difference can now be found between European and Asian countries, including China.8, 9 The Heart Failure Association (HFA) Atlas aimed to establish a reliable contemporary European dataset on HF epidemiology, resources, and reimbursement policies.10 In this survey, the median incidence of HF was 3.2 cases [interquartile range (IQR) 2.66–4.17] per 1000 person-years, while the median HF prevalence was 17.20 (IQR 14.30–21) cases per 1000 people (Figure 1).5

image Prevalence of heart failure in population-based studies worldwide, shown as percentage of the total population (upper panel, from Groenewegen et al.2) and in Europe, shown as number per 1000 people (lower panel, from Seferović et al.5). Sex-related differences

Overall, the lifetime risk of HF in men and women is comparable.11, 12 Women more frequently develop HF with preserved ejection fraction (HFpEF), probably due to the higher prevalence of obesity and diabetes mellitus (DM),13 whereas men mainly develop HF with reduced ejection fraction (HFrEF), because of their predisposition to ischaemic cardiomyopathy.14 Sex differences in biomarker profiles have been highlighted.15

Differences in outcomes were investigated in 9428 patients with chronic HF from the European Society of Cardiology (ESC) HF Long-Term Registry. Compared with men, women had lower rates of all-cause mortality and HF hospitalization at 1 year.7 Sex was not an independent predictor of outcome. The use of guideline-directed medical therapy (GDMT) was lower in women than in men, probably due to older age and comorbidity. Even though no sex-related differences have been noted in the effect of therapies, a recent post hoc analysis including eight major randomized clinical trials (RCTs) suggested that women might benefit from treatment also with higher left ventricular ejection fraction (LVEF) values (Figure 2).16 Of note, women are consistently under-represented in HF clinical trials, contributing to remarkable research bias.17, 18

image Variation of treatment effect with left ventricular ejection fraction (LVEF) in heart failure. Dotted curves show normalized distribution of LVEF in men and women. Solid lines show a continuous hazard ratio for the primary composite and its components, according to treatment group in the range of LVEF included. The shaded areas represent the 95% confidence intervals. Primary outcome (heart failure hospitalization/cardiovascular death): (A) candesartan vs. placebo; (B) mineralocorticoid receptor antagonist (MRA) vs. placebo; (C) sacubitril/valsartan vs. renin–angiotensin–aldosterone system inhibitor. Heart failure hospitalization: (D) candesartan vs. placebo; (E) MRA vs. placebo; (F) sacubitril/valsartan vs. renin–angiotensin–aldosterone system inhibitor. Cardiovascular death: (G) candesartan vs. placebo; (H) MRA vs. placebo; (I) sacubitril/valsartan vs. renin–angiotensin–aldosterone system inhibitor (from Dewan et al.16). Comorbidities

Comorbidities have a substantial impact on clinical presentation and outcomes in HF patients.19 Screening for and treatment of cardiovascular (CV) comorbidities and non-CV comorbidities is recommended.1 CV comorbidities include hypertension,20 coronary artery disease,21 atrial fibrillation (AF),22 ventricular arrhythmias, valvular heart disease,23-25 cerebrovascular disease, and pulmonary hypertension. Non-CV comorbidities include chronic kidney disease26, 27 and electrolyte disorders,28, 29 DM,30 obesity,31-34 cachexia,35-38 sarcopenia,37-42 chronic obstructive pulmonary disease,19, 43 iron deficiency44, 45 and anaemia,46, 47 thyroid disorders,48 cancer,49-51 infection,52, 53 arthritis,54, 55 frailty,56, 57 and depression. The clinical burden of comorbidities differs between patients with HFrEF and those with HFpEF.58-60 Some examples of the role of comorbidities are given below.

Frailty and muscle wasting have been object of active research in these last years. Frailty is defined as a state of vulnerability related to elderly age, which confers a poor prognosis due to increased rates of mortality, institutionalizations, falls, and hospitalizations.37, 57, 61-64 It is the result of impaired homeostatic mechanisms and reduced resistance to stressors that might be the consequence of bone65 and muscle wasting (sarcopenia) or cachexia, both of which have been shown to be independently associated with increased mortality.31, 39, 66 Muscle wasting has been described across a vast spectrum of HF aetiologies including ischaemic cardiomyopathy and Chagas disease,67 and the importance of more clinical and therapeutic action has been highlighted in recent years.63, 64, 68 In a retrospective analysis of PARADIGM-HF [Prospective comparison of angiotensin receptor-neprilysin inhibitors with angiotensin-converting enzyme inhibitors to Determine Impact on Global Mortality and morbidity in HF] and ATMOSPHERE (Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure), 63% of patients with HF were considered frail, based on a Frailty Index > 0.21.62 HFA of the ESC has recently proposed a new Frailty Score, based on four main domains—clinical, functional, psycho-cognitive, and social.57

Diagnosis and prognosis

The diagnosis of HF requires the presence of symptoms and/or signs of HF (e.g. breathlessness, fatigue, ankle swelling, pulmonary crackles, elevated jugular venous pressure, and peripheral oedema) and objective evidence of cardiac dysfunction.1, 69 Because signs and symptoms are often non-specific, investigation through biomarkers and imaging is essential for the diagnosis and management.1, 69, 70

Clinical signs

Vital signs are predictors of outcome. The role of heart rate in patients with AF and HF may differ in patients in sinus rhythm or AF.71 Higher heart rate was found to be an independent predictor of CV poor outcome in patients with HFrEF in sinus rhythm but not in those with AF, although an effect of a higher heart rate on mortality was found during the first years of follow-up also in patients with AF in one study from the Swedish HF registry.71, 72

Laboratory exams

Assessment of biomarkers is a cornerstone of HF management.73-76 Abnormalities of serum potassium levels are associated with poorer outcomes either when low or high. Studies showed a U-shaped association between serum potassium concentrations and mortality, with a potassium level of 4.2 mmol/L related to the lowest risk of death.77 In a cohort of patients from the Swedish HF Registry, hypokalaemia was associated with increased mortality both in short term and in long term, whereas hyperkalaemia in short term only. Hyperkalaemia can lead to underuse and premature discontinuation of renin–angiotensin–aldosterone system inhibitors (RAASi) and be associated with increased mortality mainly through this mechanism.1

Imaging

Imaging techniques allow the evaluation of left and right ventricular function, valvular disease, congestion, and pulmonary pressure. Clinical presentation and natural history of HFrEF may change depending on left ventricular (LV) geometry remodelling.78 Initial ventricular dysfunction leads to early shortening of LV systolic ejection time (SET) and lengthening of pre-ejection periods (PEPs). Among 545 ambulatory patients with HF, median SET was shorter and median PEP was longer in those with reduced LVEF compared with those with preserved LVEF. In addition, longer SET was independently associated with improved outcome in HFrEF but not in HFpEF patients.79 Pulmonary hypertension and right ventricular dysfunction are further markers of poor outcome.80

Two-dimensional and three-dimensional echocardiography, myocardial deformation, computed tomography (CT), and cardiac magnetic resonance (CMR) allow the assessment of atrial size and function. ‘Atrial disease’, also referred as atrial failure or myopathy, represents an intersection of subclinical structural, electrophysiological, and functional changes that primarily affect the atria with the potential to produce clinical consequences.1 In a cohort of subjects with LVEF ≥ 50% referred for assessment of exertional dyspnoea, who underwent simultaneous echocardiography and right heart catheterization, left atrial (LA) reservoir and pump strain correlated with exercise pulmonary capillary wedge pressure. Reservoir strain at cut-off of ≤33% predicted invasively verified HFpEF diagnosis with 88% sensitivity and 77% specificity, providing diagnostic utility in patients with exertional dyspnoea.81

Risk predicting models

Prognostic scores can be important to guide therapeutic strategies in HF and machine learning techniques may provide additional accuracy.82 The Machine learning Assessment of RisK and EaRly mortality in Heart Failure (MARKER-HF) score is a new predicting risk score derived from a machine learning algorithm based on eight simple variables (diastolic blood pressure, creatinine, blood urea nitrogen, haemoglobin, white blood cell count, platelets, albumin, and red blood cell distribution width) that showed high power in predicting mortality (area under the curve 0.88).83 In a hospital-based cohort of 4064 patients, MARKER-HF was substantially more accurate than LVEF in predicting mortality and was highly accurate in all three HF subgroups according to LVEF (HFrEF, HFmrEF, and HFpEF), with c-statistics between 0.83 and 0.89.84

Specific causes of heart failure Cardiomyopathies

Cardiomyopathies, including dilated (DCM), hypertrophic (HCM), restrictive (RCM), arrhythmogenic right ventricular (ARVC), and non-classified cardiomyopathies, represent a heterogeneous group of heart muscle diseases causing HF.85-88 The electrocardiogram (ECG) may be very helpful for the first approach to patients with suspected DCM. Red flags based on ECG or clinical signs can help identifying specific DCM forms.89, 90 Survival of patients with DCM is improved. Over 20% of patients with DCM can show LV reverse remodelling, with a much favourable prognosis compared with other forms of cardiomyopathies.91

Hypertrophic cardiomyopathy is a genetic disorder causing LV hypertrophy, hypercontractility, and impaired diastolic function. Novel treatment strategies are being developed, including pharmacotherapy (e.g. mavacamten, a modulator of cardiac β-myosin, causing reversible inhibition of actin–myosin cross bridging), septal reduction techniques (e.g. surgical papillary muscle realignment and radiofrequency ablation), biventricular pacing,92 mitral valve manipulation (e.g. percutaneous repair in order to reduce systolic anterior motion-septal contact in patients who are unsuitable for septal reduction techniques), and gene-based therapies.93

A consensus document summarizing recommendations for the CV management in Fabry disease has been recently published.94 Fabry disease is a lysosomal storage disorder caused by total or partial deficit of α-galactosidase A enzyme activity. Early diagnosis and treatment with enzyme replacement or small pharmacological chaperones may prevent cardiac involvement.

Cardiac amyloidosis

Cardiac amyloidosis (CA) is an underestimated cause of HF. Transthyretin (TTR) CA (ATTR-CA) accounts for 12–13% of HFpEF cases95 and between 8% and 16% cases of severe aortic stenosis (AS) scheduled for percutaneous aortic valve replacement.96 Of note, amyloid deposition did not worsen prognosis of patients undergoing transcatheter aortic valve replacement (TAVR).96 A novel algorithm for the diagnosis of CA has been recently proposed (Figure 3).1, 97 In the last years, major advances occurred in the treatment of ATTR-CA. Targeted therapies interfering with TTR deposition include TTR tetramer stabilizers (tafamidis, diflunisal, and epigallocatechin-3-gallate), TTR silencers (inotersen and patisiran), and fibril disruptors (monoclonal antibodies, doxycycline, and tauroursodeoxycholic acid).98 Tafamidis is now recommended in patients with TTR-CA and New York Heart Association (NYHA) class I or II symptoms to reduce symptoms, CV hospitalization, and mortality.1

image Diagnostic algorithm for cardiac amyloidosis. AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CMR, cardiac magnetic resonance; ECG, electrocardiogram; SPECT, single photon emission computed tomography; TTR, transthyretin (from Garcia-Pavia et al.97). Cancer

Cancer and HF have a bidirectional relationship.99-102 First, muscle wasting caused by cancer, that is, sarcopenia, can involve also the heart causing ‘cardiac wasting-associated cardiomyopathy’ (Figure 4).102 Moreover, cancer therapies are often cardiotoxic.51, 103 Main cardiotoxic drugs include anthracyclines, fluoropyrimidines, tyrosine kinase inhibitors, HER2-targeted therapies such as trastuzumab, and immune checkpoint inhibitors.51 In a cohort of 569 women who underwent breast cancer treatment, Jacobse et al. found that anthracyclines were associated with impaired myocardial function [decrease in LVEF, impaired global longitudinal strain (GLS), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels]. The risk of HF increased with cumulative doses of anthracyclines.104 Radiotherapy without anthracyclines was not associated with increased risk of HF.105 Troponins and NP should be measured during treatment being important markers of early cardiac injury.51, 106 In a recent meta-analysis, lower levels of cardiac troponin in patients undergoing cancer therapy showed a negative predictive value for LV dysfunction of 93%. On the other hand, NT-proBNP levels, despite increasing during cancer treatment, apparently did not predict LV dysfunction.107 In a study on 548 treatment-naïve patients, a higher heart rate at rest was associated with higher levels of cardiac biomarkers and higher rates of all-cause mortality, especially in lung and gastrointestinal cancers.108 In a prospective study including 120 unselected patients with lung, colon, or pancreatic cancer and 43 healthy controls, the prevalence of non-sustained ventricular tachycardia was higher in cancer patients vs. controls and it was associated with a higher risk of mortality.109 A CV risk stratification at baseline is useful in order to optimize the primary and secondary prevention. Closer surveillance should be deserved for patients at high CV risk.110

image The heart of cancer patients. CAD, coronary artery disease (from Anker et al.102). Treatment of heart failure with reduced ejection fraction

Pharmacotherapy is the cornerstone of HFrEF treatment in order to reduce mortality, prevent worsening HF, and improve clinical status, functional capacity, and quality of life (QOL).1, 111 GDMT includes neurohormonal antagonists and the novel sodium-glucose co-transporter 2 (SGLT2) inhibitors. New compounds may expand the spectrum of HFrEF pharmacotherapy with the possibility of an individualized approach112 (Figure 5).

image

Foundational therapies in HFrEF patients and new compounds that may expand the spectrum of HFrEF pharmacotherapy, with the possibility of an individualized approach. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor-neprilysin inhibitor; FCM, ferric carboxymaltose; HFrEF, heart failure with reduced ejection fraction; HR, heart rate; ID, iron deficiency; MRA, mineralocorticoid receptor antagonist; OM, omecamtiv mecarbil; SGLT2, sodium-glucose co-transporter 2; SR, sinus rhythm.

Neurohormonal modulators

Neurohormonal modulators include the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan (possibly as first-line therapy), or an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB) if ACEi is not tolerated, a beta-blocker and a mineralocorticoid receptor antagonist (MRA).1 Despite the widespread knowledge about the importance of initiating and titrating GDMT,113 only a minority of eligible patients receive all the medications proven to be effective in preventing death and hospitalizations.114 Moreover, a significant proportion of patients never receives target doses used in the landmark trials.111, 115, 116 The underuse and underdosing is particularly evident in elderly subjects.7, 111 In an analysis of the Swedish HF Registry, beta-blockers were associated with a reduced risk of all-cause mortality and CV events also in older patients.117

European real-world evidence about sacubitril/valsartan treatment in HFrEF has been recently reviewed.118 Sacubitril/valsartan may be safely initiated in hospital or early after discharge in patients hospitalized for acute HF.119 Sacubitril inhibits neprilysin, a protease responsible for BNP cleavage. Effects of sacubitril/valsartan treatment on NPs trajectory have been studied, showing an increase in atrial natriuretic peptide (ANP) and no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in NT-proBNP concentrations.120

In a recent subgroup analysis of the TRANSITION study (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event), the use of sacubitril/valsartan as a first-line therapy was associated with a better risk–benefit profile in patients with de novo HF than those with known HFrEF, with more subjects reaching the target dose, greater decrease in NT-proBNP and high-sensitivity cardiac troponin T levels, and lower rates of HF or all-cause hospitalization.121 The OUTSTEP-HF study was a randomized controlled trial comparing short-term effects of sacubitril/valsartan vs. enalapril on daily physical activity in patients with chronic HFrEF. After 12 weeks of treatment, a trend towards longer distance 6 min walking test was observed in patients receiving sacubitril/valsartan, albeit not statistically significant.122

Sodium-glucose co-transporter 2 inhibitors

Type 2 DM is a risk factor for incident HF, a common comorbidity in patients with established HF, and it is associated with significant morbidity and mortality.123 Randomized trials in patients with DM at risk of CV events showed a reduction in HF hospitalizations and renal endpoints with multiple SGLT2 inhibitors.1, 30, 124-126 In 2019, DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) was the first trial proving benefits of dapagliflozin in patients with HFrEF, regardless of diabetes history, with a 26% reduction of the composite endpoint of CV death or worsening HF [hazard ratio (HR), 0.74; 95% confidence interval (CI), 0.65 to 0.85; P < 0.001] as well as its components of CV death and first HF events.127, 128 In 2020, the Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) trial confirmed these positive results with empagliflozin in HFrEF patients with a slightly increased risk for HF events likely because of the higher NT-proBNP levels required for study entry.129 Compared with placebo, empagliflozin reduced the primary outcome of CV death or HF hospitalizations by 25% (HR, 0.75; 95% CI, 0.65 to 0.86; P < 0.001).130 The empagliflozin group also showed a slower decline of the estimated glomerular filtration rate (eGFR) compared with the placebo group (−0.55 vs. −2.28 mL/min/1.73 m2 of body surface area per year, P < 0.001).130 In the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial, patients with a recent episode of worsening HF (irrespective of LVEF) and diabetes were randomized to sotagliflozin (a combined SGLT1/2 inhibitor) or placebo. Sotagliflozin was effective in the reduction of the total number of deaths from CV causes and hospitalizations or urgent visits for HF.131 SGLT2 inhibitors have therefore shown beneficial effects on the clinical course of HF and kidney dysfunction, independent from neurohormonal mechanisms.4, 30, 125, 126 Their mechanisms of action are likely multifactorial and include enhanced natriuresis and osmotic diuresis, anti-inflammatory and antioxidant effects, improved myocardial metabolism and function, autophagy stimulation, and intracellular sodium reduction.123, 132, 133

Dapagliflozin and empagliflozin are now recommended in all patients with HFrEF to reduce mortality and HF events.1 This class of drugs is a cost-effective treatment in the European health care systems.134

Diuretic therapy

Most patients with chronic HF are on loop diuretic therapy to relieve congestion and improve symptoms.135 Higher doses of loop diuretics are associated with worse outcomes, and guidelines recommend usage of the lowest effective dose of loop diuretics needed to relieve congestion.1, 28, 136 In an analysis from the ESC-EORP Heart Failure Long-Term Registry, Kapelios et al. showed that an increase in diuretic dose was associated with HF death, while down-titration with a trend for better outcomes.135

Iron deficiency

Clinical or subclinical iron deficiency is a common finding in HF patients, affecting up to 50% of ambulatory patients and leading to poorer prognosis and exercise intolerance.137, 138

Treatment of iron deficiency with ferric carboxymaltose (FCM) infusion improved symptoms, functional capacity, and QOL in chronic HFrEF.139-141 Efficacy on symptoms may be slightly larger in patients with HFrEF than with HFpEF.142 In the Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute Heart Failure and Iron Deficiency (AFFIRM-HF), the use of intravenous FCM in patients hospitalized for acute HF, an LVEF < 50%, and with evidence of iron deficiency reduced HF hospitalization at a 52 week follow-up (rate ratio, 0.74; 95% CI, 0.58 to 0.94, P = 0.013).143 This effect was consistent with previous meta-analyses,144 and independent from many baseline variables, including LVEF and kidney function.143 Treatment of iron deficiency with intravenous FCM is therefore indicated to improve symptoms and reduce HF rehospitalizations in either outpatients with chronic HF or patients hospitalized for acute HF with an LVEF < 45–50%.1, 145

Soluble guanylate cyclase stimulators

Vericiguat is an oral soluble guanylate cyclase (sGC) stimulator.146 It may improve endothelial function and reduce oxidative stress and inflammation.147 In the Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction (VICTORIA) trial, vericiguat, in addition to guideline-based medical therapy, reduced the composite outcome of death from CV causes or first hospitalization for HF (HR, 0.90; 95% CI, 0.82 to 0.98; P = 0.02) in patients with a history of recent hospitalization or who had received intravenous diuretic therapy.148 According to this trial, it may be considered in patients with a recent HF event to improve outcomes.1, 149

Myosin activators

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that targets only the sarcomere with no influence on Ca2+ transients. In the G

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