Are you giving men with heart failure the best care?

Heart failure is a leading cause of morbidity and mortality worldwide. Management involves a comprehensive multidisciplinary approach focusing on symptom control, preventing disease progression and improving patients’ quality of life. Significant advances in recent years, including the introduction of combination angiotensin receptor‐neprilysin inhibitors and sodium‐glucose co‐transporter 2 inhibitors, have led to an improvement in long‐term prognosis.

H eart failure is a clinical syndrome defined by the European Society of Cardiology as symptoms of breathlessness and fatigue, which may be accompanied by signs such as peripheral oedema, pulmonary crackles and elevated jugular venous pressure.It is due to impaired cardiac function caused by structural or functional factors leading to reduced cardiac output or elevated intracardiac pressures (Table 1). 1 Heart failure is a leading cause of morbidity and mortality worldwide, affecting about 1-2% of all adults.Incidence and prevalence rise sharply with age and the average age of diagnosis in the UK is 77 years. 2 Patients with heart failure are admitted to hospital on average 1.3 times per year and represent 5% of acute hospital admissions, 2% of NHS bed days and 2% of the overall NHS budget. 2 Due to the progressive ageing of the UK population and rise in obesity, the overall number of patients with heart failure is increasing despite improvements in cardiovascular care. 3e primary causes of heart failure in developed countries are coronary artery disease, followed by hypertension. 4Mortality rates remain poor with five-year survival rates around 50%. 5 On average, men are almost five years younger than women at time of first diagnosis, and despite more evidence-based treatment have worse survival rates than women. 6his is likely in keeping with evidence demonstrating significantly higher relative risk of ischaemic heart disease in men compared with women, with a mortality rate ratio of 4-5 in middle age. 7here have been significant advances in the management of chronic heart failure in recent years, including the introduction of combination angiotensin receptor-neprilysin inhibitors (ARNi) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), with improvements in long-term prognosis for patients treated with these drugs. 8,9assification Heart failure can be classified in multiple ways -by acuity, symptom severity, cause or by left ventricular ejection fraction.
The New York Heart Association (NYHA) functional classification places patients in one of four classes based on limitations to physical activity (Table 2).The NYHA scale has been in use for nearly a century and is easily applied by health care providers without further investigations; however, it is acknowledged to be subjective with poor reproducibility. 10eart failure is frequently classified according to left ventricular ejection fraction as laid out in Table 3.Approximately 60% of patients have heart failure with reduced ejection fraction (HFrEF), 24% have heart failure with mildly reduced ejection fraction (HFmrEF) and 16% have heart failure with preserved ejection fraction (HFpEF). 11

Assessment
The initial assessment of heart failure is clinical, and patients presenting with dyspnoea, exercise limitation, fatigue, ankle swelling, paroxysmal nocturnal dyspnoea or orthopnoea should be considered for further investigation for heart failure.Initial workup is with chest X-ray, ECG and measurement of N-terminal-pro B-type natriuretic peptide (NT-proBNP). 2-proBNP is an inactive fragment peptide released by myocardial cells during the cleavage of precursor molecules into B-natriuretic peptide during episodes of myocardial wall stress.A threshold of <400ng/L is defined as the cut-off, and patients with symptoms of heart failure and elevated NT-proBNP should proceed to further investigations.Patients with elevated NT-proBNP should be referred for specialist assessment and ECHO within six weeks, and within two weeks if NT-proBNP is >2000ng/L. 2NT-proBNP increases with age and tends to be higher in women; it can also be elevated by conditions other than heart failure, which can lead to false-positive results (Box 1).

Management
Heart failure management involves a comprehensive approach focusing on symptom control, preventing disease progression and improving patients' quality of life.Treatment modalities include lifestyle modifications, drug therapy, device implantation and, in severe cases, heart transplantation.

Lifestyle
Lifestyle measures include effective control of hypertension alongside advice to stop smoking, remain at a healthy weight, take regular exercise and

Medical management
Inpatient management of symptomatic fluid overload secondary to heart failure is initially with loop diuretics such as furosemide or bumetanide, with target weight loss of 1kg/day, and daily measurement of renal function in those on intravenous diuretics. 2Although effective in producing diuresis and relieving symptoms, these drugs do not improve mortality after the first 30 days following discharge. 13edical management of chronic heart failure has seen significant advances in recent years, with several new drugs showing evidence of improvements in mortality.Treatment aims to improve mortality, reduce hospital admissions and improve symptoms and quality of life for patients.The distinction between HFrEF, HFmrEF and HFpEF guides strategies for long-term management.
In patients with HFrEF and HFmrEF, European Society of Cardiology (ESC) guidelines suggest combination treatment with four therapeutic agents: an angiotensin converting enzyme inhibitor (ACEi) or ARNi; beta-blockers; mineralocorticoid receptor antagonists (MRA), and SGLT2i (Figure 1).Both ARNi and SGLT2i are relatively new drugs offering a novel therapeutic approach and proven mortality benefit, and their introduction represents a significant advance in the management of heart failure.Historically initiation and uptitration of these drugs has been stepwise and incremental.However, recent trials have suggested a significant mortality benefit to rapid commencement and uptitration of all four agents within two weeks of discharge. 14vabradine, an I f channel inhibitor that reduces heart rate, may be used in symptomatic patients who have a left ventricular ejection fraction (LVEF) ≤35% if they are in sinus rhythm and have a resting heart rate <70 beats per minute, with evidence suggesting its use reduces heart failure hospitalisations and death. 2 There is also a limited role for hydralazine and isosorbide dinitrate in Black patients with LVEF ≤35% to reduce heart failure, hospitalisation and death. 2 Evidence for generalisation of this recommendation to other ethnic groups is not available, but the use of a combination of hydralazine and isosorbide dinitrate may be trialled in patients with symptomatic HFrEF who are unable to tolerate any ACEi, ARNi or ARB. 2 Heart failure is independently linked to iron deficiency, although the mechanisms remain unclear.ESC guidance advises periodic screening of heart failure patients for iron deficiency and anaemia, and repletion of iron stores if low, with trials suggesting this reduces heart failure admissions and death from cardiovascular causes. 2,15anagement of patients with HFpEF has proved challenging and historically  focused on diuresis for symptom control, without any demonstrated prognostic benefit from the treatment strategies used in HFrEF.However, recent trials have found that SGLTi (Figure 2) are the first drugs to show a mortality benefit in these patients, and addition of SGLT2i to diuretic therapy has recently been recommended in patients with HFpEF by NICE. 16,17any patients ultimately progress to persistent symptoms despite maximal medical therapy, and in those not suitable for mechanical circulatory support or consideration for heart transplant, palliative care may be an appropriate course. 2 Low-dosage opioids are frequently used to help with persistent symptomatic breathlessness and this is particularly relevant for patients with palliative heart failure who often suffer from severe breathlessness at rest.

Devices
Device therapy is indicated in patients with LVEF ≤35% due to their increased risk of sudden cardiac death.Implantable cardioverter-defibrillator devices reduce mortality in those with HFrEF, and this benefit is more pronounced in those with heart failure secondary to ischaemic heart disease. 18n patients with LVEF ≤35% and prolonged QRS morphology (≥130ms), cardiac resynchronisation therapy (CRT) may be indicated. 1CRT aims to use simultaneous pacing of the left and right ventricles to re-establish coordinated cardiac contraction in systole, improving cardiac output and leading to reductions in heart failure morbidity and mortality. 19CRT can be used alone (CRT-P) or combined with defibrillator if indicated (CRT-D).
Patients with advanced heart failure despite maximal medical therapy have a very poor prognosis.Carefully selected members of this subgroup may be candidates for left ventricular assist devices or heart transplant. 1 Use of left ventricular assist devices is currently limited to bridging therapy for patients awaiting cardiac transplant, although due to long wait times patients may remain on left ventricular assist devices for years. 1

Recent advances in heart failure
Sacubitril/valsartan is the only current ARNi.It combines valsartan, a well established angiotensin receptor blocking drug, with sacubitril, a neprilysin inhibitor.Neprilysin is an extracellular metalloprotease with a wide range of functions, including the degradation of vasoactive neurohormones such as natriuretic peptides, bradykinin and adrenomedullin.These neurohormones have significant beneficial neurohormonal effects such as diuresis and vasodilation.
Neprilysin also degrades angiotensin II, a key element of the renin-angiotensinaldosterone system (RAAS), and its inhibition raises levels of angiotensin II, counteracting its other favourable effects.The use of valsartan in combination with sacubitril permits effective neprilysin inhibition, while blocking receptors for Na + 2 Cl - K + ↑ Magnesium reabsorption Mg and K + redistribution from in to out cells

Sodium
angiotensin II, thereby reducing the deleterious effects on the RAAS system.ARNi is recommended as an alternative to ACEi in the guidelines.However, it has been shown to have a significant mortality benefit when compared with ACEi and is suggested as an alternative first-line treatment. 1,9he SGLT2i were initially developed to treat diabetes.They block the sodium-glucose co-transporter in the kidney, preventing both glucose and sodium resorption, and leading to effective natriuresis and glycosuria.Initial trials in patients with diabetes suggested a potential benefit in patients with heart failure, which has been confirmed in several large clinical trials. 20In addition, they appear to have renoprotective benefits and have an important role in the management of chronic kidney disease.SGLTi further improve outcomes when added to current best therapy and are recommended for all patients with HFrEF, regardless of presence of diabetes, unless contraindicated. 21,22ture horizons in heart failure treatment Novel therapeutic targets for treatment of heart failure have been identified and there are several promising approaches.
Soluble guanylate cyclase is a key element in the downstream nitric oxide signalling pathway, and its activation by nitric oxide has a number of beneficial effects, including vasodilation and decreased platelet aggregation.In heart failure it has the potential to decrease cardiac afterload, in addition to potential benefits in reversing heart failure associated cardiac fibrosis. 24Recent trials have shown a survival benefit in patients treated with vericiguat, a soluble guanylate cyclase stimulator. 25 Heart failure has long been known to be associated with elevated levels of arginine vasopressin, leading to inappropriate fluid retention and hyponatraemia.Initial trials with vasopressin receptor II (VRII) antagonists such as tolvaptan demonstrated favourable renal effects compared with furosemide for diuresis; however, no survival benefit was seen in heart failure patients. 26asopressin receptor Ia antagonists lead to vasodilation; however, no long-term data exist on any clinical benefit. 26Current trials are ongoing into the effects of balanced VRIa and VRII antagonists to assess for a potential survival benefit. 27

Heart failure considerations in men
Due to their earlier presentation, higher risk of having HFrEF and poorer prognosis, men are more likely to benefit from these recent advances in the care of chronic heart failure and clinicians involved in their care should be aware of the improvement in prognosis, as well as specific challenges.
Approximately 60-90% of patients with heart failure report sexual problems, and patients with heart failure report significantly more erectile dysfunction than age-matched peers. 28,29The underlying cause is often multifactorial, with dyspnoea, the effect of heart failure medications and physiological factors all feeding into symptoms. 30.The majority of heart failure medications mediate their beneficial effects at least partly through natriuresis, leading to increased urine output and frequency.Patients with long-term urological issues such as incontinence, or who have catheters, may find the increased frequency particularly challenging with significant effects on quality of life.
SGLT2i carry a particular risk, as they have their primary effect through glycosuria.They are therefore associated with an increased risk of genital infection. 31In patients with a propensity to urological infections, their use should be carefully considered for this reason and their use suspended in those with ongoing infection.

Conclusion
Recent developments in heart failure management have led to improved long-term outcomes for patients and ongoing research on novel drug targets holds the hope of further advances. 32or men in particular these advances are likely to be beneficial due to their earlier presentation and poorer prognosis compared with women.Clinicians should therefore ensure they are aware of the new developments and how best to implement them in the care of patients with heart failure.

Key points
• Patients with heart failure are admitted to hospital on average 1.3 times per year and represent 5% of acute hospital admissions, 2% of NHS bed days and 2% of the overall NHS budget • Mortality rates are poor with historic five-year survival rates around 50% • Heart failure can be classified in multiple ways -by acuity, symptom severity, cause or left ventricular ejection fraction • Heart failure management involves a comprehensive multidisciplinary approach focusing on symptom control, preventing disease progression and improving patients' quality of life • Patients with elevated NT-proBNP should be referred for specialist assessment and ECHO within six weeks, and within two weeks if NT-proBNP >2000ng/L • There have been significant advances in the management of chronic heart failure in recent years, including the introduction of combination angiotensin receptor-neprilysin inhibitors and sodiumglucose co-transporter 2 inhibitors

Figure 1 .
Figure 1.European Society of Cardiology (ESC) guidance on management of chronic stable heart failure in patients with reduced ejection fraction. 1(From McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J 2021;42;3599-726.www.escardio.org/Guidelines.By permission of Oxford University Press on behalf of the European Society of Cardiology)

Figure 2 .
Figure 2. Effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on serum electrolytes. 23(From Cianciolo G, De Pascalis A, Gasperoni L, et al.The off-target effects, electrolyte and mineral disorders of SGLT2i.Molecules 2020;25:2757, under the terms of https://creativecommons.org/licenses/by/4.0/) TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European

Heart failure is a leading cause of morbidity and mortality worldwide. Management involves a comprehensive multidisciplinary approach focusing on symptom control, preventing disease progression and improving patients' quality of life. Significant advances in recent years, including the introduction of combination angiotensin receptor-neprilysin inhibitors and sodium-glucose co-transporter 2 inhibitors, have led to an improvement in long-term prognosis.
Are you giving men with heart failure the best care?George Hogan, IMT Trainee; 1 Hiten Patel, Consultant Cardiologist; 1 Nikhil R Patel, Consultant Cardiologist and Cardiovascular Director 2 1. Eastbourne District Hospital, UK; 2. East Sussex NHS Healthcare Trust, UK 2History should assess for previous cardiovascular disease,

Table 1 .
Causes of heart failure

Table 2
. New York Heart Association (NYHA) classification of heart failure by function Class Heart failure classification by function Class I No limitation of physical activity Class II Slight limitation of physical activity.Comfortable at rest.Ordinary physical activity results in fatigue, palpitation, dyspnoea Class III Marked limitation of physical activity.Comfortable at rest.Less than ordinary activity causes fatigue, palpitation or dyspnoea Class IV Unable to carry on any physical activity without discomfort.Symptoms of heart failure at rest Eur Heart J 2021;42;3599-726.www.escardio.org/Guidelines.By permission of Oxford University Press on behalf of the European Society of Cardiology) Abbreviations: ACEi, angiotensin converting enzyme inhibitor; ARNi, angiotensin receptor-neprilysin inhibitor; CRT-D, cardiac resynchronisation therapy with defibrillator; CRT-P, cardiac resynchronisation therapy pacemaker; ICD, implantable cardioverter-defibrillator; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; QRS, Q, R, and S waves of an ECG; SR, sinus rhythm.a As a replacement for ACEi.b Where appropriate.