Heart Failure with Preserved Ejection Fraction (HFpEF)

One of the most complicated and quickly expanding cardiovascular disorders in the world today is heart failure with preserved ejection fraction (HFpEF). HFpEF is now recognised as a separate clinical syndrome linked to significant morbidity, frequent hospitalisations, impaired functional capacity, poor quality of life, and mortality rates comparable to those of heart failure with reduced ejection fraction (HFrEF), which was once thought to be a milder or less malignant form of heart failure.^{[1][2][8][10]} HFpEF has become a significant unmet need in modern cardiovascular medicine due to its rising prevalence and the scarcity of disease-modifying treatment options. Exertional dyspnoea, exhaustion, exercise intolerance, pulmonary congestion, and peripheral oedema are among the common symptoms and indicators of heart failure that are present in patients with a left ventricular ejection fraction (LVEF) ≥50%. In addition, there is objective evidence of cardiac structural abnormalities, functional impairment, and/or elevated left ventricular filling pressures.^[3] In order to establish the diagnosis, diagnostic frameworks like the HFA–PEFF algorithm highlight the integration of clinical symptoms, echocardiographic measures, natriuretic peptide levels, and functional tests.³ Despite these developments, the dynamic nature of haemodynamic disorders and symptom overlap with non-cardiac diseases make diagnosing HFpEF difficult.
From a pathophysiological standpoint, HFpEF and HFrEF are essentially distinct. HFpEF is defined by aberrant ventricular–vascular coupling, concentric left ventricular remodelling, increased myocardial stiffness, and poor diastolic relaxation, whereas systolic dysfunction predominates in HFrEF. ^[1][11] Exercise intolerance and congestion are caused by these anomalies, which raise left ventricular filling pressures, especially during exertion. Beyond the heart, endothelial dysfunction, persistent low-grade inflammation, microvascular dysfunction, autonomic imbalance, and involvement of extracardiac organs such as the kidneys, lungs, skeletal muscle, and adipose tissue are all part of the growing recognition of HFpEF as a systemic condition. ^[1][2][4] Significant socioeconomic and demographic shifts are reflected in the epidemiology of HFpEF. Due in large part to population ageing and the growing burden of cardiometabolic comorbidities such hypertension, obesity, diabetes mellitus, atrial fibrillation, and chronic renal disease, the prevalence of HFpEF has gradually increased over the past 20 years. Significant socioeconomic and demographic shifts are reflected in the epidemiology of HFpEF. Due in large part to population ageing and the growing burden of cardiometabolic comorbidities such hypertension, obesity, diabetes mellitus, atrial fibrillation, and chronic renal disease, the prevalence of HFpEF has gradually increased over the past 20 years. ^[5][6] Currently, at least 50% of all cases of heart failure are HFpEF, with a disproportionately higher prevalence among women and older people. According to temporal trend analysis, the incidence of HFpEF is rising in comparison to HFrEF, and as life expectancy increases globally, HFpEF is expected to become the predominant heart failure phenotype. ^[6][11] Clinically, patients with HFpEF have a chronic, relapsing course characterised by numerous hospital hospitalisations and recurrent episodes of decompensation. Volume overload, uncontrolled hypertension, arrhythmias, especially atrial fibrillation, or deteriorating non-cardiac diseases are frequently the causes of these events. ¹ Hospitalisation rates in HFpEF are comparable to those in HFrEF, and results after release are still subpar. Crucially, long-term mortality in HFpEF is similar to that of HFrEF, refuting the long-held belief that a good prognosis is associated with retained ejection fraction. ^[7][8][10] One distinguishing feature and significant issue with HFpEF is its substantial fluctuation. Instead of being a single disease entity, HFpEF is a syndrome with a range of clinical symptoms brought on by multiple overlapping pathophysiological pathways. ^[12] Phenotypic variations may be affected by dominant comorbidities such as obesity, hypertension, atrial fibrillation, pulmonary hypertension, or renal dysfunction that lead to distinct biochemical pathways and clinical trajectories. This heterogeneity has been widely blamed for the inability of traditional heart failure medications, which were mostly developed for HFrEF, to consistently demonstrate mortality benefits in HFpEF groups. ^[2][9][10] Therapeutic development has been made more difficult by the use of left ventricular ejection fraction as the main categorisation criterion. Ejection fraction by itself fails to effectively represent the underlying biology of HFpEF and obscures important mechanistic targets, according to recent investigations and expert consensus.^[11] In order to identify populations most likely to benefit from tailored interventions, modern research has evolved towards refined phenotyping, biomarker-driven techniques, and precision medicine strategies.^[11] When taken as a whole, these revelations highlight the necessity of a paradigm change in the knowledge, diagnosis, and treatment of HFpEF.

2. Epidemiology and Risk Factors

2.1 Epidemiology

Heart failure with preserved ejection fraction (HFpEF) accounts for a significant and increasing share of the burden of heart failure worldwide. According to recent epidemiological research, HFpEF makes up at least 50% of all cases of heart failure, and its incidence is still rising in comparison to heart failure with reduced ejection fraction (HFrEF)).^{[12] [15]}The increased frequency of cardiometabolic risk factors, better survival from cardiovascular illnesses, and demographic changes are all contributing causes to this epidemiological shift. The incidence and prevalence of HFpEF have steadily increased over the previous two to three decades, according to population-based research from North America and Europe. According to temporal trend analysis, the incidence of HFpEF has continued to climb while that of HFrEF has stabilised or decreased, making HFpEF the predominant heart failure phenotype in many areas. ^[13], Similar patterns, which coincide with urbanisation, population ageing, and rising incidence of hypertension, obesity, and diabetes mellitus, are increasingly being documented from low- and middle-income nations ^[15][16] Elderly people are disproportionately affected by HFpEF, and its prevalence rises significantly after the age of six. This connection is influenced by age-related cardiac stiffness, vascular dysfunction, and the development of comorbidities. ^[12][14]Furthermore, women are more likely to have HFpEF; in many cohorts, they account for nearly two-thirds of affected patients. Hormonal effects, sex-related variations in ventricular remodelling, and the increased incidence of obesity and hypertension in older women have all been suggested as contributing causes. ^[17][18] HFpEF is linked to significant morbidity and unfavourable outcomes even while systolic function is intact. Recurrent admissions are a characteristic of the course of the disease, and hospitalisation rates for HFpEF are similar to those seen in HFrEF. Over long-term follow-up, mortality rates in HFpEF, although marginally lower in some studies, approach those of HFrEF, especially among older patients and those with a substantial comorbidity burden. üge Crucially, a higher percentage of deaths in HFpEF than in HFrEF are due to non-cardiovascular reasons, such as infections, renal failure, and metabolic problems, highlighting the systemic character of the condition. ^[14][19][20]

2.2 Risk Factors

Numerous cardiovascular and non-cardiovascular risk factors, many of which work in concert to cause myocardial, vascular, and systemic dysfunction, are closely linked to HFpEF. Chronic pressure overload, metabolic stress, inflammation, and multisystem comorbidity are the main causes of HFpEF, in contrast to HFrEF, where ischaemic heart disease predominates. ^[21]

Age

The biggest non-modifiable risk factor for HFpEF is getting older. higher myocardial fibrosis, poor calcium handling, endothelial dysfunction, and arterial stiffening are all linked to ageing and can lead to diastolic dysfunction and higher ventricular filling pressures.

Sex

One independent risk factor for HFpEF is female sex. Concentric left ventricular remodelling, increased arterial stiffness, and increased sensitivity to pressure overload are more common in women. Women may be more susceptible to HFpEF due to hormonal changes that occur after menopause as well as sex-specific inflammatory and microvascular reactions. ^[17][18]

Hypertension

Up to 60–90% of individuals have hypertension, which is the most common and potent modifiable risk factor for HFpEF. Long-term pressure overload causes myocardial stiffness, poor relaxation, and left ventricular hypertrophy. Hospitalisation and HFpEF decompensation are frequently caused by poorly managed hypertension. ^[12][16]

Obesity

A unique HFpEF phenotype is defined by obesity, which is a key factor in the pathophysiology of HFpEF. Systemic inflammation, insulin resistance, increased plasma volume, elevated cardiac workload, and poor ventricular–vascular coupling are all facilitated by excess obesity. Lower natriuretic peptide levels, difficulties with diagnosis, and worsened exercise intolerance are common in obese patients with HFpEF. ^[22][23]

Diabetes Mellitus

Patients with HFpEF frequently have diabetes mellitus, which is linked to poorer outcomes. Insulin resistance, hyperglycemia, and advanced glycation end products accelerate diastolic dysfunction by causing cardiac fibrosis, microvascular dysfunction, and decreased energy efficiency. ^[21][24]

Atrial Fibrillation

HFpEF and atrial fibrillation (AF) often coexist and have reciprocal pathophysiological connections. The symptoms of HFpEF are made worse by increased atrial pressure, uneven ventricular filling, and loss of atrial contraction. ^[25]

Chronic Kidney Disease

Volume overload, neurohormonal activation, inflammation, and vascular calcification are all exacerbated by chronic kidney disease (CKD), which is prevalent in HFpEF. Due to diuretic resistance and a lack of effective treatments, CKD worsens prognosis and makes management more difficult.

Additional Contributing Elements

Anaemia, systemic inflammatory states, obstructive sleep apnoea, chronic obstructive pulmonary disease, and coronary microvascular dysfunction are additional risk factors. The idea that HFpEF is a multisystem ailment rather than a singular heart condition is supported by these comorbidities. ^[20][21]

3. Pathophysiology Of HFPEF

Heart failure with preserved ejection fraction (HFpEF) is a complex, multifactorial disease that is caused by interactions between myocardial, vascular, systemic, and extracardiac issues. Although left ventricular systolic function is preserved, heart failure with reduced ejection fraction (HFpEF) is characterised by abnormalities in diastolic function, ventricular–vascular coupling, and systemic inflammation. These abnormalities ultimately lead to elevated cardiac filling pressures and exercise intolerance. Heart failure with reduced ejection fraction (HFrEF), on the other hand, is mostly brought on by compromised systolic function. ^[27][28]

1. Left ventricular diastolic dysfunction

Diastolic dysfunction is one of the primary features of HFpEF. It comprises inadequate myocardial relaxation in early diastole and increased passive stiffness in late diastole. Anomalies in calcium handling inside cardiomyocytes that lead to delayed relaxation include decreased sarcoplasmic reticulum calcium reuptake and altered phosphorylation of regulatory proteins. Increased myocardial stiffness is caused by hypertrophy, concentrated left ventricular remodelling, and excessive interstitial collagen deposition. Changes in the major sarcomeric protein titin, particularly hypophosphorylation, further enhance cardiomyocyte stiffness. ^[29] These changes lead to elevated left ventricular end-diastolic pressures both at rest and, more prominently, during exercise.

2. Abnormalities in Ventricular–Vascular Coupling
Abnormal ventricular–vascular coupling, which reflects increased arterial stiffness and decreased vascular compliance, is a characteristic of HFpEF. Increased aortic stiffness, which raises systolic blood pressure and widens pulse pressure, is a result of ageing, hypertension, and endothelial dysfunction. ^[27][30] Through concentric remodelling, the left ventricle adapts, maintaining ejection fraction while compromising diastolic filling. Exaggerated increases in filling pressures and a reduced cardiac output reserve are the results of this maladaptive interaction between the ventricle and artery system, which increases haemodynamic stress, especially during exercise. ^[28][31]

3. Endothelial Dysfunction and Microvascular Disease

The pathogenesis of HFpEF is significantly influenced by coronary microvascular dysfunction. Chronic low-grade inflammation is encouraged by systemic comorbidities such obesity, diabetes, and hypertension. This results in endothelial activation and decreased nitric oxide bioavailability. Nitric oxide–cyclic guanosine monophosphate–protein kinase G (NO–cGMP–PKG) signalling impairment causes cardiac hypertrophy and fibrosis and decreases cardiomyocyte relaxation. ^[28][32]Even in the absence of obstructive coronary artery disease, myocardial ischaemia is made worse by microvascular rarefaction and reduced coronary flow reserve, which contribute to diastolic dysfunction.^[32]

4. Systemic Inflammation and Comorbidity-Driven Mechanisms

It is becoming more well acknowledged that HFpEF is a systemic inflammatory condition caused by cardiometabolic comorbidities. Increased inflammatory signalling, oxidative stress, and metabolic dysregulation are linked to obesity, diabetes mellitus, chronic renal disease, and ageing. Adverse ventricular remodelling, endothelial dysfunction, and myocardial fibrosis are all facilitated by pro-inflammatory cytokines. Obesity-related adipose tissue dysfunction exacerbates myocardial stiffness by increasing circulating leptin, decreasing adiponectin, and activating profibrotic pathways. ^[33][34]

5. Left Atrial Dysfunction and Atrial Fibrillation

One of the main characteristics of HFpEF is left atrial (LA) dysfunction, which is caused by persistently high left ventricular filling pressures. Reservoir, conduit, and contractile function are all compromised by progressive LA fibrosis and expansion. HFpEF often coexists with atrial fibrillation (AF), which worsens symptoms by causing irregular ventricular filling, loss of atrial contraction, and further increase of filling pressures. Bidirectional pathophysiological mechanisms, such as inflammation, fibrosis, and neurohormonal activation, are shared by AF and HFpEF. ^[35][36]

6. Pulmonary Hypertension and Right Ventricular Dysfunction

Many individuals with HFpEF develop post-capillary pulmonary hypertension as a result of persistent rise of left-sided filling pressures. A combination pre- and post-capillary phenotype may develop over time as a result of pulmonary vascular remodelling. A significant predictor of poor outcomes in HFpEF is right ventricular dysfunction, which is made more likely by elevated pulmonary pressures. ^[37][38]Exercise ability and prognosis are considerably worsened when right-sided failure develops.

7. Reduced Cardiac and Chronotropic Reserve
During exercise, patients with HFpEF have restricted capacity to increase cardiac output, heart rate, and stroke volume. Exertional intolerance is caused by a combination of chronotropic incompetence, reduced contractile reserve, and aberrant peripheral oxygen extraction. ^[31][39] Exercise performance is further restricted by skeletal muscle abnormalities, such as decreased capillary density and mitochondrial dysfunction, underscoring the systemic aspect of HFpEF.^[39]

8. Multiorgan Involvement

Beyond the heart, several organ systems are impacted by HFpEF. Inflammation, neurohormonal activation, and salt and water retention are all facilitated by renal failure. While skeletal muscle failure lowers aerobic capacity, pulmonary congestion hinders gas exchange. The idea that HFpEF is a multisystem disorder rather than a single heart condition is supported by these extracardiac symptoms. ^[28][35]

4.HFpEF as a Heterogeneous Syndrome (Phenotyping)

 There is growing recognition that heart failure with preserved ejection fraction (HFpEF) is not a single disease entity but rather a very heterogeneous condition.^[40][41] The various pathophysiologic pathways, comorbidities, and organ system involvement that comprise HFpEF give rise to this heterogeneity, which contributes to the historically unsatisfactory outcomes of conventional "one-size-fits-all" therapy approaches.^[40][42]It is essential to comprehend HFpEF heterogeneity by phenotyping in order to create focused medication, personalised care, and risk stratification.^[40][41]

4.1 HFpEF Phenogroups

Different HFpEF phenogroups, characterised by clinical traits, comorbidities, and pathophysiologic processes, have been found in recent investigations. ^[42][43] Among the most well-known phenogroups are:
Patients with central obesity, metabolic syndrome, and diabetes are primarily affected by obese HFpEF. Characterised by cardiac microvascular dysfunction, volume overload, and systemic inflammation. ^[44] Frequently displays increased natriuretic peptide levels and exercise intolerance that are out of proportion to structural cardiac alterations ^[45]

1. Atrial Fibrillation (AF)-HFpEF:

 Individuals with concurrent AF have higher left atrial pressures, a higher risk of thromboembolic events, and a reduced atrial contribution to ventricular filling. Patients with AF-HFpEF may react differently to rate versus rhythm management techniques, are frequently older, and have a higher comorbidity burden. ^[46]

2. Hypertensive HFpEF:

Characterised by concentric LV hypertrophy and chronic hypertension. The pathogenesis is dominated by increased ventricular stiffness and arterial afterload. Frequently responds to blood pressure-lowering treatment, but less so to traditional heart failure medications that target systolic dysfunction. . ^[47]

Other phenogroups:

These include pulmonary hypertension HFpEF, CKD-associated HFpEF, and elderly/frailty HFpEF, each with distinct causes, clinical trajectories, and treatment implications. ^[48]

4.2 Why “One-Size-Fits-All” Therapy Failed

Due in significant part to the variability of the disease, clinical trials in HFpEF have consistently failed to show a mortality benefit. ^[40][41][49]

Key causes consist of:

• Diverse pathophysiology: A single treatment target is insufficient since patients may have diastolic dysfunction caused by cardiac fibrosis, vascular stiffness, metabolic inflammation, or a mix of these. ^[40][42]
• Comorbidity burden: Treatment response and outcome evaluation are complicated by multimorbidity, which includes obesity, AF, CKD, and pulmonary disease. ^[40][43]
• Variable responsiveness to therapies: Certain subgroups benefit from agents like beta-blockers, mineralocorticoid receptor antagonists, and RAAS inhibitors, whereas the general HFpEF population does not. ^[40][44]

Phenotypic overlap: Many patients have features of multiple phenogroups, further diluting the effects observed in unstratified clinical trial These insights have shifted the field toward phenotype-specific trials and individualized therapy. For example, SGLT2 inhibitors have shown consistent reduction in HF hospitalization across HFpEF phenotypes, although precise mechanisms may differ between subgroups. ^[43][44]

4.3 Clinical Relevance of Phenotyping

The classification of HFpEF based on phenotype has significant clinical implications:

• Targeted therapy: Precision-guided therapies that improve symptom control and results are made possible by determining the prevailing mechanism (e.g., obesity-related inflammation versus hypertension-induced ventricular stiffness).^[40][41]
• Risk stratification: Phenogroups help with prognostication by correlating with mortality, exercise capacity, and hospitalisation risk.^[43][45]
• Trial design: Phenogroup-based patient stratification improves signal identification in clinical trials and lowers heterogeneity-driven failures. ^[49]
• Multidisciplinary care: The necessity for integrated care combining cardiology, nephrology, endocrinology, and rehabilitation is highlighted by the recognition of extracardiac factors (such as obesity, chronic kidney disease, and pulmonary illness).^[40][42]

In conclusion, there are a variety of phenotypes associated with HFpEF, each with a unique aetiology and clinical course. Phenotype-based classification is becoming recognised as crucial to contemporary HFpEF care since it offers a foundation for tailored treatment, better clinical results, and logical trial design. ^[40][41]

5. Clinical Features

The symptoms of heart failure with preserved ejection fraction (HFpEF) are usually vague, making early detection difficult. ^[50][51]Exertional dyspnoea, exercise intolerance, and volume overload in advanced stages are the most common clinical symptoms, which are indicative of systemic comorbidity burden, diastolic dysfunction, and decreased ventricular–vascular coupling.

Dyspnoea during exertion

The initial and most noticeable sign of HFpEF is frequently exertional dyspnoea.^[50] It happens as a result of increased myocardial stiffness and poor left ventricular (LV) relaxation, which raise LV filling pressures during physical exercise.^[52] In contrast to heart failure with decreased ejection fraction (HFrEF), diastolic filling pressures in HFpEF are frequently normal at rest but rise dramatically with exertion, hence symptoms may not be present at rest.^[50]Patients may have dyspnoea when walking long distances, ascending stairs, or performing daily tasks, which is frequently out of proportion to their apparent heart performance.^[52]

Exercise Intolerance

A defining feature of HFpEF is exercise intolerance, which is indicative of decreased circulatory reserve and multisystem involvement, including abnormalities of the skeletal muscles, endothelial dysfunction, and chronotropic incompetence.^[50][51] Patients often have decreased peak oxygen consumption (VO₂ max), early exhaustion, decreased endurance, and limited functional capacity.^[53]The degree of diastolic dysfunction, ventricular–vascular stiffness, and comorbidity burden are correlated with the severity of exercise intolerance, highlighting the intricate pathophysiology causing HFpEF.^[50]

Volume Overload in Advanced Stages

Volume overload becomes more noticeable as HFpEF worsens, frequently showing up as orthopnea, lung congestion, peripheral oedema, and abrupt weight gain.^[50][51] These symptoms typically appear later on as the left atrium enlarges and LV diastolic pressures rise steadily.^[52]Hospitalisations are often caused by intercurrent illness, arrhythmias (especially atrial fibrillation), nutritional indiscretion, or uncontrolled hypertension.^[53] A physical examination may show lower extremity oedema, bibasilar crackles, and jugular venous distension, but these symptoms are frequently less noticeable than in HFrEF, making diagnosis more difficult.^[50]

Additional Considerations

• It can be challenging to distinguish between HFpEF symptoms and pulmonary, renal, or metabolic comorbidities, particularly in older individuals.
• Subtle pulmonary congestion, exercise-induced hypotension, and fatigue may be mistakenly linked to ageing or deconditioning, delaying diagnosis and treatment.
• All things considered, the clinical manifestation of HFpEF is modest and exertion-dependent, necessitating a high index of suspicion, especially in comorbid, elderly, and hypertensive populations. For prompt diagnostic evaluation and the start of phenotype-specific treatment, early detection of these symptoms is crucial. ^[50][51]

Diagnostic Algorithms

The preserved left ventricular ejection fraction (LVEF) and symptoms that overlap with other comorbidities make an accurate diagnosis of HFpEF difficult. ^[54] To increase diagnostic precision and direct treatment, structured diagnostic algorithms that integrate clinical characteristics, echocardiography, and biomarkers are crucial. ^[55]

Echocardiography's function

The foundation of HFpEF assessment is transthoracic echocardiography (TTE), which offers quantitative evaluation of haemodynamic parameters, structural remodelling, and diastolic function. ^[54][55] Key echocardiographic parameters include:

• E/e′ ratio: Left ventricular filling pressures are estimated by dividing early mitral inflow velocity (E) by early diastolic mitral annular velocity (e′). Increased LV diastolic pressures are strongly suggested by a high E/e′ (>14).
• Left atrial volume index (LAVI): Left atrial enlargement is caused by persistently high LV filling pressures. LAVI >34 mL/m² indicates long-term diastolic load and supports the diagnosis of HFpEF. ^[56]
• Tricuspid regurgitation (TR) velocity: Peak systolic TR velocity >2.8 m/s, which is frequently observed in HFpEF, is indicative of pulmonary hypertension brought on by increased left-sided pressures. ^[55]
• LV mass, wall thickness, and relative wall thickness are further echocardiographic measurements that aid in characterising the concentric remodelling frequently observed in hypertensive HFpEF. ^[54][55] Diastolic stress echocardiography, strain imaging, and tissue Doppler imaging may also help detect subclinical dysfunction and exercise-induced filling pressure rise.^[55]
• BNP and NT-proBNP are natriuretic peptides.
  Biomarkers for HFpEF that indicate myocardial wall stress and filling pressures include B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP).^[54]
• Elevated levels, especially in patients with dyspnoea of unknown cause, support the diagnosis of HFpEF. ^[55]
• Obesity-related limitations: Despite severe diastolic dysfunction, natriuretic peptide levels may be erroneously low in obese individuals. This is probably because of increased clearance and decreased myocardial secretion. ^[56][57]
• Additional influencing factors: Atrial fibrillation, age, and renal function all have an impact on natriuretic peptide concentrations, which calls for interpretation in a clinical setting. ^[56]

Integrated Diagnostic Approach

For a precise diagnosis, current systematic reviews highlight the combination of clinical evaluation, echocardiographic data, and natriuretic peptides.^[55][56] These elements are used by diagnostic algorithms like HFA-PEFF and H₂FPEF scores to produce probabilities of HFpEF, which direct additional testing and treatment.^[55] While biomarkers improve diagnostic confidence and aid in ruling in or ruling out HFpEF, especially in complex or borderline situations, echocardiography continues to be the predominant noninvasive assessment method.^[55]

Diagnostic Scores

Standardised diagnostic scoring systems have been created to increase accuracy, repeatability, and risk stratification because of the complexity and heterogeneity of HFpEF. ^[58][59]Two of the most often used techniques are the H₂FPEF score and the HFA-PEFF algorithm, which incorporate clinical, echocardiographic, and biomarker data to estimate the likelihood of HFpEF.

H₂FPEF Score

A straightforward, clinically focused method for identifying patients with HFpEF among those with unexplained dyspnoea is the H₂FPEF score. ^[60]

The H₂FPEF score consists of the following components:

• H-Heavy: BMI >30 kg/m²
• H-Hypertensive: at least two antihypertensive drugs
  F stands for atrial fibrillation (AF); P for pulmonary hypertension (estimated pulmonary artery systolic pressure >35 mmHg); and E for elderly (age >60).
• F: Filling pressures: E/e′ >9
  A weighted score is given to each variable; the total goes from 0 to 9, with higher scores denoting a higher likelihood of HFpEF. ³ Advantages:
• Uses easily accessible clinical and echocardiographic data;
• Is simple and straightforward to use in ordinary clinical practice;
• Offers quick prediction of HFpEF likelihood without complicated computations
  Limitations:
• Does not take into consideration extracardiac comorbidities like CKD or obesity-related HFpEF variations;
• Does not include natriuretic peptides or sophisticated imaging;
• Is less reliable in borderline situations or unusual phenotypes

HFA-PEFF Algorithm

The European Society of Cardiology recommends a more thorough, evidence-based grading method called HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptides, Functional testing, Final aetiology).^[58]
Important characteristics:

• Combines the morphological, biomarker, and functional domains:

- Functional: LV global longitudinal strain, TR velocity, and E/e′

- Morphological: relative wall thickness, LV mass index, and LAVI

- Biomarker: levels of BNP or NT-proBNP

• Assigns points to each domain; patients are classified as having a high, intermediate, or low chance of HFpEF based on their overall score. ^[58]

Strengths:

• All-encompassing, taking into account several aspects of HFpEF pathophysiology;
• Capable of directing additional testing, such as exercise echocardiography or invasive haemodynamics for instances with intermediate probability
• Offers a methodical framework for clinical diagnosis and research.

Limitations:

• Compared to H₂FPEF, more complicated and time-consuming
• Needs access to biomarkers and sophisticated echocardiography
• Additional testing is frequently required for intermediate results, which may not be possible in all situations.

Clinical Implications

When HFpEF is suspected but not overt, both scoring systems increase diagnostic accuracy. ^[60][61]

• H2FPEF is appropriate for quick bedside evaluation, particularly in primary care or basic cardiology assessment.
• When thorough phenotyping is required in speciality care or research settings, HFA-PEFF works well.
• Because of the diverse phenotypes and comorbidity burden of HFpEF, integrating scores with clinical judgement, imaging, and biomarkers is still crucial. ^[58][59]

6. Prognostic Markers and Risk Stratification In HFPEF

Due to varying organ involvement, comorbidity burden, and varied aetiology, heart failure with preserved ejection fraction (HFpEF) is a multisystem disease with significantly varying patient outcomes. ^[62] Therefore, risk stratification is essential for identifying high-risk patients, directing tailored treatment, and providing prognostic information. The most reliable prognostic insights come from a multifaceted approach that includes haemodynamic, vascular, autonomic, biochemical, imaging, and functional measurements. ^[62][63]

6.1 Arterial Stiffness (Pulse Wave Velocity)

A major factor in the pathophysiology of HFpEF is arterial stiffness, which is a reflection of the loss of vascular compliance. ^[64]

• Mechanism: Large artery stiffness increases systolic blood pressure, increases left ventricular afterload, and encourages ventricular–vascular uncoupling. The main characteristics of HFpEF, LV hypertrophy, poor relaxation, and higher filling pressures, are all influenced by chronic afterload stress. ^[64][65]
• Measurement: The gold standard for quantifying aortic stiffness is carotid-femoral pulse wave velocity (PWV). Poorer diastolic function is correlated with higher PWV values, which show less arterial compliance. ^[63]
• Prognostic significance: Independent of conventional risk variables, elevated PWV predicts exercise intolerance, repeated HF hospitalisation, and higher death. ^[63][64]
• Clinical implication: PWV can be utilised as a noninvasive risk assessment measure and may assist in tracking the impact of treatments that target vascular stiffness, including SGLT2 inhibitors or antihypertensive medication. ^[64]

6.2 Heart Rate Recovery

A straightforward, noninvasive indicator of autonomic function and cardiovascular reserve is heart rate recovery (HRR) following physical activity. ^[62]

• Mechanism: Following exercise, sympathetic withdrawal and parasympathetic reactivation are reflected in HRR. HRR is delayed in HFpEF due to autonomic instability and poor chronotropic response. ^[62][63]
• Prognostic significance: Higher rates of HF hospitalisation, worse exercise tolerance, and all-cause mortality are all independently linked to abnormal HRR. ^[63]
• Clinical relevance: HRR can be evaluated during standard cardiopulmonary exercise testing (CPET), offering an inexpensive, repeatable prognostic indicator to support imaging and biochemical evaluations. ^[62]
  3. Biomarkers and Imaging Markers

• In order to assess cardiac stress, fibrosis, and structural remodelling, biomarkers and sophisticated imaging are essential.
• Elevated levels of natriuretic peptides (BNP, NT-proBNP) signify elevated filling pressures and LV wall stress. Although obesity may reduce their levels and necessitate cautious interpretation, they are a robust predictor of HF hospitalisation and mortality.