Retinal Vascular Changes in Heart Failure with Preserved Ejection Fraction Using Optical Coherence Tomography Angiography.

Background: Systemic microvascular regression and dysfunction are considered important underlying mechanisms in heart failure with preserved ejection fraction (HFpEF), but retinal changes are unknown. Methods: This prospective study aimed to investigate whether retinal microvascular and structural parameters assessed using optical coherence tomography angiography (OCT-A) differ between patients with HFpEF and control individuals (i.e., capillary vessel density, thickness of retina layers). We also aimed to assess the associations of retinal parameters with clinical and echocardiographic parameters in HFpEF. HFpEF patients, but not controls, underwent echocardiography. Macula-centered 6 × 6 mm volume scans were computed of both eyes. Results: Twenty-two HFpEF patients and 24 controls without known HFpEF were evaluated, with an age of 74 [68-80] vs. 68 [58-77] years (p = 0.027), and 73% vs. 42% females (p = 0.034), respectively. HFpEF patients showed vascular degeneration compared to controls, depicted by lower macular vessel density (p < 0.001) and macular ganglion cell-inner plexiform layer thickness (p = 0.025), and a trend towards lower total retinal volume (p = 0.050) on OCT-A. In HFpEF, a lower total retinal volume was associated with markers of diastolic dysfunction (septal e', septal and average E/e': R2 = 0.38, 0.36, 0.25, respectively; all p < 0.05), even after adjustment for age, sex, diabetes mellitus, or atrial fibrillation. Conclusions: Patients with HFpEF showed clear levels of retinal vascular changes compared to control individuals, and retinal alterations appeared to be associated with markers of more severe diastolic dysfunction in HFpEF. OCT-A may therefore be a promising technique for monitoring systemic microvascular regression and cardiac diastolic dysfunction.

Detection of cardiac amyloidosis on routine bone scintigraphy: an important gatekeeper role for the nuclear medicine physician.

Cardiac amyloidosis (CA)-mostly transthyretin-related (ATTR-CA)-has recently gained interest in cardiology. Bone scintigraphy (BS) is one of the main screening tools for ATTR-CA but also used for various other reasons. The objective was to evaluate whether all CA cases are detected and what happens during follow-up. All routine BS performed at the Maastricht University Medical Center (May 2012-August 2020) were screened for the presence of CA. Scans performed for suspected CA were excluded. A Perugini stage ≥1 was classified as positive necessitating further examination. The electronic medical record system was evaluated for any contact with cardiology or other specialists until 2021. Of the 2738 BS evaluated, 40 scans (1.46%; median age 73.5 [IQR: 65.8-79.5], 82.5% male) were positive (Perugini grade 1: 31/77.5%, grade 2: 6/15%, grade 3: 3/7.5%); the potential diagnosis ATTR-CA was not seen in 38 patients (95%) by the nuclear medicine specialist. During follow-up, 19 out of those 40 patients (47.5%) underwent cardiac evaluation without diagnosing CA. Available echocardiograms of patients with a positive BS showed left ventricular hypertrophy, a preserved ejection fraction, and diastolic dysfunction ≥2 in 9/47%, 10/53%, and 4/21% of patients, respectively. Additionally, 20 (50%) patients presented to at least one specialty with symptoms indicative of cardiac amyloidosis. The prevalence of a positive BS indicating potential CA in an unselected population is low but substantial. The majority was not detected which asks for better awareness for CA of all involved specialists to ensure appropriate treatment and follow-up.

Webtool to enhance the accuracy of diagnostic algorithms for HFpEF: a prospective cross-over study.

AIMS: Diagnosis of heart failure with preserved ejection fraction (HFpEF) can be challenging. This study aimed to evaluate the potential of a webtool to enhance the scoring accuracy when applying the complex HFA-PEFF and H2 FPEF algorithms, which are commonly used for diagnosing HFpEF. METHODS AND RESULTS: We developed an online tool, the HFpEF calculator, that enables the automatic calculation of current HFpEF algorithms. We assessed the accuracy of manual vs. automatic scoring, defined as the percentage of correct scores, in a cohort of cardiologists with varying clinical experience. Cardiologists scored eight online clinical cases using a triple cross-over design (i.e. two manual-two automatic-two manual-two automatic). Data were analysed in study completers (n = 55, 29% heart failure specialists, 42% general cardiologists, and 29% cardiology residents). Manually calculated scores were correct in 50% (HFA-PEFF: 50% [50-75]; H2 FPEF: 50% [38-50]). Correct scoring improved to 100% using the HFpEF calculator (HFA-PEFF: 100% [88-100], P < 0.001; H2 FPEF: 100% [75-100], P < 0.001). Time spent on clinical cases was similar between scoring methods (±4 min). When corrections for faulty algorithm scores were displayed, cardiologists changed their diagnostic decision in up to 67% of cases. At least 67% of cardiologists preferred using the online tool for future cases in clinical practice. CONCLUSIONS: Manual calculation of HFpEF diagnostic algorithms is often inaccurate. Using an automated webtool to calculate HFpEF algorithms significantly improved correct scoring. This new approach may impact the eventual diagnostic decision in up to two-thirds of cases, supporting its routine use in clinical practice.

Association of left ventricular strain-volume loop characteristics with adverse events in patients with heart failure with preserved ejection fraction.

AIMS: Patients with heart failure with preserved ejection fraction (HFpEF) are characterized by impaired diastolic function. Left ventricular (LV) strain-volume loops (SVL) represent the relation between strain and volume during the cardiac cycle and provide insight into systolic and diastolic function characteristics. In this study, we examined the association of SVL parameters and adverse events in HFpEF. METHODS AND RESULTS: In 235 patients diagnosed with HFpEF, LV-SVL were constructed based on echocardiography images. The endpoint was a composite of all-cause mortality and Heart Failure (HF)-related hospitalization, which was extracted from electronic medical records. Cox-regression analysis was used to assess the association of SVL parameters and the composite endpoint, while adjusting for age, sex, and NYHA class. HFpEF patients (72.3% female) were 75.8 ± 6.9 years old, had a BMI of 29.9 ± 5.4 kg/m2, and a left ventricular ejection fraction of 60.3 ± 7.0%. Across 2.9 years (1.8-4.1) of follow-up, 73 Patients (31%) experienced an event. Early diastolic slope was significantly associated with adverse events [second quartile vs. first quartile: adjusted hazards ratio (HR) 0.42 (95%CI 0.20-0.88)] after adjusting for age, sex, and NYHA class. The association between LV peak strain and adverse events disappeared upon correction for potential confounders [adjusted HR 1.02 (95% CI 0.96-1.08)]. CONCLUSION: Early diastolic slope, representing the relationship between changes in LV volume and strain during early diastole, but not other SVL-parameters, was associated with adverse events in patients with HFpEF during 2.9 years of follow-up.

Evaluating subclinical left ventricular and left atrial dysfunction in idiopathic atrial fibrillation: A speckle-tracking based strain-analysis.

OBJECTIVE: A subset of patients with atrial fibrillation (AF) presents without established AF risk factors and normal left ventricular (LV) systolic function, called idiopathic AF (IAF). Traditionally, echocardiography derived LV dimensions and ejection fraction (EF) are used to exclude LV dysfunction in IAF, but their sensitivity is limited. Our objective is to evaluate the presence of subtle alterations in LV function despite normal LVEF in patients with IAF compared to healthy controls, using speckle-tracking echocardiography (STE) based global longitudinal strain (GLS). METHODS: Standard transthoracic echocardiography was performed in 80 patients with IAF and 129 healthy controls. Patients with overt cardiac disease as well as known established AF risk factors were excluded. STE analysis was performed to assess GLS of the LV, and left atrial strain (LAS). RESULTS: LVEF was normal and comparable between patients with IAF and healthy controls (63 ± 4% for both groups; p = 0.801). Mean GLS was within normal limits for both groups but statistically significantly more negative in patients with IAF (-20.6 ± 2.5% vs. -19.7 ± 2.5%; p = 0.016), however not when indexed for ventricular cycle length (p = 0.784). No differences in LA volume or non-indexed LAS were seen in patients with IAF compared to healthy controls. CONCLUSIONS: In this selected group of IAF patients, STE did not detect any overt LV or LA dysfunction compared to healthy controls. Thus, IAF occurred in these patients not only in the absence of established AF risk factors but also without evidence of ventricular or atrial dysfunction.

Left ventricular strain-volume loops and diastolic dysfunction in suspected heart failure with preserved ejection fraction.

BACKGROUND: Presence of left ventricular diastolic dysfunction (DD) is key in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, non-invasive assessment of diastolic function is complex, cumbersome, and largely based on consensus recommendations. Novel imaging techniques may help detecting DD. Therefore, we compared left ventricular strain-volume loop (SVL) characteristics and diastolic (dys-)function in suspected HFpEF patients. METHOD AND RESULTS: 257 suspected HFpEF patients with sinus rhythm during echocardiography were prospectively included. 211 patients with quality-controlled images and strain and volume analysis were classified according to the 2016 ASE/EACVI recommendations. Patients with indeterminate diastolic function were excluded, resulting in two groups: normal diastolic function (control; n = 65) and DD (n = 91). Patients with DD were older (74.8 ± 6.9 vs. 68.5 ± 9.4 years, p < 0.001), more often female (88% vs 72%, p = 0.021), and more often had a history of atrial fibrillation (42% vs. 23%, p = 0.024) and hypertension (91% vs. 71%, p = 0.001) compared to normal diastolic function. SVL analysis showed a larger uncoupling i.e., a different longitudinal strain contribution to volume change, in DD compared to controls (0.556 ± 1.10% vs. -0.051 ± 1.14%, respectively, P < 0.001). This observation suggests different deformational properties during the cardiac cycle. After adjustment for age, sex, history of atrial fibrillation and hypertension, we found an adjusted odds ratio of 1.68 (95% confidence interval 1.19-2.47) for DD per unit increase in uncoupling (range: -2.95-3.20). CONCLUSION: Uncoupling of the SVL is independently associated with DD. This might provide novel insights in cardiac mechanics and new opportunities to assess diastolic function non-invasively.

Association between phonocardiography and echocardiography in heart failure patients with preserved ejection fraction.

Aims: Heart failure with preserved ejection fraction (HFpEF) is associated with stiffened myocardium and elevated filling pressure that may be captured by heart sound (HS). We investigated the relationship between phonocardiography (PCG) and echocardiography in symptomatic patients suspected of HFpEF. Methods and results: Consecutive symptomatic patients with sinus rhythm and left ventricular ejection fraction >45% were enrolled. Echocardiography was performed to evaluate the patients' diastolic function, accompanied by PCG measurements. Phonocardiography features including HS amplitude, frequency, and timing intervals were calculated, and their abilities to differentiate the ratio between early mitral inflow velocity and early diastolic mitral annular velocity (E/e') were investigated. Of 45 patients, variable ratio matching was applied to obtain two groups of patients with similar characteristics but different E/e'. Patients with a higher E/e' showed higher first and second HS frequencies and more fourth HS and longer systolic time intervals. The interval from QRS onset to first HS was the best feature for the prediction of E/e' > 9 [area under the curve (AUC): 0.72 (0.51-0.88)] in the matched patients. In comparison, N-terminal pro-brain natriuretic peptide (NT-proBNP) showed an AUC of 0.67 (0.46-0.85), a value not better than any PCG feature (P > 0.05). Conclusion: Phonocardiography features stratify E/e' in symptomatic patients suspected of HFpEF with a diagnostic performance similar to NT-proBNP. Heart sound may serve as a simple non-invasive tool for evaluating HFpEF patients.

Interatrial Block Predicts Life-Threatening Arrhythmias in Dilated Cardiomyopathy.

Background Interatrial block (IAB) has been associated with supraventricular arrhythmias and stroke, and even with sudden cardiac death in the general population. Whether IAB is associated with life-threatening arrhythmias (LTA) and sudden cardiac death in dilated cardiomyopathy (DCM) remains unknown. This study aimed to determine the association between IAB and LTA in ambulant patients with DCM. Methods and Results A derivation cohort (Maastricht Dilated Cardiomyopathy Registry; N=469) and an external validation cohort (Utrecht Cardiomyopathy Cohort; N=321) were used for this study. The presence of IAB (P-wave duration>120 milliseconds) or atrial fibrillation (AF) was determined using digital calipers by physicians blinded to the study data. In the derivation cohort, IAB and AF were present in 291 (62%) and 70 (15%) patients with DCM, respectively. LTA (defined as sudden cardiac death, justified shock from implantable cardioverter-defibrillator or anti-tachypacing, or hemodynamic unstable ventricular fibrillation/tachycardia) occurred in 49 patients (3 with no IAB, 35 with IAB, and 11 patients with AF, respectively; median follow-up, 4.4 years [2.1; 7.4]). The LTA-free survival distribution significantly differed between IAB or AF versus no IAB (both P<0.01), but not between IAB versus AF (P=0.999). This association remained statistically significant in the multivariable model (IAB: HR, 4.8 (1.4-16.1), P=0.013; AF: HR, 6.4 (1.7-24.0), P=0.007). In the external validation cohort, the survival distribution was also significantly worse for IAB or AF versus no IAB (P=0.037; P=0.005), but not for IAB versus AF (P=0.836). Conclusions IAB is an easy to assess, widely applicable marker associated with LTA in DCM. IAB and AF seem to confer similar risk of LTA. Further research on IAB in DCM, and on the management of IAB in DCM is warranted.

Global Longitudinal Strain is Incremental to Left Ventricular Ejection Fraction for the Prediction of Outcome in Optimally Treated Dilated Cardiomyopathy Patients.

Background Speckle tracking echocardiographic global longitudinal strain (GLS) predicts outcome in patients with new onset heart failure. Still, its incremental value on top of left ventricular ejection fraction (LVEF) in patients with nonischemic, nonvalvular dilated cardiomyopathy (DCM) after optimal heart failure treatment remains unknown. Methods and Results Patients with DCM were included at the outpatient clinics of 2 centers in the Netherlands and Italy. The prognostic value of 2-dimensional speckle tracking echocardiographic global longitudinal strain was evaluated when being on optimal heart failure medication for at least 6 months. Outcome was defined as the combination of sudden or cardiac death, life-threatening arrhythmias, and heart failure hospitalization. A total of 323 patients with DCM (66% men, age 55±14 years) were included. The mean LVEF was 42%±11% and mean GLS after optimal heart failure treatment was -15%±4%. Twenty percent (64/323) of all patients reached the primary outcome after optimal heart failure treatment (median follow-up of 6[4-9] years). New York Heart Association class ≥3, LVEF, and GLS remained associated with the outcome in the multivariable-adjusted model (New York Heart Association class: hazard ratio [HR], 3.43; 95% CI, 1.49-7.90, P=0.004; LVEF: HR, 2.13; 95% CI, 1.11-4.10, P=0.024; GLS: HR, 2.24; 95% CI, 1.18-4.29, P=0.015), whereas left ventricular end-diastolic diameter index, left atrial volume index, and delta GLS were not. The addition of GLS to New York Heart Association class and LVEF improved the goodness of fit (log likelihood ratio test P<0.001) and discrimination (Harrell's C 0.703). Conclusions Within this bicenter study, GLS emerged as an independent and incremental predictor of adverse outcome, which exceeded LVEF in patients with optimally treated DCM. This presses the need to routinely include GLS in the echocardiographic follow-up of DCM.

Improving diagnosis and risk stratification across the ejection fraction spectrum: the Maastricht Cardiomyopathy registry.

AIMS: Heart failure (HF) represents a clinical syndrome resulting from different aetiologies and degrees of heart diseases. Among these, a key role is played by primary heart muscle disease (cardiomyopathies), which are the combination of multifactorial environmental insults in the presence or absence of a known genetic predisposition. The aim of the Maastricht Cardiomyopathy registry (mCMP-registry; NCT04976348) is to improve (early) diagnosis, risk stratification, and management of cardiomyopathy phenotypes beyond the limits of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: The mCMP-registry is an investigator-initiated prospective registry including patient characteristics, diagnostic measurements performed as part of routine clinical care, treatment information, sequential biobanking, quality of life and economic impact assessment, and regular follow-up. All subjects aged ≥16 years referred to the cardiology department of the Maastricht University Medical Center (MUMC+) for HF-like symptoms or cardiac screening for cardiomyopathies are eligible for inclusion, irrespective of phenotype or underlying causes. Informed consented subjects will be followed up for 15 years. Two central approaches will be used to answer the research questions related to the aims of this registry: (i) a data-driven approach to predict clinical outcome and response to therapy and to identify clusters of patients who share underlying pathophysiological processes; and (ii) a hypothesis-driven approach in which clinical parameters are tested for their (incremental) diagnostic, prognostic, or therapeutic value. The study allows other centres to easily join this initiative, which will further boost research within this field. CONCLUSIONS: The broad inclusion criteria, systematic routine clinical care data-collection, extensive study-related data-collection, sequential biobanking, and multi-disciplinary approach gives the mCMP-registry a unique opportunity to improve diagnosis, risk stratification, and management of HF and (early) cardiomyopathy phenotypes beyond the LVEF limits.

The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a condition with increasing incidence, leading to a health care problem of epidemic proportions for which no curative treatments exist. Consequently, an urge exists to better understand the pathophysiology of HFpEF. Accumulating evidence suggests a key pathophysiological role for coronary microvascular dysfunction (MVD), with an underlying mechanism of low-grade pro-inflammatory state caused by systemic comorbidities. The systemic entity of comorbidities and inflammation in HFpEF imply that patients develop HFpEF due to systemic mechanisms causing coronary MVD, or systemic MVD. The absence or presence of peripheral MVD in HFpEF would reflect HFpEF being predominantly a cardiac or a systemic disease. Here, we will review the current state of the art of cardiac and systemic microvascular dysfunction in HFpEF (Graphical Abstract), resulting in future perspectives on new diagnostic modalities and therapeutic strategies.

The prognostic impact of mechanical atrial dysfunction and atrial fibrillation in heart failure with preserved ejection fraction.

AIMS: This study assessed the prognostic implications of mechanical atrial dysfunction in heart failure with preserved ejection fraction (HFpEF) patients with different stages of atrial fibrillation (AF) in detail. METHODS AND RESULTS: HFpEF patients (n = 258) systemically underwent an extensive clinical characterization, including 24-h Holter monitoring and speckle-tracking echocardiography. Patients were categorized according to rhythm and stages of AF: 112 with no history of AF (no AF), 56 with paroxysmal AF (PAF), and 90 with sustained (persistent/permanent) AF (SAF). A progressive decrease in mechanical atrial function was seen: left atrial reservoir strain (LASr) 30.5 ± 10.5% (no AF), 22.3 ± 10.5% (PAF), and 13.9 ± 7.8% (SAF), P < 0.001. Independent predictors for lower LASr values were AF, absence of chronic obstructive pulmonary disease, higher N-terminal-pro hormone B-type natriuretic peptide, left atrial volume index, and relative wall thickness, lower left ventricular global longitudinal strain, and echocardiographic signs of elevated left ventricular filling pressure. LASr was an independent predictor of adverse outcome (hazard ratio per 1% decrease =1.049, 95% confidence interval 1.014-1.085, P = 0.006), whereas AF was not when the multivariable model included LASr. Moreover, LASr mediated the adverse outcome associated with AF in HFpEF (P = 0.008). CONCLUSION: Mechanical atrial dysfunction has a possible greater prognostic role in HFpEF compared to AF status alone. Mechanical atrial dysfunction is a predictor of adverse outcome independently of AF presence or stage, and may be an underlying mechanism (mediator) for the worse outcome associated with AF in HFpEF. This may suggest mechanical atrial dysfunction plays a crucial role in disease progression in HFpEF patients with AF, and possibly also in HFpEF patients without AF.

Iron deficiency impacts prognosis but less exercise capacity in heart failure with preserved ejection fraction.

AIMS: Whether and how iron deficiency (ID) impacts patients with heart failure (HF) with preserved ejection fraction (HFpEF) remain unclear. The aim of our study was to investigate the impact of ID on functional status, exercise capacity, and prognosis in HFpEF. METHODS AND RESULTS: The study population consisted of 300 HFpEF patients. ID was defined as serum ferritin <100 µg/L or 100-300 µg/L and transferrin-saturation <20%. Baseline functional status, quality of life (HADS score and EQ 5D index), 6 min walking test, echocardiography, and outcome (all-cause mortality and combined all cause-mortality and HF hospitalization) were evaluated. ID was found in 159 (53%) patients. Patients with ID had a worse prognosis with a higher combined endpoint of all-cause mortality and HF hospitalization after 4 years of follow-up (log rank = 0.008). Pulmonary hypertension, depression, and thyroid disease were more prevalent in the ID group. Multivariable analysis showed that ID was independently associated with body mass index (P = 0.003), pulmonary hypertension (P = 0.008), and thyroid disease (P = 0.01). Although patients with ID had a lower exercise capacity compared with patients without ID (393 m [294-455] vs. 344 m [260-441], P = 0.008), there was no significant correlation after multivariable correction for age, BMI, NT-proBNP, DM, and depression. CONCLUSIONS: Heart failure with preserved ejection fraction patients with ID have a worse prognosis and impaired exercise capacity compared with those without ID. However, although a trend was observed, after multivariable correction ID was no longer significantly associated with a reduced exercise capacity. This reflects that impaired exercise capacity in HFpEF is complex and seems multifactorial. Interestingly, pulmonary hypertension was an independent predictor of both ID and exercise capacity.

Future perspective of heart failure care: benefits and bottlenecks of artificial intelligence and eHealth.

Tweetable abstract #eHealth and #ArtificialIntelligence (AI) bring new possibilities for #HeartFailure (HF) care. We elaborate on potential benefits of #AI in #HF and highlight important bottlenecks for its implementation. #Editorial #Cardiology.

Long-term outcome after deferred revascularization due to negative fractional flow reserve in intermediate coronary lesions.

OBJECTIVES: The aim was to assess long-term outcome after deferring intervention of coronary lesions with a fractional flow reserve (FFR) value of >0.80 in a real-world patient population and then to identify factors associated with deferred target lesion failure (DTLF). BACKGROUND: Deferring coronary interventions of intermediate lesions based on FFR measurement is safe, irrespective of the extent of coronary artery disease. However, FFR values near the cut-off of >0.80 may have less favorable outcome. METHODS: A retrospective analysis was performed in patients with deferred coronary intervention based on FFR value >0.80. The primary endpoint was DTLF, a composite of acute coronary syndrome (ACS) and any coronary revascularization, related to the initially deferred stenosis. RESULTS: A total of 600 patients, mean age of 66 ± 10 years, and 751 coronary lesions with negative FFR values (mean 0.88 ± 0.04) were included. The mean follow-up was 27 ± 15 months. DTLF occurred in 44 patients (7.3%), revascularization in 42 (7%), and ACS without revascularization in 2 patients (0.3%). Patients with DTLF more often had diabetes mellitus, previous coronary artery bypass grafting, multivessel disease (MVD), and lower FFR at inclusion. Multivariable regression analysis showed that lower deferred FFR values [FFR 0.81-0.85: hazard ratio (HR) 2.79 (95% CI [confidence interval]; 1.46-5.32), p .002], MVD [HR 1.98 (95% CI; 1.05-3.75), p .036], distal lesions [HR 2.43 (95% CI; 1.29-4.57), p .006], and lesions located in a saphenous vein graft (SVG) [HR 6.35 (95% CI; 1.81-22.28), p .004] were independent predictors for DTLF. CONCLUSIONS: The long-term rate of DTLF of initially deferred coronary lesions was 7.3%. Independent predictors for DTLF are lower deferred FFR value, the presence of MVD, distal lesions, and lesions in SVG.

Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review.

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.